key: cord-1034084-s7ekcsf3 authors: Anand, Pria; Lau, K. H.Vincent; Chung, David Y; Virmani, Deepti; Cervantes-Arslanian, Anna M.; Mian, Asim; Takahashi, Courtney E. title: Posterior Reversible Encephalopathy Syndrome in Patients with Coronavirus Disease 2019: Two Cases and a Review of the Literature date: 2020-07-30 journal: J Stroke Cerebrovasc Dis DOI: 10.1016/j.jstrokecerebrovasdis.2020.105212 sha: e140eddb7226aa69581b22136fcbad1873bc98a1 doc_id: 1034084 cord_uid: s7ekcsf3 Introduction: Encephalopathy is a common complication of coronavirus disease 2019. Although the encephalopathy is idiopathic in many cases, there are several published reports of patients with posterior reversible encephalopathy syndrome in the setting of coronavirus disease 2019. Objective: To describe the diverse presentations, risk factors, and outcomes of posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019. Methods: We assessed patients with coronavirus disease 2019 and a diagnosis of posterior reversible encephalopathy syndrome at our institution from April 1 to June 24, 2020. We performed a literature search to capture all known published cases of posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019. Results: There were 2 cases of posterior reversible encephalopathy syndrome in the setting of coronavirus 2019 at our institution during a 3-month period. One patient was treated with anakinra, an interleukin-1 inhibitor that may disrupt endothelial function. The second patient had an underlying human immunodeficiency virus infection. We found 13 total cases in our literature search, which reported modest blood pressure fluctuations and a range of risk factors for posterior reversible encephalopathy syndrome. One patient was treated with tocilizumab, an interleukin-6 inhibitor that may have effects on endothelial function. All patients had an improvement in their neurological symptoms. Interval imaging, when available, showed radiographic improvement of brain lesions. Conclusions: Risk factors for posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019 may include underlying infection or immunomodulatory agents with endothelial effects in conjunction with modest blood pressure fluctuations. We found that the neurological prognosis for posterior reversible encephalopathy syndrome in the setting of coronavirus disease 2019 infection is favorable. Recognition of posterior reversible encephalopathy syndrome in this patient population is critical for prognostication and initiation of treatment, which may include cessation of potential offending agents and tight blood pressure control. posterior reversible encephalopathy syndrome. One patient was treated with tocilizumab, an interleukin-6 inhibitor that may have effects on endothelial function. All patients had an improvement in their neurological symptoms. Interval imaging, when available, showed radiographic improvement of brain lesions. Conclusions: Risk factors for posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019 may include underlying infection or immunomodulatory agents with endothelial effects in conjunction with modest blood pressure fluctuations. We found that the neurological prognosis for posterior reversible encephalopathy syndrome in the setting of coronavirus disease 2019 infection is favorable. Recognition of posterior reversible encephalopathy syndrome in this patient population is critical for prognostication and initiation of treatment, which may include cessation of potential offending agents and tight blood pressure control. Keywords PRES, COVID-19, immunosuppression Background Central nervous system (CNS) manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include encephalopathy, encephalitis, meningitis, acute disseminated encephalomyelitis, and stroke [1], both as a result of direct viral invasion of the central nervous system [2] [3] [4] [5] and as a consequence of critical illness and systemic infection [6] . Coronavirus disease 2019 may also cause significant changes in endothelial morphology, including disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane [7] . However, posterior reversible encephalopathy syndrome (PRES), which may result from such endothelial dysfunction, has rarely been reported in patients with . The diverse etiologies and risk factors of PRES in this unique population warrant close examination, as they may elucidate strategies to prevent or treat the syndrome in select patients with COVID-19. This study protocol was approved by the Boston Medical Center's Institutional Review Board. Two cases were identified through surveillance of patients admitted to the neurocritical care service between April 1, 2020 and June 24, 2020 with positive nasopharyngeal swab testing for SARS-CoV-2 and a clinical diagnosis of PRES. A literature review for published cases of PRES in patients with COVID-19 was conducted on July 20, 2020 by searching PubMed and Medline using the terms "posterior reversible encephalopathy syndrome AND COVID" and "PRES AND COVID". A previously healthy 61-year-old woman presented with one week of dyspnea, headaches, fever, and cough. She was diagnosed with COVID-19 based on a positive nasopharyngeal PCR for SARS-CoV-2 and was treated with remdesivir and anakinra. Her hospital course was complicated by worsening respiratory failure requiring intubation on hospital day 5, subsequent proning for respiratory distress syndrome, ventilator dyssynchrony requiring significant sedation and periodic paralysis, and septic shock with hypotension requiring vasopressors. On hospital day 15, a head CT was obtained because