Faculty Bibliography

OBJECTIVE:To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS:This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS:< 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION/CONCLUSIONS:Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

Background: In many of the inflammatory neurologic diseases (IND) of the central nervous system, such as MS, total white blood cell count in the cerebrospinal fluid (CSF) is normal or only mildly elevated, yet ratios of lymphocyte subtypes differ from those seen in the non-inflammatory neurological disease (NIND).
Objective(s): 1. To determine whether lymphocyte ratios in CSF, as assessed by flow cytometry can be used to discriminate between IND and NIND; 2. To determine whether lymphocyte ratios can be used to differentiate between MS and other CNS neuro-inflammatory diseases (such as meningitis, MOG Antibody Syndrome, Susac's syndrome).
Method(s): We retrospectively reviewed the charts of 100 consecutive patients evaluated by NYU neurologists between 1/2013 - 3/2019 for whom lymphocyte subtyping in CSF was carried out. The following lymphocyte markers were assessed: CD19, CD20, kappa-light chain, lambda-light chain, CD20-large (B immunoblasts), CD20-large kappa, CD20-large lambda, CD38bright+/ CD19+/CD20- (plasma cells), CD38bright+/CD19+/CD20- Kappa, CD38bright+/CD19+/CD20- lambda, CD3, CD4, CD8, CD3-/CD7+ (NK-cells), and CD3-/CD4dim + (monocytes). Regression modelling was used to identify lymphocyte subsets that predicted IND vs NIND, as well as MS vs non-MS inflammatory disorder.
Result(s): 62 patients had IND (45 MS, 17 non-MS), 25 had NIND, and 13 did not receive a definitive diagnosis. Regression model that best separated IND from NIND, included CD19+ (higher in IND, p=0.019), CD4+ (higher in IND, p=0.015) and CD3 (nonsignificantly lower in IND, p=0.065). When used as individual predictors, CD19+ >=2% predicted IND with sensitivity of 44%, specificity 88%, positive predictive value of 90% and negative predictive value of 39%, while CD4+ >=55% predicted IND with sensitivity 49.1%, specificity 84.2%, positive predictive value 90% and negative predictive value 35.6%. No NIND patients and 10 IND patients (16%) had CD19+>=5%. Only 2 NIND patients (8%) and 18 IND patients (29%) had CD4+ count >60%. Lymphocyte counts were not useful for differentiating MS from non-MS subgroups except that CD3+ count was lower in the MS group.
Conclusion(s): Flow cytometry of CSF is a useful adjunct in the diagnosis of IND. Higher CD19+ and CD4+ counts were rarely observed in NIND and could be regarded as strong supportive evidence of IND. These results will need to be confirmed in a larger prospective cohort

Objective/UNASSIGNED:To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods/UNASSIGNED:To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results/UNASSIGNED:As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions/UNASSIGNED:Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Background: Natalizumab (NTZ) is a highly efficacious therapy for relapsing forms of multiple sclerosis (MS), but is associated with risk of progressive multifocal leukoencephalopathy (PML). A previous study demonstrated that extending NTZ dosing to every 35-43 days (EID) was associated with lower PML risk than the standard (every 28 days) dosing (SID). This finding raises the important question of whether NTZ should be administered as EID.
Method(s): MS patients receiving NTZ prior to May 31, 2018 at NYU (New York, NY) or Rocky Mountain (Salt Lake City, UT) MS centers were retrospectively identified. EID cohorts were defined similarly to definitions used for the previous PML risk study. For definition 1 (DEF 1), the last 18 months of treatment was considered (<=15 infusions in the last 18 months) while definition 3 (DEF 3) considered the entire infusion history (mean of <=10 infusions/year). Eligible patients were required to have >=24 months of treatment; >=1 MRI available for review; no gaps > 3 months on treatment; no infusions <= 21 days apart; and had no PML. Disease activity was identified by review of MRI radiology reports evaluating for presence of gadolinium (Gd) and new T2 lesions. Generalized Estimating Equation (GEE) logistic models and SAS 3.4 were used in the data analyses.
Result(s): 690 patients met the criteria. For DEF 1, no difference was observed between EID and SID in the odds of presence of Gd lesions (n=500) (OR/month increse 1.1; 95% CI 0.93, 1.31; p=0.27) or new T2 lesions (n=450) (OR/month increase 1.11; 95%CI 0.99, 1.24; p=0.07). Similarly, for DEF 3 no difference was observed between EID and SID in the odds of presence of Gd lesions (n =401) (OR/month increase1.00; 95%CI0.983, 1.025; p=0.75). There is a small increase in the odds of presence of new T2 lesions in EID group (n =437) (OR/month increase1.05; 95% CI 1.01, 1.10; p=0.02). GEE models included adjustments for the frequencies of MRIs for Gd lesions.
Conclusion(s): The study helps address a currently unmet need for evaluating EID NTZ efficacy. These findings suggest that EID of NTZ does not result in significant increased radiological MS disease activity compared to SID, providing further evidence that NTZ efficacy is comparable with EID

