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Featured Clinical Reviews

September 22/29, 2020

Neurology and COVID-19

Author Affiliations
  • 1Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco
  • 2Editor, JAMA Neurology
  • 3Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine, New York, New York
  • 4Deputy Editor, JAMA Neurology
JAMA. 2020;324(12):1139-1140. doi:10.1001/jama.2020.14254

In the early days of the coronavirus disease 2019 (COVID-19) pandemic, involvement by neurologists seemed unnecessary. The virus was thought to lead to a respiratory illness, largely sparing the brain and the rest of the nervous system. However, early reports from large outbreaks in China quickly changed this view. A study of more than 200 patients hospitalized in 3 COVID-19–focused hospitals in Wuhan demonstrated that more than one-third experienced a variety of neurologic manifestations, including altered mental status and acute cerebrovascular diseases, most commonly in those with severe respiratory illness.1 These findings quickly changed the perspective of neurologists worldwide and focused efforts toward both understanding the mechanisms responsible for this neurologic involvement and devising systems of care to identify and effectively treat these increasingly recognized complications.

Multiple studies have demonstrated that patients with COVID-19 may develop ischemic stroke, although the exact frequency and risk factors remain unclear. While some reports have described a small number of patients with mild forms of the virus, most cases occur in those who are otherwise moderately or severely ill. Systemic illness alone does not seem to explain this association; in one study, the risk of ischemic stroke in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (n = 31 patients) was higher than in patients with seasonal influenza (n = 3 patients) (1.6% vs 0.2%; odds ratio, 7.6; 95% CI, 2.3-25.2).2 Mechanisms of stroke in COVID-19 are likely numerous. The hypercoagulability that accompanies severe forms of the disease is likely a major driver, as are coexisting cardiac complications that lead to central embolic sources.

Management of patients with COVID-19 and stroke remains an area in need of further investigation. Hospital protocols that screen for and quickly recognize stroke are complicated by coexisting respiratory and other complications in these patients, which may require deep sedation in those who are critically ill, obscuring recognition of neurologic changes. Stroke networks, designed to rapidly triage patients to centers where acute stroke treatments including thrombectomy can be rapidly performed, have been disrupted by fractured transfer protocols in hospital systems stretched to the limit at the height of the pandemic. Secondary prevention strategies including antithrombotic medications may need to be modified in patients who increasingly present with both clotting and hemorrhagic complications.

Despite the increased recognition of stroke as a complication of COVID-19, stroke hospitalizations have decreased substantially in the United States and in other countries during the pandemic, as demonstrated by multiple regional reports and an analysis of a national radiology data set of computed tomography perfusion software use.3 This decline in patients presenting with stroke, which as yet has no clear explanation, has accompanied an overall decrease in emergency department visits nationwide in the US and likely represents, in part, patients not seeking care for acute neurologic symptoms, perhaps driven by concern about contracting infection during interactions with the health care system. The effect of this delayed cerebrovascular care is difficult to quantify, but given substantial improvement in the management of acute stroke, it likely will leave a lasting effect on health that neurologists will need to manage for years to come.

A nonspecific confusional state has increasingly been described in hospitalized patients with COVID-19, especially among older patients and those with severe disease. These patients share common risk factors for hospital-acquired delirium, and these cognitive complications are likely underrecognized in the setting of critical illness. While the etiology of this encephalopathy is probably multifactorial, the possibility of long-term cognitive effects will need to be addressed as with other causes of delirium, potentially leading to a major public health issue long after the pandemic has ended. In rare case reports, some of these patients have been diagnosed as having encephalitis, either infectious or postinfectious in etiology. However, in most patients who have undergone intensive investigation, spinal fluid analysis has not demonstrated inflammation, and polymerase chain reaction has not identified SARS-CoV-2 viral DNA in cerebrospinal fluid. Most reports of brain autopsy have not shown a robust inflammatory or viral infiltrate in cases of COVID-19, but rather, mainly signs of the influence of systemic hypoxia as well as occasional endothelial dysfunction and microthrombi.4

Neurologic complications have not been limited to the central nervous system (CNS). Like other SARS viruses, reports of SARS-CoV-2 neuromuscular complications have emerged, including cases of presumably postinfectious Guillain-Barré syndrome and a muscle disorder characterized by myalgias and elevated creatine kinase levels in serum.1 While less common than CNS manifestations, peripheral nervous system involvement is more likely to be underreported, requiring further studies of patients using electrophysiology as well as neuropathology of nerve and muscle to determine the true incidence and characteristics of these manifestations.

