Acute and Chronic Neurological Disorders in COVID-19

Potential Mechanisms of Disease

Erin F. Balcom; Avindra Nath; Christopher Power

Brain. 2022;144(12):3576-3588.

Literature Search Strategy and Selection Criteria

Studies were selected from the peer-reviewed literature using NCBI and Google Scholar. We searched the databases using the following keywords: central and peripheral nervous systems, COVID-19, SARS-CoV-2, coronavirus, stroke, encephalopathy, neurocognitive impairment, hypercoagulability, encephalitis, neurologic infection, seizure and neuroinflammation. We also reviewed bibliographies of relevant articles. Non-peer-reviewed studies and single case reports were not included as references unless they were highly informative.

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Abbreviations
COVID-19 = coronavirus disease 2019; CVST = cerebral venous sinus thrombosis; ICU = intensive care unit; IVIg = intravenous immunoglobulin

Acknowledgements
The authors thank Brittney Hlavay for creation of figures, Nathalie Arbour for helpful discussions, Rebecca Folkerth, New York University for providing the post-mortem tissue images and Govind Nair for providing the MR images of the brain.

Funding
No specific funding was received towards this work.

Competing interests
The authors report no competing interests.

Abstract and Introduction
Acute Neurological Syndromes
Chronic Neurological Sequelae
Mechanisms of Neurological Disease
Future Perspectives
Literature Search Strategy and Selection Criteria
References

Table 1. Proposed neuropathogenic mechanisms in SARS-CoV-2 infection
Acute neurological syndromes	Proposed mechanisms	References	Proposed therapies
Anosmia/ageusia	Direct infection of olfactory bulb Inflammation of olfactory tract	Meinhardt et al.,¹⁴ Lu et al. ¹⁵	None
Stroke	Hypercoagulability/endothelial damage	Hernández-Fernández et al.,¹⁶ Goshua et al.,¹⁷ Yaghi et al. ¹⁸	Prophylactic anticoagulation is currently under investigation; no clear guidelines to date Successful treatment with thrombolysis and mechanical thrombectomy reported
Encephalitis	Viral neuro-invasion	Nampoothiri et al.,¹⁹ Meinhardt et al. ¹⁴	Favourable responses to systemic corticosteroids, tocilizumab, and PLEX are observed in a subset of cases
	Disrupted blood–brain barrier	Alexopoulos et al. ²⁰
	Autoimmunity	Cao et al.,²¹ Guilmot et al.,²² Pilotto et al. ^23,24
Encephalopathy	Metabolic dysfunction Hypoxia/ischaemia Cerebral microthrombi Cytokine storm (systemic)	Bryce et al.,²⁵ Antony and Haneef,²⁶ Lee et al.,²⁷ Lin et al. ²⁸	Generally supportive, reported success with tocilizumab in case reports
Peripheral neuropathy	Critical illness neuropathy	Cabañes-Martínez et al. ²⁹	Supportive
Peripheral neuropathy	Molecular mimicry (GBS and variants)	Dalakas,³⁰ Temme et al.³¹	Standard therapy: IVIg, PLEX
Myositis	Bioenergetic dysfunction Immune-mediated myositis	Beydon et al.,³² Dalakas,³⁰ Zhang et al. ³³	Favourable responses to steroids, IVIg and tocilizumab reported
Chronic neurological sequelae
Fatigue	Chronic neuroinflammation Neuroendocrine dysfunction Persistent respiratory and cardiac damage	Pandharipande et al.,³⁴ Raman et al.,³⁵ Mongioì et al. ³⁶	None
Cognitive impairment	Chronic neuroinflammation Frontoparietal hypometabolism	Blazhenets et al.,³⁷ Guedj et al. ³⁸	None, demonstrated to improve over months
Depression/altered mood	Stress (isolation, post-traumatic stress)	Rogers et al. ³⁹	No specific therapies proposed or tested for post-COVID-19 patients