Teri Schreiner

A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA

BACKGROUND Clusters of acute flaccid paralysis or cranial nerve dysfunction in children are uncommon. We aimed to assess a cluster of children with acute flaccid paralysis and cranial nerve dysfunction geographically and temporally associated with an outbreak of enterovirus-D68 respiratory disease. METHODS We defined a case of neurological disease as any child admitted to Childrens Hospital Colorado (Aurora, CO, USA) with acute flaccid paralysis with spinal-cord lesions involving mainly grey matter on imaging, or acute cranial nerve dysfunction with brainstem lesions on imaging, who had onset of neurological symptoms between Aug 1, 2014, and Oct 31, 2014. We used Poisson regression to assess whether the numbers of cases during the outbreak period were significantly greater than baseline case numbers from a historical control period (July 31, 2010, to July 31, 2014). FINDINGS 12 children met the case definition (median age 11·5 years [IQR 6·75-15]). All had a prodromal febrile illness preceding neurological symptoms by a median of 7 days (IQR 5·75-8). Neurological deficits included flaccid limb weakness (n=10; asymmetric n=7), bulbar weakness (n=6), and cranial nerve VI (n=3) and VII (n=2) dysfunction. Ten (83%) children had confluent, longitudinally extensive spinal-cord lesions of the central grey matter, with predominant anterior horn-cell involvement, and nine (75%) children had brainstem lesions. Ten (91%) of 11 children had cerebrospinal fluid pleocytosis. Nasopharyngeal specimens from eight (73%) of 11 children were positive for rhinovirus or enterovirus. Viruses from five (45%) of 11 children were typed as enterovirus D68. Enterovirus PCR of cerebrospinal fluid, blood, and rectal swabs, and tests for other causes, were negative. Improvement of cranial nerve dysfunction has been noted in three (30%) of ten children. All ten children with limb weakness have residual deficits. INTERPRETATION We report the first geographically and temporally defined cluster of acute flaccid paralysis and cranial nerve dysfunction in children associated with an outbreak of enterovirus-D68 respiratory illness. Our findings suggest the possibility of an association between enterovirus D68 and neurological disease in children. If enterovirus-D68 infections continue to happen in an endemic or epidemic pattern, development of effective antiviral or immunomodulatory therapies and vaccines should become scientific priorities. FUNDING National Center for Advancing Translational Sciences, National Institutes of Health.

MRI findings in children with acute flaccid paralysis and cranial nerve dysfunction occurring during the 2014 enterovirus D68 outbreak.

MRI findings in 11 patients with acute flaccid paralysis are described and most commonly included extensive spinal cord lesions affecting the gray matter, especially the anterior horns, ventral cauda equina, and cervical ventral nerve roots as well as the pontinetegmentum. BACKGROUND AND PURPOSE: Enterovirus D68 was responsible for widespread outbreaks of respiratory illness throughout the United States in August and September 2014. During this time, several patients presented to our institution with acute flaccid paralysis and cranial nerve dysfunction. The purpose of this report is to describe the unique imaging findings of this neurologic syndrome occurring during an enterovirus D68 outbreak. MATERIALS AND METHODS: Patients meeting a specific case definition of acute flaccid paralysis and/or cranial nerve dysfunction and presenting to our institution during the study period were included. All patients underwent routine MR imaging of the brain and/or spinal cord, including multiplanar T1, T2, and contrast-enhanced T1-weighted imaging. RESULTS: Eleven patients met the inclusion criteria and underwent MR imaging of the brain and/or spinal cord. Nine patients presented with brain stem lesions, most commonly involving the pontine tegmentum, with bilateral facial nerve enhancement in 1 patient. Ten patients had longitudinally extensive spinal cord lesions; those imaged acutely demonstrated involvement of the entire central gray matter, and those imaged subacutely showed lesions restricted to the anterior horn cells. Ventral cauda equina nerve roots enhanced in 4 patients, and ventral cervical nerve roots enhanced in 3, both only in the subacute setting. CONCLUSIONS: Patients presenting with acute flaccid paralysis and/or cranial nerve dysfunction during the recent enterovirus D68 outbreak demonstrate unique imaging findings characterized by brain stem and gray matter spinal cord lesions, similar to the neuroimaging findings described in previous outbreaks of viral myelitis such as enterovirus 71 and poliomyelitis.

