This page collects key resources on COVID-19 from across the scientific literature and other learning resources. All articles and resources are freely available.

Prof. Pratibha Singhi on COVID-19 and CNS involvement in children for the FLICNA Live Talk Series

Kate Oyieke, Mohamed Oshi, Jo Wilmshurst
Red Cross War Memorial Children’s Hospital, Cape Town, South Africa

Respiratory diseases caused by viral agents are one of the most critical problems in public health, as every year they are responsible for high rates of morbidity and mortality, mainly of young children, the elderly and immunocompromised individuals [1-3]. Viral respiratory pathogens have come to the fore as a major cause for pandemics and therefore a better understanding of their disease spectrum is of great public health significance [4, 5]. The current challenges (in case definition, symptom profiling, estimation of morbidity burden, surveillance) being experienced worldwide as a result of the COVID -19 pandemic is evidence of the need to gain a better understanding of the underlying mechanisms of disease and to fully characterise the disease profile in order to improve our responses and ultimately improve outcomes. In view of the emerging reports of neurologic involvement in the context of COVID -19, a better understanding about the characteristics and mechanisms involved in the neurological manifestations of coronavirus and specifically SARS COV-2 is necessary. This journal watch outlines the available knowledge on the neurologic complications of SARS COV-2.

This article will review literature on:

• Neurologic manifestations of coronavirus infections in general
• Hypothesised routes of CNS invasion by coronaviruses using mouse models
• Hypothesised routes of CNS invasion in humans by coronaviruses and specifically SARS-COV-2
• Current studies and reports describing neurologic manifestations of COVID – 19 disease in humans

Neurologic manifestations of coronavirus infections in general (what has been described prior to COVID 19)

Coronaviruses are a group of viruses that belong to the Coronaviridae family and the Nidovirales order. [6,7]. They are responsible for a wide range of respiratory and enteric diseases in several hosts, such as rodents, cats, pigs and humans [8]. There are several pathogenic Human CoV (HCoV), among which are included HCoV-OC43, HCoV-229E, Middle East respiratory syndrome CoV (MERS-CoV) and severe acute respiratory syndrome CoV (SARS-CoV), all of them with their respective different genotypes [9 – 11]. Non-structural proteins which occur with coronavirus are the leading cause of host immune system modulation and they also play a role in the replication of the genetic material of the virus [12]. Following viral entry the virus can replicate its RNA and translate it into proteins. [13, 14] Among the cells that are permissive to murine coronavirus infection are macrophages, microglia and astrocytes [14, 15].

Coronavirus presence in human CNS-related samples date back as early as 1980, where the first detection of this virus was performed in autopsy of patients with multiple scerosis [17] The prevalence of HCoV-OC43 in multiple sclerosis samples was statistically higher than in control patients, and this was the first report to provide a significant indication of the neurotropic capacity of these respiratory pathogens [20]. The first case of SARS-CoV infection with neurological manifestations was reported in 2003 in a 59-year-old woman with swinging fevers, severe respiratory compromise and seizures [21]. The following year, another case of SARS-CoV infection with detection of genetic material in CSF samples was reported in a 32-year-old woman [22].

In 2004, there was a case report of HCoV-OC43 detection in nasopharyngeal and CSF samples from a child who was subsequently diagnosed with acute disseminated encephalomyelitis [23]. Following this, characterization of the cytokine profile in the CNS induced by SARS-CoV-infection found that both chemokine induced by IFN-γ (CXCL9, a CXC chemokines family member) and IFN-γ-inducible protein 10 (CXCL10) were highly induced in brain samples from a deceased patient [24]. Li et al in 2016 described encephalopathic features of HCoV. From the 183 children hospitalized with suspected acute encephalitis, 22 were positive for HCoV infection, and vomiting, headache and fever were the most recurrent symptoms among them [25].

Hypothesised routes of CNS invasion by coronaviruses using mouse models

The capacity for coronaviridae to invade the CNS after nasal infection is described in mice, particularly for HCoV-OC43.

