Neurologic complications of COVID-19

Acute ischemic stroke

Cases of acute ischemic strokes were reported during the SARS-CoV and MERS-CoV epidemics. In patients with COVID-19, a case series from New York City reported large-vessel ischemic stroke in 5 patients younger than 50 years.⁷ Each presented with acute stroke symptoms with lymphopenia and elevated inflammatory markers on admission laboratory testing, but 2 had no COVID-19 symptoms.

Lupus anticoagulants and prolonged activated partial thromboplastin time have also been frequently reported among hospitalized COVID-19 patients, with a prevalence of 45% to 91% for lupus anticoagulants.^8,9 While there is no clear association between lupus anticoagulants and thrombosis in these studies, a case series reported antiphospholipid antibodies in 3 critically ill COVID-19 patients with bilateral cerebral infarcts in multiple vascular territories.¹⁰ This suggests that an acquired antiphospholipid syndrome was the underlying cause, but unlike the 5 young patients who had large-artery strokes,⁷ the patients with antiphospholipid antibodies were over 60 years of age.

These reports show that the prevalence of antiphospholipid antibodies varies in patients with COVID-19, but it is likely higher than expected in the general population. As the clinical significance is not yet known, these laboratory values should not be routinely checked in COVID-19 patients without thrombosis.

Other causes of ischemic stroke, such as viral-induced central nervous system vasculitis, have been considered in COVID-19 patients with brain lesions in vascular patterns but without clear cerebrovascular etiology. A postmortem histologic analysis of 3 patients with COVID-19 revealed lymphocytic endotheliitis within the endothelial cells of multiple organs, including the lungs, heart, kidneys, small intestine, and liver.¹¹ Endotheliitis can cause microcirculatory vasoconstriction and endothelial dysfunction with consequent ischemia and apoptosis. However, histopathologic analyses of the central nervous system have been limited, and it remains unclear if lymphocytic endotheliitis has been established in COVID-related central nervous system vasculitis.

Venous thromboembolism

Patients with severe COVID-19 also may be at risk of thromboembolic events from COVID-19–associated coagulopathy.^12,13 In hospitalized patients with COVID-19, the increased coagulation activity is marked by elevated D-dimer concentrations.^3,12,13 Further, patients with COVID-19 and cerebrovascular disease had higher D-dimer levels than those without cerebrovascular disease (6.9 mg/L vs 0.5 mg/L, P < .001).⁶ At this time, however, it is unclear if elevated D-dimer levels in patients with COVID-19 are directly associated with either arterial or venous ischemic stroke.

A case series and systematic review¹⁴ reported 14 cases of cerebral venous sinus thrombosis, with a median of 7 days from initial COVID-19 symptoms to diagnosis of the thrombosis. Initial imaging revealed cerebral venous sinus thrombosis-related intracranial hemorrhage with involvement of the transverse (75%), sigmoid (50%), and deep venous sinuses (33%) at presentation. The mortality rate was high despite therapeutic anticoagulation.

Overall, the incidence of COVID-19-related cerebral venous sinus thrombosis remains much lower than that of acute ischemic stroke.¹⁵

Encephalitis, meningitis

Encephalitis is characterized by brain inflammation that can cause morbidity and death if left untreated.¹⁶ In acute viral encephalitis, the virus replicates in brain tissue, leading to significant central nervous system insults. Studies in mice have shown that the human coronavirus can infect neurons and subsequently cause persistent infection in human neural-cell lines.¹⁷

Ellul et al¹⁸ tallied 8 cases of encephalitis from various sources. These patients presented with a range of symptoms, including irritability, confusion, seizures, and nuchal rigidity. Cerebrospinal fluid analysis in 5 patients detected lymphocytic pleocytosis. Most brain imaging was normal, but electroencephalography completed in 5 patients showed generalized slowing, focal epileptiform discharges, and 1 case of nonconvulsive status epilepticus. No specific treatment was noted in these patients; however, 1 patient responded quickly to high-dose steroids.

The low reported rate of central nervous system infection in patients with COVID-19 is likely an underestimation, as the subtle symptoms of encephalitis may be missed, and performing a lumbar puncture in patients with severe COVID-19 infection requires a substantial risk-benefit consideration.

