Neurology January 2013 Volume 80 Issue 1

Objectives: Age and stroke severity are major determinants of stroke outcomes, but systematically incorporating these prognosticators in the routine practice of acute ischemic stroke can be challenging. We evaluated the effect of an index combining age and stroke severity on response to IV tissue plasminogen activator (tPA) among patients in the National Institute of Neurological Disorders and Stroke (NINDS) tPA stroke trials.Methods: We created the Stroke Prognostication using Age and NIH Stroke Scale (SPAN) index by combining age in years plus NIH Stroke Scale (NIHSS) >=100. We applied the SPAN-100 index to patients in the NINDS tPA stroke trials (parts I and II) to evaluate its ability to predict clinical response and risk of intracerebral hemorrhage (ICH) after thrombolysis. The main outcome measures included ICH (any type) and a composite favorable outcome (defined as a modified Rankin Scale score of 0 or 1, NIHSS <=1, Barthel index >=95, and Glasgow Outcome Scale score of 1) at 3 months. Bivariate and multivariable logistic regression analyses were used to determine the association between SPAN-100 and outcomes of interest.Results: Among 624 patients in the NINDS trials, 62 (9.9%) participants were SPAN-100 positive. Among those receiving tPA, ICH rates were higher for SPAN-100-positive patients (42% vs 12% in SPAN-100-negative patients; p < 0.001); similarly, ICH rates were higher in SPAN-100-positive patients (19% vs 5%; p = 0.005) among those not receiving tPA. SPAN-100 was associated with worse outcomes. The benefit of tPA, defined as favorable composite outcome at 3 months, was present in SPAN-100-negative patients (55.4% vs 40.2%; p < 0.001), but not in SPAN-100-positive patients (5.6% tPA vs 3.9%; p = 0.76). Similar trends were found for secondary outcomes (e.g., symptomatic ICH, catastrophic outcome, discharge home).Conclusion: The SPAN-100 index could be a simple method for estimating the clinical response and risk of hemorrhagic complications after tPA for acute ischemic stroke. These results need further confirmation in larger contemporary datasets.(C)2013 American Academy of Neurology

Objective: To characterize and follow the diffuse gray and white matter (GM/WM) metabolic abnormalities in early relapsing-remitting multiple sclerosis using proton magnetic resonance spectroscopic imaging (1H-MRSI).Methods: Eighteen recently diagnosed, mildly disabled patients (mean baseline time from diagnosis 32 months, mean Expanded Disability Status Scale [EDSS] score 1.3), all on immunomodulatory medication, were scanned semiannually for 3 years with T1-weighted and T2-weighted MRI and 3D 1H-MRSI at 3 T. Ten sex- and age-matched controls were followed annually. Global absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) were obtained for all GM and WM in the 360 cm3 1H-MRSI volume of interest.Results: Patients' average WM Cr, Cho, and mI concentrations (over all time points), 5.3 +/- 0.4, 1.6 +/- 0.1, and 5.1 +/- 0.7 mM, were 8%, 12%, and 11% higher than controls' (p <= 0.01), while their WM NAA, 7.4 +/- 0.7 mM, was 6% lower (p = 0.07). There were increases with time of patients' WM Cr: 0.1 mM/year, Cho: 0.02 mM/year, and NAA: 0.1 mM/year (all p < 0.05). None of the patients' metabolic concentrations correlated with their EDSS score, relapse rate, GM/WM/CSF fractions, or lesion volume.Conclusions: Diffuse WM glial abnormalities were larger in magnitude than the axonal abnormalities and increased over time independently of conventional clinical or imaging metrics and despite immunomodulatory treatment. In contrast, the axonal abnormalities showed partial recovery, suggesting that patients' lower WM NAA levels represented a dysfunction, which may abate with treatment. Absence of detectable diffuse changes in GM suggests that injury there is minimal, focal, or heterogeneous between cortex and deep GM nuclei.(C)2013 American Academy of Neurology

Objective: Alemtuzumab is potentially a highly effective treatment for relapsing multiple sclerosis (MS) acting via complement-mediated lysis of circulating lymphocytes. Variability in posttreatment lymphocyte recovery time is observed, with some patients showing striking durability in the efficacy of treatment. This study aims to establish whether this observed variation affects clinical and imaging parameters of disease activity.Methods: A total of 56 patients were followed for a median of 39.5 months post alemtuzumab treatment with interval clinical assessments, lymphocyte immunophenotyping, and MRI. Timing and degree of CD4+, CD8+, and CD19+ recovery were correlated with the re-emergence of disease activity defined as clinical relapse, increasing disability, and new T2/enhancing lesions on MRI.Results: New disease activity was recorded in 14% of patients. Mean time to CD19+, CD8+, and CD4+ reconstitution was 6, 10, and 36 months. No differences were observed in CD8+ and CD19+ reconstitution between patients with active disease and those in remission. Patients with active disease showed an accelerated recovery of CD4+ cells (p = 0.001) with a difference in absolute CD4+ counts at 24 months (p = 0.009). CD4+ counts <388.5 x 106 cells/mL predicted MRI stability.Conclusions: Differential lymphocyte recovery in MS following alemtuzumab may be a biomarker for relapse and also inform monitoring and treatment protocols.Classification of evidence: This study provides Class IV evidence that differential lymphocyte reconstitution after alemtuzumab treatment may be a biomarker for relapse.(C)2013 American Academy of Neurology