Replication in the CNS leads to a rapid death by acute encephalitis of infected mice [26]. HCoV exhibits an intrinsic capability to infect neural cells and spread from CNS to the periphery via a transneural route, as has also been seen for MHV [27]. Glial primary cultures of MHV-A59-infected cells showed an increase in the secretion of IL-12 p40, TNF-α, IL-15 and IL-6 compared with a non-neurotropic MHV, suggesting that the infection with a neurotropic virus activates glial cells and induces a pro-inflammatory state [31].

Routes of CNS invasion by coronaviruses in humans and proposed pathophysiologic mechanisms

For the proper functioning of the CNS, it is essential to maintain homeostasis. Both, the blood-brain and the blood-CSF barriers play an important role in protecting the brain of free passage of unwanted molecules, pathogens and cells [32].

Several routes of CNS invasion can be used by viral pathogens, among these are included the hematogenous route—which is the infection of the endothelium or the “Trojan Horse” mechanism—and the peripheral nerves or olfactory sensory neurons [32, 33, 34]. An alternative route for neuroinvasion is the transport through olfactory neurons [34]. This pathway is an excellent mechanism to access CNS for viruses that enter the body intranasally [35]. The olfactory nerve has the peculiarity of being in communication with the nasal epithelium and also with the olfactory bulb, the gateway to the CNS potentially providing a conduit for direct viral seeding and trans-synaptic infiltration [34, 35]. This route is commonly used by respiratory viruses that infect the CNS, and is emerging as a possible chief route for CNS penetration by SARS-COV-2.

The above studies may offer insight into the increasingly recognised phenomenon of anosmia/ hyposmia/ ageusia in the current COVID 19 symptom profile. The capacity of CoV to infect CNS in humans is not well characterized, with their detection in these samples performed mainly by detection of viral RNA, exhibiting persistent infection [20].

Multisystemic cytokine storm

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was first discovered in September 2012 in Saudi Arabia[36,37]. The clinical course of the disease ranges from asymptomatic infection to severe lower respiratory tract illness with multiorgan involvement and death with evidence of a multi systemic inflammatory cytokine storm. The disease can cause pulmonary, renal, hematological, and gastrointestinal complications. Emerging reports from centres in th UK and USA of a paediatric multi systemic inflammatory syndrome (PMIS) being attributed to the current COVID 19 pandemic also suggest the likely possibility that SARS-Cov-2 induces a multi systemic cytokine storm accounting for its varied presentation [38].

Neuronal spread of SARS-COV-2

Recent study claims that the genomic sequence is similar between SARS-CoV and SARS-CoV-2 [39], especially the receptor-binding domains of SARS-CoV is structurally similar to that of SARS-CoV-2 [40]. The virus then latches onto ACE-2 receptors, which are primarily located in the lungs (hence the lung infections we’re seeing with COVID-19), but also in other human cells , including the nervous system and cerebral vessels [41].

Neurology related current basic science reports for COVID-19.

Baig AM1, Khaleeq A1, Ali U2, Syeda H3. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-998. doi: 10.1021/acschemneuro.0c00122. Epub 2020 Mar 13.

Brief summary: This is a basic science review. The authors documented pathophysiology and tissue distribution of angiotensin converting enzyme 2 in the central nervous system and proposed a neurotropic mechanism. The purpose of the article related to COVID 19 targeting the central nervous system , and highlights that pathophysiology is not clear. The authors described the mechanism of how the virus enters the central nervous system but the role of the cribriform plate as an entry route is not clear. The authors focus mainly on the impact that the density of expression of ACE 2 receptors in neurological tissue has on the degree of severity of COVID 19 disease manifestations.

Abstract
The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and has evoked a scare of epic proportion regarding its potential to spread and infect humans worldwide. As we are in the midst of an ongoing pandemic of COVID-19, scientists are struggling to understand how it resembles and differs from the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreak, it has been shown that, similar to SARS-CoV, COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) (a cardio-cerebral vascular protection factor), receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurological tissue and determining the possible contribution of neurological tissue damage to the morbidity and mortality caused by COIVD-19. Here, we investigate the density of the expression levels of ACE2 in the CNS, the host-virus interaction and relate it to the pathogenesis and complications seen in the recent cases resulting from the COVID-19 outbreak. Also, we debate the need for a model for staging COVID-19 based on neurological tissue involvement.

Useful aspects of the report

Further clinical questions are generated such as

• Could the imbalance between ACE 1 and 2 have a role in the pathophysiology of COVID 19?
• Could overstimulation of ACE 2 receptors cause hypercytokinemia?