Burden of multiple sclerosis on direct, indirect costs and quality of life: National US estimates.

BACKGROUND MS imposes a significant burden on patients, caregivers, employers, and the healthcare system. OBJECTIVE To comprehensively evaluate the US MS burden using nationally representative data from the Medical Expenditure Panel Survey. METHODS We identified non-institutionalized patients aged ≥18 with MS (ICD-9 code 340) from 1998 to 2009 and compared them to individuals without an MS diagnosis (non-MS) during the interview year. The cohorts were compared using multivariate regression on direct costs, indirect costs (measured in terms of employment status, annual wages, and workdays missed), and health-related quality of life (HRQoL; measured using Short Form 12, SF-6 Dimensions, and quality-adjusted life years [QALYs]). RESULTS MS prevalence was 572,312 (95% CI: 397,004, 747,619). Annual direct costs were

Acute flaccid myelitis: A clinical review of US cases 2012–2015

24,327 higher for the MS population (n=526) vs. the non-MS population (n=270,345) (95% CI:

Pediatric Neurological Complications of 2009 Pandemic Influenza A (H1N1)

22,320,

A case-control study of dietary salt intake in pediatric-onset multiple sclerosis.

26,333). MS patients had an adjusted 3.3-fold (95% CI: 2.4, 4.5) increase in the odds of not being employed vs. non-MS individuals and a 4.4-fold higher adjusted number of days in bed (95% CI 2.97, 6.45). On average, MS patients lost 10.04 QALYs vs. non-MS cohort. CONCLUSIONS MS was associated with higher healthcare costs across all components, reduced productivity due to unemployment and days spent in bed, and lower HRQoL.

Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

This review highlights clinical features of the increasing cases of acute flaccid paralysis associated with anterior myelitis noted in the United States from 2012 to 2015. Acute flaccid myelitis refers to acute flaccid limb weakness with spinal cord gray matter lesions on imaging or evidence of spinal cord motor neuron injury on electrodiagnostic testing. Although some individuals demonstrated improvement in motor weakness and functional deficits, most have residual weakness a year or more after onset. Epidemiological evidence and biological plausibility support an association between enterovirus D68 and the recent increase in acute flaccid myelitis cases in the United States. Ann Neurol 2016;80:326–338

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

OBJECTIVE To analyze the spectrum of neurological manifestations in children hospitalized with pandemic influenza A H1N1 virus of 2009 (pH1N1). DESIGN Retrospective case series of children hospitalized from May 1, 2009, through November 30, 2009. SETTING Tertiary-care childrens hospital in Colorado. PATIENTS All hospitalized patients with pH1N1 with neurological consult or diagnosis, lumbar puncture, electroencephalogram, or neuroimaging were selected as suspected cases. These were systematically reviewed and selected for final analysis if confirmed by pre-established definitions as a neurological complication. RESULTS Of 307 children with pH1N1, 59 were selected as having suspected cases of neurological complications. Twenty-three children were confirmed to have a neurological complication. Of these 23, 15 (65%) required intensive care monitoring. The median length of stay was 4 days. Seventeen (74%) had a preexisting neurological diagnosis. The most common manifestation was seizure with underlying neurological disease (in 62% of cases) followed by encephalopathy with or without neuroimaging changes (in 26% of cases). Results from a lumbar puncture showed elevated protein levels in 3 of 6 patients but no significant pleocytosis. Seven of the 9 electroencephalograms showed diffuse slowing, and findings from magnetic resonance imaging were abnormal in 5 of 6 children. Deaths occurred in 13% of patients, and short-term disability in 22%. CONCLUSIONS Children infected with pH1N1 presented with a wide spectrum of neurological manifestations, which occurred primarily in individuals with preexisting neurological conditions. These individuals had a severe disease course, evidenced by need for intensive care services and relatively high rates of mortality or neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.

Defining a new biomarker for the autoimmune component of Multiple Sclerosis: Th40 cells

BACKGROUND High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis. OBJECTIVE We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study. METHODS Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status. RESULTS Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84). CONCLUSIONS Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children.

Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis

Objective: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). Methods: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). Results: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non–human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. Conclusions: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.