Acute Neurological Syndromes
Anosmia and ageusia were among the first focal neurological symptoms described in COVID-19, and generated interest in SARS-CoV-2's potential neurotropism. Anosmia was reported in 5–35% of hospitalized patients, and may be higher among non-hospitalized patients with COVID-19. In some cases, it is the sole reported symptom, or persists far beyond the acute respiratory symptoms, negatively influencing the quality of life of survivors. Infection of the nasal mucosa and sustentacular cells with dissemination throughout olfactory nerve projections is one proposed mechanism of neuropathogenesis in COVID-19. Viral RNA has also been found in the olfactory bulb at post-mortem of some patients, although its association with neurological injury is not established.
Altered mental status is a commonly reported neurological finding associated with COVID-19 hospitalization. Abnormalities in EEG in COVID-19 related encephalopathy correlate with disease severity. Frontal slowing is the most common pattern observed and has been proposed as a biomarker for COVID-19 encephalopathy. Seizures are uncommon among COVID-19 patients; in a retrospective cohort of 1043 patients, 0.7% developed seizures in hospital and an even smaller proportion of those seizures occurred outside the context of pre-existing epilepsy although a recent retrospective study indicated that epileptiform abnormalities are frequently detected (48.7%) of hospitalized patients with COVID-19. Altered mental status, coma and seizures in COVID-19 are almost certainly multifactorial but can be stratified into metabolic/non-inflammatory versus inflammatory (e.g. encephalitis) categories.
Many patients with COVID-19 and altered mental status (e.g. lethargy, confusion, coma) have clinical courses complicated by hypoxia, renal failure, electrolyte disturbances, sedating medications and underlying comorbidities. A third of critically ill patients with COVID-19 present with encephalopathy, often with frontal lobe-associated features,[43,44] either at the onset of illness or during the course of hospitalization, and encephalopathy is associated with increased mortality and poor functional outcome.[37,45,46] Although encephalopathy has been reported in COVID-19 patients at all ages, patients beyond the sixth decade of life and those with pre-existing neurologic conditions (stroke, dementia, Parkinson's disease) are most affected, particularly in the context of severe respiratory illness.[45,47] While encephalopathy in the aforementioned circumstances is probably multifactorial, reports of patients with encephalopathy in the absence of severe respiratory illness suggest other possible mechanisms including bioenergetic failure and vascular dysfunction in SARS-CoV-2 infection. The association between encephalopathy and morbidity exists independently of respiratory disease, similar to that observed in sepsis-associated encephalopathy. Encephalopathy in non-COVID-19 patients is attributed to mitochondrial dysfunction, excitotoxicity and macro- or micro-ischaemic injury. One recent post-mortem analysis in New York revealed cerebral microthrombi in a subset of 67 hospitalized, deceased COVID-19 patients. Small, subcortical ischaemic events may result in confusion and cognitive dysfunction. Patients can also manifest multifocal cerebral microhaemorrhages or vascular leakage (Figure 2) due to compromise of the cerebral endothelial cells.[50,51] Radiographic findings in COVID-associated encephalopathy include non-specific white matter hyperintensities, diffusion restriction, microhaemorrhage and leptomeningeal enhancement.[50,52] In one study of intensive care unit (ICU) patients with COVID-19 and encephalopathy, bilateral frontotemporal hypoperfusion was evident in all patients who underwent perfusion imaging for altered mental status, although this finding was disputed and has not been replicated. Surprisingly, brain MRI was normal in up to 46% of patients with COVID-19 and associated encephalopathy. In another study, patients with COVID-19 and cognitive impairment showed decreased metabolism in the fronto-parietal regions on fluorodeoxyglucose (FDG)-PET scans. Indeed, correlations between neuropathology and brain MRI findings (including normal imaging) have yet to be established.
Microvascular diseases with COVID-19. (A) Multiple congested blood vessels and microhaemorrhages are observed in the basal ganglia at post-mortem. (B) MRI of the same block of tissue shows hyper and hypointense signals corresponding to the blood vessels in A. The hyperintense signals represent fibrin clots while the hypointense signals are microhaemorrhages. (C) MRI of the pons shows similar punctate hypointense signals (arrows).
