Erin E. Longbrake

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients.

Background: Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients. Objective: To phenotypically characterize circulating leukocytes in DMF-treated MS patients. Methods: Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. Results: Lymphopenic DMF-treated patients had significantly fewer circulating CD8+ and CD4+ T cells, CD56dim natural killer (NK) cells, CD19+ B cells and plasmacytoid dendritic cells when compared to controls. CXCR3+ and CCR6+ expression was disproportionately reduced among CD4+ T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56hi NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls. Conclusions: DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8+ T-cells, which may affect their immunocompetence.

Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance

Background Dimethyl fumarate (DMF), a disease-modifying therapy for multiple sclerosis (MS), causes lymphopenia in a fraction of patients. The clinical significance of this is unknown. Several cases of progressive multifocal leukoencephalopathy in lymphopenic fumarate-treated patients have raised concerns about drug safety. Since lymphocytes contribute to MS pathology, lymphopenia may also be a biomarker for response to the drug. Objective The objective of this manuscript is to evaluate risk factors for DMF-induced lymphopenia and drug failure in a real-world population of MS patients. Methods We conducted a retrospective cohort study of 221 patients prescribed DMF at a single academic medical center between March 2013 and February 2015. Results Grade 2–3 lymphopenia developed in 17% of the total cohort and did not resolve during DMF treatment. Older age (>55), lower baseline absolute lymphocyte count and recent natalizumab exposure increased the risk of developing moderate to severe lymphopenia while on DMF. Lymphopenia was not predictive of good clinical response or of breakthrough MS activity on DMF. Conclusions Lymphopenia develops in a significant minority of DMF-treated patients, and if grade 2 or worse, is unlikely to resolve while on the drug. Increased vigilance in lymphocyte monitoring and infection awareness is particularly warranted in older patients and those switching from natalizumab.

Dimethyl Fumarate Associated Lymphopenia in Clinical Practice

Dimethyl fumarate (DMF) was approved in the United States for the treatment of relapsing multiple sclerosis in March, 2013. Grade 3 lymphopenia (absolute lymphocyte count (ALC) <500) developed in approximately 5% of patients in the phase III clinical trials (1, 2). With the approval of the Washington University Human Research Protection Office, we conducted a retrospective chart review of all patients prescribed DMF at our Center from March 2013 to August 2014 (n=144) to assess the prevalence of grades 2 (ALC 500–799) and 3 lymphopenia in a real world setting. Approximately 6% (9/144) of the total cohort developed grade 3 lymphopenia and 14% (20/144) developed grade 2 or 3 lymphopenia. Lymphopenia usually developed after patients had been taking DMF for at least 4 months. Thus, by 4–6 months post-initiation, 10% of patients (4/40) had grade 3 lymphopenia. At >12 months, 28.6% (4/14) had ALC <500; this was significantly higher than the predicted frequency of 5%. Once lymphocyte counts fell, they remained stably low or continued to drop; recovery into the normal range was not observed. Patients over 55 years old were significantly more likely to develop grade 3 lymphopenia compared to younger patients (p=0.034, Fisher’s exact test), which is notable because older patients were excluded from the phase 3 trials of DMF. No clear trends linked lymphopenia to prior treatment with any specific DMT. Sex and race were not significant predictors of lymphopenia. This retrospective study had insufficient numbers and intensity of surveillance to reliably detect any increased incidence of infection in lymphopenic patients. In the group of patients with grade 1 lymphopenia (ALC 800–1000), one developed an infection with HSV-1, and one had shingles. Both recovered fully. Of patients with grades 2–3 lymphopenia, one developed cellulitis. Otherwise, no infections were reported to the treating neurologists. The practical significance of lymphopenia due to DMF has yet to be elucidated. Opportunistic infections, including JC virus infection leading to progressive multifocal leukoencephalopathy (PML), are a known complication of lymphopenia. PML has been described in patients with idiopathic CD4 lymphopenia (3) in addition to those with known risk factors such as HIV or natalizumab therapy. It is unknown whether DMF-induced lymphopenia predisposes to PML. No cases have been reported, but DMF has been in widespread use for only about two years. Moreover, a few cases of PML have occurred in lymphopenic patients who were prescribed older fumarates (4, 5). Guidelines for these older fumarates recommend following blood counts every 3 months and discontinuing the drug if grade 3 lymphopenia develops. However, current prescribing information for DMF simply recommends checking CBC every 6–12 months and does not offer guidelines about when to discontinue therapy. The present study is limited by its retrospective nature and the small number of patients with long-term follow up. Nevertheless, it raises important questions regarding the mechanism and possibly the safety of DMF, particularly in older patients, and suggests that more frequent monitoring may be needed. Further study is needed to guide clinicians in the management of patients who develop low ALCs on DMF. ADDENDUM Since acceptance of this letter, a 54 year old patient treated with DMF for 54 months has died from PML. This patient had been persistently lymphopenic (ALC 290-580) for about 3.5 years prior to her diagnosis with PML.

