Correlating phenotype and genotype in the periodic paralyses.

BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide. CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Can we eliminate placebo in ALS clinical trials?

BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial. METHODS: A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared. RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores. CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: 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. RESULTS: 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. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients.

OBJECTIVE: This study examined central and peripheral effects of fatiguing exercise (3 min maximal grip) in healthy controls (n=10) and multiple sclerosis (MS) subjects with weakness, MS-W (n=16) and normal motor function, MS-NM (n=16) in the studied extremity. METHOD: Transcranial magnetic stimulation (TMS) was used to assess resting and facilitated motor-evoked potentials (MEPs) of abductor pollicus brevis (APB) and flexor carpi radialis (FCR) muscles before and after fatiguing exercise. Exercise-induced depletion and recovery of phosphocreatine (PCr) were measured using (31)P magnetic resonance spectroscopy ((31)PMRS) in FCR. RESULTS AND CONCLUSION: MS subjects demonstrated significantly lower peak force and a faster decline in force than controls. Contralateral muscle activation (hand grip) before the fatigue protocol resulted in significantly increased MEP amplitudes in all groups. Contralateral hand grip following fatiguing exercise resulted in significantly higher MEP amplitudes in controls and MS-NM subjects, but not MS-W subjects. Fatiguing exercise resulted in prolonged central motor conduction time (CMCT) in MS subjects, but not controls. No group differences in PCr depletion or resynthesis were observed. All groups demonstrated significant post-exercise depression (PED) of MEP amplitude that persisted beyond the time course of PCr recovery, indicating fatigue was central in origin. MS subjects were less able than controls to increase cortical excitability using contralateral muscle activation following fatiguing exercise, possibly indicating impaired conduction in the corpus callosum.

Effect of precooling on physical performance in multiple sclerosis.

Many individuals with MS experience heat sensitivity that may be associated with transient increases in the frequency of clinical signs and symptoms. Although physical activity may be beneficial for those with MS, induced thermal loads may preclude participation in exercise and other daily activities. This project was designed to evaluate the effects of precooling on physical function. Six thermosensitive MS patients were studied. Participants performed a graded exercise test to determine maximal oxygen uptake (VO2max) on a combined arm-leg ergometer. Thermal load was induced by 30 min of exercise under noncooled and precooled conditions at a workrate corresponding to 60% VO2max. Precooling consisted of 30 min lower body immersion in 16 - 17 degrees C water. Fatigue and 25-ft walk performance were assessed before, immediately after, and 30 min following exercise. No treatment differences in VO2 were observed. Rectal temperature, heart rate, and rating of perceived exertion (RPE) were significantly lower during the precooled exercise trial compared to the noncooled trial. Immediately following exercise, 25-ft walk performance and fatigue scores showed significantly greater deterioration in the noncooled condition. Precooling was effective in preventing gains in core temperature with physical work and may allow heat-sensitive individuals with MS to exercise with greater physical comfort.

Changes in excitability of motor cortical circuitry in primary restless legs syndrome.

OBJECTIVE: To investigate the excitability of segmental and suprasegmental systems in patients with primary restless legs syndrome (pRLS) by measuring the cortical silent period (C-SP) and the peripheral silent period (P-SP). BACKGROUND: There is some evidence that RLS may be the motor manifestation of normal CNS periodicity that becomes disinhibited under certain conditions. The mechanism of this disinhibition is unclear. DESIGN/METHODS: Ten patients with pRLS and 10 normal age-matched subjects were studied. The mixed nerve P-SP produced by electrical stimulation of the median and common peroneal nerves was recorded during maximal contraction of the abductor pollicis brevis (APB) and tibialis anterior (TA) muscles. The C-SP produced by a single magnetic shock to motor cortex at 150% of resting threshold was also measured during maximal contraction of the APB and TA muscles. The average of 5 to 10 trials at each site was obtained and compared using Student's t-test. RESULTS: Resting central motor threshold was not significantly different between pRLS patients and the control group. The average duration of the C-SP was shorter in the APB (74.5+/-37.7 versus 129.56+/-35.95 msec, p<0.05) and TA (66.81+/-25.63 versus 136.1+/-40.35 msec, p<0.05) in patients with pRLS. The P-SP duration, however, was not significantly different between two groups in either limb. CONCLUSION: The supraspinal inhibitory system is impaired in pRLS.

Recommendations for physical activity in patients with multiple sclerosis.

For many years, patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system, have been advised to avoid exercise. MS is believed to be autoimmune in origin, mediated by activated T cells which penetrate the blood-brain barrier and attack myelin. The pathophysiology, with respect to function is an impairment of saltatory conduction, specifically, slowing of conduction speed and/or conduction block. Symptoms can temporarily worsen on exposure to heat or during physical exercise. Exercise programmes must be designed to activate working muscles but avoid overload that results in conduction block. Fatigue, often severe, affects about 85% of MS patients and, along with motor and sensory symptoms, results in decreased mobility and reduced quality of life. Physical activity and recreation are reduced in patients with MS. Before developing recommendations, physical activity patterns and the physical effects of MS should be assessed in individual patients. Patients may then be functionally classified. Physical activity can also be classified in a pyramid structure, with the most basic functions forming the base and the most integrated functions on top. The muscular fitness pyramid progresses through passive range of motion, active resistive, specific strengthening and integrated strength exercises Overall physical activity may be increased according to functional level by performing activities of daily living, incorporating inefficiencies into daily living, pursuing more active recreation and eventually developing a structured exercise programme. The importance of the proper exercise environment, balance and coordination issues and factors related to adherence are discussed.

Toward earlier diagnosis of amyotrophic lateral sclerosis: revised criteria. rhCNTF ALS Study Group.

