Neurological Involvement with COVID-19 Review

Abstract

The available literature on neurological disorders reported in the context of the current COVID-19 pandemic documents an array of manifestations affecting the central nervous system (CNS), the peripheral nervous system (PNS) and muscle. These are based on case reports and small number series mainly from Wuhan, northern Italy and New York. A dearth of knowledge exists in the understanding of whether the neurological manifestations are caused by or merely associations with COVID-19 infection.

CNS involvement is observed more commonly, and includes headache, decreased level of consciousness, seizures, encephalopathy and disturbance of smell and taste. The latter has emerged as a prominent often early symptom and is considered an indicator of the neurotropic properties of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The profound and often times fatal respiratory failure associated with severe COVID-19 possibly has a neurogenic component with involvement of respiratory brainstem nuclei as a result of transneural viral spread from olfactory or bronchopulmonary receptor nerve endings progressing to the medullary respiratory centres. A generalised endotheliitis and prothrombotic inflammatory state leads to cerebrovascular complications with ischaemic strokes (often large vessel), intracerebral haemorrhage and occasionally cerebral venous thrombosis. Acute haemorrhagic necrotising encephalopathy has been described as a neurological manifestation of the cytokine storm. Postinfectious myelitis has been documented. The PNS involvement includes cases of Guillain–Barré syndrome and some of its variants or formes frustes; myositis of varying degree and severity is encountered.

Direct viral neurotropic disorders need to be distinguished from secondary neurological disease resulting from systemic multi-organ illness and from mere coincidental co-occurrence of COVID-19 and a neurological condition. Future clinicopathological studies will need to clarify some of these questions.

Main article text

INTRODUCTION

The emergence of COVID-19 in Wuhan, the capital of Hubei Province, China, during late December 2019, and its rapid spread to be declared a pandemic by 11 March 2020, has propelled the causative novel Coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the spotlight of global attention and apprehension.

The genome of SARS-CoV-2 was published on 17 January 2020, in the National Centre for Biotechnology Information (NCBI) database.(1) It is a single-stranded positive-sense RNA virus particle comprising a 30 kB genome and three main proteins found in the envelope: S (spike protein), M (membrane protein) and E (envelope protein).(2) The glycosylated spike protein is responsible for most of the antigenic properties of the virus and mediates viral entry, thus determining the potential host organism, cell tropism and disease spectrum.(3) Coronaviruses are zoonotic, and if transmitted to humans are classically regarded as respiratory tract pathogens as seen in the previous severe acute respiratory syndrome (SARS) and Middle East Respiratory syndrome (MERS) outbreaks and in the current COVID-19 pandemic. SARS-CoV-2 recognises and binds the largely cell membrane localised angiotensin-converting enzyme 2 (ACE2) as receptor for entry which is strongly expressed on ciliated bronchial epithelial cells and type II pneumocytes explaining the dominant pulmonary involvement.(3) The ACE2 receptor, however is widely expressed elsewhere including prominently in neurons and endothelial cells, possibly implying that SARS-CoV-2 with its higher affinity to this receptor compared to SARS-CoV-1 may have a higher neuroinvasive potential.(4)

NEUROTROPISM

Neurotropism requires both of its components, neuroinvasion and neurovirulence, to be present. Entry of virions across the blood-brain barrier (or blood-nerve barrier) during viraemia is possibly directly mediated by epithelial damage from endotheliitis and resulting microcirculatory change with slowing of flow and extravasation.(5) Another route of access for virus to enter the nervous system is via the blood–brain barrier lacking circumventricular organs, and via dorsal root and autonomic ganglia both also lacking a blood–nerve barrier.(6,7) A further pathway for coronavirus to propagate into and within the nervous system is the neuronal and trans-synaptic route facilitated by the unique neuronal property of ante- and retrograde axonal transport. This neuronal propagation might, for example, occur trans-cribriform, involving the bipolar cells of the olfactory bulb, or from bronchopulmonary chemo- and baroreceptor nerve endings whose central processes end in the nucleus of the solitary tract in the brainstem closely associated with the groups of nuclei involved in respiratory and cardiac control.(4,8) Evidence from animal experiments corroborates transneuronal spread of coronaviruses from olfactory and trigeminal nerve endings in the nasal mucosa and from airway mechanoreceptors and chemoreceptors to the medullary cardio-respiratory centres.(9,10) The former correlates well with the not infrequently encountered symptom of anosmia or hyposmia in COVID-19, the latter might explain a central respiratory component contributing to the profound respiratory failure in severe disease and possibly the low oxygen saturation seen in patients in the absence of overt respiratory distress.(11,12) Neurovirulence of coronavirus has been demonstrated and confirmed in animal studies and pathologically proven in SARS patients.(13–16) It is thus clear that neurotropism is a definite and possibly major contributor to the pathophysiology of SARS-CoV-2 infection.

