Claire Riley

Inter-individual Variability in the Capacity for Motor Recovery After Ischemic Stroke

Background. Motor recovery after stroke is predicted only moderately by clinical variables, implying that there is still a substantial amount of unexplained, biologically meaningful variability in recovery. Regression diagnostics can indicate whether this is associated simply with Gaussian error or instead with multiple subpopulations that vary in their relationships to the clinical variables. Objective. To perform regression diagnostics on a linear model for recovery versus clinical predictors. Methods. Forty-one patients with ischemic stroke were studied. Impairment was assessed using the upper extremity Fugl-Meyer Motor Score. Motor recovery was defined as the change in the upper extremity Fugl-Meyer Motor Score from 24 to 72 hours after stroke to 3 or 6 months later. The clinical predictors in the model were age, gender, infarct location (subcortical vs cortical), diffusion weighted imaging infarct volume, time to reassessment, and acute upper extremity Fugl-Meyer Motor Score. Regression diagnostics included a Kolmogorov-Smirnov test for Gaussian errors and a test for outliers using Studentized deleted residuals. Results. In the random sample, clinical variables explained only 47% of the variance in recovery. Among the patients with the most severe initial impairment, there was a set of regression outliers who recovered very poorly. With the outliers removed, explained variance in recovery increased to 89%, and recovery was well approximated by a proportional relationship with initial impairment (recovery ≅ 0.70 × initial impairment). Conclusions. Clinical variables only moderately predict motor recovery. Regression diagnostics demonstrated the existence of a subpopulation of outliers with severe initial impairment who show little recovery. When these outliers were removed, clinical variables were good predictors of recovery among the remaining patients, showing a tight proportional relationship to initial impairment.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUNDnPrimary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials.nnnMETHODSnSPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening.nnnRESULTSnA total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017.nnnCONCLUSIONnSPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Association of Deep Gray Matter Damage With Cortical and Spinal Cord Degeneration in Primary Progressive Multiple Sclerosis

IMPORTANCEnThe investigation of cortical gray matter (GM), deep GM nuclei, and spinal cord damage in patients with primary progressive multiple sclerosis (PP-MS) provides insights into the neurodegenerative process responsible for clinical progression of MS.nnnOBJECTIVEnTo investigate the association of magnetic resonance imaging measures of cortical, deep GM, and spinal cord damage and their effect on clinical disability.nnnDESIGN, SETTING, AND PARTICIPANTSnCross-sectional analysis of 26 patients with PP-MS (mean age, 50.9 years; range, 31-65 years; including 14 women) and 20 healthy control participants (mean age, 51.1 years; range, 34-63 years; including 11 women) enrolled at a single US institution. Clinical disability was measured with the Expanded Disability Status Scale, 9-Hole Peg Test, and 25-Foot Walking Test. We collected data from January 1, 2012, through December 31, 2013. Data analysis was performed from January 21 to April 10, 2015.nnnMAIN OUTCOMES AND MEASURESnCortical lesion burden, brain and deep GM volumes, spinal cord area and volume, and scores on the Expanded Disability Status Scale (score range, 0 to 10; higher scores indicate greater disability), 9-Hole Peg Test (measured in seconds; longer performance time indicates greater disability), and 25-Foot Walking Test (test covers 7.5 m; measured in seconds; longer performance time indicates greater disability).nnnRESULTSnThe 26 patients with PP-MS showed significantly smaller mean (SD) brain and spinal cord volumes than the 20 control group patients (normalized brain volume, 1377.81 [65.48] vs 1434.06 [53.67] cm3 [P = .003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm3 [P = .045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm3 [P = .02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm3 [P =u2009.001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm3 [P < .001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm3 [P =.002]). The amount of damage in deep GM structures, especially with respect to the thalamus, was correlated with the number and volume of cortical lesions (mean [SD] thalamus volume, 8.89 [1.10] cm3; cortical lesion number, 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm3; r = -0.52; P < .01). Thalamic atrophy also showed an association with cortical lesion count in the frontal cortex (mean [SD] thalamus volume, 8.89 [1.1] cm3; cortical lesion count in the frontal lobe, 5.0 [5.7]; r = -0.60; P < .01). No association was identified between magnetic resonance imaging measures of the brain and spinal cord damage.nnnCONCLUSIONS AND RELEVANCEnIn this study, the neurodegenerative process occurring in PP-MS appeared to spread across connected structures in the brain while proceeding independently in the spinal cord. These results support the relevance of anatomical connectivity for the propagation of MS damage in the PP phenotype.

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation

OBJECTIVEnThe objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment.nnnMETHODSnEighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patients white matter (VT ratio=VTr), to consider physiologic variability.nnnRESULTSnTest-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter.nnnCONCLUSIONnA reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database

BackgroundnAppropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA.nnnMethodsnWe analyzed data from Tevas global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population.nnnResultsnPregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population.nnnConclusionsnThese data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll‐like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal‐appearing brain tissue, the thickness of the retinal nerve‐fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was ‐0.0010 per year with ibudilast and ‐0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain‐tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT‐MS ClinicalTrials.gov number, NCT01982942.)

Cognitive phenotypes in multiple sclerosis

BackgroundCognitive impairment is a debilitating symptom experienced byxa0~xa050% of multiple sclerosis patients, with processing speed (PS) and memory most affected. Until now, the field has considered cognition in a binary fashion: patients are designated as impaired or not impaired. This designation is typically arrived at by administering a full cognitive battery and assigning a cutoff (e.g., 4 of 11 tests failed) to distinguish impaired/non-impaired. This relatively coarse approach yields a heterogeneous group of “impaired” patients, some of whom may have isolated memory or PS deficits, others with combined deficits. The goal of this study is to determine whether predominant patterns of deficits, “cognitive phenotypes”, can be identified in a large sample of MS patients. Proportional representation of four cognitive phenotypes will be evaluated: (1) not impaired, (2) PS-impaired only, (3) memory-impaired only, (4) PSxa0+xa0memory impaired.MethodsCognition was measured in 128 relapsing–remitting MS patients using validated tests of verbal/visual memory, and PS. Cognitive phenotype representation was evaluated. Differences in age, education, disease duration, and IQ across cognitive phenotype groups were evaluated.ResultsFour cognitive phenotype groups were represented: 56.3% not impaired, 7.8% PS-impaired, 18.8% memory-impaired, 17.2% PSxa0+xa0memory impaired. Across groups, there were no differences in age, education, disease duration. IQ in non-impaired was higher than PSxa0+xa0memory impaired.ConclusionsAdopting a novel classification taxonomy for cognitive phenotypes will advance understanding of cognitive impairment and enable a precision medicine approach to the development of effective, targeted treatments for cognition in persons with MS.

Multiple Sclerosis in the Elderly: Considerations in the Geriatric Population for Diagnosis and Management

Multiple sclerosis is less commonly diagnosed among the elderly. Careful consideration of potential mimics is critical. History, physical exam, and magnetic resonance imaging are important, as are serum and often cerebrospinal fluid testing in diagnosing multiple sclerosis. In the elderly, multiple sclerosis is more often of the progressive subtype and may lead to greater disability. When disease-modifying therapy is offered to a newly or remotely diagnosed elderly patient, the physician must carefully consider the potential risks and benefits. There is limited data from clinical trials to predict the response to these treatments in the elderly. Symptomatic therapies for multiple sclerosis may modify gait impairment, mood disturbance, bladder and bowel dysfunction, neuropathic pain, and spasticity. Interventions include pharmacotherapies, physical and occupational therapies, and rehabilitative strategies to maximize function. In this review, existing data on the features unique to multiple sclerosis in the elderly population are discussed.