Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

BACKGROUND: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. METHODS: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. FINDINGS: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). INTERPRETATION: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. FUNDING: None.

Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation.

Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.

Upper airway microbial colonization in patients with neuromuscular disorders.

BACKGROUND AND OBJECTIVE: Inherited neuromuscular disorders (NMD) inevitably result in severe lung volume restriction and cough insufficiency associated with high morbidity and mortality. The aim of this retrospective study was to evaluate whether the airways of patients with NMD are colonized with potential pathogenic microorganisms that might contribute to the pulmonary morbidity in NMD. METHODS: In this cross-sectional study, cough swabs were obtained and cultured for microbiological analyses from 77 patients with NMD and different degrees of lung volume restriction and cough insufficiency. Upper airway microbial colonization was compared to lung function parameters and cough peak flow values. RESULTS: Upper airway microbial colonization with potential pathogenic pathogens was identified in 39/77 (51%) of the subjects. Upper airway microbial colonization was associated with lower forced vital capacity (% pred.) 26.6 ± 19.7 versus 41.8 ± 20.4, P < 0.001 and cough peak flow (l/min) 125 ± 55 versus 207 ± 100, P < 0.001. In the subgroup colonized with potential pathogenic Gram-negative bacteria or Staphylococcus aureus forced vital capacity and cough peak flow remained significantly lower compared with subjects without upper airway colonization (FVC (% pred.): 22.6 ± 16.5 vs 37.9 ± 21.5, P = 0.003; CPF (l/min): 123 ± 60 vs 179 ± 93, P = 0.013). CONCLUSION: Severe respiratory compromise in patients with NMD is associated with upper airway microbial airway colonization, which might contribute to respiratory morbidity/insufficiency.

Neuromuscular and central nervous system manifestations of Clostridium perfringens infections.

Infections with Clostridium perfringens usually manifest locally or spread to sepsis with multiorgan involvement, hemolysis or septic shock. Central nervous system (CNS) manifestations are rare and most frequently comprise meningitis with or without pneumencephalon, encephalitis, plexitis, cerebral abscess, or subdural empyema. The course of CNS affections is usually foudroyant and the outcome fatal. Neuromuscular manifestations of C. perfringens infections are much more frequent than CNS manifestations and comprise myonecrosis (gas gangrene), rhabdomyolysis, myositis, fasciitis, affection of the neuromuscular transmission, or affection of the peripheral nerves. C. perfringens infections usually start from the site of a recent surgical wound or trauma, a gastrointestinal or urogenital problem, or occur in association with malignancy. In quite a number of cases the source of origin remains speculative. Treatment of choice is surgical debridement of the infectious focus with radical removal of all necrotic tissue, resection of the corresponding lymphatics in addition to antibiotic therapy with penicillin G, aminoglycosides, or clindamycin or hyperbaric oxygenation. Despite these therapeutic options, the prognosis of CNS and neuromuscular involvement in an infection with C. perfringens is still poor. Only focal infections or clostridial brain abscesses may eventually have a more favorable outcome, if surgery and antibiotics are instantly provided. Generally, early recognition of the infectious agent is of paramount importance to prevent from spreading and the development of severe hemolysis, septic shock, or death.

Poliomyelitis-like paralysis during recovery from acute bronchial asthma: possible etiology and risk factors.

A poliomyelitis-like paralytic disease during recovery from an attack of bronchial asthma is described in two young children. They presented at the age of 13 and 22 months, respectively, with acute flaccid paralysis of one or both lower limbs and preserved sensation. Cerebrospinal fluid examinations revealed mild protein elevation in both and pleocytosis in the second infant. Enteroviruses were isolated in a nasal swab and stools of the second patient. Acute onset of flaccid paralysis with absent motor action potential and normal sensory responses, detected by electrophysiologic studies, are highly suggestive of motor anterior horn cell disease in these infants. A multifactorial setup of immune suppression, stress, and neurotoxic drugs during an acute bronchial asthma attack triggered by a viral disease may render the patient vulnerable to viral invasion of the anterior horn cell with enteroviruses other than poliovirus. The overall experience of 22 patients with this serious complication is reviewed.

[The formation of infectious scrapie-like structures in the persistence of the agent of amyotrophic leukospongiosis in a brain cell culture]. / Formirovanie infektsionnykh skrepipodobnykh struktur pri persistentsii agenta amiotroficheskogo leikospongioza v kul'ture kletok mozga.

Electron microscopic analysis of specimens from guinea-pig brain cell cultures infected with amyotrophic leucospongiosis agent (belonging to "unconventional" viruses) revealed accumulation in the culture fluid of abnormal filamentous structures similar to scrapie-associated fibrils (SAF) differing in morphology. Most of these SAF-like structures 10-15 nm in diameter contained helically wound protofilaments with a repeat at certain intervals (50-150 nm). When these structures were inoculated into guinea-pig brain astrocyte cultures they produced dystrophic-destructive changes in some (25%) astrocytes, and their intracerebral inoculation to guinea pigs produced an experimental disease. The abnormal SAF-like structures were reisolated from the brains of the inoculated animals which indicated the relationship between these structures and infectivity.

