Neurologic Aspects of Coronavirus Disease of 2019 Infection

Catherine E. Hassett; Jennifer A. Frontera

Curr Opin Infect Dis. 2021;34(3):217-227.

Abstract and Introduction

Abstract

Purpose of Review: Central and peripheral nervous system manifestations of coronavirus disease 2019 (COVID-19) have been frequently reported and may cause significant morbidity and mortality. This review details the latest evidence on the neuropathogenesis and neurologic complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Recent Findings: Commonly reported neurologic complications include toxic-metabolic encephalopathy, acute cerebrovascular disorders, seizures, and anoxic-brain injury. These complications represent secondary injury due to COVID-19 related hypoxia, sepsis, hypercoagulability, or hyperinflammation. Postinfectious complications, such as encephalitis, postinfectious demyelination, and Guillain-Barre[Combining Acute Accent] syndrome have been reported, but are rare. Recent reports of persistent neurocognitive symptoms highlight the possibility of lasting impairment.

Summary: Although some neurologic complications should be treated with standard practices, further investigations are still needed to determine the optimal treatment of COVID-related neurologic complications, such as ischemic stroke. Entering into the next phase of the pandemic, investigations into the long-term neurologic and cognitive impacts of SARS-CoV-2 infection will be needed. Clinicians must have a high clinical suspicion for both acute and chronic neurologic complications among COVID-19 patients.

Introduction

In December 2019, a cluster of pneumonias of unknown etiology occurred in Wuhan, China leading to the discovery of a novel beta-coronaviruses.^[1] The Coronaviridae family contains several human-susceptible viruses including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV).^[2] The novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19), has rapidly spread throughout the world causing significant morbidity and mortality.^[1] While mostly contributing to lung and heart injury, there is substantial evidence for SARS-CoV-2 related neurologic complications through both direct and indirect mechanisms. We aim to provide a review of the acute neurologic manifestations of COVID-19 (Table 1).

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Table 1. Neurological disorders described following SARS-CoV-2 infection
Neurologic complication	Type of studies	Comments
Acute toxic-metabolic encephalopathy	Prospective, multi-center [32–35]	One of the most common neurological complications of COVID-19, underlying causes include infection, sepsis, hypoxia, hypercarbia, hyponatremia, and hyperinflammatory state
Hypoxic-ischemic encephalopathy	Prospective, multi-center [17,19,29,32,36–40]	Supportive MRI imaging of diffusion restriction in primarily gray matter structures (basal ganglia, thalami, cerebellum, hippocampus, cerebral cortex), cerebral microbleeds, and leukoencephalopathy and delayed posthypoxic leukoencephalopathy
Acute ischemic stroke	Prospective, multi-center [32,41–50]	Predictors include mostly older patients with comorbidities, elevated D-dimer, higher severity of critical illness, cryptogenic mechanism, embolic stroke of unknown source, worse outcomes than non-COVID stroke
Intracerebral hemorrhage	Prospective, multi-center [32,41,55]	Significantly associated with coagulopathy secondary to therapeutic anticoagulation, can be multifocal and multicompartmental
Cerebral venous sinus thrombosis	Retrospective case series [42,58]	Venous and hemorrhagic infarcts; lower incidence than ischemic and hemorrhage stroke, medullary vein thrombosis observed
Anosmia and agesuia	Prospective, multi-center [62–65]	Evidence on 3 T MRI of reversible olfactory cleft obstruction, evidence of injury to olfactory mucosa and support cells
Seizures	Prospective, multi-center [59–61]	Generalized and/or focal convulsions, nonclinical electrographic seizures
Acute inflammatory polyneuropathy/Guillain-Barré syndrome	Case series [12,66–68]	Most commonly diagnosed as acute axonal or demyelinating acute inflammatory polyneuropathy. Other variants, such as Miller Fisher syndrome, Pharyngeal–cervical–brachial, and polyneuritis cranialis have been described
Encephalitis	Case reports [69–71]	Limited data with convincing clinical, pathological and CSF evidence of primary SARS-CoV-2 central nervous system involvement. Postinfectious, encephalitis has been described
Acute necrotizing encephalopathy	Case reports [72]	Classic MRI imaging of bithalamic injury with necrosis and heterogenous enhancement
Acute disseminated encephalomyelitis	Case reports [72–74]	Postinfectious, monophasic course with T2/FLAIR, confluent hyperintensities in deep white matter and at grey/white junction. Treatment with pulsed IV steroids reported with good neurologic response
Postinfectious or autoimmune encephalitis	Case reports [71,82]	Studies of routine autoimmune and paraneoplastic panels have been negative
Transverse myelitis	Case reports [83,84]	Acute onset ascending symmetric paraplegia with T2 hyperintensity with predominantly lymphocytic pleocytosis and elevated CSF protein
Neuromuscular junction disorders	Case reports [85]	No reports of de novo occurrence but reports of COVID-19 infection-related myasthenia gravis exacerbation
Critical illness myopathy & polyneuropathy	Nonpeer reviewed Ccase series [85,86]	Acute flaccid quadriparesis with EMG findings consistent with axonal sensorimotor polyneuropathy during prolonged critical illness
Myositis	Retrospective case series [85–88]	Acute generalized muscle weakness and pain in the setting of elevated creatine kinase levels; muscle biopsies with necrotic fibers
Post-COVID neuropsychologic syndrome	Case reports [75–79]	Emerging evidence of prolonged neurocognitive deficits, including memory deficits, fatigue, and behavior disturbance

COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; EMG, electromyography.

Table 2. Neuropathological data among COVID-19 patients
Study	Number of brain specimen	Neurologic symptoms	SARS-CoV-2 RNA detected	SARS-CoV-2 spike protein immuno-histochemistry	Electron microscopy	Hypoxic-ischemic injury	Neuropathology findings/comments
Matsche, et al. Lancet 2020	43	NA	48% (13/27 cases) had SARS-CoV-2 RNA PCR in frontal lobe and/or medulla (median 4700 copies) *PCR cycle threshold not reported	40% (16/40 cases) had SARS-CoV-2 protein immunohistochemistry positive (spike protein > nucleocapsid protein) in medulla and cranial nerves (IX and X)	NA	Not described	Path: microglial activation and cytotoxic T cells in brainstem, olfactory bulb, astrogliosis, microgliosis No clinco-pathologic correlates: not clear if patients had symptoms referable to this pathology Presence of SARS-CoV-2 did not correlate with severity of other neuropathologic changes Low viral RNA PCR levels may be blood derived Immunostaining for viral proteins is prone to artefact No age or sex-matched controls
Meinhardt, et al. Nature Neuroscience 2020	33 and 13 controls	Impaired consciousness (n=5), intraventricular hemorrhage (n = 2), headache (n=2), behavioural changes (n=2)	76% (25/33 cases) had at least one positive SARS-CoV-2 RNA PCR. The highest level of viral RNA noted within the olfactory mucosa, olfactory bulb/tubercle, oral mucosa, trigeminal ganglion, medulla obloganta, and cerebellum. 6% (2/13 cases) SARS-CoV-2 was positive by in situ hybridization in olfactory mucosal cells. No detection of RNA by in situ hybridization in neuronal cells	42% (14/33 cases) had SARS-CoV-2 spike protein immunohistochemistry positive in medulla, cerebellum, olfactory neuronal and mucosal cells	NA	Not described	Path: no endotheliitis Co-localization of SARS-CoV-2 spike protein and neuronal markers was noted within the olfactory mucosal, but this was not demonstrated in other neuronal or glial cells Both control and COVID-19 brain tissue had SARS-CoV-2 spike protein staining in the medulla Log₁₀ SARS-CoV-2 RNA copies/10 000 cells 1.21–4.4 in olfactory bulb, olfactory tubercle, medulla, trigeminal ganglia or cerebellum and range from 1.32 to 8 in olfactory mucosa
Solomon, et al. N Engl J Med 2020	18	Headache (n=2), dysgeusia (n=1), myalgias (n=3)	None detected by RT-PCR Low levels of RNA (5.0–59.4 copies/mm³) in six brain sections (three medulla & three frontal/olfactory nerves) interpreted as blood contamination or in situ virions	Absent staining noted in neurons, endothelium, immune cells	NA	Hypoxic-ischemic changes in cerebral cortex, hippocampus, and Purkinje cell layer	Path: no thrombi or vasculitis No evidence of encephalitis No relationship of low level of viral RNA detected and interval from onset of symptoms to death
