Animal Models of Enterovirus D68 Infection and Disease.

Human enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen that is associated with the development of acute flaccid myelitis (AFM) in children. Currently, there are no approved vaccines or treatments for EV-D68 infection, and there is a paucity of data related to the virus and host-specific factors that predict disease severity and progression to the neurologic syndrome. EV-D68 infection of various animal models has served as an important platform for characterization and comparison of disease pathogenesis between historic and contemporary isolates. Still, there are significant gaps in our knowledge of EV-D68 pathogenesis that constrain the development and evaluation of targeted vaccines and antiviral therapies. Continued refinement and characterization of animal models that faithfully reproduce key elements of EV-D68 infection and disease is essential for ensuring public health preparedness for future EV-D68 outbreaks.

Comparison of acute flaccid myelitis and transverse myelitis in children and evaluation of diagnostic criteria.

BACKGROUND AND PURPOSE: Acute flaccid myelitis (AFM) and transverse myelitis (TM) are serious conditions that may be difficult to differentiate, especially at onset of disease. In this study, we compared clinical features of pediatric AFM and TM and evaluated current diagnostic criteria, aiming to improve early and accurate diagnosis. METHODS: Two cohorts of children with enterovirus D68-associated AFM and clinically diagnosed TM were compared regarding presenting clinical features, additional investigations, and outcome. Current diagnostic criteria for AFM and TM were applied to evaluate their specificity. RESULTS: Children with AFM (n = 21) compared to those with TM (n = 36) were younger (median 3 vs. 10 years), more often had a prodromal illness (100% vs. 39%), predominant proximal weakness (69% vs. 17%), and hyporeflexia (100% vs. 44%), and less often had sensory deficits (0% vs. 81%), bowel and/or bladder dysfunction (12% vs. 69%), and hyperreflexia (0% vs. 44%). On magnetic resonance imaging, brainstem involvement was more common in AFM (74% vs. 21%), whereas supratentorial abnormalities were only seen in TM (0% vs. 40%). When omitting the criterion of a sensory level, 11 of 15 (73%) children with AFM fulfilled the diagnostic criteria for TM. Of children with TM, four of 33 (12%) fulfilled the diagnostic criteria for probable/definite AFM. CONCLUSIONS: Although there is considerable overlap between AFM and TM in children, we found important early differentiating clinical and diagnostic features. Meeting diagnostic criteria for AFM in children with TM and vice versa underlines the importance of thorough clinical examination and early and accurate diagnostic studies.

Acute flaccid myelitis and Guillain-Barré syndrome in children: A comparative study with evaluation of diagnostic criteria.

BACKGROUND AND PURPOSE: Differentiation between acute flaccid myelitis (AFM) and Guillain-Barré syndrome (GBS) can be difficult, particularly in children. Our objective was to improve the diagnostic accuracy by giving recommendations based on a comparison of clinical features and diagnostic criteria in children with AFM or GBS. METHODS: A cohort of 26 children with AFM associated with enterovirus D68 was compared to a cohort of 156 children with GBS. The specificity of the Brighton criteria, used for GBS diagnosis, was evaluated in the AFM cohort and the specificity of the Centers for Disease Control and Prevention (CDC) AFM diagnostic criteria in the GBS cohort. RESULTS: Children with AFM compared to those with GBS had a shorter interval between onset of weakness and nadir (3 vs. 8 days, p < 0.001), more often had asymmetric limb weakness (58% vs. 0%, p < 0.001), and less frequently had sensory deficits (0% vs. 40%, p < 0.001). In AFM, cerebrospinal fluid leukocyte counts were higher, whereas protein concentrations were lower. Spinal cord lesions on magnetic resonance imaging were only found in AFM patients. No GBS case fulfilled CDC criteria for definite AFM. Of the AFM cases, 8% fulfilled the Brighton criteria for GBS, when omitting the criterion of excluding an alternate diagnosis. CONCLUSIONS: Despite the overlap in clinical presentation, we found distinctive early clinical and diagnostic characteristics for differentiating AFM from GBS in children. Diagnostic criteria for AFM and GBS usually perform well, but some AFM cases may fulfill clinical diagnostic criteria for GBS. This underlines the need to perform diagnostic tests early to exclude AFM in children suspected of atypical GBS.

