Vanessa Battista

Quantitative objective markers for upper and lower motor neuron dysfunction in ALS

Objective: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. Methods: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging (1H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. Results: 1H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale–Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. Conclusions: 1H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

The ALSFRSr predicts survival time in an ALS clinic population

Objective: To determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr), a predictor of survival time in ALS clinical trials, predicts survival time in an ALS clinic population. Methods: The authors prospectively evaluated 267 consecutive patients with ALS at first visit to an ALS clinic using the ALSFRSr and pulmonary function testing. The association of ALSFRSr score at baseline with death or tracheostomy in ALS was examined using Cox proportional hazards models, adjusting for age at baseline, sex, and symptom duration. Results: Of 267 patients with ALS, 103 (39%) reached the endpoint, defined as either death (79 patients) or tracheostomy (24 patients), during a mean follow-up of 1.0 ± 0.7 years. Among the 103 patients who reached the endpoint during follow-up, 77 (75%) had a baseline ALSFRSr score of less than 38 (the median baseline score of all patients), compared to 53 of 164 (32%) who remained alive without tracheostomy. Patients with a total ALSFRSr score below the median had a 4.4-fold increased risk of death or tracheostomy compared to those who scored above the median (HR: 4.38, 95% CI: 2.79 to 6.86, p < 0.001). Both the total ALSFRSr score at baseline (HR: 0.94, 95% CI: 0.91 to 0.98, p < 0.001) and forced vital capacity at baseline (HR: 0.99, 95% CI: 0.98 to 1.00, p = 0.02) were associated with death or tracheostomy when included in the same Cox model. Conclusions: In an ALS clinic population, the total Amyotrophic Lateral Sclerosis Functional Rating Scale–revised score at baseline is a strong predictor of death or tracheostomy independently of forced vital capacity and after adjustment for age at baseline, sex, and symptom duration.

Consensus statement on standard of care for congenital muscular dystrophies

Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.

Prospective cohort study of spinal muscular atrophy types 2 and 3

Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.

A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS

Background: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs. Objective: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)—a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial. Methods: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr) score from baseline to 9 months. Results: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage. Conclusions: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.

Excellent inter‐rater, intra‐rater, and telephone‐administered reliability of the ALSFRS‐R in a multicenter clinical trial

We wished to determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale‐revised (ALSFRS‐R) is reliable when used as primary outcome measure in a multicenter clinical trial. To establish inter‐rater reliability, we randomly assigned 19 primary raters and 11 back‐up raters to score nine amyotrophic lateral sclerosis (ALS) patients using the ALSFRS‐R. To assess intra‐rater reliability and reliability of telephone administration, we randomly assigned consecutive participants of the Clinical Trial of High Dose Coenzyme Q10 in ALS (QALS) to have in‐person ALSFRS‐R interviews at both screening and baseline visits (n = 41 patients) or to have the ALSFRS‐R interview by telephone at screening and in person at the baseline visit (n = 27). An intraclass correlation coefficient (ICC) of reliability was calculated using a one‐way random effects analysis of variance model. In the inter‐rater reliability assessment, the primary raters performed 54 ratings on nine patients with ICC = 0.93 (95% CI 0.84–0.98). For back‐up raters, 32 ratings on nine patients resulted in ICC = 0.93 (95% CI 0.82–0.98). The intra‐rater reliability for in‐person interviews was ICC = 0.95 (95% CI 0.92–0.98). The reliability of telephone administration compared to in‐person interviews was ICC = 0.97 (95% CI 0.93–0.98). We conclude that the ALSFRS‐R shows excellent inter‐ and intra‐rater reliability, and reliability of telephone administration when used as primary outcome measure in a multicenter ALS trial.

Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype.

Objective: To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning. Methods: We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives). Results: Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives. Conclusions: Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.

Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy

Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m(2)), fat-free (FFMI, lean mass/height in m(2)) and fat (FMI, fat mass/height in m(2)) mass indexes were estimated in 25 children (aged 5-18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was 50th percentile in 11 (44%) and 85th in 5 (20%). FFMI was reduced (p<0.005) and FMI was increased (p<0.005) in the overall study cohort. FMI was 50th, 85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75th, 50th and 3rd percentiles maximized sensitivity and specificity for FMI 95th, 85th and 50th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA.

Reliability of telephone administration of the PedsQL Generic Quality of Life Inventory and Neuromuscular Module in spinal muscular atrophy (SMA).

Clinical research visits are challenging for people with SMA because of limited mobility and intercurrent illnesses. Missing data threaten the validity of research results. Obtaining outcomes remotely would represent a solution. To evaluate reliability of telephone administration of the PedsQL Pediatric Generic Core Quality of Life Inventory 4.0 (Generic) and Neuromuscular Module 3.0 (NM) in SMA, we recruited 21 participants of a Natural History Study for telephone administration of both modules no more than 7 days before or after an in-person study visit. We found excellent reliability between telephone and in-person administration of both modules with the NM slightly better than the Generic. Reliability of the child and parent forms was similar. We concluded that both modules can be administered reliably over the telephone to SMA patients and caregivers, expanding the utility of these tools in clinical trials. Notably, telephone administration is reliable in children as young as 8 years.

Muscle volume estimation by magnetic resonance imaging in spinal muscular atrophy.

Thigh muscle volume was assessed using magnetic resonance imaging in 16 subjects with spinal muscular atrophy. Scans were successful for 14 of 16 subjects (1 type 1, 6 type 2, and 7 type 3) as young as 5.7 years. Muscle volume with normal and abnormal signal was measured using blinded, semiautomated analysis of reconstructed data. Results were compared with segmental lean mass estimated by dual-energy X-ray absorptiometry and correlated with clinical and electrophysiological measures of disease severity. Muscle volume was reduced with abnormal signal quality. Test-retest reliability (r = .99) and correlation with dual-energy X-ray absorptiometry (r = .91) were excellent. Type 2 subjects had lower volume (3.5 ± 1.6 vs 6.3 ± 2.8 mL/cm height; P = .06) and higher percentage of muscle with abnormal signal (68% ± 20% vs 47% ± 27%; P = .14) than type 3. Reproducibility, tolerability, and strong correlation with clinical measures make magnetic resonance imaging a candidate biomarker for clinical research.