Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Go Zika Go: A Feasibility Protocol of a Modified Ride-on Car Intervention for Children with Congenital Zika Syndrome in Brazil.

Children with congenital Zika syndrome (CZS) present severe motor disability and can benefit from early powered mobility. The Go Zika Go project uses modified ride-on toy cars, which may advance the body functions, activities, and participation of children. This paper describes the study protocol aiming to assess the feasibility of a modified ride-on car intervention for children with CZS in Brazil. A mixed-methods design with a multiple 1-week baseline, 3-month intervention, and 1-month follow-up will be implemented. Modified ride-on car training sessions will be conducted three times a week at the participants' home or in the clinic. The primary outcome will be a narrative description of study feasibility (photovoice method, focus groups, parent feasibility questionnaire and assessment of learning powered mobility). Secondary outcomes will be switch activation, driving sessions journal, social-cognitive interactions, mobility (pediatric evaluation of disability inventory computer adaptive test), goal attainment scaling (GAS), and participation (young children's participation and environment measure). Go Zika Go is expected to be viable and to improve function, activity, and participation of children with CZS, providing a low-cost, evidence-based rehabilitation option that will be relevant to early child development in a global perspective.

Zika virus-induced acute myelitis and motor deficits in adult interferon αß/γ receptor knockout mice.

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/ß receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.

Motor Abnormalities and Epilepsy in Infants and Children With Evidence of Congenital Zika Virus Infection.

Initial reports of congenital Zika virus (ZIKV) infection focused on microcephaly at birth with severe brain anomalies; the phenotype has broadened to include microcephaly that develops after birth and neurodevelopmental sequelae. In this narrative review, we summarize medical literature describing motor abnormalities and epilepsy in infants with evidence of congenital ZIKV infection and provide information on the impact of these conditions. Specific scenarios are used to illustrate the complex clinical course in infants with abnormalities that are consistent with congenital Zika syndrome. A search of the English-language medical literature was done to identify motor abnormalities and epilepsy in infants with evidence of congenital ZIKV infection by using Medline and PubMed, Embase, Scientific Electronic Library Online, Scopus, the OpenGrey Repository, and the Grey Literature Report in Public Health. Search terms included "Zika" only and "Zika" in combination with any of the following terms: "epilepsy," "seizure," "motor," and "cerebral palsy." Clinical features of motor abnormalities and epilepsy in these children were reviewed. Thirty-six publications were identified; 8 were selected for further review. Among infants with clinical findings that are consistent with congenital Zika syndrome, 54% had epilepsy and 100% had motor abnormalities. In these infants, impairments that are consistent with diagnoses of cerebral palsy and epilepsy occur frequently. Pyramidal and extrapyramidal motor abnormalities were notable for their early development and co-occurrence. Prompt identification of potential disabilities enables early intervention to improve the quality of life for affected children. Long-term studies of developmental outcomes and interventions in children with congenital ZIKV infection are needed.