Introduction: Although often characterized as a disease of white matter, gray matter (GM) pathology has been shown to play an important role in multiple sclerosis (MS).
Objective(s): We used diffusion kurtosis imaging (DKI), a clinically feasible extension of diffusion tensor imaging (DTI) to characterize pathology in cortical and subcortical GM regions in MS patients compared to controls and study how selected DKI parameters correlate with disease severity in comparison to traditional volumetric approaches.
Method(s): 36 MS patients and 24 age and gender matched controls were enrolled in the study. MS patients completed a Patient Determined Disease Steps Score (PDDS). All patients received MRI on a 3T MR Scanner (Siemens, Skyra, or Prisma), which included whole brain 3D magnetization-prepared rapid gradientecho (MPRAGE) (1 mm³ isotropic resolution) for extracting volumetrics and monopolar diffusion-weighted echo-planar imaging (EPI) (voxel size = 1.7 x 1.7 x 3 mm³, b=0, 250, 1000, and 2000 s/m² along 84 directions, TE/TR = 100/3500 ms, GRAPPA with acceleration 2, and multiband 2) for deriving diffusion metrics. Volume metrics from automatic segmentation from MPRAGE and diffusion metrics which included mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA) were derived for 7 subcortical and 5 cortical GM regions. We determined the partial correlations between PDDS and either GM volume or diffusion parameters covarying for gender and age. We also determined the differences in volume and diffusion metrics between MS patients and controls using ANCOVA with age as the covariate.
Result(s): We observed statistically significant differences in volumes between MS patients and controls for the amygdala, caudate, putamen, nucleus accumbens, cingulate lobe, and subcortical gray volumes with p-values ranging from 0.001 to 0.044. Statistically significant group differences were observed in a majority of the ROI for FA, MD, and MK. Overall, FA was increased, MD was increased, and MK was decreased for most ROI in MS patients compared to controls. There was an increased number of significant partial correlations between PDDS and diffusion metrics compared to PDDS and volume metrics, specifically positive correlations for occipital lobe MD and FA and negative correlations for hippocampal FA.
Conclusion(s): Our results suggest that DKI metrics are sensitive to changes in GM and complimentary to GM volumetrics as an index of GM pathology

Introduction: A 2017 analysis of the TOUCH database demonstrated significantly lower progressive multifocal leukoencephalopathy (PML) risk in anti-JC virus (JCV) seropositive multiple sclerosis patients on natalizumab extended interval dosing (EID) than on standard interval dosing (SID; 300 mg infusion every 4 weeks).The risk assessments did not consider anti-JCV index, a risk factor for the development of PML. A lower index in EID vs SID patients could bias the EID cohort toward lower PML risk.
Objective(s): To compare anti-JCV antibody index values in anti- JCV seropositive patients on natalizumab EID and SID in the 2017 TOUCH analysis of PML risk.
Method(s): De-identified TOUCH patient and Quest Diagnostics index data were matched. Only anti-JCV seropositive patients with available index were included. Analysis cohorts were as prespecified in the 2017 risk analysis: primary (EID or SID in the previous 18 months), secondary (any prolonged period of EID or SID), and tertiary (dosing history consisting primarily of EID or SID). For PML patients, the maximum index value >6 months prior to PML diagnosis was used. For non-PML patients, the overall maximum index value was used.
Result(s): Anti-JCV antibody index was available for 1555 (78.3%) EID and 9027 (68.8%) SID patients (primary analysis), 2494 (74.9%) EID and 10,453 (67.8%) SID patients (secondary analysis), and 647 (79.4%) EID and 15,835 (68.4%) SID patients (tertiary analysis). Patients with available index values had similar natalizumab exposure as the overall analysis populations (median total doses 34-53 vs 32-51 [EID] and 27-47 vs 26-46 [SID]) and identical average dosing intervals (median 34-41 days [EID] and 29-30 days [SID]). In each analysis cohort, the median anti-JCV index was higher in EID patients than in SID patients (primary 1.7 vs 1.3; secondary 1.5 vs 1.4; tertiary 1.6 vs 1.4). Greater proportions of EID than SID patients had index values >0.9 and >1.5 in the primary (index >0.9: 70.2% vs 61.1%; index >1.5: 55.0% vs 45.9%), secondary (index >0.9: 66.1% vs 63.5%; index >1.5: 51.0% vs 48.5%) and tertiary (index >0.9: 70.5% vs 63.2%; index >1.5: 53.9% vs 48.4%) analyses.
Conclusion(s): For each analysis of PML risk, EID patients had numerically higher anti-JCV index values than SID patients. Thus, the lower risk of PML with EID compared to SID is not due to lower anti-JCV index among EID patients. This supports the conclusion that natalizumab EID is associated with a lower risk of PML than SID

