|Adapted from: Drug treatment for myotonia: a systematic review. The Cochrane Database of Systematic Reviews 2006 Jan 25; (1): CD004762. |
Synopsis Drug therapy to treat myotonia in myotonic disorders
Myotonia is an abnormal delay in the relaxation of skeletal muscles after contraction. It is a key symptom in a number of muscle diseases called myotonic disorders (myotonic dystrophy and non-dystrophic myotonias). It can be mild or severe, and could sometimes interfere with daily activities such as walking, climbing stairs or opening and closing the eyelids. It can especially be worse after periods of rest or triggered by cold or fatigue. People with mild myotonia can manage their disease without medication but in severe cases treatment is usually necessary. Drugs that have been used to treat myotonia include sodium-channel blockers such as mexiletine, carbamazepine, phenytoin and procainamide, tricyclic antidepressant drugs such as clomipramine or imipramine, benzodiazepines, calcium antagonists, taurine and prednisone. This review describes nine randomised controlled trials in which the effectiveness of twelve different drug treatments were evaluated. The nine trials included a total of 137 patients of which 109 had myotonic dystrophy and 28 had myotonia congenita. Trials were generally small and of poor quality. Meta-analysis was not possible due to a lack of appropriate trials and data. Two small studies indicated that clomipramine and imipramine had a short-term beneficial effect in myotonic dystrophy and one small study indicated that taurine had a long-term beneficial effect in myotonic dystrophy. Minor side effects such as dry mouth and dizziness were reported with clomipramine and imipramine, but not with taurine. No good randomised controlled trials were found for the treatment of myotonia in non-dystrophic myotonias. Therefore, it was not possible to determine whether drug therapy is safe and effective for myotonia in patients with non-dystrophic myotonias. Large, randomised controlled trials are needed to determine effectiveness for the treatment of myotonia in myotonic dystrophy as well as in non-dystrophic myotonias. For clinical practice expert opinion suggests mexiletine as first choice for non-dystrophic myotonias. Second and third choice are carbamazepine and phenytoin, respectively.
Abnormal delayed relaxation of skeletal muscles, known as myotonia, can cause disability in myotonic disorders (myotonic dystrophy and non-dystrophic myotonias). Sodium-channel blockers, tricyclic antidepressive drugs, benzodiazepines, calcium-antagonists, taurine and prednisone may be of use in reducing myotonia.
To consider the evidence from randomised controlled trials on the efficacy and tolerability of drug treatment in patients with clinical myotonia due to a myotonic disorder.
We searched the Cochrane Neuromuscular Disease Group trials register (April 2006), MEDLINE (January 1966 to December 2006) and EMBASE (January 1980 to December 2006). Grey literature was handsearched and reference lists of identified studies and reviews were examined. Authors, disease experts and manufacturers of anti-myotonic drugs were contacted.
We considered all (quasi) randomised trials of participants with myotonia treated with any drug treatment versus no therapy, placebo or any other active drug treatment. The primary outcome measure was:
reduced clinical myotonia using two categories: (1) no residual myotonia or improvement of myotonia or (2) No change or worsening of myotonia. Secondary outcome measures were:
(1) clinical relaxation time; (2) electromyographic relaxation time; (3) stair test; (4) presence of percussion myotonia; and (5) proportion of adverse events.
Data collection & analysis
Two authors extracted the data independently onto standardised extraction forms and disagreements were resolved by discussion.
Nine randomised controlled trials were found comparing active drug treatment versus placebo or another active drug treatment in patients with myotonia due to a myotonic disorder. Included trials were double-blind or single-blind crossover studies involving a total of 137 patients of which 109 had myotonic dystrophy type 1 and 28 had myotonia congenita. The studies were of poor quality. Therefore, we were not able to analyse the results of all identified studies. Two small crossover studies without a washout period demonstrated a significant effect of imipramine and taurine in myotonic dystrophy. One small crossover study with a washout period demonstrated a significant effect of clomipramine in myotonic dystrophy. Meta-analysis was not possible. No good randomised controlled trials were found for non-dystrophic myotonias.
Due to insufficient good quality data and lack of randomised studies, it is impossible to determine whether drug treatment is safe and effective in the treatment of myotonia. Small single studies give an indication that clomipramine and imipramine have a short-term beneficial effect and that taurine has a long-term beneficial effect on myotonia in myotonic dystrophy. No good randomised trials are available for non-dystrophic myotonias. Larger, well-designed randomised controlled trials are needed to assess the efficacy and tolerability of drug treatment for myotonia.
