key: cord-0878338-grts0fn3
authors: Lallana, Sofía; Chen, Austin; Requena, Manuel; Rubiera, Marta; Sanchez, Anna; Siegler, James E.; Muchada, Marián
title: Posterior reversible encephalopathy syndrome (PRES) associated with COVID-19 Clinical paper – Case series
date: 2021-03-23
journal: J Clin Neurosci
DOI: 10.1016/j.jocn.2021.03.028
sha: f3d6fcd61f371150b6c46dc26005fef47991f427
doc_id: 878338
cord_uid: grts0fn3

The novel human coronavirus disease (COVID-19) has been associated with vascular and thrombotic complications, some of which may result from endothelial dysfunction, including the posterior reversible encephalopathy syndrome (PRES). We report a case series of 8 patients with COVID-19 and PRES diagnosed at two academic medical centers between March and July of 2020. The clinical, laboratory and radiographic data, treatment, and short-term outcomes were retrospectively analyzed. The mean age was 57.9±12 years, and 50% were women. Four patients had previous vascular comorbidities. All the patients suffered from severe pneumonia, requiring intensive care unit admission. Five patients were not hypertensive at presentation (all SBP<127 mmHg). Neurologic symptoms included seizures in 7 patients; impaired consciousness in 5 patients; focal neurological signs in 3 patients; and visual disturbances in 1 patient. All patients underwent brain magnetic resonance imaging which indicated asymmetric T2 prolongation or diffusion changes (50%), extensive fronto-parieto-occipital involvement (25%), vascular irregularities (12.5%) and intracranial hemorrhage (25%). Four patients were treated with tocilizumab. Three patients were discharged without neurologic disability, 2 patients had persistent focal neurologic deficits and 2 expired. One patient’s prognosis remains guarded. Together, these data support the relationship between PRES and endothelial dysfunction associated with severe COVID-19. In patients with severe COVID-19, PRES can be triggered by uncontrolled hypertension, or occur independently in the setting of systemic illness and certain medications. Like other infectious processes, critically ill patients with COVID-19 may be at greater risk of PRES because of impaired vasoreactivity or the use of novel agents like Tocilizumab.

Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in Wuhan (China) at the end of 2019, over one hundred million people have been diagnosed with coronavirus disease 2019 (COVID- 19) , with more than two million deaths to date [1] .

The majority of COVID-19 patients present with asymptomatic or mild infection, developing symptoms like fever, cough, myalgias and headache. Pneumonia is the most frequent serious manifestation of the disease, with acute respiratory distress syndrome being a major complication in severe cases [2] , [3] . Neurological symptoms have been observed in over one-third of severe COVID-19 patients, [4] [5] some of which have been attributed to the systemic involvement of the disease, including headache, dizziness, myalgias, or even cerebrovascular diseases that might have been triggered by a hypercoagulable state. However, other more specific manifestations have been observed, like hyposmia and hypogeusia, polyneuropathy, encephalitis, and encephalopathy that raise the possibility of direct neural invasion of SARS-CoV-2 [6] .

Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications, but the pathophysiology of neurologic damage caused by SARS-CoV-2 is still being studied. Neurotropism of SARS-CoV-2 is not yet defined, with several theories being explored at the moment. It has been suggested that the virus might enter the brain through the transcribial route described in other CNS pathogens in the past, or by leveraging the ACE-2 receptors on endothelial and glial tissue [6] , which would justify the cerebral edema detected in some COVID-19 patients [7] .

In this case series we sought to review one manifestation of endothelial dysfunction associated with COVID-19, the posterior reversible encephalopathy syndrome (PRES).

We report a case series of 8 patients diagnosed during the pandemic, from March to July 2020, with severe COVID-19 infection and PRES at Vall d'Hebron University Hospital, Barcelona, and Cooper University Hospital, Camden.

All patients had a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test on a nasopharyngeal specimen at the moment of developing PRES, as well as COVID-19 symptomatology. Pneumonia was defined as severe if the patient had SpO2<94% on room air, respiratory rate>30, PaO2/FiO2<300 mmHg or lung infiltrates>50% on chest radiograph [8] . In addition to pulmonary disease, these patients all experienced septic shock and/or multiple organ dysfunction. Patients met clinical and/or radiographic criteria for PRES [9] , with acute neurological symptoms in the appropriate clinical context (i.e. in the presence of pronounced hypertension, renal failure, severe infection), and brain imaging (brain CT or MRI) that revealed vasogenic edema.

