Review 2: "Neurological manifestations associated with COVID-19: a nationwide registry"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

BACKGROUND

Neurological complications associated with SARS-CoV-2 infection, so-called coronavirus disease 2019 (COVID-19), have garnered a great deal of attention during the ongoing pandemic. Data regarding the characterization, frequency, and outcome of these complications are valuable to help guide diagnostic considerations and direct healthcare utilization, and many recently published and ongoing efforts globally have focused on generating such data. These prior reports have found encephalopathy (whether in the presence or absence of demonstrable encephalitis), acute cerebrovascular disease (predominantly ischemic stroke disproportionately caused by large vessel occlusion associated with inflammatory hypercoagulability), headache, seizure, olfactory or gustatory dysfunction, peripheral neuropathy and myopathy to be the most common manifestations, especially in patients with severe infection.1-6

Meppiel et al.7 join these efforts in examining exclusively de novo neurological complications (defined as neurological symptoms that occurred 5 days before to 35 days after COVID-19 symptoms in the absence of sedative therapy), as opposed to acute exacerbations or complications of pre-existing neurological disease, associated with coronavirus disease 2019 (COVID-19) in 222 patients evaluated at 46 medical centers in France through a multicenter survey.

MAIN FINDINGS

Their primary findings were the predominance of neurological involvement caused by central nervous system dysfunction (85%, including encephalopathy in 38%, acute ischemic stroke or transient ischemic attack in 26%, and encephalitis in 10%) versus peripheral nervous system dysfunction (13%, mostly due to Guillain-Barré syndrome in 7% and critical illness-associated neuropathy in 5%). These neurological complications occurred throughout the early course of COVID-19, from being noted at onset to being detected after sedation is withheld over 2 weeks after onset. Consistent with prior studies, these manifestations were often more prevalent among patients with severe or critical COVID-19, and pre-existing cardiovascular disease and neurodegenerative disease were more common among patients with stroke and encephalopathy, respectively.

Many patients underwent thorough neurological evaluation with neuroimaging, lumbar puncture, electroencephalography, and electroneuromyography, however absent from the study are descriptions of inflammatory or coagulability profiles that have been reported in other cohorts of COVID-19 patients. These evaluations revealed that acute ischemic cerebrovascular syndromes were frequently cryptogenic, and a notable proportion were caused by large vessel occlusion or multi-territory infarctions. Encephalitis (defined by the authors as encephalopathy in the presence of either cerebrospinal fluid pleocytosis or an acute radiographic lesion) occurred in a minority of patients with encephalopathy, was associated with a low rate of SARS-CoV-2 detection in cerebrospinal fluid, and was correlated with a favorable short-term prognosis without directed treatment suggestive of a para-infectious mechanism rather than direct viral invasion.

The overall short-term mortality in this cohort was 12.6%; death was most frequently due to acute respiratory distress syndrome, and was more common among patients with stroke and encephalopathy who were more likely to have severe or critical COVID-19, however the impact of neurological complications on mortality could not be evaluated without a severity-matched control group of COVID-19 patients without neurological complications. Notably, a substantial proportion of patients (42%) experienced resolution of their neurological symptoms at median follow-up of 24 days, however this was not largely attributable to directed treatments as rates of thrombolysis, thrombectomy, and anticoagulation were not specified, and, with the exception of intravenous immunoglobulin for treating Guillain-Barré syndrome, the use of immunosuppression or immunomodulation for treating encephalitis and COVID-19-associated encephalopathy was infrequent.

STUDY REVIEW

Strength of Evidence: Reliable

Claims are generally supported by the data and methods used. Decision-makers should consider the claims in this study actionable with limitations based on the methods and data.