For clinical practice expert opinion suggests mexiletine as first choice for non-dystrophic myotonias. Second and third choice are carbamazepine and phenytoin, respectively.
Myotonia is a clinical phenomenon, which refers to a delayed muscle relaxation after voluntary or evoked muscle contraction.1 It is a cardinal feature of myotonic disorders including myotonic dystrophy and non-dystrophic myotonias. Myotonia may be present in every skeletal muscle. Clinical examination reveals action myotonia and/or percussion myotonia, which are both best tested in hand muscles: following a forceful grip, the ability to relax the grip is delayed (action myotonia or grip myotonia). Mechanical stimulation, for example a blow with the percussion hammer on the thenar muscles, will also contract the muscle for a few seconds (percussion myotonia). Furthermore, an acute muscle contraction may give a transient decline in muscle force in some myotonic disorders (transient paresis).2, 3 Repeated contraction and relaxation may improve myotonia as well as muscle force, which is called the 'warm-up' phenomenon. However, in a condition called paramyotonia, myotonia worsens after repetitive contractions (paradoxical myotonia). A number of conditions are associated with delayed relaxation of muscles in a way that resembles myotonia but they do not have the characteristic electrophysiological features of true myotonia (pseudomyotonia).4 Because such pseudomyotonia may have a different physiological basis from true myotonia, we excluded these conditions from our review. These conditions include McArdle's disease (Glycogenosis type V), Hoffman's disease (myotonia in hypothyroidism), Brody's disease (sarcoplasmic reticulum-Ca2+ATPase deficiency), neuromyotonia, neuroleptic malignant syndromes and tetanus. Schwartz-Jampel syndrome (chondrodystrophia myotonia) was also excluded because myotonic activity in this disease persists during general anaesthesia, which does not happen in true myotonia.5 True myotonia syndromes included in this review are discussed below.
Myotonic dystrophy type 1 is an autosomal-dominant disorder in which myotonia is accompanied by a characteristic pattern of muscle weakness and by the involvement of several organs.6-8 This condition is caused by an expanded CTG (cytosine-thymine-guanine) trinucleotide repeat in the DMPK-gene on chromosome 19q.9, 10 The inheritance is characterised by anticipation, that is an earlier and more severe onset of the disease in successive generations.11 The prevalence of myotonic dystrophy type 1 varies from 2 to 12 per 100,000.12 Myotonia is clinically detectable in almost every symptomatic patient. Recently, myotonic dystrophy type 2 was described, which differs from type 1 in its predominant proximal muscle weakness. It was, therefore, originally named proximal myotonic myopathy (PROMM).13, 14 Myotonic dystrophy type 2 is caused by an increased CCTG repeat in the ZNF9 gene on chromosome 3. We have included patients with clinical myotonia due to both types of myotonic dystrophy.
Clinically non-dystrophic myotonias have myotonia with or without periodic paralysis.15 Recently the molecular basis of these disorders has been discovered, but it is still difficult to make a diagnosis only on the basis of the clinical picture because no obvious genotype-phenotype correlation exists.16-18 Over the past decade, a combination of electrophysiologic and molecular biological studies have led to a reclassification of this group of diseases.2, 15, 19, 20 They are now classified as chloride- or sodium-channel diseases.
There are two forms of chloride-channel disorders: autosomal-recessive myotonia congenita (Becker's disease) 21, 22 and autosomal-dominant myotonia congenita (Thomsen's disease).23 Both diseases are characterised by clinical myotonia. Autosomal-recessive myotonia congenita also shows transient paresis.2, 3 The disorders are caused by a mutation in the skeletal muscle chloride-channel gene (CLCN1) on chromosome 7q.24-26 The prevalence of chloride-channel diseases varies in different studies between 2 to 7.3 per 100,000.22, 27, 28 We included patients with dominant as well as recessive myotonia congenita in our review.