JC Polyomavirus, progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome: a review.

The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.

Cerebrovascular manifestations of herpes simplex virus infection of the central nervous system: a systematic review.

BACKGROUND: Intracerebral hemorrhage and ischemic stroke are increasingly recognized complications of central nervous system (CNS) infection by herpes simplex virus (HSV). AIM OF THE STUDY: To analyze clinical, imaging, and laboratory findings and outcomes of cerebrovascular manifestations of HSV infection. METHODS: Systematic literature review from January 2000 to July 2018. RESULTS: We identified 38 patients (median age 45 years, range 1-73) comprising 27 cases of intracerebral hemorrhage, 10 of ischemic stroke, and 1 with cerebral venous sinus thrombosis. Intracerebral hemorrhage was predominantly (89%) a complication of HSV encephalitis located in the temporal lobe. Hematoma was present on the first brain imaging in 32%, and hematoma evacuation was performed in 30% of these cases. Infarction was frequently multifocal, and at times preceded by hemorrhage (20%). Both a stroke-like presentation and presence of HSV encephalitis in a typical location were rare (25% and 10%, respectively). There was evidence of cerebral vasculitis in 63%, which was exclusively located in large-sized vessels. Overall mortality was 21% for hemorrhage and 0% for infarction. HSV-1 was a major cause of hemorrhagic complications, whereas HSV-2 was the most prevalent agent in the ischemic manifestations. CONCLUSION: We found a distinct pathogenesis, cause, and outcome for HSV-related cerebral hemorrhage and infarction. Vessel disruption within a temporal lobe lesion caused by HSV-1 is the presumed mechanism for hemorrhage, which may potentially have a fatal outcome. Brain ischemia is mostly related to multifocal cerebral large vessel vasculitis associated with HSV-2, where the outcome is more favorable.

Epidemiology and outcomes of acute encephalitis.

PURPOSE OF REVIEW: This review seeks to describe recent advances in the epidemiology, outcomes, and prognostic factors in acute encephalitis. RECENT FINDINGS: Infectious causes continue to account for the largest proportion of encephalitis cases in which a cause is identified, although autoimmune causes are increasingly recognized. Type-A gamma-aminobutyric acid (GABAa) receptor antibodies have been recently identified in encephalitis with refractory seizures, whereas the roles of antibodies to the glycine receptor and dipeptidyl peptidase-like protein 6 have been defined in progressive encephalomyelitis with rigidity and myoclonus. Recent findings in the US cases of encephalomyelitis presenting with acute flaccid paralysis raise the possibility that enterovirus D68, a common respiratory pathogen, may cause central nervous system disease. Mortality from acute encephalitis occurs in about 10% of cases, with a large proportion of survivors suffering from cognitive or physical disability. In addition to delay in institution of appropriate antiviral or immune therapy, several potentially reversible factors associated with poor prognosis have been identified, including cerebral edema, status epilepticus, and thrombocytopenia. SUMMARY: Encephalitis imposes a significant worldwide health burden and is associated with poor outcomes. Supportive treatment and early institution of therapy may improve outcomes. Careful neurocognitive assessment of survivors of encephalitis is needed to better define long-term outcomes.

CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation.

