Neurologic complications of coronavirus infections

I thank Bandeo et al. for the interest in my article.¹ They correctly point out the importance of stroke as a complication of COVID-19. Since I wrote the editorial, the association of stroke in COVID-19 patients has become much stronger, the pathophysiology seems complex, and treatment guidelines are being developed (Table). Stroke may be the presenting symptom of the infection,¹ and it may occur during the acute phase or days and weeks after the resolution of the acute viral phase. It is abundantly clear that during the acute phase, patients have a hypercoagulable state² and hence can get multiple arterial or venous occlusions that may involve not only the cerebral vasculature but also multiple organ systems. The hypercoagulable state is thought to be related to the acute inflammation and is associated with increased D-dimer levels.² Some patients may present with benign intracranial hypertension, presumably due to venous sinus occlusions.³ The virus is also known to infect endothelial cells, which can lead to an inflammatory response in the vasculature.⁴ This may result in microthrombi or microhemorrhages. Cerebral hemorrhages may also occur due to reperfusion injury. Myocardial injury can occur in these patients due to inflammation of the heart and due to autonomic dysfunction.⁵ This may result in embolic infarcts to the brain. Patients with premorbid conditions such as hypertension and diabetes are at particular risk for stroke. However, in patients who develop strokes after recovery from the acute viral phase, the possibility of an autoimmune phenomenon such as antiphospholipid antibodies should be considered.⁶

Table: Strokes in patients infected with SARS-CoV-2

Presentation

• Venous occlusion
• Multiple arterial occlusions
• Watershed infarcts
• Microvascular thrombosis
• Microhemorrhages

Pathophysiology

• Coagulopathy
• Endothelialitis
• Antiphospholipid antibodies
• Embolism from heart

Risk factors

• Myocarditis
• Known vascular risk factors
• Acute respiratory distress syndrome and multiorgan impairment

Disclosure

The author reports no relevant disclosures. Contact [email protected] for full disclosures.

References

1. Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med 2020;382:e60.
2. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost 2020;120:998–1000.
3. Noro F, Cardoso FM, Marchiori E. COVID-19 and benign intracranial hypertension: A case report. Rev Soc Bras Med Trop 2020;53:e20200325.
4. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417–1418.
5. Kochi AN, Tagliari AP, Forleo GB, Fassini GM, Tondo C. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol 2020;31:1003–1008.
6. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med 2020;382:e38.

We read with interest the editorial by Avindra Nath.¹ Stroke is briefly mentioned and it is not included in the table that summarizes the clinical syndromes associated with SARS-CoV-2 infection.

Ischemic and hemorrhagic strokes have been reported in up to 22% of patients with COVID-19 infection and were associated with a ~2.5 fold increased disease severity.² Moreover, stroke may be the first clinical manifestation of COVID-19 infection even in young patients lacking cardiovascular risk factors.^3,4 It is likely that the frequency of stroke might be even higher considering that acute cerebrovascular disease in critically ill patients may not be diagnosed due to impaired consciousness or confounding systemic illness.³

Several different pathophysiology mechanisms may explain stroke in COVID-19 patients, including renin angiotensin aldosterone dysbalance, vasculopathy, thromboinflammation, and cardiac damage.⁵

Neurologists should have high awareness of COVID-19 infection among patients presenting with stroke. Strategies like early imaging of the lungs as well as prompt screening for SARS-CoV-2 infection and adequate protection of the exposed neurologists attending patients with stroke should be implemented.⁶

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.

References

1. Nath A. Neurologic complications of coronavirus infections. Neurology 2020;94:809–810. doi:10.1212/WNL.0000000000009455.
2. Aggarwal G, Lippi G, Henry BM. Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature. Int J Stroke 2020;15:385–389.
3. Yaghi S, Ishida K, Torres J, et al. SARS2-CoV-2 and stroke in a New York healthcare system. Stroke. 2020 Epub May 20.
4. Khosravani H, Rajendram P, Notario L, Chapman MG, Menon BK. Protected Code Stroke: Hyperacute Stroke Management During the Coronavirus Disease 2019 (COVID-19) Pandemic. Stroke 2020;51:1891–1895.
5. Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020;507:167–173.
6. Leira EC, Russman AN, Biller J, et al. Preserving stroke care during the COVID-19 pandemic: Potential issues and solutions. Neurology 2020 Epub May 8.

