Jan Mendelt Tillema

Cortical Reorganization of Language Functioning Following Perinatal Left MCA Stroke

OBJECTIVE Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. METHODS Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. RESULTS Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. INTERPRETATION This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.

Gut microbiota composition and relapse risk in pediatric MS: A pilot study.

We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples) in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8 months follow-up. From the Kaplan-Meier curve, 25% relapsed within an estimated 166 days from baseline. A shorter time to relapse was associated with Fusobacteria depletion (p=0.001 log-rank test), expansion of the Firmicutes (p=0.003), and presence of the Archaea Euryarchaeota (p=0.037). After covariate adjustments for age and immunomodulatory drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio=3.2 (95% CI: 1.2-9.0), p=0.024). Further investigation is warranted. Findings could offer new targets to alter the MS disease course.

Everolimus alters white matter diffusion in tuberous sclerosis complex

Objective: Diffusion tensor imaging (DTI) analysis was performed on patients with tuberous sclerosis complex (TSC) to investigate potential changes in normal-appearing white matter after treatment with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Methods: Recently, a phase I/II trial of everolimus demonstrated significant reductions in subependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency. Subgroup analysis was performed on DTI data available from this study. TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5–15 ng/mL. DTI (1.5 T, 15 directions) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivity within regions of interest (ROIs). Baseline scans were compared to 12–18 months post-treatment and compared to a TSC age- and gender-matched nontreatment control cohort. Results: Of 28 enrolled patients, 20 had sufficient DTI data. Comparing baseline values with those acquired 12–18 months after treatment, a significant change in FA was observed in the corpus callosum, internal capsule, and geniculo-calcarine region (p < 0.05). Mean change in FA was 0.04 (p < 0.01), driven primarily by a significant decrease in radial diffusivity. Mean diffusivity of the combined ROIs decreased slightly (p < 0.05), axial diffusivity remained stable. The control group showed no change over time. Conclusion: Significant changes in FA and radial diffusivity were observed after treatment with everolimus in patients with TSC, suggesting that the genetic defect of TSC in the brain may be modified pharmacologically, even in normal-appearing white matter.

Daclizumab Use in Patients With Pediatric Multiple Sclerosis

BACKGROUND Daclizumab, a humanized monoclonal antibody specific for the interleukin 2 receptor α chain, reduces clinical and magnetic resonance imaging disease activity in patients with adult-onset multiple sclerosis (MS) as monotherapy or add-on therapy with interferon. OBJECTIVE To report the use of daclizumab in pediatric-onset MS. DESIGN Case series. SETTING Two comprehensive pediatric MS centers. PATIENTS Seven patients with pediatric-onset MS with clinical and magnetic resonance imaging disease activity despite first-line disease-modifying therapy. INTERVENTION Intravenous daclizumab, 1 mg/kg monthly. MAIN OUTCOME MEASURES Annualized relapse rates, Expanded Disability Status Scale scores, contrast-enhancing lesions, and adverse effects. RESULTS Treatment with daclizumab, primarily combined with interferon, was associated with reductions in annualized relapse rates and contrast-enhancing lesions and with reduction or stabilization of Expanded Disability Status Scale scores in each patient. However, 4 patients had relapses and new contrast-enhancing lesions during daclizumab treatment. No significant adverse effects occurred. CONCLUSION Daclizumab may be a safe and at least partially effective treatment option for patients with pediatric-onset MS with disease activity despite first-line disease-modifying therapy.

The Spectrum of Neuromyelitis Optica (NMO) in Childhood

The evaluation of inflammatory central nervous system disorders in childhood with predominant involvement of the optic nerves and spinal cord has been greatly enhanced over the last decade with identification of a group of disorders unified by the detection of neuromyelitis optica (NMO)–IgG, an antibody targeting the central nervous system–predominant water channel aquaporin-4. Clinical syndromes are predominated by the relapsing form of NMO but also include encephalopathic variants that can mimic acute disseminated encephalomyelitis. Maintenance immunotherapy is used to prevent relapses in NMO-IgG–seropositive patients. In contrast, NMO-IgG–seronegative children with NMO more commonly have a monophasic course (simultaneous occurrence of optic neuritis and transverse myelitis) and do not require remission-maintaining immunotherapy, but close surveillance is advised. Current clinical, pathological, and pathogenetic knowledge is reviewed with a focus on clinical presentation, neuroimaging findings, serological investigations, and treatment of children with disorders within the spectrum of central nervous system aquaporin-4 autoimmunity.

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

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.

Dietary salt intake and time to relapse in paediatric multiple sclerosis

Background Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS). Objective To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS. Methods Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case–control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders. Results 174 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p=0.25) and 1.37 (95% CI 0.74 to 2.51, p=0.32) compared with patients in the lowest tertile, respectively. Conclusions Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS.

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

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.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis

To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis.

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

The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.