CLINICAL SPECTRUM OF NEUROLOGICAL DISEASE IN COVID-19

With publication of the first few case series of this primarily respiratory tract viral infection, it became apparent that neurological involvement is a definite feature. This may occur at varying levels of disease severity and in a wide variety of guises affecting both the peripheral nervous system (PNS) and more frequently the central nervous system (CNS).(17–20) Despite this there still is a relative dearth of reports dedicated to the neurological manifestations of COVID-19 as evident in a systemic review e-published on 11 April 2020, which only found six such articles up to March 2020.(21) In addition, it still needs to be determined and dissected which of the reported manifestations are direct neurotropic complications of the virus versus secondary or indirect effects on the nervous system as a consequence of COVID-19 multisystem and multi-organ involvement. The most comprehensive and most recently updated (30 April 2020) summary report on COVID-19 neurology was published in the Journal of Neurological Sciences on 7 May 2020.(22) Table 1 is adapted from this paper (with permission).

Table 1:

The neurology of COVID-19 (adapted from Román (22), with permission)

Neurologic diagnosis	Features	City/Country	Author
CNS symptoms
Headache	6% to 8% (all patients) 6.5% (all patients) 13% (stroke patients)	Wuhan, China Beijing, China Wuhan, China	Various Tian et al. Chen et al. Li et al.
Agitation and delirium	69% agitation (58 ICU patients) 65% delirium (58 ICU patients) 67% pyramidal tract signs	Strasbourg, France	Helms et al.
Impaired consciousness	22% (fatal cases vs. 1% non-fatal cases) 14.8% (severe cases vs. 2.4% non-severe cases)	Wuhan, China Wuhan, China	Chen et al. Mao et al.
Anosmia, hyposmia	5.1% (cases from 3 hospitals) 85.6% (cases from 12 hospitals)	Wuhan, China Europe	Mao et al. Lechien et al.
Dysgeusia	5.6% (cases from 3 hospitals) 88% (cases from 12 hospitals)	Wuhan, China Europe	Mao et al. Lechien et al.
CNS diseases
Cerebrovascular disease	2.4% (6/214) Ischemic stroke 5 Haemorrhagic stroke 15.8% (13/221) Large-vessel ischemic stroke 11 Haemorrhagic stroke 1 Cerebral sinus thrombosis 1 1% to 6% (pooled analysis) 23% (3/13 ICU patients from 2 hospitals) Ischemic strokes 3 Large-vessel ischemic strokes	Wuhan, China Wuhan, China China (6 case-series) Strasbourg, France New York, US	Mao et al. Li et al. Aggarwal et al. Helms et al. Oxley et al.
Frontotemporal hypoperfusion	58 ICU patients with severe COVID-19, 45 survived (33% had frontal lobe behavioural signs) 11/11 CBF-ASL-MRI frontotemporal hypoperfusion	Strasbourg, France	Helms et al.
Subarachnoid haemorrhage	1 patient with Immune thrombocytopenic purpura	France	Zulfiqar et al.
Acute Haemorrhagic Necrotizing Encephalopathy	Brain MRI showed bilateral haemorrhagic rim-enhancing lesions in the thalami, medial temporal lobes, and subinsular regions, probably associated with cytokine storm syndrome	Detroit, USA	Poyiadji et al.
Meningoencephalitis	Seizures, neck rigidity, CSF pleocytosis (12/μ/L). CSF-RT-PCR positive for SARS-CoV-2.	Japan	Moriguchi et al.
Encephalopathy	Decreased level of consciousness with COVID-19. Negative CSF and CT brain; EEG: diffuse encephalopathy Confusion, myalgias, meningeal signs, CSF opening pressure 220 mmHg, normal CT brain.	Florida, USA Wuhan, China	Filatov et al. Ye et al.
Seizures	Recurrent generalised tonic-clonic seizures; normal CT/MRI, CSF-RT-PCR negative for SARS-CoV-2	Iran	Karimi et al.
Myelitis	COVID-19 pneumonia, high fever (40°C), acute flaccid paraplegia	Wuhan, China	Zhao et al.
PNS and muscle
Neuritic pain	8.9%	Wuhan, China	Mao et al.
Guillain–Barré syndrome	First case in China 61-year-old woman First case in USA 54-year-old man Three cases from northern Italy	Shanghai, China USA Italy	Zhao et al. Virani et al. Toscano et al.
Miller-Fisher syndrome, Polyneuritis cranialis Neurosensory hearing loss	50-year-old man with diplopia due to external ophthalmoplegia, ataxia and areflexia 39-year-old man with diplopia from bilateral abducens palsy, global areflexia but no ataxia Old woman from Thailand	Madrid, Spain Bangkok, Thailand	Gutiérrez-Ortiz et al.Sriwijitalai and Wiwanitkit
Myalgia	36% early symptom in >1200 COVID-19 patients 26–51% muscle fatigue	Wuhan, China Wuhan, China	Several Huang et al.
Myopathies	10.7% (19.3% severe vs. 4.8% non-severe)	Wuhan, China	Mao et al.
Rhabdomyolysis	33% have increased CK Early sign in 2 case reports	China Wuhan, China	Several Jin and Tong Suwanwongse et al.