BACKGROUND: Laboratory diagnosis of Lyme neuroborreliosis (LNB) is partly based on the detection of intrathecal Borrelia burgdorferi-specific antibody production (increased antibody index (AI)). However, AI can be negative in patients with early LNB and, conversely, can remain elevated for months after antibiotic treatment. Recent studies suggested that the chemokine CXCL13 in the cerebrospinal fluid (CSF) is a biomarker for active LNB. Also, CSF neopterin-level determination has been used to assess the degree of neuroinflammation in a wide variety of diseases. METHODS: CXCL13 concentrations were analyzed in CSF samples of 366 retrospectively identified individuals. The samples represented pretreatment LNB (38 patients), non-LNB comparison patients, tick-borne encephalitis, central nervous system (CNS) varicella zoster virus infection, CNS herpes simplex virus infection, CNS HHV6 infection, CNS enterovirus infection, and untreated neurosyphilis. The panel included also samples from patients with multiple sclerosis and other neuroinflammatory conditions. Of the LNB patients, 24 posttreatment CSF samples were available for CXCL13 analysis. Neopterin concentrations were determined in a subset of these samples. RESULTS: The CXCL13 concentrations in CSF samples of untreated LNB patients were significantly higher (median, 6,480 pg/ml) than the concentrations in the non-LNB group (median, <7.8 pg/ml), viral CNS infection samples (median, <7.8 pg/ml), or samples from patients with noninfectious neuroinflammatory conditions (median, <7.8 pg/ml). The use of cut-off 415 pg/ml led to a sensitivity of 100% and specificity of 99.7% for the diagnosis of LNB in these samples. CSF CXCL13 median concentrations declined significantly from 16,770 pg/ml before to 109 pg/ml after the treatment.CSF neopterin concentration was significantly higher among the untreated LNB patients than in the non-LNB group. The use of neopterin concentration 10.6 nM as the cut-off led to a sensitivity of 88.6% and a specificity of 65.0% for the diagnosis of LNB. The CSF neopterin concentrations decreased statistically significantly with the treatment. CONCLUSIONS: These results clearly indicate that highly elevated CSF CXCL13 levels are strongly associated with untreated LNB. CXCL13 outperformed neopterin and appears to be an excellent biomarker in differentiating LNB from viral CNS infections and from other neuroinflammatory conditions.

Rehabilitation Outcomes in Children With Acute Flaccid Myelitis From 2014 to 2019: A Multicenter Retrospective Review.

BACKGROUND: Acute flaccid myelitis (AFM) is a childhood illness characterized by sudden-onset weakness impairing function. The primary goal was to compare the motor recovery patterns of patients with AFM who were discharged home or to inpatient rehabilitation. Secondary analyses focused on recovery of respiratory status, nutritional status, and neurogenic bowel and bladder in both cohorts. METHODS: Eleven tertiary care centers in the United States performed a retrospective chart review of children with AFM between January 1, 2014, and October 1, 2019. Data included demographics, treatments, and outcomes on admission, discharge, and follow-up visits. RESULTS: Medical records of 109 children met inclusion criteria; 67 children required inpatient rehabilitation, whereas 42 children were discharged directly home. The median age was 5 years (range 4 months to 17 years), and the median time observed was 417 days (interquartile range = 645 days). Distal upper extremities recovered better than the proximal upper extremities. At acute presentation, children who needed inpatient rehabilitation had significantly higher rates of respiratory support (P < 0.001), nutritional support (P < 0.001), and neurogenic bowel (P = 0.004) and bladder (P = 0.002). At follow-up, those who attended inpatient rehabilitation continued to have higher rates of respiratory support (28% vs 12%, P = 0.043); however, the nutritional status and bowel/bladder function were no longer statistically different. CONCLUSIONS: All children made improvements in strength. Proximal muscles remained weaker than distal muscles in the upper extremities. Children who qualified for inpatient rehabilitation had ongoing respiratory needs at follow-up; however, recovery of nutritional status and bowel/bladder were similar.

Central nervous system infection in a pediatric population in West Java.

Central nervous system (CNS) viral infections are critical causes of morbidity and mortality in children; however, comprehensive data on etiology is lacking in developing countries such as Indonesia. To study the etiology of CNS infections in a pediatric population, 50 children admitted to two hospitals in Bandung, West Java, during 2017-2018 were enrolled in a CNS infection study. Cerebrospinal fluid and serum specimens were tested using molecular, serological, and virus isolation platforms for a number of viral and bacteriological agents. Causal pathogens were identified in 10 out of 50 (20%) and included cytomegalovirus (n = 4), Streptococcus pneumoniae (n = 2), tuberculosis (n = 2), Salmonella serotype Typhi (n = 1) and dengue virus (n = 1). Our study highlights the importance of using a wide range of molecular and serological detection methods to identify CNS pathogens, as well as the challenges of establishing the etiology of CNS infections in pediatric populations of countries with limited laboratory capacity.

