June 2020, Volume XXXIV, Number 3
The coronovirus pandemic
Assessing neurological complications
oronaviruses are a large family of viruses that are believed to cause between 15–30% of common colds. SARS-CoV2 is one member of this family. Until recently, it was known to be endemic only in bats and is believed to have jumped species to infect humans, probably through an as yet unidentified intermediate host. The first human cluster was identified in December 2019 in Wuhan, China and, within a matter of months, rapidly spread across the globe. As of June 10, 2020, there have been over 7.3 million cases reported worldwide, with over 400,000 deaths.
About the virus
SARS-CoV2 is a relatively large single-strand RNA virus with about 30k nucleotides that code for several non-structural and four structural proteins, of which the best known is the spike protein located on the outer surface of the viral envelope, giving it a crown-like appearance. SARS-Cov2 shares approximately 80% genetic commonality with the SARS-Cov1 virus (responsible for the SARS epidemic in 2003) and the MERS (Middle Eastern Respiratory Syndrome) virus. The Coronavirus genome is remarkably stable probably due to a robust proofreading mechanism. Isolates of the OC43 strain (which can cause “common cold”) from 1961 and 2000, show only two amino acid differences. Nonetheless, mutations do occur and three major strains of SARS-Cov2 have been identified; the clinical significance of the mutants is uncertain. The primary method of human-to-human spread is through airborne transmission. The primary target of the virus is the respiratory tract where the spike protein binds with the Angiotensin Converting Enzyme 2 (ACE2) receptor. The virus then enters the cell and hijacks the host cell protein synthesis machinery. The viral RNA is translated and various subgenomes direct the synthesis and post-translational modification of viral proteins, eventually producing copies of the virus that are released from the host cell by exocytosis.
Knowledge of these syndromes will help in earlier recognition
While SARS-Cov2 primarily causes respiratory illness of varying severity in most symptomatic individuals, the virus can have widespread effects on the body. In the initial patient cluster in Wuhan, neurological symptoms were reported by 36% of individuals hospitalized with COVID-19. Several reported symptoms were non-specific (e.g. headache, depressed level of consciousness, dizziness, or seizure), while others were more specific such as loss of smell (anosmia), loss of taste (ageusia), or myopathy.
The nervous system
There are several known mechanisms of viral involvement of the nervous system such as direct infection (West Nile Virus–WNV), reactivation of latent infection (Varicella Zoster Virus–VZV), or immune-mediated, where antibodies produced in response to viral infection can attack the brain (Acute Disseminated Encephalomyelitis–ADEM), spinal cord (transverse myelitis) or peripheral nerves (Guillain-Barré syndrome). Recently, an unusual mechanism has been described where Herpes Simplex Virus 1 (HSV-1) encephalitis can be followed a few months later by an anti-NMDA receptor antibody encephalitis. It is believed that the HSV-1 virus alters the NMDA receptor making it antigenic. Viral infections of the nervous system can occur in immunocompetent (e.g. HSV-1, WNV) or immunocompromised hosts (Cytomegalovirus, JC Virus, Epstein-Barr Virus). Interestingly, viruses can sometimes produce neurological disease years or decades after the primary infection, for e.g., SSPE in adolescence following measles infection in childhood. Viruses can be highly neurotropic and affect very specific cell types or groups, such as Polio virus, which predominantly attacks anterior horn cells in the spinal cord and various nuclear groups in the brain stem.
SARS-CoV2 and neurological diseases
There may be several potential mechanisms by which the SARS-CoV2 virus produces neurological disease including direct invasion possibly through the hematogenous route or through the cribriform plate of the ethmoid bone with invasion of the olfactory nerves and transsynaptic spread, or indirect mechanisms via proinflammatory cytokines (e.g. IL6) or antibodies that cross-react with neural antigens.
Over the past several months there have been numerous case reports and series describing various neurological complications of SARS-CoV2 infection. Our knowledge is evolving very rapidly, almost week to week. Some of the major clinical syndromes associated with SARS-CoV2 are described below:
Strokes. Strokes due to viral brain infections are distinctly rare though have been previously described with VZV infection. There have been several short case series reporting the occurrence of ischemic strokes in patients infected with SARS-CoV2. Many affected patients were young, without the traditional risk factors for stroke such as hypertension, diabetes mellitus, hyperlipidemia, or history of smoking. Further, the strokes were large and were caused by thrombosis of intracranial vessels such as the internal carotid or middle cerebral arteries. Eligible patients were treated with intravenous alteplase and mechanical thrombectomy but despite interventions, many had significant residual disability. Unfortunately, there were significant delays in seeking medical care after stroke symptoms had developed, which generally translates to a worse prognosis for recovery. The clinical manifestations of stroke caused by SARS-CoV2 are not unique and depend upon the size and location of the affected area of the brain. Although the precise mechanism causing strokes is elusive thus far, it is believed that severe SARS-CoV2 infections produce a systemic prothrombotic state, with endothelial dysfunction and hypercoagulability leading to arterial and venous thromboses. Many centers are now routinely treating patients hospitalized with severe SARS-CoV2 with anticoagulants, such as lovenox or heparin.
