COVID-19: Neurologic complications and management of neurologic conditions

INTRODUCTION — Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. The disease rapidly spread, and, in February 2020, the World Health Organization designated the disease coronavirus disease 2019 (COVID-19) [1]. The World Health Organization declared COVID-19 a pandemic on March 11, 2020 [2]. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Understanding of COVID-19 is evolving. Interim guidance has been issued by the World Health Organization and, in the United States, by the Centers for Disease Control and Prevention [2,3] and the National Institutes of Health COVID-19 Treatment Guidelines Panel [4]. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

Neurologic complications in patients with COVID-19 are common in hospitalized patients [5-12]. More than 80 percent of hospitalized patients may have neurologic symptoms at some point during their disease course [12]. Rates vary by geographical location and patient characteristics. Myalgias, headache, encephalopathy, and dizziness may be most common, occurring in approximately one-third of patients in China, Europe, and the United States [5,8,12-14]. Neurologic symptoms such as dysgeusia or anosmia may be less common, but accurate ascertainment of symptoms may be limited in patients with severe cognitive or cardiorespiratory dysfunction [13,14]. Stroke, movement disorders, motor and sensory deficits, ataxia, and seizures appear uncommon [12,13]. Critically ill patients have a higher proportion of neurologic complications than patients with less severe illness [5,12]. As the frequency and severity of acute presentations of COVID-19 have decreased due to vaccination and social distancing strategies, some patients have reported persisting neurologic symptoms such as cognitive dysfunction, headache, and numbness [15].

This topic will review the neurologic complications of COVID-19 and the management of patients with neurologic conditions who develop COVID-19. Other aspects of COVID-19 are described separately:

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Clinical features".)

●(See "COVID-19: Diagnosis".)

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Management of the intubated adult".)

●(See "COVID-19: Clinical manifestations and diagnosis in children".)

●(See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

●(See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

NEUROPATHOGENESIS — The underlying mechanisms of neurologic complications in patients with COVID-19 are diverse and, in some cases, multifactorial. Neurologic complications arise most frequently from systemic response to the infection [13,16]. Distinct mechanisms include:

●Neurologic injury from systemic dysfunction – Hypoxemia, prevalent in patients with severe COVID-19, is likely to play a role in many patients with encephalopathy, as are metabolic derangements due to organ failure and medication effects. Neurochemical evidence of astrocytic and neuronal injury documented in plasma of patients with moderate and severe COVID-19 does not suggest a specific pathogenesis [17].

Neuropathologic case series of patients who succumbed to COVID-19 revealed acute hypoxic ischemic damage in nearly all patients, as well as the presence of hemorrhagic and bland infarcts, microglial activation with microglial nodules, and neuronophagia in many [16,18]. In other series, neuroimaging findings appeared consistent with a delayed posthypoxic leukoencephalopathy and are similar to those described in patients with acute respiratory distress syndrome (ARDS) unrelated to COVID-19 [19-21]. (See 'Evaluation and management' below and 'Encephalopathy' below.)

●Renin-angiotensin system dysfunction – Maladaptive activity of the renin-angiotensin system (RAS) may be another relevant pathophysiologic mechanism of COVID-19 infection. SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2), a membrane-bound protein, as its point of entry into cells. ACE2 functions to convert angiotensin II into angiotensin-(1-7), which has vasodilator, antiproliferative, and antifibrotic properties [22,23]. By binding to ACE2, the SARS-CoV-2 virus may damage vascular endothelial cells by inhibiting mitochondrial function and endothelial nitric oxide synthetase activity resulting in secondary cardio- and cerebrovascular effects [24]. (See 'Cerebrovascular disease' below.)

●Immune dysfunction – A dysregulated systemic immune response to SARS-CoV-2 has been implicated [25,26].

•Proinflammatory state – Critically ill patients with COVID-19 often develop signs of severe systemic inflammation consistent with a cytokine release syndrome-like presentation that manifests with persistent fever, elevated inflammatory markers (eg, D-dimer, ferritin), and elevated proinflammatory cytokines [27,28]. Markers of inflammation (eg, peripheral tumor necrosis factor [TNF], TNF-alpha, and interleukin 6 [IL-6]) are elevated in patients with severe COVID-19 [29,30]. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)'.)

High levels of circulating proinflammatory cytokines can cause confusion and alteration of consciousness [9,31]. A single case series described five patients with delayed awakening after ventilation for COVID-19-related ARDS who underwent brain vessel wall magnetic resonance imaging (MRI), which revealed abnormal contrast enhancement in the vascular wall of the basal skull arteries, a finding interpreted as possible endotheliitis [32]. However, evidence of resolution of these imaging abnormalities after corticosteroid treatment was not presented nor was there pathological confirmation of inflammation. (See 'Encephalopathy' below.)

A proinflammatory state also may be associated with thrombophilia ("thromboinflammation"), increasing risk of stroke and other thrombotic events [33]. Complement activation may also lead to thrombotic microvascular injury in patients with severe COVID-19 [34]. (See 'Cerebrovascular disease' below.)

Cytokine release may also lead to brain injury by microglial activation and a systemic inflammatory response. In case series and reports, microglial nodules and neuronophagia were found in brain tissue without evidence of direct viral invasion [16,35]. Microglial activation to phagocytose hypoxic neurons has been seen with other viral infections.

•Parainfectious and postinfectious triggers – The timing of symptoms relative to initial symptoms of COVID-19 infection suggests that Guillain-Barré occurs as a parainfectious rather than a postinfectious complication in most patients. In one case, weakness preceded the onset of fever and respiratory symptoms [36]. Other cases report a longer interval between the onset of viral illness and weakness, consistent with its occurrence as a postinfectious complication. (See 'Guillain-Barré syndrome' below.)

●Direct viral invasion of the nervous system – Some reports provide evidence for direct viral invasion of the nervous system [37-39]. In postmortem case series, SARS-CoV-2 was detected in most brain specimens, but these findings were unrelated to the severity of neuropathological findings [16,37,38]. This suggests that neural injury may be due to a systemic inflammatory response triggered by the SARS-CoV-2 virus rather than the infection itself.

It is uncertain if SARS-CoV-2 directly infects the cerebral vessels. Autopsy studies have reported potential evidence of direct endothelial invasion by the SARS-CoV-2 virus with a possible associated endotheliitis in the lung, heart, kidney, liver, and small intestine [40,41]. However, this remains controversial, as structures on electron microscopy thought to represent viral particles in the endothelium of blood vessels in the kidney may actually be normal structures or artifacts [42,43]. Case reports suggest the possibility of multifocal ischemic and hemorrhagic lesions consistent with endothelial involvement, microthrombosis, or small vessel vasculitis, though pathology was not performed [44,45]. Neuropathological studies have not confirmed frank cerebral vasculitis with SARS-CoV-2 [16].

SMELL AND TASTE DISORDERS — Anosmia and dysgeusia have been reported as common early symptoms in patients with COVID-19, occurring in greater than 80 percent of patients in one series [46]. In a meta-analysis of 83 studies involving more than 27,000 patients, olfactory dysfunction was reported in 48 percent (95% CI 41.2-54.5) [47]. These symptoms may be an initial manifestation of COVID-19 and can occur in the absence of nasal congestion or discharge; however, these are rarely the only clinical manifestations of COVID-19. (See "COVID-19: Clinical features", section on 'Initial presentation'.)

