key: cord- -qp rrwr authors: martin, r.; martens, u.; sticht-groh, v.; dörries, r.; krüger, h. title: persistent intrathecal secretion of oligoclonal, borrelia burgdorferi-specific igg in chronic meningoradiculomyelitis date: journal: j neurol doi: . /bf sha: doc_id: cord_uid: qp rrwr in the cerebrospinal fluid igg of five patients with lymphomeningoradiculitis (bannwarth's syndrome) and radiculomyelitis studied by immunoblot technique an oligoclonal pattern was found. most of these oligoclonal bands were specific for borrelia burgdorferi. in patients suffering from chronic meningoradiculomyelitis, repeated csf examination by this technique showed persistent secretion of identical igg bands. thus, the specific humoral immune response and the disease activity could be documented over the course of the disease. lyme disease is a tick-borne spirochetal infection which, particularly in europe, often involves the central nervous system (cns). in most cases, the disease starts with a characteristic skin rash, erythema chronicum migrans (ecm), and symptoms of general illness such as fever, headache and arthralgia (stage ) [ , ] . weeks or months later, specific organs such as heart, joints and cns are involved (stage ) [ , ] . without appropriate treatment by antibiotics the disease may then progress into a subacute or chronic stage in which there may be acrodermatitis chronica atrophicans, chronic oligoarthritis or progresssive encephalomyelitis (stage ) [ , , ] . neurological manifestations of lyme disease include lymphomeningoradiculitis, radiculomyelitis or even progressive encephalomyelitis [ , , , , ] . characteristic cerebrospinal fluid (csf) findings are lymphocyte and monocyte pleocytosis, increased total protein and immunoglobulins. investigations of csf immunoglobulins during different stages consistently show the restricted heterogeneity of csf igg by the presence of oligoclonal bands [ , , ] . the diagnosis is confirmed by high titres of serum and csf antibodies, specific for borrelia burgdorferi, which has recently been identified as the aetiological agent of lyme disease and bannwarth's syndrome [ ] . the purpose of our study was to answer the questions whether the csf immunoglobulin g (igg) in lymphomeningoradiculitis is locally produced, whether its antigen specificity can be determined, and whether the persistence of a specific distribution pattern can be recorded over the course of the disease. the recently described immunoblot technique [ ] , which combines isoelectric focusing (ief) of unconcentrated or diluted csf with blotting to an antigen-loaded nitrocellulose filter, was used. the five patients studied were treated in our clinic in . their ages ranged between and years. three of the patients remembered a tick bite and/or ecm. the clinical diagnosis of meningoradiculitis or radiculomyelitis was confirmed by antibodies against b. burgdorferi [immunofluorescence test (ift): significant positive serum igg titre > : ; significant positive csf igg titre > : ; elisa: significant positive csf igg titre > : ] in the serum and the csf, elevated total protein and igg of csf and a lymphocytic csf pleocytosis. all five patients suffered from either meningitis with accompanying radiculoneuritis or from meningomyelitis (table ) and were treated with × units/day penicillin g for days either once or repeatedly, according to the persistence of clinical symptoms. according to the course of the disease and the persistence of pathological csf findings, we only used the term chronic meningoradiculitis or radiculomyelitis when both clinical and laboratory findings were present for longer than months without any improvement. relevant laboratory findings of the sera and csf, which were always collected on the same day, are shown in table . patient c had already been treated by corticosteroids and antibiotics when csf and serum were collected. the antibody titre was therefore comparatively low. in this patient, proliferative testing of peripheral blood lymphocytes with b. borgdorferi antigen further confirmed the diagnosis. all csf and serum samples were drawn with informed consent of the patients. as a positive control, monoclonal antibody h specific for b. burgdorferi (kind gift of dr.a.barbour, university of texas, san antonio, usa) was used. sera and csf samples of patients suffering from either meningeosis carcinomatosa or multiple sclerosis (both seronegative for b. burgdorferispecific antibodies) were taken (data not shown). determination of csf and serum protein concentrations. all protein and igg concentrations were determined by lasernephelometry (behring laser nephelometer, b ehring-werke, marburg, frg) and expressed in milligrams per decilitre (rag/ dl). antibodies to b. burgdorferi were tested by ift and elisa as described previously [ ] . the igg coefficient was calculated according to the method of delpech and lichtblau [ ] . b. burgdorferi antigen preparation. lyme disease spirochetes (b. burgdorferi strain m ; kind gift of dr. r.ackermann, department of neurology, university of cologne, frg) were prepared as described by pachner et al. [ ] . briefly, the , prepared as described above. the filters were incubated at room temperature overnight on a rocker platform and then rinsed in pbs for min. unoccupied protein binding sites were blocked by incubation in % bovine serum albumin (bsa; serva, munich, frg) in pbs (ph . ) for lh. after washing in pbs, . % np (sigma, taufkirchen. frg) in pbs and pbs ( min each cycle), the filters were ready for blotting. ief of csf and serum was carried out on the following agarose gel: % agarose (ief grade, pharmacia, freiburg, frg) containing % sorbitol (sigma, taufkirchen, frg), lml pharmalyte, ph - , . ml pharmalyte, ph - . (pharmacia, freiburg, frg). the dimensions of the gels were x x . mm (length, width, height). csf samples were adjusted to ~tg igg/ml by dilution with saline ( . %) and . gl aliquots were applied to the gel with application strips (serva, munich, frg; . x mm). ief was performed at w constant power in an lkb ultrophor electrofocusing unit (lkb, bromma, sweden) at °c for h. blotting of immunoglobulins to nitrocellulose filters was accomplished by afffinity-driven transfer. for this purpose, the moist filter was laid on top of the gel to avoid air bubbles. then it was covered with a pbs-moistened filter paper (lkb), three sheets of dry filter paper, a glass plate and x g weight. after lh, three washing cycles (as decribed above) followed. the filters were now incubated in ml pbs containing . mg/ml peroxidase-labelled rabbit anti-human igg (dakopatts, hamburg, frg) for h. after three washing cycles the filters were stained in a solution of mg -amino- -ethylcarbazole (sigma, taufkirchen, frg), , ml dimethylformamide (sigma), . ml mm/ sodium acetate solution (ph . ) and ~ hydrogen peroxide %. after staining for min a final washing in distilled water was performed. the five patients with typical clinical and laboratory findings of meningoradiculitis and radiculomyelitis showed raised total csf protein and elevated csf immunoglobulins with igg ranging up to mg/dl. as shown by ift (table ) , antibodies specific for b. burgdorferi were present both in the sera and the csf. although igg coefficients according to delpech and lichtblau were elevated in all cases, b. burgdorferi specific igg, determined by ift, was always lower in the csf ( table ). for the determination of a restricted pattern of intrathecally produced igg, immunoblotting of diluted csf and serum was performed using filters precoated with rabbit anti-human igg. thus, the oligoclonal nature of csf igg could be demonstrated. in fig. the igg distribution patterns within the sera and the csf are shown in parallel. the csf of each patient demonstrates an individual distribution of igg bands which cannot be compared with one another. in the sera, however, only homogeneous staining or single faint bands could be seen. it should be noted that sera and csf samples were adjusted to the same igg concentration of ~tg/ml. in a further step, we tried to identify the antigen specificity of the oligoclonal igg bands found. for this purpose, b. burgdorferi coated nitrocellulose filters were used for the immunoblotting procedure. figure the stable distribution pattern demonstrates the persistent secretion of specific antibodies by single b-cell clones. for the corresponding immunoblot for total igg, see fig. . pl, isoelectric point in addition, we studied the distribution pattern of intrathecally produced igg in one patient (e), who continuously suffered from radicular pain and paraparesis, over a period of months. laboratory values of five csf samples collected at approximately -month intervals are summarized in table . the igg concentration continuously dropped with time, whereas the ift titre for b. burgdorferi-specific antibodies remained the same. figure shows the configuration of oligoclonal total igg bands in all five csf samples of this patient. the corresponding immunoblot of b. burgdorferi-specific csf igg is demonstrated in fig. . both figures reveal that, during the -month period, no overt differences in the banding pattern could be detected, although the patient had three courses of treatment with penicillin g ( × units/day over days) in the meantime. in the present study, we used a rapid and sensitive immunoblotting technique [ ] to detect and characterize intrathecally produced igg in five patients suffering from chronic meningoradiculitis (bannwarth's syndrome) or radiculomyelitis. in earlier reports it was shown that the determination of b. burgdorferi-specific antibodies of either igg or igm type is a useful diagnostic criterion for lyme disease and bannwarth's syndrome [ ] . the patients studied in this report suffered from meningoradiculitis or radiculomyelitis in either a subacute or chronic stage. three patients (a, c, e) are still suffering from persistent clinical symptoms such as radicular pain, brisk tendon reflexes and positive babinski sign; for this reason the term "chronic" should only be used for these patients. after treatment by antibiotics patients b and d markedly improved within month and we would therefore prefer to consider these disease courses as subacute. all of them exhibited oligoclonal igg shown by both ief of unconcentrated csf and blotting to nitrocellulose filters coupled with rabbit antihuman igg. this observation is also well documented in other viral or bacterial cns infections such as tuberculous meningitis, neurosyphilis, subacute sclerosing panencephalitis and mumps meningitis [ , , , ] . in a further step the antigen specificity of csf igg for the aetiological agent b. burgdorferi was shown by using the same blotting technique, but coupling b. burgdorferi antigen to the nitrocellulose filters. thus, we found oligoclonal, b. burgdorferi-specific igg bands in the csf samples of all patients. the presence in three patients of minor bands in the sera which had been adjusted to the same igg content can be taken as an indicator of the intrathecal production of specific antibodies. this is confirmed by the high igg indices which had been calculated according to the method of delpech and lichtblau [ ] . the presence of weak bands seen in the serum track at the same position as the corrsponding csf bands may either be due to parallel formation of the antibodies in the csf and the peripheral blood or to passive diffusion of csf igg to the peripheral blood via the blood-csf barrier. apart from the demonstration of the antigen specificity of oligoclonal igg bands, this highly sensitive method can also be used to follow the persistent secretion of specific igg in single b cells. this issue was pursued by repeated immunoblotting of csf samples which had been collected over a longer period of time. owing to the restriction of space, the blots are only shown for patient e over a period of months. it is clearly demonstrated that the distribution pattern of both total igg and b. burgdorferi-specific igg remained exactly the same (figs. , ; tracks - ). this is an in-dication that a restricted number of b cells is continuously forming specific antibody. although unlikely, it cannot completely be excluded, however, that one single band contains two or more antibodies of different specificities but of the same electrophoretic mobility. as ift titres were comparatively low, it may be postulated that the persistence of b. burgdorferi-specific oligoclonal bands is a better indicator of disease activity than ift titres alone. in our patients, this notion is further supported by the co-existence of clinical symptoms. the presence of oligoclonal igg bands in the csf and not in the serum of patients suffering from meningoradiculitis or radiculomyelitis strongly favours the intrathecal production of these antibodies and was firstly demonstrated by kriiger et al. [ ] . murray et al. [ ] also investigated the question of antigen specificity of oligoclonal csf igg by staining ief bands with i-labelled b. burgdorferi antigen. in addition, they immunoprecipitated i-labelled b. burgdorferi antigen by either serum or csf and used this mixture for sds gel electrophoresis. applying such techniques, they detected b. burgdorferi-specific oligoclonal bands only in the csf of one out of nine patients. because few clinical data are given in their report, we cannot explain whether this difference resulted from a difference in disease severity or stage or whether their technique was less sensitive. henriksson et al. [ ] investigated igg-, igm-and iga-producing b-cells in the serum and csf, ig indices and also oligoclonal total igg bands over the course of lymphocytic meningoradiculitis. apart from a high proportion of igg-, igm-and iga-secreting b-cells and a prolonged igm response, they found oligoclonal igg bands in the csf of all patients. comparing our results with those reported in the literature, it seems that our method is more sensitive; it is rapidly performed and easily detects oligoclonal csf igg as well as characterizing its antigen specificity in patients suffering from subacute and chronic meningoradiculitis and radiculomyelitis. obvious advantages are the possibility of using unconcentrated or diluted csf and the rapid application with no need for radioactive substances. the technique can easily be used for the detection of intrathecally produced, b. burgdorferispecific igg because ief of csf is a standard procedure for the diagnosis of multiple sclerosis in most neurology clinics. the disadvantages of the immunoblot technique are the large amount of antigen necessary and the difficulty of identifying simultaneously the specificity of csf igg for subfractions of the b. burgdorferi antigen. for this purpose, western blot analysis, as described by wilske et al. [ ] , should be used. it should also be mentioned that the direct comparison of the patterns of oligoclonal igg bands with those specific for b. burgdorferi antigen may be difficult because the transfer conditions for total igg and b. burgdorferi specific igg are different, as already noted by d rries and ter meulen [ ] . in all patients, we were able to demonstrate prominent, oligoclonal igg bands in the csf but not in the serum. most of these bands were specific for b. burgdorferi, with only a few weak bands seen in the sera. the persistent secretion of specific igg is paralleled by the presence of clinical symptoms such as radicular pain, mono-and paraparesis over long periods of time. this is not a unique finding in meningoradiculitis, but can also be demonstrated after recovery from acute herpes virus encephalitis, mumps virus and varicella zoster meningoencephalitis [ ] [ ] [ ] and in relapsing subacute encephalomyelitis induced by corona virus in rats [ ] . in all these cases of persistent antibody secretion within the csf, the question arises whether live bacteria or viruses or only antigen fragments persist within the cns or whether the immune response against the invading pathogen cannot be suppressed in certain individuals. to elucidate further the cause of persistent csf antibody secretion, it will be necessary to isolate b. burgdorferi antigen from the csf and to characterize the cellular immune response within the cns, in patients suffering from chronic menigoradiculitis and radiculomyelitis, in more detail. progressive borrelien-enzephalomyelitis lyme disease, a tick-borne spirochetosis? lyme disease antibody response in lyme disease: evaluation of diagnostic tests l~tude quantitative des immunoglubulines get de l'albumine du liquide cephalorachidien detection and identification of virus-specific, oligoclonal igg in unconcentrated cerebrospinal fluid by immoblot technique analysis of the intrathecal humoral immune response in brown norway (bn) rats, infected with the murine corona-virus jhm immunoglobulin abnormalities in cerebrospinal fluid and blood over the course of lymphocytic meningoradiculitis (bannwarth's syndrome) characterization of antibody activity in oligoclonal immunoglobulin g synthesized within the central nervous system in a patient with tuberculous meningitis demonstration of oligoclonal immunglobulin g in guillain-barr syndrome and lymphocytic meningoradiculitis by isoelectric focusing viral antibodies in oligoclonal and polyclonal igg synthesized within the central nervous system over the course of mumps meningitis comparison of an indirect fluorescent-antibody test with an enzyme-linked immuno-sorbent assay for serological studies of lyme disease lyme disease specificity of csf antibodies against components of borrelia burgdorferi in patients with meningopolyneuritis garin-bujadoux-bannwarth demonstration of elec-trophoreticauy restricted virus-specific antibodies in serum and cerebrospinal fluid by imprint electroimmunofixation antigenspecific proliferation of csf lymphocytes in lyme disease neurologic abnormalities of lyme disease demyelinating encephalopathy in lyme disease mumps meningitis: specific and non-specific antibody responses in the central nervous system long-term persistence of intrathecal virus-specific antibody responses after herpes simplex encephalitis intrathecal synthesis of virus-specific oligoclonal igg, iga and igm antibodies in a case of varicella zoster meningoencephalitis neurosyphilis: intrathecal synthesis of antibodies to treponema pallidum chronic progressive neurological involvement in borrelia burgdorferi infection intrathecal production of specific antibodies against borrelia burgdorferi in patients with lymphocytic meningoradiculitis (bannwarth's syndrome) acknowledgements. the authors thank d. drenkard and n. gropp for excellent technical assistance. the study was supported by grant sti / - from the deutsche forschungsgemeinschaft. key: cord- -pfepyvaw authors: edlmann, ellie; whitfield, peter c. title: the changing face of neurosurgery for the older person date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: pfepyvaw increased life expectancy and illness prevention and treatment have led to a growing population of older patients. these changes in patient population are apparent in neurosurgery; however, relatively little is reported about specific outcomes and prognostication in this group. this review summarises the challenges and management changes occurring in the treatment of three common neurosurgical pathologies; aneurysmal subarachnoid haemorrhage, head injury, and haemorrhagic stroke. a move towards less invasive neurosurgical techniques has implications on the risk–benefit profile of interventions. this creates the opportunity to intervene in older patients with greater co-morbidity, as long as improved outcomes can be evidenced. a critical part of assessing appropriateness for surgical intervention in older patients may be to change from a mindset of age to one of frailty and growing interest in scales assessing this may aid treatment decisions in the future. increased life expectancy, lower operative morbidities, and enhanced expectations from patients and their families has led to an increasing population of older patients with pathology that may be amenable to neurosurgical treatment. in , chibbaro showed that the proportion of patients aged and over admitted to a parisian neurosurgical unit increased from % in to % in [ ] . surgical interventions also increased from % to % in this group, with a particular rise in brain tumour surgery. such trends are set to continue and a recent report from a uk regional neurosurgical centre showed continued increases in elderly admissions from to , particularly in emergency conditions such as traumatic head injury and spontaneous subarachnoid haemorrhage [ ] . an important driver of increased admissions is the perceived improvement in outcomes in older patients. chibbaro showed a dramatic drop in the immediate mortality rate, from to . % in older patients [ ] . shifting treatment algorithms, such as endovascular coiling rather than aneurysm clipping, account, in part, for improved outcomes. however, poor outcomes still prevail in older patients with emergency presentations: whitehouse reported -year mortality of around % in neurosurgical patients over admitted as an emergency compared with less than % in elective patients [ ] . mortality is particularly increased within months of neurosurgical treatment and, therefore, surgical approaches and their associated complications need to be carefully considered to improve outcomes. in this review, we consider changes in practice and current treatment outcomes in older patients with aneurysmal subarachnoid haemorrhage, traumatic head injury, and haemorrhagic strokes. we focus on the assessment of frailty in older patients and how this can help to inform future treatment planning. incidental, unruptured cerebral aneurysms pose a risk of rupture over time; factors including size and location influence this risk [ ] . it is logical, that as people live longer, there is a greater lifetime risk of incidental aneurysm rupture and presentation with a subarachnoid haemorrhage (sah). conversely, the first detection of an incidental cerebral aneurysm in later life means that there is a reduced effect of any preventative treatment due to the deceased remaining life expectancy in the elderly. in addition, the outcomes, in terms of quality of life and mortality, from treated aneurysmal sah in older patients are variable. as such, it is important that we have robust data on all these aspects, to guide the management of both ruptured and unruptured aneurysms in the older person. in , nieuwkamp et al. reported outcomes in patients aged ≥ years presenting with aneurysmal sah, where only % of patients were clipped and % coiled [ ] . overall, half the patients died and only one in six returned to independent function by discharge. of their patients admitted in a poor condition (those with a glasgow coma score of or less), none were independent at discharge. the strongest predictor of poor outcome in good-grade admissions was re-bleeding. compared to younger sah patients, those aged and over were more likely to be female (perhaps due to greater life expectancy) and suffer with medical complications and hydrocephalus. the authors suggested that the early treatment of patients in a good condition may prevent re-bleeding and thus improve outcomes. in , scholler analysed patients over the age of with aneurysmal sah, with % aged between and and only % over [ ] . challenges identified in this older population included increased co-morbidities ( % had at least one), the use of anti-thrombotic drugs (in %) and increased prevalence of hydrocephalus requiring an evd in those aged - years ( %) compared to - -year-olds ( %). interventional treatment was undertaken in % of cases, with clipping in % and coiling in %, the latter more commonly in those aged over . outcome was clearly associated with age; death or poor outcome at discharge occurred in % of over years old compared with % of - years old. condition at presentation was also important with no poor grade at presentation patients (wfns - ) aged over experiencing a good outcome at discharge. it is important to note that although % of conservatively managed patients died, none were due to re-bleed, suggesting that it is the nature of the initial bleed and not any failure to treat, that results in the poor outcome. there has also been a significant shift in practice in the last years towards coiling, rather than clipping since the international subarachnoid aneurysm trial (isat) [ ] . subsequent sub-group analysis of patients aged years and over suggested a trend towards better outcomes with endovascular treatment compared to clipping, although this was subject to aneurysm location [ ] . lower rates of infectious and pulmonary complications and epilepsy occurred in the endovascular group. this was supported by the barrow ruptured aneurysm trial (brat) which showed significantly poorer outcomes at year in patients over years old treated with clipping [ ] . a recent systematic review of endovascular treatment of ruptured aneurysms in patients aged over reported good outcomes in %, with a mortality rate of around % at year [ ] . with an % complete or near-complete occlusion rate at long-term follow-up, endovascular treatment is preferred to clipping and probably reduces risks for older patients. koffijberg analysed the cost-effectiveness of treating ruptured aneurysms in patients aged over , identifying key parameters including patient age (and thus life expectancy), good or poor clinical condition on presentation, conservative or occlusive treatment (clipping or coiling) and good or poor outcomes [ ] . perhaps surprisingly, occlusive treatment of aneurysms translated into a health benefit for all older patients presenting within days of sah, regardless of the good or poor condition at presentation. a later presentation, particularly days or more after sah, was more likely to result in no or minimal treatment benefits. however, occlusive treatment was only found to be cost-effective in women aged - , and men aged - presenting in a good condition, within days of sah. thus, although potentially offering some clinical benefit, occlusive treatment is clearly more costly than conservative management and may be particularly difficult to justify in those aged years and over presenting in a poor condition. it is, however, also important to highlight that studies assessing interventions such as this will contain inherent selection bias, by virtue of the fact that the patients undergoing intervention differ from those that were not. such results should be treated with caution until clear, prospective, evidence is available. it is apparent that patients presenting in a poor condition and aged over are likely to have a poor outcome, and a conservative approach may be appropriate in these patients. more prospective research is needed to understand the risk-benefit profile of treating well patients, particularly those aged over . the current literature supports active intervention for those under , with an awareness of the increased risk of complications, but more data are needed specifically in relation to outcomes with endovascular intervention. the vast majority of older patients admitted to a neurosurgical unit with head injury have a subdural haematoma, most commonly chronic subdural haematoma (csdh), followed by mixed and then acute subdural haematoma (asdh) [ ] . a csdh is a condition almost exclusively confined to the elderly, with a median age of in the uk [ ] . the post-traumatic pathophysiology is complex; it takes weeks to months for the collection of blood and fluid to expand: evidences support the theory that this is, at least in part, due to an escalating inflammatory process [ ] . many patients have no recollection of significant trauma and presentation is usually with cognitive impairment, gait disturbance, limb weakness, or headache. the mainstay of treatment has been surgical drainage [ , ] . however, recent trials have focused on medical treatments, such as steroids, for controlling the inflammatory response in csdh, and, therefore, either reducing csdh recurrence following surgery or even as a first-line treatment [ , , , ] . any treatment which reduces csdh recurrence has the potential to reduce mortality, which can be as high as % at months [ ] . the outcome of these steroid trials is still awaited, but a move to more conservative treatments of csdh could benefit older patients with multiple co-morbidities who are at increased risk from anaesthesia and surgical treatment. asdhs are traditionally considered to occur in higher impact trauma, leading to coma and hence a poorer prognosis, particularly in the elderly. however, due to co-existent cerebral atrophy in older patients, lower energy forces (falls) cause most traumatic brain injuries in this age group, and the onset of neurological deterioration secondary to an asdh may be delayed. this provides an opportunity for definitive management, following an early ct scan, as recommended by nice guidelines [ ] . asdh following a minor fall is often exacerbated by the fact that nearly two-third of these patients are on anti-thrombotic medications [ ] . the increased use of these medications and an aging population are probably contributing to growing rates of asdh in the elderly. a recent review of asdhs in a german hospital reported . % of them occurring in patients aged or over [ ] . importantly, although % of the patients aged ≥ years of age underwent surgery, only % experienced a favourable outcome at discharge (glasgow outcome scale - ), increasing to % at -months. the mortality rate was high, % at months, and predictors of an unfavourable outcome included > co-morbidities, gcs ≤ at admission and hours, re-bleeding, and pneumonia. the use of anti-thrombotic medications at presentation is also clearly a risk factor for poor outcome in all patients [ ] . another series reported no survivors in patients with an asdh aged over and only one survivor out of aged over presenting with a gcs of less than [ ] . a recent systematic review of asdh in the elderly reported on only seven eligible studies with the mean patient age ranging from to years [ ] . outcomes varied with a mortality rate ranging from to %, and a good functional outcome in - % but with a presenting gcs ≤ representing a poor prognostic factor. however, overall, the studies were classified as low quality and were particularly lacking in assessments of patient frailty which may aid future research in this field. it is clear that poor neurology from the outset is associated with poor outcome; however, as the incidence of this pathology appears to be increasing in older patients, effective surgical decision-making tools are needed. in patients over years old, with multi-morbidity and poor neurology, caution should be applied; however, it could be advocated that in all other circumstances surgical treatment should at least be considered. attempts have been made at producing scoring systems to aid prognostication in elderly patients with asdh, but more widespread validation of this is required [ ] . it is notable that several large-scale studies assessing interventions for severe traumatic brain injury (tbi) in general, including decompressive craniectomy [ , ] , icp monitoring [ ] , and cooling [ ] , have either excluded older patients or had minimal numbers of them. whilst this makes understanding treatment in this age group challenging, it may also just be a reflection of the reality that fewer older patients are considered likely to survive intervention. this is supported by collaborations such as impact (international mission for prognosis and analysis of clinical trials in tbi) and crash (corticosteroid randomisation after significant head injury), who have used available evidence to develop prognostic calculators for tbi, where age is a corestratifying component and significantly increases chances of a poor outcome [ , ] . overall, it is recognised that a lack of evidence has led to varying practices and understanding about interventions for tbi in older patients, but it is clear that functional and cognitive recovery is significantly worse in this age group [ ] . understanding patient baseline function and morbidity is important, but recognising the high chance of a poor outcome in this age group often leads clinicians to follow a conservative route, avoiding neurointensive care. intracranial haemorrhage (ich) in older people is often the result of long-standing underlying pathological vascular disease. a patient, therefore, has the intracranial pressure effects and focal neurological deficits associated with the ich in addition to the systemic co-morbidities of cardiac, peripheral vascular disease, and often anti-thrombotic medication use. furthermore, secondary haemorrhage is always a concern. the stich i and ii trials did not demonstrate any overall benefit from early surgery compared with initial conservative management for supratentorial (including lobar) ich. [ , ] . the median patient age for stich i was years (iqr - ) and years (iqr - ) for stich ii. the inference from these studies is that surgeons are already appropriately undertaking selective, targeted surgery to the patients that are most likely to benefit from it. when there is equipoise about whether to operate, these studies suggest that it is reasonable to manage the patient conservatively in the first instance and then re-assess. more recently, there has been a move towards minimallyinvasive surgery (mis) for ich, with the potential benefits of being less traumatic, quicker, and more focused than a craniotomy. however, controversy exists concerning the widespread clinical application of such techniques. a recent meta-analysis ( ) on mis for hypertensive ich (the most common cause of spontaneous ich), reported a positive effect on patient prognosis (using gos) compared to both craniotomy and conservative treatment [ ] . mortality rates were lower for mis compared to conservative treatment and post-operative re-bleeding rates were lower for mis compared to craniotomy. as this review only included eight randomised controlled trials and most studies also excluded patients that were > years old, more high-quality studies and in a wider population of older patients are needed before firm conclusions can be drawn. this is particularly important as - % of patients diagnosed with an ich are ≥ years old, and this patient group has significantly higher rates of in-hospital mortality and unfavourable outcome [ , ] . scaggiante also published a meta-analysis of mis in , assessing rcts that mainly deployed endoscopic and/or stereotactic thrombolytic techniques [ ] . this consolidated the finding that mis improved outcome compared to both craniotomy and conservative treatment. different mis techniques (endoscopy and stereotactic thrombolysis) both showed significant improvements, but these techniques have not been compared directly. earlier mis evacuation of an ich appeared to be associated with a better chance of achieving functional independence. conversely, the final results of the mistie (minimially invasive surgery with thrombolysis in ich evacuation) trial showed that aspiration and thrombolytic irrigation of an ich with alteplase via an image directed catheter did not improve functional outcomes compared with standard care for large ichs [ ] . a modest survival benefit was identified. this trial only included patients aged - years old, so caution must be exercised in applying the conclusions to older patients. the comprehensive geriatric assessment (cga) is an established tool used to assess the needs of older people and implement investigations and treatments to improve long-term outcomes. the use of this tool has been shown to improve post-operative outcomes in older patients undergoing elective surgery across specialties [ ] . it is, therefore, clear that older people have different needs, which when identified and addressed can improve outcomes. the cga is a robust but cumbersome assessment including different domains (medical, mental health, functional capacity, social circumstances, environment, and risk score). identification of simpler tools, possibly even specific to neurosurgery, are necessary. understanding what is meant by frailty is also important, as, although there is some cross-over with disability and co-morbidity, it actually refers to a physiological state of increased vulnerability to stressors due to decreased physiological reserve [ ] . a frailty score based on the assessment of data from , cranial neurosurgical cases has been reported, where higher scores had good sensitivity and specificity for predicting increased -day mortality [ ] . the score considered predictors of mortality, with the most significant including ascites, ventilator dependency and renal failure, alongside more common problems such as anti-hypertensive medication use, high white cell count and low body mass index. the disadvantages are that this score still contains a large number of variables and requires prospective evaluation. tools such as the modified frailty index (mfi), that have already been well validated in surgical populations, may be more useful [ , ] . youngerman reviewed patients with brain tumours and found increased higher mfi scores were associated with increased mortality, severe neurological complications and prolonged length of stay [ ] . combined assessment of mfi, age and asa (american society of anaesthesiologists) classification gave the best predictive ability on overall outcome. a simpler scale, the clinical frailty scale, has also been applied in neurosurgical patients, predicting prognosis in operated csdh [ , ] . frailty has also been correlated with poor outcome in older patients with aneurysmal sah, however this was a very simplistic assessment of frailty based on haemoglobin, albumin and bmi [ ] . standardised assessments of frailty are needed, with validation in large cohorts of neurosurgical patients across a range of pathologies. this may then support the development of prognostication tools and aid clinical decisionmaking and family discussions. at what point we consider a person to be "elderly" is shifting, as patients are fitter and more independent until later in life. there are also neurosurgical advances which may preferentially benefit older patients with multiple co-morbidities such as endovascular coiling and mis surgery for ich. patients aged over years of age certainly do benefit from acute neurosurgical interventions, but there is more uncertainty and risk for those aged over . an age cut-off itself may not be helpful, but rather frailty should be considered instead, and we advocate improved reporting of this metric in future trials and studies. most importantly, given the lack of robust evidence, determining patient eligibility for intervention is often left to the treating clinician. whilst it is always possible to intervene, it is not always appropriate and a significantly lower likelihood of maintaining the quality of life in older patients for the conditions discussed must be recognised. on the other hand, a therapeutic nihilism may be deterministic and thwart development of improved clinical practice in this group of patients. conflicts of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. development of the subdural hematoma in the elderly (she) score to predict mortality hypothermia for intracranial hypertension after traumatic brain injury spontaneous intracerebral hemorrhage in the elderly population (s . ) the management and outcome for patients with chronic subdural hematoma: a prospective, multicenter, observational cohort study in the united kingdom global neurotrauma research g ( ) a trial of intracranial-pressure monitoring in traumatic brain injury neurosurgery and elderly: analysis through the years decompressive craniectomy in diffuse 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anticoagulant therapy: management and outcome the modified frailty index and -day adverse events in oncologic neurosurgery a prognostic model for early post-treatment outcome of elderly patients with aneurysmal subarachnoid hemorrhage key: cord- -wqu t n authors: maideniuc, catalina; memon, anza b. title: acute necrotizing myelitis and acute motor axonal neuropathy in a covid- patient date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: wqu t n a -year-old woman with covid infection developed acute necrotizing myelitis (anm) and acute motor axonal neuropathy (aman), a rare variant of guillain-barré syndrome (gbs) without systemic signs of infection. mri of the cervical spine demonstrated longitudinally extensive transverse myelitis, and emg was consistent with the diagnosis of aman. csf testing was negative for sars-cov- . high dose steroids followed by plasma exchange were administered, and the patient made a clinical recovery. immunotherapy has some role in fastening the improvement of immune-mediated neurological conditions associated with covid- . electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. the variety of neurological disorders described in covid- could be attributed to one of several mechanisms of injury that have been described with other viral infections such as herpes simplex infections [ ] . there are several mechanisms involved for viral dissemination to the nervous system, including direct binding of the virus to the ace receptors expressed in the nasal epithelium or the olfactory bulb through a retrograde trans-synaptic mechanism, hematogenous, lymphatic and migration of infected immune cells. the critical test required for confirmation of the cns infection by sars-cov- is the detection of its rna by rt-pcr in the csf. however, the sensitivity of the csf sars-cov- rt-pcr is unknown. here we present a unique case of covid patients with acute necrotizing myelitis (anm) and acute motor axonal neuropathy (aman), a rare variant of guillain-barré syndrome (gbs) without systemic signs of infection. a -year-old right-handed woman with a history of hypertension, hyperlipidemia, hypothyroidism, and a remote history of nasopharyngeal and uterine cancer presented to the emergency department with progressive weakness. two weeks before her presentation, she had contact with a covid- positive coworker. a week before her presentation, she developed a runny nose and chills. she had no fever, cough or shortness of breath. three days before her admission, she started experiencing a tingling sensation in her fingers and toes. over the next day, symptoms progressed, and she lost feeling from the chest down and developed progressive weakness in her extremities, and lost her ability to walk. she has not had a bowel movement in a week and developed bladder retention. neurological examination showed increased tone in the lower extremities with weakness in the upper and lower extremities, worse in the lower extremities. reflexes were normal in the upper extremities but brisk in the lower extremities with upgoing toes bilaterally. the patient had a sensory level at c . nasopharyngeal sars-cov rt-pcr was positive. covid labs were all within the normal range (appendix). brain mri was normal. however, mri cervical spine showed patchy t hyperintensities within the central cord extending from below the foreman magnum, proximal electronic supplementary material the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. c -c , to cervicothoracic junction (fig. a--c) , with spinal cord slightly increased in overall caliber at c and c , and patchy enhancement obscured by the motion artifact (fig. e) . these changes were associated with a slight hypointense signal on the t images at the c -c level (fig. d) . mri thoracic and lumbar spine were normal. the patient had an extensive diagnostic work up, which was negative for nutritional deficiencies, infectious, autoimmune diseases (lupus, sjogren's vasculitis, syphilis, aquaporin- and myelin oligodendrocyte glycoprotein antibodies). aquaporin- antibody tested negative in both csf and serum. the patient had a spinal fluid analysis that showed a hemorrhagic tap (red blood cells /mm ) with normal white blood cells ( /mm ) elevated protein ( mg/ dl) and glucose ( mg/dl). csf igg index was normal ( . ), and no oligoclonal bands were present. csf gram stain and culture was negative. csf vdrl was negative. csf viral pcr for other microbes was recommended by the neurology team but was not collected. csf testing for sars-cov- was negative. csf paraneoplastic panel (mayo clinic, appendix) was also negative. the patient was treated with methylprednisolone g iv for days without improvements. the patient continued to progress and became quadriparetic. on neurological re-evaluation, weeks after her initial onset of symptoms, the patient was found to be areflexic in all extremities. she had a repeat spinal tap ( days after the first one), and an emg performed ( weeks after her initial presentation) to evaluate for gbs. repeat spinal fluid analysis demonstrated albuminocytological dissociation with elevated csf protein ( mg/dl) and normal white blood cell count ( / mm ), red blood cells ( mm ) , and glucose ( mg/dl). emg showed evidence of acute motor axonal neuropathy with normal sensory conductions (supplementary table) . the patient received five rounds of plasma exchange and was discharged to an inpatient rehabilitation facility. she started to make some clinical recovery - weeks after her clinical presentation. the patient started to stand up . spinal cord swelling is seen at c -c level with associated t hypointensity (d, white arrow). stir short inversion-time inversion recovery, flair fluid-attenuated inversion recovery, letm longitudinal extensive transverse myelitis with the assistance and was able to take few steps with the walker at the rehabilitation facility. acute necrotizing encephalitis, myelitis and variants of gbs such as axonal, demyelinating, and miller fisher syndrome have been reported with the covid [ ] [ ] [ ] [ ] . here we present the first case of covid patients who presented with gbs and anm at the same time without any systemic manifestation. in most of these cases, sars-cov- rt-pcr was positive in the nasopharyngeal swab but negative in the csf, including our case. all patients made a clinical recovery after immunotherapy. form these cases; we learn that the immunotherapy has some role in fastening the improvement of immune-mediated neurological conditions associated with covid- . funding not applicable. informed consent waiver for consent, consent is not needed for the case report per irb. availability of data and material available upon request. : . double-stranded dna-negative myeloperoxidase antibody-negative virus-induced neuronal dysfunction and degeneration covid- -associated acute necrotizing myelitis covid- -associated acute hemorrhagic necrotizing encephalopathy ct and mri features guillain-barré syndrome associated with sars-cov- miller fisher syndrome and polyneuritis cranialis in covid- key: cord- -mip mkef authors: jo, sungyang; chang, jun young; jeong, suyeon; jeong, soo; jeon, sang-beom title: newly developed stroke in patients admitted to non-neurological intensive care units date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: mip mkef background: little is known about newly developed stroke in patients admitted to the intensive care unit (icu). objective: this study aimed to investigate characteristics and outcomes of newly developed stroke in patients admitted to the non-neurological intensive care units (icu-onset stroke, ios). methods: a consecutive series of adult patients who were admitted to the non-neurological icu were included in this study. we compared neurological profiles, risk factors, and mortality rates between patients with ios and those without ios. results: of , patients admitted to the icu for non-neurological illness, ( . %) developed stroke (ischemic, n = ; hemorrhagic, n = ). the most common neurological presentation was altered mental status (n = ), followed by hemiparesis (n = ), and seizures (n = ). the most common etiology of ios was cardioembolism ( % [ / ]) for ischemic ios and coagulopathy ( % [ / ]) for hemorrhagic ios. in multivariable analysis, the acute physiology and chronic health evaluation ii (apache ii) score (adjusted odds ratio [aor] = . , % ci = . − . , p < . ), prothrombin time (aor = . , % ci = . − . , p = . ), cardiovascular surgery (aor = . , % ci = . − . , p < . ), mechanical ventilation (aor = . , % ci = . − . , p < . ), and extracorporeal membrane oxygenation (aor = . , % ci = . − . , p < . ) were related to the development of ios. stroke was associated with increased -month mortality after hospital discharge (aor, . ; % ci, . – . ; p < . ), after adjustment for apache ii and comorbidities. conclusions: patients who developed ios had characteristics of initial critical illness and managements performed in the icu as well as neurological presentations. the occurrence of ios was related to high morbidity and mortality. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. in conjunction with high incidence, in-hospital stroke showed lower rates in reperfusion therapy and greater risk of mortality compared with community-onset stroke [ ] [ ] [ ] . patients admitted to intensive care unit (icu) have distinct features such as unstable vital signs, coagulopathies, inflammation, as well as multiple comorbidities, and they often receive invasive procedures or surgical treatments. thus, there may be high risks of stroke as well as delays in the diagnosis of stroke during admission to the icu, leading to suboptimal management of critically ill patients [ , ] . early detection of acute stroke is imperative for saving viable brain tissues and recovery of neurologic deficits [ ] . time saving measures are being implemented at every step from symptom recognition, imaging studies, and treatments. however, early detection of stroke symptoms in icu-onset stroke (ios) is challenging, not only due to comorbidities, but also due to immobilization, medical equipment, and use of sedative agents [ , ] . accordingly, there are substantial barriers to the conduct of neuroimaging studies to reveal ios in the context of general critical care. comprehensive studies regarding ios are lacking, which limit the development of strategies for the prevention, early detection, and proper managements of ios. here, we aimed to investigate the neurological and radiological profiles, risk factors, and clinical outcomes of ios. furthermore, we aimed to investigate differences of such characteristics between ischemic and hemorrhagic strokes. this study was performed at asan medical center, a bed tertiary hospital in seoul, republic of korea. for this study, medical records of a consecutive series of icu patients between november st, and march st, were retrospectively evaluated. we included patients who ( ) were years of age or older, ( ) were admitted to clinical departments other than neurology and neurosurgery, and ( ) did not have acute stroke before icu admission. this study was approved by the institutional review board of asan medical center, and the need for written informed consent was waived because of the retrospective design of the study. according to the routine practice of our icus, neurological evaluations, including the glasgow coma scale, a pupillary size, light reflexes, and muscle strength (the medical research council scale), were performed and documented by nurses every − h. when nurses detected abnormal neurological findings during their routine evaluations, they notified such findings to treating doctors perform computed tomography (ct) or magnetic resonance imaging (mri) scans of the brain. we reviewed electronic medical records for patients' baseline characteristics, laboratory findings, and acute physiology and chronic health evaluation ii (apache ii) score at the time of admission to the icus [ ] . we investigated whether the patients underwent surgery (cardiovascular vs. non-cardiovascular surgery) and invasive cardiovascular interventions before the occurrence of stroke. moreover, we assessed the application of life-support modalities such as inotropic agents, mechanical ventilation, continuous renal replacement therapy, or extracorporeal membrane oxygenation (ecmo). systemic inflammatory response syndrome (sirs) was defined in accordance with international guidelines [ ] . we defined ios if ( ) ct and/or mri scans of the brain were performed during icu admission and ( ) ct and/ or mri images revealed findings compatible with acute infarcts, intracerebral hemorrhage (ich), or subarachnoid hemorrhage (sah). we dichotomized ios into ischemic ios (infarcts) and hemorrhagic ios (ich and sah). for patients with a diagnosis of ios, we categorized their symptoms (or signs) into categories such as altered mental status, seizures, pupillary changes (size and light reflexes), hemiparesis, and others. time domains such as last-knownnormal time, first-found-abnormal time, and time to initial neuroimaging studies were also reviewed. clinical outcomes included length of icu stay, length of hospital stay, mortality before icu discharge, mortality before hospital discharge, mortality at days after hospital discharge, and mortality at days from icu admission. we evaluated for the presence of vascular stenosis (> % reduction of vascular diameter) or occlusion, if the patient underwent cerebral angiography. the subtypes of ischemic ios were determined according to the classification of the trial of org , in acute stroke treatment (toast) [ ] . for patients with ich, we measured the ich score as well as the lesion location and volume [ ] . we categorized the etiologies of ich into hypertension, cerebral amyloid angiopathy, coagulopathy, medication (antiplatelet agents or anticoagulants), and unknown cause groups [ ] . for patients with sah, we reviewed ct brain scans to identify the presence of ruptured aneurysms and assessed sah severity using the modified fisher scale. neuroimaging studies (ct, mri, and angiographic studies) were reviewed jointly by two investigators and a third investigator was consulted in case of disagreements. treatment modalities for ischemic ios included antiplatelet agents, anticoagulants, intravenous thrombolysis, intraarterial thrombectomy, and neurosurgery, and those for hemorrhagic ios were categorized into either neurosurgical or medical treatments. we compared baseline demographics, comorbidities, apache ii score, the presence of sirs, laboratory findings, and treatment modalities between patients with ios and those without ios using χ tests, t tests, and kruskal-wallis tests, as appropriate. variables with a p value of < . by univariate analysis were included as candidate variables in multivariable analysis. backward stepwise selection was conducted to find factors associated with ios in multivariable logistic regression models. we further performed all analyses using a forward selection procedure to confirm the final model. we also compared the aforementioned variables between patients with ischemic ios and those with hemorrhagic ios. a cox proportional hazards model was used to assess the hazard ratios of -day mortality from icu admission according to the presence of stroke, with adjustments for demographics, comorbidities, and apache ii scores. kaplan-meier survival curves were also plotted for mortality of patients with ios and patients without ios. additionally, we evaluated the association between stroke and mortality, with adjustments for demographics, comorbidities, and apache ii scores using multivariate logistic regression. all statistical analyses were performed using r, version . . (r foundation for statistical computing, vienna. austria) and spss version . (ibm corp., armonk, ny, usa). a total of , patients were admitted to adult icus during the study period. of these, we excluded patients younger than years of age (n = ), those who were admitted to neurological and neurosurgical departments (n = ), and patients diagnosed with acute stroke before admission to the icu (n = ). thus, we finally included , patients. the median age of included patients was . years (iqr, . − . years) and , ( . %) patients were male. table shows baseline characteristics of the finally included , patients. altered mental status (n = ) was the most common neurological manifestation of ios (the reason to conduct neuroimaging studies), followed by hemiparesis (n = ), seizures (n = ), pupillary changes (n = ), and aphasia (n = ). comatose state ( . % vs. . %; p < . ) and pupillary changes ( . % vs. . %; p < . ) were more common in patients with hemorrhagic ios than those with ischemic ios, while aphasia ( . % vs. %; p < . ) and hemiparesis ( . % vs. . %; p < . ) were more common in patients with ischemic ios than those with hemorrhagic ios. (table i the main reasons for delays in stroke recognition included the use of sedative agents following surgery (n = ) or mechanical ventilation (n = ), presumed metabolic encephalopathy (n = ), and missed findings of neurological deficits during routine hourly evaluations (n = ) (as described for patients who had such a time interval beyond the median time of . h). patients with altered mental status as an initial stroke manifestation had time delays to the stroke recognition than patients without altered mental status (p = . ), while patients with seizure as an initial stroke manifestation had shorter time intervals for the stroke recognition than patients without seizure (p = . ). the main reasons for delays in neuroimaging study included unstable vital signs (n = ), the application of ecmo (n = ), poor cooperation of patients (n = ), and unknown reasons (n = ) (as described for patients who had a time interval beyond the median time of . h). patients with hemiparesis or pupillary changes as a stroke manifestation had shorter time intervals for neuroimaging studies than patients without those symptoms (p = . and . , respectively) ( table ) . radiological findings and presumed etiologies of ischemic ios and hemorrhagic ios are shown in table . of the patients with ischemic ios, cardioembolism ( . %) was the most common etiology of ischemic ios, followed by undetermined etiology ( . %), other determined etiology ( . %), large-artery disease ( . %), and small-vessel disease ( . %). other determined etiologies included cancer-related stroke (n = ), cerebral air embolism (n = ), and arterial dissection (n = ), and meningitis-related stroke (n = ). of the patients with ich, the most common etiology of ich was coagulopathy (n = ), and the presumed causes of such coagulopathy were liver disease (n = ), sepsis (n = ), and hematologic malignancy (n = ). among patients with sah, modified fisher scale was in patients and in patient, and only patient had a ruptured aneurysm. in the univariable analysis, risk factors associated with ios were older age, apache ii score, sirs, cardiovascular surgery, non-cardiovascular surgery, use of mechanical ventilation, continuous renal replacement therapy, and use of ecmo. the following laboratory findings were also associated with ios: hemoglobin level, platelet count, and prothrombin time (p < . for all variables of the patients with ischemic ios, antithrombotic agents (antiplatelet agents and anticoagulants) were given to patients. antithrombotic agents were not given to patients due to thrombocytopenia (n = ), hemoptysis (n = ), large infarct size (n = ), and for uncertain reasons (n = ). the reperfusion therapy rate for ios was . % ( / ; intravenous thrombolysis, n = ; intraarterial thrombectomy, n = ) in our study population. intravenous thrombolysis (infusion of alteplase) was attempted in patients. the reasons not to perform intravenous thrombolysis in the remaining patients were as follows: neuroimaging studies were performed beyond . h from the last-known-normal time (n = ), patients underwent recent major surgery (n = ), had large hemispheric infarct (n = ), prolonged activated partial thromboplastin time (n = ), mild neurological deficits (n = ), delays in decision-making (n = ), and uncertain reasons (n = ). of patients with large-artery occlusion, intraarterial thrombectomy was performed in patients. of the remaining patients, intraarterial thrombectomy was not attempted due to reasons such as the patients having absence of diffusion-perfusion mismatch (n = ), recent aortic surgeries (n = ), rapidly resolving neurological symptoms (n = ), unstable vital signs (n = ), or for uncertain reasons (n = ). two patients received decompressive craniectomy for large hemispheric infarcts. of the patients with hemorrhagic ios, ( . %) underwent surgical treatments including decompressive hemicraniectomy (n = ), decompressive hemicraniectomy with hematoma evacuation (n = ), and bilateral frontotemporal decompressive craniectomy (n = ). the length of icu stay was longer in patients with ios compared with those without ios (median days, . [iqr, (fig. ) . in the multivariable logistic regression analysis, patients with ios had higher mortality before icu discharge (aor, . ; % ci, . − . ; p = . ), before hospital discharge (aor, . ; % ci, . − . ; p < . ), and at days after hospital discharge (aor, . ; % ci, . - . ; p < . ) than patients without ios, after adjustments for apache ii score and comorbidities. the cox proportional hazard model showed that patients with ios had a hazard ratio of . in terms of mortality at days after hospital admission ( % ci, . - . ; p = . ) after adjusting for apache ii score and comorbidities (fig. ) . this is one of the largest studies reported to date on the rate of newly developed stroke during icu care in patients with non-neurological disease. we found the incidence of ios among adult patients admitted to icu with non-neurological critical illnesses was . % ( / , ). the proportions of patients with ischemic and hemorrhagic ios were % and %, respectively. cardiovascular surgery was associated with ischemic ios, and prothrombin time prolongation was associated with hemorrhagic ios; higher apache ii scores, mechanical ventilator and ecmo were associated with both ischemic and hemorrhagic ios. patients with ios had high mortality rates before hospital discharge ( %) and at days after hospital discharge ( %), which were approximately twice as high as the mortality rates of patients without ios. furthermore, the occurrence of ios was independently associated with . -fold increased risk of mortality at days from hospital discharge. the incidence of ios was higher than expected. during a median . days of their icu admission, . of patients developed ios, which was much more common compared with general population in korea (stroke incidence, per , person-years) [ ] . moreover, risk factors for ios in the current study were very different from well-known risk factors for community-onset stroke: critical conditions (e.g., apache ii score, cardiovascular surgery, mechanical ventilation, and ecmo), but not the premorbid conditions (e.g., old age, hypertension, diabetes mellitus, and atrial fibrillation), were related to ios. cardiovascular surgery was also a risk factor for in-hospital stroke [ ] . prothrombin time prolongation, which suggests increased bleeding tendency, was associated with hemorrhagic ios. this is in line with the most common etiology of ich; coagulopathy from sepsis, liver failure, and hematologic malignancy. we also found that the application of mechanical ventilation and ecmo was related to both ischemic and hemorrhagic ios. positive pressure ventilation may provoke thromboembolism by inducing hypercoagulable state, opening unrecognized patent foramen ovale, and new-onset atrial fibrillation [ ] [ ] [ ] [ ] [ ] . in addition, weaning from mechanical ventilation may induce hemodynamic changes and cardiac failure [ ] . exposure of blood to the ecmo circuit may result in the formation and embolization of thrombi. ecmo may also lead to platelet dysfunction and coagulopathy, and the use of anticoagulants may contribute to the occurrence of ich [ ] . these conditions might invoke or trigger both ischemic and hemorrhagic ioss in vulnerable patients who were admitted to the icu. the current study showed that neurological manifestations may differ between ischemic and hemorrhagic ios. aphasia and hemiparesis were more common in patients with ischemic ios than in patients with hemorrhagic ios, while altered mental status and pupillary changes were more common in patients with hemorrhagic ios than in patients with ischemic ios. the diagnosis of stroke based on clinical findings is important in ios, because there are high risks in transporting patients to the outside of the icu for neuroimaging studies [ , ] . it is important to recognize altered mental status as a potential clinical presentation of ios. the recognition of stroke is probably the first step to perform urgent brain and vascular imaging and allow rapid treatments. in patients admitted to the icu, however, altered mental status related to sedative agents are likely difficult to be differentiated from altered mental status as the presenting symptom of ios. the most common reason for delays in stroke recognition in our patients was the use of sedative agents following surgery and mechanical ventilation. unfortunately, altered mental status was also the most common neurological manifestation of ios. thus, delays in symptom recognition were substantial in our patients with altered mental status. to reduce delays in the stroke recognition for patients requiring sedative agents, targeting light sedation, interrupting sedative agents daily, and administering sedative agents with short contextsensitive half-time may be helpful [ , ] . patients with hemiparesis and pupillary changes had significantly shorter time intervals from the recognition of stroke symptoms to the performance of neuroimaging studies. such differences of time intervals according to neurological symptoms may be in part due to the physician's confidence of the occurrence of ios, otherwise, coexisting medical conditions such as unstable vital signs and applications of medical equipment could have interfered with the performance of neuroimaging studies. time delays in diagnosing stroke may contribute to low rates of reperfusion therapy, which may result in worse outcomes. reperfusion therapy was performed in only . % in patients with ischemic ios (intravenous thrombolysis, . %; intraarterial thrombectomy, . %), which is much lower than the reperfusion therapy rate in our previous study of emergency room treatment of community-onset stroke (intravenous thrombolysis and/or intraarterial thrombectomy, . %; intravenous thrombolysis, . %; intraarterial thrombectomy, . %) as well as that in korean nation-wide statistics for patients with community-onset stroke (intravenous thrombolysis, . %; and intraarterial thrombectomy, . %) [ , ] . notably, in % ( / ) of patients with ischemic ios, the reason to not conduct intravenous thrombolysis was delays in identifying stroke beyond . h from the last-known-normal time. these patients could have received thrombolytic therapy if their strokes were detected earlier, and such therapy could have improved their outcomes. these findings suggest that special attention is necessary to expedite assessments and therapies for patients with ios. the mortality rate at any stage from icu discharge to days after discharge was significantly higher in patients with ios than those without ios. we evaluated increased risk of mortality by stroke both at days after hospital discharge and days after admission, because stroke onset time was wide-ranging. the mortality rate at days after hospital discharge in patients with ios was %, which is approximately three times higher compared with mortality rate in patients without ios ( %) and mortality rate in patients with community-onset stroke ( %) [ ] . it is uncertain whether the high mortality rate of patients with ios resulted from ios per se or if the high rate resulted from an underlying medical illness or an interaction between an underlying illness and ios. however, the occurrence of ios was associated with mortality, even after adjustments for apache ii scores and comorbid conditions. these findings underline the importance of early detection and proper management of stroke in patients admitted to the icu with non-neurological critical illness. as most patients with ios are taken care of by general physicians and intensivists who do not specialized in stroke management, the activation of stroke code and specialized teams may be needed for patients with stroke symptoms [ ] . our study has limitations. first, this is a single-center retrospective study; thus, our findings should be interpreted cautiously for patients in other centers. second, the incidence of ios might be underestimated in our study. we defined stroke according to the findings on ct and/or mri images of the brain, but only % of icu patients underwent such neuroimaging studies, so patients who developed stroke but did not undergo neuroimaging studies, due to very unstable vital signs and early death soon after admission to the