Postinfectious demyelination

Acute disseminated encephalomyelitis is a monophasic, demyelinating disease of the central nervous system characterized by multifocal white matter demyelination in the setting of a rapidly progressive encephalopathy. An antecedent infectious process before the onset of central nervous system symptoms is common; however, the cause is typically only found in a small percentage of cases.

Two cases of probable acute disseminated encephalomyelitis have been reported in the COVID-19 population, with bilateral, extensive, nonenhancing T2-FLAIR signal changes noted in the cerebral white matter, involving the subcortical brain parenchyma and cervical spinal cord.^19,20 The cerebrospinal fluid was negative for SARS-CoV-2 by polymerase chain reaction testing in both cases. One patient was treated with intravenous immunoglobulin and the other with a 5-day course of a high-dose corticosteroid with a 10-day taper. Neurologic improvement was noted in both patients.

Acute necrotizing hemorrhagic encephalopathy

A case report presented details of a SARS-CoV-2–infected woman in her late 50s who presented with fever, cough, and altered mental status.²¹ Computed tomography (CT) without contrast depicted symmetric hypoattenuation in the bilateral medial thalami with a normal CT angiogram and venogram. MRI demonstrated hemorrhagic, enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. Cerebrospinal fluid analysis revealed negative bacterial cultures and viral testing. The reason for not testing the cerebrospinal fluid for SARS-CoV-2 was not reported. Based on imaging and clinical context, she was given a diagnosis of probable acute necrotizing hemorrhagic encephalopathy and started on intravenous immunoglobulin therapy. No further information is available on her clinical course.

Acute necrotizing hemorrhagic encephalopathy in children with virulent influenza infections has been well described.²² This complication is pathologically distinguished from acute disseminated encephalomyelitis by causing blood-brain barrier breakdown without direct viral invasion or demyelination.²³

Critical illness polyneuropathy and myopathy

Patients in the intensive care unit are at risk of developing severe weakness secondary to critical illness polyneuropathy, critical illness myopathy, or both, with a reported incidence of up to 33%.²⁷ To date, there have been no definitive reports of either disorder in patients with COVID-19. However, a study from Wuhan, China, reported 23 COVID-19 patients with acute muscle injury (defined as myalgia and serum creatine kinase level above 200 U/L).⁴

Thus, clinicians should suspect critical illness polyneuropathy or critical illness myopathy in patients with COVID-19 presenting with sepsis or complications leading to prolonged mechanical ventilation and intensive care unit length of stay.

Acute inflammatory demyelinating polyneuropathy

Acute inflammatory demyelinating polyneuropathy (more commonly known as Guillain-Barré syndrome), is an autoimmune demyelinating disorder of the peripheral nervous system usually following an antecedent infection. It is characterized by parathesias, areflexia, and ascending weakness that may lead to respiratory failure.

There are several cases of patients developing acute inflammatory demyelinating polyneuropathy after the onset of COVID-19 symptoms.^28–30 A case series from Italy described 5 patients presenting with paraplegia, facial muscle weakness, and areflexia 5 to 10 days after the onset of COVID-19 symptoms.²⁸ Of those, 3 patients had pathognomonic cerebrospinal fluid findings of albuminocytologic dissociation consistent with acute inflammatory demyelinating polyneuropathy. All 5 patients were treated with intravenous immunoglobulins, but after 4 weeks only 1 had been discharged and was able to walk independently.

Although it is important to recognize the classic symptoms of acute inflammatory demyelinating polyneuropathy, a case series from Spain reported 2 rare variants of it, ie, Miller Fisher syndrome and polyneuritis cranialis.³⁰

Olfactory neuropathy

Anosmia and dysgeusia are common symptoms associated with COVID-19, and are likely due to the virus directly accessing the olfactory bulb.³¹

A study of 417 patients with mild to moderate COVID-19 symptoms in 12 European hospitals reported sudden-onset olfactory dysfunction in 86%, and gustatory dysfunction in 88%.³² At 2 weeks, 25% of the patients had recovered both their sense of smell and their sense of taste.

Anosmia and dysgeusia are now recognized as presenting COVID-19 symptoms by the US Centers for Disease Control and Prevention.