Lee, et al. N Engl J Med 2020	18	Delirium (n=1)	None detected by RT-PCR & immunohistochemistry *PCR cycle threshold above 40 cycles were negative	Absent staining	11.5 T MRI microscopy	Hypoxic-ischemic changes seen scattered in cortex, hippocampus and temporal neocortex	Path: perivascular-activated microglial, macrophage infiltrates & hypertrophic astrocytes, focal fibrinogen leakage from microvessels into brain parenchyma Multifocal microvascular changes in the brainstem and olfactory bulb without evidence of viral infection
Remmelink, et al. Crit Care 2020	17	NA	82% (9/11 cases SARS-CoV-2 RNA PCR) in CNS tissue, specific location not reported *PCR cycle threshold not reported	NA	NA	NA	Path: cerebral hemorrhage, diffuse and focal spongiosis, focal ischemic necrosis, edema
Schaller, JAMA 2020	10	NA	SARS-CoV-2 PCR negative in CSF	NA	NA	NA	Path: no encephalitis or vasculitis
Hanley, Lancet Microbe 2020	5	NA	None detected by RT-PCR & immunohistochemistry	NA	NA	Hypoxic-ischemic changes in cortical neurons and white matter	Path: moderate to intense microglial activation, Mild T-cell vessel infiltration No extensive inflammatory cell infiltration
Deigendesch, Acta Neuropathol 2020	7 and 13 controls (5 septic & 8 nonseptic)	Agitation (n=1), vertigo (n=1), coma (n=1)	57% (4/7 cases) SARS-CoV-2 RNA PCR in olfactory bulb and 29% (2/7 cases) SARS-CoV-2 RNA PCR in optic nerve *PCR cycle threshold not reported	NA	NA	Mild hypoxic-ischemic changes identified, location not specified	Path: microglial activation in brainstem, medulla, olfactory bulb No meningitis, encephalitis identified Changes in COVID patients were similar to non-COVID septic patients
Kantonen, et al. Brain Pathol 2020	4	Impaired consciousness (n=3), aguesia (n=1)	None detected by RT-PCR *PCR cycle threshold above 37 considered negative	Absent staining in olfactory mucosa, cerebrum, & carotid body	NA	Mild-severe hypoxic-ischemic changes identified, location not specified	Path: microhemorrhages
Hernandez-Fernandez, Neuropath Brain 2020	2	Brain biopsy after intracerebral hemorrhage	NA	NA	NA	NA	Path: paucity of endothelial cells in arterioles, venules, & capillaries No evidence of inflammation to suggest direct viral involvement or endotheliitis
Paniz-Mondolfi, J Med Virol 2020	1	Parkinson's disease with baseline confusion	None detected by RT-PCR	NA	Virus in neural & capillary endothelium in frontal lobe	NA	No immunohistochemistry or in situ hybridization studies completed. Rough endoplasmic reticulum likely mistaken for viral particles (Dittmaye et al. Lancet, 2020)
Reichard Acta Neuropathol 2020	1	Acute disseminated encephalomyelitis	NA	NA	NA	Hypoxic-ischemic changes within subcortical white matter	Path: microscopic infarcts, necrosis and axonal injury
Jaunmuktane Acta Neuropathol 2020	2	NA	NA	NA	NA	Hypoxic-ischemic changes within bilateral pallidal and cortical, white	Path: neocortical infarcts, small microhemorrhages