Study limitations: There are a limited number of references. The authors acknowledged that the available evidence is extrapolated from established physiology reports of the renin angiotensin aldosterone system. The authors did not describe the systematic methods used to search for evidence for this report, the extent to which consensus was reached and by what technique, what specific criteria were used for the selection or specific descriptions on how the body of evidence was evaluated for bias.

Neurologic manifestations in children of COVID – 19 disease during this current pandemic

Neurological complications in COVID-19 infected patients have not been widely reported with very few large studies. At the moment, one large observational study and a few case reports are all that is available with little focus on paediatrics. One of the key common complications in the eldery are encephalopathy – this is referred to as “silent hypoxia” and relates to the insiduous respiratory complications which can be poorly recognised especially in the elderly. Other adult case reports noted complications of Acute Hemorrhagic Necrotizing Encephalopathy , Meningitis/Encephalitis , Miller Fisher Syndrome and polyneuritis cranialis (n=2) and Charcot Marie Tooth disease. The need for more paediatric focused studies has been raised especially with regard to exploring how the neurotrophic mechanisms in COVID-19 relate to neuropyschological outcomes in this group. Overall, as illustrated below, children currently are not being reported with significant neurologic complications directly related to COVID-19 infections. This remains an important area which requires further study. The key resports being generated relate more to approaches to care in the settling of a vulnerable patient and how COVID may de-stablise their management.

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q | display-authors=etal (2020) Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China.JAMA Neurol ():. DOI: 10.1001/jamaneurol.2020.1127 PMID: 32275288.

Brief summary: The paper, a retrospective observational study, looked at 214 adult patients who had tested positive for COVID-19, found that infected people frequently experienced neurological effects in addition to and also independent of respiratory symptoms. Of those in the group, 36% experienced some type of neurological symptom. On the mild end of the spectrum, people commonly experienced the loss of taste and smell. Headache was reported in 13% of the patients, dizziness was observed in about 17%, and muscle inflammation and nerve pain occurred in about 19%. In general, the more severe the infection got, the more frequent and intense the neurological complications (confusion, seizure and stroke). Sometimes these symptoms were present in tandem with respiratory symptoms, such as a cough or fever. But in other instances, people experienced the neurological symptoms alone with no signs of respiratory distress.

Abstract

Objective To study the neurologic manifestations of patients with COVID-19. Design, Setting, and Participants This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. This retrospective, observational study was done at 3 centers (Main District, West Branch, and Tumor Center) of Union Hospital of Huazhong University of Science and Technology (Wuhan, China). These 3 centers are designated hospitals assigned by the government to treat patients with COVID-19. We retrospectively analyzed consecutive patients from January 16, 2020, to February 19, 2020, who had been diagnosed as having COVID-19, according to WHO interim guidance.

A confirmed case of COVID-19 was defined as a positive result on high-throughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of throat swab specimens. Throat swab samples were collected and placed into a collection tube containing preservation solution for the virus. A SARS-CoV-2 infection was confirmed by real-time reverse-transcription polymerase chain reaction assay using a SARS-CoV-2 nucleic acid detection kit according to the manufacturer’s protocol (Shanghai bio-germ Medical Technology Co) We reviewed electronic medical records, nursing records, laboratory findings, and radiologic examinations for all patients with laboratory-confirmed SARS-CoV-2 infection and collected data on age, sex, comorbidities (hypertension, diabetes, cardiac or cerebrovascular disease, malignancy, and chronic kidney disease), typical symptoms from onset to hospital admission (fever, cough, anorexia, diarrhea, throat pain, abdominal pain), nervous system symptoms, laboratory findings, and CT scan (chest and head if available). Subjective symptoms were provided by patients who were conscious, cognitively and mentally normal, and linguistically competent to respond to interview. Any missing or uncertain records were collected and clarified through direct communication with involved patients, health care clinicians, and their families. We defined the degree of severity of COVID-19 (severe vs nonsevere) at the time of admission using the American Thoracic Society guidelines for community-acquired pneumonia. All neurologic manifestations were reviewed and confirmed by 2 trained neurologists. Major disagreement between 2 reviewers was resolved by consultation with a third reviewer. Neurologic manifestations were categorized into 3 categories: central nervous system (CNS) manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system (PNS) manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Impaired consciousness includes the change of consciousness level (somnolence, stupor, and coma) and consciousness content (confusion and delirium). To avoid cross-infection during the outbreak, we had to minimize patients going out for examination. Therefore, the diagnosis of nervous system manifestations mainly depended on the subjective symptoms of patients and the examinations available. Acute cerebrovascular disease includes ischemic stroke and cerebral hemorrhage diagnosed by clinical symptoms and head CT. Seizure is based on the clinical symptoms at the time of presentation. Skeletal muscle injury was defined as when a patient had skeletal muscle pain and elevated serum creatine kinase level greater than 200 U/L (to convert to microkatals per liter, multiply by 0.0167).

