Neurologic complications of COVID-19

Acute ischemic stroke

Occurrences of acute ischemic stroke 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 of age.⁷ Each presented with acute stroke symptoms with lymphopenia and elevated inflammatory markers on admission labs, but 2 had no COVID-19 symptoms.

The presence of lupus anticoagulants and pro-longed 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 of lupus anticoagulants with thrombosis in these studies, a case series that reported the presence of 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 reported series of large artery strokes in 5 young patients,⁷ these patients with antiphospholipid antibodies were over 60 years of age.

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

Other causes of ischemic stroke, such as viral-induced central nervous system (CNS) vasculitis, have been questioned in COVID-19 patients with brain lesions in vascular patterns but without clear cerebrovascular etiology. A postmortem histological analysis of 3 patients with COVID-19 revealed lymphocytic endotheliitis within the endothelial cells of multiple organs, including lung, heart, kidney, small intestine, and liver.¹¹ Endotheliitis can cause micro-circulatory vasoconstriction and endothelial dysfunction with consequential ischemia and apoptosis. Histopathologic analysis of the central nervous system is still needed to determine if COVID-19–related CNS vasculitis can occur due to lymphocytic endotheliitis.

Venous thromboembolism

Studies show that patients with severe COVID-19 also may be at risk for thromboembolic events from COVID-19–associated coagulopathy (CAC).^12,13 In hospitalized patients with COVID-19, the increased coagulation activity is marked by increased D-dimer concentrations.^3,12,13 Furthermore, patients with COVID-19 and cerebrovascular disease had higher D-dimer levels than those without cerebrovascular disease (6.9 mg/L vs 0.5 m/L, P <.001).¹³ At this time, however, it is unclear if elevated D-dimer levels in patients with COVID-19 are directly associated with either or both arterial and venous ischemic stroke. The reported incidence of cerebral venous sinus thrombosis has been much lower than that of acute ischemic stroke (0.5% vs 5%).¹⁴

Encephalitis, meningitis

Encephalitis is characterized by brain inflammation that can cause morbidity and mortality if left untreated.¹⁵ In acute viral encephalitis, viral replication occurs in the brain tissue leading to significant central nervous system insults. In-vivo studies of mice have shown that the human coronavirus can infect neurons and subsequently cause persistent infection in human neural-cell lines.¹⁶

The first case of COVID-19–associated meningoencephalitis was reported in a 24-year-old male with no prior medical history who suffered convulsive seizures in the setting of presumed SARS-CoV-2 infection with paranasal sinusitis.¹⁷ Lumbar puncture results depicted a neutrophilic pleocytosis and detected SARS-CoV-2 infection. A brain MRI depicted diffusion restriction of the inferior horn of the right lateral ventricle with fluid-attenuated inversion recovery (FLAIR) hyperintensities of the right mesial temporal lobe and hippocampus. He was diagnosed with meningoencephalitis and started on empiric antibiotic coverage but remained critically ill.

Interestingly, an autopsy study on 8 patients with confirmed SARS-CoV-2 infection reported that all the patients had SARS genome detected in the cytoplasm of hypothalamic and cortex neurons.¹⁸ The low reported rate of CNS infection in patients with COVID-19 is likely an underestimation as performing a lumbar puncture in patients with severe COVID-19 infection requires a substantial risk- benefit consideration.

Postinfectious demyelination

Acute disseminated encephalomyelitis (ADEM) 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 prior to the CNS symptoms is common; however, the cause is typically only found in a small percentage of cases. Two cases of probable ADEM 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 (CSF) SARS-CoV-2 polymerase chain reaction test was negative in both cases. One patient was treated with intravenous immunoglobulin and the other with a 5-day course of high-dose corticosteroid with a 10-day taper; neurologic improvement was noted in both patients.

Acute necrotizing hemorrhagic encephalopathy

A recent 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 Her noncontrast brain CT imaging depicted symmetric hypoattenuation in the bilateral medial thalami with a normal CT angiogram and venogram. MRI imaging demonstrated hemorrhagic, enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. A CSF analysis revealed negative bacterial cultures and viral testing. The reason for not performing SARS-CoV-2 CSF test was not reported. Based on imaging and clinical context, she was given a diagnosis of probable acute necrotizing hemorrhagic encephalopathy and started on IV immunoglobulin therapy. No further information is available on her clinical course.

Prior reports of acute necrotizing hemorrhagic encephalopathy in the setting of virulent influenza infections have been well described in the pediatric population.²² It is pathologically distinguished from ADEM by causing blood-brain barrier breakdown without direct viral invasion or demyelination.²³

Critical illness polyneuropathy and myopathy

Patients in the intensive care unit (ICU) are at risk for developing severe weakness secondary to critical illness polyneuropathy (CIP) and/or critical illness myopathy (CIM) with a reported incidence of up to 44%.²⁷ To date, there have been no reports of definitive CIP or CIM in patients with COVID-19; however, a study from Wuhan, China, reported 23 COVID-19 patients with acute muscle injury (defined as myalgia and elevated serum creatinine kinase level above 200 U/L).⁴ Thus, clinicians should have a high suspicion for CIP or CIM in patients with COVID-19 presenting with sepsis or complications leading to prolonged mechanical ventilation and ICU length of stay.

Acute inflammatory demyelinating polyneuropathy

Acute inflammatory demyelinating polyneuropathy (AIDP), 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 AIDP after onset of COVID-19 symptoms.^28⇓-30 A case series from Italy reported 5 patients presenting with paraplegia, facial muscle weakness, and areflexia 5 to 10 days after COVID-19 symptom onset.²⁸ Of those, 3 patients had pathognomonic CSF findings of albuminocytologic dissociation consistent with AIDP. All 5 patients were treated with IV immunoglobulins, but only 2 patients had clinical improvement at the time of publication. Although it is important to recognize the classic symptoms of AIDP, a case series from Spain reported 2 rare AIDP variants, including Miller Fisher Syndrome and polyneuritis cranialis.³⁰

Olfactory neuropathy

Anosmia and dysgeusia are common symptoms associated with COVID-19, likely secondary to the direct olfactory bulb access.³¹ A study of 417 patients with mild to moderate COVID-19 symptoms in 12 European hospitals reported sudden onset olfactory and gustatory dysfunction with a prevalence of 86% and 88%, respectively.³² There was a 25% recovery from both symptoms within 2 weeks. Anosmia and dysgeusia are now recognized as presenting COVID-19 symptoms by the Centers for Disease Control and Prevention.