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.

[Infection of the central nervous system by Epstein-Barr virus: clinical manifestations and prognosis]. / Infección del sistema nervioso central por el virus de Epstein-Barr: manifestaciones clínicas y pronóstico.

INTRODUCTION: The role of Epstein-Barr virus (EBV) in central nervous system (CNS) infections is not fully resolved. We wanted to describe the clinical manifestations of patients with EBV infection in cerebrospinal fluid. PATIENTS AND METHODS: We reviewed the clinical records of all adult patients EBV PCR-positive in cerebrospinal fluid, without lymphoproliferative disease, during 2004 to 2020. RESULTS: We identified 27 patients, 22 (81.5%) were men, and median age was 54 years. Twenty-three (82.1%) patients were immunosuppressed, 16 HIV-positive. In 15 (55.6%) patients coinfection with another microorganism was diagnosed and in 12 (44.4%) patients it was detected as the only pathogen. Of the 12 patients, three (25%) was immunocompetent patients, one had Guillain Barre syndrome (GBS), another had disseminated multiphasic encephalitis, and another had lymphocytic meningitis; 9 (75%) immunosuppressed, 7 HIV-positive, 4 had encephalitis that resolved without sequelae and 4 had encephalopathy, two HIH-positive had moderate cognitive impairment as a sequela. CONCLUSIONS: In our study, EBV produced encephalitis, meningitis, polyradiculomyelitis and GBS, mainly in immunosuppressed patients. In more than half of the cases, it is associated with other pathogens where the role of EBV is unclear. In immunocompetent patient, the infection can be serious and leave sequelae and in HIV-positive patients with encephalopatic involvement without encephalitis, the neurological damage could be greater, so we consider it of interest to carry out studies to evaluate the prognosis as well as the role of antivirals in the evolucion of these clinical pictures.

TITLE: Infección del sistema nervioso central por el virus de Epstein-Barr: manifestaciones clínicas y pronóstico.Introducción. El papel del virus de Epstein-Barr (VEB) en las infecciones del sistema nervioso central no siempre está claro. Nuestro objetivo fue describir las manifestaciones clínicas y la evolución de los pacientes con detección del VEB en el líquido cefalorraquídeo (LCR). Pacientes y métodos. Se revisaron las historias clínicas de todos los pacientes adultos con detección del VEB en el LCR por reacción en cadena de la polimerasa diagnosticados desde 2004 hasta 2020 sin enfermedad linfoproliferativa. Resultados. Se diagnosticó a 27 pacientes, 22 (81,5%) hombres, con una mediana de 54 años; 23 (82,1%) pacientes eran inmunodeprimidos, 16 positivos para el virus de la inmunodeficiencia humana (VIH). En 15 (55,6%) pacientes, el VEB se detectó en coinfección con otro microorganismo, y en 12, como único patógeno. De los 12 pacientes, tres (25%) eran inmunocompetentes, uno presentó un síndrome de Guillain-Barré, otro una encefalitis diseminada multifásica y otro una meningitis linfocitaria; y nueve (75%) inmunodeprimidos, de los que cuatro presentaron encefalitis que se resolvieron sin secuelas, y cuatro encefalopatía, dos de ellos positivos para el VIH, que presentaron secuelas (deterioro cognitivo moderado). Conclusiones. En nuestro estudio, el VEB produjo cuadros de encefalitis, meningitis, polirradiculomielitis y SGB, principalmente en inmunodeprimidos. En más de la mitad de los casos se asocia a otros patógenos, en donde el papel del VEB no está claro. En inmunocompetentes, las infecciones pueden ser graves y dejar secuelas, y en pacientes con VIH con encefalopatía sin encefalitis, el daño neurológico podría ser mayor, por lo que consideramos de interés realizar estudios que evalúen el pronóstico y el papel de los antivirales en la evolución de estos cuadros clínicos.

Cerebrospinal Fluid Analysis.

Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include suspected central nervous system infection or subarachnoid hemorrhage. CSF analysis is not necessarily diagnostic but can be useful in the evaluation of other neurologic conditions, such as spontaneous intracranial hypotension, idiopathic intracranial hypertension, multiple sclerosis, Guillain-Barré syndrome, and malignancy. Bacterial meningitis has a high mortality rate and characteristic effects on CSF white blood cell counts, CSF protein levels, and the CSF:serum glucose ratio. CSF culture can identify causative organisms and antibiotic sensitivities. Viral meningitis can present similarly to bacterial meningitis but usually has a low mortality rate. Adjunctive tests such as CSF lactate measurement, latex agglutination, and polymerase chain reaction testing can help differentiate between bacterial and viral causes of meningitis. Immunocompromised patients may have meningitis caused by tuberculosis, neurosyphilis, or fungal or parasitic infections. Subarachnoid hemorrhage has a high mortality rate, and rapid diagnosis is key to improve outcomes. Computed tomography of the head is nearly 100% sensitive for subarachnoid hemorrhage in the first six hours after symptom onset, but CSF analysis may be required if there is a delay in presentation or if imaging findings are equivocal. Xanthochromia and an elevated red blood cell count are characteristic CSF findings in patients with subarachnoid hemorrhage. Leptomeningeal carcinomatosis can mimic central nervous system infection. It has a poor prognosis, and large-volume CSF cytology is diagnostic.