Main Outcomes and Measures Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations.

Results Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). Conclusions and Relevance Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

What this paper adds:
Currently, this is the first and largest account of the neurological profile of patients diagnosed with COVID 19 and offers insight into the broad range of neurologic manifestations of the disease and offers opportunity for further study and exploration of neurological manifestations. This paper categorises the neurologic manifestations according to severity in an attempt to describe the burden of neurologic disease in the context of COVID 19. The data was collected from three centres in Wuhan which was the epicentere for the first viral outbreak and therefore serves as a benchmark from which all further studies base their information on.

Limitations: The study largely focusses on adult data so it is difficult to generalise or extrapolate findings to the paediatric population. The study design was retrospective, therefore confounded by limitations in comprehensiveness and consistency of data relating to differential investigations, assessments and reporting of symptoms which may be inaccurate and biased. There is no comparison group to appropriately assess the exposure of the cohort

Li Y, Wang M, Zhou Y, Chang J. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Available at SSRN: https://ssrn.com/abstract=3550025 March 3, 2020.

Brief summary: This paper, a retrospective observational study, looked at cerebrovascular complications as a specific subset of neurologic complications in a cohort of adult patients admitted with COVID 19 at a single centre in Wuhan, China.

Abstract

Background: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19. Therefore, we described the clinical characteristics, laboratory features, treatment, and outcomes of CVD complicating SARS-CoV-2 infection.

Methods: We conducted a single center, retrospective, observational analysis of consecutive COVID-19 patients admitted to Union Hospital, Wuhan, China from 16 January 2020 to 29 February 2020. Demographic and clinical characteristics, laboratory findings, treatments, and clinical outcomes were extracted from electronic medical records and compared between COVID-19 patients with and without new onset of CVD.

Results: Of 221 patients with COVID-19, 11 (5%) developed acute ischemic stroke, 1 (0·5%) cerebral venous sinus thrombosis (CVST), and 1 (0·5%) cerebral hemorrhage. COVID-19 with new onset of CVD were significantly older (71·6 ± 15·7 years vs 52·1 ± 15·3 years; p<0·05), more likely to present with severe COVID-19 (84·6% vs. 39·9%, p<0·01) and were more likely to have cardiovascular risk factors, including hypertension, diabetes, and previous medical history of cerebrovascular disease (all p<0·05). In addition, they were more likely to have increased inflammatory response and hypercoagulable state as reflected in C-reaction protein (51·1 [1·3-127·9] vs 12.1 [0·1-212·0] mg/L, p<0·01) and D-dimer (6.9 [0·3-20·0] vs 0.5 [0·1-20·0] mg/L, p<0·001). Of 11 patients with ischemic stroke, 6 received antiplatelet treatment with Aspirin or Clopidogrel and 3 of them died. The other 5 patients received anticoagulant treatment with Clexane and one of them died. As of Feb 29, 2020, 5 patients with CVD died (38%).

Conclusions: Acute cerebrovascular disease is not uncommon in COVID-19. Our findings suggest that older patients with risk factors are more likely to develop CVD. The development of CVD is an important negative prognostic factor, which require further study to identify optimal management strategy to combat the COVID-19 outbreak.

What this paper adds: This paper illustrates the cerebrovascular complications of COVID 19 and further stratifies the risk of cerebrovascular co-morbidity along the lines of age, presence of other pre existing co-morbidities, severity of COVID 19 illness presentation and inflammatory markers/hypercoagulable states as identifiable risk factors. The authors also attempt to define the presence of cerebrovascular disease as a potential prognostic indicator as evidenced by the pooerer outcomes described in this paper.

