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Muscle & Nerve 01/2013; · 2.37 Impact Factor
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ABSTRACT: Efficacy of Prednisone in the Treatment of Ocular Myasthenia (EPITOME) is a multicenter, randomized, double blind, placebo-controlled trial that is being conducted under the auspices of the Muscle Study Group. EPITOME is the first randomized control trial in patients with ocular myasthenia and aims to evaluate the efficacy and tolerability of prednisone over a period of four months in patients with newly diagnosed ocular myasthenia whose symptoms have failed to remit in response to a trial of cholinesterase inhibitor therapy.
Annals of the New York Academy of Sciences 12/2012; 1275(1):17-22. · 3.15 Impact Factor
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ABSTRACT: Background: With the establishment of a national amyotrophic lateral sclerosis (ALS) registry in the United States, methods are needed to ascertain the completeness of case ascertainment, especially in view of the proposal to rely largely on existing data sources. Methods: Data about ALS patients residing in the 5-county metropolitan Atlanta area (within the State of Georgia) from 2001 to 2005 were categorized according to their source - ALS Association, clinical (Emory Healthcare, community neurologist, Veterans Health Administration, Veterans Benefits Administration), Medicare and death certificates. ALS diagnoses were verified using chart review. Capture-recapture analyses were carried out using log-linear modeling, stratified by age and race. Results: The final model (based on 798 cases), which included the 4 main sources and 3 two-way interaction terms, yielded an estimated total population of 880 (95% CI 816-965), indicating that the combination of case-finding methods identified about 90.7% of cases. The estimated 5-year period prevalence is 38.5/100,000 (95% CI 35.66-42.19). Conclusion: This study highlights gaps in data based on existing data sources and illustrates a method for combining data from multiple sources to help facilitate the successful establishment of a US national ALS registry.
Neuroepidemiology 10/2012; 40(2):133-141. · 2.31 Impact Factor
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Neurology 10/2012; 79(16):1732-9. · 8.31 Impact Factor
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Michael Benatar,
Donald B Sanders,
Ted M Burns,
Gary R Cutter,
Jeffrey T Guptill,
Fulvio Baggi,
Henry J Kaminski,
Renato Mantegazza,
Matthew N Meriggioli,
Joanne Quan,
Gil I Wolfe
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ABSTRACT: The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.
Muscle & Nerve 06/2012; 45(6):909-17. · 2.37 Impact Factor
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Michael Benatar,
Mbchb,
Donald B Sanders,
Ted M Burns,
Gary R Cutter,
Jeffrey T Guptill,
Fulvio Baggi,
Henry J Kaminski,
Renato Mantegazza,
Matthew N Meriggioli,
Joanne Quan,
Gil I Wolfe,
America
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ABSTRACT: The recommendations for clinical research standards published in 2000 by a task force of the Medical Sci-entific Advisory Board (MSAB) of the Myasthenia Gravis Foun-dation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and ac-ceptance of more effective and less noxious therapies for MG.
Muscle & Nerve 06/2012; 45(909-917). · 2.37 Impact Factor
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Yevgeniya Abramzon,
Janel O Johnson,
Sonja W Scholz,
J P Taylor,
Maura Brunetti,
Andrea Calvo,
Jessica Mandrioli, Michael Benatar,
Gabriele Mora,
Gabriella Restagno,
Adriano Chiò,
Bryan J Traynor
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ABSTRACT: We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for <1% of this form of disease.
Neurobiology of aging 05/2012; 33(9):2231.e1-2231.e6. · 5.94 Impact Factor
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Alan E Renton,
Elisa Majounie,
Adrian Waite,
Javier Simón-Sánchez,
Sara Rollinson,
J Raphael Gibbs,
Jennifer C Schymick,
Hannu Laaksovirta,
John C van Swieten,
Liisa Myllykangas, [......],
Amalia Dutra,
Evgenia Pak,
John Hardy,
Andrew Singleton,
Nigel M Williams,
Peter Heutink,
Stuart Pickering-Brown,
Huw R Morris,
Pentti J Tienari,
Bryan J Traynor
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ABSTRACT: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Neuron 09/2011; 72(2):257-68. · 14.74 Impact Factor
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ABSTRACT: Mutations in the valosin-containing protein gene (VCP) have been identified in neurological disorders (inclusion body myopathy--early Paget's disease of the bone--frontotemporal dementia and amyotrophic lateral sclerosis) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic Parkinson's disease (PD). We screened the coding region of the VCP gene in a large cohort of 768 late-onset PD cases (average age at onset, 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD.
