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. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis. Modified constraint induced therapy: a randomized feasibility and efficacy study. The value of muscle exercise in patients with amyotrophic lateral sclerosis. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial.
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. Ciliary neurotrophic factor (CNTF) is a neuroactive cytokine found in Schwann cells, which appears to be released in response to nerve injury. The ALS CNTF Treatment Study (ACTS) clinical trial was a phase II-III randomized, placebo-controlled, double-blind study designed to evaluate the safety, tolerability, and efficacy of subcutaneous administration of recombinantly produced human CNTF (rHCNTF) in slowing disease progression in 730 patients with amyotrophic lateral sclerosis (ALS). Patients were randomized to receive 30 micrograms/kg or 15 micrograms/kg rHCNTF or placebo subcutaneously three times a week for 9 months. The primary endpoint of the study, the slope of decline of isometric muscle strength in treated versus placebo patients, showed no statistically significant difference between rHCNTF and placebo-treated patients, and was complicated by an initial statistically significant decrease in strength early in rHCNTF-treated patients. Mortality was similar in all three study arms. There were no statistically significant treatment effects among the secondary measures. Side effects of rHCNTF included anorexia, weight loss, and cough and were sufficient to limit dosing in many patients. The treatment of amyotrophic lateral sclerosis (ALS) is still disappointing. Repetitive transcranial magnetic stimulation (rTMS) has been suggested to modify the rate of disease progression in ALS.
                In a pilot controlled study, we tested the effect of 5-Hz rTMS on motor performance, fatigue and quality of life (QoL) in ALS.
                Ten ALS patients underwent a two-week period of daily active or sham 5-Hz rTMS. Outcome measures were assessed with functional, fatigue and QoL scales. Muscle strength was evaluated with the MRC scale and measured with isometric and isokinetic dynamometer.
                Significant difference at the end of rTMS treatment was found for QoL, maximum voluntary isometric contraction and isokinetic average power when comparing active vs sham treatment. These changes were transitory and outcome measures were not significant two weeks after discontinuation of rTMS.
                Though preliminary, our results suggest that 5-Hz rTMS may improve motor function and QoL in ALS. The present data indicate the need of a double-blind therapeutic trial of rTMS in ALS. This case series examined the feasibility and efficacy of a modified constraint induced therapy (CIT) protocol administered on an outpatient basis. The Fugl-Meyer Assessment of Motor Recovery After Stroke (Fugl), Action Research Arm Test (ARA), Wolf Motor Function Test (WMFT), and Motor Activity Log (MAL) were administered to six patients between 2 and 6 months poststroke (CVA) exhibiting stable motor deficits and learned nonuse of the affected limb. Two patients then participated in half-hour physical and occupational therapy sessions three times/week for 10 weeks. During the same period, their unaffected arms and hands were restrained 5 days/week during 5 hours identified as times of frequent use. Two other patients received regular therapy and two control patients received no therapy. The ARA, Fugl, WMFT, and MAL were again administered after 10 weeks. Patients receiving modified CIT exhibited substantial improvements on the Fugl, ARA, and WMFT, as well as increases in amount and quality of use of the limb using the MAL. Patients receiving traditional or no therapy exhibited no improvements. Results suggest that modified CIT may be an efficacious method of improving function and use of the affected arms of patients exhibiting learned nonuse. The role of physical activity for patients with amyotrophic lateral sclerosis (ALS) is controversial. Twenty-five ALS patients were randomized to receive a moderate daily exercise program (n=14) or not to perform any physical activity beyond their usual daily requirements (n=11). At baseline and after 3, 6, 9 and 12 months, patients were assessed by manual muscle strength testing, the Ashworth spasticity scale, ALS functional rating scale (FRS), fatigue severity scale, a visual analogue scale for musculoskeletal pain and the quality-of-life scale (SF-36). At 3 months, patients who performed regular exercise showed less deterioration on FRS and Ashworth scales, but not on other parameters. At 6 months, there was no significant difference between groups, although a trend towards less deterioration in the treated group on most scales was observed. At 9 and 12 months, there were too few patients in each group for statistical evaluation. Our results show that a regular moderate physical exercise program has a short-lived positive effect on disability in ALS patients and should be recommended. To evaluate the efficacy of 4-aminopyridine sustained release (4AP SR) (fampridine, EL-970) using quantitative measures of motor function in multiple sclerosis (MS) patients.
                In vitro, 4AP improves conduction through demyelinated axons. A previous multicenter trial of 4AP SR using the Expanded Disability Status Scale (EDSS) as the primary outcome was unable to establish clinical efficacy.
                Ten MS patients with stable motor deficits (EDSS 6.0-7.5) were given 4AP SR 17.5 mg bid and placebo for 1 week each in a double-blind, placebo-controlled, crossover trial. Time to walk 8 meters, time to climb four stairs, maximum voluntary isometric contraction measured quantitatively (MVICT), manual muscle testing (MMT), grip strength, EDSS, and the patient's global impression were measured.
                Timed gait was improved on 4AP SR compared with placebo in 9 of 10 subjects (p = 0.02). Timed stair climbing, MVICT, MMT, grip strength, and EDSS showed nonsignificant improvements on 4AP SR. Based on their global impressions, seven subjects preferred 4AP SR over placebo; only one preferred placebo. There were no serious side effects.
                4AP SR improved motor function in MS patients. The quantitative outcomes used in this study permit more sensitive evaluation of the therapeutic effect and promise to be useful in future trials of symptomatic treatments for MS. We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted. We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated. A randomized clinical trial on the effects of strength training was performed in myotonic dystrophy (MyD) patients and patients with hereditary motor and sensory neuropathy (HMSN). Training and most measurement tools involved the proximal lower extremity muscles. The participants trained 3 times a week for 24 weeks with weights adapted to their force. Strength was evaluated by isokinetically measured knee torque. Fatiguability was assessed by the time an isometric contraction could be sustained. Functional performance was measured by timed motor performance and by questionnaires on functional performance. Serum myoglobin (Mb) levels were determined to detect changes in muscle fiber membrane permeability. The MyD group included 33 participants, and the HMSN group included 29 participants. Within each diagnostic group, patients were individually matched and subsequently randomized for treatment allocation. In the MyD patients, none of the measurement techniques showed any training effect. Neither were there signs of deterioration caused by the training. In the HMSN group, knee torques increased. Timed motor performance did not change, although the questionnaires showed an improvement on items related to upper-leg function. Mb levels did not change significantly as a result of the training. In conclusion, the MyD group showed neither positive nor negative effects of the training protocol, whereas the training produced a moderate increase in strength and leg-related functional performance in the HMSN group.
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.