Soe Mar

Atypical resting-state functional connectivity of affective pain regions in chronic migraine.

Chronic migraineurs (CM) have painful intolerances to somatosensory, visual, olfactory, and auditory stimuli during and between migraine attacks. These intolerances are suggestive of atypical affective responses to potentially noxious stimuli. We hypothesized that atypical resting‐state functional connectivity (rs‐fc) of affective pain‐processing brain regions may associate with these intolerances. This study compared rs‐fc of affective pain‐processing regions in CM with controls.

Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis

OBJECTIVE Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. DESIGN Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls. RESULTS Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. CONCLUSION Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.

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.

Long-Term Prognosis of Pediatric Patients With Relapsing Acute Disseminated Encephalomyelitis

Although long-term follow-up data are available for cases with acute disseminated encephalomyelitis, the findings range widely because of the lack of consistent definitions. Using the International Pediatric Multiple Sclerosis Study Group definitions strictly, we determined the long-term prognosis of children with acute disseminated encephalomyelitis, especially concerning relapsing cases. In our cohort of 86 children who presented with a first event of inflammatory demyelinating disease of central nervous system, 33 patients (38%) met the Study Group criteria for acute disseminated encephalomyelitis of which 9 patients had relapses. The mean follow-up duration was 12.8 years for relapsing cases and 9.2 years for all patients with acute disseminated encephalomyelitis. The risk of developing relapses is 27% but the risk of developing multiple sclerosis from acute disseminated encephalomyelitis is low at 6%. All relapsing cases had a benign course on prolonged follow-up, in spite of multiple relapses in the first 3 years.

Axonal damage in leukodystrophies.

Recent advances in radioimaging and immunocytological techniques have enhanced investigations of neurometabolites and axons, giving rise to renewed interest in human white-matter disorders. A strong correlation between axonal loss and disability in some demyelination diseases (e.g., multiple sclerosis) led to several studies examining the mechanisms of axonal damage. We review the relationship between demyelination, axon loss, and neurologic progression, and the role of advanced neuroimaging in children with different types of leukodystrophies, i.e., X-linked adrenoleukodystrophy, metachromatic leukodysrtophy, Krabbes disease, Pelizaeus-Merzbacher disease, and Alexanders disease.

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.

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.

Acute disseminated encephalomyelitis in 228 patients A retrospective, multicenter US study

Objective: To analyze the range of demographic, clinical, MRI, and CSF features of acute disseminated encephalomyelitis (ADEM), a rare, typically monophasic demyelinating disorder, and analyze long-term outcomes including time and risk factors for subsequent clinical events as well as competing diagnoses. Methods: We performed a retrospective, multicenter study in 4 US academic medical centers of all patients clinically diagnosed with ADEM. Initial presentation of pediatric and adult ADEM and monophasic and multiphasic disease were compared. The Aalen-Johansen estimator was used to produce estimates of the probability of transitioning to a multiphasic diagnosis as a function of time since initial diagnosis, treating death and alternative diagnoses as competing risks. Results: Of 228 patients (122 children, age range 1–72 years, 106 male, median follow-up 24 months [25th–75th percentile 6–67], 7 deaths), approximately one quarter (n = 55, 24%) experienced at least one relapse. Relapsing disease in children was more often diagnosed as multiphasic ADEM than in adults (58% vs 21%, p = 0.007), in whom MS was diagnosed more often. Encephalopathy at initial presentation (hazard ratio [HR] 0.383, p = 0.001), male sex (HR 0.394, p = 0.002), and increasing age at onset (HR 0.984, p = 0.035) were independently associated with a longer time to a demyelinating disease relapse in a multivariable model. In 17 patients, diagnoses other than demyelinating disease were concluded in long-term follow-up. Conclusions: Relapsing disease after ADEM is fairly common and associated with a few potentially predictive features at initial presentation. Age-specific guidelines for ADEM diagnosis and treatment may be valuable, and vigilance for other, mostly rare, diseases is imperative.

A Long-Term Follow-Up Study Using IPMSSG Criteria in Children With CNS Demyelination

OBJECTIVE To evaluate the practical application of International Pediatrics Multiple Sclerosis study group definitions in children with inflammatory demyelination of the central nervous system and to identify predictors of multiple sclerosis. METHODS Baseline data on 123 children with a first episode of acute central nervous system demyelination were collected. The initial diagnosis according to the International Pediatrics Multiple Sclerosis study group was recorded and compared with final diagnosis. RESULTS Forty-seven (38.2%) children met International Pediatrics Multiple Sclerosis study group criteria for acute disseminated encephalomyelitis and 67 (54.4%) had clinically isolated syndrome at the initial presentation. Four (3.2%) had the diagnosis of neuromyelitis optica and five (4%) did not meet any specific diagnosis per the study group criteria. Clinical follow-up was available on 118 of 123 children (95.9%), with a median of 61.5 months (quartile range 23, 110 months). Conversion from clinically isolated syndrome to multiple sclerosis occurred in 26 of 67 children (38.8%); acute disseminated encephalomyelitis to multiple sclerosis occurred in 4 of 47 children (8.5%). Adjusted multivariate logistic regression analysis for an outcome of future development of multiple sclerosis showed the following predictors: female gender (odds ratio 12.44; 95% confidence interval 1.03-149.3); initial diagnosis of monofocal brain stem or hemispheric dysfunction (odds ratio 24.57; 95% confidence interval 3.06-196.78); and Callen magnetic resonance imaging criteria if met (odds ratio 122.45; 95% confidence interval 16.57-904.57). CONCLUSION International Pediatrics Multiple Sclerosis study group criteria affirm that children with initial clinically isolated syndrome are more likely to develop future multiple sclerosis compared with those with an acute disseminated encephalomyelitis initial diagnosis. In addition, female gender, brain stem or hemispheric involvement, and Callen magnetic resonance imaging criteria predict the diagnosis of multiple sclerosis.

Neuropathologic Correlates for Diffusion Tensor Imaging in Postinfectious Encephalopathy

Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children.