icu, may not have been identified as having ios. moreover, among patients who underwent brain scans for this study, as many as . % underwent ct scans without mri. it is possible that ct scans could have missed acute infarcts, because the sensitivity of ct for detecting acute infarct is lower than mri (diffusion-weighted imaging). third, neurological outcomes as evaluated with validated scales, such as the modified rankin scale, were not available for this retrospective study. the mortality and length of stay at icu and at hospital may be insufficient to evaluate clinical outcomes of stroke victims. patients with initially severe illness, cardiovascular surgery, prothrombin time prolongation, and application of mechanical ventilation and ecmo had high risks for developing acute stroke during their admission to the icu. substantial time delays ensued in the evaluation and management of ios. ios was associated with increased morbidity and mortality. these results call for strategies for prevention, early detection, and proper managements for ios. author contributions sj, jyc, and s-bj contributed to the concept and design of the study. sj, jyc, sj, sj, s-bj contributed to the acquisition and analysis of the data. sj and s-bj contributed to drafting the text, which was reviewed and revised by all co-authors. data availability all deidentified data that support the findings of this study are available upon reasonable request to the corresponding author from other researchers if ethical approval is granted. the authors have no conflicts of interest to declare. ethical standards this study was approved by the institutional review board of asan medical center. ethics approval and consent to participate this study was approved 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intrahospital transport of critically ill patients: safety and outcome of the necessary "road trip recommendations for the intra-hospital transport of critically ill patients clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the icu management of pain and agitation for patients in the intensive care unit multidisciplinary approach to decrease in-hospital delay for stroke thrombolysis neurological emergencies in patients hospitalized with non-neurological illness hemorrhagic transformation within hours of a cerebral infarct: relationships with early clinical deterioration and -month outcome in the european cooperative acute stroke study i (ecass i) cohort key: cord- -p s p fd authors: decavèle, maxens; gatulle, nicolas; weiss, nicolas; rivals, isabelle; idbaih, ahmed; demeret, sophie; mayaux, julien; dres, martin; morawiec, elise; hoang-xuan, khe; similowski, thomas; demoule, alexandre title: one-year survival of patients with high-grade glioma discharged alive from the intensive care unit date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: p s p fd introduction: only limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. we sought to quantify -year mortality and evaluate the association between mortality and ( ) functional status, and ( ) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit. patients and methods: retrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between january and june . functional status was assessed by the karnofsky performance status. anticancer therapy after discharge was classified as ( ) continued (unchanged), ( ) modified (changed or stopped), or ( ) initiated (for newly diagnosed disease). results: ninety-one high-grade glioma patients ( % of whom had glioblastoma) were included and ( %) of these patients were discharged alive from the intensive care unit. anticancer therapy was continued, modified, and initiated in %, %, and % of patients, respectively. corticosteroid therapy at the time of icu admission [odds ratio (or) . ] and cancer progression (or . ) was independently associated with continuation of anticancer therapy. the mortality rate year after icu admission was %. on multivariate analysis, continuation of anticancer therapy (or . ) and karnofsky performance status on admission (or . ) were independently associated with lower -year mortality. conclusion: the presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge. previous presentation: preliminary results were presented at the most recent congress of the french intensive care society, paris, . electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. patients with solid tumor or hematologic malignancies account for % of intensive care unit (icu) admissions [ , ] . because the prognosis of cancer patients is similar to that of non-cancer patients [ , ] , a diagnosis of cancer should not preclude icu admission. this general rule also applies to patients with primary malignant brain tumors admitted to the icu [ ] . the outcome of patients with primary malignant brain tumors has been described in terms of short-term and medium-term mortality [ ] [ ] [ ] . however, data on -year mortality in these patients discharged alive from the icu are lacking [ ] [ ] [ ] [ ] [ ] , and previous series included mixed highgrade gliomas (hgg), low-grade gliomas, and primary central nervous system lymphomas which have a heterogeneous prognosis [ ] [ ] [ ] . in addition, the impact of an icu stay on health-related performance status and the opportunity to continue anticancer therapy remains unclear [ ] [ ] [ ] [ ] . these last two points are of utmost importance, as a marked reduction of performance status is commonly observed in patients electronic supplementary material the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. requiring mechanical ventilation or vasopressors [ ] [ ] [ ] [ ] [ ] . in turn, this poor performance status at icu discharge may jeopardize long-term outcome by postponing or canceling anticancer therapy [ , ] . this risk is particularly high in patients with primary malignant brain tumors, as these tumors are known to reduce performance status [ ] [ ] [ ] , especially in patients with hgg. we designed the present study to identify factors associated with -year outcomes in patients with hgg who survived an unplanned medical icu stay. in addition, we examined changes in performance status and changes in the management of anticancer therapy after icu discharge. this study focused on a homogeneous population of hgg, corresponding to majority of primary brain tumors with the most severe prognosis and raising the most challenging decisions concerning icu admission. our hypotheses were that, among hgg patients discharged alive from the icu: ( ) a substantial proportion of patients would still be alive year after icu discharge, with relatively good performance status, ( ) anticancer therapy could be continued in a substantial proportion of patients, and ( ) the performance status at icu admission and maintenance of anticancer therapy were associated with a higher -year survival rate. the study was conducted from january to june in two medical icus: a -bed icu in a pulmonology department and a -bed icu in a neurology department. both icus are located in a university hospital with a strong neurological orientation including a specific neuro-oncology department (about newly diagnosed patients each year) and the national reference center for high-grade oligodendroglial tumor (i.e., pola network). this study was approved by the french intensive care society institutional review board (ce srlf - ) and information was given to the patients or their relatives. data from this cohort have been previously published [ , ] . data were extracted from a prospectively managed database that comprehensively describes all patient stays in the two icus (fusion, varimed, france). the database of the two icus comprised , records, corresponding to % of admissions over the study period. in patients with several readmissions, only the first stay was included in the analysis. this set of , records was retrospectively searched for all consecutives cases of hgg, defined as grade iii (anaplastic astrocytoma and oligodendroglioma) and grade iv (glioblastoma) glioma according to the world health organization (who) classification of tumors of the central nervous system [ ] . patient who underwent recent neurosurgery (< weeks) or any other recent surgery (< weeks) and patients under the age of years were excluded. at the time of admission, gender, age, comorbidities using the charlson comorbidity index (cci) [ ] , physiological variables such as body temperature, respiratory rate, heart rate, systolic blood pressure, and glasgow coma scale and various laboratory variables were recorded. severity on admission was assessed by the simplified acute physiology score (saps) ii [ ] and the sequential organ failure assessment (sofa) [ ] . performance status was assessed during the week before icu admission and , , , , and months after icu admission, using the karnofsky performance status scale [ ] . the tumor type was determined histologically on either the resection specimen or a biopsy. idh / mutation and p/ q codeletion molecular status were also collected when available (systematic testing in our center since ). the reason for admission was determined retrospectively from the conclusions of the medical records. in case of admission for coma, the diagnosis of seizures was adopted when abnormal movements highly suggestive of seizures were observed, with or without electroencephalographic confirmation, or in the absence of suggestive movements, by consciousness alteration associated with electroencephalographic confirmation of seizures. cancer disease status was classified as controlled (partial response, complete response, or stable disease), in progression, or newly diagnosed when the cancer was diagnosed during or after icu admission or when the cancer was diagnosed during the weeks preceding the icu stay and no anticancer therapy had yet been delivered. anticancer therapy after icu discharge was classified as follows: ( ) continued, when the anticancer therapy planned and initiated before icu admission was continued unchanged after icu discharge, ( ) modified, when the anticancer therapy planned and initiated before icu admission was changed or stopped after icu discharge, and ( ) initiated, when, for patients with newly diagnosed cancer, anticancer therapy was initiated during or after the icu stay. anticancer therapy only comprised chemotherapy and radiation therapy. we also recorded whether or not patients were receiving corticosteroid therapy at the time of icu admission. the presence of corticosteroids at admission was not considered to constitute anticancer therapy. finally, advanced life support measures taken during the icu stay and vital status year after icu admission ( -year mortality) were recorded. continuous variables were reported as median and interquartile interval, and categorical variables were reported as frequencies (%). categorical variables were compared using the chi-square test or fisher's exact test, as appropriate. continuous variables were compared using the mann-whitney test or the kruskal-wallis test. all tests were two-sided and p values < . were considered statistically significant. multivariate logistic regression was performed to identify factors associated with one-year mortality after icu admission. in patients receiving anticancer therapy prior to admission, multivariate logistic regression was performed to identify factors associated with continuation of anticancer therapy. factors yielding p values < . or considered to be clinically relevant were entered in the model and missing data (l. %) were imputed by the nearest-neighbor method. odds ratios (ors) and their % confidence intervals (ci) were calculated for significant factors. one-year survival according to continuation of anticancer therapy after icu discharge was evaluated using kaplan-meier survival function estimates. the impact of anticancer therapy on survival was assessed with the log-rank test. the karnofsky performance status was analyzed using a linear mixed model with anticancer therapy and times as fixed-effect factors, and the patient as random-effect factor. the linear mixed model was fitted with the restricted maximum-likelihood method. post hoc tests of significance of the fixed-effect factor between pairs of conditions were performed with a likelihood ratio test. statistical analyses were performed using r version . . . and matlab version . . . (r a). figure displays the study flowchart. of the patients included, ( %) were admitted to the medical icu and ( %) were admitted to the neurological icu. the diagnosis of hgg was confirmed histologically in all patients and was based on examination of the surgical resection specimen for ( %) patients or a biopsy specimen for ( %) patients. the main characteristics of the patients are displayed in table . tumor types were distributed as follows: ( %) glioblastomas (grade iv), ( %) anaplastic astrocytomas (grade iii), and ( %) anaplastic oligodendrogliomas (grade iii). the cancer diagnosis was initiated or established during the icu stay for ( %) patients and was established prior to icu admission for the remaining ( %) patients; median time between cancer diagnosis and icu admission was ( - ) months. icu and hospital lengths of stay were ( - ) and ( - ) days, respectively. seventy-eight patients ( %) were discharged alive from the icu. among the icu survivors, anticancer therapy was continued in ( %) patients, modified in ( %) patients, and initiated in ( %) patients. table shows the factors associated with continuation or modification of anticancer therapy after icu discharge. on multivariate logistic regression, two factors were independently associated with continuation of anticancer therapy after icu discharge: cancer progression at icu admission (or . , % ci . - . , p = . ) and use of corticosteroids (or . , % ci . - . , p = . ) at icu admission. the mortality rate year after icu discharge was % ( / patients). table depicts the factors associated with mortality year after icu admission identified by univariate analysis. on multivariate logistic regression analysis, two factors were independently associated with lower mortality year after icu admission: continuation of anticancer therapy after icu discharge (or . , % ci . - . , p = . ), and karnofsky performance status at icu admission (or . , % ci . - . , p < . ). cumulative survival probability significantly differed between patients in whom anticancer therapy was continued, modified, or initiated (fig. ) , with the greatest survival probability observed among patients in whom anticancer therapy was continued. figure shows changes in karnofsky performance status from icu admission to year after icu discharge in icu survivors, according to management of anticancer therapy. karnofsky performance status was significantly different between the three anticancer therapy strategies and was the lowest in patients with anticancer therapy modified. karnofsky performance status year after icu admission was > % in more than % of patients in whom anticancer therapy was initiated or continued. the main results of the study can be summarized as follows: in hgg patients discharged alive after an unplanned medical icu stay ( ), we observed a substantial proportion of survivors year after icu admission (more than one quarter of patients) and most of these patients exhibited relatively favorable performance status even year after icu admission, ( ) continuation of anticancer therapy was possible in almost % of patients and was strongly associated with cancer progression and use of corticosteroids at admission, and ( ) continuation of anticancer therapy and karnofsky performance status at admission were associated with higher -year survival rates. to the best of our knowledge, this is the first report based on a homogeneous cohort of patients with hgg discharged alive after an icu stay, focusing on -year mortality, health-related functional status, and management of anticancer therapy after icu discharge. first of all, the low icu mortality rate observed in this study ( %) is consistent with recent findings, showing that icu mortality is not higher in patients with primary malignant brain tumor than in patients with other types of solid cancer ( , - ) and patients without cancer [ , ] . the survival rate of hgg patients year after icu admission observed in the present study was non-negligible ( %) and most patients still presented favorable performance status at year (> %). indeed, considering the median time between cancer diagnosis and icu admission [ ( - ) months] and considering the median survival of patients with hgg [ ] , the % survival after icu admission observed in this study appears to be substantial and encouraging. moreover, the survival rate year after icu admission was fairly similar to that observed in patients with other types of solid cancer [ , , [ ] [ ] [ ] [ ] or hematologic malignancies [ ] [ ] [ ] [ ] [ ] . young age, limited comorbidities, and a high proportion of rapidly reversible causes, such as seizures, could explain this relatively high -year survival rate. the performance status observed over the study period is consistent with a previous report of primary malignant brain tumor patients admitted to the icu [ ] . in addition, our study shows that more than one-half of patients achieved a performance status, indicating that they were able to selfcare at home (karnofsky performance status ≥ %) [ ] . this is a valuable observation when assessment of functional outcome is considered to be essential to evaluate the relevance of icu admission or maintenance of intensive therapy. to date, only a few studies have explored the impact of an icu stay on anticancer therapy and the long-term outcome after icu discharge [ ] [ ] [ ] ] . the rate of continuation of anticancer therapy observed in our study was similar to that reported in other studies [ ] [ ] [ ] [ ] . two factors, cancer progression and use of corticosteroids, were independently associated with failure to continue anticancer therapy in icu survivors. while there is an obvious relationship between cancer progression and modification of anticancer therapy, the link between the use of corticosteroids and modification of anticancer therapy is less obvious and could be explained by the fact that corticosteroid prescription is generally driven by the presence of perilesional brain edema or neurological symptoms, which are both surrogates for disease activity [ ] . corticosteroid administration is a marker of poor disease control, often requiring modification of anticancer therapy. this finding is also in line with the fact that the cumulative corticosteroid dose delivered to patients with primary malignant brain tumor is associated with higher mortality [ ] and decreased progression-free survival [ ] . the strong influence of anticancer therapy management after icu discharge on -year survival is also in line with the other reports concerning patients with solid cancer or hematologic malignancies, in whom -month [ , ] and -year [ ] survivals were higher in patients in whom anticancer therapy was continued after icu discharge. interestingly, we did not observe a higher survival rate in patients in whom anticancer therapy was initiated for a newly diagnosed cancer, which is consistent with the previous reports on patients admitted to the icu with a newly diagnosed cancer, supporting the idea that critically ill patients with underlying undiagnosed cancer are likely to present locally advanced or metastatic disease with poor medium- [ ] and long-term prognosis [ ] . in these reports, karnofsky performance status at icu admission was also independently associated with long-term mortality [ , ] . the present study has several limitations. first, it was a retrospective study, which implies a potential bias in patient selection or data collection. however, data were extracted from a prospectively managed database and the rarity of the disease remains a major obstacle to prospective studies, even with a multicenter design. second, the relevance of karnofsky performance status as a health-related functional endpoint in this very specific population could be questioned. it is possible that other decisive aspects of quality of life, psychological states, and cognitive function, all likely to be impaired in hgg [ , ] , were ignored. third, while we report data for patients admitted to the icu, we did not report the proportion of hgg patients for whom icu admission was refused during the study period, or the policies or criteria that motivated these refusals, and it is possible that patients with the poorest prognosis were, therefore, not admitted to the icu and, thus, not included in this analysis. finally, because molecular testing has been systematically performed only since , whereas the study period started in , this study comprises many missing data and consequently failed to demonstrate any association between molecular testing and prognosis [ ] . in conclusion, we report that a high proportion of hgg patients who survived an icu stay may benefit from continuation of anticancer therapy after discharge, with preserved performance status, and can, therefore, expect a non-negligible survival year after icu admission. simple factors, which can be easily identified before icu admission, such as cancer progression, use of corticosteroids, or karnofsky performance status at admission, are strongly associated with outcomes. if decisions concerning life-sustaining interventions are no longer considered to be futile in patients with active cancer, even metastatic cancer, a similar attitude could also be applied to hgg patients, who have probably been unreasonably denied icu admission for many years. these results will certainly contribute to refine icu admission policies which, in every case, should take into account the neuro-oncologists' experience and the patient's willingness. from norgine and alpha-wasserman and consultant fees from med-day pharmaceuticals. ahmed idbaih reports research funding from la fondation arc pour la recherche sur le cancer, carthera, beta-innov, and intselchimos; travel funding from hoffmann-la roche; and personal fees from novartis, la lettre du cancérologue, bms, and cipla unrelated to the submitted work. other authors had no conflict of interest to 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retrospective multicenter study-a groupe de recherche respiratoire en reanimation en onco-hématologie (grrr-oh) study lung cancer in critical care (lucca) study investigators characteristics and outcome of patients with newly diagnosed advanced or metastatic lung cancer admitted to intensive care units (icus) determinants of -year survival in critically ill acute leukemia patients: a grrr-oh study outcomes and prognostic factors in patients with haematological malignancy admitted to a specialist cancer intensive care unit: a yr study outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication outcome of critically ill allogeneic hematopoietic stemcell transplantation recipients: a reappraisal of indications for organ failure supports time trend analysis of long-term outcome of patients with malignancies admitted at dutch intensive care units use of dexamethasone in patients with high-grade glioma: a clinical practice guideline impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients steroids use and survival in patients with glioblastoma multiforme: a pooled analysis idh mutation status and role of who grade and mitotic index in overall survival in grade ii-iii diffuse gliomas affiliations maxens decavèle , · nicolas gatulle · nicolas weiss , · isabelle rivals , · ahmed idbaih · sophie demeret · julien mayaux · martin dres , · elise morawiec · khe hoang-xuan service de pneumologie brain liver pitié-salpêtrière (blips) study group, inserm umr_s acknowledgements we thank anthony saul for his help with english style and grammar. availability of data and material our data are available to ensure transparency. key: cord- - k pkh authors: buchanan, sarah m.; parker, thomas d.; lane, christopher a.; keshavan, ashvini; keuss, sarah e.; lu, kirsty; james, sarah-naomi; murray-smith, heidi; wong, andrew; nicholas, jennifer; cash, david m.; malone, ian b.; coath, william; thomas, david l.; sudre, carole; fox, nick c.; richards, marcus; schott, jonathan m. title: olfactory testing does not predict β-amyloid, mri measures of neurodegeneration or vascular pathology in the british birth cohort date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: k pkh objective: to explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ years. methods: cross-sectional observational cohort study. largely healthy and cognitively normal older adults were recruited from the mrc national survey of health and development ( british birth cohort) and investigated for olfactory identification deficits, as measured by the university of pennsylvania smell identification test. outcome measures were imaging markers of brain health derived from t mri scanning (cortical thickness, entorhinal cortex thickness, white matter hyperintensity volumes); ( )f florbetapir amyloid-pet scanning; and cognitive testing results. participants were assessed at a single centre between march and january . results: mean (± sd) age was . (± . ) years, . % were female. . % had hyposmia and . % anosmia. olfaction showed no association with β-amyloid status, hippocampal volume, entorhinal cortex thickness, ad signature cortical thickness, white matter hyperintensity volume, or cognition. conclusion and relevance: in the early s, olfactory function is not a reliable predictor of a range of imaging and cognitive measures of preclinical ad. olfactory identification deficits are not likely to be a useful means of identifying asymptomatic amyloidosis. further studies are required to assess if change in olfaction may be a proximity marker for the development of cognitive impairment. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. simple, non-invasive markers of preclinical alzheimer's disease (ad) are needed. odour identification (oi) deficits have been proposed as a potential risk marker for ad. clinically, individuals diagnosed with ad and mild cognitive impairment (mci) have poorer oi, and oi deficits are associated with cognitive decline and conversion to mci and ad [ ] ; and ad pathology affects olfactory pathways in older adults [ ] and animal models [ ] . while the evidence for these associations in clinically defined groups is strong, the evidence regarding imaging biomarkers is more mixed. table summarises the previous literature investigating associations between oi and imaging markers of preclinical ad. considering the two largest cohorts, vassilaki et al. [ ] and growdon et al. [ ] each found associations between poorer oi and imaging markers of neurodegeneration. amyloid status was positively associated with poorer oi in the former, and at trend level in the latter study. in smaller studies, associations were not found [ , ] , or only seen when individuals with mci or ad were included in pooled analyses [ , ] . associations between poorer oi and ad signature cortical thickness, and lower hippocampal volumes have been described [ , , , ] . associations with entorhinal cortex thickness or white matter hyperintensity volume have been present or absent in various studies [ - , , ] . a useful marker for preclinical ad would be positive early in the disease course, allowing a window for treatment. as the prevalence of ad pathology increases steeply with age, younger cohorts may be useful to investigate the earlier stages of disease. in the current study, we explored associations between oi and markers of cerebral β-amyloid deposition (using f-florbetapir pet scanning), neurodegeneration, and cognition in a uniquely well-characterised cohort of near identical age drawn from the mrc national survey of health and development (nshd; the british birth cohort). the insight study included older adults recruited from the nshd [ ] , a representative sample of singleton births in one week in march originally comprising individuals who have been followed prospectively throughout their lives [ ] . ethical approval was granted by the national research ethics service committee london (reference /lo/ ); participants provided written informed consent. participants attended a one-day visit at university college london between may and january (age - years). the cohort profile and recruitment information has been published [ ] . we excluded participants without high-quality imaging (t -weighted mri and amyloid-pet), and those with mild cognitive impairment (mci), neurodegenerative conditions, or conditions likely to affect olfactory function including previous sinus surgery or upper respiratory tract infection (supplementary data). the university of pennsylvania smell identification test (upsit) is a validated "scratch-and-sniff" test comprising micro-encapsulated odorants, with four-option forcedchoice answers [ ] . participants completed the "british" version at the study visit or soon thereafter. where there was missing data for four or fewer items, a correction factor of . per missing item was applied, in line with other studies [ ] . for categorical analyses, hyposmia was defined as upsit score ≤ for males, ≤ for females, and anosmia as upsit score ≤ [ ] . normative data for the upsit british version have not been published; a comparison to norms for the upsit american version is shown in table . the cognitive battery included the mini-mental status examination (mmse), logical memory, digit-symbol substitution test, and the face-name test [ ] . these tests were combined into a modified version of the preclinical alzheimer clinical composite (pacc) score as described in lu et al. [ ] . participants underwent pet-mri scanning on the same -t siemens biograph mmr scanner [ ] . β-amyloid deposition was assessed over a -min period, min after injection of f-florbetapir ( mbq). a standardised uptake value ratio (suvr) was generated from a grey matter cortical composite, with eroded white matter as the reference region. gaussian mixture models determined a suvr cut-point of . to categorise binary amyloid status. hippocampal volume, entorhinal cortex thickness and ad signature cortical thickness were used as markers of neurodegeneration [ , ] . hippocampal volumes were determined using steps [ ] with manual edits where appropriate. ad signature cortical thickness (a composite of temporal cortex regions as described in [ ] ) and entorhinal cortex measurements were determined using freesurfer . . total intracranial volume was calculated using spm (statistical parametric mapping, https ://www.fil.ion.ucl.ac.uk/ spm/) [ ] . white matter hyperintensity volume (wmhv) was derived using bayesian model selection (bamos) [ ] . data were analysed using stata . (statacorp lp). chisquared or wilcoxon rank-sum tests were used for unadjusted analyses comparing oi category with binary or continuous demographic variables, respectively. logistic regression was used for adjusted analysis of (binary) amyloid status, linear regression for hippocampal volumes, ad signature cortical thickness, entorhinal cortex thickness and pacc score. as wmhv was non-normally distributed, we used a general linear model with gamma log link. for each of these outcomes, we fitted models with continuous upsit score or oi impairment category as the predictor variable, and age, sex, and (where appropriate) tiv as covariates. full data on individuals were available for analysis: mean age at visit was . (sd . ) years, and . % were female. table compares the distribution of upsit scores in this cohort with those of a large cohort of similar age assessed using the upsit (american version); the distribution of scores is similar. demographic and background features of the normosmic ( . %), hyposmic ( . %) and anosmic ( . %) groups are shown in table . there were no significant differences in sex, age, socio-economic position, smoking, history of head injury, apoe status, or mmse score between groups. there was no significant relationship between continuous upsit score and binary amyloid status, adjusting for age and sex (or . , % ci . - . , p = . ). there was no evidence that adding upsit score to a base model of age and sex improved prediction of amyloid status (fig. ) . hippocampal volume, entorhinal cortex thickness, cortical thickness, pacc, or wmhv was not associated with continuous upsit scores, or when comparing groups categorically (table ) after adjusting for age and sex. there was similarly no relationship between upsit score and any of the components of the pacc (data not shown). in this study of cognitively normal individuals around the age of years, our main findings were ( ) ~ / of individuals fulfil criteria for hyposmia, and ( ) that there were no associations between low scores on olfactory identification testing and imaging evidence of β-amyloid pathology, fig. receiver operating characteristic curve illustrating the predictive value of age, sex and upsit score for amyloid status. area under the curve for age and sex alone, . ( % confidence interval: . - . ), versus . ( % confidence interval . - . ) when upsit score is added to the model p = . ). this indicates that the addition of upsit score has very limited additional discriminatory value to predict amyloid status neurodegeneration or cerebrovascular disease, or cognitive performance. the strongest associations between olfaction and imaging metrics relevant to ad were reported in the mayo clinic cohort [ ] , which also has the highest average age ( years). the harvard cohort (mean age years) [ ] found a trend level association with amyloid status, and significant associations with imaging markers of neurodegeneration. noting that our cohort was ~ and years younger than these, respectively, and as older individuals would be expected to have a shorter time to ad onset, this suggests that if oi impairment is not a useful screening tool for asymptomatic pathology, it may however be useful as a proximity marker for the emergence of cognitive impairment. the finding in smaller studies that associations between oi and imaging markers were strengthened by the inclusion of individuals with mci (who are closer to disease onset) may also indicate this [ , ] limitations of this study include its cross-sectional design and lack of a marker of tau pathology, as there is evidence from pathological [ ] and biomarker [ , ] studies that tau deposition may be more closely linked to olfactory changes. longer term follow-up of this cohort and the addition of markers of tau pathology will be able to address the latter and the potential proximal relationship of oi to the development of cognitive impairment. whether or not olfactory loss than can be seen in patients infected with covid- relates to damage to olfactory epithelium or neuronal injury is the subject of ongoing debate, but at the current time, there is no evidence that this is related to alzheimer pathology [ ] . in summary, the high prevalence of oi impairment in populations at this age and lack of relationship between oi and markers of β-amyloid and neurodegeneration we find, indicate that the upsit is unlikely to be a reliable predictor of preclinical ad in its very earliest stages (tables , ) . conflicts of interest dr fox's research group has received payment for consultancy or for conducting studies from avid radiopharmaceuticals, biogen, eli lilly research laboratories, general electric healthcare, and roche; dr fox receives no personal compensation for these activities. dr schott reports grants from weston brain foundation during the conduct of the study and personal fees from axon neuroscience, roche, eli lilly, general electric healthcare, merck sharp & dohme, oxford university press, biogen, and eu horizon outside the submitted work. ethics approval ethical approval was granted by national research ethics service committee london (reference /lo/ ), and the study was conducted in accordance with the ethical standards laid down in the declaration of helsinki and its later amendments. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. olfactory deficits predict cognitive decline and alzheimer dementia in an urban community the relationship between cerebral alzheimer's disease pathology and odour identification in old age aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo neuroimaging biomarkers and impaired olfaction in cognitively normal individuals odor identification and alzheimer disease biomarkers in clinically normal elderly episodic memory of odors stratifies alzheimer biomarkers in normal elderly olfactory identification in subjective cognitive decline and mild cognitive impairment: association with tau but not amyloid positron emission tomography odor identification ability predicts pet amyloid status and memory decline in older adults olfactory deficits and amyloid-β burden in alzheimer's disease, mild cognitive impairment, and healthy aging: a pib pet study olfactory identification deficits and mci in a multi-ethnic elderly community sample relationships between lower olfaction and brain white matter lesions in elderly subjects with mild cognitive impairment study protocol: insight -a neuroscience sub-study of the mrc national survey of health and development cohort profile: the national birth cohort (mrc national survey of health and development) using a birth cohort to study brain health and preclinical dementia: recruitment and participation rates in insight university of pennsylvania smell identification test: a rapid quantitative olfactory function test for the clinic olfactory identification and incidence of mild cognitive impairment in older age cognition at age : life course predictors and associations with brain pathologies steps: similarity and truth estimation for propagated segmentations and its application to hippocampal segmentation and brain parcelation different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings accurate automatic estimation of total intracranial volume: a nuisance variable with less nuisance bayesian model selection for pathological neuroimaging data applied to white matter lesion segmentation odor identification as a biomarker of preclinical ad in older adults at risk neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease : a review the smell identification test (tm) administration manual buchanan s.buchanan@ucl.ac.uk cash d.cash@ucl.ac.uk key: cord- -zk s x authors: tatu, laurent; nono, sandra; grácio, simone; koçer, serdar title: guillain–barré syndrome in the covid- era: another occasional cluster? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: zk s x nan we read with interest the letter from gigli et al. entitled 'guillain-barré syndrome in the covid- era: just an occasional cluster?' [ ] . the authors reported an unusual cluster of seven patients affected by guillain-barré syndrome (gbs) in an italian region (friuli venezia-giulia), which coincided with the descending curve of the covid- pandemic. all patients had a negative sars-cov- nasopharyngeal swab and all but one had negative igm and igg sars-cov- serology. the authors wondered if similar clusters had been observed elsewhere. in our region, which spans the french-swiss border, we have also been surprised by an abnormal number of gbs cases during the march-april period corresponding to the peak of the covid- pandemic. in this area, patients with gbs in the acute and subacute stages are admitted to one of two hospitals, centre hospitalier universitaire de besançon (france) and hôpital du jura (porrentruy-delémont-switzerland). using the same procedure as gigli et al., we re-examined the typology of the disease. in the public health crisis of march-april , we encountered an unusually high number of gbs cases, admitting seven patients. in each of the previous years, in the same time period and region, the number of gbs cases ranged from to . one of our cases was related to an epstein-barr viral infection. the clinical, biological, and electrophysiological characteristics of the other six patients are detailed in table . the sars-cov- nasopharyngeal swab and sars-cov- serology were negative in all six patients. patient developed the first gbs signs days after an influenza vaccination, but his biological evaluation showed a slight hepatic cytolysis as well as a positive hepatitis e serology. even if the patient expressed no clinical signs of hepatitis, a relationship between gbs and hepatitis e could be argued [ ] . no other potential etiology was found in our patients (table ) . only one patient (patient ) had an acute motor-sensory axonal neuropathy (amsan); acute inflammatory demyelinating polyneuropathy (aidp) was found in the other five patients. all patients were treated with intravenous immunoglobulins. three of them were admitted to an intensivecare unit. the neurological progression was favorable in five cases. two of the patients (patients and ) relapsed, one of whom died from a severe acute respiratory syndrome. one patient (patient ) had a two-stage evolution with a sudden worsening (tetraparesis and cranial nerve paralyses) days after symptom onset, suggesting a bickerstaff-like encephalitis. extrapulmonary complications of covid- frequently include the nervous system, due to a particular tropism of sars-cov- [ ] . some authors report a possible correlation between acute symptomatic covid- infection and gbs [ , ] . nevertheless, the issue raised by gigli's cases and those in this series is different: an abnormally high frequency of gbs amid the sars-cov- pandemic in patients without a covid infection. the specificity and sensitivity of swab-test and serologies are better known now than at the time of writing for gigli et al., as is the curve of the humoral immune response to this new virus. nevertheless, as expressed by gigli et al., it is possible that asymptomatic or paucisymptomatic infections may not develop an antibody response sufficient enough to be detected [ ] . another hypothesis is that an asymptomatic contact with sars-cov- could be a precipitating factor for the preceding event, causing an immunologic cascade that leads to gbs. such a concomitant immunologic mechanism could potentially be observed in other autoimmune diseases. conflicts of interest the authors declare that they have no conflict of interest. ethical approval no specific ethics approval was required. guillain-barré syndrome in the covid- era: just an occasional cluster? hepatitis e virus-associated guillain-barre syndrome: revision of the literature the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients guillain-barré syndrome associated with sars-cov- infection: causality or coincidence? guillain-barré syndrome related to covid- infection key: cord- - r j l authors: talamonti, g.; colistra, davide; crisà, francesco; cenzato, marco; giorgi, pietro; d’aliberti, giuseppe title: spinal epidural abscess in covid- patients date: - - journal: j neurol doi: . /s - - -z sha: doc_id: cord_uid: r j l objective: to report the peculiarity of spinal epidural abscess in covid- patients, as we have observed an unusually high number of these patients following the outbreak of sars-corona virus- . methods: we reviewed the clinical documentation of six consecutive covid- patients with primary spinal epidural abscess that we surgically managed over a -month period. these cases were analyzed for what concerns both the viral infection and the spinal abscess. results: the abscesses were primary in all cases indicating that no evident infective source was found. a primary abscess represents the rarest form of spinal epidural abscess, which is usually secondary to invasive procedures or spread from adjacent infective sites, such as spondylodiscitis, generally occurring in patients with diabetes, obesity, cancer, or other chronic diseases. in all cases, there was mild lymphopenia but the spinal abscess occurred regardless of the severity of the viral disease, immunologic state, or presence of bacteremia. obesity was the only risk factor and was reported in two patients. all patients but one were hypertensive. the preferred localizations were cervical and thoracic, whereas classic abscess generally occur at the lumbar level. no patient had a history of pyogenic infection, even though previous asymptomatic bacterial contaminations were reported in three cases. conclusion: we wonder about the concentration of this uncommon disease in such a short period. to our knowledge, cases of spinal epidural abscess in covid- patients have not been reported to date. we hypothesize that, in our patients, the spinal infection could have depended on the coexistence of an initially asymptomatic bacterial contamination. the well-known covid- -related endotheliitis might have created the conditions for retrograde bacterial invasion to the correspondent spinal epidural space. furthermore, spinal epidural abscess carries a significantly high morbidity and mortality. it is difficult to diagnose, especially in compromised covid- patients but should be kept in mind as early diagnosis and treatment are crucial. the first case of coronavirus disease (covid- ) was diagnosed in lombardy on february , . afterwards, the contagion rapidly spread throughout the region. up to today (june , ), , lombards have contracted covid- and , have died, which makes lombardy (a region of about million inhabitants) one of the most plagued areas of the world. the lombard health system had to be reorganized to face the outbreak: our department suspended all elective procedures and managed only neurosurgical emergencies. during the last three months, six patients with sars-corona virus- (sars-cov- ) were referred to us for acute spinal cord syndrome due to primary spinal epidural abscess (sea) [ ] . no adjacent spondylodiscitis or other infection sources were evident. this time-concentrated incidence of primary sea is quite unusual in our practice, and a relationship with covid- is conceivable. to our knowledge, to date there are no published cases of sea in patients with covid- . during the peak of the epidemic (march to may ), we had to surgically manage six covid- patients with sea. their clinical charts, radiological documentation, and surgical reports were carefully reviewed looking for possible peculiarities for what concerns both the viral infection and the neurological disease. the main clinical features are summarized in table . four men and two women (mean age = . years) were referred to us because of progressively worsening spinal cord dysfunction. all these patients presented with few day histories of back pain and a diagnosis of covid- . on admission to our department, the diagnosis of covid- had already been ascertained in three patients and was highly suspected in a fourth. in particular, one patient was still hospitalized because of interstitial pneumonia (ip), whereas two patients had recently been discharged after recovery from ip. these three individuals had had positive nasopharyngeal swabs for sars-cov- and their chest-computed tomography (ct) had shown the typical ground-glass appearance. therapy had included tocilizumab, antibiotics, corticosteroids, anticoagulants, and antiviral agents. the fourth patient had been admitted to another department because of dyspnea, fever, and anosmia. he had a known history of deep vein thrombosis and chest-ct had shown pulmonary infarction and ip. nasopharyngeal swabs were negative. serologic tests were initially unavailable. subsequently, such tests were planned but never performed because this patient deteriorated to a pre-agonic state owing to new pulmonary infarction. these four patients had required respiratory assistance (cpap, nimv, or intubation), but two had completely overcome the disease. the remaining two patients had histories of recent flu episodes but never presented clear symptoms of covid- . they had negative nasopharyngeal swabs, but serologic tests revealed exposure to sars-cov- . on admission to our department, three patients were quadriparetic, two were paraparetic, and one was paraplegic. neurological conditions were rapidly worsening in all cases. all patients underwent magnetic resonance imaging (mri) (fig. ) , which showed epidural abscesses at cervical ( patients), thoracic ( patients), and lumbar ( patient) levels. in no case did the mri show spondylodiscitis or any other possible sources of infection. mild fever was reported only in one patient. slight neutrophil increase and lymphopenia were present in all cases. procalcitonin was increased in three cases and c-reactive protein (crp) was increased in all cases but one. all patients underwent emergency hemi-laminectomy with pus drainage and spinal cord decompression. in all cases, cultural assay of the surgical material revealed methicillin-sensitive staphylococcus aureus (mssa). during the following days, mssa was also found in the blood of two patients despite no sign of sepsis being evident. in all cases, antibiogram allowed adequate and effective antibiotic therapy. postoperatively, the infectious disease specialist carefully searched for possible hidden sources of infection, but clinical examination, total body ct-scan, orthopantomography, and cultural assays of several fluids and secretions were all negative. no other associated infections were found. the previous clinical histories were also carefully examined. all six patients had never presented clinical evidence of pyogenic infection. however, when we managed them for the sea, we retrospectively reconstructed that, some weeks before, staphylococcus aureus (sa) had been found in the expectoration and oropharyngeal swabs of two and one patients, respectively. at that time, the patients were asymptomatic for bacterial infection and these findings were interpreted as sample contamination. no patient was an intravenous drug abuser. predisposing factors for sea (obesity and obesity plus diabetes) were reported in two cases only. chronic arterial hypertension was present in five cases. repeated mri documented the abscess resolution in all cases. within a couple of weeks all patients were referred to rehabilitation units. one month later, the patient with known deep vein thrombosis was still quadriplegic, suffered a new pulmonary infarction, and rapidly deteriorated. two months after surgery, partial recovery was evident in four patients, whereas one was completely paraplegic. furthermore, no patient completely recovered from the initial spinal cord syndrome. risk factors for sea include diabetes, immunosuppressed state, intravenous drug abuse, chronic renal or liver failure, spinal surgery, obesity, and bacteremia [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the incidence of sea is quite low ranging from . to per , hospitalized patients [ , , ] . cases of primary sea, which are cases without any evident infective source, are even rarer accounting for % of all seas [ , ] . sa, usually the mssa, is responsible for % of cases [ , , , , ] . pain is constant, fever is present in less than % of cases, and true neurological deficits affect a minority of patients [ - , , ] . onset of symptoms may be sudden, or slowly progressive but back pain often evolves to paraplegia within a few days [ ] . accordingly, early diagnosis is crucial, but it is difficult, and half of cases are initially misdiagnosed [ ] [ ] [ ] [ ] [ ] ] . the white blood cell (wbc) count is normal in about half of patients, while erythrocyte sedimentation rate and crp are generally elevated [ , , , [ ] [ ] [ ] . bacteremia causing or arising from sea is detected in % of patients [ ] [ ] [ ] . mri with contrast is the diagnostic method of choice: sea is generally seen as a t hypointense, t hyperintense mass with an enhancing capsule in the epidural space [ ] [ ] [ ] [ ] . most seas are lumbar and posterior because infections are more likely in larger fatty epidural spaces [ ] . decompressive laminectomy and drainage together with systemic antibiotics are mandatory in patients with neurological symptoms [ , ] . pending the identification of the causative organism, empiric therapy should start using broad spectrum antibiotics [ ] . there are no guidelines for the duration of therapy, but patients typically require - weeks of therapy [ ] [ ] [ ] [ ] [ ] ] postoperative recovery depends on age, health status, comorbidities, and history duration [ ] [ ] [ ] [ ] but above all on the patient's neurologic status immediately before surgery [ , , , ] . despite recent improvements, outcomes of sea remain poor, with mortality ranging from to % and neurological morbidity ranging from to % [ - , , ] . covid- is primarily a respiratory tract infection with significant impaction on different systems [ ] [ ] [ ] . recent studies show that the sars-cov- provokes diffuse damage to the vascular endothelium triggering a sort of disseminated intravascular coagulation [ ] [ ] [ ] . in a large autoptic series [ ] , all cases presented a more or less degree of endothelial damage and arteriolar thrombosis was evident in % of cases. the ip that complicates covid- can be de facto considered as diffuse micro-infarctions of the lung. lymphocytes and monocytes often decrease with a possible impaired immune response to exogenous infective agents [ , , ] . bacterial infections have been reported in half of patients [ - , , ] . from a practical point of view, covid- may consist of a complex clinical situation including disseminated micro-embolisms, bleeding diathesis, diffuse vasculitis, and autoimmune aggression with during the last ten years, we surgically treated a total of seven patients with primary sea that means without spondylodiscitis or an evident infective source. following the outbreak of covid- , we received six patients in a couple of months. three of these patients complained of fullblown severe covid- . in another patient, the diagnosis was only based on clinical symptoms, but we think it was highly probable. in two patients, the viral infection was almost asymptomatic and was just revealed by the serologic tests. accordingly, the clinical severity of covid- was not correlated to the sea occurrence. moreover, when sea occurred, only two patients were still fighting against active covid- . these six patients presented some differences from classical sea patients: they were relatively younger; none was a drug abuser; only two were obese and only one of these was diabetic; the typical lumbosacral location was present in only one case. however, apart from the relatively unusual cervical and thoracic locations, there was no peculiar mri feature in comparison with classical seas. all these patients had lymphopenia and three had previously received immunomodulators to counter the viral infection. mild immunodeficiency cannot be excluded even in the two patients fig. a chest ct-scan obtained in a -year-old man to control the evolution of interstitial pneumonia due to covid- . the "atoll sign" (arrow), that is expression of organizing pneumonia, is evident. b spinal mri obtained the following day showing an epidural abscess extending from th to th (arrows). c postoperative mri showing the good drainage of the abscess with three-level emi-laminectomy who were asymptomatic for covid- . nonetheless, we do not believe that immunodeficiency played a major role in the sea development. as previously mentioned, an immunocompromised state represents a risk factor for developing sea and lymphopenia is quite common in covid- patients. accordingly, an increased sea incidence could be expected in covid- patients. conversely, to our knowledge, cases of sea in covid- patients have not yet been published. theoretically, sea could have been underdiagnosed in comatose or severely compromised covid- patients. otherwise, sea simply may not have been reported because physicians focused on other aspects of the disease. in two patients, mssa was also subsequently found in blood cultures. perhaps, bacteremia could have caused the sea, but it is also possible that the bacterium secondarily entered the blood from the sea [ ] [ ] [ ] . both these patients were apyretic, never presented signs of sepsis, and wbcs and neutrophils were just moderately increased. none of the patients had ever presented clinical evidence of pyogenic infection. nosocomial infections may be perhaps suspected in the two hospitalized patients, but these presented no sign of sepsis or other infection. three patients had a history of recent asymptomatic sa presence in the pharynx and expectoration, which had been interpreted as sample contamination. when sea occurred, neither pharyngeal nor pulmonary infections were evident. interestingly, within a few weeks, the two patients with contaminated expectoration developed thoracic sea, the one with a contaminated swab suffered from cervical sea. taking into account that cervical and thoracic locations are relatively unusual for sea, retrograde spinal invasion is conceivable. as previously mentioned, the coronavirus is typically responsible for diffuse endothelial damage [ , ] . in two of our patients with ip, the chest-ct-scan ( fig. ) also showed the "atoll-sign", which is a well-known expression of inflammation and granulomatous reaction in organizing pneumonia and is classically associated to angio-invasive agents [ ] . all patients but one had a history of arterial hypertension. we wonder if arterial hypertension could have played a role in damaging the vascular endothelium, thus favoring the vascular penetration of sa even in the absence of a clear sa infection. in this way, sa could have retrogradely reached the correspondent spinal epidural space causing progressive cellulitis of the epidural fat with the ultimate formation of the sea. if this was the case, the higher than normal sea incidence in this population might be explained. of course, we are not stating that covid- was responsible for sea development but a role can be hypothesized. the viral infection might create the conditions for spinal invasion in subjects that are predisposed owing to the presence of a bacterium in a given location. this might also account for the cervical and thoracic seas that are relatively uncommon in classic sea patients. even the late onset of sea following recovery from covid- might be explained by the time to retrogradely invade the epidural space. covid- patients may present problems that can seriously hamper surgeries [ ] . however, we did not encounter particular surgical problems in these six patients, whose platelets were normal and immunological, respiratory, and circulatory states were acceptable. despite relatively prompt treatment, no patient completely recovered from the spinal cord damage. since the preoperative status is the main determinant of a favorable outcome [ , , , ] and sea may be encountered at unexpected rates, careful neurological examination of covid- patients is mandatory. following the outbreak of covid- , we noticed an unusual high incidence of primary sea which indeed should be quite uncommon in non-drug abuser patients. in our mind, if the sea development were just related to an immunocompromised state or to simple nosocomial superinfections, we should encounter much more patients with sea considering the magnitude of the pandemic. instead, no case has yet been published even though we suspect that the incidence might be higher. we hypothesize that sea may develop because an asymptomatic bacterial colonization co-exists with damage to the vascular endothelium induced by covid- at the same level. this could favor retrograde spinal invasion at the correspondent level. since the outcome of sea often remains poor mainly because of delayed diagnosis and treatment, physicians should be aware that covid- patients may have some greater risk of sea than the general population. informed consent this is a retrospective work that does not require informed consent. all authors have approved publication of the manuscript. title comparison of primary and secondary spinal epidural abscesses: a retrospective analysis of cases primary pyogenic infection of the spine in intravenous drug users spinal epidural abscess brain and spinal epidural abscess spinal epidural abscess evaluation and management of spinal epidural abscess spinal epidural abscess mortality, complication risk, and total charges after the treatment of epidural abscess spinal epidural abscess: a series of cases spinal epidural abscess; a meta-analysis of patients musculoskeletal infections in the emergency department the anterior stand-alone approach (asaa) during the acute phase of spondylodiscitis: results in consecutively treated patients epidural abscess in the lumbar spine: a single institution's experience with nonsurgical and surgical management spinal epidural abscess: report on cases how best to manage the spinal epidural abscess? a current systematic review spinal epidural abscess successfully treated with biportal endoscopic spinal surgery. medicine (baltimore) :e covid- : consider cytokine storm syndromes and immunosuppression hematological findings and complications of covid- new understanding of the damage of sars-cov- infection outside the respiratory system venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in pulmonary postmortem findings in a series of covid- cases from northern italy: a two-centre descriptive study coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up clinical course and outcomes of critically ill patients with sars cov pneumonia in wuhan, china: a single centered, retrospective, observational study. lancet respir med the reversed halo sign: update and differential diagnosis letter: covid- infection affects surgical outcome of chronic subdural hematoma the authors thank the other components of the key: cord- -jbc nml authors: princiotta cariddi, lucia; tabaee damavandi, payam; carimati, federico; banfi, paola; clemenzi, alessandro; marelli, margherita; giorgianni, andrea; vinacci, gabriele; mauri, marco; versino, maurizio title: reversible encephalopathy syndrome (pres) in a covid- patient date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: jbc nml recently who has declared novel coronavirus disease (covid- ) outbreak a pandemic. acute respiratory syndrome seems to be the most common manifestation of covid- . besides pneumonia, it has been demonstrated that sars-cov- infection affects multiple organs, including brain tissues, causing different neurological manifestations, especially acute cerebrovascular disease (ischemic and hemorrhagic stroke), impaired consciousness and skeletal muscle injury. to our knowledge, among neurological disorders associated with sars-cov infection, no posterior reversible encephalopathy syndrome (pres) has been described yet. herein, we report a case of a -year old woman with covid infection who developed a pres, and we suggest that it could be explained by the disruption of the blood brain barrier induced by the cerebrovascular endothelial dysfunction caused by sars-cov- . a -year-old woman was admitted to our hospital with a -day history of fever and dyspnea treated at home with ceftriaxone. her medical history included hypertension, gastroesophageal reflux disease, hyperuricemia, dyslipidemia, obstructive sleep apnea and paroxysmal atrial fibrillation. her medications were: irbesartan/hydrochlorothiazide, acetylsalicylic acid, pantoprazole, rosuvastatin, allopurinol and bisoprolol. she was febrile ( °c) with marked dyspnea. neurological examination was unremarkable. laboratory tests were significant for lymphocytopenia with increased transaminases and ldh. oxygen saturation was low, thereby oxygen therapy was administered (table ) . chest x-ray showed reduction of the parenchymal transparency in basal region of right lung. a continuous positive airway pressure had to be started. a nasopharyngeal swab resulted positive for sars-cov- ; antiviral therapy with darunavir/cobicistat, associated with hydroxychloroquine were started. after h, she was taken to intensive care unit: she was sedated and mechanical ventilation was started. antiviral plus antibiotic therapies were continued for days. after days bronchial aspirate turned negative for sars-cov- . on day she woke up when sedation was weaned; she was drowsy and complained of blurred vision. she showed lucia princiotta cariddi and payam tabaee damavandi contributed equally as first authors. marco mauri and maurizio versino contributed equally as last authors. an altered mental status, a decreased left nasolabial fold, the tone and the strength were slightly decreased in the legs, and all deep tendon reflexes were reduced symmetrically. brain ct and cta were consistent with hemorrhagic posterior reversible encephalopathy syndrome (pres; fig. a, b) . in the following days spontaneous breathing was restored. no epileptic seizures were reported during hospitalization. on day a brain mri showed a reduction of the bilateral edema with bilateral occipital foci of subacute hemorrhage ( fig. c, d) . a second nasopharyngeal swab was negative for sars-cov- , and she was alert and fully oriented with a normalization of blurred vision. pres is characterized by acute impairment in level of consciousness, headache, visual disturbances and seizures, with cortical/subcortical vasogenic edema, involving predominantly the parietal and occipital regions bilaterally [ ] . pres is commonly associated with blood pressure fluctuations, renal failure, autoimmune conditions, sepsis, preeclampsia or eclampsia and immunosuppressive-cytotoxic drugs. in our patient the sepsis (table ) was due to staph. epidermidis, that has never been associated with pres, and did not induce a shock condition as is usually the case in septic pres [ ] [ ] [ ] . none of the drugs given to our patient has been associated with pres [ ] . several studies suggested a key role of endothelial dysfunction (ed), combined with hemodynamic stress (hypertensive crisis) and immunological activation with release of cytokines (tnf-α, ifn-γ, il- ) able to activate endothelial cells, thus increasing vascular permeability. ed is a principal determinant of microvascular perfusion: by shifting the vascular equilibrium towards a more pro-inflammatory, pro-coagulant and proliferative state, it leads to ischaemia and inflammation with edema [ ] . this is the second report of hemorrhagic pres in covid- , and these other two patients were very similar to ours. [ ] . mounting evidence suggests that the sars-cov directly infects endothelial cells causing diffuse inflammation [ ] [ ] [ ] . the pivotal host cell receptor for the entry of sars-cov- into the cells is the angiotensin-converting enzyme , which is also expressed by the brain endothelium [ , ] . varga et al. [ ] showed the presence of viral elements within endothelial cells in different vascular beds, suggesting a role of an ed in the systemic toxicity caused by the virus. in our patient we can rule out the causes of pres listed above. a contribution from the respiratory distress was unlikely since pres developed during mechanical ventilation. we hypothesize that sars-cov- may have caused a cerebrovascular ed which in turn was responsible for both the hemorrhagic lesions and the for the disruption of the blood brain barrier with vasogenic edema. our data are available upon request to the corresponding author. funding this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ethics approval not applicable. this case has been described retrospectively, without the patient undergoing procedures and tests other than those she already had to undergo to treat her clinical condition. this research was performed in accordance with gcp and the ethical standards laid down in the declaration of helsinki. fig. radiological findings. a brain axial ct on day shows posterior frontal and temporo-parieto-occipital symmetric bilateral hypodensity of the subcortical white matter, and a tiny left occipital parenchymal hemorrhage. b para-axial cta scan confirms the absence of vascular malformation and alterations of posterior circle vessel caliber, suggestive of vasoconstriction mechanism. c axial t flair image on day shows that vasogenic edema is reduced but still detectable and d t gradient-echo reveals the onset of right temporal hypodensity, correlated to hemorrhagic process a reversible posterior leukoencephalopathy syndrome posterior reversible encephalopathy syndrome in infection, sepsis, and shock posterior reversible encephalopathy syndrome (pres) and infection: a systematic review of the literature posterior reversible encephalopathy in the intensive care unit posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome: clinical and radiological considerations posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of covid- infection coronavirus disease (covid- ) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus infection hypertension, thrombosis, kidney failure, and diabetes: is covid- an endothelial disease? a comprehensive evaluation of clinical and basic evidence endothelial cell infection and endotheliitis in covid- does sars-cov- invade the brain? translational lessons from animal models key: cord- - um