Faculty Bibliography

Currently used classification schemes for multiple sclerosis (MS) have not taken into account disease severity, instead focusing on disease phenotype (ie, relapsing vs. progressive). In this article, we argue that disease severity adds a crucial dimension to the clinical picture and may help guide treatment decisions. We outline a practical, easy-to-implement, and comprehensive scheme for severity grading in MS put forward by our mentor, Professor Joseph Herbert. We believe that severity grading may help to better prognosticate individual disease course, formulate and test rational treatment algorithms, and enhance research efforts in MS.

BACKGROUND: Dimethyl fumarate (DMF) was approved by the US Food and Drug Administration (FDA) for treatment of relapsing-remitting multiple sclerosis (RRMS) based on two phase III randomized clinical trials (RCTs). There were not enough non-White patients enrolled in these RCTs to allow for subgroup analysis based on race. Efficacy and tolerability of DMF therapy across various racial groups is unknown. METHODS: Retrospective chart review was performed on all patients with RRMS who were started on DMF in two tertiary multiple sclerosis (MS) clinics. Efficacy and tolerability of DMF was compared across three self-identified racial groups: White-American (WA), African-American (AA) and Hispanic-American (HA). RESULTS: A total of 390 RRMS patients were included in the study: 261 (66.9%) WA, 69 (17.7%) AA and 52 (13.3%) HA. When comparing 'pre-DMF' (1 year) and 'on DMF' (mean follow up of 14 months) periods, statistically significant reduction in rates of annualized relapses (WA from 0.44 to 0.19, AA from 0.39 to 0.15, and HA from 0.39 to 0.14; no differences between groups), new T2 lesions (WA from 45% to 23%, AA from 39% to 23%, HA from 52% to 26%; no difference between groups), and Gd+ lesions (WA from 25% to 13%, AA from 24% to 7%, HA from 23% to 12%; no difference between groups) were seen. DMF was relatively well tolerated across all groups, with an overall discontinuation rate of 20% (no difference between the three groups). CONCLUSION: Efficacy of DMF in our clinic population did not differ across three major ethnic groups, WA, AA and HA, and was comparable with results observed in the pivotal studies. These 'real-life' data suggest that race is not a factor that needs to be taken into account when initiating DMF.

Objective: Investigate when extending Natalizumab (NTZ) dosing interval may attenuate CD34+ cell mobilization from bone marrow. Background: NTZ extended interval dosing (EID) (35 - 58 days) is an approach being explored to reduce the risk of PML without compromising effectiveness of drug. PML susceptibility has been associated, in part, to NTZ-induced mobilization of JC virus from the bone marrow into peripheral circulation via CD 19+ and CD34+ cells. Less frequent NTZ dosing may reduce mobilization of these cells, thereby decreasing risk of passage of JCV infected cells into the CNS. Methods: Blood from RRMS NTZ treated patients was separated using flow cytometry into CD34+, CD19+, and CD3+ subsets. DNA templates prepared using quantitative PCR for JCV DNA identification. Plasma was tested for anti-JCV antibodies by ELISA (NINDS) and compared to commercial assay (Focus). Patients on EID NTZ (35 - 58d) were compared to those on standard interval dose (SID) schedule (28 - 34d). Results: 20 EID and 7 SID patients: mean age (range) EID 45 (28-70); SID 43 (19-59) years ; EID 50% SID 57% female; mean of MS diagnosis (range) EID 14.1 (3-30) SID 9.8 (1-26) years; duration of NTZ treatment mean (range) EID 5.3 (2-9) SID 3.7 (1-7) years; mean (range) duration on EID 28 (14-64) months; JCV index mean (range) EID 0.58 (0.19 -2.82) and in SID 0.16 (0.09 - 0.26). Extent of CD34+ cell mobilization was similar in both groups. 1/20 EID patients and 1/7 SID patients are viremic with JCV. SID patient was seronegative (antibody titer, 640)(NINDS);JCV index of 0.12 (Focus). EID patient was seropositive (antibody titer 2560) (NINDS); JCV index 0.22 (Focus). Conclusion: This ongoing study is evaluating biological effects of EID NTZ dosing that may be pertinent to PML risk. Preliminary data does not show reduced CD34+ mobilization with EID NTZ schedule. Additional patient samples from time points further removed from previous NTZ dosing should be evaluated

BACKGROUND: There is substantial overlap between MRI of acute spinal cord lesions from neuromyelitis optica (NMO) and spinal cord infarct (SCI) in clinical practice. However, early differentiation is important since management approaches to minimize morbidity from NMO or SCI differ significantly. OBJECTIVE: To identify MRI features at initial presentation that may help to differentiate NMO acute myelitis from SCI. METHODS: 2 board-certified neuroradiologists, blinded to final diagnosis, retrospectively characterized MRI features at symptom onset for subjects with serologically-proven NMO (N=13) or SCI (N=11) from a single institution. Univariate and multivariate analyses were used to identify factors associated with NMO or SCI. RESULTS: SCI was more common in men and Caucasians, while NMO was more common in non-Caucasian women (P<0.05). MRI features associated with NMO acute myelitis (P<0.05) included location within 7-cm of cervicomedullary junction; lesion extending to pial surface; 'bright spotty lesions' on axial T2 MRI; and gadolinium enhancement. Patient's age, lesion length and cross-sectional area, cord expansion, and the "owl's eyes" sign did not differ between the two groups (P>0.05). CONCLUSION: Along with patient demographic characteristics, lesion features on MRI, including lesion location, extension to pial border and presence of 'bright spotty lesion' can help differentiate acute myelitis of NMO from SCI in the acute setting.

