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Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using blood-oxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences., (© The Author(s) 2015.)

Background: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research., Objective: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials., Methods: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place., Results: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed., Conclusion: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting., (© The Author(s), 2014.)

Background: Transverse myelitis (TM) is an inflammatory disease of the spinal cord. In pediatric TM patients, cognitive and psychological problems have been described only anecdotally., Objectives: Study aims include describing cognitive dysfunction among a cohort of pediatric TM patients as well as qualitatively exploring the impact of depression, medication, and fatigue on cognitive functioning., Methods: Twenty-four consecutive TM patients referred to a pediatric demyelinating diseases clinic completed neuropsychological screening. Means, standard deviations (SD), and percentages of patients performing at or below 1.0, 1.5, and 2.0 SD from the mean on tests administered are presented., Results: Means were generally average across domains; however, scores ranged widely across subjects within each domain. The highest rate of deficits was observed in fine-motor speed/dexterity. Slightly higher frequencies of impairment were observed in attention and memory as compared to processing speed and verbal fluency. Results did not suggest a clear association between cognitive problems and depression or medication use but did suggest that fatigue may impact cognitive functioning., Conclusions: This study is the first to document cognitive deficits in pediatric TM and raises questions regarding our understanding of the central nervous system (CNS) injury associated with TM. Findings warrant further exploration of neuropsychological outcomes in TM to inform appropriate intervention.

Background: Neuromyelitis optica (NMO) is an autoimmune condition that predominantly causes severe optic neuritis and transverse myelitis. Rituximab therapy has dramatically improved patient care, but standardized dosing regimens and guidelines are lacking., Objectives: The objective of this study was to define a rituximab dosing strategy for NMO patients that achieves the lowest rate of relapses., Methods: This was a retrospective chart review of patients treated with various doses of rituximab., Results: Combining data from the NMO and multiple sclerosis (MS) patients, identified that the mean number of days after a 100 mg dose of rituximab until the CD19 population was greater than 2% was 99 days (standard deviation 36, range 43-172). When allowed to rise, the mean number of days after a 1000 mg dose of rituximab until the CD19 population was greater than 2% was 184 (standard deviation 72, range 52-288). The median number of days until a CD19 percentage of 2% was achieved was 133 days in the 100 mg dosing arm and 259 days in the 1000 mg dosing arm. Analysis of the survival curves via both the Mantel-Cox log-rank test and the Wilcoxon test determined that the difference between medial survival for 100 and 1000 mg doses was statistically significant with p-values <0.0001., Conclusions: Low doses of rituximab have a high rate of early B-cell repopulation. Any NMO patient treated with rituximab should be followed with monthly CD19 counts in order to identify the rare, but clinically significant, early repopulators.

Background: Memantine, an NMDA antagonist, is effective for moderate to severe Alzheimer's disease., Objective: Determine whether memantine improves cognitive performance (CP) among subjects with multiple sclerosis (MS) and cognitive impairment (CI)., Methods: This double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov NCT00300716) compared memantine 10 mg twice a day (4 week titration followed by 12 weeks on the highest tolerated dose) with placebo. The primary outcome was the change from baseline to exit on the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test-II (CVLT-II) Long Delay Free Recall (LDFR). Secondary outcomes included additional neuropsychological tests; self-report measures of quality of life, fatigue, and depression; and family/caregiver reports of subjects' CI and neuropsychiatric symptoms., Results: The differences between the groups on the change on the PASAT (placebo-memantine = 0.0 correct responses, 95% CI 3.4, 3.4; p = 0.9) and on CVLT-II LDFR (placebo-memantine =-0.6 words, 95% CI -2.1, 0.8; p = 0.4) as well as on the other cognitive tests were not significant. Subjects on memantine had no serious adverse events (AEs) but had more fatigue and neurological AEs as well as, per family members' reports, less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo., Conclusion: Memantine 10 mg twice a day does not improve CP in subjects with MS, ages 18-65, without major depression, who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II (total recall or delayed free recall).

Objective: To study the relation of retinal nerve fiber layer thinning to clinical and physiologic measures of visual function in patients with MS or neuromyelitis optica and unilateral optic neuropathy., Methods: We studied a cohort of control subjects (n = 64) and patients (n = 24) with evidence of unilateral thinning of their average retinal nerve fiber layer as measured by optical coherence tomography in order to characterize the relationship between ganglion cell axonal degeneration and its impact upon vision and pupillary light reflex metrics using infrared pupillometry., Results: When compared to the normal fellow eye, and with respect to normal subjects' eyes, we confirmed significant abnormalities in retinal nerve fiber layer thickness, total macular volume, low-contrast letter acuity, and pupillary reflex metrics in the eye with the thinner retinal nerve fiber layer. For each -5% change in pupil diameter, there was a corresponding 7.1 Amicrom reduction in the average retinal nerve fiber layer thickness. There was a significant difference between the pupillary metric of percent change in diameter and a decrease in low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a substantial 3.4 line loss of low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a 0.2 mm(2) decrease in total macular volume (P < 0.001)., Conclusion: These findings further corroborate the hypothesis that the retina can be utilized as a model to advance our understanding of the mechanisms of axonal and neurodegeneration, and the corresponding impact of these processes upon the pathophysiology of MS and related disorders.

We describe two multiple sclerosis patients who developed pancytopenia following treatment with azathioprine. They were found to have the homozygous polymorphism for thiopurine methyltransferase deficiency and recovered after cessation of drug therapy. We review the literature concerning this molecular derangement and underscore the importance of performing surveillance testing for allelic characterization prior to treatment intervention with this agent for immune-mediated disorders.

Background: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMAs). Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies., Conclusion: Skin reactions in response to injectable DMA therapy in MS are generally mild. However, some reactions can evolve into potentially serious lesions culminating in infection, necrosis, and in some circumstances requiring surgical repair.

Objective: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions., Background: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis., Conclusions: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.