We read with interest the call to action by Nath.¹ As clinicians and researchers focus on the primary task of maximizing survival from serious COVID-19 infection, we echo the need to pro-actively anticipate morbidities that survivors may encounter.

Serious COVID-19 infection elicits a robust systemic inflammatory response.² Clinical reports thus far highlight multiple sensory system vulnerabilities.³ The ear may also be a target, via direct middle ear connection with membranes lining the nasopharynx and by involvement of inner ear sensory/neural structures as demonstrated for other systemic infections.^2–6

Aggressive treatment of COVID-19 includes medications that individually carry some risk of inner ear toxicity.⁵ This risk could be heightened when medications are combined and delivered in the setting of an ICU.^2,6

The impact and costs of chronic hearing or vestibular dysfunction are well-documented.⁷ Patient reports of diminished hearing, tinnitus, vertigo, or other ear symptoms during or following COVID-19 infection and its treatment will be of interest.

Clinicians can assist by capturing relevant information during systems review and physical examination. If theoretical risks translate to clinical observations, these data could help prioritize public healthcare and research efforts and optimize patient outcomes.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.

References

1.  Nath A. Neurologic complications of coronavirus infections. Neurology 2020 Epub Mar 30.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
3. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol 2020 Epub Apr 6.
4. Cohen BE, Durstenfeld A, Roehm PC. Viral causes of hearing loss: a review for hearing health professionals. Trends Hear 2014;18.
5. Bortoli R, Santiago M. Chloroquine ototoxicity. Clin Rheumatol 2007;26:1809–1810.
6. Koo JW, Quintanilla-Dieck L, Jiang M, et al. Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med 2015;7:298ra118.
7. Mohr PE, Feldman JJ, Dunbar JL, et al. The societal costs of severe to profound hearing loss in the United States. Int J Technol Assess Health Care 2000;16:1120–1135.

I read the editorial by Dr. Nath with interest.¹ One aspect of Central Nervous System (CNS) involvement in SARS-CoV2 infection that has attracted little interest so far is the medium or long-term consequences on patients with neurodegenerative diseases (NDD). It is known that chronic neuroinflammation has been associated with the neuropathophysiology of some NDDs such as multiple sclerosis, Parkinson disease, Alzheimer disease (AD), and others.² In the case of AD, in presence of proinflammatory cytokines/chemokines, the microglia loses ability to phagocytize the Aβ protein, favoring the pathogenic deposits.³ Similar evidence exists in other NDD.⁴ The cytokine storm of SARS-CoV2 infection involves the activation of a neuroinflammatory cascade similar to that described in NDD.⁵ Furthermore, the possibility that this molecular movement may be persistent over time after acute infection is eliminated, in a similar way to what occurs in the so-called "Persistent Inflammation-immunosuppression and Catabolism Syndrome."⁵ Finally, we do not know whether SARS-CoV2 may have the ability to remain latent in the CNS in a similar way as other coronaviruses do,⁶ increasing the possibility of sustained neuroinflammation. The repercussion on the population vulnerable to NDD is unknown but will force us to be attentive to the future of our patients.

Disclosures

The author reports no relevant disclosures. Contact [email protected] for full disclosures.

References

1. Nath A. Neurologic complications of coronavirus infections. Neurology 2020 Epub Mar 30.
2. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009;4:47.
3. Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 2005;25:8240–8249.
4. McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988;38:1285–1291.
5. Hawkins RB, Raymond SL, Stortz JA, et al. Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome. Front Immunol 2018;9:1511.
6. Jacomy H, Fragoso G, Almazan G, Mushynsi WE, Talbot PJ. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology 2006;349:335–346.

