Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS. A clinical trial of creatine in ALS. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Motor cortex stimulation for ALS: a double blind placebo-controlled study. A randomized controlled trial of resistance exercise in individuals with ALS. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Modified constraint-induced therapy in acute stroke: a randomized controlled pilot study. A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients.
Many patients with amyotrophic lateral sclerosis (ALS) experience cramps during the course of the disease but so far, none of the medications used has been of proven benefit. The objective was to determine the effect of orally administered tetrahydrocannabinol (THC) on cramps in ALS patients.
                The authors conducted a randomised, double-blind, placebo-controlled crossover trial in 27 ALS patients suffering from moderate to severe (visual analogue scale (VAS); VAS≥4) daily cramps. There were 7 women and 20 men with a mean age of 57 years and a mean functional ALS score (ALSFRS-R) of 38.4. Patients were randomly assigned to receive 5 mg THC twice daily followed by placebo or vice versa. Each treatment period lasted for 2 weeks and was preceded by a 2-week drug-free observation period (run-in, wash-out period respectively). The primary outcome measure was change in cramp intensity as assessed by a VAS. Secondary outcome measures included the number of cramps per day, number of cramps during daytime and bedtime, intensity of fasciculations (VAS) as well as validated measures of quality of life (ALSAQ-40), quality of sleep (SDQ), appetite (FAACT) and depression (HADS).
                Complete data were available from 22 patients. THC was well tolerated. There was no evidence for a treatment effect on cramp intensity, number of cramps, fasciculation intensity or any of the other secondary outcome measures.
                This interventional study with orally administered THC 5 mg twice daily did not demonstrate subjective improvement of cramp intensity in ALS patients. Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing. Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons.
                The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly.
                Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials.
                Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS. Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure. In a transgenic mouse model of ALS, creatine monohydrate showed a promising increase in survival. We performed a double-blind, placebo-controlled, sequential clinical trial to assess the effect of creatine monohydrate on survival and disease progression in patients with ALS. Between June 2000 and December 2001, 175 patients with probable, probable-laboratory supported, or definite ALS were randomly assigned to receive either creatine monohydrate or placebo 10 gm daily. A sequential trial design was used with death, persistent assisted ventilation, or tracheostomy as primary end points. Secondary outcome measurements were rate of decline of isometric arm muscle strength, forced vital capacity, functional status, and quality of life. The trial was stopped when the null hypothesis of indifference was accepted. Creatine did not affect survival (cumulative survival probability of 0.70 in the creatine group vs 0.68 in the placebo group at 12 months, and 0.52 in the creatine group vs 0.47 in the placebo group at 16 months), or the rate of decline of functional measurements. Creatine intake did not cause important adverse reactions. This placebo-controlled trial did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with ALS. Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS) of the brain may produce a modest slowing of disease progression in amyotrophic lateral sclerosis (ALS). The present study was designed to test the hypothesis that rTMS given as continuous theta burst stimulation (cTBS), repeated monthly for one year, would affect ALS progression. We performed a double blind, placebo-controlled trial. Twenty patients with ALS were randomly allocated to blinded real or placebo stimulation. cTBS of the motor cortex was performed for five consecutive days every month for one year. Primary outcome was the rate of decline as evaluated with the revised ALS functional rating scale (ALSFRS-R). Treatment was well tolerated. There was no significant difference in the ALSFRS-R score deterioration between patients treated with real or placebo stimulation. ALSFRS-R mean scores declined from 32.0 (SD 7.1) at study entry to 23.1 (SD 6.3) at 12 months in patients receiving real cTBS and from 31.3 (SD 6.9) to 21.2 (SD 6.0) in those receiving placebo stimulation. Although cTBS proved a safe procedure, on the basis of the present findings a larger randomized confirmatory trial seems unjustified in ALS patients, at least in advanced stage of the disease. To determine the effects of resistance exercise on function, fatigue, and quality of life in individuals with ALS.
