American Academy of Neurology policy on pharmaceutical and device industry support.

OBJECTIVE: To examine the American Academy of Neurology (AAN)'s prevention and limitation of conflicts of interest (COI) related to relationships with pharmaceutical and medical device manufacturers and other medically related commercial product and service companies (industry). METHODS: We reviewed the AAN's polices governing its interactions with industry, mechanisms for enforcement, and the recent findings of the board-appointed COI task force, in the context of the 2009 David Rothman and colleagues' article in JAMA, the Council of Medical Specialty Societies (CMSS) Code for Interactions with Companies (Code), efforts of the American Medical Association in this area, and increased public and Congressional scrutiny of physician/physician organizations' relationships with industry. RESULTS: The AAN's Policy on Conflicts of Interest provides 4 mechanisms for addressing COI: avoidance, separation, disclosure, and regulation. The AAN's Principles Governing Academy Relationships with External Sources of Support, including recent amendments proposed by the COI task force, regulate industry interaction with AAN programming, products, and leadership. With the Policy, Principles, and other methods of COI prevention, the AAN meets or exceeds all recommendations of the CMSS Code. CONCLUSIONS: With its adherence to the Principles since 2004, the AAN has been a leader among professional medical associations in appropriately managing COI related to interactions with industry. Recent amendments to the Principles maintain the AAN's position as a leader in a time of increased public scrutiny of physicians' and professional medical associations' relationships with industry. The AAN is responsive to the recommendations of the COI task force, and has adopted the CMSS Code.

Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype.

OBJECTIVES: Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype. METHODS: We identified a total of 74 genotyped patients for this study. These included patients who were referred over a 15-year period to the only U.K. referral center or to a Chinese center and who underwent extensive clinical evaluation. For all genotyped patients, the response to acetazolamide therapy in terms of attack frequency and severity was documented. Direct DNA sequencing of CACNA1S and SCN4A was performed. RESULTS: Only 46% of the total patient cohort (34 of 74) reported benefit from acetazolamide. There was a greater chance of benefit in patients with mutations in CACNA1S (31 responded of 55 total) than in those with mutations in SCN4A (3 responded of 19 total). Patients with mutations that resulted in amino acids being substituted by glycine in either gene were the least likely to report benefit. CONCLUSIONS: This retrospective study indicates that only approximately 50% of genotyped patients with hypokalemic periodic paralysis respond to acetazolamide. We found evidence supporting a relationship between genotype and treatment response. Prospective randomized controlled trials are required to further evaluate this relationship. Development of alternative therapies is required.

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment.

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

Primary episodic ataxias: diagnosis, pathogenesis and treatment.

Primary episodic ataxias are autosomal dominant channelopathies that manifest as attacks of imbalance and incoordination. Mutations in two genes, KCNA1 and CACNA1A, cause the best characterized and account for the majority of identified cases of episodic ataxia. We summarize current knowledge of clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of episodic ataxia syndromes. We focus on unresolved issues including phenotypic and genetic heterogeneity, lessons from animal models and technological advancement, rationale and feasibility of various treatment strategies, and shared mechanisms underlying episodic ataxia and other far more prevalent paroxysmal conditions such as epilepsy and migraine.

The primary periodic paralyses: diagnosis, pathogenesis and treatment.

Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.

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.

Reporting clinical trials: full access to all the data.

Authors' right to access to all data obtained in their study

Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy.

BACKGROUND/OBJECTIVES: Animal and human studies suggest that beta(2)-adrenergic agonists exert anabolic effects on muscles, inducing and preventing atrophy after a variety of insults. Based on data from an open-label trial of albuterol in 15 patients with facioscapulohumeral dystrophy (FSHD), the authors conducted a randomized, double-blind, placebo-controlled trial of sustained-release albuterol in this disease. METHODS: Ninety patients were randomized to three groups: placebo; 8.0 mg albuterol twice daily; or 16.0 mg albuterol twice daily. Patients were treated for 1 year with assessments at baseline and weeks 13, 26, and 52. The primary outcome was the 52-week change in global strength by maximum voluntary isometric contraction testing (MVICT). Secondary outcomes included changes at 52 weeks in strength by manual muscle testing (MMT), grip strength, functional testing, and muscle mass assessed by dual energy x-ray absorptiometry (DEXA). RESULTS: Eighty-four patients completed the study. The mean changes in composite MVICT scores were not significantly different between the groups (mean +/- SD: placebo 0.20 +/- 0.91; low dose -0.04 +/- 0.84; high dose 0.08 +/- 0.98). Similarly, there were no differences in the mean MMT change (placebo 0.04 +/- 0.16; low dose -0.03 +/- 0.13; high dose 0.00 +/- 0.15). Grip improved in both treatment groups compared to placebo (placebo -0.53 +/- 4.13, low dose +1.90 +/- 3.34 [p = 0.02], high dose +1.70 +/- 4.13 [p = 0.03]). The high-dose group had a significant increase in lean mass by DEXA (+1.57 +/- 1.71 kg) compared to placebo (0.25 +/- 2.24; p = 0.007). Albuterol was well tolerated; side effects included cramps, tremors, insomnia, and nervousness. CONCLUSIONS: Although albuterol did not improve global strength or function in patients with FSHD, it did increase muscle mass and improve some measures of strength.

Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis.

A novel mutation in a family with hypokalemic periodic paralysis is described. The mutation R672S is located in the voltage sensor segment S4 of domain II in the SCN4A gene encoding the human skeletal muscle voltage-gated sodium channel. Functional expression of the R672S channels in human embryonic kidney 293 cells revealed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. These two defects are mainly due to a slow recovery of the mutant channels from fast and/or slow inactivation. Our data may help explain the mechanism underlying hypokalemic periodic paralysis and the patient's worsening from acetazolamide.

A prospective natural history study of inclusion body myositis: implications for clinical trials.

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.

A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy.

BACKGROUND: A pilot study suggested that oxandrolone, an anabolic steroid, improved strength in boys with Duchenne dystrophy (DD) and indicated the need for a more definitive study. METHODS: A 6-month, randomized, double-blind, placebo-controlled study of oxandrolone in boys with an established diagnosis of DD, using the change from baseline to 6 months in the average muscle strength score (MMT) as the primary efficacy measure. RESULTS: The mean change from baseline for the oxandrolone group was +0.035 and that for the placebo group was -0.140. Although the oxandrolone group did not get worse and the placebo patients showed some deterioration in strength, the difference was not significant (p = 0.13). The average of the four quantitative muscle tests (QMT) showed a significant improvement in the oxandrolone-treated boys as compared with placebo. No adverse reactions attributable to oxandrolone were recorded. CONCLUSIONS: Although oxandrolone did not produce a significant change in the average manual muscle strength score as compared with placebo, the mean change in QMT was significant. Because oxandrolone is safe, accelerates linear growth, and may have some beneficial effect in slowing the progress of weakness, it may be useful before initiating corticosteroid therapy.