CNS DISEASE

Headache, confusion, seizures and altered level of consciousness represent the classic symptoms and signs of the somewhat diffuse meningo-encephalitic presentation seen in many viral infections. From the available data, it can be concluded that early-onset headache and decreased responsiveness may be harbingers of neurological involvement and severe disease.(17) There are reports of meningitis and encephalitis with cerebrospinal fluid (CSF) testing reverse transcription-polymerase chain reaction (RT-PCR) positive for SARS-CoV-2 confirming the presence of virus in this compartment.(23) Other authors anecdotally denote an ill-defined encephalopathy characterised as a ‘mute, quiet delirium with hallucinations’, again rather non-specific, but possibly explained by a constellation of multiple phenomena including metabolic derangements, hypoxia, ictal and post-ictal states, cerebrovascular disturbances and others.(22) Brain MRI, when obtained in these cases, was often reported normal.

Acute haemorrhagic necrotising encephalopathy (AHNE) has been described in a patient from Detroit with classic clinical and radiological manifestations.(24) Brain MRI showed bilateral haemorrhagic, ring-enhancing lesions occupying the thalami, medial temporal lobes and subinsular areas. AHNE is not considered an encephalitis as CSF typically shows no pleocytosis, but is regarded as a parainfectious disease representing the CNS manifestation of a ‘cytokine storm’ resulting from massive elevation and activation of proinflammatory mediators in the systemic circulation.(25)

Disturbance of smell and taste is recognised as a common symptom manifesting in COVID-19 patients. Anosmia, hyposmia or hypogeusia, dysgeusia was reported in about 5% of patients from a Wuhan cohort and in as many as 85.6% of patients for olfactory dysfunction and 88% for gustatory dysfunction in a large multi-centre European study.(17,26) Both smell and taste alterations often occurred together, early recovery of olfaction took place in 44%. Loss of smell and taste presented alone before any other complaints in almost 12% of severe COVID-19 cases.(26) Importantly, these symptoms appear in the absence of nasal congestion, rhinitis, rhinorrhoea or similar settings, implying that olfactory neural pathways are the site of involvement, rendering further credence to the notion that viral neurotropism forms part of the pathophysiology.(8,27) Anosmia and dysgeusia have been added as primary symptoms in many SARS-CoV-2 screening tools.

