Mechanisms of Neurological Disorders in COVID-19

Abstract and Introduction

Abstract

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection and is associated with both acute and chronic disorders affecting the nervous system. Acute neurological disorders affecting patients with COVID-19 range widely from anosmia, stroke, encephalopathy/encephalitis, and seizures to Guillain–Barré syndrome. Chronic neurological sequelae are less well defined although exercise intolerance, dysautonomia, pain, as well as neurocognitive and psychiatric dysfunctions are commonly reported. Molecular analyses of CSF and neuropathological studies highlight both vascular and immunologic perturbations. Low levels of viral RNA have been detected in the brains of few acutely ill individuals. Potential pathogenic mechanisms in the acute phase include coagulopathies with associated cerebral hypoxic-ischaemic injury, blood–brain barrier abnormalities with endotheliopathy and possibly viral neuroinvasion accompanied by neuro-immune responses. Established diagnostic tools are limited by a lack of clearly defined COVID-19 specific neurological syndromes. Future interventions will require delineation of specific neurological syndromes, diagnostic algorithm development and uncovering the underlying disease mechanisms that will guide effective therapies.

Introduction

Since its discovery in Wuhan, China in late 2019, coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 3 million deaths (https://covid19.who.int/) and placed unprecedented pressure on social, economic and health care systems worldwide.

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
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

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

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

Acute and Chronic Neurological Disorders in COVID-19

Potential Mechanisms of Disease

Abstract and Introduction

Abstract

Introduction

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Acute and Chronic Neurological Disorders in COVID-19

Potential Mechanisms of Disease

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

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