Characteristics of Upper Extremity Recovery in Acute Flaccid Myelitis: A Case Series.

BACKGROUND: Clinical characteristics and timing associated with nonsurgical recovery of upper extremity function in acute flaccid myelitis are unknown. METHODS: A single-institution retrospective case series was analyzed to describe clinical features of acute flaccid myelitis diagnosed between October of 2013 and December of 2016. Patients were consecutively sampled children with a diagnosis of acute flaccid myelitis who were referred to a hand surgeon. Patient factors and initial severity of paralysis were compared with upper extremity muscle strength outcomes using the Medical Research Council scale every 3 months up to 18 months after onset. RESULTS: Twenty-two patients with acute flaccid myelitis (aged 2 to 16 years) were studied. Proximal upper extremity musculature was more frequently and severely affected, with 56 percent of patients affected bilaterally. Functional recovery of all muscle groups (≥M3) in an individual limb was observed in 43 percent of upper extremities within 3 months. Additional complete limb recovery to greater than or equal to M3 after 3 months was rarely observed. Extraplexal paralysis, including spinal accessory (72 percent), glossopharyngeal/hypoglossal (28 percent), lower extremity (28 percent), facial (22 percent), and phrenic nerves (17 percent), was correlated with greater severity of upper extremity paralysis and decreased spontaneous recovery. There was no correlation between severity of paralysis or recovery and patient characteristics, including age, sex, comorbidities, prodromal symptoms, or time to paralysis. CONCLUSIONS: Spontaneous functional limb recovery, if present, occurred early, within 3 months of the onset of paralysis. The authors recommend that patients without signs of early recovery warrant consideration for early surgical intervention and referral to a hand surgeon or other specialist in peripheral nerve injury. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Acute Flaccid Myelitis: A Single Pediatric Center Experience From 2014 to 2019.

BACKGROUND: Acute flaccid myelitis has emerged as the leading cause of acute flaccid paralysis in children. Acute flaccid myelitis leads to significant physical disability; hence, objective outcome measures to study disease severity and progression are desirable. In addition, nerve transfer to improve motor function in affected children needs further study. METHODS: Retrospective study of acute flaccid myelitis subjects managed at Children's Healthcare of Atlanta from August 2014 to December 2019. Clinical, electromyography and nerve conduction study, neuropsychological functional independence (WeeFIM), and nerve transfer data were reviewed. RESULTS: Fifteen children (11 boys and 4 girls) mean age 5.1±3.2 years (range 14 months to 12 years) were included. All subjects (n = 15) presented with severe asymmetric motor weakness and absent tendon reflexes. Motor nerve conduction study of the affected limbs in 93% (n = 14) showed absent or markedly reduced amplitude. Ten patients received comprehensive inpatient rehabilitation and neuropsychological evaluation. Admission and discharge WeeFIM scores showed deficits most consistent and pronounced in the domains of self-care and mobility. Multiple nerve transfer surgery was performed on 13 limbs (9 upper and 4 lower extremities) in 6 children. Postsurgery (mean duration of 10.4 ± 5.7 months) follow-up demonstrated improvement on active movement scale (AMS) in 4 subjects. CONCLUSION: Acute flaccid myelitis affects school-age children with asymmetric motor weakness, absent tendon reflexes, and reduced or absent motor amplitude on nerve conduction study. Comprehensive rehabilitation and nerve transfer led to improvement in motor function on neuropsychology WeeFIM and AMS scores.

Molecular and Histologic Diagnosis of Central Nervous System Infections.

Infections of the central nervous system cause significant morbidity and mortality in immunocompetent and immunocompromised individuals. A wide variety of microorganisms can cause infections, including bacteria, mycobacteria, fungi, viruses, and parasites. Although less invasive testing is preferred, surgical biopsy may be necessary to collect diagnostic tissue. Histologic findings, including special stains and immunohistochemistry, can provide a morphologic diagnosis in many cases, which can be further classified by molecular testing. Correlation of molecular, culture, and other laboratory results with histologic findings is essential for an accurate diagnosis, and to minimize false positives from microbial contamination.

Acute Neuromuscular Disorders in the Pediatric Intensive Care Unit.