Introduction: A model of individual response to therapy based on demographic and clinical information ('The MSBase model'; Brain. 2017, 140:2426) improves clinicians' ability to predict how individual patient will fare on specific disease-modifying therapy (DMT) during a 4-year follow up period. However, the range of predicted outcomes is often too wide to make it the arbiter of decision- making. MS severity score (MSSS), a decile rank of Extended Disability Severity Scale (EDSS) scores in patients from the reference dataset, was shown to be longitudinally stable in MS cohorts, but not for individual patients.
Objective(s): To test whether the addition of MSSS will improve the accuracy and robustness of the existing MSBase predictive model.
Method(s): All eligible patients from the global MSBase cohort who commenced a new DMT during the prospectively recorded follow-up were included. For each DMT, Andersen-Gill survival models were constructed for confirmed disability and relapse events. Principal component analysis was used to reduce dimensionality of the models, as previously described. MSSS was added to these models separate from the principal components.
Result(s): Among 13,780 MSBase enrollees (72% female; 86% with Relapsing MS; age 38.4 [10.6] years, disease duration 8.49 [7.73] years, EDSS 2.65 [1.80]), the most common DMTs were Interferon (IFN)b-1a sc (18%), IFNb-1b sc (12%) and Glatiramer acetate (11%). Higher MSSS was associated with an increased chance of 6-month confirmed recovery from disability (Hazard ratio (HR) 1.17-1.64 p< 0.003; no evidence of association only for alemtuzumab) and with relapse risk (HR 1.03-1.18 p< 0.04, and non-significant for 3 DMTs), but did not predict risk of confirmed disability progression for any DMT. The amount of variance that MSSS helped to explain in addition to the original MSBase model was modest, largest for disability regression (partial adjusted R2 0.01-0.05) and less substantial for risk of relapses (partial adjusted R2 - 0.001-0.026).
Conclusion(s): Mostly independent of DMT identity, higher MSSS was positively associated with a chance of confirmed disability regression, and relapse risk, but not disability worsening. Addition of MSSS to the MSBase model yielded improvements in its predictive accuracy, especially with regard to disability regression and relapse risk. MSSS adds to the prediction of recovery from disability and relapse activity but is not a suitable indicator of individual treatment response

Background/UNASSIGNED:Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS. Methods/UNASSIGNED:Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS. Results/UNASSIGNED:Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS. Conclusions/UNASSIGNED:We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Linear scleroderma "en coup de sabre" (LSES) variant is a cephalic subtype of localized scleroderma that can be associated with extracutaneous stigmata, such as epilepsy, dementia syndromes, as well as focal central nervous system neurologic deficits. While the pathophysiology of cutaneous linear scleroderma includes endothelial cell injury and up regulation of pro-fibrogenic pathways, the basis of LSES-associated neurologic complications is largely unknown. We report a patient with a history of LSES who developed intractable epilepsy and cognitive decline. Magnetic resonance imaging (MRI) of the brain exhibited numerous persistently enhancing brain lesions. Due to progressive neurologic deterioration over a period of 7 years, despite interventional therapy, a brain biopsy was performed. Neuropathologic analysis exhibited acute and chronic cortical ischemia associated with a small vessel lymphocytic vasculitis. Direct immunofluorescent studies showed C5b-9 and IgG deposition on endothelium while indirect immunofluorescent studies demonstrated reactivity of the patient's serum with the microvasculature of the patient's own brain tissue and generic human umbilical vein endothelial cells indicative of anti-endothelial cell antibodies. Therapy focusing on damaged endothelium was implemented. The interleukin-6 (IL-6) receptor inhibitor tocilizumab was used and the patient improved dramatically, likely reflecting the drug's effect on the replenishment of endothelial progenitor cells.

Spinal dural fistulas (SDAVFs) occasionally arise from the same segmental artery as the radiculomedullary branch to the anterior spinal artery. In such cases, selective fistula embolization that does not endanger the anterior spinal artery is not possible, and surgical fistula disconnection is recommended. We present an exceptional case in which rational embolization strategy of SDAVF was feasible because of separate origins from a common segmental artery pedicle of the ventral radiculomedullary artery and the dorsal radicular artery branch supplying the fistula.