Faculty Bibliography

Multiple Sclerosis (MS) is a chronic inflammatory/demyelinating and neurodegenerative disease of the central nervous system (CNS). Most patients experience a relapsing-remitting (RR) course, while about 15-20% of patients experience a primary progressive (PP) course. Cognitive impairment affects approximately 40-70% of all MS patients and differences in cognitive impairment between RR-MS and PP-MS have been found. We aimed to compare RR-MS and PP-MS patients in terms of cognitive performance, and to investigate the MRI correlates of cognitive impairment in the two groups using measures of brain volumes and cortical thickness. Fifty-seven patients (42 RR-MS, 15 PP-MS) and thirty-eight matched controls underwent neuropsychological (NP) testing and MRI. PP-MS patients scored lower than RR-MS patients on most of the NP tests in absence of any specific pattern. PP-MS patients showed significantly lower caudate volume. There was no significant difference in MRI correlates of cognitive impairment between the two groups except for a prevalent association with MRI measures of cortical GM injury in RR-MS patients and with MRI measures of subcortical GM injury in PP-MS patients. This suggests that although cognitive impairment results from several factors, cortical and subcortical GM injury may play a different role depending on the disease course.

Objective: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria and single region studies limit the generalizability of prior results. The aim of this study was to determine if there is a temporal variation in onset of relapses in both hemispheres and to determine if seasonal peak relapse probability varies with latitude. Methods: The MSBase international registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultra-violet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. Results: 32 ,762 relapses from 9811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10 degrees of latitude away from the equator was associated with a mean decrease in ultra-violet radiation trough to subsequent relapse peak lag of 28 .5 days (95 % CI 3 .29 , 53 .71 , p=0 .028 ). Interpretation: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern. ANN NEUROL 2014. (c) 2014 American Neurological Association.

Adult-onset, chronic progressive spastic paraparesis may be due to a large number of causes and poses a diagnostic challenge. There are no recent evidence-based guidelines or comprehensive reviews to help guide diagnostic work-up. We survey the literature on chronic progressive spastic paraparesis, with special emphasis on myelopathies, and propose a practical, MRI-based approach to facilitate the diagnostic process. Building on neuro-anatomic and radiographic conventions, we classify spinal MRI findings into six patterns: extradural; intradural/extramedullary; Intramedullary; Intramedullary-Tract specific; Spinal Cord Atrophy; and Normal Appearing Spinal Cord. A comprehensive differential diagnosis of chronic progressive myelopathy for each of the six patterns is generated. We highlight some of the more common and/or treatable causes of progressive spastic paraparesis and provide clinical pointers that may assist clinicians in arriving at the diagnosis. We outline a practical, comprehensive MRI-based algorithm to diagnosing adult-onset chronic progressive myelopathy.

OBJECTIVES: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. METHODS: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. RESULTS: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. CONCLUSION: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Importance: Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS). Objective: To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS. Design, Setting, and Participants: A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF. Main Outcomes and Measures: Cerebrovascular reactivity was calculated as the percent increase of normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS. Results: A significant decrease of mean (SD) global gray matter CVR was found in patients with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a significant negative correlation between gray matter CVR and lesion volume (R = 0.6, P = .004) and a significant positive correlation between global gray matter CVR and gray matter atrophy index (R = 0.5, P = .03). Conclusions and Relevance: Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.

OBJECTIVE: To determine the impact of therapeutic infusion of IV immunoglobulin (IVIg) on John Cunningham virus antibody (JCV Ab) serostatus and level in serum. METHODS: We carried out a retrospective analysis of serum levels of JCV Ab among STRATIFY-2 trial enrollees from 2 multiple sclerosis centers who were exposed to IVIg during the trial. For the subset of eligible patients, we estimated mean linear trends while on IVIg and after stopping IVIg with a linear mixed-effects model. RESULTS: The JCV Ab seropositivity rate in the group of patients that was recently exposed to IVIg was 100%, which is significantly higher than in the IVIg-naive population (58%, p < 0.001). The seropositivity rate in the patient group with remote IVIg exposure was similar to that in the IVIg-naive population (67%, p = 0.68, Fisher exact test). The slope of the linear trend line after stopping IVIg decreased significantly by -0.310 units per 100 days (95% confidence interval, -0.611 to -0.008; p = 0.04). CONCLUSIONS: Recent IVIg exposure is invariably associated with JCV Ab seropositivity. After stopping IVIg, JCV Ab levels tend to decrease with time, and seroreversion to innately Ab-negative status can occur.