ntvi authors: de havenon, adam; ney, john p.; callaghan, brian; yaghi, shadi; majersik, jennifer j. title: excess neurological death in new york city after the emergence of covid- date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: um ntvi nan ending / / , we stratified by -week periods ending / / - / / and / / - / / , to calculate percentage change and test for differences using student's t test. for / / - / / , the average weekly number of natural deaths in nyc was (range - ), while for / / - / / , the average was (range - ), a % increase (p < . ) (fig. a) . figure a shows excess deaths return to a near normal level after / / . during / / - / / , covid- deaths averaged a week, failing to account for the entirety of excess death. figure b shows the concept of excess non-covid deaths, which averaged /week during / / - / / . the causes of non-covid excess death are shown in fig. c , illustrating a prominent increase in cardiac death, which was the most common non-covid excess cause of death. an interactive figure of all the covid- and non-covid excess deaths is at https ://www.iclou d.com/pages / vw y m- -pwn m iar f dth q#figur e_ d. the percentage changes are in fig. e . deaths attributed to cerebrovascular and alzheimer's disease increased . % and . %, respectively, from an average of . to . a week for cerebrovascular (p = . ) and . to . a week for alzheimer's (p = . ). in mid-march , after the rise in covid- infections in nyc, excess non-covid deaths increased for cerebrovascular and alzheimer's disease, but this increase was far less than multiple other causes of death. lack of widespread covid- testing during this period [ ] means that many of the excess non-covid deaths were likely due to complications from undiagnosed covid- . while neurologic complications have been reported with covid- infection, they are not as common as other organ systems [ , ] . the relatively small . % increase in cerebrovascular death suggests that while stroke may complicate covid- infection, it may not be as fatal as other complications. the larger . % increase in alzheimer's deaths may reflect their goals of care or older age [ , ] . the other possible explanation for the excess non-covid deaths is that there was reduced access to healthcare during the pandemic in nyc. the main limitation of our study is that nchs cause of death may not reliably identify the underlying cause of death, particularly in the absence of widespread covid- testing. these data are also provisional and are subject to revision. despite these limitations, we found that the two most common neurological causes of death, cerebrovascular and alzheimer's disease, increased comparatively less than pulmonary, cardiac, and diabetic deaths in nyc during the recent peak of covid- mortality. funding dr. de havenon is supported by nih-ninds k ns . availability of data the data are publicly available from the centers for disease control. conflicts of interest dr. de havenon has received investigator initiated funding from amag and regeneron pharmaceuticals. dr. callaghan consults for a pcori grant, dynamed, and performs medical legal consultations including consultations for the vaccine injury compensation program. dr. majersik reports nih/ninds funding u ns , funding for associate editor at stroke, consulting fees for foldax scientific advisory board, and is an editorial board member of neurology. the remaining authors report no potential conflicts of interest. ethical approval irb approval was not required for this retrospective analysis of deidentified data per the university of utah institutional review board guidelines. global, regional, and national burden of stroke, - : a systematic analysis for the global burden of disease study diagnostic testing for the novel coronavirus coronavirus disease (covid- ): complications presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area key: cord- -v e zzfg authors: rinkel, l. a.; prick, j. c. m.; slot, r. e. r.; sombroek, n. m. a.; burggraaff, j.; groot, a. e.; emmer, b. j.; roos, y. b. w. e. m.; brouwer, m. c.; van den berg-vos, r. m.; majoie, c. b. l. m.; beenen, l. f. m.; van de beek, d.; visser, m. c.; van schaik, s. m.; coutinho, j. m. title: impact of the covid- outbreak on acute stroke care date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: v e zzfg background and purpose: there are concerns that the coronavirus disease (covid- ) outbreak negatively affects the quality of care for acute cardiovascular conditions. we assessed the impact of the covid- outbreak on trends in hospital admissions and workflow parameters of acute stroke care in amsterdam, the netherlands. methods: we used data from the three hospitals that provide acute stroke care for the amsterdam region. we compared two -week periods: one during the peak of the covid- outbreak (march th–may th ) and one prior to the outbreak (october st–december th ). we included consecutive patients who presented to the emergency departments with a suspected stroke and assessed the change in number of patients as an incidence-rate ratio (irr) using a poisson regression analysis. other outcomes were the irr for stroke subtypes, change in use of reperfusion therapy, treatment times, and in-hospital complications. results: during the covid- period, patients presented with a suspected stroke compared to patients in the pre-covid- period (irr . %ci . – . ). the proportion of men was higher during the covid- period ( % vs. %, p < . ). there was no change in the proportion of stroke patients treated with intravenous thrombolysis ( % vs. %, p = . ) or endovascular thrombectomy ( % vs %, p = . ) or associated treatment times. seven patients (all ischemic strokes) were diagnosed with covid- . conclusion: we observed a % decrease in suspected stroke presentations during the covid- outbreak, but no evidence for a decrease in quality of acute stroke care. the coronavirus disease (covid- ) outbreak has put health care systems worldwide under enormous pressure, potentially impairing the quality of care for patients with acute cardiovascular conditions [ ] [ ] [ ] [ ] . at the same time, studies suggest that covid- may increase the risk of thromboembolic diseases, including stroke [ , ] . intravenous thrombolysis (ivt) and endovascular thrombectomy (evt) are the cornerstone of acute ischemic stroke treatment, but their effects on clinical recovery are highly timedependent [ , ] . we assessed the impact of the covid- outbreak on trends in hospital admissions for (suspected) stroke, patient characteristics, and workflow parameters of acute stroke care in amsterdam, the netherlands. we conducted a retrospective multicenter cohort study, using data from the prospective stroke registries of the only three hospitals ( primary, comprehensive stroke center) that provide acute stroke care for the amsterdam area (approximately . million inhabitants). we included consecutive patients who were presented to the emergency departments of these hospitals with acute-onset focal neurological symptoms suggestive of an acute stroke (= suspected stroke or code stroke). in-hospital cases were also included. to verify completeness of the stroke registries, we cross-referenced the data with all suspected stroke pre-notifications during the two time periods. we compared data of two time periods of weeks: one during the peak of the covid- outbreak in the netherlands (march th-may th ) and one prior to the worldwide outbreak of the disease (october st-december th , pre-covid- /control period). march th was the first day that strict nationwide lockdown measures were implemented, including working from home and closure of schools and restaurants. the sample size of two -week periods was based on an estimated % decrease in the weekly number of suspected stroke presentations during the covid- outbreak (from to presentations per week, alpha . , and power of . ). diagnoses were categorized as: ischemic stroke, transient ischemic attack (tia), intracranial hemorrhage (intracerebral or subarachnoid hemorrhage), or others (e.g., seizure, functional neurological symptoms, and peripheral vestibular disorder). patients who were clinically suspected of having covid- were tested using pcr. patients with pcr confirmed covid- were admitted to designated covid- wards. the study was approved by the ethical review board of each hospital and the need for written informed consent was waived. study outcomes were: ( ) change in the number of emergency department presentations; ( ) change in proportion of stroke patients treated with ivt and evt; ( ) change in ivt and evt treatment times; and ( ) in-hospital complications. incidence-rate ratios (irr) comparing the covid- period to the pre-covid- period were calculated using a poisson regression. for the other outcomes, we performed independent samples t test, mann-whitney u test, fishers' exact test, or chi-square test, as appropriate. statistical analyses were done with r software (version . . , r foundation). in total, patients presented with a suspected stroke during in the covid- period compared to during the pre-covid- control period [irr . , % confidence interval (ci) . - . , table ]. during the covid- period, patients were diagnosed with an ischemic stroke or tia compared to in the control period (irr . , %ci . - . ), and patients compared to were diagnosed with an intracranial hemorrhage (irr . , %ci . - . ). baseline characteristics were mostly similar, but patients in the covid- cohort were more often men ( % vs. %, p < . , table ). there was no difference in nihss score ( vs. , p = . ), proportion of large vessel occlusions ( % vs. %, p = . ), or onset-to-door time ( vs. min, p = . ). in the covid- cohort, a total of / ( %) patients were clinically suspected of having covid- and were tested by means of pcr. of these, covid- was confirmed in patients ( %, three men). all seven patients had an ischemic stroke and two had a large vessel occlusion. one patient was treated with endovascular treatment and two with intravenous thrombolysis. one patient was admitted to a covid- designated intensive-care unit and died during admission. none of the other patients with pcr confirmed covid- died during admission or within days. there was no difference in the proportion of stroke patients treated with ivt ( % vs. %, p = . ) or evt ( % vs. %, p = . , table ) in the covid- and control period, respectively. treatment times were comparable between periods (door-to-needle time vs. min, p = . ; first-door-to-groin times min vs. min, p = . ). complication rates and discharge destinations also did not differ. we observed a % decrease in the number of patients with a suspected stroke in the hospitals in the amsterdam area during the height of the covid- outbreak compared to a pre-covid- control period. the proportion of patients who underwent reperfusion therapy did not change during the outbreak, nor did we observe a difference in treatment times, but the study was not powered for these outcomes. seven ischemic stroke patients ( %) also had covid- . there are several potential explanations for the decreased number of suspected stroke presentations. first, people may have been more reluctant to call emergency services or go to the hospital during the pandemic out of fear of contracting covid- . general practitioners also may have had a higher threshold to refer patients during the outbreak. second, stroke symptoms are often not recognized by patients themselves and the initiative to seek medical help frequently comes from bystanders. due to the social distancing measures, some strokes may have remained unrecognized, especially in elderly who are more often socially isolated [ ] . third, stroke symptoms may have been overlooked in patients with suspected covid- , especially early in the pandemic when the risk of thromboembolic disease in these patients was not well known. fourth, we cannot exclude the possibility that social distancing measures somehow decrease the risk of stroke, for instance because of improved air quality or because of a decrease in incidence of other transmissible diseases [ , ] . another contributing factor may have been general changes in inpatient and outpatient services of hospitals during the covid- outbreak. in the three participating hospitals, virtually, all outpatient visits were suspended during the outbreak, with the exception of acute outpatient referrals. all other non-acute care was done via telephone. however, since stroke patients in our region rarely are presented through outpatient clinics, the influence of suspension of outpatient services on acute stroke care is probably minimal. none of the hospitals had a reduction in capacity for inpatient stroke, i.e., no change in the number of available stroke beds and no restrictions in stroke services during the outbreak. this included performance quality indicators such as swallowing assessment, access to ancillary exams, and in-hospital rehabilitation which should, therefore, should not have differed between the two time periods, although specific data on these individual performance indicators were not available for comparison. of note, the proportion of men who presented to the emergency department was approximately % higher during the covid- outbreak. this could indicate that the threshold to come to the hospital was somehow higher for women. another possible explanation for this observation is the sex-related age disparity in stroke, i.e., that women table other outcomes data on reperfusion therapy and process measures only regard patients with ischemic strokes iv indicates intravenous; iqr interquartile range; covid- coronavirus disease ; icu intensive-care unit; sich symptomatic intracranial hemorrhage a defined as extended thrombolysis in cerebral infarction score of b- . missing values, n (%): b ( ), c for transfer patients, the first-door-to-groin time is calculated as the time interval between presentation at the primary stroke center and groin puncture at the comprehensive stroke center, missing values, n (%) ( ) d ( ), e ( ) covid- cohort (n = ) ( ) / ( ) are generally older than men and may, therefore, more frequently have been socially isolated [ ] . this age difference could also imply that women more frequently resided in a nursing home at the onset of symptoms and these patients may have been less likely to be referred to the emergency room for treatment. unfortunately, data on living conditions prior to the stroke were not available. men with covid- also appear to have a higher risk of a complicated disease course [ ] , but the sex ratio of stroke patients with confirmed covid- was not skewed in our study. one of the strengths of our study is that we used data from the only hospitals that provide acute stroke care in the amsterdam area. hence, the decrease in patients cannot be explained by a diversion of patients with a suspected stroke to other hospitals in the region. our study also has several limitations. first, data collection was retrospective, but the number of patients with missing data was low and by crossreferencing data with emergency room stroke pre-notifications, the chance that we missed patients is small. second, we report regional and not national data and it is unknown whether the covid- outbreak had a similar effect on acute stroke care in other areas of the country. third, we were unable to reliably report on key performance quality indicators such as swallowing assessment and in-hospital rehabilitation to assess any difference between the two time periods. fourth, we did not compare incidences with the exact same time period year before. instead, we used a time period closer to the outbreak, because the proportion of stroke patients who are treated with reperfusion therapy has lately increased in our region after publication of studies that showed efficacy of ivt and evt in the extended time-window [ , ] . also, the data on whether there is a seasonal effect on the epidemiology of stroke are conflicting, but if such an effect exists, the risk appears to be the highest in may, [ ] which could indicate that our study underestimated the decrease in stroke presentation during the covid- outbreak. fifth, we were unable to reliably report on key performance quality indicators such as swallowing assessment and in-hospital rehabilitation to assess any difference between the two time periods. finally, we were unable to report data on long-term functional outcome in this study, since the day duration of follow-up has not yet elapsed for patients presenting during covid- outbreak. future studies should address this, ideally using data from (inter)national collaborations, as functional outcome at days is an important factor in assessing the influence of the covid- outbreak on acute stroke care. in summary, we found a substantial decrease in the number of suspected stroke presentations during the covid- outbreak in the amsterdam area, but no evidence for a change in quality of acute stroke care. funding none. reduced rate of hospital admissions for acs during covid- outbreak in northern italy essential care of critical illness must not be forgotten in the covid- pandemic trobia g ( ) delayed access or provision of care in italy resulting from fear of covid- impact of coronavirus disease (covid- ) outbreak on st-segment-elevation myocardial infarction care in hong kong neurologic manifestations of hospitalized patients with coronavirus disease large-vessel stroke as a presenting feature of covid- in the young time to treatment with recombinant tissue plasminogen activator and outcome of stroke in clinical practice: retrospective analysis of hospital quality assurance data with comparison with results from randomised clinical trials time to reperfusion and treatment effect for acute ischemic stroke covid- and the consequences of isolating the elderly infectious causes of stroke air pollution and hospital admissions for ischemic and hemorrhagic stroke among medicare beneficiaries sex differences in stroke epidemiology gender differences in patients with covid- : focus on severity and mortality thrombectomy for stroke at to hours with selection by perfusion imaging thrombolysis guided by perfusion imaging up to hours after onset of stroke incidence of stroke and season of the year: evidence of an association conflicts of interest dr majoie reports grants from cvon/dutch heart foundation, twin foundation, european commission, dutch health evaluation program, and stryker outside the submitted work; and is shareholder of nico.lab, a company that focuses on the use of artificial intelligence for medical imaging analysis. dr. coutinho reports grants from medtronic and boehringer outside the submitted work. all other authors report no disclosures.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -hd tjj b authors: padroni, marina; mastrangelo, vincenzo; asioli, gian maria; pavolucci, lucia; abu-rumeileh, samir; piscaglia, maria grazia; querzani, pietro; callegarini, claudio; foschi, matteo title: guillain-barré syndrome following covid- : new infection, old complication? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: hd tjj b nan resolved in a few days. the epidemiological survey had revealed a previous hospital visit to an inpatient in an area with high incidence for covid- (piacenza, italy) on feb- , . at the ed admission bt was . °c, oxygen saturation was % on room air. arterial blood gas analysis showed po = mmhg with normal p/f ratio (= ). hematological investigations revealed slightly increased white blood cells ( . × /l, normal = - × /l) with . × /l neutrophils (normal = - × /l) and lymphocytes in the normal range. d-dimer, creatine phosphokinase, blood glucose, hepatic and renal function were normal, as well as c-reactive protein, erythrocyte sedimentation rate, folate and vitamin b blood levels. a chest high-resolution computed tomography revealed some small "ground glass" areas in both lungs. a repeated nasopharyngeal swab for sars-cov- -rna was negative. mycoplasma pneumoniae and cytomegalovirus (cmv) serology (igm and igg), legionella pneumophila and streptococcus pneumoniae urinary tests were unrevealing. the neurological examination disclosed moderate (medical research council grade / ) symmetric distal upper and lower limbs weakness, loss of deep tendon reflexes, preserved light touch and pinprick sensation. on mar- a lumbar puncture was performed. the cerebrospinal fluid (csf) analysis revealed slight albumino-cytological dissociation (csf proteins = mg/dl, normal = - mg/dl, white blood cells = × /l, normal = - × /l). microbiologic testing on csf was negative (including herpes simplex virus, varicella zoster virus, epstein-bar virus, cmv, hiv- , borrelia burgdorferi igm and igg). neurophysiologic findings were consistent with a diagnosis of gbs (table ), according to current criteria [ ] . a trial with mg/die intravenous immunoglobulin (ivig) for days was started. on apr- the patient was intubated and mechanical ventilation was applied, because of respiratory failure due to the worsening of muscle weakness. to date, only a prior case of gbs concomitant with sars-cov- infection and a parainfectious profile has been reported [ ] . in our patient, the temporal evolution of neurological manifestations resembles that of a postinfectious etiology, although a single repeated negative nasopharyngeal swab was available. therefore, we may speculate an association between the acute polyradiculopathy and sars-cov- infection. this hypothesis is supported by the notion of -days home isolation before the onset of neurological symptoms and by the comprehensive exclusion of most table results of neurophysiologic study soleus h reflex was absent bilaterally. evocable distal compound muscle action potentials (cmaps) showed reduced amplitude because of temporal dispersion due to demyelination. needle electromyography disclosed reorganization of motor units with polyphasic and long-duration potentials, without signs of acute denervation common infectious agents related to gbs (negative igm/ igg for cmv and mycoplasma pneumoniae, negative history for enteritis). however, we could not rule out with certainty a covid- parainfectious neurological syndrome, given the reported suboptimal sensitivity of the rt-pcr for swab due to laboratory error or insufficient viral material in the specimen [ ] . moreover, other less common infectious agents (eg. west nile and toscana viruses), which were not tested but are endemic in northern italy, might be responsible for the present clinical picture [ ] . a shortcoming of our report is the lack of antiganglioside antibody testing to identify specific targets of the autoimmune gbs process [ ] . furthermore, we did not perform a complete paraneoplastic/ autoimmune screening in the acute phase including testing for serum onconeural and vasculitis-related antibodies (e.g. antineutrophil cytoplasmic antibodies-anca). hence, we could not exclude the possibility of an autoimmune or paraneoplastic polyradiculoneuropathy mimicking gbs [ ] . nevertheless, the postinfectious onset, the acute clinical course and the typical neurophysiologic findings (polyradiculoneuropathy with predominant demyelination of both motor and sensory fibers, sural sparing pattern), together with the negative history for autoimmune, neoplastic or neurologic antecedences, make these alternative diagnoses less suitable. another major limitation relies on the unavailability of sars-cov- serology and csf validated test (e.g. pcr on csf) in our center. taking together all these findings, the causal association between gbs and covid- remains speculative, but more probable, given that gbs and bickerstaff's encephalitis have been already described as postinfectious complications of other coronavirus, sharing similarities with sars-cov- (middle east respiratory syndrome, mers-cov) [ ] . if our hypothesis will be confirmed in larger case series, neurologists and other clinicians should be aware of the important early recognition and treatment of the potential neuromuscular and autonomic worsening leading to cardio-respiratory failure in patients with gbs and mild or controlled pulmonary covid- notwithstanding the causative relationship remains unproved, we believe that our case description provide further evidence to the heterogenous and multi-systemic complications associated with sars-cov- . future researches and data acquisition are needed to clarify the possible pathophysiological correlation, as well as to characterize the clinical/electrophysiological pattern of new cases of gbs observed in the context of covid- pandemic. deidentified data and material inherent to the case report and not included in the manuscript are available on request to the corresponding author by any qualified investigator. author contributions pm: acquisition of data, analysis and interpretation of data, drafted the manuscript for intellectual content. mv, agm, pmg, ars, qp: acquisition of data, revised the manuscript for intellectual content. cc: acquisition of data, table creation, revised the manuscript for intellectual content. fm: study concept and design, acquisition of data, figure creation, analysis and interpretation of data, study supervision, drafted and revised the manuscript for intellectual content. funding not targeted funding reported. conflicts of interest the authors declare no conflicts of interest relevant to the manuscript. ethical approval this article does not contain any studies involving human participants performed by any of the authors. informed consent written informed consent was collected from the patient for the inclusion of deidentified clinical data in a scientific publication, in accordance with the declaration of helsinki. who ( ) coronavirus disease (covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study guillain-barré syndrome the electrodiagnosis of guillain-barré syndrome subtypes: where do we stand? guillain-barré syndrome associated with sars cov- infection: causality or coincidence chest ct for typical -ncov pneumonia: relationship to negative rt-pcr testing toscana virus associated with guillain-barré syndrome: a case-control study antiganglioside antibodies in neurological diseases mimics and chameleons in guillain-barré and miller fisher syndromes neurological complications during treatment of middle east respiratory syndrome key: cord- -ux twpt authors: chiaravalloti, nancy d.; amato, maria pia; brichetto, giampaolo; chataway, jeremy; dalgas, ulrik; deluca, john; meza, cecilia; moore, nancy b.; feys, peter; filippi, massimo; freeman, jennifer; inglese, matilde; motl, rob; rocca, maria assunta; sandroff, brian m.; salter, amber; cutter, gary; feinstein, anthony title: the emotional impact of the covid- pandemic on individuals with progressive multiple sclerosis date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: ux twpt objective: individuals with pre-existing chronic illness have shown increased anxiety and depression due to covid- . here, we examine the impact of the covid- pandemic on emotional symptomatology and quality of life in individuals with progressive multiple sclerosis (pms). methods: data were obtained during a randomized clinical trial on rehabilitation taking place at centers in north america and europe. participants included individuals with pms. study procedures were interrupted in accordance with governmental restrictions as covid- spread. during study closure, a covid impact survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and ms symptomatology that were previously administered pre-pandemic. results: % of respondents reported covid- infection. no significant changes were noted in anxiety, quality of life, or the impact of ms symptomatology on daily life from baseline to lockdown. while total hads-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the hads threshold for clinically significant depression. no significant relationships were noted between disease duration, processing speed ability or edss, and changes in symptoms of depression or anxiety. most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being. the perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of ms symptomatology on daily life, as well as changes in depression. conclusions: overall, little change was noted in symptoms of depression or anxiety or overall quality of life. coronavirus disease (covid- ) was declared a pandemic on march , by the world health organization [ ] . neurological involvement is common in covid- , with greater symptoms in more severe cases [ ] . individuals with underlying neurological impairment are vulnerable to infection, and those infected have worse outcomes [ ] . individuals with multiple sclerosis (ms) are typically on immunosuppressive/modulating medication placing them at-risk of infection from viruses [ ] and are hypothetically at-risk for developing more severe forms of covid- [ ] . these individuals additionally have increased vulnerability to the neuropsychiatric concomitants of covid- , due to pre-existing neuropsychiatric symptomotology [ ] . the covid- pandemic has shown enormous psychological and social impact in the general population [ ] , not unlike other infectious diseases [ ] . mental health symptoms that can significantly impair functioning in otherwise healthy individuals [ ] , including stress, helplessness, and fear of becoming ill and dying, have been observed [ , ] . the requirement to remain in quarantine has resulted in anger, confusion, anxiety, and stress [ ] . a recent systematic review and meta-analysis reported a % prevalence of anxiety and % prevalence of depression in the general population [ ] with higher rates in females [ ] [ ] [ ] [ ] [ ] and individuals reporting symptoms consistent with covid- and poor perceived health [ ] . pre-existing chronic illness is thus associated with increased psychiatric distress due to the spread of covid- [ , ] , specifically increased stress, anxiety, and depression [ , , ] , placing individuals with ms in a uniquely vulnerable position to experience greater psychiatric symptomatology. we hypothesized that patients with progressive multiple sclerosis (pms) would demonstrate increased depression and anxiety and poorer qol during the covid- pandemic, as compared with prior to the pandemic. data for the current study were obtained during the course of a multi-arm, randomized, blinded, sham-controlled trial that includes a follow-up period. the parent study includes four arms with different combinations of cognitive rehabilitation (cr), exercise (ex), sham cognitive rehabilitation (cr-s), and sham exercise (ex-s). participants are randomized to a study arm upon completion of baseline testing. data are collected at sites in countries [canada ( site), us ( sites), uk ( sites), denmark ( site), belgium ( site), and italy ( sites)]. outcome measures include neuropsychological assessment, patient-reported outcomes (pros), and neuroimaging. see feinstein et al. [ ] for the full study protocol. participants included individuals with a clinically definite diagnosis of pms (primary or secondary) of the participants enrolled in the parent rct. the mean age of the sample was years (sd = . ), with a mean disease duration of . years (sd = . ). see table for demographic data. given that these patients are generally the most impaired subtype of ms patients, they are thus the most likely to develop psychiatric symptomatology when facing a pandemic. patients were recruited via specialized in and outpatient ms clinics, as well as via media advertising prior to the covid- pandemic, and were at various points in study participation when study procedures were stopped at all sites due to the pandemic. prior to initial study enrollment, all potential subjects completed a two-step screening procedure, including a pre-screening examination in person or via telephone to collect basic information and a detailed face-toface screening for neurological, psychiatric, cognitive, and medical variables. inclusion and exclusion criteria are summarized in table by the screening step. the parent rct received ethics approval at all institutions and a modification was approved at all institutions for additional pros, including a covid impact survey, to be administered during lockdown. ongoing study procedures were interrupted at each individual data collection site in accordance with governmental restrictions as covid- spread worldwide and all data collection sites were under lockdown orders. during the study closure, all sites contacted participants by telephone on a weekly basis to maintain contact with the participants and update them on any new information regarding the anticipated continuation of study procedures. during this time, the study team developed a covid impact survey, which was administered by a data collector via telephone or email to all enrolled participants between may , and july , . all participants additionally completed selected patient-reported outcomes (pros) that were previously administered at study enrollment (baseline) to evaluate changes in depression, anxiety, quality of life (qol), and ms symptomatology during the time period in which lockdown restrictions were in place. survey administration occurred after lockdown orders and the resultant implications were evident across all data collection centers as lockdown was in place; this is an important methodological detail due to the fact that higher mean levels of psychiatric symptoms (stress, anxiety, and depression) have been observed after the sampled population began to experience the effects of stay at home orders [ ] . the time between baseline pro completion and lockdown survey completion varied (m = . months, sd = . months). . ( . ) baseline sdmt score (z), mean (sd) − . ( . ) edss score, median ( th percentile, th percentile) . ( , . ) assessments in the current study included the covid impact interview and several pros administered at baseline and re-administered during lockdown. the covid impact interview was developed by the study team specifically for use in this study in an effort to evaluate the impact of the covid- pandemic and lockdown orders on individuals with pms across the participating centers, representing countries in north america and europe. it consists of questions related to self and family exposure to covid- , length of time under lockdown orders, activities during lockdown, disease symptomatology, and interactions with healthcare providers. a set of questions assessing the impact of the pandemic on psychological, financial, and physical well-being were included with responses recorded on an integer scale ( - , with being no impact and being maximal impact). the survey was administered in the individual's native language. results were examined in response to each specific question. the hospital anxiety depression scale (hads) is widely used to assess psychological distress in non-psychiatric patients. it consists of two subscales, measured via items, seven items for the anxiety subscale (hads-anxiety) and seven for the depression (hads-depression) subscale [ ] . overall, it has demonstrated satisfactory psychometric properties in several different populations, including ms [ ] [ ] [ ] [ ] . each item is scored on a response scale with four alternatives ranging between and and a higher score indicates greater anxiety or depression. the hads-depression cut-off for clinical depression was defined as scores ≥ . [ ] . the beck depression inventory -ii (bdi-ii) [ ] is an easily administered, -item scale that assesses various aspects of depression, useful in determining the presence and severity of depressive symptoms. each item is concerned with a specific aspect of depression (mood, motivation, and appetite) and contains four statements of graded severity expressing how a person might think or feel about that particular aspect of depression. the total score is the sum of all statements endorsed by the participant. a higher score indicates greater depression. the multiple sclerosis impact scale (msis- ) is a disease-specific measure of the impact of ms. it consists of -items, associated with a physical scale, and associated with a psychological scale; the sum of each scale is transformed to a scale of - and higher scores indicating worse health [ ] . items ask about the impact of ms on day-to-day life in the past weeks, rated on a five-point likert scale. the msis- has strong reliability and validity in ms samples [ ] , with existing evidence supporting its responsiveness in rehabilitation trials [ ] . the euroqol (eq d) [ ] is a widely used measure of qol developed in europe, often used in cost-effectiveness changes in responses from baseline to lockdown were evaluated using paired t tests and wilcoxon signed-rank tests. independent sample t tests were utilized to examine sex differences (male versus female) in response patterns. pearson (or spearman, when appropriate) correlation coefficients examined the relationships between the covid- impact interview and changes in specific pros as well the relationship between edss, ms-disease duration, baseline processing speed scores and changes in depression and anxiety. mean scores on the outcome measures across both time points are presented in table . in regard to the impact of covid- on ms symptomatology in daily life, no significant differences were noted on the msis- from baseline to lockdown. two measures of depressive symptoms were administered. no significant differences were noted on the bdi-ii from baseline to lockdown; however, a significant difference was noted on the hads-depression scale from baseline to lockdown (p = . ), with a small increase in depression symptoms noted at the lockdown follow-up (table ). further analyses indicate that this difference was driven by a substantial increase in depressive symptoms in the sample from belgium, while the remaining five countries show the similar levels of change (p < . ; table ). no significant difference was noted in regard to the number of patients meeting the hads-depression cut-off for clinical depression, defined as scores ≥ . . no significant difference was noted from baseline to lockdown on the hads-anxiety scale or any of the eq d scales. independent sample t tests were utilized to examine sex differences (male versus female) in response patterns. no significant differences were noted between males and females in symptoms of depression and anxiety, or overall qol. in regard to the impact of covid- on the study population, only of the respondents reported that he/ she had been infected with covid- , with reporting infections in other family members. individuals knew someone that died from the virus. the majority of participants reported some impact of the virus on their psychological well-being (fig. ) , while little financial impact was reported. in regard to activities during lockdown, % of respondents reported undertaking some form of cognitive activity, while % reported participating in some form of physical activity (fig. a, b) . overall, respondents reported a high level of social support (with % responding , , or on a -point likert scale). only % of respondents reported any interaction with their medical team during lockdown orders, with a comparable proportion reporting ms symptom changes during the same time period ( %). with only of the respondents reporting covid- infection, statistical significance between these respondents and the non-infected respondents could not reliably be determined. however, some identifiable differences in these five individuals are worth noting qualitatively. an increase from baseline to lockdown was noted in the msis mental score in those who were infected with covid- , with an increase of . (sd = . ) noted; this indicates a selfperceived worsening of challenges in daily life due to mental symptomatology. a similar decrement was noted in the msis-physical score, with an increase of . (sd = . ) noted. depressive symptoms also appeared to be negatively impacted, with a -point increase on the bdi (sd = . ) and a . -point (sd = . ) increase on the hads depression. no significant relationships were noted between ms-disease duration, edss, or sdmt z-score (processing speed) and changes in depression and anxiety (range of r values: − . to . ). significant correlations were noted between differences in the msis- mental scale from baseline to lockdown and the degree to which the respondents felt the pandemic impacted their physical well-being (r = − . , p = . ), psychological well-being (r = − . , p < . ), and ms-disease course (r = − . , p = . ). as the perceived impact of ms symptoms on mental functioning increased during lockdown, participants similarly reported a greater impact on physical and psychological well-being and ms-disease course. significant correlations were also noted between differences in the hads-depression scale and the degree to which the pandemic negatively influenced ms-disease course (r = − . , p = . ) and the eq d anxiety/ depression scale and the degree to which the respondent felt that the pandemic impacted his/her psychological wellbeing (r = − . , p = . ). no statistically significant changes in perceived ms symptomatology were noted from baseline to the covid followup conducted during lockdown in our sample of individuals with pms. despite the fact that the majority of participants reported some impact of the virus on their psychological well-being on the covid impact interview, we saw little change in regard to symptoms of depression and anxiety and overall qol on standardized pros. the international composition of our sample indicates that these findings are largely consistent across widely dispersed geographical locations. there are several potential explanations for this pattern of results. first, one must consider the impact of diligence in self-protection on psychological well-being. others have hypothesized that individuals with a significant medical history may feel increased vulnerability to covid- [ ] . it is possible that individuals with pms were diligent about protecting themselves from very early in the pandemic because of their increased risk of infection and subjective feelings of vulnerability. their efforts for self-protection may have increased their level of comfort, because they were diligent in following safety precautions, thus mitigating their anxiety and depression. this may have resulted in less anxiety and depression symptoms than what might be expected under normal circumstances and seen in the general population. additionally, individuals with pms already experience a substantial physical disability that often leads to some degree of isolation in daily life. thus, the drastic societal changes in social interaction due to lockdown orders may have been less impactful for this population due to the fact that their activities have already been significantly restricted for quite some time. social isolation has been shown to have a significant impact on mental health in numerous studies [ ] , with social isolation and loneliness being associated with depression in the general population [ ] . it may be that our sample of individuals with pms was already accustomed to some degree of social isolation, thus easing the transition to lockdown. the impact of experience in living with medical uncertainly also cannot be overestimated. studies conducted fig. a engagement in cognitive activities during lockdown. b. engagement in physical activities during lockdown early in the covid- outbreak in china concluded that fear of the unknown and uncertainty can lead to increased stress, anxiety, and depression [ ] . zandifar and colleagues similarly highlighted the role of unpredictability, uncertainty, and seriousness of the disease in such psychiatric symptomatology [ ] . however, individuals with ms live with medical uncertainty from the time of diagnosis and thus have experience dealing with the associated discomfort. individuals with pms thus may not be experiencing the psychological discomfort that comes with such uncertainty in the face of covid- . the psychiatric symptomatology which they are experiencing is thus less than that which is seen in the general population. finally, the large majority of our sample additionally reported engagement in both cognitive and physical activities during lockdown. this is an encouraging finding and likely contributed to the little change observed in psychiatric symptomatology over the same time period. one of the aims of the parent rct of the present study is to encourage a more active lifestyle and participants were all within some phase of the rct when lockdown was initiated. had the rct run its full course prior to lockdown, engagement in cognitive and physical activities may have influenced changes in psychiatric symptomatology in a significantly positive way. these same factors may be at play in the lack of significant differences seen in depression or anxiety between males and females in our pms sample. this is contrary to that which is observed in the general population, in which females present with higher rates of anxiety and depression as compared with males [ ] [ ] [ ] [ ] [ ] . our sample is, indeed, % female, consistent with ms being more common in females. this larger proportion of females in which uncertainty may already be a normal component of life could potentially lead to less depression and anxiety in our female sample as compared to that which has been seen in the general population. it is interesting to note that only of the respondents reported that he/she had been infected with covid- ; this represents a % infection rate. this is, however, a higher infection rate than that which is seen in the general population within each country represented. the impact of the infection on ms symptoms was also quite evident, with those infected with covid- showing worsening on both the msis- mental score ( -point increase) and the msis- physical score ( -point increase). this is compared to a change of less than on each of these scores in the full sample, indicating that infection with covid- had a tremendous impact on the ms-related symptomatology and daily limitations that individuals with pms experience. the change in depression scores in this subgroup, however, was consistent with changes noted in the full sample. no relationship was noted between baseline ms-diseaserelated variables (disease duration, processing speed ability, and edss) and changes in depression, anxiety, and qol from baseline to lockdown. however, relationships were noted between changes in responses to the pros and covid impact interview. the perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of ms symptomatology on daily life, as measured by the msis- mental scale, as well as changes in psychiatric symptomatology (hads depression, eq d anxiety/depression). these relationships attest to the importance of one's perception of the impact of the pandemic on standardized measures of disease symptomatology, emotional functioning, and qol. there are some limitations to the current study that deserve mention. given that the full rct through which these data were collected did not include a measure of stress, we did not measure changes in stress from baseline to lockdown. given that elevated stress has been documented in the general population during the covid- pandemic, these data would have been advantageous. additionally, no questions were included regarding the severity of infection if an individual was indeed infected. we, therefore, could not examine the relationship between the severity of covid- and changes in psychiatric symptomatology or the impact of ms on daily life. another factor not examined in the current study was exposure to the news and potential misinformation. in the general population, depressive symptoms can be exacerbated by misinformation and fabricated reports about covid- [ ] , and people who follow covid- the most in the news experience more anxiety [ ] , but we were unable to examine this relationship in pms. in addition, the lockdown follow-up was completed toward the end of the lockdown period across all sites. it is possible that the time in lockdown had afforded patients the time to adjust emotionally to the lockdown and thus exhibit less emotional symptomology. sample bias could have also potentially impacted our pattern of results. the current sample engaged/or was engaging in a -month intensive training study; these individuals could potentially have higher levels of self-efficacy and/or resilience. the many strengths of the study, however, far outweigh these limitations. specifically, the ongoing parent rct allowed the comparison of pre-pandemic depression, anxiety, and qol to the same ratings completed during lockdown in a fairly large sample of individuals with pms in six different countries. these unique data thus provide comparative values that are rarely available. overall, findings indicate that individuals living with pms through the covid- pandemic are adapting well to date. that is, minimal change was noted from pre-covid status to assessments conducted during covid- lockdown on depression, anxiety, and qol. minimal changes were additionally noted in the impact of ms-related symptoms on daily life functioning on the limited measures utilized to assess this construct, with the exception of those infected with covid- . while the infection rate observed in our sample was higher than that which is seen in the general population, even those who contracted covid- showed minimal change from pre-covid depression, anxiety, and qol to ratings of depression, anxiety, and qol collected during lockdown. supported by the ms society of canada (grant # egid ). author contributions ndc: design and conceptualized study; major role in the acquisition of data; interpreted the data; drafted the manuscript for intellectual content. mpa: major role in the acquisition of data; revised the manuscript for intellectual content. gb: major role in the acquisition of data; revised the manuscript for intellectual content. jc: major role in the acquisition of data; revised the manuscript for intellectual content. ud: major role in the acquisition of data; revised the manuscript for intellectual content. jd: design and conceptualization of study; interpreted the data; revised the manuscript for intellectual content. cm: major role in the acquisition of data. nm: major role in the acquisition of data. pf: major role in the acquisition of data; revised the manuscript for intellectual content. mf: major role in the acquisition of data; revised the manuscript for intellectual content. jf: major role in the acquisition of data; revised the manuscript for intellectual content. mi: major role in the acquisition of data; revised the manuscript for intellectual content. rwm: major role in the acquisition of data; revised the manuscript for intellectual content. mar: major role in the acquisition of data; revised the manuscript for intellectual content. bs: major role in the acquisition of data; revised the manuscript for intellectual content. as: analyzed the data; assisted in interpretation of data; revised the manuscript for intellectual content. gc: revised the manuscript for intellectual content. af: design and conceptualized study; major role in the acquisition of data; revised the manuscript for intellectual content. conflicts of interest nancy d. chiaravalloti is on an advisory board for akili interactive and is a member of the editorial boards of multiple sclerosis journal and frontiers in neurotrauma. maria pia amato received compensation for consulting services and/or speaking activities from bayer, biogen idec, merck-serono, novartis, roche, sanofi genzyme, and teva pharmaceutical industries; and receives research support from biogen idec, merck-serono, roche, pharmaceutical industries, and fondazione italiana sclerosi multiplav. giampaolo brichetto has no disclosures to report. jeremy chataway has received support from the efficacy and evaluation (eme) programme, a medical neurologic manifestations of hospitalized patients with coronavirua disease in wuhan, china scoping review of prevalence of neurologic comorbidities in patients hospitalized for covid- covid- occurring during natalizumab treatment: a case report in a patient with extended interval dosing approach covid- infection in a patient with multiple sclerosis treated with fingolimod moghadasib an ( ) neuropsychiatric and cognitive effects of the covid- outbreak on t multiple sclerosis patients stress, anxiety, and depression levels in the initial stage of the covid- outbreak in a population sample in the northern spain -ncov epidemic: address mental health care to empower society generalized anxiety disorder, depressive symptoms and 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validation of the hospital anxiety and depression scale for use with multiple sclerosis patients manual for the beck depression inventory-ii the multiple sclerosis impact scale (msis- ) a new patient-based outcome measure how responsive is the multiple sclerosis impact scale (msis- )? a comparison with some other self report scales euroqol- d (eq- d): an instrument for measuring quality of life tt -l'euroqol- d (eq- d): uno strumento per la misura della qualità della vita social isolation, depression, and psychological distress among older adults social isolation, loneliness and depression in young adulthood: a behavioural genetic analysis anxiety, depression and post traumatic stress disorder after critical illness: a uk-wide prospective cohort study public responses to the novel coronavirus ( -ncov) in japan: mental health consequences and target populations iranian mental health during the covid- epidemic world health organization. world health o. mental health and psychosocial considerations during the covid- outbreak research council (mrc) and national institute for health research (nihr) partnership and the health technology assessment (hta) programme (nihr), the uk ms society, the us national ms society, and the rosetrees trust. he is supported in part by the national institute for health research, university college london hospitals, biomedical research centre, london, uk. he has been a local principal investigator for commercial trials funded by: actelion, biogen, novartis, and roche; has received an investigator grant from novartis; and has taken part in advisory boards/consultancy for azadyne, biogen, celgene, medday, merck, and roche. ulrik dalgas has received research support, travel grants, and/or teaching honorary from biogen idec, merck serono, novartis, bayer schering, and sanofi aventis as well as honoraria from serving on scientific advisory boards of biogen idec and genzyme. john deluca is an associate editor of the archives of physical medicine and rehabilitation, and neuropsychology review; received compensation for consulting services and/or speaking activities from biogen idec, celgene, medrhythms, and novartis; and receives research support from biogen idec, national multiple sclerosis society, consortium of multiple sclerosis centers, and national institutes of health. cecilia meza has no disclosures to report. nancy b. moore has no disclosures to report. peter feys is editorial board member of nnr and msj, provides consultancy to neurocompass and was board of advisory board meetings for biogen key: cord- -d ylykc authors: lazzarin, serena marita; cannizzaro, miryam; russo, tommaso; sangalli, francesca; callea, marcella; colombo, bruno; moiola, lucia; filippi, massimo title: successful treatment of hiv-associated tumefactive demyelinating lesions with corticosteroids and cyclophosphamide: a case report date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: d ylykc nan and onconeural antibodies was negative. search for vzv, cmv, ebv, syphilis (tpha), hcv, hbv, m. tuberculosis was negative too. a th-generation hiv test was positive, subsequently confirmed by western blotting and polymerase chain reaction, showing plasma hiv- -rna levels of , copies/ml; serum cd count was /µl. additional serological tests for toxoplasmosis and cryptococcosis were negative. combined antiretroviral therapy (cart) with tenofovir alafenamide, emtricitabine and bictegravir was started. histology from stereotaxic biopsy of the right frontal lobe lesion demonstrated several areas of demyelination. pcr for jc virus and toxoplasma gondii on biopsy was negative, as well as mycobacterium tuberculosis complex and acidalcohol-resistant bacilli tests (fig. ) . neuroradiological and pathological findings were suggestive of tumefactive demyelinating lesions (tdls). intravenous -g methylprednisolone was administered for days. two days after the last dose, a follow-up brain mri showed dimensional decrease of both frontal lesions, with disappearance of mass effect; gadolinium enhancement was substantially decreased (fig. ). however, a new small capsulo-lenticular lesion with analogous features was noted. lumbar puncture showed mild lymphocytic pleocytosis ( / µl), proteinorachia ( mg/dl) and no oligoclonal bands; csf glucose was mg/dl. csf was negative for infectious agents, including pcr for jc virus; csf hiv-rna count was copies/ml. due to the persistent inflammatory activity observed at brain mri, a single dose of cyclophosphamide ( mg/m i.v.) was administered, with benefit. at hospital discharge, the patient was oriented, with mild persisting memory deficits and sporadic anomia. at -month follow-up mri, a marked reduction of flair hyperintensities and absence of post-contrast enhancement were observed (fig. ). neurological examination was normal, as well as cognitive function. a clinical and neuroradiological -month follow-up has been scheduled to assess the stability of patient's condition; [ ] , but we cannot even exclude a direct role for hiv in the demyelinating process. the co-occurrence of hiv infection and tdls implies obvious concerns about the treatment of this particular condition. intravenous high-dose steroid treatment was reported to be successful in sparse cases [ , ] . however, in literature, no data are available for steroid-unresponsive tdls in hiv patients [ ] . given the concern to expose an hiv patient to prolonged lymphopenia, we chose cyclophosphamide to induce a quick-onset and short-duration immunosuppressive effect. we planned to administer a pulse regimen of mg/m every weeks. however, due to the sars-cov- pandemic, the further doses were not administered. nevertheless, after months from the first dose, we observed a normalization of neurological examination and a significant improvement of neuroradiological findings. in conclusion, in our case quick initiation of cart and cyclophosphamide led to a significant clinical and radiological amelioration, likely secondary to the restoration of para-physiological immune function. based on our experience, a treatment with cyclophosphamide may be a valid alternative in steroid-resistant hiv patients with tdls. author contributions sml contributed to paper conception, data collection, analysis and interpretation, literature review and paper drafting. cm and tr contributed to data collection, analysis and interpretation, literature review and paper drafting. sf, cm, cb and ml contributed to data collection, analysis and critical review. fm contributed to paper conception, supervised data analysis and interpretation, critically reviewed the paper. funding not applicable. ethics approval the ethics committee of san raffaele scientific institute waived the need for ethics approval for publication of case reports. consent to participate written informed consent was obtained from the patient's spouse for the usage of clinical data in anonymized fashion. consent for publication informed consent for publication was obtained verbally from the spouse. the consent was audio-recorded in the presence of an independent witness. fig. ( ) serial . -t mri axial brain scans, performed after admission (a), at one (b) and months (c) after the clinical onset of a frontal lobe syndrome due to large tumefactive demyelinating lesions. ( ) a-d images of brain parenchyma sample from stereotactic biopsies, haematoxylin and eosin-stained section showing increased cellularity due to the presence of numerous intraparenchymal foamy macrophages (a, × ); those cells are highlighted by anti-cd antibody (b, × ). kluver-barrera staining shows loss of myelin (c and d, × ). e-g brain parenchyma sample with perivascular cuff is composed by mononuclear inflammatory cells stained with haematoxylin and eosin (e, × ); perivascular cuff is made of macrophages immunoreactive for anti-cd antibody (f, × ) and by t lymphocytes highlighted by anti-cd antibody (g, × ). the fab: a frontal assessment battery at bedside tumefactive demyelination in a patient with human immunodeficiency virus tumefactive demyelination-an unusual neurological presentation of hiv hiv and autoimmunity tumefactive demyelinating lesions: a comprehensive review key: cord- - ewdy l authors: domingues, renan barros; mendes-correa, maria cássia; de moura leite, fernando brunale vilela; sabino, ester cerdeira; salarini, diego zanotti; claro, ingra; santos, daniel wagner; de jesus, jaqueline goes; ferreira, noely evangelista; romano, camila malta; soares, carlos augusto senne title: first case of sars-cov- sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease date: - - journal: j neurol doi: . /s - - -w sha: doc_id: cord_uid: ewdy l the association between coronaviruses and central nervous system (cns) demyelinating lesions has been previously shown. however, no case has been described of an association between the novel coronavirus (sars-cov- ) and cns demyelinating disease so far. sars-cov- was previously detected in cerebrospinal fluid (csf) sample of a patient with encephalitis. however, the virus identity was not confirmed by deep sequencing of sars-cov- detected in the csf. here, we report a case of a patient with mild respiratory symptoms and neurological manifestations compatible with clinically isolated syndrome. the viral genome of sars-cov- was detected and sequenced in csf with . – % similarity between the patient virus and worldwide sequences. this report suggests a possible association of sars-cov- infection with neurological symptoms of demyelinating disease, even in the absence of relevant upper respiratory tract infection signs. the novel coronavirus (sars-cov- ) is associated with respiratory symptoms. there have been reports of covid- associated neurological manifestations. the viral genome was demonstrated by rt-pcr technique in cerebrospinal fluid sample (csf), suggesting that the virus has the ability to infect central nervous system (cns) [ ] . the association between other coronaviruses and cns demyelinating lesions has been studied [ , ] . however, no case has been described of an association between sars-cov- and cns demyelinating disease so far. a year-old patient, resident in são paulo, sought neurological consultation due to paresthesias of the left upper limb, later progressing to left hemithorax, and hemiface. upon neurological examination, she had hypoesthesia in the above-mentioned regions. the patient also had mild respiratory symptoms that included coryza and nasal obstruction without fever for weeks. rt-pcr for sars-cov- of nasal and pharyngeal swab and cerebrospinal fluid (csf) was carried out. she had a similar neurological clinical picture years ago with spontaneous full recovery of symptoms. as the symptoms were exclusively sensitive and due to the association with sars-cov- infection, the patient was not treated with corticosteroids. the patient had full recovery after weeks. specific sars-cov- rna primers and probe directed to rdrp- gene described who (charité, berlim) were used. a control csf examination was carried out days later. blood cell counts, transaminases, bilirubin, cpk, coagulogram, electrolytes, renal function, and c-reactive protein were all normal. csf analysis showed wbc/mm , protein of mg/dl, and glucose of mg/dl. no csf oligoclonal bands were demonstrated. brain magnetic resonance to confirm the identity of the virus in csf identified in the csf sample, we deep sequenced the material using the minion platform from oxford nanopore technology as described in (https ://www.proto cols.io/view/ncov- seque ncing proto col-bbmui k w). reads were mapped against mn . reference genome using clc genomic workbench v. (qiagen). due to the low viral load resent on the lcr, a full-genome consensus was not obtained. regions having the better coverage of the genome (> ) were used to the analysis. therefore, two fragments from orf a were obtained and concatenated resulting in a -nucleotide long sequence that was multiple-aligned together to worldwide representative sars-cov- reference genomes (available at gisaid). an identity matrix was generated, and revealed . - % similarity between the patient virus and worldwide sequences. no additional regions from the patients sars-cov- genome other than the used for similarity analysis were obtained with enough quality to allow a more detailed investigation on putative nucleotide or aminoacid particular substitutions. institutional ethical board approval and written consent were obtained. here, we report a case of sars-cov- infection with a clinical presentation compatible with cis [ ] . the diagnosis of cis was established, since the patient had a clinical attack involving a single anatomical region and did not have dissemination in space either clinically or by mri, no oligoclonal bands were found, and no better explanation was found by clinical investigation [ ] . the lesion site seems to justify the symptoms, including facial symptoms, due to possible involvement of spinal trigeminal nucleus. to the best of our knowledge cns demyelinating disease has not been associated with covid- so far; however, other coronaviruses were previously associated with cns demyelinating autoimmune diseases, including ms exacerbations [ ] and autoreactive t cells able to recognize myelin antigens [ , ] . a possible explanation is that sars-cov- entry into the cns may have led to this exacerbation. one single report describes csf positivity for sars-cov- by the rt-pcr technique [ ] . to the best of our knowledge, this is the first report to confirm the identity of sars-cov- in csf with deep sequencing. there are multiple proposed mechanisms for sars-cov- entry into the cns. as already studied for other coronaviruses, sars-cov- could move via olfactory nerve [ ] or by hematogenous spread [ ] . the fact that the pcr was negative in the oropharyngeal swab may be due to the duration of the symptoms, since the patient had respiratory symptoms for weeks when the swab was collected. however, the present case does not suggest chronic cns infection, since the csf control rt-pcr was negative. one possibility is that sars cov- infection is more persistent in the cns, since it is a more immunoprivileged site. another possibility is that after the initial stage of replication in cells of the respiratory system, the sars-cov- infects blood cells that can cross blood-brain barrier allowing virus to pass into the cns [ ] . this case report suggests a possible association between cns focal symptoms compatible with demyelinating disease and sars-cov- infection. this report should alert clinicians to this possible association, even in the absence of relevant upper respiratory tract infection signs. conflicts of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. a first case of meningitis/encephalitis associated with sars-coronavirus- coronaviruses in brain tissue from patients with multiple sclerosis acute and persistent infection of human neural cell lines by human coronavirus oc diagnosis of multiple sclerosis: revisions of the mcdonald criteria detection of antibodies to human coronaviruses e and oc in the sera of multiple sclerosis patients and normal subjects long-term human coronavirus-myelin cross-reactive t-cell clones derived from multiple sclerosis patients human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace multiple organ infection and the pathogenesis of sars neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease : a review key: cord- - q q a authors: di carlo, davide tiziano; montemurro, nicola; petrella, giandomenico; siciliano, gabriele; ceravolo, roberto; perrini, paolo title: exploring the clinical association between neurological symptoms and covid- pandemic outbreak: a systematic review of current literature date: - - journal: j neurol doi: . /s - - -y sha: doc_id: cord_uid: q q a object: the novel severe acute respiratory syndrome (sars)-cov- outbreak has been declared a pandemic in march, . an increasing body of evidence suggests that patients with the coronavirus disease (covid- ) might have a heterogeneous spectrum of neurological symptoms methods: a systematic search of two databases was performed for studies published up to may th, . prisma guidelines were followed. results: we included studies evaluating , patients with laboratory-confirmed covid- infections. the median age of patients was . (iqr . ), and the