The following groups of variables were collected and retrospectively analyzed: demographic data, clinical data related to PRES and COVID-19, laboratory parameters and radiological findings. Statistical analysis was performed using SPSS software ver 25.0. Categorical variables were presented as absolute values and percentages and continuous variables as means (+-standard deviation (SD)) as indicated.

We present 8 patients with radiographically confirmed PRES (4 at each site), who were identified out of a series of 2812 consecutively admitted patients with laboratoryconfirmed COVID-19 (2.8 per 1,000 COVID-19 admissions). Four of them were women (50%), with a mean age ± SD at presentation of 57.9±12 years. Four patients (50%) did not have any relevant medical history, with a mean age of 51 years. The other 4 patients (50%), with a mean age of 64.7 years, had a medical history of cardiovascular diseases and other conditions ( Table 1) .

As comorbidities they presented: high blood pressure (3 patients, 37.5%), dyslipidemia The mean time from COVID-19 diagnosis to PRES development was 31 days (SD 23), varying from a mean of 23 days in patients without comorbidities recorded to a mean of 39.5 for those with them. The most common clinical manifestations were seizures, which appeared in 7 patients (87.5%), with 2 patients evolving into status epilepticus. Altered mental status was present in 5 patients (62.5%), focal neurological signs in 3 patients (37.5%) and visual disturbance in 1 patient (12.5%). As per our institutional protocols, sedation is temporarily interrupted to permit frequent neurologic assessments of all patients, which permitted recognition of new neurologic symptoms and detailed examinations.

Regarding treatment of PRES, hypertensive patients were treated with afterload reduction [10] and antiepileptic drugs (AEDs) were used for seizure control. Immunosuppressive therapy was discontinued in one patient (patient 5 was receiving Tacrolimus due to liver transplant). One patient (patient 1) presented with focal signs (right hemianopsia and hemiparesis) within less than 4.5 hours of evolution, without hypodensities or hemorrhages in the head CT (although CT angiography showed proximal stenosis in both posterior cerebral arteries). Given the initial suspicion of arterial ischemic stroke and the known relationship between COVID-19 and embolic stroke, intravenous thrombolysis was administrated. Diagnostic arteriography was performed immediately after, demonstrating the presence of luminal irregularities in the posterior cerebral arteries (Fig   2.) , and local intra-arterial nimodipine was administrated for three times, with clinical improvement in vessel caliber-suggesting vasospasm rather than atherosclerosis. Oral nimodipine therapy was administered over the next ten days.

PRES was confirmed radiographically using brain CT (n=3) or magnetic resonance imaging (n=5) with characteristic findings in 7 patients. One patient demonstrated bilateral areas of T2/FLAIR hyperintensity with restricted diffusion in the subcortical white matter, with an atypical pattern for ischemia, but could have been consistent with hypoxic ischemic encephalopathy. However, this patient was not hypoxemic at any time during the ICU admission despite severe pneumonia. The most common location of the vasogenic edema was the parieto-occipital region (75%) with an extensive fronto-parietooccipital involvement in 2 patients (25%) (Fig. 1) . Lesions were asymmetric in 4 patients (50%). In one patient there was vasoconstriction associated with the vasogenic edema (Fig. 2) , and hemorrhagic manifestations (microbleeds) were present in 2 patients (25%) (Fig. 3) . Follow-up neuroimaging available for 4 patients based on availability and clinical stability of these patients, with significant resolution of the preexisting edema (Fig. 4) .

The median length of stay at the hospital was 45.8 days (range 9-87) with 4 patients being discharged home and 1 discharged to a nursing facility. Three patients (37.5%) were neurologically asymptomatic at discharge and 2 patients (50%) had persistent focal neurologic signs, including moderate limb paresis. Two patients (25%) expired, one of whom died as a consequence of ongoing seizure activity, and another because of respiratory failure. In 1 patient, the short-term prognosis remains guarded as the patient was transferred to another hospital after stabilization.