Many crucial questions still remain to be answered in these early stages of understanding the neurology of COVID-19. Perhaps most important, discerning the extent and frequency of direct viral involvement of the nervous system will have wide-ranging implications on treatment approaches as well as prediction of any long-lasting effects of the illness. Currently, it is thought that most neurologic complications are due to systemic effects of the disorder, including cytokine release, immune-mediated inflammatory syndromes, and hypercoagulability; however, if a substantial proportion of patients have active virus in the CNS, treatments of these neurologic conditions will need to be designed with good CNS penetrance in mind.

There is reason to suspect that CNS viral involvement may potentially occur. The well-described loss of smell reported by many patients with SARS-CoV-2 infection likely represents direct viral involvement of the nasal epithelium, a structure on the “doorstep” of the CNS. A report of involvement of the olfactory regions of the brain in a patient with anosmia and COVID-19 raises the possibility that the virus can directly involve the brain in some patients.5 Viral invasion could occur through entry at the level of the olfactory nerve but also could take place via the vascular endothelium, by transsynaptic transfer across infected neurons, or by migration of white blood cells across the blood-brain barrier.6 Additional neuropathological studies and novel approaches to identifying the virus in cerebrospinal fluid in vivo will be essential to further understanding mechanisms driving these neurologic manifestations as well as facilitating their early detection. Based on the rarity of encephalitic presentations and limited autopsy data reported thus far, it is hoped that direct viral invasion of the CNS will remain a rare feature of this disease.

While most studies to date have focused on modest-sized cohorts of COVID-19 patients with neurologic disorders, more comprehensive epidemiological studies are required in large populations to accurately quantify the incidence of these complications, especially because a preponderance of case reports and small case series have dominated dissemination to the public via the popular press. Designing longitudinal studies to follow up patients who have recovered from mild and severe forms of the illness will allow for better understanding of the long-term consequences of neurologic involvement. Delayed neuropsychological testing and advanced neuroimaging is needed to more fully investigate the mild to moderate cognitive impairment that has anecdotally emerged among some patients who have recovered from COVID-19.

As important as these questions of biology are to the understanding of COVID-19, the pandemic has focused neurologists on designing effective systems of care for patients with various neurologic disorders. Patients with multiple sclerosis and others with inflammatory neurologic conditions are traditionally treated with immunosuppressive medications. These individuals are likely at higher risk of more severe COVID-19 illness, and the neurologic community has educated these patients regarding continued treatment of their underlying illness while utilizing unique care delivery models including teleneurology to ensure that they are still receiving the necessary safe, longitudinal care they require.7

The pandemic has also once again made neurologists keenly aware of striking disparities of care in the field. Well-established differences in the rates and severity of conditions such as stroke, epilepsy, and dementia among patients with varied socioeconomic and ethnic backgrounds have been compounded by a pandemic that disproportionally affects many of these same groups. Neurologists are challenged more than ever to directly address these disparities to ensure the provision of equitable and outstanding care for all persons with diseases of the nervous system, regardless of their background.

The COVID-19 pandemic has placed neurologists squarely in the middle of a health care system that has at times been challenged to provide care for large numbers of patients with this emerging disease. While there are perhaps more neurologic questions than answers at this stage, the focus of academic neurologists and those in community practice needs to remain on rapidly and effectively understanding the mechanisms, diagnosis, and treatment of COVID-19–related neurologic syndromes during this generational health care crisis.

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Article Information

Corresponding Author: S. Andrew Josephson, MD, UCSF Department of Neurology, 505 Parnassus Ave, Box 0114, San Francisco, CA 94143 (andrew.josephson@ucsf.edu).