A minority of patients with COVID-19 encompass established diagnostic criteria for infectious encephalitis. There are convincing reports of encephalitis-like presentations associated with elevated levels of soluble IL-6, IL-18, TNF-α, CXCL10 and markers of glial and astrocyte activation in CSF.[20,24,55,56] Radiological findings associated with COVID-19 meningoencephalitis include mesial temporal lobe T2/FLAIR hyperintensities, varying from punctate to diffuse in subcortical white matter, the brainstem and claustrum, often accompanied by cerebral oedema.[57–59] Case reports indicate that COVID-19 can present with an ADEM phenotype,[52,60] including oculomotor dysfunction, seizures and coma. Others have reported cases of acute necrotizing haemorrhagic encephalopathy that present initially with symmetric lesions in the thalami and are thought to be cytokine mediated. Some patients may present with isolated pseudotumor cerebri/benign intracranial hypertension presumably from meningitis.[62,63] Opsoclonus-myoclonus syndrome, which has been observed in association with infections such as Epstein–Barr virus (EBV), chikungunya and Mycoplasma pneumoniae, has also been reported in patients with COVID-19, including those with mild respiratory disease. Most patients with COVID-19 and opsoclonus-myoclonus syndrome had partial recovery at 4 weeks after treatments including pulse steroids, intravenous immunoglobulin (IVIg) and anti-epileptic medications.[64–66]
For presumed COVID-19 associated encephalitis, favourable therapeutic responses to corticosteroids and plasma exchange (PLEX) were observed in a subset of patients, although factors predicting a beneficial therapeutic response remain to be defined.[21,67] Whether the neuroinflammation observed clinically, neuroradiologically and neuropathologically is due to direct viral invasion, para-infectious or autoimmune processes remains unknown. In most COVID-19 cases with encephalitis, SARS-CoV-2 RNA is not detectable in CSF via PCR with reverse transcription (RT-PCR), favouring an immune-mediated mechanism of disease.[21,22,55,68]
Patients with COVID-19 have an increased rate of stroke compared to other disease cohorts, with higher NIHSS scores compared to non-COVID-19 associated stroke. Over half of strokes among patients with COVID-19 are cryptogenic, with a higher proportion of large vessel occlusions. Some series have reported higher than expected rates of posterior circulation strokes (35.3%).[16,18] Hypercoagulability induced by systemic and focal inflammation has been implicated in COVID-19 associated strokes that include both arterial and venous thromboembolic events. Cerebral venous sinus thrombosis (CVST) among patients with COVID-19 can also occur with an abnormally activated prothromboplastin time (aPTT) and elevated D-dimer levels.[70,71] COVID-19 associated CVST has an estimated in-hospital mortality of 40% in a cohort that included non-ventilated patients. In fact, CVST represents 4% of cerebrovascular complications in COVID-19 with an estimated frequency of 0.08% among hospitalized patients. In comparison, CVST accounts for 0.5–1% of all strokes among non-COVID-19 patients and occurs in ~2–5 per million people each year (0.0002–0.0005%). Elevated D-dimer levels are more common among COVID-19 patients presenting with both ischaemic and haemorrhagic stroke and are associated with higher all-cause mortality. As there is an increased risk of thromboembolism during COVID-19, multiple studies have compared standard dose thromboprophylaxis to high and intermediate-dose prophylactic anticoagulation in hospitalized patients with COVID-19. The largest of these trials, INSPIRATION randomized clinical trial found no difference in all-cause mortality or venous thromboembolic events in patients treated with standard versus intermediate-dose thromboprophylaxis in critically ill patients with COVID-19, in contrast to earlier retrospective studies showing potential benefit in ICU patients. Interim unpublished results of the multiplatform merged randomized control trial (mpRCT) ATTACC/REMAP-CAP/ACTIV-4A found similar results in the critically ill cohort as well as a signal towards harm with therapeutic anticoagulation. Interestingly, this study found improved survival in moderately ill patients with COVID-19 treated with intermediate-dose anticoagulation, suggesting severity of disease may be important in determining appropriate thromboprophylaxis in hospitalized patients.[76,77] Further studies are required to determine whether prophylactic anticoagulation specifically reduces the risk of stroke in COVID-19, particularly because of reports of haemorrhagic stroke in hospitalized patients while receiving therapeutic anticoagulation. Indeed, the risk of haemorrhagic stroke is higher than predicted among COVID-19 patients and is associated with elevated serum ferritin. Similarly, microhemorrhages and acute haemorrhagic necrotizing encephalitis have been reported in patients with COVID-19. Outcomes including risk of death and duration of hospitalization following intracerebral or subarachnoid haemorrhages are worse among patients with COVID-19.
