key: cord-0701220-tva13zwx authors: Luis, María Belén; Liguori, Nora Fernández; López, Pablo Adrián; Alonso, Ricardo title: SARS-CoV-2 RNA DETECTION IN CEREBROSPINAL FLUID: PRESENTATION OF TWO CASES AND REVIEW OF LITERATURE. date: 2021-06-08 journal: Brain Behav Immun Health DOI: 10.1016/j.bbih.2021.100282 sha: 55070658b47e28c730d130609794192a9754f208 doc_id: 701220 cord_uid: tva13zwx Neurological manifestations of SARS-CoV-2 infection are multiple and heterogeneous. However, confirmation of nervous system impairment by viral RNA detection in cerebrospinal fluid (CSF) is uncommon. We report two cases of central nervous system (CNS) involvement with positive real-time reverse-transcriptase polymerase chain reaction (RT-PCR) test in CSF. Since the beginning of the ongoing SARS-CoV-2 pandemic, several studies describing the neurological manifestations of the disease have been published. Although this virus has special predilection for the respiratory and cardiovascular systems, its potential neurotropism is also known 1 . The most common neurological manifestations are smell and taste disturbances, headache, myalgia, dizziness and impaired consciousness. Other reported clinical pictures include ataxia, neuropathies, meningoencephalitis, demyelinating disorders and cerebrovascular disease 2,3 . As described in previous reports, patients with severe forms of the disease are more prone to developing CNS impairment than those with mild to moderate infections 4, 5 . The exact explanation for SARS-CoV-2 CNS involvement is not well established yet, but two possible mechanisms have been proposed: direct viral CNS invasion or cytokine cascade induced by the virus 6, 7 . Despite the wide variety of published literature about neurological disorders associated with SARS-CoV-2 infection, there are few reported cases with viral RNA detection in CSF. We present two cases of young patients with CNS disease due to SARS-CoV-2, with positive viral RT-PCR test in CSF. A 25-year-old female was referred to our hospital due to acute impairment of consciousness. She had a personal history of anxiety disorder and had been diagnosed with mild COVID-19 (odynophagia and hyposmia) four months before admission with complete recovery of symptoms afterwards. Ten days before hospitalization the patient began with a holocranial headache, vomits and fever, and one week later she had a tonic-clonic seizure. At initial evaluation in another hospital, neck stiffness was noted. Brain computed tomography (CT) scan was unremarkable and there were no positive findings in blood tests. Analysis of CSF yielded hypoglycorrhachia (37 mg/dl), hyperproteinorrachia (247 mg/dl) and no cells. Acute bacterial meningitis was suspected and treatment with Ceftriaxone was started. The patient quickly developed an altered mental state, and antimicrobial therapy was switched to Meropenem, Vancomycin and Acyclovir. She was then transferred to our hospital. At the initial neurological examination, mutism and stupor were observed. The pupils were symmetrical and reactive to light. There were no signs of cranial nerve involvement. She had nuchal rigidity and upper limbs hypertonia. Shortly after admission she developed a comatose state and a nonconvulsive status epilepticus was ruled out by EEG. The new CSF examination revealed normal opening pressure, lymphocytic pleocytosis (380/mm3 -90% lymphocytes), hyperproteinorrachia (98.3 mg/dl), normal glucose level (57 mg/dl) and increased lactate concentration (4.32 mmol/l). Brain and spinal cord magnetic resonance imaging (MRI) were abnormal (Figures 1-2) . Extensive work-up was conducted to exclude secondary causes such as infection, autoimmune, metabolic and endocrinological diseases ( Table 1 ). The RT-PCR test for SARS-CoV-2 was performed on samples from nasopharyngeal swab and CSF. The specific SARS-CoV-2 RNA was detected in CSF whereas the nasopharyngeal swab test was negative. After one week in intensive care unit (ICU) with mechanical ventilation, the physical examination revealed bradylalia, square wave jerks, ataxia, myoclonus in four limbs and urinary retention. The patient developed subsequently significant clinical recovery, remaining only with mild gait disturbance. She was finally discharged after three weeks of hospitalization. Tau Inversion Recovery (STIR) sequence extending from C2 to Th3 level and from Th5 to Th10 (longitudinally extensive myelitis) , with patchy and eccentric contrast enhancement. T1 post contrast cervical and lumbar pial enhancement associated to conus medullaris enhancement. A 41-year-old male, with a history alcoholism, iron deficiency anemia and chronic cardiovascular disease, was hospitalized because of a septic shock secondary to a skin and soft tissue infection. He had a favorable clinical course and completed antibiotic therapy. As part of our institutional protocol, he was performed a nasopharyngeal swab RT-PCR test for SARS-CoV-2 that resulted positive. The chest computed tomography scan was normal and the patient remained asymptomatic. After 20 days, he developed disorientation, psychomotor agitation and rapidly reached a stuporous state. The rest of the neurological examination was unremarkable. Blood test yielded only a mild chronic hyponatremia. Brain MRI exhibited no pathological features. A lumbar puncture was performed and the CSF showed mildly