Neurobiology of aging 09/2011; 33(1):209.e1-2. · 5.94 Impact Factor
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Muscle & Nerve 09/2011; 44(3):457. · 2.37 Impact Factor
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Muscle & Nerve 04/2011; 43(4):461-3. · 2.37 Impact Factor
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ABSTRACT: Our objective was to investigate the utility of existing data sources for identifying cases of amyotrophic lateral sclerosis (ALS) and related motor neuron diseases (MND) in the State of Georgia. Data were acquired from Medicare, Medicaid, Veterans Administration, Emory Healthcare, community neurologists, the ALS Association, and mortality records for ALS/MND patients residing in Georgia during 2001-2005. A neurologist used abstracted medical records to verify the diagnosis of ALS/MND. The positive predictive value (PPV) of an ICD code for a verified diagnosis of ALS was estimated. Simple 'rules' were developed to improve PPV. Results showed that a total of 2413 unique potential cases were identified in existing data sources. Medical records of 579 cases were available for review; the diagnosis of ALS (or a related MND) was confirmed in 486 (PPV = 84%) cases. Predictive rules, which permitted classification of ∼80% of the chart-reviewed population, improved PPV to 96-98%. In conclusion, existing data sources are useful for identifying cases of ALS/MND; most data sources contribute a substantial number of unique cases. Predictive algorithms may permit correct classification of a large proportion of cases without the need for verification based on medical record review.
Amyotrophic Lateral Sclerosis 03/2011; 12(2):130-5. · 3.40 Impact Factor
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ABSTRACT: The Pre-familial Amyotrophic Lateral Sclerosis (Pre-fALS) study is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis. Our goals were to (1) explore participants' decisions of whether to learn results of presymptomatic testing or not; (2) understand the psychosocial impact of these decisions; and (3) assess preferences for receiving results by telephone or in person.
The sample for this substudy comprised 20 participants drawn randomly from autosomal dominant mutant superoxide dismutase 1 families in the Pre-fALS study. Twenty participants completed a semistructured phone interview; prominent themes were identified and rated.
Fourteen participants chose to learn results; six had mutant superoxide dismutase 1 and eight had wild-type superoxide dismutase 1. Of the six who initially elected nondisclosure, three were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short term.
We recommend that (1) those considering presymptomatic genetic testing should undergo professional counseling to help decide whether to learn results; (2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; and (3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves.
Genetics in medicine: official journal of the American College of Medical Genetics 01/2011; 13(4):342-8. · 3.92 Impact Factor
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ABSTRACT: The objective of this study was to use magnetic resonance spectroscopy (MRS) to compare metabolite ratios in the cervical spinal cord of ALS patients to healthy controls. Fourteen ALS patients and 16 controls were scanned using a 3T scanner. A rectangular voxel (8 × 5 × 35 mm) was placed along the main axis of the cord with the lower limit at the inferior aspect of the C2 vertebral body. MRS was performed with a point-resolved spectroscopy (PRESS) sequence. Water signals were suppressed using a three-pulse chemical shift selective (CHESS) saturation sequence. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and NAA were computed from metabolite peaks. Differences in metabolite ratios between ALS patients and controls were assessed with a Wilcoxon rank-sum test. The relationship of metabolite ratios to clinical measures (ALSFRS-R and FVC) was determined by Pearson correlation. The NAA/Cr and NAA/Myo ratios were reduced by 40% and 38%, respectively, in ALS patients. The reduction in NAA/Myo and NAA/Cho correlated significantly with FVC, with correlation coefficients of 0.66 and 0.60, respectively. In conclusion, MR spectra can reliably be obtained from the cervical spinal cord in ALS. MRS of the cervical cord may be a useful biomarker of disease progression.
