Neurology February 2009 Volume 72 Issue 5

Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.Methods: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.Results: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed.Conclusion: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.(C)2009AAN Enterprises, Inc.

Objectives: To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and [chi]2 McNemar tests.Results: There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p = 0.0029).Conclusion: Our study focused on posterior fossa anomalies, which are an integral part of cobblestone complex lissencephalies but previously have not been well categorized for other lissencephalies. According to our results and the review of the literature, we propose a new classification of human lissencephalies.(C)2009AAN Enterprises, Inc.

Background: Treatment of neurodegenerative diseases is likely to be most beneficial in the very early, possibly preclinical stages of degeneration. We explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. The availability of a definitive genetic test for Huntington disease (HD) provides an excellent metric for judging the performance of such methods in gene mutation carriers who are free of symptoms.Methods: Using the gray matter segment of MRI scans, this study explored the usefulness of a multivariate support vector machine to automatically identify presymptomatic HD gene mutation carriers (PSCs) in the absence of any a priori information. A multicenter data set of 96 PSCs and 95 age- and sex-matched controls was studied. The PSC group was subclassified into three groups based on time from predicted clinical onset, an estimate that is a function of DNA mutation size and age.Results: Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned to the PSC group 69% of the time. Accuracy improved to 83% when regions affected by the disease were selected a priori for analysis. Performance was at chance when the probability of developing symptoms in 5 years was less than 10%.Conclusions: Presymptomatic Huntington disease gene mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic scans, without additional a priori information. Prior information is required to allow separation when degenerative changes are either subtle or variable.(C)2009AAN Enterprises, Inc.

Objective: To assess the efficacy and tolerability of the nondopaminergic agent XP13512/GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS).Methods: Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 pm with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression-Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters.Results: A total of 222 patients were randomized (XP13512 = 114, placebo = 108) and 192 patients (XP13512 = 100, placebo = 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (-13.2) compared with placebo (-8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of -4.0 (95% confidence interval [CI], -6.2 to -1.9; p = 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p < 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted.Conclusions: XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS.(C)2009AAN Enterprises, Inc.

Objective: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses.Method: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction.Results: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD.Conclusions: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making.(C)2009AAN Enterprises, Inc.