rate of male patients was . % ( % ci . – . %). the most common reported comorbidities were hypertension and diabetes ( . %, % ci – . % and . %, % ci . – . %, respectively). headache was reported in . % of patients ( % ci . – . %), and dizziness in . % ( % ci . – . %). hypo/anosmia, and gustatory dysfunction were reported in . and . %, of patients, respectively. symptoms related to muscular injury ranged between and %. three studies reported radiological confirmed acute cerebrovascular disease in % of patients ( % ci . – . %). conclusions: these data support accumulating evidence that a significant proportion of patients with covid- infection develop neurological manifestations, especially olfactory, and gustatory dysfunction. the pathophysiology of this association is under investigation and warrants additional studies, physicians should be aware of this possible association because during the epidemic period of covid- , early recognition of neurologic manifestations otherwise not explained would raise the suspect of acute respiratory syndrome coronavirus infection. electronic supplementary material: the online version of this article ( . /s - - -y) contains supplementary material, which is available to authorized users. in december , several cases of atypical pneumonia occurred in the wuhan province in china, and then spread to rest of the country, then to europe, north america, and asia. the outbreak was confirmed to be caused by severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . this new coronavirus belongs to human β-coronaviruses, that also includes middle east respiratory syndrome (mers)-cov, and sars-cov- . these viruses are mainly associated with respiratory-related diseases, such as pneumonia, ards, and pulmonary edema [ ] [ ] [ ] . in march , the who declared the coronavirus disease (covid- ) as an outbreak pandemic, and as of may th, more than million people were confirmed positive, and there were more than , deaths globally [ ] . according to the clinical investigations from asia, common clinical manifestations include fever, cough, dyspnea, diarrhea, and fatigue associated with typical laboratory findings and lung abnormalities on a computed tomography (ct) scan [ ] . additionally, some patients with covid- presented neurologic manifestations, such as headache, loss of sense of smell, stroke and seizures, suggesting that sars-cov- , like mers-cov and sars-cov- , displays neurotropism and enters the central nervous system [ , ] . the aim of this systematic review was to investigate the occurrence of different neurologic symptoms associated with covid- and to assess their rate. a comprehensive literature search of two databases (pub-med and ovid embase) was conducted by an experienced librarian with input from the authors on may th, in accordance with prisma guidelines (preferred reporting items for systematic reviews and meta-analysis) [ ] . the key words and the detailed search strategy are reported in table . the inclusion criteria were the following: ( ) series reporting patients with laboratory diagnosis of covid- infection, and ( ) cohort studies, case-controls studies, case series. exclusion criteria were the following: ( ) review articles, ( ) studies published in languages other than english with no available english translations, ( ) studies with overlapping patient population, ( ) studies with no neurological evaluation, ( ) case report or series with no epidemiological data. in cases of overlapping patient populations, only the series with the largest number of patients or most detailed data were included. two independent readers (d.d.c. and g.p.) screened articles in their entirety to determine eligibility for inclusion. senior author solved discrepancies (p.p.). from each study, we extracted the following: ( ) demographic data, ( ) patients' comorbidity, and ( ) clinical symptoms at presentation. symptoms including emesis, nausea, diarrhea, and abdominal pain were collected as "digestive symptoms". neurological symptoms were categorized into three categories, as follows: central nervous system (cns) manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizures), peripheral nervous system (pns) manifestations (taste impairment and smell impairment), and muscular injury manifestations (myalgia, muscular pain, fatigue) [ ] . data were obtained for the whole population and subsequently we divided it into two groups: severe patients and non-severe patients, according to the american thoracic society guidelines for community-acquired pneumonia [ ] outcomes the primary objective of this systematic review was to analyze the overall rate of neurologic symptoms among covid- patients. secondary objective was to compare the results between patients with severe and non-severe infection. a modified version of the newcastle-ottawa scale [ ] was used for the quality assessment of the included studies. the quality assessment was performed by two authors independently, and the senior author solved discrepancies. inter-observer agreement was tested with cohen's kappa coefficient (k). the wald method was used to calculate confidence intervals for event rates. fisher's exact test was used for categorical variables. statistical analyses were performed with spss version (spss inc. spss ® chicago, il, usa). studies included in our systematic review are summarized in table . intra-observer agreement was . . the search flow diagram is shown in fig. . nineteen studies [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and , patients with laboratory-confirmed covid- infection were included in our study. there was complete agreement between the two reviewers for the examined articles. twelve studies were retrospective single-center designed, whereas five studies were multicentric investigations. all papers were rated as "high quality" (table ) . two publications were letters to the editor. accordingly, they were rated as "low quality" evidence, due to the type of the publication. overall, the median age of patients was . (iqr . ), and the proportion of male patients was . % ( % ci . - . %). hypertension was the most common comorbidity ( . %, % ci - . %) among our population, whereas fever was the most common clinical presentation . %, % ci . - . %). detailed data and ci are reported in table . when considering the severity of the beltran-corbellini et al. [ disease, the two sub-groups were not homogeneous in terms of comorbidity in our analysis. indeed, patients with a history of hypertension, cardiovascular disease, diabetes, and concurrent malignancy were significantly more common in the "severe" subgroup (p < . ) ( table ). among cns symptoms, headache was reported in ten studies and in . % of patients ( % ci . - . % . %, p < . ). the rate of pns were compared between severe and non-severe populations only in one study, and no significant difference arose from the analysis (table ) . furthermore, three studies showed an overall rate of radiological confirmed acute cerebrovascular disease of % ( % ci . - . %). limited reports described neurologic complications of sars-cov- and mers-cov, mainly restricted to axonal peripheral neuropathy, acute disseminated encephalomyelitis, and stroke [ , ] . our systematic review of patients reported the occurrence of a wide spectrum of neurologic complications in hospitalized patients with laboratory-confirmed covid- infection, supporting the possible neuroinvasive potential of sars-cov- . a growing body of evidence suggests that sars-cov- , similarly to sars-cov- , has neuroinvasive potential, possibly through the retrograde neuronal route [ , ] . recent studies reported that the expression level of angiotensin converting enzyme (ace ) is critical for the susceptibility of sars-cov- and sars-cov- infection [ ] . the cellular receptor ace is expressed in different tissues and organs including the nervous system and skeletal muscles [ ] . autopsy samples from patients with sars clearly demonstrated the presence of sars-cov- in brain samples [ , ] . interestingly, laboratory investigations on transgenic mice for the sars-cov receptor (ace ) demonstrated that the virus enters the brain via the olfactory bulb with resultant rapid transneuronal spread to different brain regions including cortical areas (piriform and infralimbic cortices), basal ganglia (ventral pallidum and lateral preoptic regions), and midbrain (dorsal raphe). in these regions, a significant neuronal death occurs [ ] . a recent report confirmed the presence of sars-cov- in cerebrospinal fluid by genome sequencing in a patient with viral encephalitis, confirming the neurotropism of sars-cov [ , ] . they proposed that the respiratory failure in patients with covid- is related to the neuronal loss at the level of the cardiorespiratory center in the brainstem. however, type respiratory failure with low co levels and raised respiratory rate observed in patients with covd- is more likely related to pneumonia instead of brainstem dysfunction that leads to failure of breathing associated with reduced respiratory rate and high c levels (type respiratory failure) [ ] . symptoms related to skeletal muscle injury are generally associated with elevated creatine kinase and lactate dehydrogenase levels. it was initially suspected that this injury was related to the presence of ace- in skeletal muscle [ ] . however, immunohistochemistry and in situ hybridization failed to detect sars-cov in the skeletal muscle of patients who died of sars, suggesting a putative role of a systemic inflammatory response syndrome (sirs) in the pathogenesis of muscular damage [ ] . it is supposed that sirs can occur in pneumonia caused by covid- infection and promotes multiple organ failures in patients with severe infection. further clinical and laboratory investigations are required to clarify the neurotropism of sars-cov- and its neuroinvasive potential. nonetheless, some reports detected sars-cov- in the csf of patients presenting with meningoencephalitis and unremarkable medical history, strengthening the idea of a direct neuroinvasive potential of this novel coronavirus [ , ] . neurologic manifestations in patients with covid- are common. in a recent retrospective study, mao et al. reported nervous system-related clinical findings in of hospitalized patients ( . %) and categorized neurological disturbances into three groups: cns manifestations, pns manifestations, and skeletal muscular injury manifestations. interestingly, their report suggested that patients with severe infection were more likely to develop cns and muscular injury symptoms [ ] . the results of our analysis are consistent with their findings, demonstrating a significant difference among severe and non-severe patients. nonetheless, the two groups were not homogeneous in terms of clinical comorbidity, and severe patients were characterized by a significant higher rate of concomitant hypertension, cardiovascular disease, malignancy, and diabetes. accordingly, as previously discussed, a direct link between the occurrence of neurological symptoms and the clinical condition cannot be drawn at the current state of knowledge. however, the occurrence of multiorgan damage in patients with muscle injury suggests that infection-mediated immune response probably plays a role as a causative factor of skeletal muscle damage. in fact, these patients present not only significantly higher levels of creatine kinase but also higher neutrophil counts, lower lymphocyte counts, higher c-reactive protein levels, and higher d-dimer levels indicating increased inflammatory response and coagulation activation [ , ] . similar findings were reported in patients with mers and sars-cov- infection [ , ] . our study demonstrated that olfactory and gustatory function impairment were the most common neurologic manifestations in patients with covd- and were detected in approximately % of patients. lechien et al. extensively examined this topic in a multicentric investigation and reported an overall rate of olfactory and gustatory dysfunctions of roughly and %, respectively [ ] . in this study, olfactory and gustatory dysfunction were both prevalent in patients with mild-to-moderate covid- infection and hyposmia was generally observed in patients without nasal obstruction or rhinorrhea before, during or after the general symptoms. it is worth noting that the prevalence of olfactory and gustatory dysfunction was substantially higher in european cohorts compared with the asian cohorts [ , ] . this difference is poorly understood and requires further investigation. accumulating evidence suggests that sars-cov- infection is associated with a prothrombotic state, with elevated d-dimer [ ] that can eventually lead to acute cerebrovascular disease, especially in severe patients [ ] . in the series of helms et al., mri was performed in patients because of encephalopathic features and demonstrated one subacute and two acute ischemic strokes [ ] . recently, several case reports described the occurrence of ischemic and hemorrhagic stroke (see supplementary material ), confirming the association of cerebrovascular complications with severe covid- infection, older age, and the presence of multiple comorbidity [ , ] . on the other hand, our study showed an overall rate of acute cerebrovascular disease (ischemic or hemorrhagic) of % that is similar to the rate of stroke in the us [ ] . it is noteworthy that these data could be underestimated due to the number of critical patients with neurological signs that did not undergo any neuroradiological investigation during the pandemic outbreak [ ] . furthermore, it has been reported that hospitalization for infection is associated with a short-term increased risk of stroke [ ] . accordingly, even though a causal relationship between covid- infection and acute cerebrovascular disease cannot be drawn at the current state of knowledge, it is conceivable that ischemic stroke can occur in the context of a systemic highly prothrombotic state in severe patients. no definitive epidemiologic data support the link between sars-cov- infection and polyradiculopathy. nonetheless, an increasing number of studies are reporting the occurrence of guillain-barré syndrome or polyneuritis cranialis (supplementary material ) in covid- patients. although scanty information is available on this topic, two different clinical presentations are described: ( ) an interval of - days between the onset of viral illness and the first symptoms of guillain-barré [ ] ( ) and an unusual concomitant progression of both the infection and the neurological syndrome [ ] . guillain-barré syndrome is caused by an aberrant autoimmune response evocated by a cross-reaction against ganglioside components of the peripheral nerves, ensuing different viral or bacterial infections [ ] . as previously discussed, sars-cov- can cause an excessive immune reaction that lead to extensive tissue damage. clinical and laboratory data are not definitive: antiganglioside antibodies were often absent, albuminocytologic dissociation in csf was not constant [ ] [ ] [ ] [ ] , and pcr for coronavirus was negative in csf. seizure are infrequently reported in patients with covid- , and only few cases are described in the literature. viral encephalitis or a blood-brain barrier breakdown ensuing the excessive release of pro-inflammatory cytokine have been hypothesized as the cause of cortical irritation that precipitates seizures related to covid- infection [ , ] . nonetheless, data are insufficient, and no definitive conclusions can be currently drawn. our study has limitations. the series are often small, retrospective, and single-institution experiences. furthermore, due to the contemporaneity of the outbreak, the followup is short, and the occurrence of late onset neurological deficits cannot be analyzed. furthermore, only two studies [ , ] have analyzed, as primary outcome, the neurological characteristics of their patients. in addition, advanced neuroimaging (mri) and diagnostic procedures (lumbar puncture, electromyography/nerve conduction velocity) were rarely reported in the studies included. however, our review is the largest study to date that provides a representation of data concerning neurological symptoms among laboratory-confirmed covid- population. accumulating evidence suggests that a significant proportion of patients with covid- infection develops neurological manifestations, especially olfactory and gustatory dysfunction. the pathophysiology of this association is under investigation and warrants additional studies. physicians should be aware of this possible association because during the epidemic period of covid- , early recognition of neurologic manifestations otherwise not explained should raise the suspect of acute respiratory syndrome coronavirus infection. outbreak of pneumonia of unknown etiology in wuhan china: the mystery and the miracle epidemiological, demographic, and clinical characteristics of cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study coronavirus as a possible cause of severe acute respiratory syndrome epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study world health organization. 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associated with poor prognosis in patients with novel coronavirus pneumonia characteristics of ischaemic stroke associated with covid- covid- presenting as stroke stroke epidemiology: advancing our understanding of disease mechanism and therapy hospitalization for infection and risk of acute ischemic stroke: the cardiovascular health study guillain-barré syndrome associated with sars-cov- early guillain-barré syndrome in coronavirus disease (covid- ): a case report from an italian covid-hospital miller fisher syndrome and polyneuritis cranialis in covid- guillain barre syndrome associated with covid- infection: a case report acute symptomatic seizures in critically ill patients with covid- : is there an association? neurocrit care acknowledgements we thank professor beth de felici for the english revision.funding no funding was received for this research. conflicts of interest all authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. does not contain any studies with human participants or animals performed by any of the authors.ethical approval for this type of study formal consent is not required. the nature of this article did not require informed consent. key: cord- - zpnwl k authors: mateen, farrah j.; rezaei, shawheen; alakel, nicholas; gazdag, brittany; kumar, aditya ravi; vogel, andre title: impact of covid- on u.s. and canadian neurologists’ therapeutic approach to multiple sclerosis: a survey of knowledge, attitudes, and practices date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: zpnwl k objective: to report the understanding and decision-making of neuroimmunologists and their treatment of patients with multiple sclerosis (ms) during the early stages of the sars-cov- (covid- ) outbreak. methods: a survey instrument was designed and distributed online to neurologists in april . results: there were respondents (response rate . %). saw > = ms patients in the prior months (average patients) and were analyzed further ( % usa, % canada; average practice duration years; % rural, % small city, % large city, % highly urbanized). patient volume dropped an average of % ( – per month). % were aware of patients self-discontinuing a dmt due to fear of covid- with % estimated to be doing so against medical advice. % of respondents reported deferring > = doses of a dmt ( %), changing the dosing interval ( %), changing to home infusions ( %), switching a dmt ( %), and discontinuing dmts altogether ( %) as a result of covid- . changes in dmts were most common with the high-efficacy therapies alemtuzumab, cladribine, ocrelizumab, rituximab, and natalizumab. % made no changes to dmt prescribing. % expressed worry about their patients contracting covid- and % expressed the same degree of worry about themselves. > % believed high-efficacy dmts prolong viral shedding of sars-cov- and that b-cell therapies might prevent protective vaccine effects. accelerated pace of telemedicine and practice model changes were identified as major shifts in practice. conclusions: reported prescribing changes and practice disruptions due to covid- may be temporary but could have a lasting influence on ms care. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. there are > , people living with multiple sclerosis (ms) in the united states of america and approximately , in canada, with the majority treated with disease-modifying therapies (dmts) [ , ] . the hallmark of treatment in ms is immunosuppression, or in some cases immunomodulation, which has a very strong evidence base but must be continuously evaluated for its risk-benefit ratio in patients across the disease course and throughout the lifespan. there are now fda-approved dmts for multiple sclerosis with several additional therapies used in practice and others in the therapeutic pipeline [ ] . in general, people with ms have a higher risk than the general population for multiple infectious diseases, particularly when treated with high-efficacy dmts [ , ] . in march , the first case of the new sars-cov- -covid- virus was reported in the usa [ ] ; however, earlier cases in the usa, prior to widespread recognition, are now confirmed [ ] . by the end of april , there were more than > . million confirmed cases in the usa and > , covid- -attributed deaths [ ] . at the time of this report, the usa has more cases of covid- than any other country in the world and the highest absolute number of deaths. this situation, previously unimaginable only a few months earlier, has profoundly influenced inter alia neurological care [ , ] . immunosuppression is a reported risk factor for developing covid- by the u.s. centers for disease control and prevention [ ] . immunosuppression or immunomodulation could impact patient prognosis if coronavirus infection occurs. however, the cases reported among people living with ms are still being gathered and understood, with only anecdotal reports available presently. some information can be drawn through informal channels including social media. larger efforts are ongoing, but a synthesized report on ms patients and their outcomes was not yet published when our study commenced. general guidelines are emerging [ , ] , but were generally limited at the time of our study. amidst this pandemic and declared national emergency in the usa, with a parallel response in canada, neuroimmunologists are making important decisions and adjudicating complex situations of risk for their patients living with ms. this study reports the knowledge, attitudes, and practices of neurologists treating ms. we attempt to synthesize the deductions and strategies of a large sample of subspecialized neurologists in united states and canada at the early height of the pandemic, surveyed online beginning in mid-april . where discrepancies exist, we attempt to show the range of responses on a particular issue. the overall objectives of this study were threefold: ( ) to report the range of impacts of covid- on neuroimmunologists' practice across the usa and canada; ( ) to probe the ms dmt prescribing decisions and planning of neuroimmunologists in the setting of a viral pandemic; and ( ) determine the unmet needs and sources of uncertainty that dominate the care of ms patients. understanding of the present situation could identify points of contention among experts and reveal shared uncertainties that can be addressed through targeted research. consensus on current best practices among neurologists could further support patients, prescribers, and practices in future public health emergencies. the study received expedited review and approval by the massachusetts general hospital's institutional review board. a new survey instrument was designed by the authors to query the most urgent and prevalent issues that msfocused neurologists were perceived to experience in the first approximately weeks of the recognized covid- outbreak in north america. the survey questions were based on evolving reports, clinical anecdotes and experiences, and incorporation of patient-based queries until early april , when the final version of the survey instrument was confirmed and irb approved. the thematic focus of the questions was on the knowledge, attitudes, and practices of ms dmt prescribers. rather than emphasizing fact checking, the survey queried awareness of local covid- cases and patients' health practices, impressions and worries on the risk of covid- to patients taking ms dmts, and prescribing patterns in various special situations, naming the exact dmts. as an example, issues related to older patients with ms were queried, defined as age years and older (given the usual age cutoff for most dmt trials to date) or years and older (given the centers for disease control and prevention's general consideration of people aged years and older as a higher risk group) [ ] , depending on the question. the survey instrument is available as appendix . eligibility for the survey was determined based on screening questions. eligible respondents must have seen a critical number of ms patients (pre-defined as a minimum of ms patients per month in the past months). only physicians who self-declared a subspecialty expertise in ms were eligible. the survey included a combination of fillin-the-blank, multiple choice, and open-ended questions. pilot testing was performed by the authors in a sample of participants, and the accuracy and completeness of the responses were reviewed by the authors prior to wider distribution. surveys were distributed through an email link, in english, to a known panel of ms prescribers who have answered previous surveys online as well as to publicly available e-mail addresses of neuroimmunology-focused u.s. and canadian neurologists, from april , to may , , an approximately -week period. a single reminder was sent. a sample size of u.s. and canadian respondents was targeted or a study end date of may , whichever came first. invitation posts to public forums were made including the canadian network of ms clinics and the american academy of neurology's ms, neuro-infectious disease, and solo and small practices section. all responses were collected anonymously with no identifiable information gathered on the respondents by the study team. the questions were entered electronically into the zoomrx platform. each page required complete responses before advancing to the next page. where questions were relevant to only a specific subgroup of respondents who replied "yes" or "no" to prior questions, subsamples of the full sample size are reported. respondents who completed the survey in full were each offered an honorarium of usd. quality control of the survey responses was performed. responses were analyzed by each question and summarized by their proportions (percentages) for categorical variables and the mean, median, and percentiles for continuous variables. free text responses were reviewed by the authors and reported qualitatively. there were responses (estimated response rate . %) who cared for ms patients in the past months. characteristics of the respondents including the practice setting are provided in table . respondents came from of the u.s. states and canada. u.s-based respondents came from many of the states with the highest number of incident covid- cases, recognized through virus testing: new york ( %), california ( %), massachusetts ( %), florida ( %), and pennsylvania ( %). the average number of years in practice was . there were respondents who had seen at least ms patients in the prior months and analyzed further. the average number of ms patients seen by the respondents was in the prior months with in a "typical month" but in the last month (in roughly the month of april ). this reflected an average decrease in ms patients ( % drop) seen by neurologists during the covid- epidemic peak. % of respondents were aware of a case of covid- in their community, town, or city. the degree of worry for ms (and neuromyelitis optica) patients and themselves as practitioners becoming infected by the novel coronavirus is given in fig. . most respondents ( %) expressed an average or more worry about their patients contracting sars-cov- and % expressed the same degree about themselves getting the virus with % considering it a danger to their patients' health and % to their own health. moreover, % of neurologists believed that covid- is a major danger to their ms (or neuromyelitis optica) patients' health with % felt the same for their own health. % of neurologists had conducted a televisit (telephone and/or video) directly as a result of the covid- epidemic, with an estimated % of all visits already being conducted via telemedicine by the time of the survey. physicians estimated that % of patients on average made changes to their daily lives and health behaviors due to sars-cov- virus with the most common decision being "social distancing" ( %) followed by avoiding travel ( %), not going to work ( %), wearing a medical mask ( %), social isolation ( %), self-quarantine ( %), and wearing gloves ( %). among the % of specialists stating that they are aware of any of their ms patients self-discontinuing dmts due to worry about contracting the virus, an estimated % of patients had self-discontinued their prescribed dmt in the setting of covid- . in % of cases, this was against medical advice, % it was upon medical advice, and % it was neutral (neither against advice or with advice to stop). nearly all physician respondents ( %) believe that their ms patients are at an increased risk of acquiring covid- compared to the general population, with % considering this risk slightly increased, % considering it moderately increased, and % considering it significantly increased. prior to covid- , respondents estimated that their ms patients were on average taking injectable agents ( %), oral therapies ( %), and infused therapies ( %) ( table ). an estimated % of ms patients were untreated with any dmt. % of ms patients were on more than one immunosuppressive agent. % of all ms patients were estimated to be presently enrolled in a clinical trial. specific dmt prescribing patterns before and after covid- are given in table . in general, % of respondents believed that certain dmts are safer during the covid- pandemic than others; % did not think so; and % were unsure. the dmts believed to be safer during the pandemic were glatiramer acetate ( %), interferons ( %), and teriflunomide ( %). dmts that neurologists would consider starting and not consider starting in newly diagnosed ms patients are given in table . overall, high-efficacy agents were avoided and lower efficacy agents were preferred. just % of neurologists reported they would still consider prescribing any of the dmts in the context of covid- . the most commonly avoided agents in the context of covid- were alemtuzumab ( %), cladribine ( %), ocrelizumab ( %), rituximab ( %), and natalizumab ( %). four percent of neurologists, however, reported they would not start a dmt at all in the context of covid- . questions specific to older patients in ms included a combination of open-ended and targeted questions. impression on the number of weeks of an acceptable delay in dosing of a b-cell therapy for ms (i.e. rituximab or ocrelizumab) in patients years and older versus - years old are provided in fig. . respondents were queried on whether certain dmts "may not allow for a protective response to a potential sars-cov- vaccine" with % agreeing with this statement and % in disagreement. among those who thought dmts may prohibit a protective vaccine response, the medications of highest concern were ocrelizumab ( %), rituximab ( %), alemtuzumab ( %), cladribine ( %), and chronic steroids ( %) with all other dmt options leading to < % concern. only % of neurologists believed that certain dmts would prolong the period over which an ms patient sheds the novel coronavirus if exposed, whereas % stated they did not know. among those who believed that a dmt could prolong viral shedding of the virus, ocrelizumab ( % of respondents), ritxuximab ( %), and alemtuzumab ( %) were considered to be the most likely to do so (fig. ) . respondents were asked for their impressions of the covid- situation for their patients and practices in open answer form with a focus on unmet needs for ms patients. a synthesis of the responses included a range of issues. one respondent stated: "this is the most difficult time i have seen in my years of neurology." general needs included access to a vaccine and antiviral therapy for sars-cov- . however, specific needs were prominent to ms patients including a focus on patients in rural areas, those without access to technology, older patients, patients who live alone, patients with advanced disability, patients with comorbid systemic illnesses, patients who could not access routine services due to their designated "elective" nature such as laboratory testing and infusions, access to coronavirus testing including acutely and for a future antibody, and access to psychological support for patients. a recurring need for more data on dosing, safety, reported covid- -ms cases, guidance on patients' return to work, and future vaccine efficacy were called for. practice related issues included insurance barriers to home infusions, equity issues among health care workers (such that nurses and medical assistants were redeployed), financial strains, and reimbursements for telemedicine were noted. the was a general concern about the need to see some patients in person and the risk of future relapses in ms patients who were altering their current disease surveillance and treatment approaches. since eradication of the novel coronavirus appears unlikely, particularly in the usa, the impact of community spread of the novel coronavirus may impact prescribing choices in ms for the foreseeable future. an ongoing debate continues in the ms field on induction therapy or early use of higher efficacy agents versus escalation therapy which includes initiation of lower efficacy agents. treatment "sequencing" may occur since most ms patients are likely to take multiple dmts over the course of their lifetimes. the primary driving influence of this selection has often been efficacy of the dmts with a focus on the incidence of ms relapses, new t /flair hyperintense lesions on mri, and accrual of disability [ ] . additional considerations of safety, tolerability, and convenience have been included in this decision-making process. the covid- era has led to a potentially new balance in the expectations of patients and their prescribers as well as the impact on dmt selection, dosing, and continuance. ms specialists differ in their approach to mitigating the risks of immunosuppression. most ( %) neurologists are doing at least one of: deferring dmt doses, changing the dose, changing the dosing interval, discontinuing dmts altogether, switching to a different dmt, and for infused products in particular, changing to home infusions. although there is also a strong tendency to make no changes, this occurs in only a minority of specialists. in the case of b-cell therapies, a similar number of neurologists responded that they would hold the medication until after the pandemic as would choose not to defer the next dose at all. whether dosing and prescribing patterns will remain similarly disparate in the long term is uncertain. if more patients will remain off of dmts permanently or "de-escalate therapy" to choose lower efficacy injectable and oral agents in higher proportions is uncertain. the longer term impact of the fear of covid- may influence future new patient prescribing as well as in older ms patients (i.e. approximately above years), the latter whom have the least available evidence for efficacy and are at higher risk of covid- . the impact on dmts on future covid- vaccinations, if they are developed successfully, remains to be understood, particularly for dmts with long-term effects, such as b-cell depleting therapies. further studies on the dosing of dmts as well as opportunities for extended dosing intervals and lower doses are needed for the higher efficacy agents. the possibility that dmts may prolong viral shedding of the novel coronavirus is considered possible by many neurologists. other unmet needs for scientific results include an understanding of whether any of the dmts exert antiviral effects that are relevant to covid- in a clinically meaningful way. approximately, a quarter of neurologists are aware of their ms patients self-discontinuing dmts. ms specialists are aware of discontinuation in more than one in every patients. since physicians tend to over-estimate adherence in patients, and ms dmt adherence ranges from to % in non-pandemic times [ ] [ ] [ ] , the number of people living with ms taking their dmts on schedule is likely even lower than estimated here. this report is unique in that it provides systemically collected data of a large group of ms-focused neurologists at a time when the novel sars coronavirus was increasing in incidence across north america, when testing was variably present, and data on people with immunosuppression for ms as a subgroup with covid- are not yet available. we queried a high number of respondents in a short period of time, allowing a snapshot in time of a moment in crisis in the country. however, the u.s. epidemic unfolded, and continues to unfold, in different ways in different regions and groups in the country, and differently in parts of canada, reflecting the wave of covid- 's impact on patient populations by both biological and non-biological variables. some authors have suggested that immunosuppression is protective [ ] , although this remains speculative. current clinical trials for the treatment of covid- include several of the ms dmts including the interferons, sphingosine -phosphate inhibitors, fumarates, teriflunomide, and natalizumab [ ] . equipoise exists in each of these trials. high throughput screening of available drugs has implicated interferons as potentially therapeutic for covid- [ ] given their presumed antiviral effects, a drug class now being tested in a global covid- trial. in the months since this study occurred, the general worry level among neurologists may have decreased. this may be due to reports out of europe that show fewer cases than may have been expected [ ] , prognosis that is variable, and reduced infection rates. strong mitigation strategies including strict social distancing, isolation, and avoidance of risk may have contributed to these numbers and needs to be further understood among ms patients. guidelines now generally recommend continuation of ms dmts with careful discussion around individual patients who take higher efficacy agents or have highest risk profiles [ , ] . our work is subject to multiple limitations, most notably relating to the sampling of neurologists. this is a sample of convenience. there is no one registry of expert physicians in neuroimmunology in the u.s.a. by which to know if our sampling is representative of the subspecialty density in the country. our criteria included a minimum number of patients with ms seen in a -month period; however, we cannot rule out that respondents altered their responses in some way to improve their chance of inclusion or reported erroneously. since this was introduced as an academic research study, no expectations of prescribing in a certain way or a certain drug would have been pre-suggested by our survey invitation. respondents may have had differing views based on their location or time of response within the usa given that the incidence of cases and the surge of new cases were different, even in this . week period of time. this survey was designed at the beginning of the pandemic in the u.s.a.; shortly afterwards, the impact of health disparities was even more apparent, including the differential impact of covid- on lower income patient populations of african american and latinx ancestry in the usa due to a variety of factors that are not race-related but socioeconomic. our survey did not query the important specific issues on health disparities, access to telemedicine, or insurance status. future surveys should consider these key variables more closely. subgroup analyses were not performed in our dataset but could be performed in response to specific hypotheses in future work. the number of canadian respondents made comparisons to the u.s. potentially under-powered. similarly, studies of specific regions of the usa were not undertaken, since our unit of geographical classification was the state. even within states (e.g. new york), different counties, cities, neighborhoods, and health facilities had differing covid- experiences. we are not aware of similar published academic research on this topic at the time of our study, making our results foundational for future other investigations on more targeted prescribing issues as they arise. in the time of social distancing, the risk of patients on immunosuppression is likely mitigated by structural changes in society. however, as various geographic regions "open up" and "normal routines" including work and eventually travel resume, added risk may ensue for community-acquired spread of coronavius to immunosuppressed ms patients. large surveys performed rapidly across both academic and private practice settings are valuable to understanding the collective landscape in which ms patients and physicians navigate. neuroimmunologists also have high financial value, with an estimated downstream revenue generation of million usd for one full time equivalent and million dollars for accompanying testing and prescribing. although we did not study the financial impact of covid- on neuroimmunology, our results imply that the financial costs to multiple parties will be high [ ] . taken together, covid- has substantially disrupted usual patterns ms dmt practices. we provide a brief snapshot on the prevailing knowledge, attitudes, and practices of ms subspecialists during the covid- pandemic. it is uncertain if these practice changes are temporary or will instead have lasting impact. the long-term consequences of the worry, perceptions, health behaviors, prescribing, and de-prescribing for ms patients remain to be measured. data from this study will be made available to qualified investigators upon request of the authors. the prevalence of ms in the united states: a population-based estimate using health data no authors listed infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, covid- /sars-cov- for the washington state -ncov investigation team et al ( ) first case of novel coronavirus in the united states coronavirus death in california came weeks before first known u preparing a neurology department for sars-cov- (covid- ): early experiences at columbia university irving medical center and the new york presbyterian hospital treating multiple sclerosis and neuromyelitis optica spectrum disorder during the covid- pandemic consensus statement on immune modulation in multiple sclerosis and related disorders during the covid- pandemic: expert group on behalf of the indian academy of neurology association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis narrative review of the literature on adherence to diseasemodifying therapies among patients with multiple sclerosis high treatment adherence, satisfaction, motivation, and health-related quality of life with fingolimod in patients with relapsing-remitting multiple sclerosis-results from a -month, multicenter, open-label danish study factors affecting the adherence to disease-modifying therapy in patients with multiple sclerosis covid- in a ms patient treated with ocrelizumab: does immunosuppression have a protective role a sars-cov- protein interaction map reveals targets for drug repurposing an italian programme for covid- infection in multiple sclerosis ms treatment guidelines during coronavirus. national ms society the covid- pandemic and the use of ms disease-modifying therapies the financial contribution of the multiple sclerosis specialist we are grateful to our physician respondents for their time in completing the survey and zoomrx for donating their survey platform support to the study.funding this study was supported by an unrestricted investigatorinitiated grant from biogen, inc. conflicts of interest mr. alakel, ms. gazdag, and mr. kumar work for zoomrx. all other authors declare there are no conflicts of interest. the study was approved prior to commencement by the partners healthcare institutional review board. key: cord- -uhak t authors: woo, marcel s.; steins, david; häußler, vivien; kohsar, matin; haag, friedrich; elias-hamp, birte; heesen, christoph; lütgehetmann, marc; schulze zur wiesch, julian; friese, manuel a. title: control of sars-cov- infection in rituximab-treated neuroimmunological patients date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: uhak t nan dear sirs, individuals with autoimmune diseases, such as multiple sclerosis (ms) or neuromyelitis optica spectrum disorder (nmosd), that require long-term immunosuppression are regarded as particularly vulnerable in the current covid- pandemic [ ] . however, few details about the effect of individual immunotherapies have been reported, which could instruct us about the immunological control of severe acute respiratory syndrome coronavirus (sars-cov- ). specific antibodies are detectable within - days [ ] and have been extensively analyzed for diagnostic purposes [ ] and vaccine development [ ] . it is unclear whether a durable antibody response is required for recovery of covid- or whether it might even contribute to the pathogenesis by perpetuating hyperinflammation as has been shown for the closely related middle-east-respiratory-syndrome (mers) coronavirus [ ] . here, we report on two individuals with underlying neuroimmunological diseases who were under stable rituximab therapy-a b cell-depleting monoclonal antibody [ , ] -when confirmed covid- developed. infection with sars-cov- was verified in both cases by pcr. patient was a -year-old woman with a history of breast carcinoma, which was treated by breast-conserving surgery in and a relapsing-remitting ms (diagnosed ; edss . ) that has been treated with rituximab since (last infusion in january ). she was admitted with malaise, muscle ache, cough, fever and mild dyspnea, which first developed during a ski-trip in a high-risk area on march th, and she was tested positive ten days later. on the day of admission, she showed elevated inflammatory biomarkers (crp mg/l, interleukin- . ng/l, ferritin . µg/l), cardiac biomarkers (probnp ng/l) and d-dimers ( . mg/l) but normal procalcitonin (< . µg/l) and negative blood cultures. radiologic findings of bilateral infiltrations indicated atypical pneumonia. on the second day of admission sars-cov- rna was only detectable in pharyngeal swabs in low concentrations close to detection limit (ct . ). immunologically, she had normal lymphocyte counts ( . billion/ml) but absent b cells (not detectable, supplementary table ). serologically, we could not detect antibodies against sars-cov- igg. the patient was clinically and serologically stable and was discharged after four days of inpatient symptomatic treatment against fever into home quarantine. four weeks later, she electively visited our outpatient clinic and her pcr from a nasopharyngeal swab was now negative for sars-cov- rna. clinically, she was completely asymptomatic, and we did not observe neurological deterioration. serologically, she was still negative for antibodies against sars-cov- igg (fig. a) . a control x-ray of the chest showed a strong regression of pre-diagnosed bilateral pneumonic infiltrates. patient was a -year-old female with neuromyelitis optica spectrum disorder (nmosd, diagnosed , edss . ), who was directly admitted to our intensive care unit (icu) on march th, with progressive respiratory failure and infection of the urinary tract. she reported productive cough and anuria since the previous day. the patient was tested positive for sars-cov- by pcr on april th, (ct ). she had been receiving rituximab since and the last time in november . notably, the patient had well-treated hypothyroidism, myasthenia gravis in remission, well-adjusted insulin-dependent diabetes mellitus type , arterial hypertension, chronic obstructive pulmonary disease, obesity and has smoked daily cigarettes for more than years. on admission, inflammatory biomarkers (crp mg/l, interleukin- . ng/l), cardiac parameters (ck u/i, high sensitive troponin t pg/ ml, probnp ng/l) and d-dimers ( . mg/l) were elevated but procalcitonin ( . µg/l) was normal. radiologic findings included bilateral pneumonic infiltrates and pleural effusions. she had a b cell count of /µl (ref. - /µl, supplementary table ) at the day of admission and tested negative for sars-cov- -specific antibodies ( . au/ml; ref. < au/ml) on april th, , which converted to detectable antibodies on april th, ( . au/ml). during her stay at our icu she had a complicated disease course with bacterial superinfection and severe acute respiratory distress syndrome. she was intubated on april st, and subsequently received tracheotomy on april th, that was eventually removed on may th, after hemodynamic stabilization and decreasing infection parameters. other complications included pre-renal failure due to volume depletion that was treated by intermittent continuous veno-venous hemodialysis and absolute tachyarrhythmia that was terminated by treatment with amiodaron. the patient completely recovered and was submitted to regular ward on may th, . we did not observe a symptomatic exacerbation of her nmosd and she was discharged on may th, (fig. b) . in summary, we report on two patients who developed covid- while under treatment with rituximab due to neuroimmunological diseases. notably, their b cell count varied from non-detectable to markedly suppressed. we observed, that firstly only complete b cell depletion affected antibody response against sars-cov- and secondly, virologic control was possible in the absence of a detectable b cell response. thirdly, neither of the two patients showed a clinical deterioration of their underlying neurological condition during or after sars-cov- infection. thus, these two cases imply that immunological factors other than b cell-mediated antibody responses are required for covid- control. however, for individuals with b cell depletion uncertainty remains towards the robustness of viral control, the degree of immunity and risk of reinfection. an italian programme for covid- infection in multiple sclerosis antibody responses to sars-cov- in patients with covid- virological assessment of hospitalized patients with covid- developing covid- vaccines at pandemic speed molecular mechanism for antibody-dependent enhancement of coronavirus entry b-cell depletion with rituximab in relapsing-remitting multiple sclerosis safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (rin- study): a multicentre, randomised, double-blind, placebo-controlled trial acknowledgements open access funding provided by projekt deal. we thank members of the friese and schulze zur wiesch laboratories for discussions. we thank the uke covid- study group for their support. author contributions msw and ds conducted most of the data collection, interpretation and figure design. ds, vh, ch, beh, and mk were responsible for primary patient care. fh performed facs analysis. ml measured and analyzed antibodies against sars-cov- . msw, jszw and maf wrote the initial version of the manuscript. jszw and maf conceived, supervised and funded the study. all co-authors contributed to the editing and discussion of the manuscript and approved the final version. conflict of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. informed consent both patients gave written informed consent. consent to publish acquired from both patients.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -b ypt d authors: siepmann, timo; sedghi, annahita; barlinn, jessica; de with, katja; mirow, lutz; wolz, martin; gruenewald, thomas; helbig, sina; schroettner, percy; winzer, simon; von bonin, simone; moustafa, haidar; pallesen, lars-peder; rosengarten, bernhard; schubert, joerg; gueldner, andreas; spieth, peter; koch, thea; bornstein, stefan; reichmann, heinz; puetz, volker; barlinn, kristian title: association of history of cerebrovascular disease with severity of covid- date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: b ypt d objective: to determine whether a history of cerebrovascular disease (cvd) increases risk of severe coronavirus disease (covid- ). methods: in a retrospective multicenter study, we retrieved individual data from in-patients treated march to april , from covid- registries of three hospitals in saxony, germany. we also performed a systematic review and meta-analysis following prisma recommendations using pubmed, embase, cochrane library databases and bibliographies of identified papers (last search on april , ) and pooled data with those deriving from our multicenter study. of records identified, eligible observational studies of laboratory-confirmed covid- patients were included in quantitative data synthesis. risk ratios (rr) of severe covid- according to history of cvd were pooled using dersimonian and laird random effects model. between-study heterogeneity was assessed using cochran’s q and i -statistics. severity of covid- according to definitions applied in included studies was the main outcome. sensitivity analyses were conducted for clusters of studies with equal definitions of severity. results: pooled analysis included data from laboratory-confirmed covid- patients ( . % females, median age ranging from to years). patients with previous cvd had higher risk of severe covid- than those without [rr . , % confidence interval (ci) . – . ; p < . ]. this association was also observed in clusters of studies that defined severe manifestation of the disease by clinical parameters (rr . , % ci . – . ; p < . ), necessity of intensive care (rr . , % ci . – . ; p < . ) and in-hospital death (rr . , % ci . – . ; p < . ). conclusion: a history of cvd might constitute an important risk factor of unfavorable clinical course of covid- suggesting a need of tailored infection prevention and clinical management strategies for this population at risk. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. rapid transmission of the severe acute respiratory syndrome coronavirus (sars-cov- ) and a case fatality rate that is up to times higher than mortality of seasonal influenza make coronavirus disease a global threat [ , ] . the latter is largely explained by high risk of acute respiratory distress syndrome as well as sepsis, multi-organ failure and disseminated intravascular coagulopathy, which is most pronounced in the elderly and in premorbid patients with a cardiovascular risk profile [ , ] . in fact, patients with severe course of covid- have up to threefold higher rates of preexisting cardiovascular morbidity than patients with mild or moderate clinical manifestations [ ] . investigation of early cohorts of covid- patients in china focused on the effects of classic cardiovascular risk factors such as arterial hypertension and coronary heart disease or comorbidity in general [ , ] . by contrast, the importance of cerebrovascular disease (cvd) in the clinical course of covid- is poorly understood. this is a relevant research gap as patients with cvd are particularly vulnerable toward pulmonary and inflammatory complications due to their frequent disability [ , ] . at this stage of the pandemic, where overall comorbidity has been established as substantial risk factor, in-depth characterization of particularly endangered individuals might help design tailored infection prevention plans. therefore, we aimed to assess whether history of cvd is associated with severe covid- . to approach this question, we assessed individual multicenter data from three cohorts of covid- patients treated during the first months of the pandemic in germany. in order to assess consistency among regions and increase generalizability of our findings, we then went on to pool our data with published data of covid- patients who were being treated in wuhan and other regions in china. in a retrospective multicenter study, consecutive patients ≥ years with laboratory-confirmed diagnosis of covid- who have been admitted to the three participating hospitals (university hospital carl gustav carus dresden, klinikum chemnitz ggmbh, elblandklinikum meißen) in saxony, germany between march and april , were selected from the ongoing covid- registries. locations of participating hospitals are illustrated in fig. . laboratory tests for detection of sars-cov- included real-time reverse transcription polymerase chain reaction (rt-pcr) assays (realstar® sars-cov- rt-pcr kit ruo, altona diagnostics, hamburg, germany; allplex™ -ncov assay, seegene inc., seoul, republic of korea; genefindertm covid- plus realamp, osang healthcare co., gyeonggi-do, republic of korea) on respiratory specimen from nasal or oropharyngeal swab. we obtained data on age, sex and vascular comorbidities including arterial hypertension, hyperlipidemia, diabetes mellitus, atrial koch institute as of april , (www.rki.de/en/home/homep age_node.html). numbers in brackets refer to absolute numbers of patients included in the multicenter cohort fibrillation, coronary heart disease, tobacco use and past history of cvd. cerebrovascular disease was subdivided into ischemic stroke, transient ischemic attack and intracerebral hemorrhage. we also reviewed medical records and neuroimaging reports from cranial computed tomography or magnetic resonance imaging studies for evidence of previous clinically apparent or silent cvd. we detected one patient with evidence of previous lacunar stroke on cranial magnetic resonance imaging that was not diagnosed history of cvd and decided to include this patient in our analysis. in order to assess the association of past history of cvd and risk of severe clinical course of covid- , we aimed to classify all patients in our multicenter cohort into "severe" and "non-severe" covid- . however, previously published approaches to categorize severity of covid- were found to be inconsistent and all together three different most frequently reported approaches could be identified. in order to achieve comparability of outcome data with previously published cohorts, we separately applied these methods to dichotomize our patients into severe and non-severe clinical course of the disease. first, we classified severity of covid- in the patients of our multicenter cohort based on clinical parameters according to the classification by the national health commission guidelines on the diagnosis and treatment of covid- [ ] . in this classification, "mild" was defined as mild clinical symptoms with no signs of pneumonia on chest imaging; "moderate" as fever, respiratory symptoms with radiologic signs of pneumonia; "severe" as respiratory distress with respiratory rate ≥ per minute and/ or oxygen saturation at rest ≤ % and/or oxygenation index ≤ mmhg and/or progression of pulmonary lesion size > % within h, "critical" as respiratory failure requiring mechanical ventilation, hemodynamic shock, or any other organ failure with necessity of intensive care. we also categorized stages of disease by using the lean european open survey on sars-cov- infected patients (leoss) definition, comprising the following disease stages: "uncomplicated", asymptomatic or symptoms of upper respiratory tract infection, nausea, emesis, diarrhea, fever; "complicated", need for oxygen supplementation, partial arterial oxygen pressure at room air < mmhg, oxygen saturation at room air < %, aspartate aminotransferase or alanine aminotransferase > -fold upper limit normal, new cardiac arrhythmias, new pericardial effusion > cm, new heart failure with pulmonary edema, congestive hepatopathy or peripheral edema; "critical", need for catecholamines, life-threatening cardiac arrhythmia, invasive or non-invasive mechanical ventilation, liver failure with < % quick value (equaling approximately > . international normalized ratio), quick sequential [sepsis-related] organ failure-assessment score ≥ , renal failure in need of dialysis; "recovery", improvement by one phase and defervescence [ ] . second, severity of covid- was also dichotomized for in-hospital death versus survival with death equaling severe and survival indicating non-severe course. third, patients were classified into severe or nonsevere clinical course of covid- based on whether they required intensive care unit (icu) treatment or underwent regular in-patient care until discharge. this systematic review and meta-analysis complied with the preferred reporting items for systematic reviews and meta-analyses (prisma) recommendations [ ] . we systematically searched electronic databases including medline (accessed by pubmed), embase and cochrane library for identification of all available observational studies that reported on laboratory-confirmed covid- patients aged ≥ years with information given on disease severity and past history of cvd. in addition, bibliographies of identified full-text articles and those of relevant review articles were searched manually. in order to be exhaustive, we limited our search on electronic databases to search term "covid- " with combinations of associated medical subject headings (mesh) "covid- ", "severe acute respiratory syndrome coronavirus ", " -ncov", "sars-cov- ", " ncov", "wuhan", "coronavirus", " / ". the complete search algorithm is provided in online resource . our systematic search covered publications from the earliest date available until our last search date april , . no language or other restrictions were imposed. all identified articles were screened using the following eligibility criteria: ( ) observational cohorts consisting of a minimum of five patients ≥ years who have been hospitalized for covid- laboratory-confirmed by nasal or oropharyngeal swab rt-pcr; ( ) data available on past history of cvd; ( ) categorization of covid- severity according to studyspecific outcome definitions. assessment of identified articles involved three steps: screening of titles, abstracts and full texts by two independent reviewers (t.s. and k.b.). any disagreements were resolved by consensus. abstracts that did not provide sufficient information for analysis of methodology were subject to full-text evaluation. in case of missing information or any obscurities, the corresponding authors of the identified articles were contacted for clarification. two reviewers (t.s. and k.b.) independently extracted data on included studies from the full-text articles with insertion into a standardized data extraction form (excel, microsoft, redmond, wa, usa). extracted variables were first author, publication year, study design, sample size, demographic values, vascular comorbidities including history of cvd as well as definition of severity outcomes of covid- and respective absolute numbers of outcome events. we used the oxford centre for evidence-based medicine rating scale to assess the quality of evidence in the included individual studies [ ] . quality assessment was independently performed by two investigators (t.s. and k.b.) and disagreements were resolved by consensus. in the multicenter study, continuous and non-continuous variables are presented as median with interquartile range (iqr) for skewed data and percentages for proportional data. between-group comparisons were performed using chi-square test, fisher's exact test and mann-whitney u test, where applicable. multivariable logistic regression was performed to explore the predictive value of history of cvd for severity outcomes of covid- including clinical severity according to the classification by the national health commission guidelines on the diagnosis and treatment of covid- , in-hospital death and necessity of intensive care [ ]. candidate variables were identified from the betweengroup comparisons, whereas a p value of ≤ . was used for covariate inclusion in the multivariable model. the final model was conducted using a backward selection procedure, whereas covariates with a p value < . were removed from the model. in the quantitative data synthesis, risk ratios (rr) and their corresponding % confidence intervals ( % ci) for history of cvd were calculated from the absolute numbers of patients with severe and non-severe covid- outcomes as provided by each study. in our main analysis, we used a composite dichotomized outcome of severity subsuming all severity outcomes that were reported by each of the included studies comprising severity based on clinical parameters, in-hospital death versus survival and necessity of intensive care versus regular in-patient care. if included studies classified severity outcome based on clinical parameters into more than two categories (e.g., mild, moderate, severe, critical), those were subsumed under severe (i.e., severe and critical) and non-severe (i.e., mild and moderate) categories. thus, in our main analysis, all patients reported in studies identified from literature search cohort were classified into severe or non-severe covid- based on the classification used by each study. with respect to our multicenter study, we chose to apply the approach of defining severity by clinical parameters as recommended by the national health commission guidelines on the diagnosis and treatment of covid- since this tended to be the most widely acknowledged method in the literature [ ] . continuity correction of . was used for studies with a zero cell [ ] . if a study reported two or more zero-cell events, it was excluded from respective analysis. dersimonian and laird random effects model was used to compute the pooled rr for included studies. [ ] in order to allow separate assessment of clusters of studies with equal definitions of covid- in conjunction with our multicenter data, sensitivity analyses were conducted for severity outcomes. we clustered studies that used the same approach to define severity and pooled these data with our multicenter data by applying the same severity definition to our local cohorts. analyses were carried out for three clusters of studies: first, studies defining severity based on clinical parameters; second, studies defining severity based on necessity of intensive care; third, those defining severity by in-hospital death. assuming that only available cases with complete data on disease severity outcomes were reported in included studies, pairwise deletion method was used to handle missing outcome data. between-study heterogeneity was assessed using cochran's q test and i statistics, where i values of - % indicated absent or low, - % moderate, - % substantial and - % considerable heterogeneity [ ] . significance level of heterogeneity was set at p < . . publication bias was assessed by visual inspection of funnel plot and egger's linear regression test. statistical significance was set at p < . . all statistical analyses were conducted using stata software package (version . , statacorp., college station, tx). during the observational period from march to april , , patients ( . % females, median age [ - ]) with laboratory-confirmed covid- have been admitted to participating hospitals. two patients were still hospitalized at the time of data analysis. overall, of ( . %) patients showed severe or critical clinical course with necessity of icu treatment in of ( . %) patients and inhospital death in of ( . %) patients. in the entire multicenter cohort, a history of cvd was evident in ( . %) patients with higher frequencies in patients with severe course of covid- when applying the national health commission guidelines on the diagnosis and treatment of covid- with dichotomized severity categories subsuming categories mild, moderate in "non-severe" and categories severe and critical into "severe". ( . % vs. . %, p = . ) [ ] . a history of cvd was also found to be more frequent in patients with severe covid- when severity was defined by necessity of intensive care vs. regular in-patient care ( . % vs. . %, p = . ) and in-hospital death vs. survival ( % vs. . %, p = . ). a detailed description of demographic values, comorbidities and outcomes is shown in table . in multivariable analysis adjusting for selected covariates (i.e., age, sex, arterial hypertension and diabetes mellitus), past history of cvd emerged as an independent predictor of severity of covid- when severity was defined by necessity of icu treatment (adjusted rr . ; % ci . - . ; p = . ), but not by clinical severity (p = . ) or in-hospital death (p = . ). a total of abstracts were retrieved from electronic databases and from bibliographies of published literature. after exclusion of duplicates and articles that did not fulfill eligibility criteria, studies comprising laboratoryconfirmed covid- patients ( . % females, median ages