MRI signal abnormalities in one or both olfactory bulbs have been described in patients with COVID-19, which can resolve on follow-up imaging [48-52]. In two autopsy cases, pathologic findings demonstrated inflammatory infiltrate and axonal injury in the olfactory tracts but could not determine whether direct viral damage was responsible [53]. Transient anosmia may be related to inflammatory changes in the sustentacular cells within the nasal epithelium rather than direct injury to the olfactory neurons [54]. In one MRI-based study of 20 patients with anosmia, edematous obstruction was identified in the olfactory cleft of the nasal cavities [55]. At one-month follow-up, olfactory function correlated with improvement of obstruction.

Robust data on long-term prognosis are lacking [56]. In one series, among the 33 percent of affected patients who had recovered olfactory function, the mean symptom duration was eight days [46]. In a survey of nonhospitalized patients with olfactory dysfunction from Italy, 83 percent reported complete recovery at a mean of 37 days after symptom onset [57]. Among 51 patients with anosmia who underwent objective olfactory testing, full recovery at four and eight months was reported in 84 and 96 percent, respectively [58]. In some patients, anosmia and dysgeusia may persist for several months, along with other neurologic or systemic symptoms after acute COVID-19 infection [59]. (See 'Persistent neurologic symptoms after COVID-19 infection' below.)

These symptoms can occur with other viral infections and other causes; an approach to evaluation is discussed separately. (See "Taste and olfactory disorders in adults: Evaluation and management".)

ENCEPHALOPATHY — Encephalopathy is common in critically ill patients with COVID-19. In a cohort study of 2088 patients with COVID-19 admitted to an intensive care unit, delirium was common, occurring in 55 percent [60]. In a study of 509 hospitalized COVID-19 patients, 31.8 percent had encephalopathy, and those patients were older than those without encephalopathy (66 versus 55 years), had a shorter time from symptom onset to hospitalization (6 versus 7 days), were more likely to be male, and were more likely to have risk factors (including a history of any neurologic disorder, cancer, cerebrovascular disease, chronic kidney disease, diabetes, dyslipidemia, heart failure, hypertension, or smoking) [12].

Encephalopathy may be the primary symptom of COVID-19. In a study of 817 older patients (median age 78 years) evaluated in the emergency department who were diagnosed with COVID-19 infection, encephalopathy was present in 28 percent [61]. Among those patients, 37 percent lacked typical COVID-19 symptoms such as fever or dyspnea. Risk factors for encephalopathy included older age, vision impairment, history of Parkinson disease or stroke, and prior psychoactive medication use.

Clinical, laboratory, and radiologic features — Patients with COVID-19 may develop prominent delirium and agitation requiring sedation; others manifest encephalopathy with somnolence and a decreased level of consciousness [5,6]. Corticospinal tract signs (eg, hyperreflexia, extensor plantar responses) are common; seizures are described along with encephalopathy in patients with COVID-19, just as they can occur in toxic-metabolic encephalopathy in other settings [62,63]. These signs and symptoms are described separately. (See "Diagnosis of delirium and confusional states", section on 'Clinical presentation'.)

In most cases, encephalopathy develops in patients who become critically ill. In exceptional cases, delirium may be an early, and even a presenting, feature [64,65]. Cases of transient global amnesia have also been reported [66,67]. It is unclear whether a prolonged confusional state may occur in COVID-19 in the absence of respiratory symptoms or hypoxia.

Patients with encephalopathy typically have no evidence of brain inflammation on neuroimaging studies or on cerebrospinal fluid (CSF) analysis, although there are exceptions.

●MRI findings – A spectrum of neuroimaging abnormalities have been described in patients with COVID-19-related encephalopathy; some but not all of these findings indicate a specific, alternative diagnosis for the patient's mental state, such as stroke, encephalitis, reversible posterior leukoencephalopathy syndrome (RPLS), and others [6,19,52,68-70]. (See 'Other acute neurologic manifestations' below.)

In the aggregate, approximately half of neuroimaging studies in patients with COVID-19-related encephalopathy demonstrate an acute abnormality, the most common of which are acute ischemic stroke, cortical fluid-attenuated inversion recovery (FLAIR) signal abnormality, leptomeningeal enhancement (often subtle), and other manifestations of encephalitis [6,19,21,52,68,70,71].

As examples, one series reported results of MRI studies in 190 patients with severe COVID-19, most of whom had symptoms consistent with encephalopathy [68]. After excluding patients with ischemic stroke or chronic unrelated lesions, abnormalities were reported in 37 patients. Patterns of MRI abnormality included signal abnormality in the medial temporal lobe, multifocal white matter lesions visible on FLAIR and diffusion-weighted imaging with associated hemorrhage, and isolated white matter microhemorrhages. Hemorrhagic lesions were described exclusively in patients with ARDS. Another series described MRI abnormalities in 64 patients with COVID-19 and accompanying neurologic manifestations (mostly encephalopathy) [70]. Ischemic stroke was identified in 17 patients (27 percent), 10 of whom had focal or lateralizing signs on examination, which suggested possible stroke. MRI abnormalities in other patients included leptomeningeal enhancement in 17 percent and encephalitis in 13 percent; 46 percent of MRI studies were normal. Another case series described MRI findings in 115 hospitalized patients with COVID-19; 25 had cerebral microbleeds, often with concomitant leukoencephalopathy. These were most common in patients with more severe respiratory illness [21].

Cytotoxic lesions in the splenium of the corpus callosum have also been reported in adult patients with COVID-19-related encephalopathy [68,70,72,73] as well as in a few children with multisystem inflammatory syndrome in COVID-19 [69]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●Electroencephalography (EEG) findings – Patients with encephalopathy and COVID-19 who have undergone electroencephalography have typically demonstrated nonspecific findings [6,74,75].

●Cerebrospinal fluid – Abnormal findings in the CSF are nonspecific and appear in a minority of cases, including patients presenting with acute neurologic symptoms [76]. Case series reported CSF analysis from 12 patients and revealed no white cells and negative reverse transcription polymerase chain reaction (RT-PCR) assays for SARS-CoV-2 in all [6,19]. A 2021 systemic review of individual reports and case series involving 430 patients identified SARS-CoV-2 in the CSF of only 17 patients (6 percent) [76]. Oligoclonal bands were found in 3 patients among the 132 patients tested.

Patients who have elevated white blood cell count in CSF should undergo further evaluation for encephalitis and other conditions. (See 'Other acute neurologic manifestations' below.)

Underlying causes and risk factors — The etiology of encephalopathy in patients with COVID-19 is often multifactorial. Critically ill patients with COVID-19 are subject to the same causes of encephalopathy as are other critically ill patients. Common causes of agitated or hypoactive delirium are varied and include toxic metabolic encephalopathy, medication effects, cerebrovascular disease, nonconvulsive seizures, and others as outlined in more detail in the table (table 1). Factors associated with a higher risk of delirium among patients with COVID-19 admitted to an intensive care unit included mechanical ventilation, vasopressor use, use of restraints, benzodiazepine or continuous opioid infusions, and lack of family visitation [60]. These underlying causes are described separately. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Specific etiologies'.)

Other less common complications of COVID-19 may also produce altered mental status; these include ischemic or hemorrhagic stroke, encephalitis, posterior reversible encephalopathy syndrome (PRES), multisystem inflammatory syndrome, and postinfectious demyelinating disease. (See 'Cerebrovascular disease' below and 'Other acute neurologic manifestations' below.)

Evaluation and management — Patients with persistent encephalopathy that is not explained by sedating medications, hypoxemia, or other systemic factors may warrant further evaluation to rule out other causes. Patients with focal or lateralizing neurologic signs on examination should be evaluated with neuroimaging. For other patients, a decision to perform further testing depends on the clinical scenario and may include MRI with and without gadolinium, EEG to exclude subclinical seizures, and CSF sampling to rule out central nervous system infection. Patients with an elevated white blood cell count in CSF should undergo further evaluation for encephalitis and other conditions. The evaluation of patients with encephalopathy is described in detail separately. (See "Diagnosis of delirium and confusional states", section on 'Evaluation'.)