BACKGROUND: The neuromuscular disorders encountered in the pediatric intensive care unit (PICU) encompass a broad spectrum of pathologies. These include acute disorders (eg, Guillain-Barre syndrome), acute-on-chronic disorders (eg, myasthenia gravis), progressive disorders (eg, muscular dystrophy), and disorders that develop in the PICU (eg, critical illness myopathy/polyneuropathy). Familiarity with the presenting features of these disorders is of paramount importance in facilitating timely diagnosis. METHODS: We conducted a retrospective review of the medical records of patients admitted to the PICU or Intermediate Care Program (ICP) at a single tertiary children's hospital from 2006 to 2017 with an acute or acute-on-chronic neuromuscular disorder. We did not include patients with a known progressive neuromuscular disorder or critical illness myopathy/polyneuropathy. RESULTS: Twenty-four patients were admitted to the PICU/ICP with acute or acute-on-chronic neuromuscular disorders. Diagnosis and indication for ICU/ICP admission were Guillain-Barre syndrome (n = 6; respiratory failure: 3, respiratory monitoring: 2, autonomic instability: 1), myasthenia gravis (n = 5; airway clearance: 3, respiratory failure: 2), acute flaccid myelitis (n = 3; respiratory failure: 2, respiratory monitoring: 1), periodic paralysis (n = 3; intravenous potassium replacement), rhabdomyolysis (n = 3; monitoring for electrolyte derangements), infant botulism (n = 2; respiratory failure), chronic demyelinating polyneuropathy (n = 1; respiratory failure), and congenital myasthenic syndrome (n = 1; apnea). No patients were admitted to the PICU/ICP with a diagnosis of tick paralysis, acute intermittent porphyria, or inflammatory myopathy. CONCLUSIONS: Although acute and acute-on-chronic neuromuscular disorders are encountered relatively rarely in the PICU, familiarity with the presenting features of these disorders is important in facilitating timely diagnosis. This, in turn, enables the institution of effective management strategies, thereby avoiding complications associated with diagnostic delays.

Herpesvirus Infections of the Central Nervous System.

There are over 200 herpesvirus species, of which 10 affect humans. Each of these 10 herpesviruses has a unique clinical syndrome, but common to all is their ability to cause infection and pathology in the central nervous system. In this article, we discuss the epidemiology, clinical presentation, diagnostic modalities, treatment, sequelae, and availability of vaccination of each of the following herpesviruses: herpes simplex virus 1 and 2, varicella zoster virus, human cytomegalovirus, human herpesvirus 6A, 6B, and 7, Epstein-Barr virus, human herpesvirus 8, and simian herpesvirus B.

Acute flaccid myelitis and enterovirus D68: lessons from the past and present.

Acute flaccid myelitis is characterized by the combination of acute flaccid paralysis and a spinal cord lesion largely restricted to the gray matter on magnetic resonance imaging. The term acute flaccid myelitis was introduced in 2014 after the upsurge of pediatric cases in the USA with enterovirus D68 infection. Since then, an increasing number of cases have been reported worldwide. Whereas the terminology is new, the clinical syndrome has been recognized in the past in association with several other neurotropic viruses such as poliovirus.Conclusion: This review presents the current knowledge on acute flaccid myelitis with respect to the clinical presentation and its differential diagnosis with Guillain-Barré syndrome and acute transverse myelitis. We also discuss the association with enterovirus D68 and the presumed pathophysiological mechanism of this infection causing anterior horn cell damage. Sharing clinical knowledge and insights from basic research is needed to make progress in diagnosis, treatment, and prevention of this new polio-like disease. What is Known: • Acute flaccid myelitis (AFM) is a polio-like condition characterized by rapid progressive asymmetric weakness, together with specific findings on MRI • AFM has been related to different viral agents, but recent outbreaks are predominantly associated with enterovirus D68. What is New: • Improving knowledge on AFM must increase early recognition and adequate diagnostic procedures by clinicians. • The increasing incidence of AFM urges cooperation between pediatricians, neurologists, and microbiologists for the development of treatment and preventive options.

Chikungunya virus infection with severe neurologic manifestations: report of four fatal cases

Abstract Here, we present four patients with confirmed Chikungunya virus infection showing atypical neurologic manifestations and death. This case series includes patients ranging in age from five to 92 years, with or without comorbidities. This report is important, as very few cases in the literature reporting death due to atypical Chikungunya virus infection are available.

Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus in the central nervous system.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immune hyperactivation syndrome which may be primary (genetic) or secondary to various immune-related conditions including infection, immunodeficiency, and malignancies. Rapid diagnosis and treatment are essential because it can be associated with significant morbidity and mortality. Epstein-Barr virus (EBV) is a known infectious cause of acquired HLH, but EBV-associated HLH involving the central nervous system is rare and not well characterized neuropathologically. We report a case of fatal EBV-associated HLH with severe involvement of the central nervous system showing florid hemophagocytosis in the choroid plexus, with extensive neuron loss and gliosis in the cerebrum, cerebellum, and brainstem.