[The persistence of the causative agent of amyotrophic leukospongiosis and the astrocyte reaction in monolayer cultures of brain cells]. / Persistentsiia vozbuditelia amiotroficheskogo leikospongioza i reaktsiia astrotsitov v monosloinykh kul'turakh kletok mozga.

The amyotrophic leukospongiosis (AL) agent which is considered to be an unconventional virus was shown to replicate and amplify in non-neuronal monolayer brain cell cultures. The AL agent persistence was accompanied by complicated morphofunctional changes in astrocytes, some of them developing a specific cytodystrophic process. Phagocytosis in the infected astrocytes came to its end. The dose-dependent effect and selective sensitivity of these cells to the cytodestructive activity of AL was demonstrated. Astrocytes are regarded to be target cells serving as a reservoir for agent amplification.

[HTLV-I virus and associated chronic neuromyelopathies. Current data and hypotheses]. / Virus HTLV-I et neuromyélopathies chroniques associées. Données actuelles et hypothèses.

Human T cell leukemia/lymphoma virus type I (HTLV-I) isolated in 1980, is a human retrovirus. This CD4+ lymphotropic type C retrovirus is endemic in South Western Japan, the Caribbean region and Africa where it is associated with a rare form of lymphoproliferative disease, adult T cell leukemia. Recently, HTLV-I antibodies has been found in sera and CSF from patients with tropical spastic paraparesis (TSP), a chronic neuromyelopathy of unknown etiology common in tropical areas and in Japanese patients with a similar clinical myelopathy. These data suggest that HTLV-I or an antigenically related virus might be neurotropic or neurovirulent and etiologically linked to such chronic neuromyelopathies. The fact that TSP affects about 10 to 100 persons/100,000 in tropical HTLV-I endemic areas, a prevalence comparable to that of multiple sclerosis in temperate regions, increases considerably the public health interest in HTLV-I and associated diseases. The possible neurotropism or neurovirulence of this retrovirus is discussed.

The neuromuscular pathology of experimental Chagas' disease.

In this work, we describe skeletal muscle, neuromuscular junction, nerve and spinal cord lesions in the mouse model system of Chagas' disease. Myositis was a common finding and Trypanosoma cruzi amastigote nests were frequently found in the muscle fibers. Angular atrophy, targetoid fibers, groups of atrophic fibers, fibrosis, myofiber necrosis and phagocytosis of cellular debris were also observed. The neuromuscular junction studies showed degeneration of intramuscular nerve fibers, swelling and distortion of nerve endings and multiple ramifications on the same muscle fiber. Collateral, terminal and ultraterminal axonal sprouts were also present. Inflammatory neuropathy was seen in all of the infected mice. Demyelination, axonal degeneration, remyelination and axonal regeneration were observed in the transverse sections. There was an average reduction of 29% in the total number of myelin fibers. The teasing of single myelin fibers showed segmental and paranodal demyelination and remyelination more frequently than axonal degeneration and regeneration. The lumbar spinal cords presented inflammatory cell infiltration associated with tissue destruction. Amastigote nests were found in 3 out of the 8 infected mice studied. There was a mean loss of 21% of the large cytoneurons of the anterior horn of the lumbar spinal cord.

Toxicity of Diplodia maydis in farm and laboratory animals.

The acute toxicity of maize culture material of eight strains of Diplodia maydis in ducklings, as well as the ability of five of these strains to induce typical diplodiosis (a neuromuscular disease) in cattle and sheep was shown. Typical diplodiosis was induced in 17 sheep and 11 cattle. Two of the five toxic strains were isolated from maize involved in diploidiosis outbreaks, the others from commercial maize. Strains inducing diplodiosis could be isolated from commercial maize from the USA, Argentina and South Africa. There was no correlation between the toxicity of D. maydis strains in ducklings and their ability to induce diplodiosis in cattle and sheep. Some isolates were acutely toxic to ducklings and rats but were unable to induce diplodiosis in either cattle or sheep. Others, equally toxic to ducklings and rats, induced diplodiosis in cattle and sheep at low dose levels. Two doses, each of 5 g/kg, of maize culture material of isolates from the USA, Argentina and South Africa induced diplodiosis in sheep. Culture material incubated for less than 8 wk could not induce diplodiosis in cattle. Acute toxicity in ducklings and rats also increased with longer incubation periods. Cultures of non-sporulating and profusely sporulating strains were equally toxic to ducklings. Heat treatment of culture material for 48 days at 45 degrees C failed to reduce toxicity in ducklings.