Sodium-channel disorders are all autosomal-dominantly inherited or sporadic and are divided into paramyotonia congenita, potassium-aggravated myotonias (myotonia fluctuans, myotonia permanens and acetazolamide responsive myotonia congenita) and hyperkalaemic periodic paralysis (hyper PP).29-33 The sodium channelopathies are caused by a mutation in the skeletal muscle sodium-channel gene (SCN4A) on chromosome 17q encoding for SkM1, the alpha-subunit of the sodium channel.24, 34 The exact prevalence of sodium-channel diseases is not known, although the prevalence of paramyotonia congenita has been estimated at 1 per 356,000 (Becker 1970). Hyper PP can occur with myotonia or paramyotonia and sometimes without either. We excluded Hyper PP without (para)myotonia and included all other sodium- channel disorders in our review. The pathophysiological mechanisms of myotonia in several myotonic disorders differers. Recent publications suggest that the expanded CTG-repeat in myotonic dystrophy triggers aberrant splicing of chloride channel mRNA but it is also possible that the myocytes in myotonic dystrophy display an abnormal Na+ channel activity.35-37 Thus, the exact pathophysiological mechanism of myotonia in myotonic dystrophy is unknown. It could be assumed that there is an overlap with non-dystrophic myotonias. Chloride-channel myotonias are caused by a permanent reduction of the resting chloride conductance of the muscle fiber membranes.38, 39 Normal chloride conductance is necessary for a fast repolarisation of the muscle fiber membranes, otherwise these tend to stay depolarised causing myotonia or become hyper-depolarised causing a loss of excitability of the muscle fiber membrane and thereby transient paresis.40 Sodium-channel myotonias are caused by a long-lasting depolarisation of the muscle fiber membrane due to an inactivation defect of sodium channels.41, 42 These can initiate successive action potentials, which is the basis for myotonia.40 Many people with mild myotonia can manage their disease without medication. However, severe myotonia can interfere with daily activities and in these individuals treatment is often necessary. No treatment for the cause of myotonia is available, so treatment is merely symptomatic. In general drugs that block sodium-channels, independent of the disease process involved, may diminish myotonia. These agents reduce the excitability of the cell membrane of the skeletal muscle and include local anaesthetics and cardiac agents such as anti-arrhythmic drugs. The first treatment for myotonia was published by Wolf in 1936 who treated four patients with myotonia congenita with quinine, an anti-arrhythmic drug.43 Literature also suggests that procainamide, tocainide and phenytoin have favourable effects.44-49 However, procainamide and tocainide could have serious long-term side effects. Expert opinion suggests that mexiletine is the agent of first choice.28 However, there are no good published randomised clinical trials with mexiletine. Some case reports 50-52, one study with a heterogeneous population 45 and an electrophysiological evaluation 53 on the use of mexiletine in patients with myotonia are reported in literature. Acetazolamide, another possibility for the treatment of myotonia, is a carbonic anhydrase inhibitor traditionally thought of as a diuretic, and has been described as useful for myotonia in some sodium-channelopathies.54, 55 The crucial aspect to this review is how to quantify myotonia because it can be difficult to standardise this, as highlighted by a report of an experimental protocol to quantify myotonia using quantitative muscle assessment.56 The problems include the variability of myotonia between patients and within a given patient at different times of the day, and how to take account of the warm-up phenomenon, all of which exacerbate the usual problem of inter-observer variability. Possible solutions might be the use of specific devices with a computerized protocol.1, 57 One of the most used parameters of myotonia is the relaxation time after maximum voluntary contraction (MVC) as measured by stopwatch, special technical equipment or computerized protocols. A related measure is the electromyographic variant, the electromyographic (EMG) relaxation time after MVC. Another used parameter is to record the presence or absence of percussion myotonia. These parameters measure the impairment, but not the functional effect of myotonia. The stair test (time needed to climb ten stairs) or chair-test (time to stand-up, walk around it and sit down again) are possibly the best available methods for measuring functional benefit. No systematic reviews of drug treatment for myotonia are known. Two non-systematic reviews of therapy for myotonic disorders have been published.58, 59 This systematic review aims to provide the evidence on which to base treatment.
To consider the evidence from randomised controlled trials on the efficacy and tolerability of drug treatment in patients with clinical myotonia due to a myotonic disorder.
Criteria for considering studies for this review Types of studies
We included all randomised and quasi-randomised (alternate or other systematic treatment allocation) trials of any drug treatment in patients with clinical myotonia due to one of the myotonic disorders described below.