Conflict of Interest Disclosures: Dr Josephson reported serving as associate editor for Continuum Audio. Dr Kamel reported serving as co–principal investigator for the National Institutes of Health–funded ARCADIA trial (NINDS U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics, serving as a steering committee member for Medtronic’s Stroke AF trial (uncompensated), serving on an end-point adjudication committee for a trial of empagliflozin for Boehringer Ingelheim, and having served on an advisory board for Roivant Sciences related to factor XI inhibition.

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. doi:10.1001/jamaneurol.2020.1127PubMedGoogle ScholarCrossref
Merkler  AE, Parikh  NS, Mir  S,  et al.  Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza.   JAMA Neurol. Published online July 2, 2020. doi:10.1001/jamaneurol.2020.2730PubMedGoogle Scholar
Kansagra  AP, Goyal  MS, Hamilton  S, Albers  GW.  Collateral effect of Covid-19 on stroke evaluation in the United States.   N Engl J Med. 2020;383(4):400-401. doi:10.1056/NEJMc2014816PubMedGoogle ScholarCrossref
Solomon  IH, Normandin  E, Bhattacharyya  S,  et al.  Neuropathological features of Covid-19.   N Engl J Med. Published online June 12, 2020. doi:10.1056/NEJMc2019373PubMedGoogle Scholar
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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. 2020;77(8):1018-1027. doi:10.1001/jamaneurol.2020.2065PubMedGoogle ScholarCrossref
Louapre  C, Collongues  N, Stankoff  B,  et al; Covisep Investigators.  Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis.   JAMA Neurol. Published online June 26, 2020. doi:10.1001/jamaneurol.2020.2581PubMedGoogle Scholar
2 Comments for this article
Seizures and Epilepsy Care
Lecio Figueira, MD, PhD | University of Sao Paulo
This Viewpoint by Josephson and Kamel (1) reflects a lot of what we are living in Brazil during COVID-19 pandemic.

Our hospital, a university tertiary care center, had an entire building dedicated to COVID with 900 beds, including 300 Intensive Care Units beds.

We had a dedicated neurology inpatient consultation service and experienced an increased number of neurological consultations.

Most frequently, evaluations were for altered level of consciousness, psychomotor agitation, and weakness. Encephalopathy (44.4%) and stroke (12.3%) were the most common final diagnosis (2).

Seizures were the third most common diagnosis, representing 9% of
the cases (half acute, half with previous diagnosis of epilepsy). Interestingly seizures were not mentioned as an important issue in the Viewpoint. Persons with epilepsy (PWE) without seizure worsening were a frequent reason for neurological consultation regarding medication adjustments and interactions.

Outpatient clinical care for PWE during the COVID-19 pandemic is another huge challenge in Brazil, a limited resource country. Delivering appropriate care for PWEs is difficult, as many patients lack appropriate access to the health system and a continuous medication supply.

In recent months we used telephone contacts and extension of prescription duration to ensure access to medications. Also, we kept the outpatient clinic open for patients we could not reach by telephone, or those with seizure worsening, adverse effects, or mood disorders. These strategies had good results, and few patients required hospitalization.

Telemedicine emerged as an important resource in the care of neurologic patients and probably will transform neurological care (3). It’s use for PWE has been widely recommended in the pandemic.

There’s good evidence showing that management of epilepsy remains largely clinical. Physical examination and complementary investigation has little impact (4). These findings make telemedicine even more relevant and attractive in the treatment of PWE.

However, German patients responded in an audit that they appreciate the medical services onsite and considered telemedicine as an add-on service (5).

In our hospital, telemedicine was not available prior to the pandemic and its implementation was difficult due to limited resources and patients’ abilities to perform a remote encounter. After these months we learned a lot and got some lessons about inpatient and outpatient care. Changes will have to be done in order to provide better care of our patients in this new reality.