increased protein level (95.9 mg/dl), normal glycorrhachia (43 mg/dl) and no cells. RT-PCR SARS-CoV2 test was positive in CSF. Further work-up excluded other infectious etiologies. On the following days, he experienced spontaneous complete recovery. Insert here Table 1 NMDAR: N-methyl-d-aspartate receptor, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2: contactin-associated protein-like 2 receptor; LGI1: leucine-rich glioma-inactivated 1; GABABR: γ-aminobutyric acid type B receptor, GAD: Glutamic acid decarboxylase. Approximately one third of SARS-CoV-2 infected patients develop neurological manifestations that involve predominantly the CNS 3,4 . We report two cases of CNS manifestations of SARS-CoV-2 infection, confirmed by the detection of viral RNA in CSF. The first case is a female patient who presented with meningoencephalitis and myelitis four months after a mild SARS-CoV-2 infection. The second one is a patient with a SARS-CoV-2 infection entirely confined to the CNS (encephalitis), with no involvement of other organ systems. Several hypotheses have been proposed in order to explain this neurological involvement. One explanation is CNS penetration through hematogenous spread via permeable blood-brain barrier, or retrograde neuronal route through the cribriform plate and olfactory bulb 6, 8, 9 . The ability of SARS-CoV-2 spike protein to bind to angiotensin-converting enzyme 2 (ACE-2) receptors on the capillary endothelium may be responsible for facilitating viral entry into the CNS 7, 8 . Another hypothesis is based on the inflammatory cytokine release leading to a cascade of immune cells within the CNS. In the latter, the consequent endothelial dysfunction predisposes to thrombosis or hemorrhage and results in stroke 6, 7 . Furthermore, it is believed that para-and post-infectious complications due to dysregulation of the immune system may lead to antibody mediated damage of the nervous system, causing encephalitis, Guillain Barre Syndrome and its variants 10, 11 . Autopsy performed in patients with SARS-CoV-2 infection showed hyperemic and edematous brain tissue and neuronal degeneration 12 . As in our cases, it has been previously described that a positive nasal swab does not correlate with the presence or absence of the virus in the CSF of patients with neurological symptoms 6 . To date, only a small proportion of reported patients with neurological manifestations and CSF analysis, had positive RT-PCR in CSF 5, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 . Clinical and paraclinical findings of these patients are summarized in Table 2 . The most frequent CSF findings were occasionally hyperproteinorrachia and mild lymphocytic pleocytosis. Helms et al reported a cohort of 118 ICU patients with acute respiratory distress syndrome due to SARS-CoV-2 infection who developed delirium and/or abnormal neurological examination. CSF analysis was performed in 25 of those patients, with positive RT-PCR SARS-CoV-2 in only one patient 5 . Insert here Table 2 FLAIR: Fluid-attenuated inversion-recovery; DWI: Diffusion-weighted imaging; SWI: Susceptibility-weighted images; STIR: Short Tau Inversion Recovery. As far as neuroimaging is concerned, most commonly reported findings represent cases of cerebrovascular disease. Based on a recent systematic review, the possible SARS-CoV2-2 brain MRI patterns are large vessel occlusion infarction, usually with hemorrhagic transformation; lobar and cortical intracerebral hemorrhage; multiple callosal and juxtacortical white matter cerebral microbleeds and hemorrhagic necrotizing encephalopathy 24 . Nevertheless, as these features are also seen in critical ill patients, the direct association with SARS-CoV-2 infection is still to be determined. No typical feature of SARS-CoV-2 associated demyelination, leukoencephalopathy and myelitis was identified. Other imaging findings are cerebral venous sinus thrombosis, posterior reversible encephalopathy syndrome, cytotoxic lesion in the corpus callosum, basal ganglia abnormalities, leptomeningeal, cranial and spinal nerve enhancement 24, 25, 26, 27 . Up to now, seven cases of SARS-CoV-2 associated myelitis have been published, only one with viral RNA presence in CSF 28, 29, 30, 31, 32, 33, 34 . Clinical and imaging findings are described in Table 3 . Insert here Table 3 STIR: Short Tau Inversion Recovery; FLAIR: Fluid-attenuated inversionrecovery. SARS-CoV-2 can affect the nervous system in any stage of infection, and neurological complications can even represent the only manifestation of the disease. Nevertheless, they are currently underdiagnosed and viral RNA detection in CSF is infrequent. In patients with neurological symptoms, SARS-CoV-2 infection should be considered in order to avoid delayed diagnosis and prevent transmission. 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Clinical Practice and Cases in Emergency Medicine Acute myelitis after SARS-CoV-2 infection: a case report STIR signal hyperintensity extending from C2 to Th3 level and from Th5 to Th10 (longitudinally extensive myelitis), with patchy and eccentric contrast enhancement. T1 post contrast cervical and lumbar pial enhancement associated to conus medullaris enhancement.FLAIR hyperintensities involving the cerebellum, thalamus and basal ganglia. Focal area of restricted diffusion in the splenium of the corpus callosum.