Effect of Multiple Sclerosis Disease-Modifying Therapies on B Cells and Humoral Immunity

The unequivocal success of B-cell-depleting agents in reducing magnetic resonance imaging and clinical activity in therapeutic trials indicates that B cells play a vital role in mediating the clinical course of relapsing multiple sclerosis (MS). Although no agent that specifically targets B cells has yet been approved for clinical use, all existing disease-modifying therapies (DMTs) for MS modulate B-cell immunity to some degree. This review examines the effects of MS DMTs on B-cell immunity. Most MS DMTs induced a relative decrease in circulating memory B cells with concomitant expansion of circulating B-cell precursors and/or naive B cells. B-cell function was also altered; most DMTs induced B-cell production of the anti-inflammatory cytokine interleukin 10 while inhibiting B-cell expression of proinflammatory cytokines. The commonalities in the effects of approved DMTs on B-cell phenotype and function among treated patients with MS are striking and suggest that effects on B cells underlie part of their efficacy. More complete understanding of how the existing DMTs modulate B-cell immunity may identify future targets for therapeutic intervention.

Quantitative visual tests after poorly recovered optic neuritis due to multiple sclerosis

BACKGROUND Visual dysfunction in MS can be quantified using a variety of tests. Many vision tests have not been formally evaluated among MS patients with existing visual dysfunction. OBJECTIVE Evaluate several versions of visual acuity and contrast sensitivity tests, measures of central and peripheral vision, retina structure, electrophysiologic function, and quality of life among MS patients with moderate/severe visual dysfunction. METHODS Cross-sectional study of 46 patients with stable, incompletely recovered optic neuritis. Testing included Snellen eye charts, several Sloan low contrast charts, Pelli Robson (PR) contrast sensitivity charts, optical coherence tomography, visual fields, Farnsworth Munsell 100-hue test, visual evoked potentials (VEP), and visual function quality of life (VFQ-25) testing. RESULTS 98% of eyes could read two lines of the PR chart, while only 43% read the 2.5% contrast chart. Low contrast tests correlated strongly with each other and with retinal nerve fiber layer (RNFL) thickness, visual fields, and color vision but not with VEPs. For patients with RNFL <75µm, VFQ-25 scores dropped by approximately 2 points for every 1µm decrease in RNFL. CONCLUSION Among MS patients with visual impairment due to optic neuritis, PR contrast sensitivity could be utilized as a single chart. Visual quality of life was associated with RNFL thinning below 75µm.

Effectiveness of alternative dose fingolimod for multiple sclerosis

Background Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. Methods We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. Results Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). Conclusions These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. Classification of Evidence This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Streamlined EDSS for use in multiple sclerosis clinical practice: Development and cross-sectional comparison to EDSS:

Background: The Expanded Disability Status Scale (EDSS) is the standard measure of disability in multiple sclerosis clinical trials. The EDSS has limited application in the clinical setting due to required completion time and scoring complexity. Systematically recording an objective, simplified, less time-intensive, and neurologist-derived disability score would be beneficial for patient care. Objective: To develop and validate a streamlined version of the Expanded Disability Status Scale (sEDSS) for clinical monitoring. Methods: The EDSS was modified by eliminating maneuvers with no impact on function, consolidating redundancies, and simplifying scoring. This sEDSS was refined and preliminarily validated using a pilot cohort of 102 patients. Subsequently, the sEDSS was retrospectively validated using 968 patients from the CombiRx trial. We evaluated correlation and agreement between each functional system as well as the overall sEDSS and EDSS. Results: The sEDSS correlated strongly with the EDSS, both overall (Spearman’s rho = 0.93) and for each functional system (Spearman’s rho 0.65–0.97). Correlation was slightly lower for functional systems where scoring was modified for consolidation and simplification. Conclusion: The sEDSS had strong agreement and correlation with the existing EDSS and can provide a useful measure of disability in clinical practice.

Efficacy and tolerability of oral versus injectable disease-modifying therapies for multiple sclerosis in clinical practice:

Background The advent of oral disease-modifying therapies fundamentally changed the treatment of multiple sclerosis. Nevertheless, impressions of their relative efficacy and tolerability are primarily founded on expert opinion. Objective The purpose of this study was to determine whether oral disease-modifying therapies were better tolerated and/or more effective for controlling multiple sclerosis compared to injectable therapies in clinical practice. Methods Single-center, retrospective cohort study. 480 patients initiated oral (fingolimod, teriflunomide, or dimethyl fumarate) or injectable therapy between March 2013–March 2015 and follow-up data was collected for 5–31 months. Outcomes included on-drug multiple sclerosis activity and drug discontinuation. Cox proportional hazards models were used to control for baseline differences and sensitivity analyses using propensity-weighted matching were performed. Results A higher proportion of teriflunomide-treated patients experienced multiple sclerosis activity compared to those treated with injectable therapies (p = 0.0053) in the adjusted model. Breakthrough multiple sclerosis was equally prevalent among fingolimod and dimethyl fumarate-treated compared to injectable therapy-treated patients. Of patients initiating a disease-modifying therapy, 32–46% discontinued or switched treatments during the study. After controlling for baseline differences, discontinuation rates were comparable across treatment groups. Conclusions In this cohort, oral and injectable disease-modifying therapies were equally well tolerated, but teriflunomide appeared less effective for controlling multiple sclerosis activity than injectable therapies. Further study is needed.

Susac syndrome in a patient with human immunodeficiency virus infection

Susac syndrome (SS) is a diagnosis of exclusion based on findings of encephalopathy, branch retinal artery occlusions (BRAO), and hearing loss (Susac et al. 1979). These components may occur simultaneously or be temporally separated. The diagnosis is strongly supported by pathognomic involvement of the body of the corpus callosum on MRI; deep gray matter lesions, gadolinium enhancing lesions, and leptomeningeal enhancement may also be seen (Susac et al. 2003).