From the Department of Medicine, Division of Translational Medicine and Human Genetics, Center for Cytokine Storm Treatment and Laboratory (D.C.F.), and the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy (C.H.J.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. Address reprint requests to Dr. Fajgenbaum at davidfa@ pennmedicine . upenn . edu or to Dr. June at cjune@ upenn . edu.

Cytokine Storm.

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.

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Nervous system involvement after infection with COVID-19 and other coronaviruses

Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models.

/pdf/neurologic-alterations-due-to-respiratory-virus-infections-39yee5b2hl.pdf

Neurologic Alterations Due to Respiratory Virus Infections

A research committee supported by the Japanese government conducted a nationwide survey on the epidemiology of acute encephalopathy in Japan using a questionnaire. A total of 983 cases reportedly had acute encephalopathy during the past 3 years, 2007-2010. Among the pathogens of the preceding infection, influenza virus was the most common, followed by human herpesvirus-6 (HHV-6) and rotavirus. Among syndromes of acute encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most frequent, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), acute necrotizing encephalopathy (ANE) and hemorrhagic shock and encephalopathy syndrome (HSES). Influenza virus was strongly associated with ANE and MERS, HHV-6 with AESD, and rotavirus with MERS. Mortality was high in ANE and HSES, but was low in AESD, MERS and HHV-6-associated encephalopathy. Neurologic sequelae were common in AESD and ANE, but were absent in MERS.

Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

https://www.cell.com/ajhg/pdf/S0002-9297(08)00630-7.pdf

Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The first group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be beneficial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly affecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be clarified, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0404.2007.00809.x

Acute encephalopathy associated with influenza and other viral infections

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, Sugai K, Sasaki M. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. 
Acta Neurol Scand: 2010: 121: 251–256.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard.

Objective –  We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS).

Materials and methods –  Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire.

Results –  Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRe2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits.

Conclusion –  Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity.

H. Yamanouchi

Papers

Acute encephalopathy associated with influenza and other viral infections

Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.