Limitations: The study largely focusses on adult data so difficult to generalise or extrapolate findings to the paediatric population. The study design is retrospective which limits the consistency of the data collected from individual patients. There is no comparison group to appropriately assess the exposure of the cohort

Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C | display-authors=etal (2020) Neurologic Features in Severe SARS-CoV-2 Infection.N Engl J Med 382 (23):2268-2270. DOI: 10.1056/NEJMc2008597 PMID: 32294339.In a letter to the editor 

A prospective observational study describing the neurologic features of 58 of 64 consecutive patients admitted acute respiratory distress syndrome (ARDS) due to COVID-19 in two intensive care units (ICUs) in Strasbourg, France, between March 3 and April 3, 2020. Neurologic findings were recorded in 8 of the 58 patients (14%) on admission to the ICU (before treatment) and in 39 patients (67%) when sedation and a neuromuscular blocker were withheld. Agitation was present in 40 patients (69%) and 26 of 40 patients were noted to have confusion. Diffuse corticospinal tract signs were present in 39 patients (67%).

Of the patients who had been discharged at the time of , 15 of 45 (33%) had had a dysexecutive syndrome consisting of inattention, disorientation, or poorly organized movements in response to command. Magnetic resonance imaging (MRI) of the brain on 13 patients identified enhancement in leptomeningeal spaces in 8 patients, and bilateral frontotemporal hypoperfusion in all 11 patients who underwent perfusion imaging. Two asymptomatic patients each had a small acute ischemic stroke. In the 8 patients who underwent electroencephalography, only nonspecific changes were detected.

Cerebrospinal fluid (CSF) from 7 patients showed no cells; 2 patients had oligoclonal bands with an identical electrophoretic pattern in serum, and protein and IgG levels were elevated in 1 patient. RT-PCR assays of the CSF samples were negative for SARS-CoV-2 in all 7 patients. In this consecutive series of patients, ARDS due to SARS-CoV-2 infection was associated with encephalopathy, prominent agitation and confusion, and corticospinal tract signs. The authors noted that the lack of data limits determination of which of these features were due to critical illness–related encephalopathy, cytokines, or the effect or withdrawal of medication, and which features were specific to SARS-CoV-2 infection.

What this paper adds: This is the first prospective study assessing the neurologic manifestations of COVID 19.

Limitations: Data are lacking to determine which of the described neurologic features were due to critical illness–related encephalopathy, secondary cytokine storm, or the effect or withdrawal of medication, and which features were specific to SARS-CoV-2 neuro-tropism. This limitation is acknowledged by the authors. As an observational study, there is inherent lack of randomization and limited ability to draw causal inferences. The study already was limited by selection bias as only critically ill patients with ARDs were selected.

Sun D, Li H, Lu XX, Xiao H, Ren J, Zhang FR | display-authors=etal (2020) Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study.World J Pediatr ():. DOI: 10.1007/s12519-020-00354-4 PMID: 32193831.

Brief summary: This is amongst the few available studies that attempt at providing a clinical profile of COVID 19 infections in the paediatric population. Of the 8 children with severe COVID disease the most common symptom was polypnea (8/8), followed by fever (6/8), cough (6/8), expectoration (4/8), nausea/vomiting (4/8), diarrhea (3/8), fatigue/myalgia (1/8), headache (1/8) and constipation (1/8) and status epilepticus (1/8).

Abstract

BACKGROUND: An outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was first detected in Wuhan, Hubei, China. People of all ages are susceptible to SARS-CoV-2 infection. No information on severe pediatric patients with COVID-19 has been reported. We aimed to describe the clinical features of severe pediatric patients with COVID-19.

METHODS: We included eight severe or critically ill patients with COVID-19 who were treated at the Intensive Care Unit (ICU), Wuhan Children's Hospital from January 24 to February 24. We collected information including demographic data, symptoms, imaging data, laboratory findings, treatments and clinical outcomes of the patients with severe COVID-19.