Acute Flaccid Myelitis in a Pediatric Patient With Coronavirus Disease 2019.

The etiology of acute flaccid myelitis (AFM) has yet to be determined. Viral link has been suggested, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated AFM has not been reported in children. We describe a three-year-old boy, with AFM associated with coronavirus disease 2019 (COVID-19) infection. In the era of COVID-19 pandemic, patients with AFM should be tested for SARS-CoV-2.

Post-infectious opsoclonus and reversible magnetic resonance imaging changes: a case report and review of the literatures.

PURPOSE: Opsoclonus is a rare neurological disorder in adult. The etiology of opsoclonus includes parainfectious, paraneoplastic, toxic, and metabolic disorders. We reported an old female with post-infectious opsoclonus who had a benign clinical course and reversible brain MRI lesions, and its review of the literature. CASE REPORT: A 67-year-old woman presented with opsoclonus and truncal ataxia for two weeks. The magnetic resonance imaging (MRI) showed the hyperintensity lesions in bilateral medial thalamus, hypothalamus, and tegmentum of pons on Fluid-attenuated inversion recovery (FLAIR) imaging. Investigations of neoplasm and autoimmune disorders showed negative findings. Clinical symptoms subsided in two-week duration and MRI abnormalities also disappeared one month later. CONCLUSION: A benign clinical course and reversible MRI lesions could be found in the patients with postinfectious opsoclonus such as our case. However, detailed investigations and long-term follow-up are needed to exclude paraneoplastic or other systemic and immunological disorders.

[Epidemiology, diagnostics, and treatment of complications after neuroinfections: chronic fatigue syndrome].

Epidemiology information which testify to prevalence syndrome of chronic ustalostti (SV) is resulted in the article, and from some data this diagnosis is covered at more than 20% patients which carried neyroinfection. SV meets more frequent only in age 40-59, thus for women a disease is marked in 4 times more frequent, than for men. Today etiology of disease remains unknown, but the value of genetic, immunological factors, pathogens, neurogenic violations and features of feed is examined. Possibility of infectious etiology SV causes considerable interest of researchers, but at first this syndrome was examined as a sharp viral infection, where the most reliable exciter is consider the virus of Epshteyna-barr. Using of intravenous introduction of globulin for SV carries experimental character and grounded on a hypothesis about immunological or infectious etiology of this disease.

[Acute flaccid myelitis and enterovirus infection: a severe emerging disease]. / Mielitis flácida aguda e infección por enterovirus: una enfermedad grave emergente.

Acute flaccid myelitis (AFM) is a neuroinflammatory disease characterized by acute asymmetric weakness of the limbs associated with lesions of the gray matter of the spinal cord. It mainly affects children and has been increasingly identified since 2014. OBJECTIVE: To describe a severe emerging neurological disease in Chile. CLINICAL CASE: Three children (2 females), previously healthy were in cluded. The age at the onset was between 4 and 6 years. All presented an acute febrile illness associated with upper respiratory symptoms, rapid onset of proximal asymmetric limb weakness, spinal fluid pleocytosis, and enterovirus isolated from nasopharyngeal swab; two patients developed tetraparesis. The MRI of the spinal cord showed T2 hyperintensity of the grey matter. The three patients were admitted to the Pediatric Intensive Care Unit (PICU), and two required mechanical ventilation. No significant improvements were observed after the use of immunomodulatory therapy and plasma ex change. At 12 months of follow-up, one case was quadriplegic and ventilator-dependent; the second died of ventricular arrhythmia in the PICU, and the third one is under rehabilitation with partial recovery. CONCLUSIONS: We report the first cases of this severe emerging neurological disease in our country. In a child with predominantly proximal and asymmetric acute limb paralysis, pediatricians must have a high index of suspicion for AFM. Since it can progress rapidly and lead to respiratory failure, suspected AFM should be considered a medical emergency.

An Overview of Acute Flaccid Myelitis.

