Neurology September 2012 Volume 79 Issue 11

Objectives: Despite evidence that epilepsy surgery is more effective than medical therapy, significant delays between seizure intractability and surgery exist. We aimed to develop a new Web-based methodology to assist physicians in identifying patients who might benefit from an epilepsy surgery evaluation.Methods: The RAND/UCLA appropriateness method was used. Clinical scenarios were developed based on eligibility criteria from previously published surgical series. Thirteen national experts rated the scenarios for their appropriateness for an epilepsy surgery evaluation based on published evidence. All scenarios were rerated after a face-to-face meeting following a modified Delphi process. Appropriate scenarios were rerated for necessity to determine referral priority.Results: Of the final 2646 scenarios, 20.6% (n = 544) were appropriate, 17.2% (n = 456) uncertain, and 61.5% (n = 1626) inappropriate for a surgical evaluation. Of the appropriate cases, 55.9% (n = 306) were rated as very high priority. Not attempting AED treatment was always rated as inappropriate for a referral. Trial of 2 AEDs was usually rated as appropriate unless seizure-free or not fully investigated Based on these data, a Web-based decision tool ( www.epilepsycases.com) was created.Conclusions: Using the available evidence through 2008 and expert consensus, we developed a Web-based decision tool that provides a guide for determining candidacy for epilepsy surgery evaluations. The tool needs clinical validation, and will be updated and revised regularly. This rendition of the tool is most appropriate for those over age 12 years with focal epilepsy. The Rand/UCLA appropriate methodology might be considered in the development of guidelines in other areas of epilepsy care.GLOSSARY: AED: antiepileptic drugILAE: International League Against EpilepsyQOL: quality of lifeRAM: RAND Appropriateness Methodology(C)2012 American Academy of Neurology

Objective: To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis.Methods: Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2).Results: Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [adjOR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; adjOR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels (adjOR 0.549, 95% CI 0.341-0.883 in model 1; adjOR 0.560, 95% CI 0.353-0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C-reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 (adjOR 1.390, 95% CI 1.040-1.860).Conclusion: Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke.GLOSSARY: adjOR: adjusted odds ratioCI: confidence intervalHDL-C: high-density lipoprotein cholesterolIQR: interquartile rangeLDL-C: low-density lipoprotein cholesterolmRS: modified Rankin ScaleNIHSS: NIH Stroke ScaleOR: odds ratiortPA: recombinant tissue plasminogen activatorsICH: symptomatic intracerebral hemorrhageTC: total cholesterolTG: triglyceride(C)2012 American Academy of Neurology

Objectives: Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (>age 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75+ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype.Methods: The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model.Results: Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR = 0.55 [95% confidence interval (CI) 0.41, 0.74], p < 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR = 0.15 [95% CI 0.06, 0.37], p < 0.0001).Conclusions: Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial-and thus possibly genetic-successful cognitive aging.GLOSSARY: AD: Alzheimer diseaseCDR: Clinical Dementia RatingCI: confidence intervalCPRS: Computerized Patient Record SystemCRP: C-reactive proteinCVRF: cardiovascular risk factorHR: hazard ratioJJP-VAMC: James J. Peters Veterans Affairs Medical CenterMMSE: Mini-Mental State Examination(C)2012 American Academy of Neurology

Objective: To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS).Methods: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria.Results: Fifteen studies identified 761 interferon [beta]-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon [beta] exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes.Conclusion: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.GLOSSARY: DMD: disease-modifying drugGA: glatiramer acetateIFN-[beta]: interferon [beta]ILCOR: International Liaison Committee on ResuscitationMS: multiple sclerosis(C)2012 American Academy of Neurology

Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).Methods: A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.Results: Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.Conclusions: We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.GLOSSARY: BN-PAGE: blue-native polyacrylamide gel electrophoresisCMT: Charcot-Marie-ToothCMT2: Charcot-Marie-Tooth type 2dHMN: distal hereditary motor neuropathyLS: Leigh syndromemtDNA: mitochondrial DNANARP: neurogenic muscle weakness, ataxia, and retinitis pigmentosaNCS: nerve conduction studiesOXPHOS: oxidative phosphorylationUMN: upper motor neuron(C)2012 American Academy of Neurology

Objective: The aim of our study was to examine the relationship between corticostriatal A[beta]-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia.Methods: This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic A[beta]-amyloid and vesicular monoamine transporter 2 PET imaging using [11C] Pittsburgh compound B (PiB) and [11C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated.Results: Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 +/- 0.16 (distribution volume ratio; range 0.96-1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = -0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = -0.54, p = 0.0004).Conclusion: Elevated cerebral A[beta]-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort.GLOSSARY: AD: Alzheimer diseaseDLB: dementia with Lewy bodiesDTBZ: dihydrotetrabenazineDVR: distribution volume ratioMCI: mild cognitive impairmentMOCA: Montreal Cognitive AssessmentPCA: principal component analysisPiB: Pittsburgh compound BPD: Parkinson diseasePDD: Parkinson disease dementiaUPDRS: Unified Parkinson's Disease Rating ScaleVOI: volume of interestWAIS: Wechsler Adult Intelligence Scale(C)2012 American Academy of Neurology

Objective: To examine associations of welding and manganese exposure with Parkinson disease (PD) using meta-analyses of data from cohort, case-control, and mortality studies.Methods: Epidemiologic studies related to welding or manganese exposure and PD were identified in a PubMed search, article references, published reviews, and abstracts. Inclusion criteria were 1) cohort, case-control, or mortality study with relative risk (RR), odds ratio (OR), or mortality OR (MOR) and 95 confidence intervals (95% CI); 2) RR, OR, and MOR matched or adjusted for age and sex; 3) valid study design and analysis. When participants of a study were a subgroup of those in a larger study, only results of the larger study were included to assure independence of datasets. Pooled RR/OR estimates and 95% CIs were obtained using random effects models; heterogeneity of study effects were evaluated using the Q statistic and I2 index in fixed effect models.Results: Thirteen studies met inclusion criteria for the welding meta-analysis and 3 studies for the manganese exposure meta-analysis. The pooled RR for the association between welding and PD for all study designs was 0.86 (95% CI 0.80-0.92), with absence of between-study heterogeneity (I2 = 0.0). Effect measures for cohort, case-control, and mortality studies were similar (0.91, 0.82, 0.87). For the association between manganese exposure and PD, the pooled OR was 0.76 (95% CI 0.41-1.42).Conclusions: Welding and manganese exposure are not associated with increased PD risk. Possible explanations for the inverse association between welding and PD include confounding by smoking, healthy worker effect, and hormesis.GLOSSARY: CI: confidence intervalMOR: mortality odds ratioOR: odds ratioPD: Parkinson diseaseRR: relative risk(C)2012 American Academy of Neurology

The Emerging Science abstracts were originally presented at the 2012 AAN Annual Meeting. Abstracts qualify for Emerging Science presentations by having key aspects of research conducted after the October 24th abstract submission deadline and must be new and of sufficient scientific importance to warrant expedited presentation and publication.(C)2012 American Academy of Neurology