RESULTS: The onset age of the eight patients ranged from 2 months to 15 years; six were boys. The most common symptoms were polypnea (8/8), followed by fever (6/8) and cough (6/8). Chest imaging showed multiple patch-like shadows in seven patients and ground-glass opacity in six. Laboratory findings revealed normal or increased whole blood counts (7/8), increased C-reactive protein, procalcitonin and lactate dehydrogenase (6/8), and abnormal liver function (4/8). Other findings included decreased CD16 + CD56 (4/8) and Th/Ts*(1/8), increased CD3 (2/8), CD4 (4/8) and CD8 (1/8), IL-6 (2/8), IL-10 (5/8) and IFN-γ (2/8). Treatment modalities were focused on symptomatic and respiratory support. Two critically ill patients underwent invasive mechanical ventilation. Up to February 24, 2020, three patients remained under treatment in ICU, the other five recovered and were discharged home.

CONCLUSIONS: In this series of severe pediatric patients in Wuhan, polypnea was the most common symptom, followed by fever and cough. Common imaging changes included multiple patch-like shadows and ground-glass opacity; and a cytokine storm was found in these patients, which appeared more serious in critically ill patients.

What this article adds: This is a useful case series that allows a real time clinical perspective on the range of complications that children with severe COVID disease may suffer from. From this small cohort the neurological complications appear minor (headache) or secondary to septic shock and multiple organ dysfunction syndrome (MODS) (status epilepticus)

Limitations: This is a small cohort and larger prospective studies are needed.

Executive summary:

The available reports suggest that in theory, SARS-COV-2 can invade the CNS although there is no current evidence that the CNS manifestations described are due to a direct neurotropic effect of the virus rather than mediated by secondary factors. Extrapolation from adult studies reveals a small proportion of affected cases may develop neurological symptoms due to secondary effects of other organ dysfunction, dyselectrolytemia, hypoxia and adverse effects of drugs. There still remains very little paediatric data on the CNS effects of COVID 19. Children currently appear to be very resilient both in general and neurologically with small numbers affected especially in comparison to adult groups.

A subgroup of children with neurological disease can be hypothesized to be more vulnerable is the setting of contracting COVID-19, especially those with

a. neurologic conditions with vulnerable respiratory systems e.g. spinal muscular atrophy, Duchenne muscular dystrophy, cerebral palsy
b. children with neurologic conditions that require immunosuppression e.g. myasthenia gravis, autoimmune encephalitis, acquired demyelinating disorders
c. some children with epilepsy e.g. Dravet syndrome, early onset epileptic encephalopathies

However reports of these patients being specifically affected is not evident to date. Nonetheless helpful recommendations have been put forward for many of these settings and are available on the ICNApedia as well as specialty websites (e.g. ILAE)

Another issue brought to the fore is the effect of the pandemic on our capacity to deliver care to our patients due to worried families staying away from hospitals, medications running out, reliance on telemedicine for assessment of patients, staff redeployments, interuptions in training of neurologists and the overall disruption of clinical services and how this will also adversely affect the management of patients with neurologic conditions.

The extent to which the current COVID 19 pandemic will impact the practice of neurology is uncertain. The predominant limitation of this review pertains to limited available early literature. As the number of COVID-19 cases continues to rise dramatically across the world, we anticipate that the literature will also continue to evolve.  