As with other causes of encephalopathy, the management is primarily directed toward the underlying disease, which is discussed separately. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management of the intubated adult".)

The symptomatic management of patients with COVID-19 and encephalopathy is the same as the management of other critically ill patients with delirium and is described separately. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Management' and "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

The role of glucocorticoids or other immunomodulatory therapies in the management of patients with COVID-19 and encephalopathy is uncertain. Case series have identified a small number of patients with severe encephalopathy who have improved neurologically after receiving glucocorticoids with or without plasma exchange [32,77]. In one series, mechanically ventilated patients with unresponsive wakefulness in whom sedation had been withdrawn were given methylprednisolone 1 g for five days followed by plasma exchange (5 to 10 sessions) [77]. Three of five patients improved neurologically within one week but two showed no improvement. However, glucocorticoids or other immunomodulatory therapies should not be considered routine therapeutic options for patients with COVID-19-related encephalopathy unless additional data emerge to help identify immunotherapy-responsive cases.

The role of glucocorticoids in the general management of severely ill patients with COVID-19 is discussed in further detail separately. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'.)

Prognosis — Encephalopathy is a risk factor for poor outcome. In one study, hospitalized patients with COVID-19 and encephalopathy had longer lengths of stay, worse functional impairment at hospital discharge, and a higher 30-day mortality rate compared with those without encephalopathy (22 versus 3 percent) [12]. In another series, patients with normal MRI and CSF were most likely to recover earlier [78].

As with other critically ill patients, improvement in neurologic dysfunction may be delayed beyond the period when symptoms of the acute illness have resolved. Our clinical experience, as well as some published reports, suggest that some patients with a prolonged disorder of consciousness in the setting of severe COVID-19 may awaken up to several days following cessation of sedating medications and later recover [12,79-81]. In one series of 795 hospitalized patients with severe COVID-19 infection who were intubated for at least seven days, among the nearly 72 percent who eventually recovered consciousness, the median time to recovery of command-following was 30 days [82]. Variables associated with prolonged recovery included hypoxemia, duration of exposure to paralytic or sedative medications, age, and male sex. Approximately one-third of patients with encephalopathy and COVID-19 infection who subsequently recover remained subjectively cognitively impaired at the time of hospital discharge [6,12,83]. Thus, clinicians should exercise caution about withdrawal of life support measures in patients with encephalopathy in the absence of structural brain injury on neuroimaging or other evidence of futility.

CEREBROVASCULAR DISEASE

Epidemiology — − Stroke appears to be relatively infrequent in the setting of COVID-19 [84-87]. The incidence of ischemic stroke associated with COVID-19 in hospitalized patients has ranged from 0.4 to 2.7 percent, while the incidence of intracranial hemorrhage has ranged from 0.2 to 0.9 percent [5,88-99]. Cerebral venous thrombosis (CVT) has been reported in patients with COVID-19 infection [100-102]. A retrospective study of over 13,000 patients with COVID-19 identified 12 patients with CVT within 3 months, corresponding to an incidence of 8.8 per 10,000 patients [103]. In a systematic review involving 34,331 patients hospitalized with SARS-CoV-2 infection, the estimated frequency of CVT was 0.08 percent (95% CI 0.01-0.5) [104].

The risk of stroke may vary according to the severity of COVID-19. Early case series suggest that for patients with mild illness, the risk is <1 percent, while for patients in intensive care, the risk may be as high as 6 percent [5].

Most often, stroke occurs one to three weeks after onset of COVID-19 symptoms, although stroke has been the initial symptom leading to hospitalization in a minority of reported patients [90,92,105-107]. In a report that compared 86 patients with COVID-19 and imaging-confirmed stroke with 499 matched control patients who had stroke without COVID-19 one year before, COVID-19 was an independent risk factor for in-hospital stroke (odds ratio [OR] 20.9, 95% CI 10.4-42.0) [106].

The mean age of patients with COVID-19 and stroke appears similar to those without COVID-19. While some reports observed that ischemic stroke occurred in young patients with COVID-19 [100,108-110], including children [97,111,112], these appear to represent a minority of stroke cases associated with COVID-19. In a subsequent systematic analysis of 10 studies including 160 COVID-19 patients with ischemic stroke, the median age was 65 years [113]. In a United States national stroke registry that included 1143 patients with COVID-19 and acute stroke, the median age at presentation was 68 years compared with 71 years for patients without COVID-19 during the same period [114].

Risk factors and mechanisms

●Traditional stroke risk factors – Most patients with ischemic stroke associated with COVID-19 are older patients with vascular risk factors [90,93,94,115]. Traditional stroke risk factors such as hypertension, hyperlipidemia, atrial fibrillation, and/or diabetes mellitus have been identified in these patients.

●Hypercoagulability and proinflammatory state associated with infection – While several mechanisms of stroke related to COVID-19 have been postulated, thrombophilia associated with the virus or the host immune response appears to be one important mechanism, as suggested by elevated markers of hypercoagulability and inflammation [33].

Considerable evidence suggests that COVID-19 is associated with a hypercoagulable state. This is reflected in the extremely elevated D-dimer levels (a marker of clot turnover) observed in many patients over the course of the first few weeks of disease, particularly those who are more severely affected [116]. Such markedly elevated D-dimer levels appear to be present specifically in some patients with ischemic stroke as well [85,117]. D-dimer levels >10,000 ng/mL have been proposed to identify patients with cryptogenic stroke potentially attributable to COVID-19 hypercoagulability [118]. (See "COVID-19: Hypercoagulability".)

An association with antiphospholipid antibodies has also been observed with COVID-19, but the relative proportion of different antiphospholipid antibody subtypes and their pathogenicity are uncertain, and follow-up testing has been incomplete. In a series from Philadelphia, antiphospholipid antibodies testing was positive in six of eight patients with COVID-19 and stroke; all six had anticardiolipin antibodies only, while none were positive for beta-2 glycoprotein-1 antibodies or lupus anticoagulant [93]. Anticardiolipin antibodies appear to be relatively common in several other viral infectious diseases (such as HIV and hepatitis) but are not clearly correlated with an increased thrombotic risk with those infections [119].

Prior to COVID-19, some evidence suggested that serious infections could trigger acute stroke, potentially due to increased inflammation and consequent thrombosis [120-122]. For example, in the Cardiovascular Health Study, the risk of ischemic stroke increased following hospitalization for infection within the previous 30 days (OR 7.3, 95% CI 1.9-40.9) [121]. Influenza, sepsis, and minor respiratory and urinary tract infections were also associated with increased stroke risk in analyses of administrative datasets [123-125]. Coexisting high-risk features, such as valvular heart disease, congestive heart failure, renal failure, lymphoma, peripheral vascular disease, pulmonary circulatory disorders, and coagulopathy, may further increase the risk of stroke after sepsis [126].

COVID-19 appears to be associated with a higher risk of ischemic stroke compared with influenza. In a retrospective cohort study comparing patients with emergency department visits or hospitalizations for COVID-19 (n = 1916) or influenza (n = 1486), the incidence of ischemic stroke was higher among patients with COVID-19 (1.6 percent, versus 0.2 percent with influenza; adjusted odds ratio 7.6, 95% CI 2.3-25.2) [92].