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As a radiographic manifestation of many medical conditions, PRES is a heterogeneous disorder triggered by a variety of proximate causes [9] [11] [12] . The systemic illness associated with and inflammatory response to SARS-CoV-2, endothelial dysfunction, and comorbidities observed in patients with severe COVID-19 are only a few potential explanations for the development of PRES that has been reported in these patients [13] PRES has been historically characterized by a lack of brain blood vessel autoregulation after severe hypertension [9] , or as a consequence of severe infections, inflammation, or vasotoxicity. A pre-existing autoimmune condition has been identified in as many as half of patients with PRES [9] suggesting a relationship with immune dysregulation. While hypertension is the most common primary cause of PRES, less than a half of our patients were severely hypertensive at the time of their neurologic manifestations (3/8 patients).

The endothelial dysfunction associated with COVID-19 [20] Among patients with sepsis, the activation of the immune system can stimulate the cytokine production, notably increasing levels of tumor necrosis factor α and vascular endothelial growth factor, thereby increasing the blood brain barrier permeability and promoting edema formation. This has been described particularly with gram-positive sepsis [23] , but also in viral infections like influenza A [24] or parainfluenza [25] . A similar complication may occur PRES associated with COVID-19. That said, most of our patients developed concomitant bacteremia or fungal infections, which may also have predisposed them to PRES independently from their SARS-CoV-2 infection.

In order to control this exaggerated immune response to COVID-19, Tocilizumab (an IL-6 antibody) has been utilized in severe cases with some improvement in severity of symptoms [26] . Cases of PRES during treatment with Tocilizumab have been reported [27] , although the mechanism has not been well defined yet. Half of the patients in our case series were given Tocilizumab, 3 of whom lacked vascular comorbidities including hypertension (75%). It is possible that Tocilizumab may have contributed to this complication, and its use should be cautioned although PRES appears to be a rare complication of treatment.

Renal failure is also a significant risk factor for PRES [9] , and it was a frequent complication in this cohort of COVID-19 with PRES (50%). Along with the previously described risk factors for PRES, it is unlikely that renal failure alone would be responsible for this condition. There are several limitations of our case series, most importantly the small number of cases. Additionally, not all the patients underwent MRI at the time neurologic symptoms began to manifest, which would have provided more information than CT. Also, the lack of follow-up neuroimaging in half of these patients limits our understanding as to the temporal resolution of these changes. Larger studies are required to really understand the relationship between COVID-19 and PRES.

PRES appears to be a rare but serious complication of severe COVID-19, with associated seizures and focal neurologic deficits. As SARS-CoV-2 may cause more severe disease in patients with vascular comorbidities and may lead to other complications (e.g., nosocomial infections, multi-organ dysfunction), it stands to reason that PRES may be a complication of these collateral effects of the infection rather than a consequence of direct viral invasion into the nervous system. Coupled with the impaired vasoreactivity [6] and side effects of aggressive treatments (e.g., Tocilizumab), these risk factors put patients 

COVID-19) Pandemic. Geneva: World Health Organization

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy

Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19)

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

Fulminant cerebral edema as a lethal manifestation of COVID-19

Management of COVID-19. Coronavirus Disease COVID-19. NIH. Last Updated

Posterior reversible encephalopathy syndrome: Clinical and radiological manifestations, pathophysiology, and outstanding questions

Hypertensive emergencies

Posterior reversible encephalopathy syndrome, Part 2: Controversies surrounding pathophysiology of vasogenic edema

Posterior reversible encephalopathy syndrome

Hemorrhagic Posterior Reversible Encephalopathy Syndrome as a Manifestation

Posterior reversible encephalopathy syndrome (PRES) as a neurological association in severe Covid-19

Posterior reversible encephalopathy syndrome (PRES): Another imaging manifestation of COVID-19

Posterior reversible encephalopathy syndrome in patients with COVID-19

Associated posterior reversible encephalopathy syndrome (PRES) to SARS-CoV-2. Case report

Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis

Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?

Vascular endothelial glycocalyx damage in COVID-19

Microvascular dysfunction in COVID-19: the MYSTIC study

Posterior reversible encephalopathy syndrome in infection, sepsis, and shock

Posterior reversible encephalopathy syndrome and cerebral vasculopathy associated with influenza a infection: Report of a case and review of the literature

Parainfluenza virus infection associated with posterior reversible encephalopathy syndrome: A case report

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Falling stroke rates during COVID-19 pandemic at a comprehensive stroke center

Posterior hypodensities suggestive of vasogenic edema in brain CT (A) with resolution in control MRI FLAIR sequence (B) Conflict of Interest and Authorship Conformation Form Please check the following as appropriate

All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version

-There is adherence to ethical guidelines.-This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.-Declarations of interest: none