The major claims made by the authors or the presented data are: (1) COVID-19 is associated with a wide range of de novo neurological complications, particularly in patients with severe or critical COVID-19; (2) central nervous system manifestations of COVID-19 are predominant and largely consist of encephalopathy (with or without encephalitis) and stroke, while peripheral nervous system manifestations of COVID-19 largely consist of Guillain-Barré syndrome and critical illness neuropathy; and (3) neurological complications may occur throughout the early course of COVID-19. The study largely corroborates prior findings from multiple reports, but it is one of the more thorough descriptions of neurological complications in COVID-19 patients, including their temporal relationship to COVID-19 symptom onset, at multiple medical centers.

The authors acknowledged some limitations of their retrospective registry, including recall bias (favoring more severe manifestations over milder complications such as headache and anosmia) and restricted reporting of past medical history and laboratory findings. This restricted reporting did not include inflammatory or hypercoagulability profiles that have been associated with COVID-19 complications and could suggest potential mechanisms for pathogenesis and targets for directed treatments. The authors did not provide evidence to support any claims regarding the pathogenic pathways that might mediate the complications observed in their cohort, however they review potential pathways proposed by prior studies in their discussion.

Although this study was one of the first to employ standardized diagnostic criteria for clinical entities of interest in relation to COVID-19, the authors’ criteria have not been validated or supported by scientific consensus (with the exception of the study criteria for Guillain-Barré syndrome, which referenced previously published and well-accepted diagnostic criteria). For example, the breadth of the criteria for encephalitis limits the authors’ efforts to describe a clinical entity that is distinct from encephalopathy or the result of inflammatory pathophysiology. Firstly, the criterion of a “compatible acute lesion” was fairly nebulous, as evidenced by the heterogeneity of MRI findings referenced by the authors’ in their discussion. Whether a radiographic lesion was deemed compatible because it correlated with a focal neurologic deficit (the presence of which was not a listed criterion for encephalitis) or because it appeared radiographically consistent with inflammation was not specified. This is especially important given the differing training backgrounds of the survey respondents, who were mostly neurology-trained (66%), which could have resulted in variable interpretation of this criterion unless the study authors reviewed reported cases and reclassified them to ensure consistency. In patients whose diagnosis of “encephalitis” was delayed until sedation was withheld, it is not inconceivable that contrast-enhancing lesions associated with focal neurologic deficits could be due to previously unrecognized ischemic strokes rather than viral encephalitis, or that sulcal T2 hyperintensities that can be seen in iatrogenic hyperoxygenation during mechanically ventilated could be mistaken for leptomeningeal inflammation. Secondly, the authors did not specify if the cerebrospinal fluid white blood cell count (whether obtained from the first or the last aliquot of fluid) was corrected for elevated red blood cell count, that might indicate a traumatic lumbar puncture rather than active inflammation. Although the clinical entity of COVID-19 encephalitis is of great interest, the diagnostic criteria presented by the authors in the present study require further investigation. As a result, whether COVID-19 encephalopathy is a by-product of viral sepsis, systemic inflammation, endotheliitis and microvascular thrombosis versus an encephalitis due to direct neurologic invasion by SARS-CoV-2 or indirect focal parenchymal inflammation, as prior studies have aimed to demonstrate, remains to be seen.

Neurological dysfunction, including encephalopathy, polyneuropathy, and myopathy, is a significant contributor to long-term disability after critical illness. In a short period of time, the COVID-19 pandemic dramatically expanded the number of critically ill patients at risk for these neurological complications. The authors present a clear, straightforward description of COVID-19-associated neurological complications encountered at multiple French medical centers, and such descriptions are valuable for ongoing medical and public health efforts to understand and accommodate causes of short- and long-term morbidity and mortality associated with COVID-19.

REFERENCES

1. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690.

2. Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268-2270.

3. Koralnik IJ, Tyler KL. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020;88(1):1-11.

4. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol. In press.

5. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. In press.

6. Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. In press.

7. Meppiel E, Peiffer-Smadja N, Maury A, et al. Neurological manifestations associated with COVID-19: a nationwide registry. medRxiv. 2020.

8. Rubinos C, Ruland S. Neurologic Complications in the Intensive Care Unit. Curr Neurol Neurosci Rep. 2016;16(6):57.