●Cardioembolism – Cardiac dysfunction associated with COVID-19 infection may also serve as a potential embolic stroke mechanism, either directly due to SARS-CoV-2 myocarditis or indirectly due to cardiac injury or dysfunction related to general critical illness. COVID-19 has been associated with several cardiac manifestations, including arrhythmia, heart failure, and myocardial infarction, many of which may predispose to cardioembolic stroke. (See "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Myocardial infarction and other coronary artery disease issues".)

In one study of 100 consecutive COVID-19 patients evaluated with echocardiography, only 10 percent had any degree of left ventricular systolic dysfunction, suggesting that cardioembolism due to severe left heart failure is relatively uncommon [127].

●Coagulopathy and anticoagulation – Cases of spontaneous intraparenchymal and cortical subarachnoid hemorrhage have been reported with coagulopathy or anticoagulation [52]. Some of these hemorrhages may represent unrecognized ischemic events with subsequent hemorrhagic conversion. In one report of 3824 hospitalized patients with COVID-19, intracerebral hemorrhage was reported in 33 (0.9 percent) [91]. Based upon the radiologic appearance, the investigators inferred that approximately three-quarters of these may have resulted from hemorrhagic transformation of ischemic stroke. Another report of 278 hospitalized patients with COVID-19 who had neuroimaging reported intracerebral hemorrhage in 10 patients. In both studies, most of the patients with intracerebral hemorrhage had been treated with full-dose anticoagulation [52,91]. (See "COVID-19: Hypercoagulability", section on 'Bleeding'.)

Intracranial hemorrhage with COVID-19 has also been associated with use of extracorporeal membrane oxygenation (ECMO) [128-130]. In an international registry, 145 of 2346 (6 percent) patients on ECMO with COVID-19 had an intracranial hemorrhage as of early October 2020 [129]. Patients on ECMO are also at increased risk of brain ischemia, including due to air embolism. (See "COVID-19: Extracorporeal membrane oxygenation (ECMO)", section on 'Complications and outcomes of ECMO for treatment of COVID-19'.)

Diagnostic evaluation

●COVID-19 screening – During the pandemic, we recommend testing all patients with suspected stroke for COVID-19 at the time of admission [131]. This recommendation is based on the observation that many patients presenting with stroke may test positive even when systemic signs of infection are absent [90,92,105,106]. This approach ensures that appropriate isolation measures are implemented for patients testing positive and allows early recognition should systemic symptoms of COVID-19 appear. In addition, the presence of acute COVID-19 in a patient with stroke has implications for the underlying mechanism causing stroke, the long-term risk of recurrence, and potentially for the choice of optimal therapy both in the short and long term.

●Etiologic testing – Given the frequent association of stroke in COVID-19 with typical vascular risk factors and traditional stroke mechanisms, the initial diagnostic approach should otherwise be similar to the approach generally used for all patients with suspected stroke. Diagnostic testing to identify underlying stroke mechanism should include brain and neurovascular imaging and cardiac evaluation, with treatment appropriate to the identified mechanism. (See "Initial assessment and management of acute stroke" and "Neuroimaging of acute stroke".)

Routine testing recommended for all patients hospitalized with COVID-19 includes a complete blood count (CBC), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer. For patients without a defined mechanism for ischemic stroke associated with COVID-19, our approach to testing for a hypercoagulable state is otherwise similar to the approach used for patients without COVID-19. (See "COVID-19: Hypercoagulability", section on 'Routine testing' and "Overview of the evaluation of stroke", section on 'Hypercoagulable studies'.)

Other aspects of the evaluation of adults hospitalized with COVID-19 are discussed in detail elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Evaluation'.)

Management issues — The management of ischemic or hemorrhagic stroke in patients under investigation or those who are positive for COVID-19 should follow the same standards of care as for patients without COVID-19 but with necessary precautions related to infection control [132-134]. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke".)

●Thrombolytic and reperfusion therapies – Evaluation for intravenous thrombolytic therapy should be undertaken as with any stroke patient. While the safety of intravenous tissue plasminogen activator (tPA; alteplase) has not been specifically studied in the setting of COVID-19, anecdotal data do not suggest obvious safety concerns [89,135].

Similar to the approach to intravenous thrombolysis, patients with ischemic stroke and COVID-19 should be evaluated for mechanical thrombectomy, as for any patient with acute ischemic stroke. Small cohort studies of mechanical thrombectomy in patients with COVID-19 and acute large vessel occlusion have reported varying results [84,109,110]. There may be an increased risk of reocclusion after initial recanalization in patients with COVID-19, potentially related to hypercoagulability associated with the infection. (See "Mechanical thrombectomy for acute ischemic stroke" and 'Risk factors and mechanisms' above.)

●Acute antithrombotic therapy – For patients with ischemic stroke and an unambiguous indication for full-dose anticoagulation (eg, atrial fibrillation, severe heart failure), early initiation is probably reasonable given the high thrombotic risk seen in patients with COVID-19, provided the bleeding risk is tolerable. For other patients with ischemic stroke, early use of aspirin is generally indicated, regardless of COVID-19 infection status.

An individual assessment of the severity of systemic illness, presence of other potential thrombotic events, and bleeding risk should be considered in deciding on optimal antithrombotic therapy. (See "COVID-19: Hypercoagulability", section on 'Supporting evidence'.)

●Management for patients with vaccine-induced thrombotic thrombocytopenia – For patients who develop cerebral venous thrombosis with thrombocytopenia after COVID-19 vaccination, anticoagulation with a non-heparin agent (eg, a direct oral anticoagulant) and intravenous immune globulin treatment have been suggested [136]. This is discussed in greater detail separately. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Management'.)

●Treatment with ACE inhibitors and ARBs – Patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents if there is no other reason for discontinuation (eg, hypotension, acute kidney injury, need for permissive hypertension in acute phase of ischemic stroke). Initial speculation that patients with COVID-19 who are receiving these agents may be at increased risk for adverse outcomes has not been supported by findings from observational studies. This is discussed in detail elsewhere. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

●General management – The general management of adults hospitalized with COVID-19, including COVID-19-specific therapy, is reviewed in detail separately. (See "COVID-19: Management in hospitalized adults".)

●Secondary stroke prevention – Long-term treatment of vascular risk factors (eg, hypertension, diabetes, hyperlipidemia, atrial fibrillation, smoking) and appropriate use of antithrombotics should be undertaken, as with any stroke patient. (See "Overview of secondary prevention of ischemic stroke".)

●Long-term risks – The incidence of stroke may be elevated beyond the acute period of COVID-19 infection. In a study of approximately 5.8 million United States veterans, the incidence of stroke at one year was higher in patients with prior COVID-19 infection than controls (hazard ratio 1.52, 95% CI 1.4-1.6) [137]. Cerebrovascular risk was higher for patients hospitalized with COVID-19 than for patients with less severe symptoms. The etiology of this finding is uncertain and may include a proinflammatory state or endothelial dysfunction following infection or suboptimal follow-up and management of vascular risk factors during the pandemic.

Severity and prognosis — Stroke associated with COVID-19 may be more severe than stroke without COVID-19 [117,138]. In a report from a hospital in New York City, the median National Institutes of Health Stroke Scale (NIHSS) score was greater for patients with stroke and COVID-19 compared with contemporary control patients with stroke but without COVID-19 (NIHSS score 19 versus 8) [90]. In another study, with a pooled sample of patients with COVID-19 from 28 sites in 16 countries, the NIHSS score was higher among 174 patients with stroke and COVID-19 compared with propensity-matched stroke patients without COVID-19 from one of the centers (NIHSS score 10 versus 6) [139]. In addition, mortality and disability after ischemic stroke were higher among those with than without COVID-19 [117]. In one analysis, in-hospital mortality among 160 patients with COVID-19 and stroke was 34 percent [113]. This finding could reflect greater stroke severity and/or greater comorbidity from respiratory and other systemic complications of COVID-19 [90,139].