ranging from to years) were included in quantitative data synthesis as described in detail in table [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the flowchart showing systematic screening and selection process is depicted in figure . all studies included patients from china and were of descriptive observational design. in order to avoid overlapping patient populations, we excluded two multicentric reports on chinese cohorts from our quantitative synthesis because they partially comprised data from the same hospitals that were reported by other studies included in our analyses [ , ] . none of the included studies reported by what criteria history of cvd was defined. seven studies reported severity outcomes based on in-hospital death (n = ) [ , , [ ] [ ] [ ] [ ] or necessity of intensive care (n = ) [ , ] , whereas three studies [ , , ] categorized clinical course of covid- into "severe" and "non-severe" based on the national health commission guidelines on the diagnosis and treatment of covid- [ ]. one study defined severity by length of hospitalization with a cut-off of days [ ] . overall distribution of demographic data and vascular risk profiles among these studies was highly congruent with data from our local german multicenter cohort with relatively high frequencies of preexisting vascular risk factors, high ranges of median ages and a rather balanced male-to-female ratio. characteristics of included studies are detailed in table . pooled analysis including individual patient data from our multicenter cohort consisted of laboratoryconfirmed covid- patients ( . % females, median age ranging from to years). patients with a history of cvd had higher risk of severe covid- than those without (rr . , % ci . - . ; p < . ) when using a composite dichotomized outcome of severity subsuming all severity outcomes that were reported by each of the included studies. we noted substantial heterogeneity between studies (i = %, p = . , figure ). consistently, an increased risk of severe covid- in of these, evidence of low heterogeneity was observed for the icu/non-icu cluster (i = . %, p = . ), whereas no heterogeneity was noted for the clinical parameters cluster (i = %, p = . ) nor the in-hospital death cluster (i = . %, p = . ). when considering only published data from chinese cohorts in pooled analysis (n = ), history of cvd was also associated with increased risk of severity of covid- (rr . , % ci . - . ; p < . ) with similar results on sensitivity analyses for study-specific severity outcomes (clinical parameters: rr . , % ci . - . ; p = . ; necessity of intensive care: rr . , % ci . - . ; p < . and in-hospital death: rr . , % ci . - . ; p < . ). while there was evidence of moderate between-study heterogeneity for additional analyses of the icu/non-icu cluster (i = . %, p = . ), only low or absent heterogeneity was observed for the composite (i = . %; p = . ), clinical severity (i = %; p = . ) and in-hospital death (i = . %; p = . ) outcome clusters. according to oxford centre for evidence-based medicine rating scale quality, all included studies from published literature were consistently graded as level of evidence . visual inspection of funnel plot showed symmetry in both studies plotted near the average, and those more distant from the average depending on their precision, thus shaping a distribution which is not suggestive of publication bias ( figure ). no small study effect was seen on egger's linear regression test (p = . ). the major finding of our multicenter study is that a history of cvd is associated with an increased risk of developing severe course of covid- . this observation was consistent among pooled data which included descriptive observational studies from china during the rise of the pandemic and individual multicenter patient data from the first few months after the local outbreak in germany. a strength of our analysis is that we synthesized data from two countries both hit heavily by the pandemic and both showing consistent findings in our analyses with respect to association of history of cvd and measures fig. flowchart on identification of studies on covid- eligible for quantitative data synthesis. prisma flowchart illustrating systematic screening and selection process of published observational studies reporting on laboratory-confirmed covid- patients with data available on disease severity and past history of cvd of severity of covid- . furthermore, data on distribution of demographic values as well as additional vascular comorbidities and their association with severity of covid- was highly congruent between the german multicenter cohort and chinese cohorts [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in particular, patients with severe covid- were older, more frequently male and more often have had a history of arterial hypertension or diabetes. consistency of our observations is also reflected by low evidence of heterogeneity among studies with equal severity outcomes indicating probable generalizability to other populations. another strength of our synthesized analysis is the strict exclusion of overlapping study populations, which is especially important during the early phase of the pandemic where multiple descriptive studies were simultaneously derived from the ground zero region of hubei, china. while an urgent need for data on the covid- pandemic is apparent, it is important to reduce potential sources of bias that might skew pooled effect estimates [ ] . our study is limited by variance in definitions used for severity of covid- among studies extracted from the literature. however, risk factor association for history of cvd found in pooled analysis using a composite severity outcome subsuming all study-specific outcomes was consistent with those deriving from individual sensitivity analysis of clusters of studies that applied the same definition of severity. furthermore, data synthesized from the literature was limited by lack of explanation of how cvd was defined and therefore could not be analyzed regarding different types of cerebrovascular pathology in the context of covid- prognosis. in our multicenter cohort, the majority of previous cerebrovascular accidents that led to being classified as history of cvd were ischemic and only one of patients had previous intracerebral hemorrhage. whether etiology of previous cvd relates to risk of covid- severity requires further investigation. data on pre-existing pulmonary disease were not available to an extent that would have allowed a separate analysis on how this might have influenced the observed association between a history of cvd and severity of covid- . lastly, the association of past history of stroke and covid- severity was dependent on cardiovascular risk profile on multivariable analysis in our multicenter cohort when severity was classified using clinical parameters or inhospital death versus survival. however, severity defined as necessity of intensive care showed an independent association with history of stroke. this might be explained by differences in disease progression at the time of admission due to pulmonary vulnerability of stroke survivors [ , ] . however, it needs to be acknowledged that we were not able to perform a multivariate analysis in the cohorts identified through literature research as individual patient data were not available. therefore, the actual number of patients who have had an actual history of cvd included in our multicenter cohort was relatively small (n = ). moreover, individual descriptions of standardized critical care admission approaches among hospitals providing data to our multicenter analyses and those included in studies extracted from the literature were not consistently available. therefore, a possible independency of the link between past history of cvd and covid- severity requires further investigation. this analysis should be undertaken in cohorts with individual patient data available, preferably in the setting of a prospective observational study. since the outbreak of the pandemic, the impact of comorbidities on prognosis of covid- has been extensively discussed with cardiovascular pathologies in the spotlight [ ] . in particular, recent research has focused on traditional cardiovascular risk factors such as arterial hypertension and diabetes mellitus as predictors of disease severity [ , , ] . however, it might be important to take a closer look into pre-existing brain vascular pathology of covid- patients for several reasons. first, cvd is the leading cause of longterm acquired disability which increases the risk of pulmonary complications such as pneumonia [ , , ] . while this association is not specific for infection caused by sars-cov- , it might partly explain why in our analysis patients with a history of cvd displayed a higher risk of severe course of covid- , which is considered a primarily respiratory disease [ ] . second, accumulative evidence suggests that sars-cov- targets the central nervous system and may manifest with various neurological symptoms that might either be caused by direct neural damage or by neurovascular accident such as acute ischemic stroke [ ] . from a pathophysiological perspective, sars-cov- appears to increase risk of cardiovascular events, possibly mediated by systemic inflammation compromising functional and structural integrity of the vasculature by inflammatory injury of the endothelium and increasing blood coagulability [ ] . in patients, who already had experienced a cerebrovascular accident, brain vasculature might be at increased vulnerability toward these mechanisms. lastly, patients with a history of cvd frequently have cardiovascular comorbidities that fig. association of history of cerebrovascular disease and severe clinical manifestation of covid- among included studies. forest plots illustrating associations of history of cvd and severe clinical manifestation of covid- for composite severity outcome subsuming all definitions of severity as reported by included studies (a) as well as for clusters of studies defining severity by grading of clinical parameters (b), whether patients required intensive care (c), and inhospital death (d). composite outcome analysis as well as assessment of each cluster included only studies that have not shown any overlap in study populations during full text evaluation. individual patient data from german multicenter cohort were evaluated for severity based on the chinese clinical guidance for covid- pneumonia diagnosis and treatment ◂ in turn might worsen prognosis of patients suffering from covid- [ , ] . identification of populations at risk is one of the key factors in containing spread and reducing health care burden in epidemics [ ] . this is even more important in a pandemic like covid- where neither effective antiviral treatment nor vaccine is yet available to allow broad or targeted immunization of individuals at risk. in this context, knowing that a history of cvd increases risk of developing more severe disease manifestation upon infection with sars-cov- , viewed in conjunction with previous data on comorbidityrelated risk factor associations might be useful in designing risk-adapted prevention strategies. individuals who have a history of cvd are more likely to develop severe manifestation of covid- . consistency among results in our pooled analyses indicates that this observation is generalizable beyond the studied regions in china and germany. however, it remains to be answered whether the increased risk of severity observed in covid- patients included in our analyses can be explained by a past history of cvd per se or simply reflects the additive effects of concomitant cardiovascular risk factors. anonymized data will be shared by request from any qualified investigator. clinical characteristics of coronavirus disease in china word health organization ( ) coronavirus disease (covid- ) situation report- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china. a retrospective cohort study cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease (covid- ) pandemic covid- and the cardiovascular system cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study long-term neurological, vascular, and mortality outcomes after stroke one-year risk of pneumonia and mortality in patients with poststroke dysphagia: a nationwide population-based study assessment of publication bias. visual inspection of funnel plot is not indicative of publication bias . national health commission ( ) chinese clinical guidance for covid- pneumonia diagnosis and treatment escmid emerging infections task force ( ) lean european survey on sars-cov- preferred 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potentially modifiable risk factors associated with acute stroke in countries (interstroke): a case-control study managing epidemics: key facts about major deadly diseases. geneva: world health organization acknowledgements open access funding provided by projekt deal.funding none. ethical standards this study was approved by the institutional review board of technical university dresden (irb number bo-ek- ). since data were retrieved from ongoing registries informed consent was waived.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- - wpx bd authors: pelea, teodor; reuter, ursula; schmidt, christine; laubinger, raimondo; siegmund, robert; walther, bjoern wito title: sars-cov- associated guillain–barré syndrome date: - - journal: j neurol doi: . /s - - -w sha: doc_id: cord_uid: wpx bd presented herein is a severe case of sars-cov- associated guillain–barré syndrome (gbs), showing only slight improvement despite adequate therapy. to date, only few cases of gbs associated with this infection have been described. this case report summarizes the insights gain so far to gbs with this antecedent trigger. so far, attention has mostly focused on complications of the cns involvement. taking into account that gbs can cause a considerable impairment of the respiratory system, clinicians dealing with sars-cov- positive-tested patients should pay attention to symptoms of the peripheral nervous system. as far as we know from this reported case and the review of the current literature, there seems to be no association with antiganglioside antibodies or a positive sars-cov- rt-pcr in csf. an obvious frequent occurrence of a bilateral facial weakness or bilateral peripheral facial diplegia should be emphasized. neurological symptoms associated with coronavirus (cov) studies have shown that these viruses have neuro-invasive and neurotrophic characteristics [ ] . the infections with cov can affect the nervous system [ ] . . % among hospitalized patients infected with covid- have reported neurological symptoms. [ ] . the authors describe nervous system-associated symptoms as including dizziness, headache, hypogeusia, hyposmia, muscle damage, and ischemic and hemorrhagic stroke [ ] . the current hypothesis is that cov, together with the host immune mechanisms, may turn these infections into persistent infections that affect also neurological structures. first of all, central nervous system (cns) involvement is assumed. pathogenesis of nervous system injury caused by cov includes acute cerebrovascular diseases, toxic encephalopathy and viral encephalitis [ ] . the peripheral nervous system seems not to be affected by a direct virus-mediated pathway. gbs is an acute immunemediated disease of the peripheral nerves and nerve roots that is usually elicited by various infections [ ] . the diagnosis should be based on the diagnostic criteria of asbury and cornblath [ ] . respiratory tract or gastrointestinal infections, up to - weeks prior to the onset of neurological symptoms of gbs, have been reported by - % of the affected patients [ , ] . cov infections can cause multiple systemic infections. respiratory complications are the most recognizable symptoms, similar to severe acute respiratory syndrome coronavirus (sars-cov). pulmonary disorder and respiratory insufficiency are the main problems linked to the actual present pandemic, sars-cov- infection [ ] . after an incubation period of approximately . days, the prevailing symptoms include fever, cough, dyspnea, myalgia, headache, and diarrhea [ ] . therefore patients with sars-cov- infection are at risk of being affected by coincident immune-mediated neurological diseases such as gbs. a -year-old caucasian woman with a medical history of mild arterial hypertension (valsartan mg) and hypothyreosis (l-thyroxin µg) suffers from a dry cough, mild fever and a general weakness. in the context of the covid- pandemic, sars-cov- rt-pcr on nasopharyngeal swab was performed and tested positive. a quarantine at home was decreed. the presumed contact to an infected person has been days before the first symptoms appeared. seven days later, she noticed weakness of her limbs while climbing stairs and a tingling sensation in all fingertips and toes. she was admitted to our emergency department days after the occurrence of these neurological symptoms. on physical examination, the patient was afebrile with blood pressure at / mmhg, heart rate of beats/min, respiratory rate at /min, and oxygen saturation of % on room air. she was conscious and had no dyspnea at the time of hospitalization. the neurological examination showed no meningeal irritation signs or abnormalities in the cranial nerve status. the muscle strength examination showed paresis in four limbs with a medical research council (mrc) scale of / in the proximal, / in the distal upper extremities, / in the proximal, and / in distal in the lower extremities. deep tendon reflexes were generally absent and there were no signs of upper motor neuron disorder. there was a reduction in the vibration of the knees from / in the hz tuning fork test, and fine touch sensation was bilateral stocking shaped. there was no spine sensory level. meningeal irritation signs and upper motor neuron disorder signs were negative. the laboratory results were as follows: white blood cell count , cells per microliter (neutrophils = . %; lymphocytes = . %), fibrinogen . g/l, c-reactive protein < mg/l, hemoglobin . g/dl, serum glucose . mmol/l, and further normal results for blood urea nitrogen, creatinine, alat, asat, ldh, ggt, sodium, potassium, inr, ptt, igg, iga, igm, and complete urinalysis. anti-ganglioside antibodies (gm -, gq b-antibodies) were absent. the analysis of cerebrospinal fluid (csf) showed a cell count of mpt/l (lymphocytes and monocytes), protein of . g/l, glucose . mmol/l and lactate . mmol/l, and no oligoclonal bands. the sars-cov- rt-pcr in csf was performed and tested negative. biological tests were not in favor of a recent infection with borrelia, treponema pallidum, campylobacter jejuni, mycoplasma, ebv, hsv or , and hepatitis e. a ct scan of the brain and mri of the spine showed no abnormalities. lung ct at admission showed leaky infiltrates in the right lower lobe, at the tip and dorsally; infiltrates most likely began in the dorsal left in the lower lobe, increased, with maximum mm paratracheal and infracarinal lymph nodes. the patient was admitted to icu and further treatment was carried out in strict compliance with the isolation measures. our patient received pph every days, and there was a clinical deterioration in spite of this treatment during the first days. the patient developed a flaccid, severe tetraparesis of / in the proximal, / in the distal of the upper extremities and / in the proximal and / in the distal of the lower extremities for dorsal extension, / for flexion, a trunk instability, and also bilateral peripheral facial nerve palsy (house-brackmann grade ). there were autonomous symptoms with a tachycardic heart action until /min and a severe orthostatic dysregulation, with no further possibility of sitting upright. she showed a tendency for clinical improvement after the third course of pph. seven courses of pph were performed. the pph caused a slightly further clinical improvement with asymmetrical improvement of facial paresis and tetraparesis, but a clinical stagnation of the improvement during the following days. the patient was still unable to sit upright because of orthostatic collapsing and trunk instability. therefore, we added days after the last pph . g/kg/day intravenous immune globulins for a duration of days. we performed the neurophysiological study and nerve sonography only on day according to the isolation requirements. nerve sonography, as a painless technique for bedside-imaging nerve pathology, demonstrated a hypoechoic ultrasonographic cervical spinal nerve enlargement. the cross-sectional area of the c root was measured as mm and c root as mm . enlarged cervical spinal and peripheral nerves detected by ultrasound were identified as an early marker for guillain-barré syndrome [ ] . electroneurographic parameters demonstrate the typical delay of distal motor latency, and f-wave latency and decrease of conduction velocity, as well as decreased amplitudes at compound muscle action potential. there was mild decrease of conduction velocity of sensory nerve action potential changes at the arm nerves. the findings are basically consistent with acute motor accented and axonal demyelinating neuropathy (table ) . there was no fever or respiratory complaints over the time. further treatment was given in the intermediate care unit, but there was only a slight clinical improvement over the next few days. the clinical course up to the time of transfer to a rehabilitation facility and the eletroneurographic findings with evidence of an axonal motor damage can indicate a complicated course with a prolonged and possible defective healing. only one case series [ ] and a few case reports [ , ] show an association between sars-cov- infection and gbs. the presented well-documented case report shows all characteristics of a typical, but severe, course of gbs. the association with the sars-cov- infection in the present case is without a doubt because of the strict time connection. the clinical course regarding the covid disease and the respiratory symptoms was uncomplicated. the main complaint was the neurological complication with gbs. severe course of gbs-associated sars-cov- infections occur also in patients with mild respiratory symptoms, but must be taken into account with seriously ill cases. with covid- disease due to a general impairment, the neurological symptoms can be easily overlooked. since gbs can cause or exacerbate respiratory symptoms, it should take into account the suspect courses of covid . it would be helpful if clinical, paraclinical, or electrophysiological findings were found that would facilitate the diagnosis of gbs. to date, the previously described courses of the sars-cov- infection-associated gbs do not describe a special clinical pattern. to date, available references summarizing the following points include a total of nine published cases. a remarkable clinical pattern in our case was that there was bilateral peripheral facial nerve palsy. this clinical symptom has been reported in one other case report [ ] and / cases in the italian series reported a facial diplegia in one case and facial weakness in two cases [ ] . therefore, we can describe a bilateral facial involvement in five out of nine patients ( . %) and a documented bilateral facial diplegia in / patients ( , %). facial nerve involvement in gbs is a common finding in - % [ ] . there are no data available for a bilateral seventh nerve involvement in gbs. estimated data reported up to - % [ ] . the csf parameters show no specific pattern. the sars-cov- rt-pcr in csf was performed in our patient and in the italian series of five patients [ ] and was negative in all cases. antiganglioside antibodies (gm -, gq b-antibodies) may indicate special gbs subtypes. they were analyzed in our case and three out of five in the italian series [ ] tested negative. nerve conduction studies have been performed in our case and two other case reports [ , ] . an axonal affection pattern is reported in two out of three cases. except for the presented case, the clinical course of the other cases is not well documented. so the data do not allow a discussion over a prognostic value of the present electrophysiological data. so far, attention has mostly focused on complications of the cns involvement. taking into account that gbs can cause a considerable impairment of the respiratory system, clinicians dealing with sars-cov- positive-tested patients should have to pay attention to symptoms of the peripheral nervous system. as far as we know from these few reported cases, there seems to be no association with antiganglioside antibodies or a positive sars-cov- rt-pcr in csf. the occurrence of a bilateral facial weakness or bilateral peripheral facial diplegia should be emphasized. this finding and the appearance of specific electrophysiological pattern should be shown in further investigations. acknowledgments open access funding provided by projekt deal.compliance with ethical standards the authors declare that they have no conflict of interest. the patient concerned has given their consent to the publication of the data. details that might disclose the identity of the subjects under study have been omitted. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons. org/licenses/by/ . /. nervous system involvement after infection with covid- and other coronaviruses neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study guillain-barré syndrome assessment of current diagnostic criteria for guillain-barré syndrome the spectrum of antecedent infections in guillain-barré syndrome: a case-control study clinical features of patients infected with novel coronavirus in wuhan ultrasound and electrophysiologic findings in patients with guillain-barré syndrome at disease onset and over a period of months guillain-barré syndrome associated with sars-cov- guillain barre syndrome associated with covid- infection: a case report guillain-barré syndrome associated with sarscov- infection: causality or coincidence? guillain-barré syndrome associated with sars-cov- infection the facial nerve, chapter key: cord- -t hyfum authors: rifino, nicola; censori, bruno; agazzi, emanuela; alimonti, dario; bonito, virginio; camera, giorgia; conti, marta zaffira; foresti, camillo; frigeni, barbara; gerevini, simonetta; grimoldi, maria; la gioia, sara; partziguian, tania; quadri, stefano; riva, riccardo; servalli, maria cristina; sgarzi, manlio; storti, benedetta; vedovello, marcella; venturelli, elisabetta; viganò, martina; callegaro, annapaola; arosio, marco; sessa, maria title: neurologic manifestations in covid- patients admitted to papa giovanni xxiii hospital, bergamo, italy date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: t hyfum objectives: evidences from either small series or spontaneous reporting are accumulating that sars-cov- involves the nervous systems. the aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of covid- patients. methods: retrospective, observational analysis on all covid- patients admitted from february rd to april th, to asst papa giovanni xxiii, bergamo, italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. each identified neurologic complication was then classified into main neurologic categories. results: of covid- patients, presented neurologic manifestations that manifested after covid- symptoms in pts and was the presenting symptom in . neurological manifestations were classified as: (a) cerebrovascular disease [ pts ( . %)] including ischemic and haemorrhagic strokes, transient ischemic attacks, cerebral venous thrombosis; (b) peripheral nervous system diseases [ ( . %)] including guillain–barrè syndromes; (c) altered mental status [ ( . %)] including one necrotizing encephalitis and cases with rt-pcr detection of sars-cov- rna in csf; (d) miscellaneous disorders, among whom patients with myelopathy associated with ab anti-sars-cov- in csf. patients with peripheral nervous system involvement had more frequently severe ards compared to patients with cerebrovascular disease ( . % vs %; difference = . % % ci . – . ; χ( )= . ; p < . ) and with altered mental status ( . % vs . %; difference = . % % ci . – . %; χ( )= . ; p < . ). conclusion: this study confirms that involvement of nervous system is common in sars-cov- infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies. in december , an outbreak caused by a novel coronavirus ( -ncov), now named severe acute respiratory syndrome coronavirus (sars-cov- ), occurred in china and has rapidly spread all over the world causing a pandemic. the disease caused by sars-cov- was named covid- [ ] . in europe, the first case was reported in the lombardy region. although soon after all italian regions reported patients with covid- , the highest number of cases was in eastern lombardy [ ] , specifically in the bergamo's province with , confirmed covid- patients up to april th [ ] . the typical spectrum of disease severity of sars-cov- infection is highly variable, ranging from asymptomatic carriers to severe acute respiratory distress syndrome (ards) leading to death. with the increasing number of confirmed cases and the accumulating clinical data, it is now well established that, in addition to the predominant respiratory symptoms, a significant proportion of patients has neurological manifestations [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . despite available studies have drawn attention to the neurological component of sars-cov- infection and provide detailed description of the neurological complications, they still have limitations. data were collected either from limited or selected cohorts, and in the only nation-based study, case notification was on voluntary basis; diagnosis was mainly based on patient's description as cerebrospinal fluid analysis and instrumental examinations were avoided in order to reduce the risk of cross infection [ ] . moreover, scarce information regarding the impact of the neurologic involvement on clinical outcomes are available. here, we describe the neurologic manifestations observed in patients among patients with laboratory or radiology-confirmed diagnosis of covid- , admitted to the asst papa giovanni xxiii in bergamo, in the epicentre of italian pandemic, between february rd and april th, . we provide an extensive overview on the different neurological complications involving both central (cns) and peripheral (pns) nervous system, and on their impact on outcome. the present study is a retrospective, observational analysis conducted at asst papa giovanni xxiii on all adult patients of both sexes, with confirmed covid- disease, admitted from february rd to april th, . our hospital was designated to treat patients with sars-cov- infection. within a few days from the beginning of the outbreak, % of beds were reconverted to covid- patients and % staff doctors, regardless of their specialty, were redeployed to covid- units. we evaluated all neurological consultations/neurophysiological assessments/ neuroradiologic investigations requested for covid- patients during hospitalization. we included in our analysis the following main diagnosis/syndromes: (a) cerebrovascular diseases (cvd) including ischemic and haemorrhagic stroke, transient ischemic attack, and cerebral venous thrombosis, (b) altered mental status including encephalitis/ meningitis/meningo-encephalitis, (c) peripheral nervous system disorders including guillain-barrè syndromes (gbs), critical illness myopathy and neuropathy (crimyne), plexopathies and peripheral polyneuropathies. a few additional patients presenting symptoms/signs that did not fit these categories were classified as miscellaneous. wherever possible, informed consent was collected verbally. however, in most cases, due to the inability to provide informed consent by the patient or the inability to collect it in compliance with the contagion prevention measures, the principle of secondary use of data was used in accordance with art. , paragraph , letter b) of the november th, law, n. , included in the legislative decree / of art. -bis. the institutional review board at asst papa giovanni xxiii provided approval for the study ( / , / / ). demographic (age, sex), comorbidities (hypertension, diabetes, dyslipidemia, atrial fibrillation, peripheral artery disease, cardiac disease or cvd, malignancy, dementia and lung disease), onset of neurological symptoms (before, concomitant, after covid- onset), severity of ards according to the horowitz index, clinical, laboratory and imaging data were extracted from medical records using a standardized anonymized data collection form by study physicians (nr, ms, sg). covid- diagnosis was confirmed: ( ) by real-time reverse-transcriptase polymerase-chain-reaction (rt-pcr) on nasopharyngeal specimens [ ] ; or ( ) by rt-pcr on bronchoalveolar lavage (bal) obtained by bronchoscopy in case of high clinical suspicion of sars-cov- infection and negative test results on at least two nasopharyngeal swabs performed at least h apart; or ( ) in the presence of characteristic radiological interstitial pneumonia associated with typical symptoms (fever, dry cough, dyspnea), even with negative rt-pcr, with no other possible aetiologic explanation. the neurology department was reconverted to neuro-covid with neurologists specifically dedicated and supported by a team of infectious disease specialists, pneumologists and intensivists. in addition, other staff neurologists were dedicated to the emergency department and consultations in all the other covid wards. patients complaining of neurological symptoms were evaluated by means of standard neurological examinations, neurophysiological exams including electroencephalography (eeg), evoked potentials (ep), electroneurographic and electromyographic recordings (eng-emg), and brain computerized tomography (ct) and/or magnetic resonance (mr) according to standard care. cerebrospinal fluid (csf) examination, when performed, included protein and glucose levels, cell count, cytological evaluation, research for bacteria and common neurotropic viral agents (herpes simplex - , varicella zoster, cytomegalovirus, epstein barr and human herpes virus ) and for sars-cov- genome by real-time pcr, cobas ® sars-cov- test (roche) and by genefinder covid- (elitech group). ab anti-sars-cov- on serum and csf were tested by vivadiagtm covid- igm/igg immunochromatographic assay from vivachektm biotech (china), performed according to manufacturer's instructions. frequencies were compared by means of the χ test with yates' correction. continuous variables were compared by means of the wilcoxon rank sum test. because of multiple comparisons, the significance level was set at . . from february rd to april th, a total of covid- patients were admitted to asst papa giovanni xxiii and either discharged ( ) or still hospitalized ( ). among them, ( . %) developed symptoms/signs of cns/pns involvement. table shows the observed neurological complications. the more represented neurological manifestations fell into the following three categories: cvd ( patients; . %), pns diseases ( patients; . %), altered mental status ( patients; . %). their average age was . ± . (range - years); % of the patients were female. the most frequent comorbidity was hypertension (in pts; . %); diabetes was present in pts ( . %), dyslipidemia in ( . %), cardiovascular disease in ( . %), malignancy in ( . %), pulmonary disease in ( . %), and previous neurological disease in ( . %). the average number of comorbidities was . . in patients ( . %), diagnosis of sars-cov- infection was made by rt-pcr from pharyngeal swab; in the remaining ( . %) patients with a negative swab, diagnosis was formulated in the presence of characteristic radiological interstitial pneumonia associated with typical symptoms, in some cases confirmed by positive bal. pao /fio ratio was available at admission in / pts. sixty-nine patients ( . %) had a moderate or severe ards (pao /fio ratio lower than ) according to the horowitz index. fifty-five patients ( . %) required admission to intensive care unit (icu). icu admission was significantly more frequent in patients with a moderate/ severe lung injury compared to those with a non-severe respiratory distress ( . % vs . %; diff. . %- % ci . - . ; χ = . ; p < . ). the neurological complication was the presenting symptom in patients, of whom never manifested fever and there was a trend versus higher mortality in patients with cvd when compared to patients with pns involvement ( . % vs . %; χ = . ; p < . ), but not when compared to patients with altered mental status ( . % vs . %; χ = . ; ns). however, in the multivariable analysis that included age as a covariate, mortality was not significantly associated with any neurological group (data not shown). a -year-old woman with a history of hypertension, ischemic cardiomyopathy, mechanical aortic valve replacement in anticoagulant therapy, and recent hospitalization for sars-cov- infection was readmitted to the emergency department (ed) for acute onset of left sensorimotor hemiparesis and dysarthria (nihss ). pharyngeal swab for sars-cov- was negative. chest radiography showed evidence of previous bilateral interstitial pneumonia. brain ct scan was normal; ct-angiography revealed a thrombus in her basilar apex. intravenous alteplase was administered followed by mechanical thrombectomy with excellent angiographic (tici ) and clinical outcome (nihss ). the following day, for the acute onset of left hemiplegia, hypoesthesia and dysarthria, a brain and angio-ct was repeated showing occlusion of the m segment of right mca. thrombectomy was successfully performed. an additional pharyngeal swab for sars-cov was positive. cardiological investigations were unremarkable. the patient was discharged home at day fully recovered. forty-nine patients manifested disturbances of vigilance and/or consciousness. all performed either ct scan or brain mri. twenty-one pts underwent csf analysis, in all of whom sars-cov- rt-pcr was performed. based on clinical characteristics, csf data and neuroimaging, we concluded with the diagnosis of encephalitis in patients, among whom one hsv -related, one necrotizing encephalitis, and two patients with detection of sars-cov- by rt-pcr in csf. a otherwise healthy -year-old man presented to ed because of headache and confusion. he left the hospital from the waiting room, and was later found wandering and confused. on readmission, he was afebrile and eupneic, with prominent agitation followed by a generalized tonic-clonic seizure. chest radiography was normal. blood tests revealed elevated levels of d-dimer, fibrinogen, ldh, il- , and c-reactive protein; blood cell counts were normal. electroencephalogram and brain ct scan were unremarkable. csf analysis showed normal protein level and cell count; culture was sterile; rt-pcr was negative for common neurotropic virus. rt-pcr for sars-cov- resulted positive both on pharyngeal swab and csf. hydroxychloroquine ( mg twice daily) was started together with aripiprazole at a daily dose of mg. the patient was discharged home at day fully recovered. patients ( . %) manifested pns involvement: gbs, critical illness myopathy and neuropathy (crimyne), brachial plexopathies, and peripheral polyneuropathies (pnp) ( table ) . all patients performed emg-eng studies. for the diagnosis of gbs, hadden criteria were applied [ ] . csf analysis was generally avoided as the majority of the patients were treated with low molecular weight heparin at high doses in primary prevention of sars-cov- induced thrombophilia. it was performed in patients ( with gbs, with crimyne, and with pnp). moderate/severe ards was significantly more frequent in patients with pns involvement compared to patients with cvd ( . % vs %; diff. . %- % ci . - . ; χ = . ; p < . ) and to patients with altered mental status ( . % vs . %; diff. . %- % ci . - . ; χ = . ; p < . ). twenty-eight were admitted to icu. the emg-eng study confirmed the diagnosis of crimyne in nine and of gbs in sixteen patients. albumino-cytological dissociation was present in / patients with gbs. csf rt-pcr for sars-cov- was performed and negative in / . in one pt the diagnosis of gbs was formulated on clinical ground and csf results. thirteen gbs patients underwent a blink reflex test, which showed a demyelinating pattern in either the facial and/or the trigeminal nerve in all cases, suggesting a frequent cranial nerve involvement. mean length of stay was significantly longer in pts with pns involvement compared with patients with cvd (z = . ; p < . ). in addition, we observed patients ( . %) with myelitis, patients ( . %) complaining of headache, patients ( . %) with seizures, and patients ( . %) with movement disorders. patient : a otherwise healthy -year-old man presented to ed complaining of back-pain irradiating to lower extremities, sensory changes, weakness, and constipation. neurological examination showed bilateral leg motor weakness (grade / mrc scale) and diminished sensation below the t sensory dermatome. the tendon reflexes were normal bilaterally, with normal cutaneous plantar reflex. sars-cov- nasopharyngeal swab and thoracic ct scan were negative. serology testing revealed the presence of igg antibodies to covid- ( au/ml). brain mri was normal; spine mri showed diffuse degenerative changes. patient : a -year-old man had been in his usual health state until days before admission, when fever, anosmia, and ageusia developed and lasted for days. no further investigations had been performed and no treatment started. two weeks later, he complained of walking disturbances and numbness involving both lower extremities. on admission, he had bilateral leg weakness (grade / mrc scale), with reduced sensation to touch and acroparesthesia. deep tendon reflexes were brisk with bilateral distal clonus and normal cutaneous plantar reflex. a spastic paraparetic gait was observed. the nasopharyngeal swab for sars-cov- and the chest radiograph were negative. however, serology testing revealed the presence of igg antibodies to covid- ( . au/ml) and chest ct scan demonstrated small ground-glass opacities, suggestive of previous pneumonia. brain mri was normal; spine mri showed diffuse degenerative changes, with a conglutinated appearance of the roots of the cauda, which present a slight hyperintense signal in t sequences. in both patients, csf analysis revealed normal cell count and slightly increased protein level; rt-pcr for bacteria, common neurotropic virus, and sars-cov- were negative; igg anti-sars-cov- were positive. in both, emg-eng showed a reduction of maximal voluntary activity; sep and mep recorded from lower limbs showed a bilateral medullar conduction block of the long motor and sensitive pathways. therapy and outcome: pat. -the patient received methylprednisolone gr intravenously for days, followed by immunoglobulins ( . g/kg die). because of clinical worsening, immunoglobulins were stopped after days and plasma exchange started. oral steroid treatment was tapered gradually. pat -the patient received days of methylprednisolone g intravenously, followed by rounds of plasma exchange. oral steroid treatment was tapered gradually. at discharge to rehabilitation unit, both patients were able to ambulate without support, although with a paretic gait, with residual mild sensory deficits. although respiratory distress is the most distinctive clinical picture of sars-cov- infection, neurologic manifestations have been described. however, available evidence derives mainly from scanty series [ ] , selected populations [ ] , or single case descriptions [ ] [ ] [ ] [ ] [ ] . a larger study, launched at the beginning of april, has been recently published [ ] , which reports cases prospectively notified through online portals developed across the principal uk neuroscience bodies. the national and interdisciplinary structure of the study permitted to capture both neurological and psychiatric diagnoses nation-wide. however, although physicians were permitted to notify retrospectively recent cases, the majority of neurological complications that occurred in march are likely to be missed. in addition, because of the clinical demands of the pandemic, awareness of the study was likely to be scarce and voluntary-based case notification underreported. clinical, laboratory, and radiological findings of cases of covid- neurological disease from queen square hospital have been recently published [ ] . the spectrum of neurological syndromes was similar to what encountered in our population, apart from inflammatory syndromes. contrary to paterson's cohort, we did not observe any case of acute disseminated encephalomyelitis, despite the majority of patients with altered mental status performed brain mr (data not shown). paterson's cases were discussed in the context of multidisciplinary team meeting, thus representing a bias towards more complex and severe cases. here we report unselected neurologic manifestations on the largest covid- population ever described within a single hospital. among patients with laboratory or radiology-confirmed diagnosis of covid- disease, consecutively admitted to the asst pg in bergamo from february rd to april th , patients ( . %) developed a neurologic complication. the incidence of neurologic events observed in our population is much lower than the incidence reported by mao et al. [ ] . however, in mao series, data regarding neurologic complications are based on subjective descriptions derived from medical records, and include aspecific symptoms such as dizziness or nerve pain. on the opposite, we have included only neurologic complications documented by neurologic consultancy. in addition, we have extensively evaluated patients with neurologic involvement by appropriate instrumental tests. on the contrary, in available literature, instrumental evaluations were not systematically performed either to reduce the risk of cross infection, as in the chinese report, or likely due to the well-known difficulties in transferring patients admitted in icu for instrumental tests, as in helmes et al's report [ ] . the mean age of our patients was . years, higher than in wuhan series. the mean age observed in our series is in line with that reported from a large cohort of covid- patients admitted to icus in lombardy [ ] , and likely reflects the higher median age of the italian population. on the opposite, it is lower than the mean age of uk cases where, according to authors, an older population could be overrepresented [ ] . it is worth noting that more than % of our patients were below years of age. this observation should alert physicians that neurologic involvement is not a exclusive prerogative of the older population. in our cohort, neurologic event was the presenting manifestation in pts, % of whom never developed other covid- symptoms during hospitalization. this observation emphasizes that sars-cov- infection can manifest with predominant neurological symptoms and prompts the adoption of all specific measures to prevent contamination among patients and health professionals. as in varatharaj's study [ ] , the three principal groups of neurologic manifestations observed in our population were cvd, impaired consciousness and confusional states, and pns involvement. considering the entire covid- population analysed ( pts in bergamo cohort and pts in wuhan cohort), the prevalence of acute cvd was similar ( % vs . %). on the opposite, the prevalence of impaired consciousness and confusional states, as well as pns involvement was inferior in our cohort when compared to that in wuhan cohort ( . % vs . % and . % vs . %). the observed differences are likely due to the fact that we considered only neurologic manifestations classified by means of appropriate laboratory and/or instrumental tests into specific nosographic categories. it would be useful to compare the numbers of admissions for strokes, confusional states, and acute peripheral neuropathies in the same period of the previous year. regarding stroke, the comparison is biased by the fact that, during pandemic, lombardy region redesigned regional networks for acute conditions, centralizing stroke management in a few hubs. diagnosis of confusional states and consciousness impairment are poorly traced in electronic records, making comparison impossible. on the contrary, it is worthwhile to note that we observed a dramatic increase in gbs diagnosis, when comparing with the equivalent period of the previous year ( vs ). mean lag time from covid- symptom onset to neurologic manifestations in our population was . days, with a median of days. this observation is consistent with previous studies describing neurologic events during infections by other coronaviruses, such as sars and mers [ ] [ ] [ ] . on the contrary, mao et al. [ ] report that most neurologic manifestations occurred early at a median time of - days, but exclude from the analysis cvd and impaired consciousness, which are the main complications observed in our and varatharaj's [ ] cohorts. it is of note that, even if almost half of the complications occurs within the first weeks, still a relevant percentage can manifest late in the course of the disease, . % between and weeks and . % beyond weeks from covid- symptom onset. it has to be underlined that, among patients with detection of neurological signs beyond weeks, patients ( %) were admitted to icu, and neurologic findings were recorded when sedation and neuromuscular blockade were withheld; in eight of them a diagnosis of gbs was confirmed by emg-eng analysis. considering that response to immunoglobulin treatment shortens recovery and improves disability score when administered within the early stage of the disease [ ] , our observation is particularly relevant as it points out the need to monitor icu covid- patients either by means of sedation windows or instrumentally by neurophysiologic tests for the appearance of pns disorders. in our cohort, we describe two patients with altered mental status and two cases of myelitis with detection in csf of sars-cov- rna and igg anti-sars-cov- , respectively. direct demonstration of the sars-cov- genome has been reported only in two patients presenting with acute encephalopathy from japan [ ] and china [ ] respectively. only one case of acute necrotizing myelitis in a covid- patient has been reported so far. however, sars-cov- pcr in csf was negative and csf antibodies to covid- were not tested [ ] . an additional case presenting with acute flaccid paralysis of bilateral lower limbs and sphincter incontinence has been described. however, no csf analysis nor spinal mri were performed, making diagnosis of myelitis presumptive [ ] . our additional cases further support the neuroinvasive potential of sars-cov- and strongly suggest the need to systematically perform csf examination with pcr for sars-cov- genome and search for ab anti-sars-cov- in patients with symptoms related to cns involvement, even in the absence of respiratory syndrome at clinical and instrumental evaluations. to the best of our knowledge, this is the first study with the aim of intercepting all neurological complications of sars-cov- infections occurred in the biggest covid- population ever reported. nevertheless, it has several limitations. first of all, it is a retrospective study. however, thanks to the reorganization of the hospital, the redeployment of the neurologists in staff to covid units, and the awareness of healthcare personnel on the involvement of ns during sars-cov- infection, we are pretty confident that we could intercept the majority of relevant neurologic complications. moreover, we immediately designed a database where collecting demographic, clinical, and instrumental data of patients within an observational study approved by our institutional review board. as we did not include patients discharged by the ed, we might have lost some patients with mild neurological symptoms. however, we can speculate that patients with evolving neurological problems would have been readmitted to the ed and therefore captured later. conversely, we might have lost patients who died in the ed for severe ards and concomitant neurologic involvement. it has to be said that we evaluated all brain ct scan requested for covid- patients and therefore we should not have missed evident acute brain lesions. because of the overwhelming access of severely ill covid- patients, especially in the first weeks of the pandemic, we did not trace records of ageusia and anosmia at onset of covid- symptoms. this is a relevant limit as these symptoms may testify the involvement of the olfactory bulbs, considered one of the possible access route of the virus to cns. to circumvent this limit, we are planning to include this item in the medical history record to be administered to the patients during follow-up visits, fully aware that we will miss the data in deceased patients. even if we have data on short-term outcome, we are lacking data on the medium term. to accomplish this aim, we have planned a follow-up out-patient service for clinical and instrumental evaluations of all covid- patients discharged from asst pg , which includes neurologic evaluation at and months, together with neuropsychologic, neurophysiologic and neuroradiologic exams, when appropriate. this study confirms that involvement of ns is common in sars-cov- infection and offers clinicians useful information either for prevention or to early intercept neurologic manifestations and set the adequate therapeutic strategies. during the current pandemic caused by a novel virus, the importance of sharing worldwide data from large populations is crucial to prepare the national health systems facing all the potential complications and saving the highest number of lives. in addition, a better knowledge on the epidemiology and relevance of neurologic involvement may shed lights on the pathophysiology of the disease, help in understanding the impact on the severity of respiratory distress as well as on long-term outcome, and contribute to the development of preventive strategies against viral entry into the cns. covid- : the first documented coronavirus pandemic in history coronavirus disease (covid- ) in italy neurologic manifestations of hospitalized patients with coronavirus disease in wuhan, china neurologic features in severe sars-cov- infection guillain-barré syndrome associated with sars-cov- guillain-barré syndrome associated with sars-cov- infection: causality or coincidence? guillain barré syndrome associated with sars-cov- a first case of meningitis/encephalitis associated with sars-coronavirus- first case of novel coronavirus disease with encephalitis neurological and neuropsychiatric complications of covid- in patients: a uk-wide surveillance study the emerging spectrum of covid- neurology: clinical, radiological and laboratory findings diagnostic testing for severe acute respiratory syndrome-related coronavirus electrophysiological classification of guillain-barré syndrome: clinical associations and outcome. plasma exchange/sandoglobulin guillain-barré syndrome trial group baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region large artery ischaemic stroke in severe acute respiratory syndrome (sars) severe neurologic syndrome associated with middle east respiratory syndrome corona virus (mers-cov) neurological complications of middle east respiratory syndrome coronavirus: a report of two cases and review of the literature intravenous immunoglobulin for guillain-barré syndrome covid- -associated acute necrotizing myelitis acute myelitis after sars-cov- infection: a case report conflicts of interest the authors declare that they have no competing interest.ethical standard statement wherever possible, informed consent was collected verbally. however, in most cases, due to the inability to provide informed consent by the patient or the inability to collect it in compliance with the contagion prevention measures, the principle of secondary use of data was used in accordance with art. , paragraph , letter b) of the november th, law, n. , included in the legislative decree / of art. -bis. the institutional review board at asst papa giovanni xxiii provided approval for the study ( / , / / ). all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the helsinki declaration of , as revised in . key: cord- - g hlm authors: bracaglia, martina; naldi, ilaria; govoni, alessandra; brillanti ventura, donatella; de massis, patrizia title: acute inflammatory demyelinating polyneuritis in association with an asymptomatic infection by sars-cov- date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: g hlm nan excluded electrolytic abnormalities, heavy metal or drugs toxicity, endocrinological disorders, folate and vitamin b deficiency. blood analysis showed elevated cpk ( u/l, normal < ), crp ( · mg/dl, normal < · ), lymphocytopenia ( · × /l, normal · - ), mild increase of ldh ( u/l, normal < ), got and gpt ( and u/l, normal < ), similarly to covid- patients laboratory profile [ ] . thus, considering the rapid spread of this infection in our region and its pandemic extent, we decided to perform a rt-pcr for sars-cov- on nasopharyngeal swab, which resulted positive. we found elevation of interleukin ( pg/ml, normal < · ), also associated with covid- disease [ ] . she was transferred to covid- department and received a five days course of intravenous immune globulin (ivig), ritonavir mg and darunavir mg per day with hydroxychloroquine mg twice daily, according to our hospital protocol for covid- treatment. she never developed respiratory symptoms or fever; thoracic ct scan was normal. immediately after ivig, she significantly improved with a mrc scale of / in distal of upper limbs and / both proximal and distal in lower limbs, while facial diplegia has developed. about weeks after the onset of neurological symptoms two nasopharyngeal swabs, hours apart, resulted negative and she was transferred to rehabilitation care. to our knowledge, this is the first case of gbs in patient with asymptomatic covid- and laboratory tests consistent with sars-cov- infection. we think the infection wasn't nosocomial, although we cannot absolutely exclude it, because the swab was performed within twelve hours from hospitalization and isolation protocols of suspected patients had been applied. patient's relatives did not develop symptoms but were observed in isolation for weeks. the association between covid- and gbs has recently been described both as parainfectious [ , , ] and as post-infective event [ , , ] , similar to other infections and coronavirus [ , ] , suggesting a mechanism of molecular mimicry or part of systemic inflammatory cascade triggered by the virus. facial diplegia seems recurrent in gbs related to covid- [ , ] . interesting in our case a patient asymptomatic for covid- develops neurological impairment as a unique clinical event, probably as part of dysimmune process. unfortunately, we could not perform a serological test or csf pcr for covid- . we believe this association may not be a coincidence, more cases could be evaluated, possibly supported by serological and csf tests, and underlines the importance of looking for neurological impairment in covid- disease and address the correct treatment, such as ivig, also for respiratory function worsening independently from pneumonitis. author contributions bm treated the patient and collected the clinical information. bm, ni and pdm drafted the manuscript. bm and pdmperformed the ncs analysis. pdm provided guidance for the diagnosis and clinical management of the patient. all authors contributed to the editing of the manuscript and approved the final version. availability of data and material de-identified data and material inherent to the case report and not included in the manuscript are available on request to the corresponding author by any qualified investigator. potential neurological symptoms of covid- clinical features of patients infected with novel coronavirus in wuhan guillain-barré syndrome associated with sars-cov- infection: causality or coincidence? guillain-barrè syndrome associated with sars-cov- guillain-barré syndrome following covid- : new infection, old complication? guillain-barré syndrome associated with sars-cov- infection early guillain-barré syndrome in coronavirus disease (covid- ): a case report from an italian covid-hospital facial diplegia, a possible atypical variant of guillain-barré syndrome as a rare neurological complication of sars-cov- guillan-barré syndrome associated with covid- infection: a case report china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china zika virus infection and guillainbarré syndrome: a review focused on clinical and electrophysiological subtype neurological complications during treatment of middle east respiratory syndrome key: cord- -s h jzzs authors: di stefano, vincenzo; battaglia, giuseppe; giustino, valerio; gagliardo, andrea; d’aleo, michele; giannini, ottavio; palma, antonio; brighina, filippo title: significant reduction of physical activity in patients with neuromuscular disease during covid- pandemic: the long-term consequences of quarantine date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: s h jzzs background: quarantine was the measure taken by governments to control the rapid spread of covid- . this restriction resulted in a sudden change in people’s lifestyle, leading to an increase in sedentary behavior and a related decrease in the practice of physical activity (pa). however, in neuromuscular diseases patients need to perform regular pa to counteract the negative consequences of the disease. hence, the aim of this study was to estimate the levels of pa, measured as energy expenditure (met–minute/week), among patients with neuromuscular disease (nmd) before and during the last week of quarantine. methods: a total of italian subjects, living in sicily, completed an adapted version of the ipaq-sf. participants comprised nmd, enrolled at the neuromuscular clinic of palermo and healthy subjects (control group). the sf- questionnaire was also administered to nmd. the mann–whitney u and the kruskal–wallis rank-sum tests were used for statistical analyses. results: we observed a significant decrease of the total weekly pa level during covid- quarantine in both patients and controls. moreover, a significant difference in the total weekly pa level was found depending on the presence of neuromuscular disease, impaired walking, gender and bmi. finally, we found a correlation between sf- scores and the entity of the reduction of pa level during quarantine, thus confirming a relevant association with the quality of life in nmd. conclusion: our study confirmed that covid- quarantine has affected the practice of pa among both nmd and healthy controls. the coronavirus disease (covid- ) pandemic has grown since late , causing an unprecedented crisis and affecting the lives of millions of people worldwide [ , ] . hence, covid- has been declared a public health emergency and in many countries people were asked to live in home-confinement for several months, while hospitals have been forced to reduce their outpatient activities to cope with the high number of hospitalizations [ , ] . apart from the well-known symptoms of covid- (fever, diarrhea and respiratory impairment), neurological symptoms are reported in up to one-third of cases [ , , ] . furthermore, pandemic-associated psychological sequelae have been reported [ , ] . in fact, the restrictive measures and the quarantine imposed by the governments have contributed to further indirect effects of pandemic by influencing (negatively) many aspects of everyday life, for instance, the practice of pa. as a result of covid- pandemic, many people all around the world have suddenly become inactive v. di stefano and g. battaglia contributed equally to the manuscript. and sedentary, with important consequences for both healthy people and patients affected by several kinds of disease [ , , , ] . it is a well-known fact that inactivity and sedentarism lead to specific alterations in the skeletal muscle, contributing to insulin resistance, impairment of the oxidative function, and rapid hypotrophy [ ] [ ] [ ] [ ] . these changes in the muscle pathophysiology usually take place after a couple of weeks, but they can also be faster in older people or patients affected by neuromuscular disease [ , ] . neuromuscular diseases affect both adults and children causing a relevant disability in the lifespan [ , ] . they include disorders of: skeleton muscle (i.e. muscle dystrophies, inflammatory myopathies, muscle channalopathies), neuromuscular junction (i.e. myasthenia gravis, eaton-lambert syndrome), and peripheral nerve (i.e. familial amyloid neuropathies, chronic inflammatory demyelinating polyradiculoneuropathy). moreover, patients with neuromuscular disease (nmd) require strict follow-up, essential immunotherapies, muscle rehabilitation and physical exercise [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in particular, nmd need an active physical activity (pa), through the practice of regular exercise, to improve muscle strength, endurance ability and to prevent osteoarticular complications from disuse [ , , ] . pa and exercise should be performed under the supervision of a reference specialist and in close collaboration with physiotherapists in an integrated and individualized approach [ , , ] . for these reasons, it is not difficult to hypothesize that covid- pandemic-related italian government limitations have contributed to a significant change in the care of nmd due to the difficult access to immunosuppressive treatments and physiotherapy [ ] . notwithstanding the relevant impact of covid- pandemic on the health of nmd, scientific task forces have provided recommendations for the care of neuromuscular diseases [ , , , ] . however, very little has been discussed about the fundamental role of pa and physiotherapy in this subset of patients during the lockdown [ ] . isolation at home can lead to poor nutrition, low sleep quality, reduced pa levels and sedentary habits with different negative consequences, such as increased body fat, decreased muscle mass, insomnia and depression [ , , , , ] . therefore, it is important to highlight these unwanted consequences of quarantine to develop and provide practical and useful recommendations. in the present cross-sectional study we aimed to explore the impact of covid- lockdown on pa in nmd and to quantify the expected reduction of pa levels, as well its effect on the quality of life. the study design of the research is a cross-sectional survey conducted through a detailed interview. the survey conducted for the study included an adapted version of the international physical activity questionnaire short-form (ipaq-sf) [ , ] and a short-form health survey (sf- ) [ ] . before being admitted to the research, all participants signed informant consent. the ethical board of the university of palermo approved the study in conformity with the declaration of helsinki principles. participants, living in sicily, were recruited between april and may , (during covid- quarantine in italy). it is well-known that in this period, due to the restrictive measures adopted by the government, all sports facilities were closed and the practice of outdoor pa in public parks and gardens was forbidden [ , ] . participants were enrolled at the neuromuscular clinic of the university of palermo regarding patients with neuromuscular diseases (n = ), while healthy controls (n = ) were enrolled among not-affected partners and caregivers. the data were collected through a questionnaire administered by telephone to the participants. the adapted version of the ipaq-sf we have chosen allowed us to assess, at the same time, the levels of pa both before and during the last days of covid- quarantine [ , ] . the levels of pa were measured as energy expenditure (met-minutes/week). the adapted version of the ipaq-sf comprised questions assessing frequencies and durations of each pa intensity, i.e. sitting, walking, moderate-intensity physical activities, and vigorous-intensity physical activities. in particular, the questionnaire included questions about: demographic and anthropometric data; pa before quarantine; type of work done during quarantine; type of house where lived during quarantine; vigorous-intensity pa before and during quarantine, moderate-intensity pa before and during quarantine, walking activities before and during quarantine, sitting activities before and during quarantine; information concerning the practice of pa in home setting during quarantine [ ] . finally, a short-form health survey (sf- ) was administered to the nmd [ ] . this questionnaire consisted of two assessment domains: the physical health component score (pcs) and the mental health component score (mcs). as for the ipaq-sf adapted version, we considered the total pa level and the moderate-to-vigorous pa (mvpa) level for both before and during quarantine. furthermore, we analyzed both parameters in relation to the gender, age, and bmi variables. the