The rapid escalation in prices of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the past decade has resulted in a dramatic overall increase in the costs of MS-related care. In this article, we outline various approaches whereby neurologists can contribute to responsible cost containment while maintaining, and even enhancing, the quality of MS care. The premise of the article is that clinicians are uniquely positioned to introduce innovative management strategies that are both medically sound and cost-efficient. We describe our "top 5" recommendations, including strategies for customizing relapse treatment; developing alternative dosing schedules for Food and Drug Administration-approved MS DMTs; using off-label therapies for relapse suppression; and limiting the use of DMTs to those who clearly fulfill diagnostic criteria, and who might benefit from continued use over time. These suggestions are well-grounded in the literature and our personal experience, but are not always supported with rigorous Class I evidence as yet. We advocate for neurologists to take a greater role in shaping clinical research agendas and helping to establish cost-effective approaches on a firm empiric basis.

OBJECTIVE: To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica spectrum disorder (NMOSD) vs multiple sclerosis (MS) lesions in a cross-sectional study. METHODS: Ten patients with NMOSD and 10 patients with relapsing-remitting MS underwent 7-tesla brain MRI including supratentorial T2*-weighted imaging and supratentorial susceptibility weighted imaging. Next, we analyzed intra- and perilesional paramagnetic phase changes on susceptibility weighted imaging filtered magnetic resonance phase images. RESULTS: We frequently observed paramagnetic rim-like (75 of 232 lesions, 32%) or nodular (32 of 232 lesions, 14%) phase changes in MS lesions, but only rarely in NMOSD lesions (rim-like phase changes: 2 of 112 lesions, 2%, p < 0.001; nodular phase changes: 2 of 112 lesions, 2%, p < 0.001). CONCLUSIONS: Rim-like or nodular paramagnetic MRI phase changes are characteristic for MS lesions and not frequently detectable in NMOSD. Future prospective studies should ask whether these imaging findings can be used as a biomarker to distinguish between NMOSD- and MS-related brain lesions.

BACKGROUND: Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. OBJECTIVES: (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers. METHODS: Inclusion criteria for DMT stoppers were: age >/=18 years; no relapses for >/=5 years at DMT discontinuation; follow-up for >/=3 years after stopping DMT; not restarting DMT for >/=3 months after discontinuation. DMT stayers were required to have no relapses for >/=5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model. RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period. CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

The discovery of a highly specific biomarker of neuromyelitis optica (NMO)-the anti-aquaporin-4 (AQP4) antibody-has opened new paths to understanding disease pathogenesis and afforded a way to confirm the diagnosis in clinical practice. An important consequence of the discovery is the broadening of the spectrum of syndromes seen in the context of AQP4 autoimmunity. These syndromes have been subsumed under the rubric of NMO spectrum disorder (NMOSD). The current classification recognizes not only optic neuritis and myelitis as core syndromes of NMOSD but also cerebral, diencephalic, brainstem, and area postrema syndromes. These neurologic syndromes are the focus of our review. AQP4 is also expressed in many organs outside of the central nervous system, and this may explain some of the unusual, non-neurologic features that have been occasionally reported in NMOSD. Our review catalogues non-neurologic manifestations seen in NMOSD and concludes with a discussion of frequently associated autoimmune and neoplastic comorbidities of NMOSD.

OBJECTIVE: To quantify the periventricular venous density in neuromyelitis optica spectrum disease (NMOSD) in comparison to that in patients with multiple sclerosis (MS) and healthy control subjects. MATERIALS AND METHODS: Sixteen patients with NMOSD, 16 patients with MS and 16 healthy control subjects underwent 7.0-Tesla (7T) MRI. The imaging protocol included T2*-weighted (T2*w) fast low angle-shot (FLASH) and fluid-attenuated inversion recovery (FLAIR) sequences. The periventricular venous area (PVA) was manually determined by a blinded investigator in order to estimate the periventricular venous density in a region of interest-based approach. RESULTS: No significant differences in periventricular venous density indicated by PVA were detectable in NMOSD versus healthy controls (p = 0.226). In contrast, PVA was significantly reduced in MS patients compared to healthy controls (p = 0.013). CONCLUSION: Unlike patients with MS, those suffering from NMOSD did not show reduced venous visibility. This finding may underscore primary and secondary pathophysiological differences between these two distinct diseases of the central nervous system.