Objective: Spinal cord (SC) lesions are frequently found in multiple sclerosis (MS), but are rare in healthy aging and cerebrovascular patients. Our aim was to analyze the contribution of SC involvement in clinically isolated syndrome (CIS) in diagnosing MS according the McDonald 2010 criteria and in predicting conversion to clinically definite MS (CDMS).Methods: We prospectively followed monofocal, relapsing onset CIS patients with either SC or brain symptom onset (including optic neuritis). MRI of the brain and SC were performed shortly after onset and patients were followed for 24 to 119 months (median 64 months). SC MRI findings were assessed for their contribution to the McDonald 2010 diagnostic criteria and their effect on conversion to CDMS.Results: One hundred twenty-one patients were included (63 spinal CIS). Based on the brain scan only, 36 patients fulfilled the McDonald criteria; by including SC findings, 6 additional patients fulfilled these criteria. To diagnose 1 additional nonspinal CIS patient, the number needed to scan is 7. In nonspinal CIS patients that did not fulfill McDonald brain MRI criteria (n = 42), presence of an SC lesion was associated with a higher risk of conversion to CDMS (odds ratio: 14.4; 95% confidence interval: 2.6-80.0) and shorter time to conversion to CDMS (hazard ratio: 51.4; 95% confidence interval: 5.5-476.3).Conclusions: Presence of SC lesions facilitates diagnosing MS and is predictive for conversion to CDMS, especially in patients with nonspinal CIS who do not fulfill brain MRI criteria. We therefore recommend performing an SC scan in patients with nonspinal CIS who do not fulfill McDonald brain MRI criteria.(C)2013 American Academy of Neurology

Objective: To determine whether amyloid burden, as indexed by Pittsburgh compound B (PiB) retention, identifies patients with Parkinson disease with mild cognitive impairment (PD-MCI) compared to those with normal cognition (PD-nl). A related aim is to determine whether amyloid burden predicts cognitive decline in a cohort of subjects with PD without dementia.Methods: In this prospective cohort study, we examined 46 subjects with PD without dementia, of whom 35 had normal cognition and 11 met criteria for PD-MCI at study baseline. All subjects underwent standardized neurologic and neuropsychological examinations and PiB PET at baseline, and clinical examinations were conducted annually for up to 5 years.Results: At baseline, precuneus PiB retention did not distinguish PD-MCI from PD-nl. Subjects with PD-MCI declined more rapidly than PD-nl subjects on cognitive tests of memory, executive function, and activation retrieval. Of the 35 PD-nl subjects, 8 progressed to PD-MCI and 1 to dementia; of the 11 PD-MCI subjects, 5 converted to dementia. Both higher PiB retention and a diagnosis of PD-MCI predicted a greater hazard of conversion to a more severe diagnosis. Baseline PiB retention predicted worsening in executive function over time. The APOE [epsilon]4 allele also related to worsening in executive function, as well as visuospatial function, activation retrieval, and performance on the Mini-Mental State Examination. In contrast to its relation to cognitive decline, PiB retention did not affect progression of motor impairment.Conclusions: At baseline measurements, amyloid burden does not distinguish between cognitively impaired and unimpaired subjects with PD without dementia, but our data suggest that amyloid contributes to cognitive, but not motor, decline over time.(C)2013 American Academy of Neurology

Objectives: To determine the long-term incidence of cardiac life-threatening complications and death in patients with the m.3243A>G mutation, and to identify cardiac prognostic factors.Methods: We retrospectively included patients carrying the m.3243A>G mutation who were admitted to the Neuromuscular Disease Clinic of Pitie Salpetriere Hospital between January 1992 and December 2010. We collected information relative to their yearly neurologic and cardiac investigations, their mutation load in blood, urine, and muscle at initial admission, and the occurrence of cardiac life-threatening adverse events and death during follow-up.Results: Forty-one patients (median age = 47 years [36-55 years], men = 13) were included, of whom 38 had clinical manifestations of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and 3 were asymptomatic. One patient had a personal history of cardiac transplantation. Cardiac investigations displayed left ventricular hypertrophy, left ventricular dysfunction, or both abnormalities in 18 patients, along with Wolff-Parkinson-White syndrome in 7, conduction system disease in 4, and atrial fibrillation in 1. Over a median 5-year (3-9 years) follow-up period, 11 patients died, including 3 due to heart failure; 7 had life-threatening adverse events, including 6 hospitalizations for severe heart failure and 1 resuscitated cardiac arrest. By multivariate analysis, left ventricular hypertrophy was the only parameter independently associated with occurrence of cardiac adverse events.Conclusion: Patients with the m.3243A>G mutation have a high incidence of cardiac death and life-threatening adverse events. Left ventricular hypertrophy was the only parameter independently associated with occurrence of these events.(C)2013 American Academy of Neurology