weekly pa level of both considered parameters were calculated as energy expenditure in met-minutes/week (met-min/wk) [ ] . we used the corresponding metabolic equivalent task (met) assigned to each type of pa (i.e. . , . and . for walking, moderateintensity physical activities and vigorous-intensity physical activities, respectively) to estimate the weekly level of energy expenditure. afterwards, we computed the sum of energy expenditure of walking, moderate-intensity physical activities, and vigorous-intensity physical activities in met-min/wk for the "total pa" level and the sum of moderate-intensity physical activities, and vigorous-intensity physical activities in met-min/wk for the "mvpa" level [ , ] . hence, we multiplied the corresponding met basal level for each type of pa per minutes of practice during the week to calculate the met weekly level (https ://www.ipaq. ki.se) [ , ] . the distribution of the pa level difference between before and during quarantine was calculated for each different pa intensity and for the total pa level (i.e. the sum of walking, moderate-intensity physical activities, and vigorousintensity physical activities) in walking subjects. in fact, in patients with impaired walking ability, we did not calculate the total pa level, but, for these subjects, we considered instead the mvpa level (i.e. the sum of moderate-intensity physical activities and vigorous-intensity physical activities), which has been often used in elderly (https ://www. ipaq.ki.se) [ , ] . as regards the sf- , reference values were published for both healthy subjects and patients with neurological diseases for the italian population [ , ] . pcs and mcs scores range from to , with higher scores indicating a better health-related quality of life [ , ] . percentages were calculated to describe the categorical variables and we reported continuous variables as means with standard deviation. we compared categorical variables between groups using the chi-square test and continuous variables through the mann-whitney test. percentiles, means, and standard deviations were calculated to represent the pa level for the categorical variables. for statistical analysis, we used the labels "met pre covid- " and "met during covid- " to represent the pa level before and during quarantine, respectively; "∆met" to indicate the pa level difference between before and during quarantine. box-plots were used to graphically represent the quantitative variables. the mann-whitney u test for continuous variables was chosen to compare the distribution of the total weekly pa level before and during quarantine. subsequently, we analyzed the relationship between the parameters "met pre covid- " and "met during covid- " and the gender, age, and bmi variables through a bivariate analysis. in particular, we used the kruskal-wallis rank-sum test for the abovementioned variables (i.e. age, gender, bmi), sf- scores and disease subtype in nmd. pearson's correlation coefficient was calculated between sf- scores and ∆met parameters and mvpa. we performed all tests using spss statistic (v ) and established the level of significance at < . . a total of italian subjects, all from sicily region, both physically active and inactive, completed the questionnaire. among these, were affected by a neuromuscular disease and they were enrolled at the neuromuscular clinic of palermo, while healthy subjects were recruited as control group. among the participants of the group with neuromuscular disease ( % males), patients ( %) were able to walk independently and patients ( %) showed impaired walking ability. regarding the type of disease, patients ( %) had an acquired or hereditary myopathy (my); patients ( %) presented a diagnosis of acquired or hereditary polyneuropathy (pn); patients ( %) suffered from a disorder of the neuromuscular junction (njd); and the last group consisted of patients ( %) with a genetically confirmed degenerative disease (nd, i.e. hereditary spastic paraplegia, spinal muscular amyotrophy). there were no significant differences in age and gender between patients and healthy controls (table ) . of interest, nmd showed significantly higher bmi scores (p = . ), although this difference resulted no significant when only walking patients were considered. the distribution of ∆ met was calculated for different levels of pa intensity (i.e. vigorous-intensity pa; moderate-intensity pa; walking activity) in all subjects. the mann-whitney u test showed a significant difference in the distribution of each intensity of pa and in both parameters which we have considered for the pa level (i.e. the total pa level parameter and the mvpa level) in the before-quarantine condition as well as during quarantine condition in nmd compared to healthy subjects (table ) . in healthy controls, a significant reduction of pa was reported during quarantine compared to before quarantine for vigorous-intensity pa (p = . ), moderate-intensity pa (p = . ), walking activity (p < . ), total pa level (p < . ) and mvpa level (p = . ). in nmd, a significant reduction of pa was reported for walking activity (p < . ), total pa level (p < . ) and mvpa level (p = . ), while no difference was found for vigorous-intensity pa (p = . ) and moderate-intensity pa (p = . ), thus explaining the reason why in nmd basal levels of energy expenditure start from very low values. moreover, we estimated the impact of quarantine on each pa intensity, in the total pa level parameter and in the mvpa level calculating the difference between energy expenditure during and before quarantine (∆met) finding a significant difference in vigorous-intensity pa (p < . ), in total pa level parameter (p = . ) and in the mvpa parameter (p = . ). we did not find any significant difference in moderate-intensity pa and walking activity. ∆met measures (∆met-vigorous, ∆met-moderate and ∆met-mvpa) were not differently distributed in relation to impaired walking, gender, age, and bmi among nmd. moreover, we found no significant difference in relation to the disease subtype, except for ∆ met-walking that was higher in patients with neuromuscular junction disorder than patients of the neurodegenerative subgroup (p = . , fig. ). nmd showed reduced scores for both pcs- ( . ± . ) and mcs- ( . ± . ) domains compared to italian general population. sf- scores were not differently distributed in relation to age. of interest, among nmd both pcs- and mcs- scores were significantly lower in patients with impaired walking (p < . and p = . , respectively); men showed reduced mcs- scores (p = . ) and pcs- scores were significantly lower in patients with higher bmi (p = . ). the kruskal-wallis test reported a significant difference for both pcs- and mcs- in relation to the neuromuscular disease (p = . and p < . , respectively, fig. ). in particular, we found lower pcs- scores in nd patients when compared to my patients (p = . ); furthermore, nd patients showed lower mcs- scores compared to njd and pn patients (p = . and p < . , respectively). a linear correlation was found between pcs- scores and both ∆ met total (− . , p = . ) and mvpa (− . , p = . ). moreover, we found a in this study we investigated the impact of the covid- quarantine on pa levels and quality of life in nmd. during these last months, the quarantine has allowed to restrain the rapid spread of covid- [ ] . however, this containment measure may have had side effects on the health of the populations [ , ] . indeed, quarantine has implied a sudden change in people's lifestyle, leading to an increase in sedentary behavior [ , , ] . such a radical change in daily life can have to negative effects in high-risk patients, who need to perform regular exercise to counteract the negative consequences of certain disease, such as neuromuscular diseases [ ] . our understandings on the changes inducted in the skeleton muscle by inactivity come from several models including bed rest, limb suspension and step reduction [ , , ] . data from studies on "bed rest" established that muscle atrophy, especially in antigravity muscles, appears very soon after only two days of inactivity [ , ] . a prolonged immobilization can induce a significant reduction of protein synthesis in the muscle fibers thus conducting to muscle mass loss [ , , ] . of note, it has been recently hypothesized that physical inactivity may also cause damage at the neuromuscular junction with muscle denervation [ ] . finally, it has to be considered that a more sensible muscle mass loss is reported following physical inactivity in older people and in neuromuscular disease, compared to healthy young subjects [ , ] . hence, there is some concern about the consequences of physical inactivity especially in nmd and older people. previous studies have recently pointed out the reduction of pa levels in the general population during covid- pandemic [ , ] . in the scientific literature there are a few studies that have explored this topic in healthy subjects or in athletes [ , , ] , however, no studies have examined the consequences of quarantine in nmd. as expected, a significant reduction in pa levels during the pandemic in both nmd and healthy controls was demonstrated. moreover, in controls subjects was found a significant reduction in all pa parameters considered, while, nmd showed a significant decrease in walking activity, total weekly pa level and weekly mvpa level. these results reflect the fact that moderate-intensity pa and walking activities were similarly affected in both patients and controls, while vigorous-intensity pa seem to be more reduced in controls. this was in agreement with a recent study that reported a high level of total weekly energy expenditure before the covid- quarantine in healthy subjects [ ] . vigorous-intensity and moderate-intensity pa, which require a suitable state of health to perform certain physical efforts represented a relevant part of baseline pa levels in healthy controls, but not in nmd. anyhow, the quarantine has negatively influenced walking activities above all in nmd. the key explanation for this result could be related to the fact that walking represents a low intensity and aerobic activity characterized by easy accessibility for all the population [ ] . there is evidence that pa improves both mental and physical health [ , , ] . therefore, it is reasonable to hypothesize that a decrease in pa levels could have an impact on both health domains, as confirmed by the association between sf- scores and the extent of pa reduction that we have found. surprisingly, both pcs- and mcs- scores correlated with ∆met-total and, moreover, pcs- correlated with mvpa level. furthermore, compared to italian population [ , ] , nmd showed reduced sf- scores, especially patients with impaired walking. in particular, the mental health component resulted more affected among men, while the physical component was more altered in patients with higher bmi. finally, specific alterations resulted from different diseases: nd patients showed lower pcs- scores than my patients and lower mcs- scores compared to njd and pn patients. these results were also expected, as nd patients (sma, hsp) usually have a more significant disability level than other forms of neuromuscular diseases [ ] . in conclusion, this study highlights the negative impact of covid- quarantine on pa levels in nmd and healthy subjects. a significant reduction in pa has been reported in nmd, especially walking activities. moreover, the extent of pa reduction was related to the perceived physical and mental health of nmd, thus influencing their quality of life. sedentary behaviors can have negative consequences on the health of the entire population, in particular for those with additional risk factors and neuromuscular diseases. therefore, since outdoor activities are not practicable due to the quarantine, it is essential to maintain an active lifestyle by performing exercise in a home-based setting for healthy subjects as well as for patients. indeed, pa and physiotherapy are fundamental for nmd to avoid further loss of muscle mass and to slow the progression of the disease. this is a cross-sectional survey exploring the effect of covid-quarantine in the pa levels of nmd. our results come from comparison of the two condition, "pre" and "during" quarantine; however, the evaluation of the two conditions comes from the same interview and this may have biased the collection of data. pa levels are quite easy to recall in memory and should not be affected by the mental perception, at difference with psychological variables that may be affected by memory. for this reason, we administered sf- only during quarantine renouncing to a comparison with the before quarantine status. future studies are needed to clarify whether differences in pa levels could affect other domains of health and life in healthy subjects and in nmd. finally, we did not report data on follow-up. future studies monitoring pa levels for several months after lockdown could offer new interesting clues to the mechanisms of recovering after muscle mass loss and hypotrophy and provide more useful information to predict outcome and response to different rehabilitation strategies. are we facing a crashing wave 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vds submitted the study.funding not applicable. conflict of interest on behalf of all authors, the corresponding author states that there is no conflict of interest.ethical standards statement all human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the declaration of helsinki and its later amendments.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -stswaiep authors: vogrig, alberto; bagatto, daniele; gigli, gian luigi; cobelli, milena; d’agostini, serena; bnà, claudio; morassi, mauro title: causality in covid- -associated stroke: a uniform case definition for use in clinical research date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: stswaiep nan increasing evidence supports the association between the novel severe acute respiratory syndrome coronavirus (sars-cov- ), the etiologic agent of the coronavirus disease (covid- ), and neurological complications, including encephalopathy, encephalitis, guillain-barré syndrome, and cerebrovascular disease [ , ] . in particular, both ischemic and hemorrhagic strokes have been linked to covid- [ ] [ ] [ ] . since a substantial proportion of these reported patients had associated vascular risk factors, it is crucial to determine whether this association is causal or coincidental [ , , ] . in an effort to systematically assess this issue, shtaya et al. proposed to classify cases of covid- -related stroke in three major groups: ( ) hospital acquired; ( ) community acquired; ( ) stroke as direct complications of covid- [ ] . most of the cases of our report [ ] and other series [ , ] fulfill the criteria for the latter group as defined by the authors. conversely, we did not encounter hospital-acquired covid- infections in patients hospitalized for stroke, since protective measures were readily implemented in our institutions. although we believe that this proposed classification is valuable in highlighting a relevant clinical problem, these definitions are based on both epidemiological data (location of infection, as for pneumonia, difficult to ascertain in real-life settings) and pathogenetic aspects (as in group , for which few information is available at the moment), making their use impractical. moreover, we believe that it is possible that some patients can fit two of the proposed categories (e.g., patients with community-acquired covid- can develop stroke as direct complication of sars-cov- ). ellul et al. suggested an alternative classification, subdividing cases with "probable" (sars-cov- identified, lack of vascular risk factors) and "possible" (when vascular risk factors are present) association [ ] . we suggest some adaptations of the latter case definition as emerging data have shown distinct stroke patterns in covid- infection [ ] [ ] [ ] ] . these features (clinical, laboratory, and pathological characteristics, shown in the table ) can provide supporting evidence in favor of a link in doubtful cases. we propose a revised definition of cas, with three degrees of certainty (possible, probable, and confirmed, as illustrated in the table ). even if the world health organization (who) has provided definition for suspected, probable, and confirmed covid- cases, we believe that only patients with laboratory-confirmed sars-cov- should enter in the classification, in addition to clinic-radiological evidence of acute stroke (ischemic or hemorrhagic). these two represent the major criteria of this revised definition. minor criteria were designed to capture additional evidence of a causal and biologically plausible association: ( ) onset of stroke few days to weeks after covid- symptoms [ ] [ ] [ ] ,( ) lack of cardiovascular risk factors [ , ] ,( ) d-dimer and/or lactate dehydrogenase elevation [ ] [ ] [ ] . the presence of at least one of these features is required for "possible cas", and two for "probable cas", while confirmed cas requires pathological evidence of disappearance of endothelial cells in the affected arterioles, capillaries and venules. these findings reflect the pathogenesis of cas, which involves a thrombotic microangiopathy caused by endotheliopathy [ , ] . some additional features, such as the detection of sars-cov- in the cerebrospinal fluid (csf), can possibly provide additional evidence of a causal association, although cases with negative csf have been described [ ] . therefore, we do not believe that this represents a necessary feature. it is important to notice that the absence of the typical clinical patterns of cas should question the diagnosis. typical clinical features of covid- -related stroke include large vessel occlusion, multi-territory involvement, and posterior circulation predisposition (fig. a-g) [ ] [ ] [ ] ]. in addition, less frequent presentations were also observed: onset with seizures and/or encephalopathy [ , ] , extra-cranial dissection [ , , ] , including bilateral carotid artery dissection [ ] (fig. h-j) , and posterior reversible encephalopathy (pres) [ ] or laminar cortical damage [ ] . interestingly, if we retrospectively apply the cas criteria to the patients with community-acquired covid- reported by shtaya et al. [ ] , of their cases do not fulfill the major criteria (neuroimaging not performed). among the other nine patients, stroke developed few days to weeks later in all cases (criteria for possible cas fulfilled) and in two, there were no known vascular risk factors (criteria for probable cas fulfilled). in particular, case was a previously healthy -year-old man who developed a posterior circulation stroke days after the onset of covid- symptoms in the context of vertebral artery dissection [ ] , consistent with our proposed definition. this example suggests that the cas criteria can be useful in identifying stroke cases more likely to be causally linked to covid- , irrespective of where the infection was acquired. development of a standardized case definition for stroke of presumed infectious etiology related to sars-cov- is important for epidemiological surveillance, clinical research, outbreak investigations, as well as for allocation of healthcare resources. as the understanding of this novel disease is expanding rapidly, the proposed definition will likely need refining as more data emerge. nevertheless, this proposal represents a first step into harmonization of research studies into the topic of cas. major criteria . clinical and neuroradiological evidence of acute stroke (ischemic or hemorrhagic) . sars-cov- detection by pcr testing or detection of sars-cov- -specific antibody in serum indicating acute infection minor criteria . timing of onset (from few days to weeks after covid- symptoms) . lack of cardiovascular risk factors . d-dimer and/or ldh elevation possible cas: major criteria and minor criterion probable cas: major criteria and ≥ minor criteria confirmed cas: criteria for probable cas and consistent pathologic findings * note: the absence of the typical clinical patterns of cas ** should question the diagnosis clinical supporting features ** . large vessel occlusion . vertebrobasilar location . multi-territory involvement . onset with seizures . extra-cranial dissection . pres or laminar cortical damage pathologic supporting features * evidence of endothelial disruption fig. neuroimaging features of covid- -associated stroke. a a -year-old man with critical covid- -related ards developed acute right-sided weakness. brain ct showed a large fronto-insular ischemic lesion within the vascular territory of the left middle cerebral artery. b a -year-old man with covid- infection developed multi-organ failure. brain ct showed multiple recent ischemic lesions involving cortical-subcortical regions of both parietal lobes and centrum semiovale. c-e a -year-old man with covid- and critical ards presented myocardial infarction days after hospitalization. on day , he developed a tetraparesis. brain and spine mri were requested. as an incidental finding (given the final diagnosis of critical illness neuropathy), brain mri showed a left parieto-occipital infarction, hyperintense on t -weighted images (c) and bright on dwi (d) along the cortex, with subcortical white matter perilesional edema on flair sequence (e). f-g a -year-old man diagnosed with covid- presented with ataxia and vomiting. mri showed infarction of the postero-inferior part of the left cerebellar hemisphere and the inferior part of the vermis in the territory of pica (f, coronal flair). areas of hypointensity within the vermis, corresponding to blood degradation products, were also noted. the lesion underwent extensive hemorrhagic transformation with large parenchymal hematoma (g, axial ct). h-j a -year-old man with moderate covid- presented with intense headache and neck pain. h ct angiography showed a long stenosis of the distal part of internal carotid artery bilaterally. mri axial t -weighted images obtained with fat saturation (i) and t -weighted images (j) showed a narrowed eccentric flow void surrounded by a crescent-shaped subacute mural hematoma. this case of bilateral carotid dissection was previously reported by our group [ ] . ards acute respiratory distress syndrome, ct computed tomography, dwi diffusion-weighted imaging, flair fluidattenuated inversion recovery, mri magnetic resonance imaging, pica posterior inferior cerebellar artery neurological associations of covid- the emerging spectrum of covid- neurology: clinical, radiological and laboratory findings stroke in patients with sars-cov- infection: case series cerebrovascular disease in patients with covid- : neuroimaging, histological and clinical description characteristics of ischaemic stroke associated with covid- defining causality in covid- and neurological disorders comment on "stroke in patients with sars-cov- infection: case series" from a london hospital experience large-vessel stroke as a presenting feature of covid- in the young endothelial cell infection and endotheliitis in covid- status of sars-cov- in cerebrospinal fluid of patients with covid- and stroke covid- and cervical artery dissection: a causative association? bilateral carotid artery dissection in a sars-cov- infected patient: causality or coincidence? multifocal laminar cortical brain lesions: a consistent mri finding in neuro-covid- patients key: cord- -cjb daps authors: romagnolo, alberto; balestrino, roberta; imbalzano, gabriele; ciccone, giovannino; riccardini, franco; artusi, carlo alberto; bozzali, marco; ferrero, bruno; montalenti, elisa; montanaro, elisa; rizzone, mario giorgio; vaula, giovanna; zibetti, maurizio; lopiano, leonardo title: neurological comorbidity and severity of covid- date: - - journal: j neurol doi: . /s - - -y sha: doc_id: cord_uid: cjb daps objective: neurological symptoms of covid- patients have been recently described. however, no comprehensive data have been reported on pre-existing neurological comorbidities and covid- . this study aims at evaluating the prevalence of neurological comorbidities, and their association with covid- severity. methods: we evaluated all consecutive patients admitted to the emergency room (er) of our hospital between the rd march and the th april , and diagnosed with covid- . data on neurological and non-neurological diseases were extracted, as well as data on demographic characteristics and on severity degree of covid- . the prevalence of neurological comorbidities was calculated, and multivariate binary logistic regression analyses were used to estimate the association between neurological diseases and covid- severity. results: we included patients. neurological comorbidities accounted for . % of cases, with cerebrovascular diseases and cognitive impairment being the most frequent. neurological comorbidity resulted independently associated with severe covid- (or . ; p = . ), as well as male gender (p = . ), older age (p = . ), neoplastic diseases (p = . ), and arterial hypertension (p = . ). when neurological comorbidity was associated with non-neurological comorbidities, the or for severe covid- rose to . (p = . ). neurological patients, in particular cerebrovascular and cognitively impaired ones, received more respiratory support indication. conclusion: neurological comorbidities represent a significant determinant of covid- severity, deserving a thorough evaluation since the earliest phases of infection. the vulnerability of patients affected by neurological diseases should suggest a greater attention in targeting this population for proactive viral screening. coronavirus disease (covid- ) is an infectious disease caused by severe acute respiratory syndrome coronavirus- (sars-cov- ), declared a pandemic on march [ ] . clinical features range from the absence of symptoms to severe respiratory failure [ ] . a rapidly increasing number of articles have been published on covid- , including numerous reports and studies on associated neurological symptoms and complications [ ] , such as acute stroke [ ] , hyposmia [ ] , guillain-barrè syndrome [ ] , encephalitis [ ] . it has been shown that about one-third of covid- patients develop neurological symptoms [ , ] , in most cases associated with a more severe infection [ ] , indicating a potential neurotropism of sars-cov- as one of the possible mechanisms of neurological damage [ , ] . a recent retrospective study reported that inpatients from a neurological ward affected by covid- showed a worse outcome compared to those infection-free [ ] . however, no data have been reported yet on the prevalence and the association with infection severity of pre-existing neurological comorbidities in covid- patients. a scoping review on the occurrence of neurological diseases in covid- patients reported a prevalence of about % [ ] . nevertheless, this review highlighted the methodological heterogeneity in the reviewed papers, which limit a reliable estimation of prevalence of neurological diseases in covid- patients, as well as their association with the infection severity. the aim of our study was to evaluate, on a large cohort of consecutive patients admitted to the emergency room (er) and diagnosed with covid- , the prevalence of neurological comorbidities and their possible association with a more severe form of covid- onset. we evaluated all consecutive patients admitted to the er of the "città della salute e della scienza di torino hospital" between march and april , and diagnosed with covid- by means of a positive reverse transcription polymerase chain reaction nasopharyngeal swab. in all patients, we assessed both neurological and non-neurological comorbidities. a medical condition was attributed to the patients when: (a) defined diagnosis, and/or (b) unequivocal diagnostic test results, and/or (c) specific medical/surgical treatment, and/or (d) specific follow-up were reported. moreover, previous clinical notes available in our hospital electronic archives were reviewed. the charlson comorbidity index (cci) [ ] , defined as the sum of the weighted scores of various comorbid conditions (table ) , was calculated for each patient to grade their comorbid conditions. the severity of covid- at the time of admission to er was evaluated by means of the infectious diseases society of america/american thoracic society criteria for defining severe community-acquired pneumonia [ ] . severe disease was identified in patients presenting with one major criterion or three or more minor criteria (table ). protocol number / , approved may th, ), and patients gave their written informed consent. the main demographic and clinical features of consecutive patients evaluated are summarized in table . the mean age of the entire sample was . years: . % of patients were ≤ -year-old, while . % were ≥ -yearold. male accounted for . % of cases. the mean latency between the symptoms' onset and the er admittance was . days, ranging from to days; only two patients ( . %) with mild symptoms (sore throat and sporadic cough) had a latency of days, while . % of patients were evaluated within days from the onset, and . % between and days. the most frequent symptom at covid- onset was fever ( . %; n = ; isolated in patients, associated with ≥ other symptoms in patients), followed by cough ( . %; n = ), dyspnea ( . %; n = ), and diarrhea ( . %; n = ). the majority of patients reported a monosymptomatic onset ( . %; n = ), while . % (n = ) presented with two symptoms, and . % (n = ) with three or more symptoms. thirty-four percent of cases (n = ) entered the er with a severe form of infection. arterial hypertension was the most frequent comorbidity ( . %), followed by neurological diseases ( . %), neoplastic diseases ( . %), diabetes ( . %), chronic obstructive pulmonary disease (copd) ( . %), and renal failure ( . %). none of the patients were treated with specific antiviral drugs before admission; of them ( . %) were on hydroxychloroquine therapy ( mg bid; therapy duration . ± . days, range - ). a total of . % of patients (n = ) showed a neurological comorbidity. compared to patients not affected by neurological diseases (table ), they were disproportionately overrepresented among the severe covid- (p < . ). they were older (mean difference . years; p < . ), had a shorter interval between symptoms onset and er admittance (mean difference . days; p = . ), and were more frequently affected by hypertension, renal failure, and neoplastic diseases (p≤ . ); their cci was higher (p < . ), and they presented a higher prevalence of institutionalization (p < . ). pre-existing cerebrovascular diseases were the most common comorbidity, affecting . % of patients (n = / , including patients with hemorrhagic and with ischemic stroke), followed by cognitive impairment ( . %, including patients with mild cognitive impairment, with alzheimer's disease or alzheimer's diseaselike dementia, and with vascular dementia), migraine or chronic tension-type headache or trigeminal neuralgia ( . %; n = ), epilepsy ( . %; n = ), peripheral neuropathy ( . %; n = ), parkinson disease ( . %; n = ), and multiple sclerosis ( . %; n = ). a minority of patients ( . %; n = ) suffered only from neurological disease. the remaining patients suffered also from one ( . %; n = ), two ( . %; n = ), or three or more ( . %; n = ) other comorbidities, with arterial hypertension representing the most frequent comorbidity ( . % of cases), followed by neoplastic diseases ( . % of cases). the univariate binary logistic regression analysis (table ) revealed that a more severe form of infection was significantly associated with the presence of neurological disease (or . ; % ci . - . ; p = . ), together with male gender, arterial hypertension, diabetes, renal failure, copd, neoplastic disease, institutionalization, older age, and higher cci. on the multivariate binary logistic regression analysis (fig. a) , the presence of neurological diseases remained independently associated with severe infection (or . ; % ci . - . ; p = . ), as well as male after dividing the sample in patients without any comorbidities, patients with neurological disease without other comorbidities, patients with other comorbidities without neurological diseases, and patients with neurological disease and other comorbidities, the latter group showed the strongest association with a severe covid- (or . ; % ci . - . ; p = . ), compared with patients with neurological (or . ; % ci . - . ; p = . ) or non-neurological (or . ; % ci . - . ; p = . ) comorbidity alone (fig. b) . the association between neurological comorbidity and covid- severity varied among the different neurological diseases (table ). patients affected by cerebrovascular diseases and cognitive impairment showed a higher prevalence of severe infection, a lower rate of discharge at home and a higher rate of non-invasive mechanical ventilation or intensive care indication, significantly different from patients without neurological diseases (p < . ). conversely, patients affected by headache/facial pain, epilepsy, and peripheral neuropathy did not show any significant differences. both patients affected by multiple sclerosis and parkinson disease (not shown in table ) suffered from severe covid- that required hospitalization, without the need of mechanical respiratory support. in this study, we evaluated the prevalence of neurological pre-existing comorbidities in a large cohort of patients admitted to er and diagnosed with covid- , estimating their association with infection severity. over % of patients presented with neurological comorbidities, with cerebrovascular disease and cognitive impairment being the most frequent. patients with neurological comorbidity showed an or of . of suffering from severe covid- , even after including age and other clinical and demographic characteristics in the multivariate analysis. this association was stronger when patients suffering from a neurological condition in association with other comorbidities were compared to patients with isolated neurological or non-neurological diseases. cerebrovascular diseases and cognitive impairment showed higher rate of severe infection and respiratory support indication, and lower rate of discharge at home. to date, the incidence of new-onset neurological symptoms or syndromes associated with covid- has been reported [ ] [ ] [ ] [ ] [ ] [ ] , but the description of the relationship between pre-existing neurological comorbidities and infection severity still lacks. a recent review by herman and colleagues reported a pooled prevalence of neurological comorbidities of % among reviewed studies (range - %), without conclusive data on the association with infection severity [ ] . a recent study on inpatients from a neurological ward [ ] , showed worse clinical and functional outcomes, a more frequent use of high-flow oxygenation and antibiotic/antiviral treatments, longer hospitalization, and higher in-hospital mortality rate in patients with neurological diseases and covid- , compared to patients without infection; the vast majority of patients with covid- were hospitalized for acute cerebrovascular events. moreover, a meta-analysis reported that pre-existing cerebrovascular diseases could be an independent risk factor for covid- [ ] . in small-sample studies, cerebrovascular diseases have been associated with more frequent icu admission [ ] and with more severe forms of infection [ , ] . in addition, du and colleagues reported a . -fold higher mortality risk in patients with cerebrovascular or cardiovascular disease, without specifying the distinction between these two conditions [ ] . our data show that patients with pre-existing cerebrovascular diseases are more frequently hospitalized, needing icu admission in over % of cases, and present with a severe infection in two-thirds of cases. we observed similar findings in cognitively impaired/demented patients. a recent paper reported a prevalence of . % of dementia in a sample of italian patients who died with covid- , without assessing the association with infection severity [ ] . in our samples, we observed that patients suffering from neurological diseases were older, more affected by other comorbidities, and more institutionalized. age is a frequently reported risk factor for severe covid- [ , ] , as well as hypertension [ ] , diabetes [ , ] , neoplastic diseases [ , ] , copd [ ] , and institutionalization [ ] . these observations were confirmed in our study. the multivariate analysis showed that even correcting for age, institutionalization, and comorbidities, the presence of neurological diseases seems to be independently associated with a more severe form of infection. the strongest association with severe covid- was observed in patients with both neurological diseases and other comorbidities. this finding is consistent with the results reported by guan and colleagues, who found hazard ratios for worse infection outcomes as higher as the number of concomitant diseases increases [ ] . on the other hand, institutionalization, diabetes, renal failure, and copd showed a high association with infection severity only in the univariate analysis, but not in the multivariate analysis. the higher prevalence of severe covid- in patients affected by neurological diseases is probably multifactorial. the intrinsic frailty of chronic and often degenerative conditions, the older age, and the higher comorbidity burden observed in these patients could certainly explain this association [ ] . patients affected by neurological diseases could present a lower ability to compensate for covid- , resulting in more severe infection and higher need of er assistance. moreover, the potential neurotropism of sars-cov- , with a possible detrimental effect on pre-existing neurological diseases, should also be taken into account [ , ] , as already postulated during the sars-cov epidemic in [ ] . while waiting for more accurate pathological evidences, our data underline that patients with neurological diseases, in particular when associated with other comorbidities, represent a population at high risk for severe covid- , needing a careful health surveillance. our study presents with some limitations. first, the single-center design, which partially restricts the generalizability of our findings. second, only a minority of patients suffered from neurological diseases without other comorbidities, limiting the conclusions on the association between neurological pathology alone and severe covid- . third, the observations on the prevalence of each neurological disorder, and thus the ability to discriminate disease-specific associations with covid- , are limited by two factors: a) the evaluation of patients admitted to er, which could represent a selection bias towards older people, and b) the lack of adjustments for the relative prevalence of each neurological disease in the general population. in conclusion, our study reports the prevalence of different neurological diseases in a large cohort of patients with covid- , assessing their association with the infection severity. in our sample, patients with pre-existing neurological diseases showed a significantly higher risk for severe infection, in particular when associated with other comorbidities, suggesting that this population deserves a thorough evaluation since the earliest phases of overt or suspected covid- . finally, our findings suggest a particular attention in targeting patients with neurological diseases for proactive viral screening. acknowledgments open access funding provided by università degli studi di torino within the crui-care agreement. the authors would like to express their gratitude to all the clinicians and front line staff engaged in the care of covid- patients, and to general and health management department (g. la valle, l. angelone, v. alpe. a. scarmozzino) of "città della salute e della scienza hospital", turin, for the great work carried out during this sanitary emergency. authorship statement ar: conception and design of the study; analysis and interpretation of data; writing the first draft. rb: acquisition, analysis and interpretation of data; critical revision for important intellectual content. gi: acquisition, analysis and interpretation of data; critical revision for important intellectual content. gc: interpretation of data, revising the manuscript for content. fr: interpretation of data, revising the manuscript for content. caa: interpretation of data, revising the manuscript for content. mb: interpretation of data, revising the manuscript for content. bf: interpretation of data, revising the manuscript for content. em: interpretation of data, revising the manuscript for content. em: interpretation of data, revising the manuscript for content. mgr: interpretation of data, revising the manuscript for content. gv: interpretation of data, revising the manuscript for content. mz: interpretation of data, revising the manuscript for content. ll: conception and design of the study; analysis and interpretation of data; revising the manuscript for content. all the co-authors listed above gave their final approval of this manuscript version. all the co-authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. financial disclosures dr romagnolo has received grant support and speaker honoraria from abbvie, speaker honoraria from chiesi farmaceutici and travel grants from lusofarmaco, chiesi farmaceutici, medtronic, and ucb pharma. data access and responsibility statement a. romagnolo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. conflicts of interest dr balestrino has no financial conflicts to disclose. dr imbalzano has no financial conflicts to disclose. dr ciccone has no financial conflicts to disclose. dr riccardini has no financial conflicts to disclose. dr artusi has received travel grants from zambon and abbvie. dr bozzali has no financial conflicts to disclose. dr ferrero has no financial conflicts to disclose. dr montalenti has no financial conflicts to disclose. dr montanaro has received travel grant from ralpharma. dr rizzone has received grant support and speaker honoraria from medtronic and ucb. dr vaula has no financial conflicts to disclose. dr zibetti has received honoraria from medtronic, zambon pharma and abbvie. dr. lopiano has received honoraria for lecturing and travel grants from medtronic, ucb pharma, and abbvie. ethics approval this study received approval from the ethical standards committee on human experimentation (comitato etico interaziendale aou città della salute e della scienza di torino, ao ordine mauriziano di torino, asl città di torino; protocol number / , approved may th, ), and patients gave their written informed consent. the authors declare that they acted in accordance with the ethical standards laid down in the declaration of helsinki. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. covid- situation reports. world health organization (who) coronaviridae study group of the international committee on 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eight of them had concurrent ischemic stroke during the viral disease. here, we describe the clinical and imaging features, and outcome, of these patients. stroke occurred, while in hospital in six patients and at home in the other two patients. all of them met the diagnostic criteria for severe covid- as previously defined [ ] . detailed description of cases is provided in the supplementary material (online resources , ). one was a woman and seven ( %) were men, with a median age of . years ( table ). none of them had had a previous stroke. hypertension was the most common vascular risk factor ( %). four patients were on antithrombotic therapy prior to admission: three patients were on antiplatelets (one as a secondary prevention after myocardial infarction, and two as a primary prevention due to a high vascular risk); and one on acenocoumarol due to atrial fibrillation. all the patients who suffered in-hospital strokes were on standard thromboprophylaxis with enoxaparine since admission except for the patient with atrial fibrillation, who was on subcutaneous enoxaparine mg bid. ischemic stroke occurred a median of . days after the onset of covid- symptoms (interquartile range, iqr . - . ). among hospitalized patients, stroke occurred a median of . days after admission (iqr . - . ). bilateral lung infiltrates on chest x-ray were present in all. at the time of stroke, turbidimetric d dimer was > , µg/l in % ( / ) of patients (median , µg/l; iqr - , ; normal value < µg/l). antiphospholipid antibodies were not obtained. overall, five strokes involved one cerebral arterial territory and three involved two or more arterial territories. all of them were large artery infarctions as diagnosed by clinical and cranial ct findings (four anterior circulation infarctions, three posterior circulation infarctions, and one with both anterior and posterior circulation infarctions). magnetic resonance imaging was not performed on any patient. only one patient met definite toast criteria for the diagnosis of large artery atherosclerotic infarction, and another one had a probably cardioembolic stroke due to preexisting atrial fibrillation (incomplete evaluation) [ ] . none of the other six patients met diagnostic criteria for atherosclerotic, cardioembolic, or small vessel ischemic stroke (three with cryptogenic strokes, and three with incomplete evaluation). intraarterial thrombi with absence of significant atherosclerotic plaques were observed in the intracranial or supra-aortic arteries in three out of four patients in which ct angiograms were obtained. four patients did not undergo ct angiography due to a worsening in their respiratory and neurological performance despite therapy. limitation of the therapeutic effort was applied in these cases, and patients died early after the stroke diagnosis without additional diagnostic workup. two patients had other thrombotic disorders electronic supplementary material the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. (one with a pulmonary embolism, patient no. in supplementary table; and another one with a floating aortic arch thrombus, patient no. ) . none of the patients met criteria for receiving reperfusion therapies of the occluded arteries. two of them were started on acetylsalicylic acid, and four received subcutaneous enoxaparine mg/kg bid. on evolution, four patients ( %) died, one remains in a minimally conscious state, one has a severe focal neurological deficit (left middle cerebral artery syndrome), and two have moderate focal neurological deficits, after a median follow-up of days for survivors. in this series of eight patients, although the evidence is limited by its observational nature and sample size, severe covid- was associated with non-atherosclerotic, large artery ischemic strokes. a high frequency of vertebrobasilar territory involvement was noted, and most patients did not meet diagnostic criteria for common causes of ischemic stroke [ ] . observed cumulative incidence of ischemic stroke during the period included in this series largely exceeds the expected incidence for our , admitted subjects during the days evaluated [ ] . at this point, in the growing knowledge about the mechanisms underlying the high morbidity and mortality associated to covid- , an atypical and enhanced form of acute coagulopathy secondary to endothelial disfunction and an inflammation-mediated prothrombotic state seem to be playing an important role. in the context of severe disease, vascular wall inflammation can initiate thrombus formation by activating endothelial cells, platelets, and leukocytes, which would trigger the coagulation pathway [ ] [ ] [ ] . this may induce a prothrombotic state that confers a high risk for ischemic stroke, either by a direct damage to a previously healthy endothelial wall or by enhancing a thrombotic effect in cases where a specific cause, such as atherosclerosis, is present [ , ] . if larger prospective studies confirm these observations, hypercoagulability associated with covid- might be a contributory cause for large vessel ischemic stroke. until robust evidence is available, the observation of intraarterial thrombi in the absence of significant atherosclerosis among these patients warrants consideration of individualized enhanced thromboprophylaxis for hospitalized patients with severe forms of sars-cov- infection. clinical characteristics of coronavirus disease in china classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment sars -cov- and stroke in a new york healthcare system. stroke strokeaha stroke and transient ischemic attack incidence rate in spain: the iber-ictus study prominent changes in blood coagulation of patients with sars-cov- infection endothelial cell infection and endotheliitis in covid- characteristics of ischaemic stroke associated with covid- pathological inflammation in patients with covid- : a key role for monocytes and macrophages large-vessel stroke as a presenting feature of covid- in the young acknowledgments to the members of the "infanta leonor thrombosis research group"; to dr. pablo ryan; and to darryl solochek for editing the manuscript.funding none. conflicts of interest on behalf of all authors, the corresponding author states that there is no conflict of interest.ethical standard this study belongs to the covid- @vallecas cohort. the study has been approved by the hospital universitario infanta leonor ethics committee and has, therefore, been performed in accordance with the ethical standards laid down in the declaration of helsinki and its later amendments, and with the spanish data protection laws.consent to participate written informed consent was waived due to the retrospective nature of the study. collected data were anonymized, and each patient was identified by a unique alphanumeric identification code. key: cord- -i dh u i authors: ferini-strambi, luigi; salsone, maria title: covid- and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: i dh u i neurological disorders and coronavirus (covid- ) pandemic are two conditions with a recent well-documented association. intriguing evidences showed that covid- infection can modify clinical spectrum of manifested neurological disorders but also it plays a crucial role in the development of future diseases as long-tem consequences. in this viewpoint review, we aimed to assess the vulnerability to sars-cov- infection and development of covid- among neurological disorders. with this in mind, we tested the hypothesis that age rather than neuropathology itself could be decisive in neurodegenerative diseases such as parkinson’s disease, whereas neuropathology rather than age may be critical in neuroimmunological diseases such as multiple sclerosis. highlighting the role of potential susceptibility or protection factors from this disastrous infection, we also stratify the risk for future neurodegeneration. recent evidence links neurological disorders to coronavirus (covid- ) pandemic, a condition which from december to today has upset our lives, becoming our world a different place. it is a novel form of human coronavirus reported for the first time in wuhan, china which recognizes as causative agent sars-cov- (severe acute respiratory syndrome coronavirus ) [ , ] . sars-cov- is a nonsegmented positive-sense rna virus belonging to the family of coronaviridae and is the seventh coronavirus known to infect human [ , ] . in the context of emerging research, covid- infection can exacerbate the clinical spectrum of manifested neurological diseases. on the other hand, recent findings have been thrust into the spotlight the potential role of this novel coronavirus in the future development of neurological diseases making the neurobiological link between these two conditions even more interesting. this interaction, however, should not be unexpected. it is well-known that coronaviruses can be detected in the central nervous system (cns) of patients with parkinson's disease (pd), alzheimer disease (ad) and multiple sclerosis (ms) [ ] . human and animal models demonstrated that also sars-cov- is able to infect the brain including the brainstem [ ] entering directly through the olfactory nerves and interestingly without an initial lung involvement [ ] . a possible explanation is that the infection develops as the virus glycoprotein spike binds to ace (angiotensin-converting enzyme ) receptors. these receptors are widespread in the brain, not only cardiorespiratory centers in the medulla, but also in the dopamine neurons of striatum [ , ] . the existence of a close relationship between covid- and neurological disorders brings up some fundamental questions: first, whether the relationship is causal, specifically does one condition itself increases the incidence or morbidity/mortality of the other; second, whether and in what way covid- infection modifies the clinical course of pre-existing neurological disease. thus, it is crucial to consider not only the perspectives from which we analyze these questions but also the field of neurology in which we move, for instance neurodegenerative versus neuroimmune diseases. considering that neurodegenerative disorders may commonly occur in elderly patients whereas that neuroimmune in young people, this comparison might be intriguing. from a pathogenetic perspective, it is need to investigate whether the age rather than the neuropathology itself might be a potential risk factor and vice versa. from a clinical perspective it is important to investigate whether clinical features related to the pathology, for instance rigidity respiratory system in chronic neurodegenerative diseases as parkinson's disease (pd) may be a risk factor for the development of complications and long-term neurological sequelae. from a therapeutic perspective, it might be crucial to know whether antiviral agents such as amantadine commonly used for pd-treatment, could prevent the clinical manifestations of covid- infection. despite significant progress made from neurologists and researchers worldwide in a very short time, several issues remain still unsolved. the main goal of this viewpoint review is to assess the vulnerability to sars-cov- infection and development of covid- among neurological disorders with different pathogenesis and age-related targets such as neurodegenerative vs neuroimmunological diseases. we also highlight potential susceptibility or neuroprotective factors from this disastrous infection. in this section, we will discuss the impact of sars-cov- viral infection for patients with neurodegenerative conditions with a magnifying glass on patients with movement disorders and dementias. since sars-cov- effects on neurodegenerative, as well as neuroimmune diseases, might vary across the different pathogenesis and clinical features, we consider the evidence within three sections: (i) vulnerability to the infection; (ii) modification of the clinical course of disease, in relation to clinical neurological manifestations, disease progression and innovative strategies, to support clinicians in the management of the disease; (iii) trigger for future neurodegeneration. there are at least two well-consolidated evidence linking covid- to movement disorders, especially for pd. first, the presence of antibodies against coronavirus in the cerebrospinal fluid of patients with pd revealed more than decades ago [ ] . second, the ability of coronaviruses to enter the brain through the nasal cavity causing anosmia/ hyposmia [ ] . the facts that hyposmia is a common premotor feature of pd and that olfactory bulb is a selective target of the deposition of alpha-synuclein pathology [ ] , might to be more than just a coincidence. in a recent editorial focused on movement disorders in the world at the time of covid- , jon stoessl et al. report that to date there is no evidence that patients with movement disorders are at increased risk of coronavirus infection, compared to individuals with similar age and comorbidities [ ] . to answer emerging questions on this topic fasano et al., conducted a single-centre case-controlled survey describing clinical features/predictors of covid- infection and outcome in a relatively unselected and homogeneous large cohort of pd patients from one of the largest tertiary centers of milan, italy [ ] . they identified pd patients, confirmed and probable cases of covid- . basing on their results, covid- risk, morbidity and mortality in patients with mild to moderate pd do not differ from the general population [ ] . in line with these evidences, a retrospective cohort study conducted in japan showed that, patients with parkinsonism hospitalized for pneumonia had a lower rate of in-hospital mortality as compared to age-and sex-matched patients [ , ] . contrasting results has been reported by antonini et al., in a small simple size as pd patients of older age with longer disease duration were particularly susceptible to covid- with a substantially high mortality rate [ ] . taken together, these findings suggest that although pd patients may represent a particularly vulnerable population for age-related target, respiratory muscle rigidity related to the disease, and presence of several comorbidities, pd by itself do not appears increase the risk of being infected by sars-cov- and developing covid- ( fig. ) . eleopra et al. performed the first community-based case-control study describing the effects of symptomatic covid- on motor and non-motor symptoms [ ] . in their cohort consisting of patients with pd resident in lombardy, twelve covid- cases had mean age and disease duration similar to the controls. their pd patients experienced substantial worsening of both motor and non-motor symptoms (especially urinary issues and fatigue), during mild-to-moderate covid- illness independently of age and disease duration. fatigue as dominant non-motor symptom has been also reported during the sarscov- infection in pd cases described by antonini et al., [ ] . by contrast, cognitive functions were marginally involved, while none experienced autonomic failure [ ] . clinical deterioration observed in pd patients might be explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy and required therapy adjustment in one-third of cases [ ] . the impact of covid- on pd patients, however, cannot be restricted only to motor symptoms since indirect effects related to the prolonged immobility under lockdown, as the impact of stress, self-isolation, social distancing and anxiety should be considered. in this context, a recent iranian cross-sectional, case-control survey evaluated the level of anxiety among pd patients compared with caregivers and the general population [ ] . highest frequency of anxiety has been found in the pd subgroup followed by their caregivers. in addition, a strong correlation between severity of anxiety in pd patients and fear of getting covid has also been reported by the authors [ ] . another consequence of covid- pandemic concerns the marked reduction in physical activity [ ] . this aspect should be not remiss since physical exercise may attenuate clinical symptom progression in pd patients [ ] [ ] [ ] . in line with these evidences, shalash et al. investigated the impact of the covid- pandemic on the mental health, physical activities, and quality of life of pd patients [ ] . compared with controls, pd patients complained a negative impact on their mental health, physical activity, and health care and an interest in virtual visits [ ] . in addition, pall k et al., reporting the perceptions and implications of covid- in indian pd patients and their caregivers, confirmed the impaired mental health, physical activity, and quality of these patients [ ] . the study also highlights the importance of managing these issues and continuing care of pd patients, particularly by adopting telemedicine [ ] . the fact that pd patients shows a negative impact on their mental health during lockdown period is not surprising. sudden changes usually require a flexible adaptation to new circumstances, a condition strongly related to normal dopaminergic functioning. indeed, pd patients may experience cognitive inflexibility, as a result of nigrostriatal dopamine depletion that forms the pathophysiological substrate of pd [ , ] . to further complicate the precarious situation of coexistence with covid- infection, there was the limited access to the routine-visits to the hospital to preserve pd patients from becoming infected. thus, in this "new world" in which the care for our patients is significantly changed, the most important challenge for clinicians has been to reinvent their work and the greater opportunity, the telemedicine with digital-visits, e-mails or text messages, and simple telephone consultations. in this context, the movement disorders society (mds) telemedicine study group has created a "step-by step" guide for assisting the movement disorders neurologists worldwide [ ] . a further step forward in this direction, has been made thanks to the work of goetz cg et al., in assessing reliability and validity of video-based mds-unified parkinson's disease rating scale examinations compared with in-office visits [ ] . finally, digital rehabilitation (e-rehabilitation) strategies including virtual rehabilitation platform as an alternative mode to deliver rehabilitation services at the community level [ ] should be encouraged. although the telemedicine is not superior to the quality of care with regular in-person visits, and is not yet established universally for virtual management of patients, a growing body of evidence suggests that it is associated with comparable outcomes, and offers greater efficiency and service for pd patients [ ] . in summary, covid- complicates the clinical course of pd resulting in a worsening of motor and non-motor symptoms, increased anxiety with severe complications on the quality of the life and mental health. in the covid- era, telemedicine has had a special role. finally, several cross-sectional and longitudinal studies are, however, needed to better clarify the causal links between clinical and the severity of covid- , systemic inflammatory response with the fact that cortex and substantia nigra, the brain regions with higher possibilities of sarscov- penetration by ace are the same associated with the most frequent neurodegenerative diseases [ ] is not a simple coincidence. lippi et al. investigated the potential role of sars-cov in the future development of neurodegenerative diseases, specifically pd [ ] . a new model of neurodegeneration as sars-cov promoting the accumulation of the alpha-synuclein (asyn), the major protein component of lewy bodies in the brain, has been proposed. to explain this phenomenon, the authors put the spotlight cellular pathways affected by the viral infection such as proteostasis precious in contributing to a dynamic equilibrium and activating stress response mechanisms that appear to be the same targets involved in neurodegenerative process [ ] . in line with these evidences, the h n infection of dopaminergic cells resulted in the formation of asyn aggregates and not of other proteins suggesting am highly specific nature of this process [ ] . in addition, in vitro models indicate that triggers alterations in proteostasis might lead to the accumulation of toxic insoluble proteins [ ] . these suggestive findings indicate that sars-cov infection might trigger pd-neurodegeneration by accelerating aging in brain tissues (fig. ). in our ageing society, dementia itself has emerged as a pandemic condition [ ] . thus, the management of a pandemic in the pandemic such as the covid- , brings up some concerns. first, the combination between two potential risk factors such as age and dementia for mortality in patients affected by covid- . second, the complex impact of concomitant covid- outbreak and dementia: the impact of confinement and social distancing on neurocognitive performance of these fragile patients, need to better investigated. it is well-documented that elderly individuals are at a higher risk for mortality after sars-cov- infection. indeed, the estimated median age for all covid- related death is years, and the case fatality rate in patients aged ≥ years is > % [ ] . limited data are, however, available for covid- in older patients, and few reports have focused on patients aged ≥ years [ ] [ ] [ ] . all this has been reported in older patients without dementia. what happened when two potential risk factors (age and dementia) are coexisting? covino et al. provided a risk stratification in this population [ ] . results from this single-center, retrospective, observational study, carried out in a referral center for covid- in central italy, showed that the risk of death could be not age dependent whereas severe dementia itself may be a relevant risk factor in these patients [ ] . in line with these evidences, bianchetti et al. assessed prevalence, clinical presentation and outcomes of dementia among subjects hospitalized for covid infection. data from subjects admitted to acute hospital in brescia province, northern italy were retrospectively analyzed. compared to subjects without dementia, patients affected by dementia showed a higher mortality about % [ ] . taken together, these finding suggest dementia, especially in the advanced stages of the disease, might represent an important risk factor for mortality in covid- patients (fig. ) . patients with ad patients are vulnerable to disasters and crisis, because of their neurocognitive impairments and rich neuropsychiatric symptomatology. this is especially true during a humanitarian crisis such as covid- pandemic. about the % of ad patients may exhibit at least one neuropsychiatric symptom over the course of their disease [ ] . these features are typically fluctuating, emerging in more advanced ad, even if can also manifest in early the prodromal stages [ ] . indeed, among the ad clinical spectrum, neuropsychiatric symptoms including depression, anxiety, apathy, agitation, and hallucinations appear to be subjected to a sudden deterioration. moreover, it should also be considered the consequences of these features: (i) increased rate of disease progression and institutionalization; (ii) alteration of the treatment responses and prognosis [ ] ; (iii) decrease of the patients' quality of life [ ] . to investigate the occurrence and severity of neuropsychiatric symptoms during the covid- confinement is need. in line with this, boutoleau-bretonniere et al. offered the first investigation of the effects of confinement during the covid- crisis on neuropsychiatric symptoms in ad [ ] . their results showed that only about % of ad patients demonstrated neuropsychiatric changes during the confinement. the duration of confinement significantly correlated with the severity of symptoms, as well as with their caregivers' distress. interestingly, the confinement exacerbated neuropsychiatric symptoms in patients with low cognitive function in ad, whereas no such symptoms were induced in patients with more preserved cognition [ ] . in line with these evidences, other authors demonstrated the worsening of neuropsychiatric symptoms, with agitation, apathy and aberrant motor activity being the most affected symptoms, in ad and mci during weeks of lockdown in spain [ ] . concerning the clinical presentation of covid- in subjects with dementia, there is concordance that it may be atypical, especially in most advanced and severe diseases thus reducing early recognition of symptoms and hospitalization. indeed, in patients with ad the classic symptoms of covid- infection such as fever, dyspnea and cough were less frequent, while they mainly experienced diarrhea or drowsiness [ , ] . finally, delirium caused by hypoxia, a prominent clinical feature of covid- , could complicate the presentation of dementia thus needing for dementia care and support [ , ] . despite the preliminary nature, these findings confirmed the expected worsening of clinical spectrum, especially neuropsychiatric symptoms during covid- pandemic in ad patients. considering the complex nature of the interaction between covid- and dementia, the international recommendations suggest to provide worldwide support for patients with dementia. multidisciplinary teams, as well as a digital revolution are urgent need. responding to this need, the american academy of neurology has also developed a guidance for clinicians and practices to implement telemedicine services amid the covid- crisis [ , ] . cuffaro et al. [ ] recently suggest that telemedicine and digital technology devices, including smartphones can be really helpful in remote monitoring and care of people with dementia. moreover, technological devices as videoconference or smartphone apps might be used for follow-up visits and support to patients and to acquire digital markers of clinical progression of the disease [ ] . whether tele-rehabilitation platforms for neurorehabilitation care including physical, language and cognitive rehabilitation, exergaming, with remote supervision will be offered, this