Types of participants
Participants of all ages with clinical myotonia caused by myotonic disorders (myotonic dystrophy and the non-dystrophic myotonias) were included. It is now possible to diagnose the myotonic disorders by DNA-analysis. This was not possible at the time when most of the included studies were performed, so DNA-analysis was not an inclusion criterion in our review. We excluded patients with McArdle's disease (Glycogenosis type V), Hoffman's disease (myotonia in hypothyroidism), Brody's disease (sarcoplasmic reticulum-Ca2+ATPase deficiency), neuromyotonic diseases, neuroleptic malignant syndromes, tetanus and Schwartz-Jampel syndrome. For trials or treatment groups including patients with myotonic dystrophy and non-dystrophic myotonias we described the different diseases and the degree of myotonia separately, if this was possible.
Types of interventions
We included any drug treatment (given either singly or in combination) versus no therapy, placebo or another active drug treatment. The list of potential drugs included mexiletine, carabamazepine, phenytoin, quinine, procainamide, tocainide, and acetazolamide but this list was not exclusive.
Types of outcome measures
Since there is no consensus regarding the best measure of myotonia, leading to disparate outcome measures in each of the randomised trials, we devised a measure using categorisation of changes in clinical myotonia. We used this measure after drug treatment for each trial based on the conclusion of the original authors:
(1) improvement of myotonia with no residual clinical myotonia; (2) improvement of myotonia but still clinically detectable; (3) no change of myotonia; (4) worsening of myotonia. Secondary outcomes (1) Relaxation times: Time taken to fully open the hand after a maximum voluntary contraction (MVC) (hand-grip myotonia). This might be determined manually by stopwatch or digital by computerized protocols. When using a computerized hand-grip myometer the decline in maximum voluntary contraction from 90 to 5% during relaxation is frequently used to measure relaxation time. However, some researchers have used 50%, 75% or 100% decline from peak MVC as relaxation time. We included all such protocols. (2) Electromyographic (EMG) relaxation time: the phenomenon of myotonia can be recorded by an electromyographic needle electrode as positive waves, so called myotonic discharges or after-discharges. After MVC these myotonic or afterdischarges wax and wane and finally stop. Duration of these after-discharges is called EMG relaxation time. For example after-discharges can be recorded from the opponens pollicis muscle. (3) Stair-test or chair-test: time needed to climb ten stairs or time needed to stand up from a chair, walk around it and sit-down again. (4) Presence of percussion myotonia: percussion myotonia is myotonia occurring after a mechanical stimulus; for example tested using percussion of the thenar muscles of the hand with a reflex hammer. (5) The occurrence of one or more adverse events during treatment with the different drugs. We specified all adverse events. For all outcome measures we used a minimum treatment duration of one week and maximum treatment duration of twelve weeks and where necessary planned to adjust for different follow-up periods.
Search strategy for identification of studies
See: Cochrane Neuromuscular Disease Group search strategy. The Cochrane Neuromuscular Disease Group trials register was searched for randomised controlled trials using: "myotonia", "myotonic dystrophy"', "non-dystrophic myotonias", "myotonia congenita", "Morbus Thomsen", "Morbus Becker", "potassium-aggravated myotonia", "myotonia fluctuans", "myotonia permanens", "paramyotonia congenita", "hyperkalaemic periodic paralyses", "relaxation" AND "muscle" and "treatment" OR "therapy" as the primary search items (April 2006). We adapted this strategy to search MEDLINE (January 1966 to December 2006) and EMBASE (January 1980 to December 2006) for other randomised controlled trials. Grey literature such as neuromuscular text books and abstracts from international neuromuscular congresses were handsearched and we checked the reference lists of the identified literature and reviews concerning myotonia. We also contacted authors, disease experts and manufacturers of anti-myotonic drugs.
Electronic search strategies
See Table 02 and Table 03 in the Cochrane Database of Systematic Reviews.
Methods of the review Selecting trials for inclusion
Two authors (JT and CGF) independently reviewed titles and abstracts from the electronic search to identify relevant trials for full review. The full text of all potentially relevant studies was obtained for assessment. The authors decided which trials fitted the inclusion criteria and graded their methodological quality. Disagreement was resolved by discussion. Review authors were not blinded to trial authors' names, institutions and the journals of publication.
Assessment of methodological quality
Two independent authors (JT and CGF) assessed randomised trials for methodological quality with respect to the following items: allocation concealment, patient blinding, observer blinding, explicit diagnostic inclusion and exclusion criteria and explicit outcome measures. These items were assessed according to the Cochrane approach: A - adequate, B - unclear, C - inadequate, D - not done. Disagreement was resolved by discussion.
