Faculty Bibliography

The North American Research Committee on Multiple Sclerosis is a voluntary patient registry with more than 38,000 registrants as of 2015. In a recent collaborative project, longitudinal data on patient-perceived impairment in 11 domains commonly affected by multiple sclerosis were examined and tabulated as a function of disease duration. The patterns of disability accumulation differed by domain. Certain symptoms (sensory, fatigue) were particularly prevalent early in the disease. Other symptoms (mobility, hand function, fatigue, bowel/bladder dysfunction, spasticity) were progressively more common with longer disease duration. Some symptoms (vision, cognition, sensory, pain, depression) were relatively common early on in multiple sclerosis, but did not appear to be more frequent with longer disease duration. Ongoing research includes studies of the impact of disease-modifying therapy and symptomatic treatment on patient-perceived impairment over the disease course.

Natalizumab is an alpha4-integrin monoclonal antibody used for treatment of relapsing multiple sclerosis (MS). At least and nearly 30 cases of liver failure in natalizumab-treated patients are listed in the post-marketing FDA adverse event reporting system (FAERS) and twelve patients with severe liver injury, including several after the first infusion, have been reported (Lisotti et al., 2012; Bezabeh et al., 2010; Martinez-Lapiscina et al., 2013; Michael et al., 2007; Hillen et al., 2015). Herein, we describe a case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab. Liver biopsy demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis. Liver function normalized after natalizumab discontinuation and a subsequent liver biopsy showed resolution of hepatitis. The patient's MS has since been successfully treated with rituximab for over a year. We review the published cases of liver injury associated with natalizumab and those in the post-marketing FDA adverse event reporting system (FAERS).

Background: Vascular involvement in multiple sclerosis (MS) perivascular cuffing and thickened vein walls were described decades ago. Recently, a reduced (periventricular) venous density was reported in MS, and intra-lesional venous shrinking was suggested as an in vivo marker following inflammation. Vascular abnormalities on 7T MRI images have not been investigated in neuromyelitis optica (NMO). Objective: To compare periventricular venous density in NMO, healthy controls and MS using ultra-high field (7T) MRI. Methods: 18 patients with NMO (18 female; age mean+/-SD, range: 48+/-15, 22-71 years), 18 relapsing remitting MS patients (13 female; age mean+/-SD, range: 41+/-9, 20-53 years), and 18 healthy controls (7 female; age mean+/-SD, range: 44+/-14, 20-70 years) were investigated at 7T MRI including T2*-weighted (T2*w) and fluid-attenuated inversion recovery (FLAIR) imaging to calculate the periventricular venous area (PVA in mm²) by a blinded investigator. Results: In total, we detected 131 white matter lesions in 18 NMO patients, 368 white matter lesions were visualized in MS patients, and 139 white matter lesions were depicted in HC. We did not observe any differences in periventricular venous density measured by PVA in NMO (mean+/-SD, range: 132,33+/-24,08, 97-176 mm²) versus HC (Mann-Whitney U test, p=0.171; mean+/-SD, range: 143,33+/-27,30, 88-196 mm²). Contrarily, PVA was significantly reduced in MS (Mann-Whitney U test, p=0.019; mean+/-SD, range: 118,81+/-29,63, 61-170 mm²) compared to HC as described previously. Conclusions: The periventricular venous system appeared - in contrast to

Objectives: To compare relapse and sustained disability progression rates in previously stable MS patients who discontinued their disease- modifying therapy ('DMTs stoppers') and propensity-score matched MS patients who continued their therapy ('DMT stayers'). Background: It is not known how disease course in previously stable MS patients who discontinue DMT compares to disease course who stay on DMT. The large international MSBase Registry that prospectively follows MS patients in real-world clinical setting affords an opportunity for a prospective comparative study of patients who elected to stop DMT and those who did not. Methods: Patients were included in the 'DMT stoppers' group if they had diagnosis of MS; no relapses and no change in Expanded Disability Status Scale (EDSS) for >5 years at the time of DMD discontinuation; had continuous treatment with DMD for >3 years; were followed for >3 years after stopping DMD; did not restart DMD for >3 months after discontinuation. DMT stayers were matched 1:1 according to age, gender, disease duration, EDSS and proportion of time on prior treatment. Pairwise analysis of DMT stoppers and stayers from the international MSBase registry data was conducted using propensity-score matching. The groups were compared with respect to risk of relapses and sustained disability progression using Cox marginal model, using simultaneous censoring of the matched pair. Results: The cohort consisted of 140 DMT stoppers and 140 propensity-scored matched DMT stayers. 73% were women, mean age was 48 year; mean disease duration - 16 years; mean baseline ED

Objectives: To determine correlation between patient-reported disability as assessed with Patient Determined Disability Steps (PDDS) and clinician-rated Expanded Disability Status Scale (EDSS). Background: The EDSS is the 'gold standard' clinical assessment of disability in MS, but requires a trained examiner and is time-consuming. It would be valuable to have a patient-reported outcome measure for tracking disability that shows a high degree of concordance with EDSS and is easy to deploy in a busy clinic. Methods: Consecutive MS patients at an outpatient MS Center were asked to record their disability on the PDDS scale at routine visits, while a Neurostatus-certified physician assessed EDSS, confirmed MS diagnosis, and documented disease duration, relapse status and current disease-modifying therapy in a standardized fashion. Correlations between PDDS, EDSS and Functional System (FS) scores were computed for all patients using SAS software. EDSS-based MS Severity Score (MSSS) and PDDS-based Patient reported-MS severity Score (P-MSSS) were obtained using published reference Tables and compared. Results: 195 MS patients (age 46.4 +/-12.7 years, range=18-87; 73% female; disease duration 10.2+/- 7.4 years) were included. 82% of patients were on DMTs. 11 patients (5.6%) had a relapse at the time of the visit. Mean PDDS was 2.2 +/-2.4, range 0-7. Mean EDSS was 3.1 +/-2.3, range 0-9. PDDS strongly correlated with the EDSS (r=0.89, p< 0.0001) and P-MSSS correlated with MSSS (r=0.83, p< .0001). PDDS scores differed from the EDSS by 2 points or more in only 7 patients (3.6%). PDDS/EDSS correlation were similar among patients with and without obligate ambulatory assistance (r=0.62 for EDSS< 6 group and r= 0.56 for EDSS>5.5 group) and remained highly significant in patients with a relapse (r=0.84, p< .001). PDDS and EDSS showed strong correlation with pyramidal score (r=0.86 for PDDS and r=0.84 for EDSS) and bladder score (r=0.70 for PDDS and r=0.66 for EDSS); weak-to-moderate correlation (r from 0.3 to 0.6) with cerebellar, brainstem, sensory and cognition FS scores, and no correlation (r< 0.02) with vision score. Conclusions: The single-question PDDS is a reliable, highlyefficient and cost-effective tool for disability assessment in clinical and research settings that shows excellent correlation with the 'gold standard' EDSS