Therapeutic Approaches to the Neurologic Manifestations of COVID-19

Abstract:

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality.

In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome.

This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences.

While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

Source: Graham EL, Koralnik IJ, Liotta EM. Therapeutic Approaches to the Neurologic Manifestations of COVID-19. Neurotherapeutics. 2022 Sep;19(5):1435-1466. doi: 10.1007/s13311-022-01267-y. Epub 2022 Jul 21. PMID: 35861926; PMCID: PMC9302225. https://pmc.ncbi.nlm.nih.gov/articles/PMC9302225/ (Full text)

Post-COVID cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction: national prospective study

Abstract:

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls.

Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

Source: Benedict Michael, Greta Wood, Brendan Sargent et al. Post-COVID cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction: national prospective study, 05 January 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3818580/v1] https://www.researchsquare.com/article/rs-3818580/v1 (Full text)

Brain disorders: Impact of mild SARS-CoV-2 may shrink several parts of the brain

Abstract:

Coronavirus (COVID-19) is a highly infectious respiratory infection discovered in Wuhan, China, in December 2019. As a result of the pandemic, several individuals have experienced life-threatening diseases, the loss of loved ones, lockdowns, isolation, an increase in unemployment, and household conflict. Moreover, COVID-19 may cause direct brain injury via encephalopathy. The long-term impacts of this virus on mental health and brain function need to be analysed by researchers in the coming years.

This article aims to describe the prolonged neurological clinical consequences related to brain changes in people with mild COVID-19 infection. When compared to a control group, people those who tested positive for COVID-19 had more brain shrinkage, grey matter shrinkage, and tissue damage. The damage occurs predominantly in areas of the brain that are associated with odour, ambiguity, strokes, reduced attention, headaches, sensory abnormalities, depression, and mental abilities for few months after the first infection. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.

Source: Kumar PR, Shilpa B, Jha RK. Brain Disorders: Impact of Mild SARS-CoV-2 May Shrink Several Parts of the Brain. Neurosci Biobehav Rev. 2023 Mar 31;149:105150. doi: 10.1016/j.neubiorev.2023.105150. Epub ahead of print. PMID: 37004892; PMCID: PMC10063523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10063523/ (Full text)

Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology

Abstract:

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS).

In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften).

Source: Franke C, Berlit P, Prüss H. Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology. Neurol Res Pract. 2022 Jul 18;4(1):28. doi: 10.1186/s42466-022-00191-y. PMID: 35843984; PMCID: PMC9288923. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288923/ (Full text)

Neuro-COVID-19

Abstract:

Neuromuscular manifestations of new coronavirus disease 2019 (COVID-19) infection are frequent, and include dizziness, headache, myopathy, and olfactory and gustatory disturbances. Patients with acute central nervous system disorders, such as delirium, impaired consciousness, stroke and convulsive seizures, have a high mortality rate.

The encephalitis/encephalopathy that causes consciousness disturbance and seizures can be classified into three conditions, including direct infection with the SARS-CoV-2 virus, encephalopathy caused by central nervous system damage secondary to systemic hypercytokinemia (cytokine storm) and autoimmune-mediated encephalitis that occurs after infection.

The sequelae, called post-acute COVID-19 syndrome or long COVID, include neuromuscular manifestations, such as anxiety, depression, sleep disturbance, muscle weakness, brain fog and cognitive impairment. It is desirable to establish diagnostic criteria and treatment for these symptoms. Vaccine-induced thrombotic thrombocytopenia, Guillain-Barré syndrome, bilateral facial paralysis, encephalitis and opsoclonus-myoclonus syndrome have been reported as adverse reactions after the COVID-19 vaccine, although these are rare.

Source: Shimohata T. Neuro-COVID-19. Clin Exp Neuroimmunol. 2021 Sep 29:10.1111/cen3.12676. doi: 10.1111/cen3.12676. Epub ahead of print. PMID: 34899999; PMCID: PMC8652810.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652810/ (Full text)

Severe stealth virus encephalopathy following chronic-fatigue-syndrome-like illness: clinical and histopathological features

Abstract:

The clinical histories and brain biopsy findings of 3 patients with severe stealth virus encephalopathy are reviewed. The patients initially developed symptoms consistent with a chronic fatigue syndrome. One patient has remained in a vegetative state for several years, while the other 2 patients have shown significant, although incomplete, recovery.

Histological and electron-microscopic studies revealed vacuolated cells with distorted nuclei and various cytoplasmic inclusions suggestive of incomplete viral expression. There was no significant inflammatory response. Viral cultures provided further evidence of stealth viral infections occurring in these patients.

 

Source: Martin WJ. Severe stealth virus encephalopathy following chronic-fatigue-syndrome-like illness: clinical and histopathological features. Pathobiology. 1996;64(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/8856789

 

Chronic fatigue syndrome (myalgic encephalopathy)

Abstract:

Chronic fatigue syndrome is associated with many misconceptions. In this review, we attempt to summarize various pathogenic hypotheses for this disease and discuss new lines of insight into causes and treatments of this baffling and most frustrating condition.

 

Source: Plioplys S, Plioplys AV. Chronic fatigue syndrome (myalgic encephalopathy). South Med J. 1995 Oct;88(10):993-1000. http://www.ncbi.nlm.nih.gov/pubmed/7481975

Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome

Abstract:

A simian cytomegalovirus-related stealth virus, isolated from a patient with the chronic fatigue syndrome, induced an acute neurological illness when inoculated into cats. Histological examination of brain tissue showed foci of cells with cytoplasmic vacuolization and an absence of any inflammatory reaction. Electron microscopy confirmed the presence of herpes-like viral particles and viral-like products in the brain of an inoculated animal. These findings support the role of stealth viruses in the pathogenesis of human neurological diseases and provide an animal model to evaluate potential antiviral therapy.

 

Source: Martin WJ, Glass RT. Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome. Pathobiology. 1995;63(3):115-8. http://www.ncbi.nlm.nih.gov/pubmed/8821627