of persistently poor mental status in spite of weaning sedation and revealed significant posterior cortical paramedian hypodensity consistent with cerebral edema ( Figure 1A ). Blood pressure range was 152-187/79-98 mmHg, with no metabolic derangements. CT venogram showed no evidence of venous sinus thrombosis. In order to conserve personal protective equipment and limit healthcare worker exposure and risk, a lumbar puncture was not performed. A subsequent brain MRI on hospital day 18 revealed symmetric white matter T2 hyperintense signal abnormalities involving the parietal and occipital lobes without diffusion restriction consistent with PRES, as well as a focus of susceptibility artifact in the right frontal lobe ( Figure 1B -C). On hospital day 18, she had a clinical seizure characterized by rightward gaze deviation and right arm and leg shaking. She was treated with levetiracetam and valproic acid. Subsequent 24-hour continuous video electroencephalography (EEG) revealed rare bursts of repetitive sharp waves and spikes noted over the right hemisphere with a broad field, more prominent over the right frontal-parietal region with no clear ictal evolution. She was extubated on hospital day 21, but was re-intubated on hospital day 24 because of worsening hypoxemia, ultimately undergoing a tracheostomy. Her mental status improved over the subsequent weeks. At time of discharge on hospital day 48, she was alert, oriented, and following commands consistently. A 52-year-old woman with a history of HIV infection (CD4+ lymphocyte count 699/µL, viral load undetected) presented with fever and respiratory distress requiring intubation in the emergency department. Admission labs were remarkable for hyperglycemia to 450 mg/dL with an anion gap of 23 mEq/L, and her course was complicated by oliguric renal failure with a maximum creatinine of 4.33 mg/dL requiring continuous hemodialysis. She was diagnosed with COVID-19 based on a positive nasopharyngeal PCR for SARS-CoV-2 but did not receive specific therapies for COVID-19 because of her renal failure. Her respiratory status continued to worsen, and she underwent proning for respiratory distress syndrome. She subsequently developed ventilator dyssynchrony requiring significant sedation and periodic paralysis. Tracheostomy was placed on hospital day 23 because of an inability to extubate, and her course was further complicated by septic shock with hypotension requiring vasopressors. On hospital day 34, she had a 2-minute clinical seizure characterized by leftward gaze deviation and generalized tonicclonic movements. Blood pressure range was 140-180/70-97 mmHg. Her head CT revealed bilateral occipital hypodensities ( Figure 1D) . A 24-hour continuous video EEG revealed a reactive and continuous background without epileptiform discharges. Brain MRI on hospital day 35 revealed diffuse T2 hyperintensities involving the white matter of the bilateral parietal, occipital, frontal, and temporal lobes, with partial sulcal effacement. Similar to case 1, there were punctate microhemorrhages in the temporal and occipital lobes. (Figure 1E -F). Cerebrospinal fluid (CSF) analysis revealed an elevated protein of 95 mg/dL, glucose 78 mg/dL, elevated total nucleated cell count of 28/µL (89% polymorphonuclear), red blood cell count of 223/µL, and negative infectious studies including a meningitis and encephalitis PCR panel and a cryptococcal antigen. Her mental status gradually improved over the next several days. On hospital day 43, 9 days after onset of symptoms attributable to PRES, she was alert and oriented and began to follow commands consistently. Follow-up head CT demonstrated significant improvement in the hypodensities of the bilateral occipital, parietal, temporal and frontal lobes. We found 13 cases of PRES in patients with COVID-19 in the literature [8, 9, [11] [12] [13] [14] . There was an additional case of PRES identified via virtuopsy (post-mortem imaging) but this was excluded from our results due to limited clinical details [10] . The included patients all had positive nasopharyngeal PCR for SARS-CoV-2. Relevant clinical details for these cases are summarized in Table 1 along with the 2 patients in our series for comparison. We cared for 2 patients with COVID-19 and PRES at our institution and identified additional cases through a literature search, finding variable risk factors for developing the syndrome. Although the exact mechanisms underlying PRES are unclear, contributing factors are thought to include hypertension with subsequent cerebral hyperperfusion and endothelial dysfunction [15] . SARS-CoV-2 has been found to bind directly to angiotensin-converting enzyme 2 receptors, which can dysregulate the endothelial layer, increase blood pressure, and disrupt cerebral blood flow autoregulation [16] . The mechanism by which COVID-19 may be associated with PRES is unclear, although it is notable that neuropathological studies of patients with COVID-19 and central nervous system dysfunction have identified only hypoxic changes without specific brain changes attributable to the virus [17] . By contrast to the majority of published cases of PRES, [8, 9] the patients described here had relatively modest blood pressure fluctuations before developing the syndrome. Similar to guidance offered by other authors [8], we advocate for tight blood pressure control in patients with COVID-19 and risk factors for PRES, including renal failure, uncontrolled hypertension, or HIV infection. Two patients who developed PRES in the setting of COVID-19 were treated experimentally for the infection