Amyotrophic Lateral Sclerosis 12/2010; 12(3):185-91. · 3.40 Impact Factor
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Janel O Johnson,
Jessica Mandrioli, Michael Benatar,
Yevgeniya Abramzon,
Vivianna M Van Deerlin,
John Q Trojanowski,
J Raphael Gibbs,
Maura Brunetti,
Susan Gronka,
Joanne Wuu, [......],
Fabrizio Salvi,
Rossella Spataro,
Patrizia Sola,
Giuseppe Borghero,
Giuliana Galassi,
Sonja W Scholz,
J Paul Taylor,
Gabriella Restagno,
Adriano Chiò,
Bryan J Traynor
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ABSTRACT: Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
Neuron 12/2010; 68(5):857-64. · 14.74 Impact Factor
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ABSTRACT: Therapeutic development in amyotrophic lateral sclerosis (ALS) is hampered by the lack of suitable biomarkers that might be sensitive to spatial and temporal patterns of neurodegeneration. Diffusion tensor imaging is a useful non-invasive tool that permits detection of microstructural tissue changes due, for example, to neurodegeneration. Even though the spinal cord bears the brunt of the disease process, diffusion tensor imaging has mainly been used to study white matter changes in the brain. The aim of this study was to examine the diffusion tensor imaging parameters of the cervical spinal cord (C1 through C6 segments) and brainstem (corticospinal tracts in the pyramids and pons) among ALS patients, to compare these to findings in age-matched healthy controls, and to correlate these differences with clinical measures of disease severity. Fractional anisotropy in the white matter of the cervical cord was 12% lower (p<0.01) in ALS patients (n=14) compared to age-matched healthy control subjects (n=15), and showed significant positive correlation with the average finger and foot tapping speed (r=0.61, p<0.05) in ALS patients. Radial diffusivity in the cervical cord was 15% higher (p<0.05) in ALS patients compared to healthy control subjects. Radial diffusivity in the white matter of the cervical cord was significantly correlated with clinical measures of disease severity such as forced vital capacity (FVC % predicted, r=-0.69, p<0.01), average finger and foot tapping speed from all four limbs (r=-0.59, p<0.05), and ALSFRS-R (r=-0.55, p<0.05) in ALS patients. There were no significant differences in mean diffusivity or axial diffusivity in the cervical spinal cord, or in any diffusion tensor imaging parameters measured in the brainstem. Analysis of diffusion tensor imaging parameters from individual cervical segments as well as profile plots along the length of the cervical cord showed larger differences in fractional anisotropy and radial diffusivity at more distal cervical segments, providing evidence that supports the "dying-back" hypothesis of neurodegeneration in ALS.
NeuroImage 11/2010; 53(2):576-83. · 5.89 Impact Factor
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ABSTRACT: Objective: To investigate changes in the diffusion tensor imaging measures, axial diffusivity and radial diffusivity, in addition to the more commonly used fractional anisotropy and mean diffusivity, in patients with amyotrophic lateral sclerosis (ALS) using the voxel-based statistical analysis tool, tract based spatial statistics. Methods: We studied 12 patients with ALS and 19 normal controls using diffusion tensor imaging; tract based spatial statistics was applied to study changes in fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity values in brain white matter tracts. ALS patients were evaluated using clinical examination, administration of the revised ALS functional rating scale and measurement of the forced vital capacity. Results: In ALS patients, we found significant increases in axial diffusivity, radial diffusivity, and mean diffusivity and significant decreases in fractional anisotropy. Increases in axial diffusivity and radial diffusivity were more widespread and more prominent in the corticospinal tract than the decreases in fractional anisotropy. The decreases in fractional anisotropy were evident only in the corona radiata and genu of the corpus callosum. Conclusion: In ALS, axial diffusivity and radial diffusivity may be useful diffusion tensor imaging-derived indices to consider in addition to fractional anisotropy and mean diffusivity to aid in demonstrating neurodegenerative changes.
