Neurology August 2012 Volume 79 Issue 6

Objectives: We have shown that a Breakthrough Series-based implementation program increases the number of patients with acute ischemic stroke treated with alteplase 4.5% in real-life settings. It is unclear whether such an implementation program is cost-effective.Methods: The practice study includes 12 randomized hospitals and 5,515 patients. Its present cost-effectiveness analysis involves 1,657 patients with ischemic stroke admitted within 4 hours from onset. Defined primary outcomes are thrombolysis rate and actual health care costs up to 3 months, including additional implementation efforts. Secondary outcomes are lifetime quality-adjusted years (QALYs) and lifetime costs of individual trial patients, using a validated probabilistic, disability-stratified stroke life table. Differences in outcome include 95% confidence intervals (CI), adjusted for intracluster correlation.Results: The thrombolysis rate in the intervention group was 44.3% vs 39.8% in the control group (difference 4.5%; 95% CI 3.1% to 5.9%. Mean costs per patient at 3 months (euros were converted to 2010 USD) were $9,192 USD in the intervention group and $9,647 USD in the control group (difference -$455 USD; 95% CI -$232 to -$679 USD). Lifetime QALYs in the intervention group were 3.89 and in the control group 3.84 (difference 0.05; 95% CI -0.04 to 0.14). The mean lifetime costs in the intervention group were $22,994 USD against $24,315 USD in the control group (difference -$1,321 USD; 95% CI -$1,722 to -$921 USD).Conclusions: A Breakthrough Series implementation program of thrombolysis increases thrombolysis. It saves short- and long-term health care costs due to lower hospital admission and residential costs, increasing stroke care efficiency.GLOSSARY: CI: confidence intervalEQ-5D: EuroQol 5-dimensional questionnairemRS: modified Rankin ScaleNIHSS: NIH Stroke ScaleOR: odds ratioQALY: quality-adjusted yearsrtPA: recombinant tissue plasminogen activator.(C)2012 American Academy of Neurology

Objective: Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability.Methods: Using PET and optimized modeling and segmentation procedures, we investigated cortical 11C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29).Results: Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS.Conclusions: Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.GLOSSARY: AC-PC : anterior-posterior commissureEDSS : Expanded Disability Status ScaleGd : gadoliniumGM : gray matterMAPER : multi-atlas propagation with enhanced registrationMRS : magnetic resonance spectroscopyMS : multiple sclerosisMSIS-29 : Multiple Sclerosis Impact ScaleROI : region of interestRRMS : relapsing-remitting multiple sclerosisSPMS : secondary progressive multiple sclerosisTAC : time-activity curveTE : echo timeTI : inversion timeTR : repetition timeWM : white matter(C)2012 American Academy of Neurology

Objective: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk.Methods: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls.Results: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10-12) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10-18).Conclusions: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.GLOSSARY: ABMDR: Australian Bone Marrow Donor RegistryAH: ancestral haplotypeHARP: heterozygous ambiguity resolving primerMS: multiple sclerosisOR: odds ratioPDDD: Perth Demyelinating Disease DatabaseVDR: vitamin D receptorVDRE: vitamin D-responsive element(C)2012 American Academy of Neurology

Objective: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease.Methods: We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy).Results: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center.Conclusion: In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation.GLOSSARY: AUC: area under the curveCJD: Creutzfeldt-Jakob diseaseNPDPSC : National Prion Disease Pathology Surveillance CenterPPV : positive predictive valueROC : receiver operating characteristic.(C)2012 American Academy of Neurology

Objective: To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.Methods: We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.Results: Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).Conclusion: Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.GLOSSARY: AD : Alzheimer diseaseAUROC : area under the receiver operating characteristic curveCERAD : Consortium to Establish a Registry for Alzheimer's DiseaseDLB : dementia with Lewy bodiesGM : gray matterLB : Lewy bodiesMCI : mild cognitive impairmentNFT : neurofibrillary tangleROI : region of interest.(C)2012 American Academy of Neurology

Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan.Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.GLOSSARY: CI: confidence intervalCSF1R: colony-stimulating factor 1 receptorFLAIR: fluid-attenuated inversion recoveryHDLS: hereditary diffuse leukoencephalopathy with spheroidsMLD: metachromatic leukodystrophyMS: multiple sclerosisSI: signal intensityWM: white matterWNL: white matter lesionX-ALD: X-linked adrenoleukodystrophy(C)2012 American Academy of Neurology

Objective: To examine whether frontal lobe abnormalities on magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) correlate with poor letter fluency (LF).Methods: Twenty-five patients with ALS (20 with definite, probable, or possible ALS and 5 with progressive muscular atrophy) performed an LF task, involving F word generation in 1 minute, and underwent MRS. Comparisons were made between patients with ALS with impaired LF and unimpaired LF based on an empirically derived cutoff score. A Spearman correlation was performed between the patient's N-acetyl acetate/creatinine-phosphocreatinine ratio (NAA/Cr) and the number of F words generated.Results: LF was impaired in 50% of patients with ALS. Patients with impaired LF had reduced NAA/Cr in the DLPFC compared with those with unimpaired LF (p = 0.007). There was a significant correlation between LF and NAA/Cr in the DLPFC (r = 0.51, p = 0.0009). The ALS Functional Rating Scale score, clinical region of motor onset, and disease category had no effect on LF or NAA/Cr in the DLPFC.Conclusions: A reduced NAA/Cr in the DLPFC of patients with ALS is a marker of neuronal dysfunction and correlates with impaired performance on a clinical measure of executive function.GLOSSARY: ALS: amyotrophic lateral sclerosisALS-FRS: ALS Functional Rating ScaleANOVA: analysis of varianceAVG: averageCr: creatine-phosphocreatinineDLPFC: dorsolateral prefrontal cortexLF: letter fluencyLFi: letter fluency indexMRS: magnetic resonance spectroscopyNAA: N-acetyl aspartateNAA/Cr: N-acetyl aspartate/creatine-phosphocreatinine ratioPMA: progressive muscular atrophyTE: echo timeTR: repetition time(C)2012 American Academy of Neurology

Objective: To develop an evidence-based guideline assessing pharmacologic options for treating Huntington disease (HD) chorea.Methods: We evaluated available evidence from a structured literature review performed through February 2011.Results and recommendations: If HD chorea requires treatment, clinicians should prescribe tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) (Level B) for varying degrees of expected benefit. Occurrence of adverse events should be discussed and monitored, particularly depression/suicidality and parkinsonism with tetrabenazine and elevated liver enzymes with riluzole. Clinicians may also prescribe nabilone for modest decreases (1- to <2-point changes on the Unified Huntington's Disease Rating Scale [UHDRS] chorea score) in HD chorea (Level C), but information is insufficient to recommend long-term use, particularly given abuse potential concerns (Level U). Clinicians should not prescribe riluzole 100 mg/day for moderate (2- to < 3-point UHDRS chorea change) short-term benefits (Level B) or for any long-term (3-year) HD antichoreic goals (Level B). Clinicians may choose not to prescribe ethyl-EPA (Level B), minocycline (Level B), or creatine (Level C) for very important improvements (>3-point UHDRS chorea change) in HD chorea. Clinicians may choose not to prescribe coenzyme Q10 (Level B) for moderate improvements in HD chorea. Data are insufficient to make recommendations regarding the use of neuroleptics or donepezil for HD chorea treatment (Level U).GLOSSARY: AAN: American Academy of NeurologyAE: adverse eventCI: confidence intervalethyl-EPA: ethyl-eicosapentaenoic acidFDA: Food and Drug AdministrationHAM-D: Hamilton Depression ScaleHD: Huntington diseaseHSG: Huntington Study GroupNMS: neuroleptic malignant syndromeOR: odds ratioRCT: randomized controlled trialSAE: serious adverse eventTBZ: tetrabenazineTFC: total functional capacityTMS-4: Total Motor Score 4 subscale of the Unified Huntington's Disease Rating ScaleUHDRS: Unified Huntington's Disease Rating Scale.(C)2012 American Academy of Neurology