Limited data suggest that, in North America, prognosis for stroke associated with COVID-19 is worse for Black American patients. One retrospective study reported outcomes for 69 patients (27 Black individuals and 42 from other racial backgrounds) with acute stroke associated with COVID-19 from 14 hospitals in the United States and Canada [140]. Stroke severity on admission, as determined by the mean NIHSS score, was similar for Black Americans and Canadians compared with other groups (16.3 versus 14.9) but mortality was higher (56 versus 29 percent).

Preventive measures — For patients with a history of stroke or those at high risk, physicians should emphasize the following practices and recommendations, along with appropriate risk modifications and other secondary stroke prevention measures:

●Patients with stroke symptoms should be advised to seek emergency help just as they would prior to the pandemic. Acute stroke remains a potentially disabling and fatal illness, and patients should seek optimal medical care, which has been shown to improve stroke outcomes, even during the pandemic. Emergency wards and hospitals have rapidly become adept at separating patients with COVID-19 from other patients, practicing universal precautions against the spread of infection, and limiting the risk to their patients. Experience shows that high-quality stroke care can be delivered during the pandemic [141].

Preventive measures are discussed in detail separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

●Patients with cerebrovascular disease should consider having extra medications on hand in case of the need to quarantine at home or in case of a disruption in supply chains.

●Routine outpatient visits can often be conducted safely and effectively using telehealth [142,143]. Building on developments in the use of rapid outpatient evaluation for transient ischemic attack (TIA) patients, telehealth follow up of patients with TIA may be safe and effective [144].

●The benefits of vaccination to prevent the morbidity and mortality associated with COVID-19 infection greatly outweigh the risk of vaccine-associated immune thrombotic thrombocytopenia (VITT) [145]. The risk of thromboembolism from COVID-19 infection appears higher than the risk of VITT [104,146]. This is discussed in greater detail separately. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia' and 'Vaccination against COVID-19' below.)

NEUROMUSCULAR DISEASE

Guillain-Barré syndrome — Rare cases of Guillain-Barré syndrome (GBS) have been reported after COVID-19 infection [36,78,147-155]. However, a potential causal association of COVID-19 with the risk of GBS remains uncertain. A cohort study from the United Kingdom failed to show a specific association between GBS and COVID-19 infection [156]. In this study, the incidence of GBS between March and May of 2020 was lower than the same months in the preceding four years. This reduction was attributed to the reduced transmission of other infective triggers from societal lockdown measures during this time. Among approximately 1200 patients with COVID-19 admitted over a one-month period to three northern Italy hospitals, only five cases of GBS were identified [147,154] .

●Clinical features – Most patients with GBS and COVID-19 presented with progressive, ascending limb weakness evolving over one to four days [147]. The interval between the onset of viral illness and the development of muscle weakness is 5 to 16 days, similar to that observed for other viral infections associated with GBS [157]. In a report of 11 patients in the International GBS Outcome Study (IGOS) who developed GBS after COVID-19 infection, sensorimotor features were found in 73 percent including facial palsy in 64 percent [154]. Other reports suggest that the symptoms appear to progress more rapidly and be more severe than is typical for GBS; in one series, three of five patients required mechanical ventilation [147]. However, it was difficult to distinguish respiratory failure due to GBS from that due to COVID-19-related lung disease. Dysautonomic features were not observed in this series.

Miller Fisher syndrome [52,158] and other bulbar variant forms of GBS [159] have also been described in patients with COVID-19. These clinical syndromes and the differential diagnosis of GBS are described separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

●Diagnostic studies – GBS should be considered in the setting of progressive limb weakness and also when chest imaging findings are not commensurate with the respiratory insufficiency. The evaluation and diagnostic criteria for GBS are described separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

In one series of five patients with COVID-19, the following diagnostic test features were observed [147]:

•Cerebrospinal fluid was typical of other GBS patients with low or absent white cell count. Most patients have elevated protein level, although two of five patients in one series had normal levels. No cerebrospinal fluid (CSF) samples were positive for SARS-CoV-2.

•Electrodiagnostic studies were consistent with either the axonal variant of GBS (preserved distal motor latencies and velocity, absent F-wave, and fibrillations) or with a demyelinating process (prolonged distal motor latencies and conduction block) [157].

•MRI showed nerve root enhancement in some but not all patients.

●Management and prognosis – Patients with GBS in the setting of COVID-19 should be managed as are other patients with GBS. (See "Guillain-Barré syndrome in adults: Treatment and prognosis".)

In one series, all patients received treatment with intravenous immune globulin (IVIG); two received a second course of IVIG and one started plasma exchange [147]. At least one patient was walking independently at discharge, but information regarding long-term outcomes for these patients is still pending.

The possible risk of GBS after vaccination against COVID-19 is discussed in greater detail separately. (See "COVID-19: Vaccines", section on 'Guillain-Barre syndrome' and 'Vaccination against COVID-19' below.)

Other acute neuromuscular syndromes

●Myositis – Because myalgia and fatigue are common symptoms in COVID-19, some speculate that COVID-19 may be associated with a viral myositis; however, conclusive evidence of this is lacking [160]. In Wuhan, 11 percent of patients were reported to have evidence of muscle injury with elevated creatine kinase (CK; >200 units/L) and/or myalgia [5]. Myalgia was a common complaint in a series from Italy [161]. Three case reports have described rhabdomyolysis with CK >12,000 units/L [162-164]. In one case, muscle biopsy in one patient with COVID-19 and myopathy showed perivascular inflammation and deposition of myxovirus resistance protein A, a type I interferon-inducible protein [164]. Toxic effects of type I interferonopathies are seen in tissue in response to viral infection.

●Focal and multifocal neuropathies – Several peripheral nerve and plexus syndromes have been reported in patients with COVID-19. These include:

•Facial nerve palsy [155,165]

•Ocular motor neuropathies [52,166]

•Lower cranial neuropathy (vagus, accessory, and hypoglossal; Tapia syndrome) [167,168]

•Multiple cranial neuropathies [158,166]

•Neuralgic amyotrophy [169,170]

●Critical illness neuropathy and myopathy – This complication tends to develop later in the course of COVID-19 infection than does parainfectious GBS [160,171]. (See "Neuromuscular weakness related to critical illness".)

●Peripheral nerve injuries after prone positioning – Patients placed in prone positioning for COVID-19-related ARDS may develop peripheral nerve, typically brachial plexus, injuries [78,172,173]. In one study of 83 patients admitted to a rehabilitation facility after severe COVID-19 infection, 12 (14.5 percent) were diagnosed with a peripheral nerve injury, 11 of whom had been placed in prone positioning [172]. Nerve injuries were most frequently axonal and in the upper limb. (See "Prone ventilation for adult patients with acute respiratory distress syndrome", section on 'Complications'.)

OTHER ACUTE NEUROLOGIC MANIFESTATIONS — Isolated case reports have described the following syndromes in patients with COVID-19:

●Meningoencephalitis – Both viral and apparent autoimmune meningoencephalitis have been reported in patients with COVID-19. These complications are rare. After a prodrome of headaches, fatigue, and fever for a few days, a 24-year-old male presented with generalized seizures and altered mental status. MRI revealed signal abnormality in the right mesial temporal lobe. Cerebrospinal fluid (CSF) analysis revealed 12 mononuclear cells and 2 polymorphonuclear cells; reverse transcription polymerase chain reaction (RT-PCR) analysis detected SARS-CoV-2 in the CSF [174]. A second case with viral detection by polymerase chain reaction (PCR) in the CSF was reported in a 41-year-old female who presented with seizure and altered mental status along with lymphocytic pleocytosis in the CSF [175].