Brain research 08/2010; 1348:156-64. · 2.46 Impact Factor
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ABSTRACT: The purpose was to estimate the frequency, characteristics, and risk factors of HIV-associated distal sensory polyneuropathy (DSP) among South Africans who attend an urban community-based clinic. In a cross-sectional study, neuropathy status was determined in 598 HIV-infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects as DSP versus no DSP. Symptomatic DSP (SDSP) required the presence of at least two neuropathic signs together with symptoms. Clinical, anthropometric, and laboratory evaluations were prospectively performed. CD4 counts, antiretroviral therapy (ART), and questionnaires regarding previous tuberculosis (TB) and alcohol exposure were collected retrospectively. Approximately half (49%) of the study population were diagnosed with DSP, and 30% of the study population were diagnosed with SDSP. In multivariate analyses the odds ratio (OR) (95% confidence interval) of DSP were independently associated with ART use (OR 1.7, 1.0-2.9), age (per 10 year increment) (OR 1.7, 1.4-2.2), and prior TB (OR 2.0, 1.3-3.0). Pain or paresthesias were reported as moderately severe by 70% of those with SDSP. Stavudine use was significantly associated with DSP. DSP is a clinically significant problem in urban HIV-infected Africans. Our findings raise the possibility that the incidence of DSP may be reduced with avoidance of stavudine-containing regimens in older subjects, especially with a history of prior TB infection.
Muscle & Nerve 03/2010; 41(5):599-606. · 2.37 Impact Factor
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Michael Benatar
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ABSTRACT: Myasthenia gravis is typically an acquired autoimmune disorder in which antibodies are directed at structural components of the neuromuscular junction, most commonly the nicotinic acetylcholine receptor. The clinical manifestations of skeletal muscle weakness are broad. Patients most often report fatigable muscle weakness. The eyelid levators and extraocular muscles are most commonly affected, resulting in symptoms of ptosis and diplopia. Symptoms may be confined to the eyes (ocular myasthenia) or reflect bulbar, limb, or respiratory muscle weakness (generalized myasthenia). The diagnosis is based on a characteristic history and the finding of fatigable muscle weakness on examination, and may be supported by diagnostic tests such as finding elevated titers of acetylcholine receptor or muscle-specific receptor tyrosine kinase (MuSK) antibodies, a positive Tensilon test, a decremental response on slow repetitive nerve stimulation, and abnormal jitter on single fiber electromyography. This article presents a series of pearls to aid in the clinical and laboratory diagnosis of myasthenia gravis, emphasizing key historical features, common and characteristic findings on examination, and potential pitfalls in the use of ancillary diagnostic studies.
Seminars in Neurology 02/2010; 30(1):35-7. · 1.64 Impact Factor
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ABSTRACT: The interpretation of nerve conduction studies, as with any diagnostic test, requires an ability to differentiate normal from abnormal. To this end there have been many efforts to establish reference or normative data, but they have been hampered by a variety of methodological shortcomings. The goal of this article is to introduce a statistical method known as quantile regression, which we contend is better suited than existing methods to generate reference data, especially when there is a need to adjust for covariates.
Statistical methods previously used for generation of reference data are reviewed. Quantile regression is presented and used to estimate the lower percentiles for response amplitudes of the radial sensory and tibial motor nerves.
Using data from 190 subjects, it is possible to estimate as low as the 2nd percentile for the radial nerve. Using data from 99 subjects it is possible to estimate as low as the 4th percentile for the tibial nerve. Percentile estimation for both nerves required adjustment for age, but no other covariates.
Quantile regression is well suited to the estimation of extreme percentiles, the very percentiles that are most relevant to reference data. It is also less dependent on data distribution and permits covariate adjustment, even for continuous variables such as age, which are clinically important determinants of reference data for nerve conduction studies. We recommend the use of quantile regression for future studies of reference data.
Muscle & Nerve 11/2009; 40(5):763-71. · 2.37 Impact Factor