                Subjects with a diagnosis of clinically definite, probable, or laboratory-supported ALS, forced vital capacity (FVC) of 90% predicted or greater, and an ALS Functional Rating Scale (ALSFRS) score of 30 or greater were randomly assigned to a resistance exercise group that received a home exercise program consisting of daily stretching and resistance exercises three times weekly or to a usual care group, who performed only the daily stretching exercises. ALSFRS, the Fatigue Severity Scale (FSS), and Short Form-36 (SF-36) were completed at baseline and monthly for 6 months. FVC and maximum voluntary isometric contraction (MVIC) were monitored monthly throughout the study.
                Of 33 subjects screened, 27 were randomly assigned (resistance = 13; usual care = 14). Eight resistance exercise subjects and 10 usual care subjects completed the trial. At 6 months, the resistance exercise group had significantly higher ALSFRS and SF-36 physical function subscale scores. No adverse events related to the intervention occurred, MVIC and FVC indicated no negative effects, and less decline in leg strength measured by MVIC was found in the resistance exercise group.
                Our study, although small, showed that the resistance exercise group had significantly better function, as measured by total ALS Functional Rating Scale and upper and lower extremity subscale scores, and quality of life without adverse effects as compared with subjects receiving usual care. Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial.
                Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations.
                Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin.
                These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS. To determine modified constraint-induced therapy (mCIT) feasibility and compare its efficacy to traditional rehabilitation (TR) in acute stroke patients exhibiting upper limb hemiparesis.
                Before-after, multiple baseline, randomized controlled pilot study.
                Rehabilitation hospital.
                Ten stroke patients < 14 d poststroke and exhibiting upper limb hemiparesis and affected limb nonuse.
                Five patients were administered mCIT, consisting of structured therapy emphasizing more affected arm use in valued activities 3 d/week for 10 weeks and less affected arm restraint 5 d/week for 5 h. Five other patients received 1/2 sessions of traditional motor rehabilitation for the affected arm, which included affected limb manual dexterity exercises and stretching, as well as compensatory strategies with the unaffected limb. The TR regimens occurred 3 d/week for 10 weeks.
                The Fugl-Meyer Assessment of Motor Recovery (Fugl-Meyer), Action Research Arm Test (ARA), and Motor Activity Log (MAL).
                Before intervention, all patients exhibited stable motor deficits and more affected arm nonuse. After intervention, mCIT patients displayed increased affected arm use (+ 2.43 on the MAL amount of use scale), uniformly exhibited increases on the Fugl-Meyer and ARA (mean change scores = + 18.7 and + 21.7, respectively), and were able to again perform valued activities. TR patients exhibited nominal change in affected limb use (+ 0.07 on the MAL amount of use scale) and modest changes on the Fugl-Meyer and ARA (+ 4.4 and + 4.8, respectively). Fugl-Meyer and ARA changes were significant for the mCIT group only (P < 0.01).
                mCIT is a promising regimen for improving more affected limb use and function in acute cerebrovascular accident. However, larger confirmatory studies need to be performed. There is still no consensus as to which physiologic marker should be used as a trigger for the initiation of non-invasive positive pressure ventilation (NPPV) in patients with amyotrophic lateral sclerosis (ALS). Current practice parameters recommend that the decision to begin treatment be based upon forced vital capacity (FVC) measurements. A prospective, randomized study was performed in 20 ALS patients who had an FVC of 70-100%. Patients received baseline assessments including: ALS functional rating scale-respiratory version (ALSFRS-R), pulmonary symptom scale, Short form 36 (SF-36), FVC%, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and nocturnal oximetry. Patients were randomized to receive NPPV based upon nocturnal oximetry studies suggesting oxygen desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% ("standard of care"). At enrollment, there was no significant correlation between FVC% and the ALSFRS-R, symptom score, MEP, MIP, or duration of nocturnal desaturation <90%. An increase in the vitality subscale of the SF-36 was demonstrated in 5/6 patients randomized to "early intervention" with NPPV. Our data indicate that FVC% correlates poorly with respiratory symptoms and suggests that MIP and nocturnal oximetry may be more sensitive measures of early respiratory insufficiency. In addition, intervention with NPPV earlier than our current standard of care may result in improved quality of life.
There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.