Other cases of meningoencephalitis have been reported in patients in whom CSF was either negative for SARS-CoV-2 [78,176-180] or not tested [181-183]. It is possible that such cases do reflect viral infection with false-negative PCR testing [9]. One of these patients had evidence of viral particles in the brain on autopsy, and SARS-CoV-2 was detected in brain tissue by RT-PCR [180].

An alternative autoimmune mechanism has been postulated for these cases. Some patients have clinical syndromes and MRI findings that appear similar to autoimmune encephalitis [78]. One patient was found to have anti-N-methyl-d-aspartate (anti-NMDA) receptor antibodies [179]. Many of these patients appeared to respond to immunomodulatory treatment with glucocorticoids [78,177], plasma exchange [178], and/or intravenous immunoglobulin [179].

●Rhombencephalitis – Parainfectious complications including brainstem encephalitis or isolated cerebellitis have been reported in adults and children with COVID-19 infection [184-188]. An inflammatory cause has been suggested. Some patients with fulminant disease and brainstem compression received external ventricular drainage for hydrocephalus and have been treated empirically with glucocorticoids and lopinavir-ritonavir with good short-term outcome [186].

●Acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic necrotizing encephalopathy – A few case reports have described patients with clinical and neuroimaging findings consistent with ADEM [9,78,189-191]. Some patients have had myelitis with or without brain involvement [78]. An additional case report describes a similar syndrome, acute necrotizing encephalopathy, in a patient with COVID-19 [191]. (See "Acute disseminated encephalomyelitis (ADEM) in adults".)

Increasing numbers of patients with hemorrhagic encephalomyelitis are reported [50,78,192]. A case report described a female in her late fifties who presented with fever, cough, and altered mental status; MRI revealed hemorrhagic lesions in bilateral thalami, medial temporal lobes, and subinsular lesions [193]. Another case was reported with predominant brainstem involvement in a 59-year-old female who also suffered from aplastic anemia [194]. In another series, four of nine patients with ADEM had hemorrhagic change on MRI [78]. (See "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Acute hemorrhagic leukoencephalitis'.)

Treatment with high-dose steroids, intravenous immunoglobulin, and/or plasma exchange has been attempted in these cases with variable outcomes; many patients die or have substantial neurologic morbidity, particularly those with hemorrhagic lesions [9,78,189-191].

●Multisystem inflammatory syndrome in children – Some children with COVID-19 develop a multisystem inflammatory syndrome, similar to incomplete Kawasaki disease, which can include neurocognitive symptoms (headache, lethargy, confusion); in four patients with this syndrome, MRI revealed signal abnormality in the splenium of the corpus callosum [69]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●Seizures and status epilepticus – Seizures and status epilepticus have been reported in patients with severe COVID-19 infection [195,196]. In one series of 32 patients with COVID-19 who presented to the hospital with seizures, 40 percent had no history of epilepsy or other central nervous system diagnoses [197]. In rare instances, seizures have been the presenting symptom for patients without signs of infection who have tested positive for COVID-19 [197,198]. A systematic review of case series and reports identified 47 patients with COVID-19 who developed status epilepticus [199]. Most patients had preceding respiratory symptoms and no history of prior seizures. Neuroimaging was abnormal in approximately half of patients and 4 patients had a positive RT-PCR for SARS-CoV-2 in the CSF.

●Generalized myoclonus – One report describes three patients (ages 63 to 88 years) who developed generalized myoclonus as an apparent post-infectious complication of COVID-19 [200]. Patients were not severely ill at the time myoclonus developed, and the myoclonus could not be explained by hypoxia, metabolic cause, or drug effect. Patients were treated symptomatically with levetiracetam, valproate, clonazepam, and/or propofol sedation and appeared to recover gradually with immunotherapy (methylprednisolone and/or plasma exchange).

●Reversible posterior leukoencephalopathy syndrome (RPLS) – RPLS has been reported in patients with COVID-19 and may be due to hypertension and renal failure in some [50,52,94,96,201-205]. In one neuroimaging case series, findings consistent with RPLS were seen in more than 1 percent [52]. (See "Reversible posterior leukoencephalopathy syndrome".)

●Reversible cerebral vasoconstriction syndrome (RCVS) – RCVS has been reported in adults and children with COVID-19 infection [206-208]. Corresponding features on brain imaging of patients with a severe syndrome included subarachnoid hemorrhagic, intracerebral hemorrhage, and ischemic stroke. (See "Reversible cerebral vasoconstriction syndrome".)

PERSISTENT NEUROLOGIC SYMPTOMS AFTER COVID-19 INFECTION — Patients recovering from a severe illness or after hospitalization may report prolonged neurologic symptoms. Likewise, some patients report symptoms attributed to COVID-19 that persist for weeks to months after the acute infection [209,210]. Among patients recovering from a severe COVID-19 infection who were hospitalized, fatigue, dyspnea, memory impairment, and myalgias were most common [209-212]. This is discussed in greater detail separately. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'COVID-19 recovery'.)

In addition, patients with milder acute COVID-19 symptoms who never required hospitalization for pneumonia or hypoxemia may also report persistent neurologic and systemic symptoms [15,213]. In a survey of 180 nonhospitalized patients with COVID-19, more than 50 percent reported having at least one persistent symptom at a mean of 125 days after symptom onset [214]. Fatigue and anosmia were reported most frequently, occurring in 24 percent of symptomatic patients. In a prospective study of 100 nonhospitalized patients with COVID-19 with neurologic symptoms that persisted for at least six weeks, the most frequently reported were "brain fog" (81 percent), headache (68 percent), numbness/tingling (60 percent), dysgeusia (59 percent), anosmia (55 percent), and myalgias (55 percent) [15]. Patients showed impairments in quality-of-life (cognitive and fatigue) domains, attention, and working memory compared with controls. There was no correlation between time from disease onset and subjective impression of recovery. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Persistent symptoms'.)

The constellation of persistent symptoms after acute COVID-19 infection has been described by various terms including "long COVID," "post-COVID syndrome," "post-acute sequelae of SARS-CoV-2 infection," and "post-COVID conditions" [215]. This umbrella term covers a wide range of lingering consequences that remain four or more weeks after SARS-CoV-2 infection, which have been reported to range between 5 and 80 percent of patients [210,216-223].

