Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n =10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n =12) including encephalitis (n =2, para- or post-infectious), acute disseminated encephalomyelitis (n =9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n =1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n =8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n =8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.
The widespread effects of COVID-19 include neurological disorders but there have been, to date, no detailed clinical reports of their nature. Our London and regional cohort describes a range of neurological syndromes including encephalopathies, para- and post-infectious CNS syndromes including encephalitis, ADEM with haemorrhage and necrotic change, transverse myelitis, ischaemic stroke and GBS.
The neurological complications of SARS-CoV2 have similarities to those described in the other coronavirus epidemics, specifically severe acute respiratory syndrome (SARS) in 2003, and Middle East acute respiratory syndrome (MERS) in 2012. The cases described in those reports included encephalopathy, encephalitis and both ischaemic and haemorrhagic stroke attributed to hypercoagulability, sepsis and vasculitis, and GBS. However, overall numbers of infected individuals were much smaller, 8000 with SARS and 2500 with MERS, and neurological presentations were therefore few in comparison with those being recognized in the current pandemic.
In a series from Wuhan, 78 of 214 COVID-19 patients, recruited over 4 weeks, developed neurological manifestations. These patients tended to be more severely affected, older and with more comorbidities and, for some, the neurological symptom was the first presentation of COVID-19. However, apart from stroke in six patients (2.8%), the neurological features could be due to viral infection (loss of smell and taste) or to the consequences of severe systemic illness in an intensive care setting, such as sepsis and hypoxia. More specific details came from 64 consecutive patients reported by the Strasbourg group with agitation in 40/58 (69%), confusion in 26/40 (65%) and corticospinal tract signs in 39/59 (67%). MRI abnormalities were seen in 22 patients with meningeal enhancement, ischaemic stroke and perfusion changes. CSF examination was negative for SARS-CoV-2 in all seven cases tested. There are isolated case reports in the literature of myoclonus and demyelination.
Ten of our patients had transient encephalopathies with features of delirium, and psychosis in one. Delirium with agitation is described in case reports and in the larger studies mentioned above, and cognitive dysexecutive syndromes have been reported at discharge. While our patients had transient syndromes, detailed neuropsychological testing and follow-up is required to determine the extent of cognitive dysfunction in recovery, and to examine psychiatric and psychological factors. The underlying mechanisms for the encephalopathy may be multifactorial resulting from the combined or independent effects of sepsis, hypoxia and immune hyperstimultion (‘cytokine storm’).
Two of our cases had a probable autoimmune encephalitis, one with typical clinical features of opsoclonus and myoclonus, and another with typical radiological images as seen in ‘limbic’ encephalitis . These patients did not have NMDAR, LGI1 or related autoantibodies. The issue of whether SARS-CoV-2 will trigger a significant number of cases of autoimmune encephalitis, with probable antibody-mediated mechanisms, will become clear in time.
The cluster of cases with an ADEM-like illness warrants close surveillance. ADEM, an immune-mediated demyelinating disorder, is a disease mainly of children, with an adult incidence in the UK of 0.23/100 000. The nine cases described were accrued over a 5-week period. In Greater London (population 9 million, we would expect to see this incidence of cases in 5 months, which indicates that COVID-19 is associated with an increased incidence of ADEM. SARS-CoV-2 was not detected in CSF in any of the eight patients tested and the single neuropathological sample obtained did not confirm the presence of SARS-CoV-2 in brain tissue, and was supportive of the diagnosis of ADEM. While we cannot exclude the possibility of direct CNS infection in some cases, without further neuropathological studies or development of accurate CSF viral markers and serological testing, the imaging and clinical features are most supportive of a para- or post-infectious disease mechanism. Long-term follow-up is now required to establish the natural history of the cases that we have identified.
The GBS cases were not unexpected. The temporal relationship between the COVID-19 respiratory illness and the onset of symptoms would be consistent with a post-infectious immune-mediated mechanism. Up to two-thirds of patients with GBS describe an antecedent respiratory or gastroenterological illness. The most common pathogens include Campylobacter jejuni, cytomegalovirus, Mycoplasma pneumonia, HIV and more recently the Zika virus. The first report of GBS and SARS-CoV-2 from Italy describes five cases of GBS out of a total of 1200 admissions. The expected incidence of GBS is 0.6–2.7/100 000/year and further epidemiological and mechanistic study is required to determine if there is a true increase in incidence of GBS in COVID-19 patients. Our GBS cases appeared to be similar to conventional GBS patients with respect to clinical presentation, neurophysiology showing demyelinating changes in the majority of patients, CSF parameters and the response to treatment with IVIG.
Stroke associated with a generalized thrombotic predisposition in COVID-19 is of particular interest. Four out of the eight patients had cardiovascular risk factors for stroke including atrial fibrillation. Four also had pulmonary emboli. COVID-19 is associated with a pro-thrombotic state and highly elevated D-dimer levels, and abnormal coagulation parameters have been shown to be associated with poor outcome. The frequent occurrence of cerebral microbleeds seen in some of the patients, however, was unexpected.