emergency will produce long-term healthcare positive [ ] . in summary, despite the preliminary nature these findings confirmed the expected worsening of clinical spectrum, especially neuropsychiatric symptoms during covid- pandemic in ad patients. a digital revolution to support the clinicians in the management of these fragile patients is need. although the long-term implications of sars-cov- and its effects on the brain are not well known, its potential role in the future neurodegeneration may be of importance to the field of ad research (fig. ) . severe outcomes after sars-cov- infection are often associated with a "cytokine storm" of pronounced inflammation causing an increase of proinflammatory cytokines such interleukin- (il- ), and il- [ ] . in ad patients, this may synergize with amyloid-stimulated type i interferon (ifn) response thus creating the "perfect storm" [ ] . this might explain why pre-symptomatic people with undiagnosed ad may see an acceleration of symptoms due to a bout of systemic inflammation resulting from sars-cov- infection [ ] . in addition, other authors hypothesized that affected patients may be at higher risk of developing cognitive decline after overcoming the primary covid- infection [ ] . pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. on the basis of these findings, it possible to speculate that there may be a population at risk to develop neurodegenerative diseases unmasked through silent viral infection in the brain. in the context of emerging covid- pandemic, an urgent attention should be focused on a population of particular interest such as that neuroimmunological disorders. in this section, we will discuss the impact of the sars-cov- viral infection for patients with these conditions with a magnifying glass on patients with multiple sclerosis (ms). no consistent data are to date available for other neuroimmunological disorders such as neuromyelitis optica spectrum disorders, guillain-barré syndrome or chronic dysimmune neuropathies. it is not surprising that ms may represent a population of particular interest: first, for the immunological nature itself of the disease; second, for the clinical management regarding the disease-modifying therapies (dmts) able to alter the immune functions and thus increase the susceptibility covid- . the early identification of potential risk factors becomes crucial to identify an individual strategy concerning the clinical management of these critical patients during the covid- pandemic. the relationship between covid- and ms is complex. the coronavirus family has been previously investigated for a potential association with ms, and more recently has been utilised to make a mouse model of the disease [ ] . it has further been complex the challenge for neurologists worldwide to stratify the risk of the viral infection in ms patients, especially those receiving immunosuppressant or immunomodulatory therapy. although it has been documented that ms patients may theoretically have an increased risk of the infections compared with the general population, it remains until debated whether ms patients are or not at high-risk to be infected by sars-cov- and to develop covid- . in a recent month's journal club, willis md et al. considered three papers relevant to answer these questions [ ] . the first study aimed to characterize the infection risk of patients with ms compared with a cohort of patients without ms, using two large databases with a long followup time [ , ] . according with the results, ms patients were demonstrated to be at an increased risk generally of infections, and of infections requiring hospitalization. the second study aimed to examine the risk of serious infections associated with routinely used ms dmts as well as rituximab, which is commonly used in this population [ , ] . ms patients treated with dmts are at a generally increased risk of infections, with rituximab associated with the highest rate of serious infections [ ] . in addition, a populationbased retrospective cohort study investigated the association between ms dmts and risk of infections [ ] . their main results demonstrated that the exposure to a second generation dmt was associated with an increase in the risk while of first generation were not associated. of note, with ifn-β was associated with a lower risk of pneumonia. in line with this preliminary evidence, fan m et al. reported no increased risk of covid- infection was ms or nmosd, irrespective of whether these patients received dmds. a possible explanation for this phenomenon is that stringent preventive measures adopted by neurologists to reduce covid- infection in these patients may have contributed to low risk of covid- infection [ ] . finally, data from the world health organization, has not yet been translated in relation to this cohort of covid- patients who are on dmt [ ] . louapre et al. very recently also reported that age, edss, progressive course of ms, male sex and comorbidities including cardiovascular and pulmonary diseases, diabetes, and obesity, were identified as risk factors [ ] . the presence of dmt, however, was not associated with severity of covid- infection having a lower risk of hospitalization in their univariate analysis [ ] . taken together, these findings suggest that, although it has initially been reported an increased risk to covid- infection in ms patients, to date the risk estimate for the ms patients remains until debated. results from a pilot phase of an investigation of covid- among people with ms, based on a core set of data collected on patients from centers, indicated that the severity of covid- infection classified as mild (no pneumonia or mild pneumonia) was present in about % of the ms patients [ ] . louapre et al. also described the clinical profile and outcomes in patients with ms and covid- . these authors performed a multicenter, retrospective observational cohort study in ms patients presenting with a confirmed or highly suspected diagnosis of covid- between march , , and may , [ ] . their main outcome was covid- severity assessed on a -point ordinal scale [ranging from (not hospitalized with no limitations on activities) to (death)] with a cut off at (hospitalized and not requiring supplemental oxygen). seventy-three patients had a covid- severity score of or more. as occurring in general population, fever and dyspnea were more common in ms patients hospitalized for covid- while anosmia/ageusia and headache were more common in patients who were not hospitalized [ ] . considering that cognitive dysfunction usually affects up to % of ms patients, it is not surprising that these patients are vulnerable to develop neuropsychiatric symptoms during covid- pandemic [ ] . thus, ms specialists should adapt a strategy to monitor ms patients for neuropsychiatric complications and also opt for applicable treatment options [ ] . acute and long term effects of covid- on disease course of ms population should a subject for future research. now, it is also the time of resilience: this disastrous pandemic may be a great opportunity for databases promoting ms research and collaboration [ ] . considering the clinical relevance of this issue and that, italy was the first european country involved in a covid- pandemic, the italian multiple sclerosis society (aism), the italian multiple sclerosis foundation (fism), and the multiple sclerosis study group of the italian neurological society have set up a program to help with these crucial elements in the response to covid- in patients ms [ ] . regarding the clinical management of these critical patients, the risks and benefits of immunoactive treatments and adjustments to these treatments must be assessed [ ] . in this suggestive picture the protective role of the first-generation dmts such as interferon-beta (ifn-β) is emerging [ ] . future studies, however, to examine the efficacy of interferon ifn-β alone or in combination with other drugs to treat severe or critically ill patients with confirmed covid- compared with placebo are warranted [ ] . an interesting window in covid- era is opened on the teriflunomide in ms. recent observations suggest that teriflunomide may not need to be discontinued in ms patients who develop an active covid- infection [ ] . finally, the special role of telemedicine in covid- pandemic emerged especially in the management of ms patients. bonavita s et al. proposed a possible approach for the remote monitoring of infection risk in people with ms, especially those on immunosuppressant drugs, during the pandemic. this tool will also limit unnecessary accesses to the ms centers reducing the risk of spreading the infection [ ] . despite the existence of a close relation between neuroinflammation and neurodegeneration in ms brains [ ] , to date no enough evidence is available regarding the long-term implications of sars-cov- as potential role in the future neurodegeneration in these patients. the covid- pandemic, a novel condition that in this few months has been completely storming the planet, brings with it an intense trail of mysteries. first of all, the reason why some subjects are completely asymptomatic while others develop deadly consequences. second, the reason why some neurological diseases are more vulnerable than others to contracting the virus and developing nefarious complications. there necessarily is something that protects and similarly something that damages. with this in mind, we identified among neurological conditions with different pathogenesis and age-related targets, the protection and susceptibility risk factors against this global pandemic. it is singular that covid- risk, morbidity and mortality in pd, a population with an intrinsically increased vulnerability for many risk factors, such as age, respiratory muscle rigidity and comorbidities, do not differ from the general population. whether this is true, we can speculate that pd neuropathology itself might exercise a neuroprotective effect against covid- infection for some reasons. firstly, the modality of brain penetration of sars-cov- could be considered. it is well-known that the infection develops as the virus spike binds to ace receptors, highly expressed in the dopamine neurons of striatum [ , , ] . it is equally well-documented that pd patients show reduced nigrostriatal dopamine neurons of substantia nigra as result of the lewy-body neurodegeneration. it is likely that the sars-cov neuroinvasion may be reduced in these patients. secondly, the protective role of α-synuclein against the sars-cov- infections can be considered [ ] . it has been recently reported that α-synuclein plays a crucial role in the covid- infection: by exercising inhibiting the viral neuroinvasion, by offering protection against proinflammatory responses, by facilitating immune reactions against infections being implicated in microglia process [ , ] . thirdly, the neurobiology of sars-cov- infection in pd can be considered. gomez-pinedo et al. reviewed some pathological cases covid- reporting no gliosis, microgliosis, and markers of inflammatory signs in brain tissue while the virus was observed inside vacuoles and/or inclusions [ ] . vacuoles containing virus have been reported in mers-cov and sars-cov infection [ ] . finally, pd patients may potentially protected by the specific treatment such as amantadine, a drug for years used for the treatment of influenza. it able to inhibit the viral replication by blockade of the influenza m ion channel required to deliver viral ribonucleoprotein into the host cytoplasm [ ] . although the therapeutic implications of amantadine are unknown, it also appears block a pore in the envelope protein of sars-cov [ ] . differently from pd patients, that with ad show a higher mortality compared to subjects without dementia. this phenomenon, however, could be not age dependent and identifies other causes: first, the ad neuropathology itself. amyloid fibrils may entrap viral particles, pathogens and subsequently leading to further activation of the "microglial neurodegenerative phenotype" [ ] . this subset of microglia causes an increased expression of ifn pathway, a crucial component both in ad and covid- infection. indeed, ifn was found to stimulate complement cascade activation and promote synapse elimination with an enhancement of the immune response [ ] . in this viewpoint, the suppression of ifn response in both ad and covid- (or comorbidity of the two) might a potential strategy for controlling the excessive immune response [ ] . second possible cause is the presence of comorbidities. individuals with dementia are more likely to have cardiovascular disease, diabetes, and pneumonia compared to individuals of the same age without dementia [ ] . in particular, the co-occurrence of obesity and type diabetes could place these populations at an increased risk for severe covid- pathology and mortality [ ] . to corroborate this hypothesis, a consumption of a diet rich in fat and refined carbohydrates and sugars, and low levels of fibers activate the innate immune system and impairs adaptive immunity, leading to chronic inflammation and impaired host defense against viruses [ ] . third possible cause is the social behavior of ad patients. indeed, individuals with dementia are unable to follow the recommendations from public health authorities to reduce the transmission of covid- : hand hygiene, wearing masks, covering one's mouth and nose when coughing, maintaining physical distance from others, ignoring the warnings and lacking sufficient, could expose them to higher chance of infection [ , ] . thus, it is early to know whether dementia itself may be considered a potential risk factor for covid- infection because the presence of confounding factors linked to the inconsistent social behaviors and comorbidities. from a theoretical perspective, it is believable that covi-d pandemic virus may exacerbate ms disease. with the aim to discuss recent data indicating a strict correlation especially between edss and age and covid- severity and no association with dmts exposure, some reflections are due. first, the immunological nature of ms disease and covid- infection. in the context of emerging literature, edss has been reported associated with the highest variability of covid- severe outcome [ ] . a possible explanation is that morbidity and mortality in covid- can result from an overlapping between immune response caused by the virus and the immunological state of the subjects. to block the viral infection, both innate and adaptive immune responses are really crucial. viral infection is prevented through innate immunity with type i interferons inhibit and natural killer (nk) cells while is combatting through the adaptive immune response with immunity generated by antibodies and cytotoxic t lymphocytes (ctl), especially cd + t [ ] . thus, it is possible to speculate that in patients with pre-existing impaired regulation of immune responses such as ms, covid- infection may trigger a further amplification of immune pathways. second, age and covid- infection. age has been reported to be associate with the highest variability of covid- severe outcome [ ] . age, however, was identified as a major risk factor for the severity of covid- infection. thus it is not surprising that also in ms population consisting of a substantial number of individuals with ms are older than years, it is independent risk factors for covid- severity [ ] . third, dmts and covid- infection. do these drugs have a harmful or protective effect? dmts limit the immune response, in theory, thus allow for greater viral replication and potentially worse infection. on the other hand, limiting cytokine storm and the exaggerated immune response induced by sars-cov- infection, these drugs may have some protective and beneficial effects against this novel virus. in addition, most dmts do not particularly target the innate immune system and few have any major long-term impact on cd + t cells to limit protection against covid- [ ] . there are not, however, enough data on dmt to indicate about susceptibility or protection from civodinfection of these drugs in ms. other important point to consider in future, is whether/how dmt affect responses to vaccination, as the ultimate measure to contain the pandemic. overall, we can summarize that despite the risk estimate of covid- complications on young people with ms patients remains until debated, attention should be placed in older ms patients with a progressive course of the disease. the second outcome of our investigation has been to stratify the risk for future neurodegeneration as long-term sequelae of covid- infection. pd and ad patients showed salient differences concerning the brain neuroinvasion (reduced ace receptors in pd) and neurobiology of the virus (amyloid fibrils able to capture viral particles), but also on the pathogenic mechanisms leading to future neurodegeneration. while sars-cov infection triggers pdneurodegeneration by accelerating aging and accumulation of abnormal proteins in brain tissues, the amyloid-stimulated ifn response resulting in neuroinflammation would be the basis of ad-neurodegeneration. this is not surprising since the association between pathological levels of neuroinflammation and ad and other forms of dementia is well-known. these findings represent an important advantage in the future, opening a novel therapeutic window: ad treatments increasing acetylcholine levels has been proposed in controlling inflammation and preventing a "cytokine storm" after sars-cov- infection [ ] , thus reducing the risk of development ad-neuropathology over the time. finally, no enough evidence is available regarding the covid- implications in ms related-neurodegeneration. in this review, we asked whether age rather than neuropathology itself might make more vulnerable a specific neurological disease to covid- infection, especially neurodegenerative versus neuroimmunological disorders. thus, we entered in an intriguing but select research window and this might represent a limitation of the study. however, we are confident that most of the existing literature concerning the covid- impact on 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triage for people with multiple sclerosis in the age of the relation between inflammation and neurodegeneration in multiple sclerosis brains amit bar-or a ( ) covid- and ms disease-modifying therapies the underpinning biology relating to multiple sclerosis disease modifying treatments during the covid- pandemic acknowledgement no funding was received for this study.author contributions all authors contributed to the study concept and design, to data acquisition and analysis, and to drafting manuscript and figures. conflicts of interest the authors declare that they have no competing interests. key: cord- -zrvykzof authors: zuhorn, frédéric; omaimen, hassan; ruprecht, bertram; stellbrink, christoph; rauch, michael; rogalewski, andreas; klingebiel, randolf; schäbitz, wolf-rüdiger title: parainfectious encephalitis in covid- : “the claustrum sign” date: - - journal: j neurol doi: . /s - - -y sha: doc_id: cord_uid: zrvykzof nan included positive serum antibody indices for sars-cov- . on day , respiratory deterioration required endotracheal intubation and treatment of bacterial superinfection was started according to antibiogram. eight days later, the patient could be extubated and pcr tests were negative for sars-cov- . yet, the patient continued to show concentration difficulties and delirious behavior. subsequent mri (fig. a c) revealed signal alterations within the claustrum/external capsule region, showing reduced diffusion. cerebrospinal fluid (csf) analysis disclosed a mild lymphocytic pleocytosis with negative test results for common neurotropic viruses. tests in serum and csf were also negative for various antineuronal antibodies. the patient recovered and was discharged with only mild cognitive impairment. follow-up has been carried out four months later showing a normalization in cell count of csf and improvement of mri findings, although the claustrum lesions persisted. clinically, his neurological and cognitive status was normal. our case is characterized by evidence of parainfectious autoimmune encephalitis in the context of severe covid- pneumonia. clinically, the patient presented with various neuropsychiatric symptoms, which were reported before in other covid- patients with encephalopathy [ ] . neither sars-cov- itself nor antibodies against the virus were found positive in the csf, precluding direct viral cns infection. comprehensive laboratory tests ruled out antineuronal antibodies as well as common infectious causes of encephalitis, altogether supporting the diagnosis of parainfectious autoimmune encephalitis. in addition, the diagnostic criteria for possible autoimmune encephalitis as proposed by gaus et al. were met [ ] . while immunological markers remained unspecific and imaging findings of acute necrotizing encephalitis were absent in our patient, brain mri disclosed a unique pattern, a.k.a. the claustrum sign. previously, this sign has been coined in mri studies of autoimmune epilepsy, where an immune-inflammatory-mediated encephalopathy is suspected [ ] . the claustrum is known to play a crucial role in regulating consciousness [ ] correlating well to the randolf klingebiel and wolf-rüdiger schäbitz both authors contributed equally to this work. clinical findings of impaired levels of consciousness in the presented case. in autoimmune epilepsy, the claustrum signals normalized in the majority but not in all patients [ ] , suggesting a varying severity of claustrum damage. this is confirmed by reduced diffusion in the first mri scan of our patient, heralding irreversible tissue damage (as proven by the -month mri follow-up). at no point in time, there was evidence for other causes of diffusion reduction, i.e., hypoxemia or status epilepticus. comparable claustrum lesions have also been reported in the context of autoimmune encephalitis without epileptic or anoxic episodes, supporting inflammation as a decisive factor [ ] . a particular vulnerability of claustral neurons to hypoxic stress has been shown [ ] , without relating to the inflammatory pathogenesis of our mri findings. yet, astrocyte proliferations and microglia/macrophage infiltrations of the claustrum have been observed in non-herpetic encephalitis [ ] . to which extent other pathomechanisms, such as encephalitic hypermetabolism as known from the striatum [ ] . additionally, compromise the claustrum remains speculative. common mri findings in a recent study of covid- encephalopathy were cortical signal abnormalities on flair images ( %), accompanied by diffusion reduction, leptomeningeal enhancement and cortical blooming artifacts in some cases. these imaging findings, termed by the authors themselves as "rather unspecific", did not allow [ ] . mri findings in covid- encephalitis, especially when suggesting autoimmune encephalopathy may imply therapeutic interventions, such as immunosuppressive therapy. recently, progressive clinical improvement along with a reduction of inflammatory csf parameters has been observed in covid- encephalitis, following high-dose steroid treatment [ ] . in summary, a previously undescribed imaging pattern in parainfectious covid- encephalitis is presented that bears a strong resemblance to mri findings in autoimmune encephalitic syndromes, such as known from epileptic or encephalitis caused by antineuronal antibodies. this claustrum sign should be added to the still limited knowledge of encephalitic imaging patterns in covid- , as it most probably represents an autoimmune phenomenon that might progress from reversible signal changes to permanent tissue damage and thus may trigger appropriate as well as timely therapy. author contributions fz is lead author, analyzed and interpreted the collected data and literature, designed and wrote the manuscript. ho&ar participated in the design and coordination of the manuscript. br&cs helped in drafting the manuscript. mr&rk provided figures and data and revised the manuscript for important intellectual content. imaging (d-e), the flair-hyperintensities persist (d) whereas tissue diffusion has normalized (e). csf-cytology (f) showed a slightly elevated cell count ( /µl) with a lymphocytic predominance ( % lymphocytes, % monocytes). a meaningful plasmacytic transformation was not observed, the monocytes being only slightly activated neurologic features in severe sars-cov- infection a clinical approach to diagnosis of autoimmune encephalitis new-onset refractory status epilepticus and febrile infection-related epilepsy syndrome what is the function of the claustrum? voltage-gated potassium channel antibody-associated encephalitis with claustrum lesions claustral neurons are vulnerable to ischemic insults in cardiac arrest encephalopathy neuropathological studies of patients with possible non-herpetic acute limbic encephalitis and so-called acute juvenile female non-herpetic encephalitis striatal hypermetabolism in limbic encephalitis brain mri findings in patients in the intensive care unit with covid- infection steroidresponsive encephalitis in covid- disease key: cord- - s dv w authors: plumereau, cécile; cho, tae-hee; buisson, marielle; amaz, camille; cappucci, matteo; derex, laurent; ong, elodie; fontaine, julia; rascle, lucie; riva, roberto; schiavo, david; benhamed, axel; douplat, marion; bony, thomas; tazarourte, karim; tuttle, célia; eker, omer faruk; berthezène, yves; ovize, michel; nighoghossian, norbert; mechtouff, laura title: effect of the covid- pandemic on acute stroke reperfusion therapy: data from the lyon stroke center network date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: s dv w background: the coronavirus disease (covid- ) pandemic would have particularly affected acute stroke care. however, its impact is clearly inherent to the local stroke network conditions. we aimed to assess the impact of covid- pandemic on acute stroke care in the lyon comprehensive stroke center during this period. methods: we conducted a prospective data collection of patients with acute ischemic stroke (ais) treated with intravenous thrombolysis (ivt) and/or mechanical thrombectomy (mt) during the covid- period (from / / to / / ) and a control period (from / / to / / ). the volume of reperfusion therapies and pre and intra-hospital delays were compared during both periods. results: a total of patients were included. the volume of ivt significantly decreased during the covid-period [ ( . %) vs ( . %); p = . ]. the volume of mt remains stable over the two periods [ ( . %) vs ( . %); p = . ], but the door-to-groin puncture time increased in patients transferred for mt ( [ – ] vs [ – ]; p < . ). the daily number of emergency medical dispatch calls considerably increased ( [ – ] vs [ – ]; p < . ). conclusions: our study showed a decrease in the volume of ivt, whereas the volume of mt remained stable although intra-hospital delays increased for transferred patients during the covid- pandemic. these results contrast in part with the national surveys and suggest that the impact of the pandemic may depend on local stroke care networks. the healthcare system has been disrupted during the coronavirus disease (covid- ) pandemic outbreak, leading to a massive redistribution of health care resources. the saturation of the emergency medical dispatch (emd) with covid -related calls may have jeopardized the recognition and management of other emergencies [ ] . in addition, this pandemic has imposed containment and social distancing measures, with potential subsequent social isolation that may have contributed to a drop in stroke admissions. patients' fear of contracting the infection in hospitals may have delayed or limited their demand for care, especially for transient or minor symptoms. furthermore, the unprecedented media concentration on the pandemic may have precipitated the extinction of calls for other emergencies and insidiously replaced other healthcare needs in the collective mind [ ] . the effect of the covid- pandemic on stroke care is still debated. although some studies have reported an impact of the pandemic on acute ischemic stroke (ais) care in terms of admissions and reperfusion therapy volumes along with longer treatment times and a decrease in the use of stroke imaging compared with control periods in , other reports have not detected significant effects on revascularization procedures [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the objective of our study was to assess the impact of the covid- pandemic on the volume of ais patients treated with intravenous thrombolysis (ivt) and/or mechanical thrombectomy (mt), as well as pre and intra-hospital delays ( fig. ). data from these patients were collected within a regional emergency stroke network registry (resuval), approved by the local ethics committee (comité de protection des personnes sud-est ii, registration e- - ). this observational study was carried out in accordance with the ethical standards of the declaration of helsinki. no patient expressed opposition to the research. the lyon stroke center (tertiary university hospital), serving the greater lyon metropolitan area (population: . million), treats ∼ ischemic stroke patients each year and is the only comprehensive stroke center (csc, i.e. thrombectomy-capable) within our regional stroke network ( primary stroke centers, population: . million) (fig. ) . the analyzed period ranged from the entry into level- of the pandemic in france (february th) and the lifting of lockdown on may th. the same period in served as control. to take into account the local trend (i.e. yearly increase in case volumes), we also provided data about the total number of reperfusion procedures from january st to may th of the previous years. all consecutive patients with ais treated with ivt and/or mt in the lyon stroke center, france, were included during the covid- period and the control periods. baseline data on demographic characteristics, risk factors, and medical history were systematically collected at admission as well as times from stroke onset to hospital admission (to our csc or to primary stroke center or to emergency department as appropriate), door to imaging, door to needle, and door to groin puncture. when the time of symptoms onset was unknown, the time when patients woke up or were identified was considered as the time of symptom onset. neurological status was assessed by board certified neurologists using national institute of health stroke scale (nihss) score at admission. data about the volume of stroke admissions and the daily number of calls to emd during the covid- and the control periods were obtained from the hospital administrative database. the first-line imaging method in our csc is magnetic resonance imaging (mri), including diffusion-weighted imaging (dwi), t *-weighted imaging, fluid-attenuated-inversion-recovery (flair), d-time-of-flight mr-angiography (mra), perfusion-weighted imaging and cervical-vessels angiography were optional. if mri was unavailable or contra-indicated, non-enhanced computed tomography (ct) followed by ct-angiography were performed; ct-perfusion was optional. lesion side and baseline ischemic core size were assessed on dwi or ct using the alberta stroke program early ct score (aspects) for patients with stroke in the middle cerebral artery territory [ ] . baseline arterial occlusion site was evaluated with mra or ct-angiography. a follow-up ct performed at h classified any hemorrhagic transformation according to the european cooperative acute stroke study (ecass ii) classification [ ] . continuous variables are expressed as means (standard deviation [sd]) or medians (interquartile range [iqr]), and categorical variables as percentages. the mann-whitney u test and fisher's exact test were used to compare continuous and categorical variables, respectively. a p value < . was considered significant. data were analyzed with stata version ™ (statacorp, college station, texas usa). a total of and patients were admitted for stroke during the control and the covid- periods, respectively. of them, and patients were treated with reperfusion therapy during the control and the covid- periods, respectively, and were included in the study. patient pathways and procedures as well as main characteristics are detailed in fig. and table the volume of ivt was significantly lower during the covid- period compared to the control period [ ( . %) vs ( . %); p = . ]. in contrast, the volume of patients treated with mt remained stable over these two periods [ ( . %) during the covid- period vs ( . %) during the control period; p = . ]. the number of revascularization procedures in lyon csc steeply and yearly increased since (fig. ) . the curve of cumulative cases in early was superior to that of , but leveled off at the end of february and thereafter remained inferior to levels. onset-to-door, door-to-imaging and door-to-needle times did not differ between the two periods. in contrast, door-togroin puncture time was increased in patients transferred for mt ( [ - ] vs [ - ]; p < . ) ( table ). note that the volume of direct admissions to csc declined without reaching the statistical significance threshold. the emergency call center faced a significant increase in activity during the covid- period. the total daily number of calls increased considerably ( [ - ] vs in the control and covid- periods, respectively; p < . ). we evaluated the impact of covid- outbreak on a regional stroke care network. we observed a decrease in the volume of ivt, whereas the volume of mt remained stable although we observed a prolonged door-to-groin puncture time for transferred patients. in line with previous studies, the volume of ivt markedly decreased during the covid- period [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the main factor for limiting the use of ivt among patients treated with mt was time delay. the volume of mt remained stable between the two periods while previous studies have reported conflicting results [ ] [ ] [ ] [ ] [ ] [ ] ]. the regional variability of the impact of covid- on acute stroke care is illustrated by a german study which found a relevant effect on mt in a only one out of four centers [ ] . our result must be interpreted in relation to the resources available for stroke care delivery in our catchment area, which is likely undersized with regard to the large population base. this discrepancy between supply and demand may have propped up the number of revascularization procedures, despite a likely covid-related reduction in healthcare resources, including stroke care. nevertheless, we failed to observe our expected yearly growth in the number of reperfusion procedures. a similar observation was made by hsiao et al. [ ] . the magnitude of the covid- pandemics was also lower in our region compared to other french regions as the grand-est and could have modified its impact of the covid- on stroke care as reported in germany [ ] . an overload of emd calls was reported in catalonia during the covid- outbreak [ ] . similarly, we observed an increase of about % in the total daily number of emd calls during this period. another interesting finding is the significant decrease in patients managed for posterior circulation stroke during the pandemic period. outside the pandemic period, posterior circulation strokes are more likely misdiagnosed in part because of nonspecific clinical presentation [ ] . this phenomenon may have been exacerbated during the covid- period. in contrast to other studies, age, nihss and aspect scores did not differ between the two periods, suggesting that criteria for treatment eligibility remained unchanged [ , ] . our methodological strengths come from a prospective data collection concerning all consecutive patients treated with mt in our geographical area as our stroke center is the only one to have thrombectomy facilities within our stroke regional network. our study has some limitations. first, the sample size is limited as a result of the short study period. second, our registry was restricted to patients treated with reperfusion therapy while data about untreated patients were not collected. thus we cannot draw a clear relationship between the decrease in the volume of ivt during the covid- period and pre or intra-hospital delays. still, we prospectively collected data concerning all consecutive patients treated with mt; as our csc is the only thrombectomycapable hospital within our stroke regional network, the count of mt cases was exhaustive. last, the generalizability of these results found in our stroke regional network to other regions or countries with a different stroke care organization is uncertain. the growing reports of the covid- pandemic impact on acute stroke care call for implementing strategies to guarantee safe and hig-quality stroke care during the pandemic. the strategies adopted up to now varied depending on covid- pandemic magnitude and preexisting regional organization of stroke care pathway as reported in italy [ ] . future strategies should guarantee stroke pathway (beds, personnel) and reorganize it through specific stroke-covid pathways. emergency department and out-of-hospital emergency system ( -areu ) integrated response to coronavirus disease in a northern italy centre forgotten key players in public health: news media as agents of information and persuasion during the covid- pandemic impact of the covid- epidemic on stroke care and potential solutions acute stroke management pathway during coronavirus- pandemic mechanical thrombectomy for acute ischemic stroke amid the covid- outbreak: decreased activity, and increased care delays acute stroke care is at risk in the era of covid- : experience at a comprehensive stroke center in barcelona impact of the covid- outbreak on acute stroke pathways-insights from the alsace region in france effect of covid- on emergent stroke care: a regional experience effect of lockdown on the management of ischemic stroke: an italian experience from a covid hospital acute stroke in times of the covid- pandemic: a multicenter study validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ecass ii) avoiding misdiagnosis in patients with posterior circulation ischemia: a narrative review stroke care in italy: an overview of strategies to manage acute stroke in covid- time conflicts of interest the authors declare that they have no conflict of interest.ethical standards this research was conducted according to the ethical standards issued by the declaration of helsinki. key: cord- -ew wcr authors: jasti, madhu; nalleballe, krishna; dandu, vasuki; onteddu, sanjeeva title: a review of pathophysiology and neuropsychiatric manifestations of covid- date: - - journal: j neurol doi: . /s - - -w sha: doc_id: cord_uid: ew wcr introduction: the outbreak of coronavirus disease (covid- ) has become one of the most serious pandemics of the recent times. since this pandemic began, there have been numerous reports about the covid- involvement of the nervous system. there have been reports of both direct and indirect involvement of the central and peripheral nervous system by the virus. objective: to review the neuropsychiatric manifestations along with corresponding pathophysiologic mechanisms of nervous system involvement by the covid- . background: since the beginning of the disease in humans in the later part of , the coronavirus disease (covid- ) pandemic has rapidly spread across the world with over , , reported cases in over countries [world health organization. coronavirus disease (covid- ) situation report- .,]. while patients typically present with fever, shortness of breath, sore throat, and cough, neurologic manifestations have been reported, as well. these include the ones with both direct and indirect involvement of the nervous system. the reported manifestations include anosmia, ageusia, central respiratory failure, stroke, acute inflammatory demyelinating polyneuropathy (aidp), acute necrotizing hemorrhagic encephalopathy, toxic–metabolic encephalopathy, headache, myalgia, myelitis, ataxia, and various neuropsychiatric manifestations. these data were derived from the published clinical data in various journals and case reports. conclusion: the neurological manifestations of the covid- are varied and the data about this continue to evolve as the pandemic continues to progress. at the end of , many unexplained pneumonia cases occurred in wuhan, china, and rapidly spread to other parts of china, then to other parts of asia, europe, and recently to north america. eventually, this outbreak was confirmed to be caused by a novel coronavirus [ ] . this novel coronavirus reportedly had symptoms resembling that of severe acute respiratory syndrome corona virus (sars-cov) seen in the year [ ] . both these viruses share almost % of the amino acid sequences and use the same receptor-which is angiotensin-converting enzyme (ace ) [ ] to gain entry into the cells. hence, this virus was named sars-cov- . in february , the world health organization named the disease as coronavirus disease . coronaviruses cause multiple systemic infections affecting various organ systems, but primarily affect the respiratory system. they tend to mutate and adapt quickly to cross the species barrier, which occurred with sars-cov and middle east respiratory syndrome coronavirus (mers-cov), causing epidemics and pandemics. infection with these viruses in humans often leads to severe clinical symptoms with high mortality [ ] . all three of these novel viruses (sars-cov, sars-cov- /covid- , and mers-cov) originate from zoonotic transmission. these are enveloped, positive-stranded rna corona viruses in the betacoronoviride family. studies had demonstrated that the clinical course of sars and mers was highly similar and sars and mers may have similar pathogenesis [ ] . the genome sequence of sars-cov- also shows some similarities to that of mers-cov. the postulated common pathophysiologic mechanisms include dysregulation of cytokines/ chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, and autoimmunity [ ] . mers-cov infects cells by binding to the dipeptidyl peptidase receptor, and sars-cov acts via the angiotensin-converting enzyme receptor [ ] . as for covid- , numerous studies have described typical clinical manifestations including fever, cough, sore throat, shortness of breath, diarrhea, and fatigue. covid- also has characteristic laboratory findings and lung computed tomography abnormalities [ ] . however, there is growing literature that patients with covid- have cardiac [ ] and neuropsychiatric manifestations, as well. a recently published study that looked at cases of severe coronavirus illness treated in wuhan during the early phase of the global pandemic reported that about % of patients displayed neurological symptoms [ ] . this study reports that strokes, altered consciousness, and other neurological issues are relatively common in serious cases of covid- . these include both direct and indirect involvement of the nervous system. following this study, there have been several case reports of various neurologic diagnoses. the reported manifestations include anosmia, ageusia, stroke, aidp, acute necrotizing hemorrhagic encephalopathy, toxic-metabolic encephalopathy, headache, myalgia, central respiratory failure, myelitis, ataxia, and various neuropsychiatric manifestations. in this section, we will discuss the neuropsychiatric presentations and the possible associated pathophysiology. losses of smell and taste have been strongly linked to covid- infections [ ] . so far, there have been numerous publications about the association of loss of smell and taste with covid- infection. post-viral anosmia is one of the leading causes of loss of sense of smell in adults. this post-viral loss of smell is thought to be secondary to initial congestion of the nose, which leads to loss of fine hair like endings of the olfactory receptor cells causing them to be ineffective in picking up odor molecules from the nose. sars-cov- also appears to be highly concentrated in the nostrils of affected patients causing inflammation of the olfactory nerves and structural damage to the receptors and thereby causing anosmia [ ] . studies have shown that the tongue has a very high expression of ace receptors compared to buccal and gingival tissues, thereby posing a high risk of viral binding and ageusia from taste receptor damage [ ] . there have been a fair number of reports suggesting sars-cov- infecting the neurons, raising questions about the direct effects of the virus on the brain that play a role in patients' deaths. some of the respiratory symptoms due to the disease might actually be secondary to respiratory center involvement controlled by the nervous system. according to yan-chao li, et al. [ ] , sars-cov- infects nerve cells, particularly the neurons in the medulla oblongata, which serves as the control center for the heart and the lungs. the damage to this area could contribute to the acute respiratory failure of patients with covid- . autopsy results of patients with covid- showed that the brain tissue near brainstem was hyperemic and edematous with neuronal degeneration [ ] . by contrast, there have been a few case reports which mention no penetrance of virus into the central nervous system as evidenced by the absence of sars-cov- in csf and that the cns effects are secondary to elevated inflammatory markers as csf analyses during the acute stage showed pleocytosis with increased il- and tnf-α concentrations [ ] . researchers have reported that many human cell types express ace , including lung, heart, kidney, intestine, and brain tissue [ ] . there are at least a couple of ways that the virus could invade the central nervous system-it might circulate through the blood and then attack ace receptors in the endothelia that line blood capillaries in the brain, breaching the blood-brain barrier and invading neurons through that route (fig. ) . a breached blood-brain barrier could also cause brain swelling, compressing the brain stem there by affecting respiration. apart from these two mechanisms, it has also been demonstrated that some coronaviruses can spread by synaptic transfer from chemoreceptors and mechanoreceptors in lung to the medullary cardiorespiratory center [ ] . this process could be an implicating factor in acute onset respiratory failure in some of the covid- patients [ ] . researchers in china published the first presumptive case of acute inflammatory demyelinating polyneuropathy (aidp)/ guillain-barre syndrome (gbs) associated with covid- on apr , [ ] . reportedly, the patient initially presented with signs of the autoimmune neuropathy after returning from wuhan, china and later tested positive for the covid- . considering the temporal association, it was speculated that sars-cov- infection might have been responsible for the development of aidp. following this, a case series from italy, published by toscano et al., reported five cases of aidp that started after the onset of covid- disease [ ] . around the same time, two case reports were published from spain reporting the occurrence of miller fisher syndrome and polyneuritis cranialis in patients diagnosed with covid- [ ] . all these studies showed that aidp occurs early in the course of the disease and followed the pattern of a para-infectious profile, instead of the classic post-infectious profile. the underlying pathophysiologic mechanisms might be secondary to the neuroinvasive nature of the virus precipitating demyelination [ ] versus viral infection creating an inflammatory environment triggering an aberrant immune response (secondary to molecular mimicry) leading to peripheral demyelination [ ] . poyiadji et al. reported the first presumptive case of covid- -associated acute necrotizing hemorrhagic encephalopathy [ ] . acute necrotizing encephalopathy is a rare encephalopathy and one of the remote complications of influenza and other viral infections. this has been presumed to be due to intracranial cytokine storm, which results in the blood-brain barrier breakdown, without direct viral invasion or para-infectious demyelination [ ] . accumulating [ ] . a cytokine profile resembling secondary hemophagocytic lymphohistiocytosis (a hyperinflammatory syndrome that leads to fulminant and fatal hypercytokinaemia with multiorgan failure which is commonly triggered by viral infections [ ] ) is associated with severe covid- , characterized by increased interleukin's-il- , il- , granulocyte-colony stimulating factor, interferon-alpha, monocyte chemoattractant protein , macrophage inflammatory protein -alpha, and tumor necrosis factor-alpha [ ] . predictors of fatality from a recent retrospective, multicenter study of confirmed covid- cases in wuhan, china, included elevated ferritin and il- [ ] , suggesting that hyper inflammation might be contributing to mortality. patients with severe infection were more likely to develop neurologic manifestations, especially acute cerebrovascular disease. patients with severe infection had higher d-dimer levels than that of patients with the non-severe infection, which may be the reason why patients with severe infection are more likely to develop the cerebrovascular disease. apart from the elevated d-dimer causing a state of altered coagulation cascade, there is also a theory that there is a vasculitis type of picture created secondary to intracranial cytokine storm versus the infection by the virus itself which are believed to be the possible pathophysiologic mechanisms behind stroke/cerebrovascular accident [ ] . the virus can get access to cerebral circulation from systemic circulation, attach to endothelium ace receptors, and cause endothelial ruptures and thrombus [ ] . slow cerebral circulation compared to systemic circulation pose an increased risk of replication and rupture. also, the virus can get into brain tissue from capillary endothelium by brain-blood barrier disruption and cause neuronal damage without much inflammation (fig. ) . past studies on viral pandemics, especially involving respiratory viruses, suggest that diverse types of neuropsychiatric symptoms can arise with acute infection as well as in the post-viral infectious period [ ] . one study reported persistent neurocognitive deficits up to months post-discharge [ ] . in the acute phase, apart from being the psychosocial stressor, covid- has been reported to cause neuropsychiatric manifestations, like encephalopathy, psychosis, insomnia, and mood changes. post-traumatic stress disorder, panic attacks, anxiety are mostly seen in health care workers and survivors of sars cov infection [ ] . this is largely secondary to the mental trauma and not as a direct consequence of infection. in addition, over-reactive behavior due to fear is usually noted in the public during the pandemics [ ] . aggression, frustration, can worsen with quarantine and lockout procedures [ ] . these neuropsychiatric manifestations have been attributed to viral infection per se and also secondary to the host immune response [ ] . direct viral infiltration of the central nervous system can trigger a neuro-inflammatory reaction leading to microglial activation [ ] , which in turn triggering demyelinating processes is one of the primary etiologies for encephalopathy. in the absence of direct viral infiltration, peripheral hypercytokinaemia causing an imbalance of neurotransmitters within the central nervous system has been implicated in neuropsychiatric manifestations. the state of hypercytokinaemia triggers a neuro-inflammatory response causing disruption of the blood-brain barrier, leading to peripheral immune cell transmigration into the central nervous system and, in turn, causing imbalances in neurotransmission [ ] . ace was identified as the functional receptor to enter into a cell for sars-cov- , which is present in multiple human organs, including the nervous system and skeletal muscles. patients with severe covid- disease had muscle breakdown causing muscle weakness and this manifested as elevated creatine kinase and lactate dehydrogenase levels than those without muscle symptoms. apart from the direct tissue injury by the virus, cytokine storm damage [ ] might also be the other reason for muscle involvement with covid- . this has been commonly reported in patients with moderately severe disease. the pathophysiologic mechanisms are unclear, but could be secondary to breached blood-brain barrier and involvement of the brain stem versus elevated inflammatory markers. patients with severe disease had a prolonged icu course and were noted to be encephalopathic for more than the usually expected duration. this is most likely secondary to the use of multiple and high doses of anesthetics and sedatives as a part of the symptomatic management of severe respiratory disease. hypoxia and viremia itself are also the possible factors behind encephalopathy [ ] . headache was commonly seen in patients with mild-tomoderate disease severity. these were partly believed to be secondary to raised inflammatory mediators in the body and decreased cerebral blood flow from hypoxia and endothelial changes from viremia. seizures were also randomly reported. these have been hypothesized to be secondary to decreased seizure threshold secondary to an innate immune response from cytokine surge [ ] rather than viruses primarily causing the seizures. dense parenchyma and imperviousness of brain tissues not only protects the brain from infectious processes, but also poses a challenge to eliminate them once brain involvement occurs [ ] . cytotoxic t cells are the mainstay for the elimination of viruses from brain tissue because of the lack of major histogen compatibility antigens in neurons . therefore, more research about covid- neurogenic involvement is necessary to identify and treat the neurological disease early, rather than at an advanced stage at which it will be more challenging. patients with covid- commonly have neurologic manifestations. the data/literature on this continues to evolve. on one hand, there are very commonly reported neurologic diagnoses of anosmia, encephalopathy, and stroke, and at the same time, there have been only a few isolated case reports of acute necrotizing encephalopathy and aidp. we have to keep in mind that the current information that we have about the neurologic manifestations of covid- is in the context of purposefully avoiding advanced neurodiagnostic procedures like magnetic resonance imaging, lumbar puncture, electromyography, and nerve conduction studies to reduce the risk of crossinfection within the hospital. a prospective, observational study with a larger number of patients that includes more specific neuro-imaging 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authors: anzalone, nicoletta; castellano, antonella; scotti, roberta; scandroglio, anna mara; filippi, massimo; ciceri, fabio; tresoldi, moreno; falini, andrea title: multifocal laminar cortical brain lesions: a consistent mri finding in neuro-covid- patients date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: eo ityc nan neurologic manifestations of severe acute respiratory syndrome coronavirus (sars-cov- ) have been recently reported [ , ] , with relevance to vascular aetiology [ , ] . the neuroinvasive potential of sars-cov- has also been advocated, by infecting the cns through hematogenous or neuronal retrograde route [ ] . here we report four cases of subacute encephalopathy occurring in patients with sars-cov- infection. they are part of a series of patients presenting with neurological symptoms studied with brain mri with otherwise no significant imaging findings. a multifocal involvement of the cortex was evident in all cases (figs. , ) . the multiple areas, from punctiform to some millimeters in extension, appeared hyperintense on t -weighted and flair images and were located in the parietal, occipital and frontal regions. on diffusion mri, all but two of the lesions were characterized by the absence of apparent diffusion coefficient (adc) changes (figs. c, c). a minimum involvement of the adjacent subcortical white matter was evident in only a few lesions. susceptibility-weighted imaging (swi) sequences were acquired in all patients and did not show any alteration. very subtle contrast enhancement was detected only in a cortical lesion. in one patient a follow-up mri scan was obtained after one month, demonstrating a complete resolution of all the lesions (fig. f-l) . all patients ( men, women; age range - years) have been intubated in the first week from onset of ards and presented neurological signs of agitation and spatial disorientation after weaning from mechanical ventilation. one patient had a generalized seizure. the time interval from onset of neurological symptoms to mri was - days. diagnosis of covid- was made by detection of sars-cov- viral nucleic acid in a nasopharyngeal swab specimen. all patients received the same treatment for sars-cov- infection. none of the patients had a relevant clinical history or previous treatment or hypertension. laboratory findings revealed in all cases a second smaller c-reactive protein peak from the initial one and raise of serum level of aspartate and alanine transaminase before the onset of neurological symptoms. d-dimer elevation was present and stable during the disease course. mri lesions' characteristics are unusual but demonstrate a highly consistent pattern through all the four patients with similar neurological symptoms. they do not fulfill any typical criteria for a definite neuroradiological entity. we speculate that this pattern may be related to a possible transient dysregulation of vasomotor reactivity. in particular, the cortical involvement may suggest a possible vascular mechanism more shifted toward transient vasoconstriction. although the predominantly parieto-occipital distribution of the lesions recalls posterior reversible encephalopathy syndrome (pres) [ ] , the prevalent cortical involvement and diffusion mri pattern are not typical of pres. at the same time, an alternative hypothesis of embolic cortical infarctions is unlikely due to the absence of diffusion restriction. it is currently known that sars-cov- might dysregulate the renin-angiotensin system (ras) system by acting on ace receptors, causing microcirculation impairment possibly impacting on blood flow regulation. more recently, evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation has been reported, resulting fig. forty-seven-year-old man diagnosed with covid- and presenting neurological signs of agitation and spatial disorientation after weaning from mechanical ventilation. before the onset of neurological symptoms, laboratory findings revealed a c-reactive protein peak ( . mg/l, normal range - mg/l). a axial flair, b diffusion-weighted image (dwi), c apparent diffusion coefficient (adc) map and (d, e) sagittal flair mr images. multiple, cortical areas of punctiform and gyriform flair and dwi hyperintensity (arrows) in both parietal lobes, with no adc changes fig. fifty-four-year-old woman diagnosed with covid- and presenting neurological signs of agitation and spatial disorientation after weaning from mechanical ventilation. before the onset of neurological symptoms, laboratory findings revealed a small c-reactive protein peak ( . mg/l, normal range - mg/l) and raise of total white blood cell count ( . × /l, normal range . - . × /l). cerebrospinal fluid (csf) analysis performed on the same day was negative for the presence of sars-cov- viral nucleic acid. a-e initial mri scan. f-l follow-up mri after one month. a, d, f, i axial flair, b, g diffusionweighted image (dwi), c, h apparent diffusion coefficient (adc) map and e, l sagittal flair mr images. multifocal linear and punctiform cortical flair and dwi hyperintensities in the left parietal lobe, bilateral precentral gyri and left middle frontal gyrus (a-c), with no adc changes. bilateral occipital involvement is shown in d, e, with a cortical/subcortical flair hyperintense lesion at the level of the left occipital pole. f-l follow-up mri demonstrates a complete resolution of all the lesions in endothelial dysfunction and impaired microcirculatory function [ ] . along with inflammation, there is a tendency to thrombosis in more severe cases [ ] . nonetheless, other vasculo-mediated mechanisms including altered vasomotor reactivity may play a role and cause neurological symptoms in covid- patients [ ] . in this regard, normalization of mri findings in one patient (fig. f-l) may corroborate the hypothesis of a transient functional nature of the impaired cerebral microcirculatory function. we believe that, due to the peculiarity and subtle appearance of the mri findings, our report may alert neurologists and radiologists to the existence of this subacute neuroimaging picture in sars-cov- patients, clearly different from cortical ischemia, and also to inform clinicians about the possible spontaneous reversibility of the picture. neurologic manifestations of hospitalized patients with coronavirus disease in wuhan, china neurologic features in severe sars-cov- infection large-vessel stroke as a presenting feature of covid- in the young neuroradiologists, be mindful of the neuroinvasive potential of covid- posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions endothelial cell infection and endotheliitis in covid- microvascular covid- lung vessels obstructive thromboinflammatory syndrome (microclots): an atypical acute respiratory distress syndrome working hypothesis informed consent all patients provided signed informed consent prior to mr imaging. informed consent was collected from the patients for the inclusion of deidentified clinical data in a scientific publication, in accordance with the declaration of helsinki. key: cord- -y l cf authors: leonardi, matilde; padovani, alessandro; mcarthur, justin c. title: neurological manifestations associated with covid- : a review and a call for action date: - - journal: j neurol doi: . /s - - -z sha: doc_id: cord_uid: y l cf while the epidemic of coronavirus disease (covid- ) continues to spread globally, more and more evidences are collected about the presence of neurological manifestations and symptoms associated with it. a systematic review has been performed of papers published until april . papers related to neurological manifestations associated with covid- were examined. the results show presence of central and peripheral nervous system manifestations related to coronavirus. neurological manifestations, or neurocovid, are part of the covid- clinical picture, but questions remain regarding the frequency and severity of cns symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of covid- . further clinical, epidemiological, and basic science research is urgently needed to understand and address neurological sequalae of covid- . concomitant risk factors or determinants (e.g. demographic factors, comorbidities, or available biomarkers) that may predispose a person with covid- to neurological manifestations also need to be identified. the review shows that although more and more papers are reporting neurological manifestations associated with covid- ; however, many items remain unclear and this uncertainty calls for a global action that requires close coordination and open-data sharing between hospitals, academic institutions and the fast establishment of harmonised research priorities and research consortia to face the neurocovid- complications. reports are emerging from china and italy and increasingly from several countries of neurological symptoms associated with sars-cov- , which may be worsening clinical pictures, respiratory outcomes and mortality rates in patients with covid- . while most coronaviruses cause mild respiratory illness, it is well known that many beta-coronaviruses have nervous system involvement [ ] . sharing similar genetic traits with mers and sars [ , ] as well as a common host cell entry receptor with sars [ ] , sars-cov- may also demonstrate neurotropism via possible invasion through the cribriform plate, olfactory nerve, thalamus and brainstem resulting in suppression of central cardiorespiratory drive [ ] . reports from china describe neurological symptoms in covid- patients with one retrospective case series from wuhan, china showing of patients ( %) with neurological manifestations [ ] [ ] [ ] . observations from italy have confirmed chinese data noting a high number of patients with hyposmia, anosmia and varying patterns of possibly centrally mediated symptoms including respiratory manifestations. in the evolving pandemic, healthcare professionals, therefore, need to recognize and address neurological consequences. we summarized the available knowledge to guide further research, clinical surveillance and management protocols. we searched papers published in english by april using pubmed. search terms relating to covid- (including covid*, novel coronavirus, ncov*, *cov- , or *cov ) in titles and abstracts were crossed with terms relating to neurological symptoms or neurotropism including (neurolog*, nervous, dizz*, delirium, encephal*, cereb*, headache, hyposmia, *geusia, hypopsia, myalgia, neurotrop*, or neuroinv*) in full texts. the search resulted in papers, with unique results retrieved, of which were excluded on title/abstract screen and four were excluded on full text screen. exclusion was based on topic, outcomes covered, and full text unavailability. papers related to neurological manifestations associated with covid- were examined. respiratory distress is the most distinctive symptom ( %) reported in covid- patients [ ] . reported neurological findings fall into three categories: central (headache [ , ] , dizziness [ ] , impaired consciousness, acute cerebrovascular disease, ataxia and seizures), peripheral (hypogeusia, hyposmia) and musculoskeletal [ ] . mao et al. reported that of patients had either ischemic or haemorrhagic strokes, although it was not reported whether the strokes occurred before or after sars-cov- infection. approximately % reported hypogeusia ( . %) and/or hyposmia ( . %) [ ] . additionally, a clinical picture reminiscent of a central hypoventilation syndrome ("ondine's curse") was reported from a covid- survivor in wuhan [ ] . there have been increasing reports of delirium in covid- patients, and delirium may also be associated with more severe disease. a recent retrospective case series from china found that % of people who died from covid- experienced delirium compared with % of people who recovered [ ] . there has also been a case report of altered mental status in a covid- patient with encephalopathy on eeg [ ] and acute haemorrhagic necrotizing encephalopathy, the latter of which was thought to be due to cytokine storm [ ] . myalgia and muscle injury were reported in . % of the cases in wuhan [ ] and rhabdomyolysis has been reported in another case from wuhan [ ] . neurological manifestations have also been observed first-hand in italy's brescia province which documented covid- patients as of april , (personal observations of authors ap ml).many patients experienced hyposmia or anosmia, dysgeusia, dysarthria and either allodynia or acroparesthesias. an atypical onset has been observed in few patients characterized by a delirious presentation that occurs prior to the onset of any respiratory syndromes. within a cohort of hospitalized covid- patients, patients presented with encephalitis as the first and only symptom, of whom subsequently died. four patients presented with new onset seizures with no fever. these symptoms were then followed by the respiratory syndrome. there is evidence that many patients displayed varying patterns of respiratory manifestations. one such presentation consists of a sudden onset of respiratory failure in contrast to severe acute pulmonary failure. there also seems to be increase in number of both ischemic stroke and haemorrhagic stroke compared to historical series. finally, more recently a case report has been published about the onset of guillaine barrè syndrome (gbs) during sars-cov- , suggesting a pattern of a parainfectious profile, instead of the classic postinfectious profile [ ] . neurological manifestations or neurocovid are part of the covid- clinical picture, but questions remain regarding the frequency and severity of cns symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of covid- . further clinical, epidemiological, and basic science research is urgently needed to understand and address neurological sequalae of covid- . we identified three key priority areas for neurocovid: first, are patients with covid- in other countries experiencing neurologic symptoms and do these symptoms affect the severity and course of the illness, specifically are they associated with increased respiratory failure or death? documentation of neuropsychiatric comorbidities and drug treatment regimens is essential to aid ongoing discussions of drug-drug interactions and pharmacodynamic effects. vaccine research discoveries