1 - Josephson SA, Kamel H. Neurology and COVID-19. JAMA. 2020;324(12):1139–1140. doi:10.1001/jama.2020.14254

2 - Studart-Neto A, Guedes BF, De Luca E Tuma R, Camelo Filho AE, Kubota GT, Iepsen BD, et al. Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital. Arq Neuro-Psiquiatr. 2020 Jul. https://doi.org/10.1590/0004-282X20200089

3 - Bloem BR, Dorsey ER, Okun MS. The Coronavirus Disease 2019 Crisis as Catalyst for Telemedicine for Chronic Neurological Disorders. JAMA Neurol. 2020;77(8):927–928. doi:10.1001/jamaneurol.2020.1452

4 - Angus-Leppan H. Diagnosing epilepsy in neurology clinics: a prospective study. Seizure. 2008 Jul;17(5):431-6. doi: 10.1016/j.seizure.2007.12.010.

5 - von Wrede R, Moskau-Hartmann S, Baumgartner T, Helmstaedter C, Surges R. Counseling of people with epilepsy via telemedicine: Experiences at a German tertiary epilepsy center during the COVID-19 pandemic. Epilepsy Behav. 2020 Aug 12;112:107298. doi: 10.1016/j.yebeh.2020.107298.
CONFLICT OF INTEREST: Speaker for UCB, Livanova, United Medical
Direct virus invasion is an important pathogenic factor in COVID-19
Calixto Machado, MD, PhD, FAAN | Institute of Neurology and Neurosurgery, Havana, Cuba
Josephson and Kamel touched a key issue about how SARS-CoV-2 attacks the central nervous system (CNS) (1).

Most authors consider that the systemic expression of this disease, such as the cytokine storm, immune-mediated inflammatory syndromes, and hypercoagulability, are responsible for the majority of neurologic complications. Nonetheless, the direct invasion of the virus to the CNS is an important contributing factor (1,2). Neurotropism is a common feature of coronaviruses. SARS-CoV-2 infects the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, cranial nerves, and finally reaching the brainstem and other brain structures. Viral invasion could also
take place via the vascular endothelium, by transsynaptic transfer across infected neurons, or by migration of white blood cells across the blood-brain barrier. Nerve dissemination is possible by the polarization of neurons, giving them the skill to receive and transfer information though neural pathways, by trans-synaptic spread, retrograde or antegrade, facilitated by proteins called dinein and kinesin, which can be targets of viruses. Experimental models have demonstrated that ablation of the olfactory nerve limits its neurotropic capacities in mice. Other possible routes of SARS-CoV-2 infection have been proposed, like viral invasion via retrograde routing from the lungs through the vagal nerve to the cardiorespiratory center in the brainstem, and viral invasion through the bloodstream. Machado recently discussed that ARDS, refractory to treatments, might partially be explained by CNS invasion of SARS-Cov-2 invasion (2).

Bulfamante et al. described ultrastructural autopsy findings studying the olfactory nerve, the gyrus rectus, and the brainstem at the level of the medulla oblongata, and they remarkably observed numerous viral particles referable to SARS-Cov-2 invasion. At the medulla oblongata these authors found asymmetrical axonal swelling and disruption of the myelin sheath, and viral particles with size suspicious for a viral particle were also found in the periaxonal matrix near the outer surface of a myelin sheath (3).

Matschke et al. reported that SARS-CoV-2 RNA was detected by qRT-PCR in cryopreserved frontal lobe tissue from nine (39%) of 23 patients with available samples, and in FFPE medulla oblongata tissue from four (50%) of eight patients with available samples. In total, SARS-CoV-2 was found in the brain tissues of 13 (48%) of 27 patients who had at least one available sample (4).

Hence, I conclude that although there are other mechanisms involved in the SARS-CoV-2 infection of the brain, the direct virus invasion should be considered an important pathogenic factor (2).

1. Josephson SA, Kamel H. Neurology and COVID-19. JAMA. 2020;324(12):1139-1140.
2. Machado C. Severe Covid-19 cases: Is respiratory distress partially explained by central nervous system involvement? . Medic Review. 2020;22(2):38-41.
3. Bulfamante G, Chiumello D, Canevini MP, et al. First ultrastructural autoptic findings of SARS -Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol. 2020;86(6):678-679.
4. Matschke J, Lutgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19(11):919-929.