I read Dr. Nath’s editorial with interest.¹ The COVID-19 pandemic has pushed scientists to investigate if this new disease can affect the central nervous system (CNS). The most challenging symptoms of COVID-19 are related to respiratory distress, and most patients admitted in intensive care units cannot breathe on their own. Therefore, a crucial question is if respiratory distress can be partially explained by the CNS infection.²

SARS-CoV-2 is a beta-coronavirus that shares high similarities with SARS-CoV. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Those coronaviruses have been able to invade the brainstem via a synapse‐connected route to the medullary respiratory center, where the infected regions included the nucleus of the solitary tract and nucleus ambiguous. The vagal afferent nerves from receptors in the lung communicate with the medulla and pons respiratory control centers to coordinate inspiration and expiration. This suggests that neuroinvasion of SARS‐CoV‐2 might play a role in the acute respiratory failure of Covid-19.^3–5

Therefore, acute respiratory distress in COVID-19 can be partially explained by brainstem dysfunction, suggesting the needs of more specific and aggressive treatments with the direct participation of neurologists and neurointensivists.

Disclosure

The author reports no relevant disclosures. Contact [email protected] for full disclosures.

References

1. Nath A. Neurologic complications of coronavirus infections. Neurology 2020 Epub Mar 30.
2. Conde G, Quintana Pájaro LD, Quintero Marzola ID, Ramos Villega Y, Mascote Salazarb LT.
   Neurotropism of SARS-CoV 2: Mechanisms and manifestations. J Neurol Sci 2020 Epub Apr 8.
3. Li Z, Huang Y, Guo X. The brain, another potential target organ, needs early protection from SARS-CoV-2 neuroinvasion. Sci China Life Sci 2020 Epub Mar 31.
4. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis 2020 Epub Mar 16.
5. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020 Epub Feb 27.

Dr Nath’s timely editorial¹ lists the neurologic complications of coronavirus infections. On behalf of co-authors, I highlight the 5 patients with large artery stroke in the 2003 Severe Acute Respiratory syndrome (SARS) outbreak in Singapore, arising from SARS-CoV1 virus infection.² Of 206 patients, 48 required intensive care and 32 died. Four of the 5 patients with stroke were critically ill and 3 died. The strokes were deemed thromboembolic.  At autopsy, 1 patient had occipital lobe infarction, sterile vegetations in multiple valves, deep venous thrombosis, and pulmonary embolism; this prompted low molecular weight heparin (LMWH) use in subsequent critically ill SARS patients. Nevertheless, a significant number of patients suffered venous thromboembolism in spite of adequate treatment with LMWH.³ Three patients received intravenous immunoglobulin (IVIg) empirically, which might have contributed to stroke. The induction of hfgl2 prothrombinase gene by SARS-CoV1 in experiments raised the possibility of a direct prothrombotic effect of that coronavirus.⁴ Only 8 patients underwent autopsy; therefore, more strokes may have gone undiagnosed. It is easy to miss stroke in critically ill patients who are heavily sedated and paralyzed. With increasing anecdotal reports (https://journals.lww.com/neurotodayonline), and the use of IVIg in desperately ill COVID-19 patients,⁵ we reiterate vigilance against strokes and thrombotic complications in critically-ill corona virus infected patients.

Disclosure

The author reports no relevant disclosures. Contact [email protected] for full disclosures.

References

1. Nath A. Neurologic complications of coronavirus infections. Neurology 2020 Epub Mar 30.
2. Umapathi T, Kor AC, Venketasubramanian N, et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol 2004;251:1227–31.
3. Lew TW, Kwek TK, Tai D, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003;290:374–80.
4. Meifang Han, Weiming Yan, Yuancheng Huang, et al. The nucleocapsid protein of SARS-CoV induces transcription of hfgl2 prothrombinase gene dependent on C/EBP alpha. J Biochem 2008;144:51–62.
5. Cao W, Liu X, Bai T, et al. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with Coronavirus Disease 2019. Open Forum Infectious Diseases 2020;7;1-6.