need to be implemented while keeping in mind possible adverse events as shown by our experiences with the swine flu [ ] . second, what is the mechanism of action causing the neurological symptoms seen in patients with covid- ? it is possible that sars-cov- causes neurological sequelae via inflammation, as elevated inflammatory biomarkers in patients with covid- have been noted. pro-inflammatory cytokine release is known to cause severe pulmonary damage in covid- , termed "cytokine storm", and likely affects the cns as well. indirect cns damage, through cytokine storm, can cause high mortality rates, encephalopathy, and posterior reversible encephalopathy (pres). in acute infections, cytokine release can also result in strokes, a number of which have been reported in sars post infection [ ] . mr imaging might provide further information to elucidate the role of brainstem respiratory centres in covid- patients. third, is sars-cov- a neurotropic virus? while we know that other coronaviruses demonstrate neurotropism, it is unknown how much of this knowledge is relevant for sars-cov- . li et al. postulate that sars-cov- neuroinvasion via the olfactory nerves is partially responsible for respiratory failure [ ] . is hyposmia or anosmia part of a prodrome of symptoms in covid- ? further research is needed in this area to further understand why steroids may be counterproductive in management of covid- [ ] . this signifies the importance of carrying out research into therapeutic options systematically with shared protocols and critical comparison of results. many patients present dysgeusia, dysphagia, dysarthria (personal observation ap) indicating a possible vagal involvement which could also indicate the possibility for diaphragmatic paresis and tachycardia thus potential bulbar infections. we know that sars-cov- enters cells through the ace receptor mainly in renal, cardiovascular and gastrointestinal systems [ ] [ ] [ ] [ ] . in mice, infected hippocampal cells were isolated in the cns several days post-infection indicating that sars-cov- has the capability to spread to the cns after clearance by the lungs [ ] . in humans, sars-cov- has been found in the csf [ ] and in neurons on autopsy [ , ] . another coronavirus (swine hemagglutinating encephalomyelitis virus) travels via peripheral nerves to the brainstem via trigeminal and vagal sensory nuclei [ ] [ ] [ ] . hcov oc (a coronavirus responsible for the common cold) infects human microglia leading to persistent infection and has been found in the csf and brain tissue of patients [ ] [ ] [ ] . in mice, it travels to the cns from the olfactory bulbs and, importantly, is blocked by destroying olfactory sensory neurons [ ] . this potential mechanism becomes crucially important clinically when considering that wearing masks could likely be the most effective prevention against viral entry into the cns. finally, prospective cohort studies are needed to understand the long-term impacts of covid- on neurological functions. it is currently unknown if people who have recovered from severe covid- suffer any lasting neurological sequalae. it is certainly true and well known that several patients discharged from icu, thus also several covid patients, suffer of chronic illness myopathy or neuropathy or both which might worsen the clinical outcomes. concomitant risk factors or determinants (e.g. demographic factors, comorbidities, or available biomarkers) that may predispose a person with covid- to neurological manifestations should be identified. we are aware that this review has limitations including that it was limited to articles published in english and that there is a tremendous growth in the volume of published literature on covid- , so that findings and recommendations are constantly evolving as new evidence arises and thus other relevant information and data could be lacking. answers to all the above questions, however, require close coordination and open-data sharing between hospitals, academic institutions and fast establishment of harmonised research priorities and research consortia to face the neuro-covid- complications. conflicts of interest the authors declare no conflicts of interest. neuroinvasion by human respiratory coronaviruses measures for diagnosing and treating infections by a novel coronavirus 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central nervous system infection by sars coronavirus multiple organ infection and the pathogenesis of sars detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis immunofluorescence studies on the pathogenesis of hemagglutinating encephalomyelitis virus infection in pigs after oronasal inoculation pathogenesis of haemagglutinating encephalomyelitis virus (hev) in mice experimentally infected by different routes coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer, and the early response of satellite cells human coronavirus oc associated with fatal encephalitis acute and persistent infection of human neural cell lines by human coronavirus oc infection of primary cultures of human neural cells by human coronaviruses e and oc axonal transport enables neuron-to-neuron propagation of human coronavirus oc key: cord- -o m whe authors: chaumont, h.; san-galli, a.; martino, f.; couratier, c.; joguet, g.; carles, m.; roze, e.; lannuzel, a. title: mixed central and peripheral nervous system disorders in severe sars-cov- infection date: - - journal: j neurol doi: . /s - - -y sha: doc_id: cord_uid: o m whe nan we report four cases of severe covid- in male patients aged - with the combination of central and peripheral nervous system disorders occurring unexpectedly late after the first symptoms. patients had comorbidities and were admitted for acute respiratory distress syndrome due to a proven sars-cov- infection. all required mechanical ventilation, among whom one needed an extracorporeal membrane oxygenation support. several acute neurological syndromes have been associated with sars-cov- infection, including anosmia and ageusia [ , ] , meningoencephalitis [ , ] , acute hemorrhagic necrotizing encephalopathy [ ] , axonal or demyelinating polyradiculoneuropathy [ ] [ ] [ ] , polyneuritis cranialis [ ] . like in most of the viral infections that involve nervous system, these manifestations occurred within the first ten days after infectious symptoms. further away from the onset of the disease, when sedation and neuromuscular blocker were withheld, % of the patients with severe covid- develop encephalopathy including prominent agitation, confusion and corticospinal tract signs [ ] . in our cases neurological manifestations were detected after mechanical ventilation weaning and extubation ( fig. ). they consisted of miscellaneous symptoms such as confusion, cognitive dysfunction (memory deficit, frontal syndrome), psychiatric disorders (paranoid delusion, hallucinations), weakness, pyramidal signs, dysautonomia, swallowing dysfunction, vertical supranuclear eye palsy, upper limbs myoclonus, fasciculation and focal muscle atrophy (table ) . to note, before admission to intensive care unit, patients had no neurological symptom, except for anosmia or ageusia in two of them. one patient had a small acute sub-cortical ischemic stroke on brain mri. cerebrospinal fluid (csf) analysis showed a normal cell count and a moderate increase of protein level in the up to mg/l in two cases. rt-pcr and igm for sars-cov- in the csf were negative in all patients. on eeg, non-rhythmic frontal slow waves were observed in two patients. three patients had electrophysiological features of acute motor demyelinating polyradiculoneuropathy with delayed distal latencies and f-waves, slowed conduction velocities and conduction blocks (supplementary table) . the remaining patient had lower motor neuron features in both the upper and lower limbs. two patients had an additional decrease of sensorimotor potential amplitude compatible with a critical illness neuropathy. swallowing and eye movement improved within the first week. given the persistent muscle weakness and electromyographic features suggesting a post-infectious mechanism, an immunoglobulin therapy was introduced for days. psychiatric symptoms, cognitive impairment and dysautonomia improved thereafter, but myoclonus and motor weakness of the upper limbs persisted weeks after discharge. three patients required prolonged rehabilitation in a specialized center. we describe here delayed mixed central and peripheral disorders as a complication of severe covid- . it combines acute encephalopathy and motor demyelinating polyradiculoneuropathy or diffuse lower motor neuron involvement. persistent cognitive and motor deficit might result from a critical illness, but neurological features differ from critical illness-related encephalopathy and neuropathy. critical illness-related neuropathy is characterized by a bilateral, symmetric, axonal sensorimotor polyneuropathy resulting in an areflexic tetraplegia, without dysautonomia or cranial nerves palsy. in our patients, clinical and neurophysiological features of peripheral nervous system involvement could partly reflect critical illness neuropathy but most of them are not expected in this context and are thus more likely linked to covid- . abnormal eye movement, swallowing dysfunction and action myoclonus are unusual in activities, but able to look after own affairs without assistance; :moderate disability; requiring some help, but able to walk without assistance; :moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; :severe disability; bedridden, incontinent and requiring constant nursing care and attention critical illness-related encephalopathy and might rather result from covid -related brainstem dysfunction in our patients. our study suggests a wider spectrum than previously reported of neurological manifestations associated with covid- and further suggests that patients with severe forms of covid- should be systematically screened for neurological complications. neurologic manifestations of hospitalized patients with coronavirus disease in wuhan magnetic resonance imaging alteration of the brain in a patient with coronavirus disease (covid- ) and anosmia a first case of meningitis/encephalitis associated with sars-coronavirus- acute meningoencephalitis in a patient with covid- covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features guillain-barré syndrome associated with sars-cov- guillain-barré syndrome associated with sars-cov- infection: causality or coincidence? miller fisher syndrome and polyneuritis cranialis in covid- neurologic features in severe sars-cov- infection key: cord- -m dl a w authors: munz, maike; wessendorf, swen; koretsis, georgios; tewald, friedemann; baegi, reem; krämer, stefan; geissler, michael; reinhard, matthias title: acute transverse myelitis after covid- pneumonia date: - - journal: j neurol doi: . /s - - -w sha: doc_id: cord_uid: m dl a w nan neurological complications of sars-cov infection are increasingly recognized [ ] . recently, a sars-cov induced focal encephalitis was reported [ ] . here we describe a case of multifocal transverse myelitis following acute covid- pneumonia. a -year-old patient was first admitted to our hospital with typical respiratory symptoms of covid- infection without neurological symptoms. the polymerase chain reaction (pcr) test of the throat swab was positive for sars-cov . a chest x-ray showed mild bilateral ground-glass opacification. laboratory findings revealed elevated c-reactive protein but normal white blood cell count. the patient's previous medical history was unremarkable other than hypertension (treated with ramipril and felodipine), mild fatty liver, and ureterolithiasis. patients and family history revealed no signs of neurological disorders and he received no vaccination in the months before. he recovered rapidly from covid- pneumonia and was discharged home days later without any symptoms. three days after discharge, he developed bladder dysfunction and progressive weakness of the lower limbs. he was unable to micturate or walk unaided. on re-admission two days later, clinical examination revealed hypesthesia below the th level and a moderate spastic paraparesis. babinski's sign was positive bilaterally. cognition and cranial nerves were unaffected. general lab results were unremarkable including a nearly normalized c-reactive protein. a repeated throat swab showed a negative sars-cov pcr. magnetic resonance imaging (mri) of the spine revealed t signal hyperintensity of the thoracic spinal cord at th level suggestive of acute transverse myelitis rather than multiple sclerosis [ ] (fig. a) . brain mri showed no inflammatory changes. cerebrospinal fluid (csf) analysis was abnormal with lymphocytic pleocytosis ( /µl) and elevated protein level ( mg/l). sars-cov -pcr in the csf and oligoclonal bands were negative. further work-up was unremarkable including pcr for herpes simplex virus, varicella-zoster virus, antibodies against human herpesvirus , epstein-barr virus, and hepatitis e, antineuronal antibody panel, aquaporin- , and myelin oligodendrocyte glycoprotein antibodies. follow-up mri on day further showed a patchy hyperintensity of the thoracic myelon at th - and at th - level (fig. d) , suggestive of transverse myelitis. repeated csf analysis showed a slight increase in csf lymphopleocytosis ( /µl) and protein levels ( mg/l). repeated sars-cov -pcr in the csf was negative. there was no specific intrathecal synthesis of anti-sars-cov igg. initial treatment with aciclovir and ceftriaxone intravenously was discontinued on day after negative csf results for respective infective agents. the patients' clinical status slightly improved days after admission. because of persisting symptoms and after negative workup for active infection, methylprednisolone was started on day at a dose of mg/d. during the further course, the patient improved rapidly. follow-up csf on day showed normalization of cell count ( /µl) and regressing protein levels ( mg/l), no maike munz and swen weßendorf authors contributed equally. oligoclonal bands. the patient was discharged home on day with a slight spastic paraparesis and hypesthesia below th level, but normal bladder function. he was able to walk independently. a steroid taper scheme was initiated. this case describes multifocal myelitis occurring shortly after covid- infection. no other causes of myelitis could be identified after extensive workup. we assume a post-infectious etiology in terms of secondary immunogenic overreaction. previously, others suggested a direct infection of the central nervous system by human coronaviruses like sars or mers [ ] . the affection of the peripheral nervous system and muscles was described for sars-cov- [ ] . cases of guillain-barré syndrome in association with severe covid- infections were reported [ ] . in a series of severely affected covid- patients, % showed clinical corticospinal tract signs but received no spinal mri [ ] . only one other case with suspected focal myelitis without imaging or serological confirmation is reported from wuhan [ ] . this patient improved with empiric multiple treatments including intravenous immunoglobulins, prednisolone, and antiviral agents. our case shows that improvement might also occur with moderate steroid treatment, avoiding high doses because of uncertain effects on the immunogenic elimination of sars-cov . it remains unclear at present whether post-infectious myelitis after covid- behaves differently from other virus infections. increased awareness of spinal symptoms following covid- is recommended. conflicts of interest none. written informed consent was obtained from the patient. the authors have no relevant financial or nonfinancial relationships to disclose. neurologic manifestations of hospitalized patients with coronavirus disease in wuhan china shimada s ( ) pre-proof) a first case of meningitis/encephalitis associated with sars-coronavirus- magnetic resonance imaging findings in cases of myelitis: comparison between patients with and without multiple sclerosis the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients neuromuscular disorders in severe acute respiratory syndrome guillain-barré syndrome associated with sars-cov- neurologic features in severe sars-cov- infection preprint) acute myelitis after sars-cov- infection: a case report https key: cord- -j h ab authors: ghannam, malik; alshaer, qasem; al-chalabi, mustafa; zakarna, lara; robertson, jetter; manousakis, georgios title: neurological involvement of coronavirus disease : a systematic review date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: j h ab background: in december , unexplained cases of pneumonia emerged in wuhan, china, which were found to be secondary to the novel coronavirus sars-cov- . on march , , the who declared the coronavirus disease (covid- ) outbreak, a pandemic. objective: to clarify the neurological complications of sars-cov- infection including the potential mechanisms and therapeutic options. methods: we conducted a systematic literature search from december , to may , using multiple combinations of keywords from pubmed and ovid medline databases according to the preferred reporting items for systematic reviews and meta-analyses guidelines. we included articles with cases of covid- where neurological involvement was evident. results: we were able to identify cases of covid- with neurological complications. the mean age was . years. . % of the patients were women (n = ). . % of the patients (n = ) had cerebrovascular insults, % (n = ) had neuromuscular disorders, and % of the patients (n = ) had encephalitis or encephalopathy. conclusions: neurological manifestations of covid- are not rare, especially large vessel stroke, guillain–barre syndrome, and meningoencephalitis. moving forward, further studies are needed to clarify the prevalence of the neurological complications of sars-cov- infection, investigate their biological backgrounds, and test treatment options. physicians should be cautious not to overlook other neurological diagnoses that can mimic covid- during the pandemic. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. coronaviruses (cov) are a family of enveloped, positive-sense, single-stranded rna viruses that have been described for more than years. some strains are found to be zoonotic, whereas others may infect humans and transmit we conducted a systematic literature search from december , to may , from pubmed and ovid medline databases according to preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [ ] . the following search strategy was implemented and these keywords and their synonyms (in the all fields) were combined in each database as follows: ("covid " or "coronavirus") and ("brain" or "cns" or "spinal cord" or "nerve" or "neurologic" or "stroke" or "cerebrovascular" or "cerebral vein thrombosis" or "sinus thrombosis" or "intracerebral hemorrhage" or "hemorrhage" or "myelitis" or "gbs" or "guillain barre syndrome" or "neuropathy" or "radiculopathy" or "cranial neuropathy" or "myopathy" or "myositis" or "rhabdomyolysis" or "encephalitis" or "encephalopathy" or "meningitis" or "meningoencephalitis" or "seizure" or "convulsion" or "epilepsy") [ fig. ]. we included case series and case reports of covid- with evident neurological symptoms or signs. after exclusion of duplicates, all articles were evaluated through title and abstract screening by three independent reviewers (m.g., q.a., and g.m.). the same three reviewers performed an accurate reading of all full-text articles assessed for eligibility and performed a collection of data to minimize the risk of bias. in case of disagreement among the investigators regarding the inclusion and exclusion criteria, the senior investigator (g.m.) made the final decision. articles were included if they met the following inclusion criteria: (i) described patients with neurological signs or symptoms attributed to covid- (e.g., focal neurological deficit or impairment of consciousness); (ii) written in english language; and (iii) published in a peer-reviewed journal. the exclusion criteria were: (i) studies conducted in animals or in vitro models or basic science studies; (ii) patients age less than years; and (iii) conference proceedings, pooled analysis, clinical trials, case control studies, case reports, or case series of anosmia or mental health problems in covid- , reviews, and books. we assessed the quality of the included studies using the jbi critical appraisal tool, as shown in supplementary tables and . [ ] for each study, the following descriptive, microbiological, and clinical information was extracted: patient demographic data, sars-cov- testing from nasal swab and csf, neurological symptoms and signs and their onset in relation to respiratory or gastrointestinal (gi) symptoms or anosmia or dysgeusia, any neurological investigations and csf or any other relevant laboratory testing (such as ck, ldh, crp, d-dimer, lupus anticoagulant, fibrinogen, ganglioside antibodies), neurological diagnosis, occurrence of respiratory failure (defined as need for intubation, abnormal po in blood gas, or glasgow coma scale score less than or equal ), treatments administered for the neurological diagnosis, and final outcome. we studied the following outcomes: good, recovering, poor, and deceased. good outcome was defined as discharge of the patient to home or a quarantine facility, or the use of the following descriptive terms in the study: "no morbidity", "no worsening" or "discharged well" or "good recovery". recovering outcome was defined as discharge of the patient to a rehabilitation facility or use of the following descriptive terms: "began to improve", "recovering", or "stayed in the floor". poor outcome was defined as continuing deterioration of the patient's clinical status, need for icu admission, continued intubation, or use of the following descriptive terms: "poor" or "no improvement after a certain time of treatment", at the time of submitting the manuscript. deceased was defined as reported death within days of covid- diagnosis. through the search strategy, we could identify articles about neurological involvement by covid- . we were able to identify cases of covid- with neurological complications. the mean age was . years . . % of the patients were women (n = ) ( table ) . all but two patients had positive nasopharyngeal (np) or oropharyngeal (op) sars-cov- rt-pcr swabs. only two patients had positive csf sars-cov- rt-pcr, one of which showed negative np swab testing. . % of patients (n = ) had cerebrovascular insults (cvis), % (n = ) had neuromuscular disorders (nmds), and % (n = ) developed cns complications related to cns infection or inflammation. . % of patients (n = ) were recovering, . % (n = ) had good outcomes, . % (n = ) had poor outcomes, and . % (n = ) died. in . % of patients (n = ), the neurologic syndrome was the initial presentation of covid- , four of which developed respiratory symptoms - days after the onset of neurologic syndrome. in two patients, the neurologic syndrome was preceded by - days of gi symptoms, while in two other patients, it was preceded only by anosmia and dysgeusia (fig. ). % (n = ) of the cvis were due to cerebral vein thrombosis (cvt), % (n = ) were intracerebral hemorrhages (ich), . % (n = ) were aneurysmal subarachnoid hemorrhage and ich, and . % (n = ) were ischemic stroke. three out of patients ( %) had cardioembolic stroke, five had small vessel disease stroke ( %), and ( %) had large vessel occlusion (lvo) stroke. % (n = ) of the ischemic stroke patients had elevated d-dimer levels, % (n = ) had elevated c-reactive protein, . % (n = ) had elevated fibrinogen, and . % (n = ) were tested positive for lupus anticoagulant antibodies ( table ) . out of the lvo stroke patients, seven were under the age of , six underwent thrombectomy, four were treated with iv tpa, six with therapeutic low-molecular-weight heparin (lmwh), three with apixaban, four with dual antiplatelets (daps), and one with rivaroxaban and daps. six of those patients died. one of the ischemic stroke patients developed hemorrhagic conversion after thrombectomy. the lvo stroke were distributed in the following territories: left middle cerebral artery territory (mca) (n = ), right mca (n = ), left internal carotid artery (ica) (n = ), right ica (n = ), left common carotid artery (n = ), basilar artery (n = ), left vertebral artery (n = ), left posterior cerebral artery (pca) (n = ), right pca (n = ), bilateral multiple vascular territory infarcts (n = ), and unspecified (n = ). stroke with lvo was the presenting manifestation of covid- in eight patients, three of which were under the age of (table ) . . % (n = ) of the nmds patients had rhabdomyolysis, . % (n = ) had polyneuritis cranialis, . % (n = ) had oculomotor nerve palsy, and . % (n = ) had guillain-barre syndrome (gbs). seven out of the seventeen gbs cases had facial weakness, one of which manifested with isolated facial diplegia. in two cases, gbs was the first presentation of sars-cov- infection, while in other patients, gbs developed - days after the onset of flu-like symptoms. one patient presented weeks after anosmia and ageusia without respiratory or gi symptoms. electrophysiologic studies showed evidence of acute motor and sensory axonal variants (amsan) in five patients, mixed axonal and demyelinating patterns in two patients, and demyelinating patterns in six patients. emg was not performed in four patients, one of which was diagnosed with miller fisher syndrome and positive serum gd b-igg antibody. csf studies revealed albuminocytologic dissociation in ten patients, were normal in three patients (protein < mg/dl, wbcs - cells/μl). in one patient, csf protein and wbcs were mg/dl and cells/μl respectively, and csf was not performed in three patients. out of patients received ivig, one patient received ivig and plasmapheresis, one patient aeds antiepileptic drugs, daps dual antiplatelet therapy, ap antiplatelet, evd external ventricular drain, ivf intravenous fluid, ivig intravenous immunoglobulin, lmwh low-molecular-weight heparin, na not applicable, plex plasmapheresis, rs respiratory symptoms like cough and or shortness of breath, lvo large vessel occlusion, svd small vessel disease, ce cardioembolic, cvt cerebral vein thrombosis a defined by onset after respiratory or gastrointestinal symptoms or anosmia or dysgeusia, if the onset of neurological presentation (zero) means that it was the initial presentation of sars-cov- infection b , , , and days, respectively, after the neurological presentation, the patients developed respiratory symptoms c the patients neurological presentation proceeded by anosmia and dysgeusia; there were no respiratory symptoms d days after neurological presentation, cxr showed bl lungs densities e two patients had neurological presentation , days, respectively; after gastroenterological symptoms, there were no respiratory symptoms f patients regained consciousness after the third cycle ( ), second cycle ( ), and first cycle ( ) of plasmapheresis showed spontaneous recovery, and one patient received prednisone. six out of the seventeen patients developed respiratory failure, one of which died (table ) . we identified cases with confirmed covid- which were suspected to have encephalitis, based on the presence of one of the following criteria: (a) meningeal signs, (b) altered mental status, focal neurological signs, or seizures, without better alternative explanation, or (c) suggestive mri findings. . % (n = ) were ultimately diagnosed as meningoencephalitis, . % (n = ) as rhombencephalitis, . % (n = ) as acute necrotizing hemorrhagic encephalopathy, . % (n = ) as encephalopathy, . % (n = ) presented with status epilepticus, one of which was focal, and . % (n = ) had cns demyelinating lesions. in the meningoencephalitis cases, only four csf samples revealed lymphocytic pleocytosis, two of which had positive csf sars-cov- rt-pcr. nine patients developed respiratory failure, six received plasmapheresis, and one died. one patient showed postmortem evidence of the presence of viral particles in the neurons and capillary endothelial cells in the frontal lobe (table ) . pos ( ) neg ( ) failure to recover consciousness or severe agitation during weaning from mechanical ventilation ( ) mri: cortical or wm hyperintensities, contrast enhancement, and sulcal hemorrhages ( ) autoimmune meningoencephalitis our systematic review indicates that sars-cov- infection is not solely a respiratory illness, as neurological complications are not rare. ischemic and hemorrhagic stroke, guillain-barre syndrome, and its variants, encephalitis, and seizure have all been observed, which emphasizes the importance of neurological surveillance. in an analysis of cases of covid- in wuhan, china, ( . %) had neurological complications. patients with severe infection were more likely to have neurological manifestations like alteration in sensorium and muscle weakness ( . % vs . % in non-severe). the manifestations involved both the central and peripheral nervous system. the severity of these manifestations ranged from acute cerebrovascular disease and impaired consciousness to dizziness and headache [ ] . in our review, ischemic stroke was the most common neurological manifestation, occurring in . % of the subjects, with lvo representing % of the ischemic stroke. according to a series of covid- patients from italy, thromboembolic events occurred in % of the patients, including venous thromboembolism, ischemic stroke, and acute coronary syndrome [ ] . the exact mechanism of the hypercoagulable state is not well understood. d-dimers might play a major prothrombotic role in covid- patients. in this review, % of the ischemic stroke patients had elevated d-dimer levels, which are independently associated with poor outcome [ ] . severe covid- respiratory infection often leads to sepsis induced hypercoagulability, evident by increased intravascular platelet activation, increased fibrinogen, and mild prolongation of pt and aptt [ ] . indeed, a study in wuhan, china, showed that . % of patients who died of covid- had disseminated intravascular coagulation (dic) [ ] moreover, sars-cov- virus is known to bind angiotensin-converting enzyme (ace ) on endothelial cells which promotes a proinflammatory and vasoconstrictive state of endothelial dysfunction leading to end organ damage, including stroke. ace recombinant therapy, therefore, may be a promising targeted therapy for covid- -related stroke [ ] . transient production of antiphospholipid antibodies may also play a role. in a study by harzallah et al., out of patients with confirmed or suspected sars-cov- infection were positive for lupus anticoagulants, and five patients had either anticardiolipin or anti-β -glycoprotein i antibodies [ ] . zhang et al. detected antiphospholipid antibodies in three covid- patients; all of them had multiple cerebral infarcts [ ] . in this review, five of the lvo stroke tested positive for lupus anticoagulant. when presenting in the appropriate time window, thrombolytic treatment of covid- patients with ischemic stroke is reasonable. the role of anticoagulation, like lmwh, in this clinical context is still unclear [ ] . harzallah et al. recommended early anticoagulation therapy for individuals with sars-cov- infection and positive lupus anticoagulant [ ] . previous investigations suggested that covid- is associated with both platelet and clotting cascade activation [ ] . further clinical trials are necessary to determine the role of antiplatelets and/or anticoagulation for the treatment and prevention of thrombotic events in covid- , including milder cases. previously identified coronaviruses, including sars-cov- and mers, were associated with gbs [ ] . in our review, neuromuscular disorders are the second most commonly encountered neurological complication of sars-cov- infection ( %), especially gbs. the mechanisms of gbs related to sars-cov- are still incompletely understood. both para-and post-infectious mechanisms were proposed [ , ] . two patients, in our review, did not experience preceding fever, respiratory, or gi symptoms and gbs was the initial presentation. this suggests a para-infectious process, as has been reported recently with zika virus [ ] . one possible immunological explanation is the cytokine release syndrome (crs), caused by an exacerbated recruitment and activation of macrophages, neutrophils, and natural killer cells (nk) in response to sars-cov- infection. cytokines involved in crs include il- β, il- ra, il- , il- , tnf-α, ccl , and sil -rα; a critical step in the process is binding of il- to il- r (sil- r) causing jak-stat activation, and subsequent secretion of vascular endothelial growth factor (vegf), monocyte chemoattractant protein- (mcp- ), il- , and more il- , as well as decreased e-cadherin expression [ , ] . this cytokine storm can produce extensive tissue damage, including the peripheral nervous system [ ] , and appears to correlate with covid- severity. accordingly, several therapeutic options are under study, with the intent to stabilize the immune system in covid- and either prevent or minimize the consequences of this storm, as reviewed by diamanti et al. [ ] a second mechanism explaining gbs in covid- may be production of antibodies against ganglioside components of the peripheral nerves, owing to molecular mimicry with surface antigens of the infectious pathogen. this mechanism explains gbs following campylobacter jejuni infection [ ] , which is frequently associated with axonal findings on electrophysiology. similar molecular mimicry phenomena may occur in covid- [ ] , and in fact, five cases in our review were electrophysiologically characterized as amsan, yet the exact frequency of ganglioside antibodies remains unknown, because those antibodies were not tested in most cases that we reviewed. furthermore, sporadic reports of other autoimmune complications in the context of sars-cov- infection, such as steroid responsive encephalitis [ ] , immune thrombocytopenic purpura [ ] , and autoimmune hemolytic anemia [ ] , suggest that sars-cov- infection may serve as a trigger for autoimmune disorders. with the emergence of more cases of acute neuropathies temporally linked to sars-cov- infection, we should gain a better understanding of the underlying pathophysiology and potential therapeutic options of gbs related to covid- . since these neuropathies are treatable and they pose increased morbidity and mortality, neurologists, intensivists, and internists working with covid- patients must be vigilant of this association. coronavirus can be neuroinvasive and cause direct cns infection; this was convincingly demonstrated by the detection of particles and/or rna of sars-cov- , a virus with % genetic homology to sars-cov- [ ] , in human autopsies [ , ] . likewise, two of the cases that we reviewed showed positive csf sars-cov- pcr [ , ] , and one [ ] documented the evidence of viral particles in the neurons and capillary endothelial cells of the frontal lobe in a postmortem examination. the authors concluded that there was an active viral entry across the brain microvasculature into the neurons, as there was blebbing of viral particles coming in and out of the endothelial membrane [ ] . mechanistically, sars-cov- virus may enter the cns through hematogenous route or retrograde synaptic transmission. the ace protein, which functions as a receptor for sars-cov- , is abundantly expressed in the endothelial cells, supporting glia and neurons, and might be the binding site facilitating hematogenous entry. the systemic hyperinflammation increases the permeability of the blood-brain and blood-csf barriers, which might facilitate cns entry, as well [ , ] . retrograde synaptic transmission may occur via the olfactory nerve [ ] . this possibility is supported by the fact that anosmia is a frequent early sign of covid- [ ] . it has been proposed that sars-cov- neurotropism may explain not only the common symptoms of encephalitis, but also the respiratory failure, by involvement of the medullary respiratory centers. this mechanism has been demonstrated in animal models, but not yet in humans [ ] . it should be noted, however, that in most cases of suspected "meningoencephalitis", the virus could not be detected in the csf. there are several potential explanations for this negative result. one is that the encephalitis in covid- is more often immune-mediated, resulting from post-infectious or para-infectious mechanisms, and cytokine dysregulation, as previously discussed in gbs, rather than a result of direct viral invasion [ ] . the response of the encephalitic syndrome to plasmapheresis in five cases [ ] supports this notion, as does the occurrence of acute necrotizing encephalopathy in one case [ ] . acute necrotizing encephalopathy was previously described following influenza and other viral infections and attributed to cytokine storm [ ] . a second explanation is that the virus may cause endothelial injury and induce a thrombotic microangiopathy (tma)-like state, which can lead to severe encephalopathy with no evidence of inflammation based on csf studies. a third theory is that pcr testing in the csf has suboptimal sensitivity for the detection of sars-cov- . this limitation of pcr is well known to neurologists, as it occurs with several other neuroinvasive viruses, including west nile virus [ ] , and enterovirus-d causing acute flaccid myelitis [ ] . detection of intrathecal virus-specific antibodies and their ratio to serum antibodies, and the recently developed metagenomic sequencing technology [ , ] , may increase the sensitivity of viral detection in the csf in those cases, and it would be interesting to explore the utility of those techniques in covid- in the near future. detailed investigations, including csf studies, imaging, and, when possible, autopsy, are required to better elucidate those mechanisms. although two covid- patients in our review presented with status epilepticus, one of them had an established history of epilepsy from another cause. lu et al. studied covid- patients and concluded that none of these patients had acute symptomatic seizures or status epilepticus [ ] . the available data are too limited to make conclusions about the association of covid- with development of seizures. nevertheless, patients with severe sars-cov- infection, especially those hospitalized in intensive care units, are at risk for subclinical seizures or nonconvulsive status epilepticus (ncse), owing to polypharmacy, metabolic derangements, toxemia, hypoxic-anoxic brain injury, or less commonly stroke or encephalitis related to sars-cov- infection. therefore, continuous video eeg monitoring may be warranted in selected cases, as delayed diagnosis and treatment of ncse will increase morbidity and mortality [ ] . finally, lovati et al. reported a case of hsv- encephalitis, where the diagnosis and treatment were delayed because of anchoring on covid- and its neurological complications [ ] . despite all the reports of covid- neurological complications, other pathologies are still more common. ignoring this would result in significant delays in diagnosing and treating neurological patients. a number of recently published systematic reviews on covid- have addressed the same topic ( table ). the novelty of our review lies in the breadth of coverage, allowing it to serve as a primer for neurologists by summarizing the most recent evidence and the most important and relevant practical points. however, our study has some limitations. first, most of the used evidence is based on single case reports or small series, which limits its generalizability. second, some case reports did not complete or report the full work-up required to exclude alternative causes of the neurological syndrome presented. third, many cases are reported from specific ethnic populations, and hence, several demographics, genetic, or microbiologic variables might preclude the applicability of the conclusions in different populations. fourth, several stroke patients had multiple comorbidities and potentially causative vascular risk factors that we did not include in our analysis. fifth, due to incomplete work-up of several of the ischemic stroke studies included in the review, we did not have enough data for accurate stroke mechanism classification per toast in several cases. last but not least, because of the small number of subjects studied and the suboptimal quality of study design, it is not possible to reach firm conclusions about the causal effect of covid- for some neurological disorders. neurological manifestations of covid- are not rare, especially large vessel stroke, guillain-barre syndrome, and meningoencephalitis. they could be related to the direct cytopathic effect of the virus, the inflammatory response, hypercoagulable state, or complications of treatment and icu stay. moving forward, further studies are needed to clarify the prevalence of the neurological complications of covid- , investigate their biological background, and test treatment options. physicians should be cautious not to overlook other neurological diagnoses that can mimic covid- during the pandemic. author contributions dr. ghannam planned the search strategy, made the inclusion and exclusion criteria, and built the key words for the systematic review. dr. ghannam, dr. alshaer and dr. manousakis participated in articles screening and assessing their eligibility to the study. both dr. ghannam and dr. manousakis completed the final form of prisma flowchart of the selection of the studies for this review. dr. ghannam, dr. alshaer, dr. al-chalabi, dr. zakarna and dr. robertson were responsible for drafting and editing the manuscript. dr. ghannam was responsible for making the tables and the figures. dr. manousakis participated in critical revision of the manuscript for intellectual content. all authors read and approved the final manuscript. funding no funding was obtained for this study. data availability all the data supporting our findings are contained within manuscript. conflicts of interest the authors declare that they have no competing 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gaia; scalise, anna; surcinelli, andrea; valente, mariarosaria title: guillain-barré syndrome in the covid- era: just an occasional cluster? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: rxv batt nan the total number of gbs in the march-april interval of the previous three years is four. in , from march st to april th, we observed instead seven new cases diagnosed as gbs, in addition to a relapse in one more patient. this means . cases/month of observation (four cases in six months) in the previous three years, compared to . cases/month (seven cases in two months) during the current year, which increases to cases/month (eight cases in two months), if we consider also the patient with relapse. considering a population of , inhabitants in the province of udine ( census), the monthly incidence in march-april period of previous years was . new cases/ . inhabitants per month (in line with the epidemiological literature [ , ] ) versus . cases/ . inhabitants per month during the ongoing pandemic. accordingly, compared to years - , the increase of gbs cases in is . -fold. the suspicion that this striking difference could be due to the pandemic curve in our region is, therefore, legitimate. in fact, it is well known that gbs and related syndromes are often post-infectious (as for the influenza epidemics and more recently for zika virus [ ] ), with an usual latency of - days after infection [ ] . however, in our series, only one patient (twice negative at swab test) had positive serology and thorax ct scan. despite the serologic and swab negativity of the others, we think that the association with the descending slope of sars-cov- infection should still be evaluated, since the specificity and sensitivity of these tests are not yet completely assessed and the exact slope of the humoral immune response curve to this new virus is still unknown. it could also be possible that asymptomatic or paucisymptomatic infections may not develop an antibody response sufficient enough to be detected, especially considering that the available test is only qualitative. we wonder if similar clusters have been observed elsewhere. author contributions data access, responsibility, and analysis: am had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. funding none. conflicts of interest on behalf of all authors, the corresponding author states that there is no conflict of interest. ethical standard statement this study followed the tenets of the declaration of helsinki and was performed according to the guidelines of the institutional review board of university of udine medical school. population incidence of guillain-barré syndrome: a systematic review and meta-analysis guillain-barré syndrome guillain-barré syndrome associated with sars-cov- infection: causality or coincidence? cellex qsars-cov- igg/igm rapid test guillain-barré syndrome associated with zika virus infection in colombia pcr polymerase chain reaction, csf cerebrospinal fluid, na not available, cmv cytomegalovirus, ebv epstein-barr virus, hsv- herpes simplex virus , hsv- herpes simplex virus , hhv- human herpes virus , hpev human parechovirus, vzv varicella-zoster virus, tbe tick-borne encephalitis, wnv west-nile virus a we intend symptoms such as fever key: cord- - g mqnte authors: glasmacher, stella a.; larraz, juan; mehta, arpan r.; kearns, patrick k. a.; wong, michael; newton, judith; davenport, richard; gorrie, george; morrison, ian; carod artal, javier; chandran, siddharthan; pal, suvankar title: the immediate impact of the covid- pandemic on motor neuron disease services and mortality in scotland date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: g mqnte nan as of august , more than , deaths worldwide have been attributed to covid- , of which > , have been in the united kingdom and in scotland [ ] . people with mnd (pwmnd) may be particularly vulnerable. we completed a population-based analysis of the scottish mnd register, care-mnd [ ] and a clinician survey, to measure the impact of the pandemic on ( ) diagnostic rate, ( ) mortality rate, and, ( ) delivery of services. we compared all-cause mortality between / - / in - (comparator period) and / - / (covid- period) using multivariable poisson regression including age (< , - , > years) and year ( - ) as independent variables. the regression coefficients for - were pooled in a generic inverse variance random effects model to yield a summary coefficient. we performed chi-squared test to compare socioeconomic status (simd) [ ] between those who died and survivors during the covid- period. to investigate the impact of the pandemic on care delivery, we undertook a structured online survey of mnd healthcare professionals focussing on their access to diagnostics and interventions; the survey comprised multiple choice and free text questions. we identified pwmnd, diagnosed between / / - / / (median age [iqr - ], ( . %) male). most ( , . %) had amyotrophic lateral sclerosis. the number of new diagnoses remained constant after (range - ). two pwmnd, both with progressive muscular atrophy, died with confirmed or suspected covid- . one person had an alsfrs-r / in july , did not use non-invasive ventilation and died unexpectedly. the other person had an alsfrs-r of / in january and used non-invasive ventilation continuously. there was no difference in all-cause mortality between the covid- and comparator periods (pooled regression coefficient . % cis . , . ; p = . ). the mortality rate per cases was ( / ) in the covid- period and in the comparator period (mean, sd . ). mortality was higher above years age ( . % ci . , . ; p = . ) and lower below years age ( . % cis . , . ; p = . , fig. a ). there were no differences in socioeconomic index in those who died compared to survivors (simd & : . % vs. . %; p = . ). nine consultants and seven nurse specialists completed the survey (representing / scottish health boards). the majority reported provision of gastrostomy ( %), respiratory function testing ( %), and non-invasive ventilation ( %) were adversely affected. riluzole prescription ( %), palliative care ( %), and end-of-life care ( %) were comparatively unaffected (fig. b) . most reported reduced ability for face-to-face review. opinions about whether videoconferencing was an acceptable substitute were divided (strongly agree/agree %, strongly disagree/disagree %, remainder undecided). clinicians additionally reported - % of pwmnd were shielding, and that pwmnd expressed heightened anxiety of being exposed to covid- , experienced difficulties in receiving support from professional carers and family, felt loneliness, and fears of being denied treatment. our study is the first to demonstrate at a national level that rates of new mnd diagnoses and all-cause mortality in pwmnd have thus far been unaffected by covid- . shielding recommendations by scottish government may have contributed to the absence of excess mortality. evaluation of shielding justifies further study including comparison with healthcare systems that did not shield. comparative international data on mortality and morbidity in pwmnd has yet to be published. notably, we observed a spike in mortality in , which may be linked to a higher than usual rate of new diagnoses in . our data suggest respiratory function tests, non-invasive ventilation and gastrostomy are the worst affected services. preparations for further waves of covid- should prioritize maintenance of these. the adverse impact of covid- on longer-term quality of life, carer burden, morbidity and mortality in this vulnerable group requires longitudinal evaluation. world health organization ( ) who coronavirus disease (covid- ) dashboard clinical audit research and evaluation of motor neuron disease (care-mnd): a national electronic platform for prospective, longitudinal monitoring of mnd in scotland the scottish government ( ) scottish index of multiple deprivation (simd) . scottish government open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -j akzx authors: perry, richard; banaras, azra; werring, david j.; simister, robert title: what has caused the fall in stroke admissions during the covid- pandemic? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: j akzx nan during the current covid- pandemic there has been a decline in stroke admissions in centres all over the world [ , ] and no doubt this phenomenon has contributed to the sharp fall in the number of patients attending emergency departments in england during march [ ] . the explanation remains unclear. hypotheses fall into two main categories. either the incidence of stroke has declined during this period, or a higher proportion of patients who have strokes are never reaching stroke services [ ] . we reasoned that any change in the spectrum of stroke severity in patients presenting during the pandemic might yield important clues to distinguish between these two possibilities, as follows. if the main explanation is that a lower proportion of patients having a stroke are finding their way into stroke beds, then probably most of that decline will have been among those with the mildest strokes. these are the patients most likely to decide to manage their stroke at home, perhaps for fear of the risk of contracting covid- whilst in hospital. they are the most likely to have their neurological symptoms missed at a time of severe respiratory illness from the virus, or to be turned away from overstretched emergency services rather than being directed into the stroke pathway [ ] . finally, minor stroke symptoms are probably more likely to be overlooked in residents of care homes. on the other hand putative mechanisms for a decline in stroke incidence, such as reduced strain whilst people are not at work or lower levels of pollution [ ] , would not necessarily impact on strokes of any particular severity. we examined stroke severity in patients with a final diagnosis of acute stroke who were admitted to the hyperacute stroke unit at ucl hospitals, which provides the comprehensive stroke service for north central london in the united kingdom. figure shows the distribution of stroke severities (using the national institutes of health stroke scale) in admissions to our hyperacute stroke unit for two -day periods: before the decline in emergency admissions in england [ ] ( st february to th march, blue triangles) and after it ( st april to th may , red circles). the decline in the number of patients admitted with mild strokes (nihss ≤ ) was far more dramatic than was seen for moderate or severe strokes (nihss > ). it seems unlikely that a fall in the true incidence of stroke would have been so strongly biased towards mild strokes, and more plausible that the major factor driving this decline is that patients with mild strokes were no longer reaching our service during the second period. if patients with minor strokes are staying away from stroke inpatient services, as our data appear to suggest, then this is a worrying conclusion. without treatment about % of these patients will have a recurrent stroke within a week [ ] . on the other hand, the risk of catching the infection whilst in hospital is likely to be very low [ ] . the public health message is clear: individuals who think that they may be having a stroke, regardless of symptom severity, are much better off calling for an ambulance than staying at home. february (blue triangles, total patients) and for those presenting during the days from st april (red circles, total patients). the nihss is a score between and representing the degree of neurological impairment, higher scores representing more severe strokes. bin width = covid- and stroke-a global world stroke organization perspective the curious case of the missing strokes during the covid- pandemic emergency department syndromic surveillance system week public health england acute stroke care is at risk in the era of covid- population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services covid- : pcr screening of asymptomatic health-care workers at london hospital key: cord- -blkhfhe authors: gklinos, panagiotis title: neurological manifestations of covid- : a review of what we know so far date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: blkhfhe coronavirus disease (covid‐ ) has become a pandemic disease globally. while it mostly presents with respiratory symptoms, it has already been found that it could manifest with a series of neurological symptoms as well, either at presentation or during the course of the disease. symptoms vary from non-specific such as headache or dizziness to more specific such as convulsions and cerebrovascular disease (cvd). this study aims to give an overview of the neurological manifestations of covid- and discuss the potential pathogenetic mechanisms of central nervous system (cns) involvement. clinicians and especially internists, neurologists, and infectious disease specialists should be aware of these symptoms and able to recognize them early. prompt diagnosis and immediate management of the neurological manifestations of the novel coronavirus will not only improve the prognosis of covid- patients but will also prevent the dissemination of the disease due to misdiagnosed cases. coronavirus disease (covid- ) epidemic emerged in december in wuhan, china and has rapidly spread to the rest of the world. the outbreak has been declared a world pandemic by who on march , with more than , , cases worldwide so far [ ] . covid- is confirmed to be caused by a novel coronavirus ( novel coronavirus, -ncov) and presents with symptoms similar to those of severe acute respiratory syndrome coronavirus (sars-cov) in . both viruses shared the same receptor, angiotensin-converting enzyme (ace ) [ ] , thus, the novel virus was named sars-cov- . covid- typically presents with fever and respiratory symptoms including dry cough and dyspnea. the elderly population is more likely to develop severe disease complications, especially those with comorbidities such as hypertension, diabetes mellitus, and chronic obstructive pulmonary disease (copd). however, neurological manifestations of the novel coronavirus are not precepted by all clinicians, thus, leading to inappropriate management of covid- patients presenting with non-specific neurological symptoms initially. this article aims to review the cases, which reported neurological symptoms at presentation or during the course of the disease and discuss the potential mechanisms of central nervous system (cns) involvement in covid- . coronaviruses (covs) have an average diameter of nm, and they are spherical or oval. they are enveloped viruses with a single-strand, positive sense rna-genome. the sars-related coronaviruses are covered by spike proteins and when observed in the electron microscopy they have a typical crown-like shape. spike proteins contain a variable receptor-binding domain (rbd), which binds to angiotensinconverting enzyme- (ace- ) receptor found in the heart, lungs, kidneys, and gastrointestinal tract, thus, facilitating viral entry into target cells [ , ] . sars-cov- , along with sars-cov and middle east respiratory syndrome coronavirus (mers-cov), is among the seven known coronaviruses that can infect humans with a genome length of , nucleotide bases, which preserve the genetic information for its reproduction. the genetic similarity between sars-cov- and bat coronavirus is % whilst its genetic similarity with sars-cov is . % [ ] . therefore, it is believed that the novel coronavirus originated from bats and after mutating, it infected other animals and humans. malayan pangolin is considered the intermediate host of sars-cov- [ ] . sars-cov- is thought to be transmitted most readily by respiratory droplets. moreover, the digestive tract might be another transmission route as the virus has been detected in human stool [ ] . additionally, it is believed that it can be transmitted through aerosols under prolonged exposure, in a closed environment. two cases of sars-cov- -related encephalitis have been reported so far [ , ] . the first one, is a -year-old man in yamanashi, japan, who initially complained about headaches, fever, and fatigue. he was prescribed antipyretic agents and laninamivir under the diagnosis of influenza and was advised to stay home. however, a few days later he was found unconscious and was transferred to the hospital, where he presented with generalized seizures, glasgow coma scale (gcs) of and neck stiffness. brain magnetic resonance imaging (mri) showed hyperintensity along the wall of the inferior horn of the right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus with slight hippocampal atrophy in diffusion-weighted images (dwi) and fluid-attenuated inversion recovery images (flair), indicating right lateral ventriculitis and encephalitis mainly on right mesial lobe and hippocampus. although the specific sars-cov- rna was not detected in the nasopharyngeal swab, it was detected in csf confirming the diagnosis of meningitis/encephalitis associated with sars-coronavirus- . the other case was reported in ditan hospital, beijing, china, where a -yearold patient diagnosed with covid- developed an altered level of consciousness. although he had normal brain computerized tomography (ct) scans, cerebrospinal fluid (csf) testing for sars-cov- was positive, confirming the diagnosis of encephalitis due to the novel coronavirus. the first case was reported in detroit, miami, and is about a female airline worker in her late fifties presented with a -day history of cough, fever, and altered mental status [ ] . she was diagnosed with covid- through the detection of the rna of the novel coronavirus in the nasopharyngeal swab. however, due to a traumatic lumbar puncture, csf testing for sars-cov- was unable to be performed. noncontrast brain ct scan demonstrated symmetric hypoattenuation within the bilateral medial thalami. brain mri demonstrated hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. clinical presentation and imaging findings were consistent with the diagnosis of acute necrotizing encephalopathy (ane), a rare complication of influenza and other viral infections, which has been related to intracranial cytokine storms, resulting in blood-brain-barrier breakdown [ ] . the patient was treated with intravenous immunoglobulin. the second case concerns a -yearold patient, presented at the emergency department (ed) with fever and cough, who was initially discharged home with oral antibiotics [ ] . he returned to the ed within h with worsening symptoms, including headache, altered mental status, fever, and cough. upon examination, the patient was found encephalopathic, nonverbal, and unable to follow any commands. non-contrast, brain ct scan showed no acute abnormalities whilst electroencephalography (eeg) showed bilateral slowing and focal slowing in the left temporal region with sharply countered waves. the patient was found to be positive for covid- (nasopharyngeal swab), whilst csf testing did not reveal a central nervous system infection. two studies have been conducted so far, regarding the association of covid- and cerebrovascular disease (cvd). the first one is a retrospective, observational analysis of consecutive covid- patients admitted to union hospital, wuhan, china [ ] . it showed that cvd is not uncommon during sars-cov- infection, especially in older patients with risk factors. more specifically, % of the patients developed acute ischemic stroke, . % cerebral venous sinus thrombosis, and . % cerebral hemorrhage. patients who developed cvd were more likely to present with severe covid- , and to have cardiovascular risk factors such as hypertension, diabetes, and previous medical history of cvd. the other study is a retrospective case series in wuhan, china, which reported the neurological symptoms of covid- patients [ ] . it showed that patients with severe covid- were more likely to develop cvd as compared with non-severe cases. ( . %four cases of acute ischemic stroke and one case of cerebral hemorrhage vs. . %-one patient with ischemic stroke). however, we should mention that both studies were conducted in wuhan, china, thus, findings cannot be applied to the general population. it is well-known that viral infections including coronaviruses can lead to smell dysfunction [ , ] . post-viral anosmia is one of the leading causes of loss of sense of smell in adults, accounting for up to % cases of anosmia [ ] . the underlying cause is primarily mucosal congestion, which leads to nasal obstruction and conductive olfactory loss [ ] . however, the novel coronavirus is thought to cause olfactory and gustatory disorders without causing rhinorrhea or nasal obstruction. a multi-center european study showed that . % and . % of covid- patients developed olfactory and gustatory disorders respectively [ ] . regarding the olfactory disorders, . % of the patients were anosmic and . % were hyposmic. interestingly, among the . % of patients without nasal obstruction or rhinorrhea, . % were hyposmic or anosmic, suggesting that the inflammatory reaction of the nasal mucosa is not the cause of smell dysfunction in this case. the gustatory dysfunction consisted of reduced, discontinued, or distorted ability to taste flavors (salty, sweet, bitter, and sour) in . % and . % of patients, respectively. besides the clinical manifestations mentioned before, sars-cov- can potentially present with a number of non-specific neurological symptoms. the above-mentioned clinical case series in wuhan, china, showed that . % of covid- patients had neurological symptoms at onset. the most common neurological symptoms were dizziness ( . %), headache ( . %), skeletal muscle inflammation ( . %), and altered mental status including confusion, disorientation, and impaired level of consciousness ( . %) [ ] . nervous system symptoms were significantly more frequent in patients with severe covid- as compared to non-severe cases ( . %) vs. ( . %). the severity of covid- was defined by the international guidelines for communityacquired pneumonia [ ] . finally, a case of guillain-barré syndrome should be discussed, even though it only suggests a possible association with sars-cov- and not a proven causal relationship [ ] . a -year-old woman without respiratory symptoms presented to the hospital with acute weakness in both legs and severe fatigue, progressing within one day. upon examination she disclosed symmetric weakness ( / ) and areflexia in both legs and feet. three days after admission, her symptoms progressed. muscle strength was grade / in both arms and hands and / in both legs and feet. sensation to light touch and pinprick was decreased distally. csf testing showed increased protein levels and nerve conduction studies showed delayed distal latencies and absent f waves in early course, supporting demyelinating neuropathy. the woman was diagnosed with guillain-barré syndrome. seven days after admission she developed dry cough, fever ( . °c) and she was found to be positive for covid- (nasopharyngeal swab). although she had not initially presented with respiratory symptoms, it has been shown that sometimes sars-cov- may manifest in a non-specific way (fever in only . %). moreover, the patient's initial laboratory abnormalities (lymphocytopenia and thrombocytopenia), were consistent with the clinical characteristics of patients with covid- . unfortunately, the absence of coronavirus testing on admission does not allow us to state a causal relationship between the novel coronavirus and guillain-barré syndrome. however, it certainly suggests that a parainfectious pattern of the syndrome may exist and neurologists should be aware of the potential association. as the new epidemic is still ongoing, documentation of the neurological manifestations of sars-cov- is scarce. patients with covid- may initially present with nonspecific neurological symptoms including headache and dizziness. others can develop more specific symptoms such as seizures and cvd. it has also been shown, that the more severe the infection, the more likely it is to develop neurological symptoms, especially cvd and altered mental status [ ] . human coronaviruses have already been found to be neuroinvasive and neurotropic [ , ] . more specifically, sars-cov has been shown to induce various neurological diseases such as polyneuropathy, encephalitis, and aortic ischemic stroke [ ] . in addition, its rna has been detected in the csf of a patient with the severe acute respiratory syndrome (sars) while autopsy samples from eight patients with sars revealed the presence of sars-cov in brain samples by immunohistochemistry, electron microscopy, and real-time-pcr (rt-pcr) [ , ] . mers-cov is also a neuroinvasive coronavirus, which has been linked to a series of neurological manifestations including altered mental status, ischemic stroke, and guillain-barré syndrome [ ] . the genetic and structural similarities of sars-cov- with sars-cov and mers-cov, indicate that the novel coronavirus could potentially invade cns using the same pathophysiological mechanisms the other coronaviruses use. although, the exact pathophysiological mechanisms are not fully understood two possible theories have been proposed so far: hematogenous dissemination and neuronal retrograde dissemination. the first one requires the presence of a given virus in the blood, where it can either infect the endothelial cells of the blood-brain-barrier (bbb), or infect leukocytes that will become some sort of viral reservoir for dissemination to other sites [ ] . on the other hand, neuronal retrograde dissemination occurs when a virus migrates by infecting sensory or motor nerve endings, achieving retrograde or anterograde neuronal transport, by using the cell machinery of active transport to access the cns [ , ] . olfactory nerves and the olfactory bulb in the nasal cavity may work as a connecting channel between the nasal cavity and the cns [ ] . the latter scenario is further supported by the fact that many patients with covid- experience anosmia or hyposmia [ ] . moreover, removal of the olfactory bulb in the mice resulted in a restricted invasion of cov into the cns [ ] . regarding the occurrence of acute cerebrovascular events, patients with severe covid- are found to have increased levels of serum d-dimers, thus are more likely to develop acute embolic vascular events [ ] . also, the cytokine storm syndrome that the novel coronavirus causes, may lead to cvd as well [ ] . finally, thrombocytopenia that critically ill patients present, as well as blood pressure fluctuations in hypertensive patients due to sars-cov- binding to the ace receptor may increase the risk of cerebral hemorrhage [ ] . although the respiratory manifestations of sars-cov- are well recognized, the neurological manifestations have not been adequately studied yet. critically ill patients are at a greater risk of developing neurological 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