Systemic symptoms such as fatigue, myalgias, and dyspnea are most common after COVID-19 infection (table 2). In addition, neurologic symptoms reported in case series to persist after COVID-19 infection include:

●Headache [15,224,225]

●Anosmia/dysgeusia [15,57,58,226,227]

●Cognitive dysfunction [224,228-230]

●Autonomic dysfunction [231-233]

●Insomnia or other sleep impairments [210,234]

In a retrospective analysis based on the medical records of more than 270,000 patients with COVID-19, 37 percent had symptoms in the postacute period between 90 and 180 days [224]. In another analysis of 1438 patients from China who were hospitalized for COVID-19 infection, the incidence of cognitive impairment was 12 percent at one-year follow-up [230]. Some post-COVID conditions may share similarities with other post-viral syndromes [15,235-239]. The evaluation and management of patients with symptoms after acute COVID-19 illness are discussed in greater detail separately. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

The pathophysiology and the role of the brain in the etiology of these symptoms are uncertain. Neuronal changes in limbic and other brain regions have been reported in patients with a prior COVID-19 infection. Among 785 participants of the United Kingdom Biobank study with baseline and follow-up imaging, structural changes were likelier in those following COVID-19 infection [240]. Repeat imaging was performed at a mean of 141 days following COVID-19 infection. Patients with COVID-19 infection were found to have greater reductions in functional connectivity and structural domains (gray matter thickness in the orbitofrontal and parahippocampal cortices and global brain size) compared with controls. Brain changes were also correlated with impaired performance on cognitive testing. In another study, elevated levels of biomarkers associated with neuronal dysfunction were reported in patients with persistent neurologic symptoms following either severe or mild COVID-19 infection [241]. The persistence of these findings and their functional significance over the long term is uncertain. Further study is warranted to assess the role of these findings in patients with post-COVID neurologic symptoms.

MANAGEMENT OF PATIENTS WITH NEUROLOGIC CONDITIONS — Despite the lack of high-quality data, patients with baseline disabling neurologic disease and those on immunosuppressive therapy should be particularly vigilant about infection control measures including vaccination, social distancing, and mask-wearing.

Vaccination against COVID-19 — Patients with some neurologic conditions, including those taking immunosuppressive medications, may be at high risk for severe illness from COVID-19 (table 3). Based on available data from the general population, we encourage vaccination against COVID-19 to those without a contraindication as soon as it is available to them, in agreement with guidelines from the American Association of Neuromuscular and Electrodiagnostic Medicine and the National Multiple Sclerosis Society [242,243]. COVID-19 vaccination has been associated with a reduced risk of neurologic complications of COVID-19 infection, including stroke [244].

Immunosuppressive medications may reduce the immunogenicity and effectiveness of vaccination against COVID-19. Strategies to optimize effectiveness of vaccination against COVID-19 infection in patients taking immunosuppressive therapy are discussed separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

The benefits of vaccination to prevent the morbidity and mortality associated with COVID-19 infection greatly outweigh the risks including the risks of vaccine-induced thrombotic thrombocytopenia (VITT) and Guillain-Barré syndrome (GBS) [145,245,246]. The risk of thromboembolism from COVID-19 infection appears higher than the risk of VITT [104,146]. Similarly, the risk of GBS appears higher in the setting of COVID-19 infection than after vaccination [155,247]. Because of the possible increased risk of GBS associated with the adenovirus vector Ad26.COV2.S (Janssen/Johnson & Johnson) and ChAdOx1 nCoV-19/AZD1222 (AstraZeneca) COVID-19 vaccines, for patients with a history of GBS, we suggest other available COVID-19 vaccines until additional data emerge. (See "COVID-19: Vaccines", section on 'Specific safety concerns' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)" and "Guillain-Barré syndrome in adults: Treatment and prognosis", section on 'Subsequent immunizations'.)

●Vaccine-associated immune thrombotic thrombocytopenia – Cases of thrombotic events with thrombocytopenia, including cerebral venous thrombosis (CVT) with and without hemorrhage, have been reported in patients immunized with the adenovirus-vector ChAdOx1 nCoV-19/AZD122 (AstraZeneca COVID-19) and Ad26.COV2.S (Janssen COVID-19) vaccines [248-259]. In a cohort study of 95 patients in the United Kingdom with CVT occurring after COVID-19 vaccination, those with VITT were younger (47 versus 57 years) and less likely to have other thromboembolic risk factors (34 versus 56 percent) than those with CVT not attributed to VITT [260]. However, patients with VITT had more extensive intra- and extracranial thromboses and a higher mortality rate than those without (29 versus 4 percent). DNA from adenovirus vectors may bind to platelet factor 4 and trigger the production of autoantibodies in some individuals [136]. This autoimmune VITT syndrome occurs between 5 and 30 days post-vaccination. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

●Guillain-Barré syndrome – Cases of GBS have been observed with the adenovirus vector Ad26.COV2.S (Janssen/Johnson & Johnson) and ChAdOx1 nCoV-19/AZD1222 (AstraZeneca) COVID-19 vaccines in the United States and Europe [261-264], although a causal link has not been established. In the United States, 123 cases occurring within six weeks of immunization with the Ad26.COV2.S vaccine were reported among 13.2 million administered doses [264]. The estimated rate of post-vaccination GBS was higher than the background rate at 8.4 versus 2 per 100,000 person-years (rate ratio 4.18, 95% CI 3.47-4.98). The median time to symptom onset after vaccination was 13 days, and the rates of hospitalization and respiratory failure were 94 and 14 percent, respectively. This finding has not been reported with other COVID-19 vaccines [265]. This possible risk is discussed in greater detail separately. (See "COVID-19: Vaccines", section on 'Guillain-Barre syndrome'.)

Further information regarding vaccination against COVID-19, including guidance on vaccination dosing and boosters for patients who may be immunocompromised due to active immunosuppressive therapy (table 4), is discussed elsewhere. (See "COVID-19: Vaccines", section on 'Approach to vaccination in the United States' and "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

Managing immunosuppressive therapy — Patients with neurologic disease who are treated with immunosuppressive therapy do not appear to be at increased risk of COVID-19 infection. In most cases, immunosuppressive therapy should be continued and should be discontinued only if severe COVID-19 infection develops [266-270]. The role of switching agents or amending treatment protocols may be appropriate for some patients and is determined by assessing individual risks.

●Multiple sclerosis – Patients with multiple sclerosis treated with B cell-depleting anti-CD20 or sphingosine-1-phosphate receptor disease-modifying therapies (DMT) may have a lower antibody response to SARS-CoV-2 infection than those treated with other DMTs. Patients with multiple sclerosis should be given vaccination prior to starting an anti-CD20 DMT, if possible. For patients already on an anti-CD20 DMT, timing the infusion in selected stable patients to occur several weeks after vaccination may be used to improve humoral response and possibly vaccine effectiveness [271]. Decisions should be individualized based on disease severity and activity. DMTs for multiple sclerosis are discussed in greater detail separately. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects".)

In a cohort of 119 patients with multiple sclerosis or neuromyelitis optica spectrum disorder and COVID-19 infection, the rate of seroconversion was lower in patients taking an anti-CD20 DMT than those taking another DMT (48 versus 86 percent) [272]. The interval between anti-CD20 infusion and COVID-19 infection was longer in patients who developed an antibody response compared with those who did not (mean 3.7 months versus 1.9 months). In addition, a reduced humoral response to vaccination against SARS-CoV-2 has been reported in patients treated with ocrelizumab [273-275]. However, T cell response was retained in these patients, suggesting some efficacy of vaccination. Additional data are needed on the effects of these immunotherapies on vaccination.

●Myasthenia gravis – Immunosuppressive medications for patients with myasthenia gravis are typically continued to minimize the risk of neuromuscular deterioration. Alternative treatments may also be considered for some patients who develop COVID-19 while taking immunosuppressive therapy. As examples, immunoglobulin therapy, complement inhibitor therapy, and plasma exchange are not expected to increase the risk of COVID-19; however, such treatments are not appropriate in all patients and indiscriminate switching to these treatments is not advised [269].

In small observational studies, the effect of COVID-19 infection on patients with myasthenia gravis is variable. Respiratory failure and exacerbations have been reported in some cases [276-278]. However, other patients with myasthenia gravis well controlled with immunosuppressive agents who developed a COVID-19 infection had a mild course [279-281]. In a cohort of 93 patients with myasthenia gravis and COVID-19 infection, factors associated with a severe course (eg, hospitalization requiring respiratory support) included lower premorbid forced vital capacity, poorer functional status, older age, and higher-dose oral glucocorticoid treatment [282]. A physician-reported registry has been established to collect outcome data in patients with myasthenia gravis who develop a COVID-19 infection [276].