with interleukin inhibitors, one with the interleukin-6 inhibitor tocilizumab and one with the interleukin-1 inhibitor anakinra, which have known effects on endothelial function [18] [19] [20] . In particular, the interleukin-6 inhibitor tocilizumab has been described in association with PRES [21]. Our findings suggest that caution may be warranted when considering interleukin inhibitors to treat COVID-19 in patients with underlying PRES risk factors, that anakinra may also be associated with an increased risk of PRES in patients with COVID-19, and that these agents should be discontinued if PRES is diagnosed. One of the patients presented here also had well-controlled HIV. Multiple reports in the literature describe PRES in HIV-infected patients, most often in those with advanced immunodeficiency, though it has been rarely described in patients with well-controlled HIV [22] [23] [24] [25] . Possible mechanisms include impaired cerebrovascular reactivity even in virally suppressed patients and long-term exposure to antiretroviral therapies that may lead to mitochondrial damage in endothelial cells [25] . The HIV-infected patient presented here had a CSF profile with elevated protein and neutrophilic pleocytosis. The latter finding is rare in PRES and may be associated with a higher risk of ischemic or hemorrhagic events, consistent in this case with the small area of restricted diffusion on imaging. [26] The majority of patients had severe respiratory manifestations of COVID-19 requiring intensive care, with just one patient (Patient 4) [11] whose primary manifestation of COVID-19 was altered mental status secondary to PRES. Although chest CT findings were concerning for viral pneumonia, she had subclinical respiratory involvement, suggesting that development of PRES is possible without obvious pulmonary manifestations, and that COVID-19 should be considered in patients presenting with PRES without other obvious risk factors. Five of 7 patients had foci of susceptibility artifact on imaging consistent with various degrees of hemorrhage. In general, PRES is associated with hemorrhage at an estimated rate of 10-30% in patients. Risk factors for developing hemorrhage include bone marrow or solid-organ transplantation and coagulopathy [27, 28] . Reversible cerebral vasoconstriction syndrome, which shares findings of blood-brain barrier breakdown and cerebral edema with PRES, has also been described in association with both subarachnoid and parenchymal hemorrhage [29, 30] . Patients 1 and 8 underwent computed tomography angiography (CTA) of the head and neck to evaluate for underlying vascular abnormalities with no alternative etiologies of hemorrhage found. Patients 2, 3, 4, 6, 7, 8, and 12 all had evidence of hemorrhage on MRI susceptibility sequences but no additional work-up was performed to evaluate for alternative etiologies of hemorrhage. Our observations suggest that hemorrhage may be more likely seen with PRES in patients with COVID-19, but additional study is required to determine the clinical significance of this finding. Although hemorrhage and cytotoxic edema are risk factors for poor outcome in PRES [31], all seven patients described here had marked clinical recovery. In general, 70-90% of patients with PRES have clinical recovery and resolution of edema on neuroimaging [32] . It is unclear if patients with COVID-19 may have a higher likelihood of a favorable outcome following PRES due to its potentially distinct pathophysiology. Similar to other reports on neurologic complications of COVID-19, ours is limited by a lack of long-term follow-up. It is important, however, to describe cases early to add to the scarce literature on central nervous system injury potentially related to COVID-19. Here, we describe the diverse presentations, risk factors, and outcomes of PRES in patients with COVID-19. Based on these cases, we advocate for tight blood control for patients with COVID-19 and risk factor for PRES, and advise caution regarding the use of interleukin inhibitors in these patients. We also offer hope that COVID-associated PRES may have high likelihood of clinical recovery. Meningoencephalitis without Respiratory Failure in a Young Female Patient with COVID-19 Infection A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2 Encephalitis as a clinical manifestation of COVID-19. Brain Behav Immun 2020. Transient cortical blindness in COVID-19 pneumonia; a PRES-like syndrome: Case report Posterior reversible encephalopathy syndrome (PRES) as a neurological association in severe Covid Hemorrhagic Posterior Reversible Encephalopathy Syndrome as a Manifestation of COVID-19 Infection Posterior reversible encephalopathy syndrome in patients with COVID-19 Posterior reversible encephalopathy syndrome: Clinical and radiological manifestations, pathophysiology, and outstanding questions Inhibition of Interleukin-1 activity by anakinra improves endothelial, coronary and aortic function in patients with CAD and coexistent rheumatoid arthritis by reducing apoptosis and oxidative stress. Eur Heart J 2012. Bilateral Visual Loss as Presenting Symptom of Posterior Reversible Encephalopathy Syndrome in a Patient with HIV/Tuberculosis Coinfection: A Case Report Posterior reversible encephalopathy syndrome in an HIV-infected patient on antiretroviral treatment: what is the risk factor? Assessment of noninvasive regional brain oximetry in posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome Dr. Chung is supported by the National Institutes of Health (K08NS112601). Dr. Anand is supported by a Grinspoon Foundation Grant. None