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children.

BACKGROUND/AIMS: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. METHODS: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. RESULTS: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. CONCLUSION: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.

Divergent cerebrospinal fluid cytokine network induced by non-viral and different viral infections on the central nervous system.

BACKGROUND: Meningoencephalitis is one of the most common disorders of the central nervous system (CNS) worldwide. Viral meningoencephalitis differs from bacterial meningitis in several aspects. In some developing countries, bacterial meningitis has appropriate clinical management and chemotherapy is available. Virus-associated and virus not detected meningoencephalitis are treatable, however, they may cause death in a few cases. The knowledge of how mediators of inflammation can induce disease would contribute for the design of affordable therapeutic strategies, as well as to the diagnosis of virus not detected and viral meningoencephalitis. Cytokine-induced inflammation to CNS requires several factors that are not fully understood yet. METHODS: Considering this, several cytokines were measured in the cerebrospinal fluid (CSF) of patients with undiagnosed and viral meningoencephalitis, and these were correlated with cellularity in the CSF. RESULTS: The results demonstrate that an altered biochemical profile alongside increased cellularity in the cerebrospinal fluid is a feature of patients with meningoencephalitis that are not associated with the detection of virus in the CNS (P < 0.05). Moreover, HIV-positive patients (n = 10) that evolve with meningoencephalitis display a distinct biochemical/cytological profile (P < 0.05) in the cerebrospinal fluid. Meningoencephalitis brings about a prominent intrathecal cytokine storm regardless of the detection of virus as presumable etiological agent. In the case of Enterovirus infection (n = 13), meningoencephalitis elicits robust intrathecal pro-inflammatory cytokine pattern and elevated cellularity when compared to herpesvirus (n = 15) and Arbovirus (n = 5) viral infections (P < 0.05). CONCLUSION: Differences in the cytokine profile of the CSF may be unique if distinct, viral or presumably non-viral pathways initially trigger the inflammatory response in the CNS.

Human herpesvirus infections of the central nervous system: laboratory diagnosis based on DNA detection by nested PCR in plasma and cerebrospinal fluid samples.

Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis using cerebral spinal fluid (CSF) as a reference method. Tests on DNA extracted from plasma are noninvasive, thus avoiding all of the collateral effects and patient risks associated with CSF collection. This study aimed to determine whether plasma can replace CSF in nested PCR analysis for the detection of CNS human herpesvirus (HHV) diseases by analysing the proportion of patients whose CSF nested PCR results were positive for CNS HHV who also had the same organism identified by plasma nested PCR. In this study, CSF DNA was used as the "gold standard," and nested PCR was performed on both types of samples. Fifty-two patients with symptoms of nervous system infection were submitted to CSF and blood collection. For the eight HHV, one positive DNA result-in plasma and/or CSF nested PCR-was considered an active HHV infection, whereas the occurrence of two or more HHVs in the same sample was considered a coinfection. HHV infections were positively detected in 27/52 (51.9%) of the CSF and in 32/52 (61.5%) of the plasma, difference not significant, thus nested PCR can be performed on plasma instead of CSF. In conclusion, this findings suggest that plasma as a useful material for the diagnosis of cases where there is any difficulty to perform a CSF puncture.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

Single tube multiplex real-time PCR for the rapid detection of herpesvirus infections of the central nervous system.

Human herpesvirus infection of immunocompromised hosts may lead to central nervous system (CNS) infection and diseases. In this study, a single tube multiplex real-time PCR was developed for the detection of five herpesviruses (HSV-1, HSV-2, VZV, EBV and CMV) in clinical cerebrospinal fluid (CSF) specimens. Two primer pairs specific for the herpesvirus polymerase gene and five hybridization probe pairs for the specific identification of the herpesvirus types were used in a LightCycler multiplex real-time PCR. A singleplex real-time PCR was first optimized and then applied to the multiplex real-time PCR. The singleplex and multiplex real-time PCRs showed no cross-reactivity. The sensitivity of the singleplex real-time PCR was 1 copy per reaction for each herpesvirus, while that of the multiplex real-time PCR was 1 copy per reaction for HSV-1 and VZV and 10 copies per reaction for HSV-2, EBV and CMV. Intra and inter-assay variations of the single tube multiplex assay were in the range of 0.02%-3.67% and 0.79%-4.35%, respectively. The assay was evaluated by testing 62 clinical CSF samples and was found to have equivalent sensitivity, specificity and agreement as the routine real-time PCR, but reducing time, cost and amount of used sample.