Recent reports of vaccine-induced thrombotic thrombocytopaenia (VITT) following administration of adenovirus vector-based COVID-19 vaccines have raised concern.[81–83] As of 4 April 2021, there had been 169 cases of VITT-CVST reported to the European Medicines Agency out of 34 million doses administered of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine, with an incidence of VITT estimated at 1 per 100 000 exposures. The reported rate of VITT-CVST after administration of 6.86 million doses of the Ad26.COV2.S adenoviral vector vaccine (Johnson & Johnson/Janssen) was 0.87 cases per million (0.000087%).[84,85] Most cases occurred in females <50 years of age, and most patients displayed high levels of antibodies to platelet factor 4 (PF4)-polyanion complexes, prompting comparisons to heparin-induced thrombotic thrombocytopaenia. The precise pathophysiology of VITT is unknown to date; simultaneous thrombosis and thrombocytopaenia in VITT has only been reported for adenoviral vector vaccines although there have been five possible reports of CVST with normal platelet counts among 4 million doses of the Moderna mRNA vaccine. Among 54 million doses of the Pfizer-BioNTech mRNA vaccine, there have been 35 reports of CNS thrombosis without thrombocytopaenia (0.00006%). CSVT is a serious but rare condition associated with SARS-CoV-2 vaccination, but there remains a consensus among health authorities that the benefits of widespread vaccination outweigh the potential risks, particularly when one considers the rate of thrombosis in COVID-19 infection.
Acute PNS Disorders
Autoimmune polyradiculoneuropathies such as GBS or Miller-Fisher syndrome have been reported in patients with SARS-CoV-2 infection, with and without respiratory symptoms. These disorders can be triggered by systemic infections and have been reported in patients with other coronavirus infections such as Middle East respiratory syndrome (MERS) and SARS-CoV-1. Most case reports of GBS in COVID-19 describe the common syndrome of ascending weakness, areflexia with supporting CSF and nerve conduction studies, and are of the acute inflammatory demyelinating polyneuropathy (AIDP) type. Disease onset is between 5 and 10 days after acute COVID-19 symptoms (including anosmia, respiratory and gastrointestinal symptoms), which in the ICU settings helps distinguish GBS from critical illness neuropathy that appears later in disease course.[20,30,90] Patients with COVID-19-associated GBS respond to standard treatments (e.g. IVIg, PLEX) although how COVID-19 affects treatment responsiveness remains uncertain. Of note, a UK epidemiological cohort study showed rates of GBS have fallen during the current pandemic, probably resulting from increased public health efforts that have reduced transmission of more common infectious triggers.
Myalgia and weakness occur in 30–50% of hospitalized patients with COVID-19,[92,93] and are frequently reported by non-hospitalized patients. While myalgia is a common symptom during many viral illnesses, the mechanism by which SARS-CoV-2 infection causes debilitating muscle pain and weakness is unknown. Myositis and rhabdomyolysis as a complication of COVID-19 are well recognized with elevated serum creatine kinase (>10 000) levels as a common finding which correlates with mortality in hospitalized patients. There have also been multiple reports of muscle oedema demonstrated on MRI.[32,33] While other viruses such as influenza are known to directly invade skeletal myocytes in vitro, to date there is no evidence for infection of skeletal myocytes with SARS-CoV-2.[29,33] Myositis in COVID-19 could be triggered by host immune responses to the virus. Muscle biopsies from COVID-19 patients show perivascular inflammation including a case of type 1 interferonopathy associated myopathy in a young patient with SARS-CoV-2 infection. There are reports of COVID-19 patients with elevated creatine kinase levels and muscle weakness who respond to immunosuppression including high dose glucocorticoids as well as IVIg, prompting comparisons to immune-mediated myositis. There is also a recent report of a patient with proximal and bulbar weakness in COVID-19 with positive anti-SSA and SAE-1 antibodies who was successfully treated with the humanized monoclonal antibody against the IL-6 receptor, tocilizumab. While these neurological syndromes are observed in the acute setting, they have the capacity to exert long-term effects, as described next.
Patients who develop severe COVID-19 pneumonia often require prolonged ICU care. As expected, critical illness polyneuropathy (CIP) and myopathy (CIM) have been reported as complications of SARS-CoV-2 infection. While the pathophysiological mechanisms underlying CIM and CIP are unknown, both disorders are assumed to result from microcirculatory and metabolic changes brought on by severe physiological stress. Based on electrophysiological and pathological studies, there is no evidence that COVID-19 associated CIP/CIM has distinctive features, and treatment to date has been supportive. In fact, the lasting neurological consequences of prolonged hospitalization with or without intensive care and the associated interventions for patients with COVID-19 remain unclear.
Brain. 2022;144(12):3576-3588. © 2022 Oxford University Press