References

1. Talbot H. K., Falsey A. R. (2010). The diagnosis of viral respiratory disease in older adults. Clin. Infect. Dis. 50, 747–751. 10.1086/650486
2. Tregoning J. S., Schwarze J. (2010). Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin. Microbiol. Rev. 23, 74–98. 10.1128/cmr.00032-09
3. Englund J., Feuchtinger T., Ljungman P. (2011). Viral infections in immunocompromised patients. Biol. Blood Marrow Transplant. 17, S2–S5. 10.1016/j.bbmt.2010.11.008
4. Chan E H, Brewer T F, Madoff L C, Pollack M P, Sonricker A L., and others. 2010. “Global Capacity for Emerging Infectious Disease Detection.” Proceedings of the National Academy of Sciences of the United States of America 107 (50): 21701–6.
5. Charu V, Chowell G, Palacio Mejia L S, Echevarría-Zuno S, Borja-Aburto V H., and others. 2011. “Mortality Burden of the A/H1N1 Pandemic in Mexico: A Comparison of Deaths and Years of Life Lost to Seasonal Influenza.” Clinical Infectious Diseases 53 (10): 985–93.
6. King A. M. Q., Adams M. J., Carstens E. B., Lefkowitz E. J. (Eds). (2012). “Classification and nomenclature of viruses,” in Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses (San Diego: Elsevier; ), 1326–1327. [Google Scholar]
7. King A. M. Q., Lefkowitz E. J., Mushegian A. R., Adams M. J., Dutilh B. E., Gorbalenya A. E., et al. . (2018). Changes to taxonomy and the international code of virus classification and nomenclature ratified by the international committee on taxonomy of viruses (2018). Arch. Virol. 163, 2601–2631. 10.1007/s00705-018-3847-1
8. Desforges M., Le Coupanec A., Stodola J. K., Meessen-Pinard M., Talbot P. J. (2014b). Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis. Virus Res. 194, 145–158. 10.1016/j.virusres.2014.09.011
9. Gaunt E. R., Hardie A., Claas E. C. J., Simmonds P., Templeton K. E. (2010). Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J. Clin. Microbiol. 48, 2940–2947. 10.1128/jcm.00636-10
10. CabeçaT. K., Granato C., Bellei N. (2013). Epidemiological and clinical features of human coronavirus infections among different subsets of patients. Influenza Other Respir. Viruses 7, 1040–1047. 10.1111/irv.12101
11. Matoba Y., Aoki Y., Tanaka S., Yahagi K., Shimotai Y., Matsuzaki Y., et al. . (2015). An outbreak of human coronavirus OC43 during the 2014–2015 influenza season in yamagata, Japan. Jpn. J. Infect. Dis. 68, 442–445. 10.7883/yoken.JJID.2015.292
12. Gorbalenya A. E., Enjuanes L., Ziebuhr J., Snijder E. J. (2006). Nidovirales: evolving the largest RNA virus genome. Virus Res. 117, 17–37. 10.1016/j.virusres.2006.01.017
13. Williams R. K., Jiang G. S., Snyder S. W., Frana M. F., Holmes K. V. (1990). Purification of the 110-kilodalton glycoprotein receptor for mouse hepatitis-virus (MHV)-A59 from mouse-liver and identification of a nonfunctional, homologous protein in MHV-resistant SJL/J mice. J. Virol. 64, 3817–3823.
14. BergmannC. C., Lane T. E., Stohlman S. A. (2006). Coronavirus infection of the central nervous system: host-virus stand-off. Nat. Rev. Microbiol. 4, 121–132. 10.1038/nrmicro1343
15. Jacomy H., Fragoso G., Almazan G., Mushynski W. E., Talbot P. J. (2006). Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology 349, 335–346. 10.1016/j.virol.2006.01.049
16. St-Jean J. R., Desforges M., Almazán F., Jacomy H., Enjuanes L., Talbot P. J. (2006). Recovery of a neurovirulent human coronavirus OC43 from an infectious cDNA clone. J. Virol. 80, 3670–3674. 10.1128/jvi.80.7.3670-3674.2006
17. BurksJ. S., DeVald B. L., Jankovsky L. D., Gerdes J. C. (1980). Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients. Science 209, 933–934. 10.1126/science.7403860
18. Murray R. S., Brown B., Brain D., Cabirac G. F. (1992). Detection of coronavirus RNA and antigen in multiple sclerosis brain. Ann. Neurol. 31, 525–533. 10.1002/ana.410310511
19. Stewart J. N., Mounir S., Talbot P. J. (1992). Human coronavirus gene-expression in the brains of multiple-sclerosis patients. Virology 191, 502–505. 10.1016/0042-6822(92)90220-j