Stroke risk might be increased with COVID-19 in association with the related phenomena of inflammation, hypoxia and hypercoagulability.(22) Conversely, patients with previous stroke or new stroke are possibly at higher risk of developing more severe COVID-19. It remains difficult to discern whether stroke occurs coincidentally with COVID-19 or as a result or complication of COVID-19. Two clinical case series from Wuhan, when combined, describe 16 ischaemic strokes, 2 cerebral haemorrhages and 1 cerebral sinus thrombosis/venous stroke in 435 patients.(17,28) Stroke was more common in the severe COVID-19 group, was significantly associated with older age and correlated with more vascular risk factors like hypertension, diabetes mellitus, smoking and previous stroke history. In one study CRP values were higher in the stroke group (mean = 51.1 mg/L vs. mean = 12.1 mg/L in non-stroke cases), as were D-dimer values (mean = 6.9 mg/L for stroke patients vs. mean = 0.5 mg/L for non-stroke patients), possibly reflecting a hypercoagulable tendency.(28) In this same study, 5 stroke patients died (38% mortality). A more recent paper from New York reports a case series of 5 patients under 50 years of age, all SARS-CoV-2 PCR positive, presenting with large vessel territory infarctions and fairly mild or no COVID-19 symptoms.(29) A pooled analysis of literature data up to 31 March 2020 on severe COVID-19 and acute or previous stroke included 6 studies from China with patient numbers ranging from 52 to 1099. Current or previous stroke was associated with a 2.5-fold increased chance to develop severe COVID-19 compared to patients without stroke, but this was not statistically significant.(30) A French case series of 58 ICU patients with ARDS due to severe COVID-19 found neurological involvement in 84%, with the majority displaying agitation, delirium and corticospinal tract signs indicating encephalopathy; in 3/13 patients, MRI brain showed small ischaemic strokes and 11 patients had bilateral frontotemporal hypoperfusion on arterial spin labelling perfusion MRI.(31)

Ischaemic stroke in COVID-19 seems to affect severely ill older patients with vascular risk factors, and increased D-dimer levels possibly correlate with an enhanced risk of thrombosis and embolism.(32)

Myelitis has been reported in a patient from Wuhan with COVID-19-related fever and fatigue who then developed clinical features suggesting a (possibly longitudinally extensive) transverse myelitis with cervical motor level, thoracic sensory level and bladder/bowel incontinence.(33) Due to pandemic infection control and prevention measures, CSF studies and MRI scan were not performed, but the authors excluded other viral, bacterial and mycobacterial infections. The patient also had clinical and laboratory features compatible with a cytokine storm syndrome in response to the SARS-CoV-2 infection. There was partial clinical improvement after treatment with multiple antiviral, antibiotic and immunomodulatory medications and the authors concluded this myelitis to be post-infectious.(33). The COVID-19 registry of the Spanish Neurological Society (SEN) lists one case of post-infectious myelitis as of 11 May 2020.(34)

PNS AND MUSCLE DISORDERS

Guillain–Barré syndrome (GBS) has been reported with COVID-19 in individual case reports from China and the US, and in a series of 5 patients from northern Italy.(35–37) Patients presented on average 5 to 10 days after the onset of COVID-19 symptoms, often still in the symptomatic phase, suggesting a parainfectious rather than the classic postinfectious manifestation. CSF-RT-PCR for SARS-CoV-2 was negative in cases where it was obtained, and CSF profiles showed typical albumino-cytological dissociation with raised protein and no cells. Neurophysiological features were axonal in some and demyelinating in others; treatment was with intravenous immune globulin in most patients.(35,37)

Miller-Fisher syndrome and variants/formes frustes have been reported in 2 COVID-19 patients from Spain, one was anti-GD1b anti-ganglioside antibody positive.(38)

Myopathy is a common feature ranging from mild forms manifesting with fatigue and myalgia through myositis with increased creatine kinase (CK) levels to frank rhabdomyolysis with acute renal failure. In the initial case series from Wuhan, 36% of patients had myalgia and CK was increased in 33% of cases.(18,39,40)

Overall, it is apparent from the literature that CNS involvement with COVID-19 features more prominently than PNS and muscle pathology.

CONCLUSION

From this current up-to-date review of the literature, it is clear that COVID-19 patients frequently develop neurological symptoms. Some of these may be the result of systemic inflammatory and metabolic processes occurring in critically ill elderly patients with comorbidities admitted in the intensive care units. It is hypothesised that in addition to other factors like diffuse endotheliitis, myocardial injury and failure, and a widespread coagulopathy and thrombotic state, one of the terminal events in severe COVID-19 may be irreversible respiratory failure caused by brainstem involvement from viral neurotropism of SARS-CoV-2.(10,22) The neurotropic potential of SARS-CoV-2 and the frequency and possible long-term sequelae of its neurological complications need to be better documented and understood. Thus far in South Africa, there is a paucity of information regarding neurological involvement in patients with COVID-19 infection. We are confident that units in South Africa will join the global appeal by the Environmental Neurology Specialty Group of the World Federation of Neurology to its member societies to initiate and drive national and regional neuroepidemiological databanks go gather and document the relevant information on all acute, delayed, long-latency and chronic long-term neurological disorders associated with SARS-CoV-2 infection.(41) These registries will ultimately inform our understanding of the true neurological impact of COVID-19.

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