We modified the World Federation of Neurology (WFN) diagnostic criteria for ALS to facilitate early diagnosis and used these criteria for enrollment of ALS patients in a clinical trial. The criteria developed required lower motor neuron (LMN) involvement in at least two limbs and upper motor neuron involvement in at least one region (bulbar, cervical, or lumbosacral). The EMG finding of fibrillation potentials was required for evidence of LMN involvement. Electrodiagnostic studies, neuroimaging, and laboratory studies were also used to exclude disorders that might mimic ALS. Using these criteria, the diagnosis of ALS was made at a mean time of 9.7 months from onset of symptoms, which compares favorably with the 12-month period cited in the literature. Using clinical assessment at completion of the trial, the diagnosis of ALS was believed to be accurate in those patients entered in the trial. However, pathologic confirmation of the diagnosis of ALS was not obtained. Based on our preliminary experience, we propose that these ALS diagnostic criteria will facilitate early diagnosis of ALS. Future studies should prospectively compare these criteria with the WFN criteria currently in use.

Reliability of maximal voluntary isometric contraction testing in a multicenter study of patients with amyotrophic lateral sclerosis. Syntex/Synergen Neuroscience Joint Venture rhCNTF ALS Study Group.

Maximal voluntary isometric contraction (MVIC) is becoming widely used for monitoring disease progression in amyotrophic lateral sclerosis (ALS). We evaluated the variability of MVIC in a large multicenter (29 sites) drug trial in ALS. Intra- and interrater variability were assessed twice during the 19-month study. Intrarater reliability increased from the first to the second test, approaching the reliability reported for a single experienced clinical evaluator, but interrater reliability did not. Multiple clinical evaluators in a single site increased the variability of MVIC measurements. Rigorous quality assurance standards and monitoring of clinical evaluators should be incorporated into the design of multicenter studies using MVIC, since low variability is necessary to detect a modest treatment effect.

A brief quality-of-life measure for ALS clinical trials based on a subset of items from the sickness impact profile. The Syntex-Synergen ALS/CNTF Study Group.

We previously demonstrated a significant relationship (P<0.0001) between maximum voluntary isometric contraction (MVC) plus pulmonary function scores (the Tufts Quantitative Neuromuscular Exam Combination Megascore (TQNE CM)), and the Sickness Impact Profile (SIP) in a cohort of 524 ALS patients. Because the 136-item SIP questionnaire can be difficult to administer in this population, we examined SIP subscales and clinically derived item sets in relation to the TQNE CM in an effort to define a briefer measure of quality of life for use in clinical trials. Two 'Mini-SIP' indices performed as well as the overall SIP in reflecting the impact of muscle weakness on ALS patients' quality of life: a combination of two SIP subscales ('SIP-33'), and a 19-item set of questions independently chosen by a panel of ALS specialists ('SIP/ALS-19'). Either index potentially could be useful in ALS clinical trials. The SIP/ALS-19 is currently being used in a National ALS data base, providing an opportunity to evaluate its utility prospectively against other QOL measures in ALS patients.

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

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.

Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis.

We examined the toxicity of both single and multiple subcutaneous injections of recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, in doses ranging from 2 to 100 micrograms/kg. Adverse events were generally dose related and ranged from mild to severe. The tolerability of daily subcutaneous rhCNTF was equivalent to placebo at doses < or = 5 micrograms/kg/day. At higher doses, anorexia, weight loss, reactivation of herpes simplex virus (HSV1) labialis/stomatitis, cough, and increased oral secretions occurred.

Relationship of the Tufts Quantitative Neuromuscular Exam (TQNE) and the Sickness Impact Profile (SIP) in measuring progression of ALS. SSNJV/CNTF ALS Study Group.

The Tufts Quantitative Neuromuscular Exam (TQNE) is a standardized tool for measuring muscle strength and pulmonary function in patients with amyotrophic lateral sclerosis (ALS). We describe the relationship of TQNE scores to functional disability and health-related quality of life as measured by the Sickness Impact Profile (SIP) in 524 ALS patients. There was a significant relationship (p < 0.0001) between TQNE and SIP scores, both in cross section and over time. TQNE scores strongly relate to ALS patients' quality of life and ability to perform activities of daily living.

Impact of aerobic training on fitness and quality of life in multiple sclerosis.

Fifty-four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (VO2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 x 40-minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in VO2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very-low-density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.

A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group.

Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.

The natural history of amyotrophic lateral sclerosis.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

Discordance of the T-cell receptor alpha-chain gene in familial multiple sclerosis.

We studied restriction fragment length polymorphisms of the T-cell receptor alpha-chain (TCR alpha) gene in DNA obtained from 99 individuals of 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Six normal family members had abnormal cranial MRIs. Linkage analysis utilized constructed haplotypes of EcoRV, Sst I, and Taq I polymorphisms. With penetrance values from 0.1 to 0.7, and scoring the normal individuals with abnormal MRIs as either unknown or affected, LOD scores were between -3.16 and -7.95 for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1, the LOD scores ranged from -6.77 to -23.08. These findings do not support a direct role of TCR alpha in the inheritance of MS.

Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus.

Paramyotonia congenita (PC), an autosomal dominant muscle disease, shares some clinical and electrophysiological similarities with another myotonic muscle disorder, hyperkalemic periodic paralysis (HYPP). However, clinical and electrophysiologic differences allow differentiation of the two disorders. The HYPP locus was recently shown to be linked to a skeletal muscle sodium-channel gene probe. We now report that PC maps to the same locus (LOD score 4.4, theta = 0 at assumed penetrance of .95). These linkage results, coupled with physiological data demonstrating abnormal sodium-channel function in patients with PC, implicate a sodium-channel gene as an important candidate for the site of mutation responsible for PC. Furthermore, this is strong evidence for the hypothesis that PC and HYPP are allelic disorders.