20. Arbour N., Day R., Newcombe J., Talbot P. J. (2000). Neuroinvasion by human respiratory coronaviruses. J. Virol. 74, 8913–8921. 10.1128/jvi.74.19.8913-8921.2000
21. Hung E. C. W., Chim S. S. C., Chan P. K. S., Tong Y. K., Ng E. K. O., Chiu R. W. K., et al. . (2003). Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome. Clin. Chem. 49, 2108–2109. 10.1373/clinchem.2003.025437
22. Lau K.-K., Yu W.-C., Chu C.-M., Lau S.-T., Sheng B., Yuen K. Y. (2004). Possible central nervous system infection by SARS coronavirus. Emerg. Infect. Dis. 10, 342–344. 10.3201/eid1002.030638
23. Yeh E. A., Collins A., Cohen M. E., Duffner P. K., Faden H. (2004). Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics 113, e73–e76. 10.1542/peds.113.1.e73
24. Xu J., Zhong S., Liu J., Li L., Li Y., Wu X., et al. . (2005). Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin. Infect. Dis. 41, 1089–1096. 10.1086/444461
25. Li Y.,Li H., Fan R., Wen B., Zhang J., Cao X., et al. . (2016). Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children. Intervirology 59, 163–169. 10.1159/000453066
26. St-Jean J. R., Jacomy H., Desforges M., Vabret A., Freymuth F., Talbot P. J. (2004). Human respiratory coronavirus oc43: genetic stability and neuroinvasion. J. Virol. 78, 8824–8834. 10.1128/jvi.78.16.8824-8834.2004
27. Perlman S., Evans G., Afifi A. (1990). Effect of olfactory-bulb ablation on spread of a neurotropic coronavirus into the mouse-brain. J. Exp. Med. 172, 1127–1132. 10.1084/jem.172.4.1127
28. Jacomy H., Talbot P. J. (2003). Vacuolating encephalitis in mice infected by human coronavirus OC43. Virology 315, 20–33. 10.1016/s0042-6822(03)00323-4
29. Glass W. G., Subbarao K., Murphy B., Murphy P. M. (2004). Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 173, 4030–4039. 10.4049/jimmunol.173.6.4030
30. Wheeler D. L., Sariol A., Meyerholz D. K., Perlman S. (2018). Microglia are required for protection against lethal coronavirus encephalitis in mice. J. Clin. Invest. 128, 931–943. 10.1172/jci97229
31. Li Y.,Fu L., Gonzales D. M., Lavi E. (2004). Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J. Virol. 78, 3398–3406. 10.1128/jvi.78.7.3398-3406.2004
32. McGavernDB, Kang SS. (2011). Illuminating viral infections in the nervous system. Nat Rev Immunol.11(5):318-29. doi: 10.1038/nri2971.
33. SwansonPA 2nd, McGavern DB.(2015). Viral diseases of the central nervous system.Curr Opin Virol. 2015 Apr;11:44-54. doi: 10.1016/j.coviro.2014.12.009. Epub 2015 Feb 12.
34. Dahm et al.(2016). Neuroinvasion and Inflammation in Viral Central Nervous System Infections. Review Article, open access Article ID 8562805 https://doi.org/10.1155/2016/8562805
35. Koyuncu et al. (2013). Virus infections in the central nervous system. Cell host and microbe. Volume 13, Issue 4, 17 April 2013, Pages 379-393.
36. Hussein Algahtani, Ahmad Subahi, and Bader Shirah . Neurological Complications of Middle East Respiratory Syndrome Coronavirus: A Report of Two Cases and Review of the LiteratureCase Rep Neurol Med. 2016; 2016: 3502683.Published online 2016 Apr 28. doi: 10.1155/2016/3502683
37. Arabi Y.M., Harthi A., Hussein J., et al. Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV) Infection. 2015;43(4):495–501. doi: 10.1007/s15010-015-0720-y.
38. Elisabeth Mahase. (2020). Covid-19: concerns grow over inflammatory syndrome emerging in children. BMJ 2020;369:m1710 doi: 10.1136/bmj.m1710 (Published 28 April 2020)
39. Wen-Bin Yu,Guang-Da Tang, Li Zhang, Richard T. Corlett. (2020). Decoding the evolution and transmissions of the novel pneumonia coronavirus (SARS-CoV-2 / HCoV-19) using whole genomic data[J]. Zoological Research, 41(3): 247-257. doi: 10.24272/j.issn.2095-8137.2020.022
40. Lu et al. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 395, pp. 565-574, 10.1016/S0140-6736(20)30251-8
41. Jian Shang, Yushun Wan, Chuming Luo, Gang Ye, Qibin Geng, Ashley Auerbach, Fang Li(2020). Cell entry mechanisms of SARS-CoV-2. Proceedings of the National Academy of Sciences May 2020, 202003138; DOI: 10.1073/pnas.2003138117