Acute Flaccid Myelitis is defined by the presence of Acute Flaccid Paralysis (AFP) and a spinal cord lesion on magnetic resonance imaging that is primarily limited to the grey matter. AFM is a difficult situation to deal with when you have a neurologic illness. According to the Centers for Disease Control and Prevention (CDC), a large number of cases were discovered in the United States in 2014, with 90% of cases occurring in children. Although the exact cause of AFM is unknown, mounting evidence suggests a link between AFM and enterovirus D68 (EV-D68). In 2014, an outbreak of AFM was discovered in the United States. The condition was initially linked to polioviruses; however, it was later found that the viruses were caused by non-polioviruses Enteroviruses D-68 (EV-D68). The number of cases has increased since 2014, and the disease has been declared pandemic in the United States. The sudden onset of muscle weakness, usually in an arm or leg, as well as pain throughout the body, the change in patient's facial expression (facial weakness), and shortness of breath, ingesting, and speaking are all common symptoms in patients suffering from neurologic disease. This article includes graphic and histogram representations of reported AFM incidents and criteria for causality, epidemiology, various diagnostic approaches, signs and symptoms, and various investigational guidelines. It also includes key statements about recent clinical findings related to AFM disease.

Does acute flaccid myelitis cause respiratory failure in children?

INTRODUCTION: Acute flaccid myelitis (AFM) is a rare disease that affects spinal cord gray matter, results in acute flaccid weakness of one or more limbs and predominantly involves the cervical spinal cord, which places patients at higher risk for respiratory failure. Our study aims to describe respiratory failure in pediatric AFM patients with emphasis on the need for assisted ventilation and respiratory nerve involvement from an acute and long-term perspective. MATERIALS AND METHODS: We reviewed the medical records of patients diagnosed with AFM seen in a multidisciplinary clinic for persistent limb weakness between 2016 and 2020. RESULTS: We studied 54 patients, 35% were female. The median age of patients at illness onset was 5 years (range 7 months-19 years). The median age of patients at the time of study was 8.5 years (range 2-20 years). Eleven patients (20%) required assisted ventilation for acute respiratory failure. Of those that experienced acute respiratory failure, 81% developed chronic respiratory failure. Fifty-six percent of patients with chronic respiratory failure were able to wean off assisted ventilation by 1 year. All patients that experienced unilateral diaphragm impairment with AFM onset experienced acute and chronic respiratory failure. DISCUSSION: Many patients with AFM may experience respiratory compromise and develop chronic respiratory failure. However, most of these patients can be weaned off ventilatory support by 1 year from illness onset. Most children with unilateral diaphragm impairment can sustain adequate ventilation without the need for long-term ventilatory support.

Autoimmune autonomic ganglionopathy after a CNS infection.

We report the first Greek case of autoimmune autonomic ganglionopathy seropositive for antibodies against ganglionic acetylcholine receptors, unique for an antecedent viral cerebellitis and long, slowly progressive course, with improvement after treatment with pyridostigmine.

Viral infection of central nervous system in children: one year prospective study.

Viral infection of central nervous system (CNS) is a common problem worldwide, especially in children. The clinical manifestations of viral CNS infection are the most important clues for diagnosis and treatment. The 1-year prospective study to explore the prevalence, clinical manifestations, and laboratory findings of viral CNS infection in children, including human herpes virus (HHV) type 1, 2, 3, 4, 5, 6A, 6B, 7, enterovirus B, mumps virus, measles virus, Japanese encephalitis virus, JC virus, BK polyomavirus, Nipha virus and influenza virus (H1N1, H3N2) were performed. Total of 71 children suspected CNS infection, aged between 2 days to 12.9 years were enrolled from May 2009 to April 2010. Total 4 children with non CNS infection, 5 bacterial meningitis, 2 tuberculous meningitis CNS infection were excluded. The HHV2 (50.0%) was the most common viral CNS infection. Other viral CNS infection included HHV1 (11.60%), VZV (6.7%), HHV6 (3.3%), HHV7 (3.3%), enterovirus B (1.67%) and H3N2 (1.67%). Diarrhea, irritability and CSF pleocytosis may helpful for differentiation between subtype of viral CNS infection.