Additional advice specific to disease-modifying treatment of myasthenia gravis is presented separately. (See "Overview of the treatment of myasthenia gravis", section on 'Guidance during COVID-19 pandemic'.)

Risk for more severe COVID-19 illness — Because neurologic disease may worsen the prognosis of COVID-19, vaccination and other preventive measures are particularly important in these patients. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

●Cerebrovascular disease – Several risk factors have been associated with the risk of severe infection with SARS-CoV-2 (table 3). Patients with a history of cardiovascular disease, including stroke, appear to have worse outcomes when infected with SARS-CoV-2 [212,283-287]. There are several potential reasons for this. Patients with cerebrovascular disease often have other cardiovascular and metabolic risk factors that make them susceptible to worse outcomes from COVID-19; hypertension, obesity, and diabetes all are associated with a more aggressive course and higher mortality among COVID-19 patients [288]. The pandemic has manifested many of the same disparities by race, ethnicity, education, and income that are seen with cerebrovascular disease [105,289]. Thus, the same cardiovascular conditions, including obesity and diabetes, that predispose minority and under-resourced populations to stroke likely make them more susceptible to complications of COVID-19 [290]. In addition, the upregulation of angiotensin-converting enzyme 2 (ACE2) in those on angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) could lead to a more severe infection in patients taking those medications, although observational studies have not borne this out. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)

●Epilepsy – Patients with a history of epilepsy appear to be at an elevated risk of poor outcome after COVID-19 infection. In a meta-analysis of 13 observational studies including more than 57,000 patients hospitalized with COVID-19 infection, the risk of poor outcome was higher in patients with epilepsy than those without (odds ratio 1.71, 95% CI 1.11-2.59) [291]. This association may be due to morbidity of seizures and status epilepticus, adverse effects attributed to antiseizure medications, or worsened control of epilepsy due to reduced health care utilization. (See 'Health care utilization' below.)

●Neuromuscular weakness – Patients with baseline cardiac or respiratory dysfunction, those with severe neuromuscular weakness, and those with bulbar weakness due to other debilitating neurologic disease (eg, amyotrophic lateral sclerosis, multiple sclerosis) are likely to have a more severe course and also may not return to their prior baseline [160,267,292,293]. This is based on observations in acute infections other than COVID-19 but are likely to apply in this setting as well. One registry of patients with multiple sclerosis found an association between more severe disability (as measured by the Expanded Disability Status Scale [EDSS]) and more severe COVID-19 infection; age and obesity were also risk factors in patients with multiple sclerosis as they are in the general population [294].

●Multiple sclerosis – The hospitalization rate may be elevated for patients with multiple sclerosis taking B cell-depleting DMTs. In a multinational cohort study that included 1683 patients with multiple sclerosis, those taking either ocrelizumab or rituximab were likelier to be hospitalized than those taking other disease-modifying therapies (adjusted odds ratio [aOR] 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) [295]. Both ocrelizumab and rituximab were also associated with higher risk of admission to an intensive care unit, but neither was associated with an elevated risk of death.

Patients with neurologic disorders may be at higher risk for readmission after hospitalization for COVID-19 infection. Among 509 patients initially hospitalized with COVID-19, hospital reevaluation including readmission within the following four months occurred in 22 percent [296]. Older age, medical comorbid conditions, and preexisting neurologic disorders were associated risk factors.

An increased risk of COVID-19 and higher mortality have been suggested for patients with dementia [297] and also those with epilepsy [291,298,299].

COVID-19-specific therapy — The indications for and approach to COVID-19-specific therapy in symptomatic patients vary by clinical setting and risk profile for severe illness. Some patients are at risk for severe illness due to neurologic conditions such as those with dementia or neuroinflammatory disorders treated with immunosuppressive medications (table 3). The approach to COVID-19-specific therapy is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)

Health care utilization — Telemedicine is being increasingly used during the pandemic to manage outpatients with chronic neurologic disease. In a survey of 143 patients with epilepsy, reduced availability of ambulatory care occurred in approximately one-third of patients and was associated with exacerbation of seizures [300]. Patients with neurologic diseases (such as epilepsy and migraine) should develop rescue treatment plans that can be administered at home, if appropriate [301]. (See "Telemedicine for adults", section on 'Telemedicine during COVID-19 pandemic'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Neurologic manifestations of COVID-19 infection – Neurologic manifestations occur in approximately half of hospitalized COVID-19 patients. Myalgias, headache, and encephalopathy may be most common.

•Encephalopathy is common in critically ill patients with COVID-19 occurring in approximately 30 to 55 percent of patients. Common causes include toxic metabolic encephalopathy, medication effects, cerebrovascular disease, and nonconvulsive seizures. (See 'Encephalopathy' above.)

•Stroke has been associated with COVID-19 in approximately 1 to 3 percent of hospitalized patients, with higher rates in those with more severe COVID-19. Several stroke subtypes may occur, including ischemic stroke, intracranial hemorrhage, and cerebral venous sinus thrombosis. In addition to traditional stroke mechanisms, potential mechanisms of ischemic stroke related to COVID-19 include hypercoagulability, inflammation, renin-angiotensin-aldosterone system dysfunction, and cardiac dysfunction. (See 'Epidemiology' above.)

•Cases of Guillain-Barré syndrome and related syndromes have been described in patients with COVID-19. In general, the evaluation and management of such patients is similar to those not associated with the pandemic. (See 'Guillain-Barré syndrome' above and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Guillain-Barré syndrome in adults: Treatment and prognosis".)

•Rare neurologic manifestations of COVID-19 include meningoencephalitis, cerebellitis, acute disseminated encephalomyelitis, multisystem inflammatory syndrome, seizures, generalized myoclonus, and reversible posterior leukoencephalopathy. (See 'Other acute neurologic manifestations' above.)

●Persisting neurologic symptoms after COVID-19 infection – Some patients report symptoms attributed to COVID-19 that persist for weeks to months after the acute infection. Other patients with milder acute COVID-19 symptoms who never required hospitalization may also report persistent neurologic and systemic symptoms. The constellation of persistent symptoms after acute COVID-19 infection that remain four or more weeks has been reported to range between 5 and 80 percent of patients. (See 'Persistent neurologic symptoms after COVID-19 infection' above and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

●Management of patients with neurologic conditions – Patients with neurologic disease who are treated with immunosuppressive therapy are not at increased risk of COVID-19, and such medical treatment should be continued in uninfected patients.

If patients on such medications become infected with SARS-CoV-2, we advise an individualized approach that considers the risk associated with the specific medication, the severity of the underlying neurologic illness, and the severity of COVID-19 illness. (See 'Management of patients with neurologic conditions' above.)

Patients with a history of cardiovascular disease, including stroke, appear to be at risk of worse outcomes due to COVID-19; this likely applies to other patients with debilitating neurologic disease. Such patients should be specifically advised to adhere to preventive measures. (See 'Management of patients with neurologic conditions' above and "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

●Vaccination for patients with neurologic conditions – We encourage vaccination against COVID-19 to those without a contraindication as soon as it is available to them because patients with some neurologic conditions may be at high risk for severe illness from COVID-19. (See 'Management of patients with neurologic conditions' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mitchell SV Elkind, MD, MS, FAAN, MD, who contributed to earlier versions of this topic review.