Cerebral microbleeds are usually due to extravasation of red blood cells, and in the context of COVID-19 could be due to endothelial dysfunction related to viral binding to the ACE-2 receptors expressed on endothelial cells. Indeed, a recent report described direct viral infection of the endothelial cell and diffuse endothelial inflammation in multiple organ systems. The strokes we have encountered with COVID-19 have been severe, and further epidemiological study is required to determine the association between COVID-19 and stroke; randomized trials to determine the optimal use of antiplatelet drugs, low molecular weight heparin and other stroke therapies are required.
Muscle pain and elevated creatinine kinase have been reported as relatively common manifestations of SARS-CoV-2 infection and there are case reports of rhabdomyolysis. Like other large neurological case series, we did not observe such cases, but this could reflect referral bias to our MDT, which was set up to discuss the most challenging and severe cases.
Within our cohort of 12 patients with CNS inflammatory syndromes, a range of clinical and radiological presentations were observed, including some suggestive of post-infective ADEM or transverse myelitis and others with more unusual haemorrhagic changes that made classification challenging. A recent MRI study of 37 patients with severe COVID-19 and abnormal brain imaging found three patterns of CNS white matter changes, which could occur in isolation or in combination. Pattern 1 featured medial temporal lobe signal abnormalities similar to that seen in viral or autoimmune encephalitis; whereas patterns 2 and 3 featured microhaemorrhages, either in the context of multifocal white matter hyperintense lesions or as separate features, respectively. Whether these patterns represent the same pathology over different timelines, different immunological or other mechanisms, or combinations, is currently unclear, but could have important implications for management decisions, such as the use of steroids, and rehabilitation. In the study, haemorrhagic lesions correlated with clinical indicators of disease severity. Especially in the intensive care cohort, it can be unclear when brain injury occurs, as imaging is usually only undertaken when a patient is slow to wake after a prolonged period of ventilation.
Histopathological correlates are now emerging for some lesions. described a case similar to those described in the study and reported features of both vascular and ADEM-like pathology, with macrophages and axonal injury. Conversely, found lymphocytic panencephalitis and meningitis, and brainstem perivascular and interstitial inflammatory change with neuronal loss as prominent features in six post-mortem patients. In our one case who underwent cranial decompression, brain histology was in keeping with ADEM. Similar to the ADEM-like cases, the GBS cases also largely point to a post-infectious autoimmune mechanism, with most developing the neurological disease within 3 weeks of the documented infection. The risk factors for neurological disease remain unknown, and require further epidemiological study.
The potential mechanisms underpinning the syndromes described include either individually, or in combination, direct viral injury, a secondary hyperinflammation syndrome related to cytokines including IL-6, vasculopathy and/or coagulopathy, post-infectious inflammation including autoantibody production to neuronal antigens, and the effects of a severe systemic disorder with the neurological consequences of sepsis and hypoxia. Evidence of direct viral infection has proved elusive so far with only a few cases with SARS-CoV-2 in CSF reported, and few supportive histopathological features, though clearly further study would be helpful . Elevation of pro-inflammatory cytokines was found to correlate with COVID-19 disease severity, and some patients responded to IL-1 or IL-6 blockade ; in support of this possible mechanism, transient splenial lesions have been reported in a number of cases, including in children with multisystem inflammatory syndrome (MIS-C), in which elevated cytokines are thought to play a role. Interestingly, some of the clinical features seen in our youngest patient (Patient 39, aged 16 with pseudotumour cerebri with cranial nerve palsies) overlapped with those seen in MIS-C, including gastrointestinal symptoms, rash and cardiac involvement. Exact mechanisms in each case will be largely speculative until clear clinical, radiological and histological correlates have been drawn; given the breadth of clinical presentations, it is likely that a number or spectrum of these mechanisms are involved.
Collectively, these cases presented a considerable challenge to diagnose with MRI, neurophysiology including EEG, being difficult to obtain in an intensive care setting in addition to the demands of safe nursing and infection control. In many cases, MRI proved essential for making the diagnosis or confident exclusion of abnormalities, especially in patients in the intensive care unit who were ‘slow to wake’. In addition, controversy remains regarding the optimal treatment options including the use of high dose corticosteroids in viraemic, and often lymphopenic patients, and the potential risks of using IVIG for ADEM and GBS, in patients with pro-thrombotic risk factors such as elevated D-dimer levels.
This is a selective and retrospective study, with the limitations associated with this study design, including bias towards severe disease. Nevertheless, the study has allowed a detailed description of the neurological complications seen during and after COVID-19 infection. Further detailed clinical, laboratory, biomarker and neuropathological studies will help elucidate the underlying pathobiological mechanisms of COVID-19 neurological complications. Longitudinal follow-up studies of patients will be necessary to ascertain the long-term neurological consequences of this pandemic
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