Acute Disseminated Encephalomyelitis (ADEM). There have been many reports of patients infected with SARS-CoV2 demonstrating symptoms and signs consistent with ADEM, an immune-mediated inflammatory condition affecting the brain and spinal cord. My colleagues and I have personally seen several cases in our inpatient practice. Clinical presentation includes altered mental status, multifocal weakness and sensory disturbance, as well as seizures. Brain MRI may reflect diffusion-weighted imaging abnormalities along with multiple T2/FLAIR sequence hyperintense, bilateral, asymmetric, patchy and poorly defined lesions typically involving the subcortical cerebral white matter and cortical gray–white matter junction, thalami, basal ganglia, cerebellum, and brainstem. CSF often shows elevated protein and mild pleocytosis consistent with inflammation. High-dose corticosteroids are used as first-line therapy and intravenous immune globulin or plasma exchange are used in steroid-unresponsive cases. ADEM is typically a monophasic illness with favorable clinical recovery in most cases, as well as complete or partial resolution of MRI signal abnormalities. We do not have enough data at this time to know the prognosis of ADEM caused by SARS-CoV2. A rare variant of ADEM has also been described with SARS-CoV2—acute hemorrhagic leucoencephalitis, which is a more fulminant condition with significantly higher morbidity and mortality due to petechial hemorrhages, necrotizing vasculitis and diffuse cerebral edema. Thus far, it is not certain whether SARS-CoV2 causes encephalitis by direct invasion.
Our knowledge is evolving very rapidly, almost week to week.
Guillain-Barré syndrome (GBS). Several cases of GBS in patients with SARS-CoV2 have been reported. In most cases, the onset of GBS was preceded by respiratory symptoms by 5–10 days. In at least one reported case, the patient did not report preceding fever or respiratory symptoms but had transient loss of smell and taste and had a positive RT-PCR test for SARS-CoV2. GBS typically presents with gradually progressive sensory symptoms, motor weakness or both, beginning distally and ascending over a few days. In severe cases of GBS, patients can develop bulbar weakness and/or respiratory failure that requires intubation and mechanical ventilation. Autonomic nerve involvement can result in arrythmias and labile blood pressure. Initial diagnostic suspicion is based on clinical presentation; CSF examination often shows elevated protein with normal cell count and cases may be confirmed by EMG. Nerve conduction studies typically show slowed peripheral nerve conduction (due to demyelination), but can also demonstrate denervation due to axonal destruction in more severe cases. In early stages the diagnosis can be quite challenging when various tests can be normal. GBS is believed to occur due to antibodies produced against the SARS-CoV2 virus that cross-react with various antigens in the peripheral nerves. Treatment involves a five-day course of IVIG or plasmapheresis. Corticosteroids are contraindicated in GBS. Recovery, while generally good, can be slow and incomplete dependent largely on the extent of axonal involvement. Patients may require prolonged rehabilitation, as well as extended respiratory and nutritional support.
In addition to these well-defined syndromes, there have been isolated reports of cranial neuropathies and myopathy with muscle aches, weakness, and elevated CK enzymes in patients infected with SARS-CoV2.
Many patients with existing neurological diseases such as multiple sclerosis, myasthenia gravis, inflammatory neuropathies, or polymyositis are therapeutically immune suppressed with corticosteroids or monoclonal antibodies. This group of patients are at high risk for severe disease if they contract SARS-CoV2 and need to be especially vigilant to minimize potential exposure. Health care providers should take extra precautions when dealing with these (and other) vulnerable populations during clinic visits.
In our relatively short experience with SARS-CoV2, it is evident that the entire neuraxis—brain, spinal cord, cranial and peripheral nerves, and muscles—can be affected, directly or indirectly, by the virus. Knowledge of these syndromes will help in earlier recognition and thus better care of patients affected by COVID-19.
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