topiramate and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with non-familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether patients with familial and sporadic ALS/MND respond differently to treatment.. To systematically review the literature and to answer the specific question: 'Is there a difference in the response to treatment between patients with sporadic and familial forms of ALS?'. In May 2006 we searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to May 2006) and EMBASE (January 1980 to May 2006) for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request the necessary raw data.. Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of patients with both familial and sporadic ALS/MND.. We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment (active versus placebo), survival and ALS Functional Rating Scale scores for four large RCTs that included 822 sporadic and 41 familial ALS patients. We could not obtain data from 25 potentially eligible studies (17 trial authors could not be contacted and eight were unwilling to provide data).. There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among patients with familial ALS/MND, but the result was not statistically significant. Estimates of the rate of decline on the ALS Functional Rating Scale also suggested a slightly better response to treatment among those with familial ALS/MND, but the result was not statistically significant.. Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1 gene amongst those with familial ALS/MND.

Topics: Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Creatine; Fructose; Humans; Motor Neuron Disease; Neuroprotective Agents; Pyrazoles; Randomized Controlled Trials as Topic; Sulfonamides; Topiramate

We sought to examine the influence of medication usage and laboratory measurements on disease progression in amyotrophic lateral sclerosis (ALS). A database of 596 volunteers with ALS was generated from three clinical trials and one observational study. Disease course was measured by survival and three functional measures: the ALS Functional Rating Scale (ALSFRS), Vital Capacity (VC) and Maximum Voluntary Isometric Contraction (MVIC). Survival modeling was performed using Cox proportional hazards regression. The association of medication or laboratory measurements with disease progression was determined using a random effects model. In the multivariate analysis, survival was shorter in participants who took aspirin (HR =1.93, p =0.046); NSAIDs (HR =1.51, p =0.054); had low blood chloride (HR =0.76, p =0.020) or high bicarbonate levels (HR =1.37, p =0.006). Individuals who took calcium had better survival (HR =0.37, p =0.008) and a slower rate of decline of MVIC arm megascore (p =0.033). Vital capacity declined faster in individuals with lower serum chloride (p<0.0001), or higher bicarbonate (p =0.002) levels and those taking paracetamol (acetaminophen) (p =0.035). We conclude that aspirin or NSAID use may shorten survival in ALS, while calcium use may prolong survival. Our results support a need to further explore the role of neuroinflammation in the pathogenesis of ALS.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Aspirin; Clinical Laboratory Techniques; Female; Fructose; Humans; Male; Middle Aged; Multicenter Studies as Topic; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Topiramate

Topics: Amyotrophic Lateral Sclerosis; Analgesics; Anticonvulsants; Epilepsy; Humans; Ion Channel Gating; Models, Molecular; Mutation; Nerve Tissue Proteins; Neuroprotective Agents; Protein Binding; Sodium Channel Blockers; Sodium Channels; Stroke

The topiramate study was a 12-month randomized placebo-controlled trial in patients with ALS. Follow-up evaluation of the placebo group (n = 97) constituted a well-described cohort of patients with ALS, in whom multiple outcome measures were assessed at 3-month intervals. During the 12-month study period, the decline of forced vital capacity (FVC%) and ALS functional rating scale (ALSFRS) was linear, whereas the decline of maximum voluntary isometric contraction-arm (MVIC-arm) and MVIC-grip Z scores was curvilinear. Rates of FVC% and ALFRS decline, but not of MVIC-arm or MVIC-grip, were independent predictors of survival.

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Arm; Biomarkers; Female; Fructose; Hand Strength; Humans; Isometric Contraction; Life Tables; Male; Middle Aged; Outcome Assessment, Health Care; Predictive Value of Tests; Proportional Hazards Models; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Analysis; Topiramate; Treatment Outcome; Vital Capacity

To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.. A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.. Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).. At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Disease Progression; Double-Blind Method; Female; Fructose; Hand Strength; Humans; Life Tables; Male; Middle Aged; Muscle Contraction; Proportional Hazards Models; Safety; Survival Analysis; Thromboembolism; Topiramate; Treatment Failure; Vital Capacity

Recently an association between statins and the onset and more rapid disease course of amyotrophic lateral sclerosis (ALS) was reported, while other studies rejected such a link. The role of gender in that controversy is unclear. We evaluated the gender-specific effect of statins on the rate of functional decline in patients with ALS, based on data retrieved from the medical records of all ALS patients who participated in two previously reported clinical trials on the efficacy of topiramate and of celecoxib in ALS. The topiramate trial enrolled 294 patients, 28 (9.5%) of whom were statin users (20 males). The celecoxib trial enrolled 300 patients, 25 (8.3%) of whom were statin users (17 males). Statins had no effect on the functional decline in the celecoxib trial, but they did have a negative impact on disease course in the topiramate trial. When males and females were analyzed separately, the functional decline of females taking statins was significantly greater than that of males in both trials. Our results indicate that statins affect possibly negatively ALS progression among females but not males. They emphasize the need to consider gender in future analyses of drug effects.

Topics: Aged; Amyotrophic Lateral Sclerosis; Celecoxib; Disease Progression; Dyslipidemias; Female; Fructose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyrazoles; Randomized Controlled Trials as Topic; Severity of Illness Index; Sex Characteristics; Sulfonamides; Topiramate

Topics: Amyotrophic Lateral Sclerosis; Anticonvulsants; Clinical Trials, Phase III as Topic; Costs and Cost Analysis; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Lithium Compounds; Patient Advocacy; Risk; Topiramate; United States

Topics: Amyotrophic Lateral Sclerosis; Anticonvulsants; Clinical Trials as Topic; Follow-Up Studies; Fructose; Humans; Isometric Contraction; Maximal Voluntary Ventilation; Placebos; Retrospective Studies; Topiramate; Treatment Outcome

Topiramate is a novel anti-convulsant, structurally distinct from other known anti-convulsants. A number of independent studies suggest that topiramate has anti-excitotoxic properties. It has been found to diminish release of glutamate from neurons and block (-amino-3-hydoxy-5-methylisoxazole-4-proprionic acid glutamate receptor evoked currents. Since activation of non-N-methyl-D-aspartate glutamate receptors is thought to play a role in the selective loss of motor neurons in amyotrophic lateral sclerosis (ALS), we determined whether topiramate could protect against chronic glutamate-mediated motor neuron degeneration. An organotypic spinal cord culture system was used in which glutamate transport is inhibited by pharmacological blockade. After 3 weeks of treatment, topiramate was found to significantly prevent motor neuron degeneration in this culture model. However, the drug did not increase survival in G93A SOD1 transgenic mice, an animal model of ALS. These studies suggest that topiramate could be useful as a neuroprotectant, but were not effective in more complex motor injury paradigms such as the mouse model of ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Newborn; Fructose; Mice; Mice, Transgenic; Motor Neurons; Nerve Degeneration; Neuroprotective Agents; Organ Culture Techniques; Spinal Cord; Survival Rate; Topiramate

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Progression; Drug Evaluation, Preclinical; Fructose; Humans; Mice; Randomized Controlled Trials as Topic; Riluzole; Topiramate; Treatment Failure