Data extraction on participants, methods, intervention, outcomes and adverse events was performed by two independent authors (JT and CGF) using a data extraction form. We attempted to obtain missing data from the trial authors if this was necessary. For the primary outcome we had created a special scoring system: (1) no residual clinical myotonia; (2) improvement of myotonia but still clinically detectable; (3) no change; (4) worsening of myotonia; and data were transformed from the original studies by two authors (JT and CGF) with any disagreement being resolved by discussion.
For statistical analysis of the primary outcome we dichotomised the variable scoring system to define two groups:
(1) no residual myotonia or an improvement;
(2) no change or worsened.
Relative risks (RR) with 95% confidence intervals (CI) were calculated from the dichotomised data for each study if this was possible. Where possible the numbers needed to treat (NNT) and the numbers needed to harm (NNH) would also have been calculated. If all necessary data could be deduced from the published results, the primary outcome for crossover studies were analysed using the McNemar's test 60, 61, calculating the odds ratios. If there had been continuous data in the secondary outcomes we would have calculated the weighted mean difference (WMD) with 95% CI or presented the original statistical analysis of the study. If there had been more than one trial with the same agent in the same disease group we would have calculated a weighted treatment effect across those trials using a fixed-effect model with the Cochrane statistical package, Review Manager (RevMan). We interpreted a p value less than or equal to 0.05 as statistically significant. If chi-squared analysis showed heterogeneity of the study results (p value < 0.1), sensitivity analyses would have been carried out to explore plausible causes. If heterogeneity could still not be explained, we would have reported the results using a random-effects model. We would have analysed myotonic dystrophy and the non-dystrophic myotonias as subgroups if possible, however, we did not analyse them as a total group. We also discussed adverse events and cost benefits drawing upon non-randomised data (Dukes 2000).
Description of studies
See Tables in Cochrane Database of systematic Reviews: Characteristics of included studies and characteristics of excluded studies. Eight trials were found that compared active drug treatment with placebo for the treatment of myotonia, in a total of 99 patients with myotonic dystrophy type 1 and 28 patients with myotonia congenita.45-47, 62-66 One trial was found that compared two different drug treatments for the treatment of myotonia, in 10 patients with myotonic dystrophy type 1.67 On the basis of title or abstract a further 27 studies initially appeared to be eligible. However, by reading the full text of all potentially relevant studies sixteen were non-randomised or uncontrolled studies 48, 54, 68-81, six were case studies 82-87 and a further five did not have measures of myotonia as outcome measures.88-92 Another study 93 is awaiting assessment because at the time of writing this review the trial results were not available in sufficient detail. We were informed about this study by contacting one of the disease experts in this field and read the abstract. This trial will be included in the next update to the review.
Seven included trials were placebo-controlled, randomised, double-blind, crossover studies. The other two were placebo-controlled, randomised, single-blind, crossover studies.45, 65 All included trials were performed in a single centre and a total of 137 patients received treatment over two weeks to six months. In one study the treatment period was separated by a 30-day period washout interval.62 The other eight trials had no washout interval between the treatment periods. The trial of Kwiecinski started as a crossover study.45 Afterwards randomisation for three different study drugs took place. Remarkably the sum of the number of patients in the different treatment groups in the randomised part of the study exceeded the total number of included participants. An attempt to clarify this with the author was unsuccessful. We assumed that the second part of the study was not randomised until we receive evidence to the contrary.
The trials did not provide baseline characteristics of the individual participants or of the two separated groups. Four trials did not give the baseline characteristics at all 46, 47, 63, 66, the other trials gave characteristics of the entire study population. Five trials included patients with myotonic dystrophy only and four trials 45-47, 66 included participants with myotonic dystrophy as well as myotonia congenita. Four trials did not define explicit inclusion criteria.46, 64, 66, 67 Only Antonini et al. defined explicit exclusion criteria.62 In this trial cardiac, ophthalmologic or urologic diseases were excluded. Since cardiac and ophthalmologic diseases are symptoms of myotonic dystrophy this trial probably included a selected group of patients.
The regimens of treatment varied between studies (see characteristics of included studies). Most studies used drugs that block sodium-channels, (procainamide, disopyramide, phenytoin, quinine, tocainide and mexiletine) in which myotonia is diminished by reducing the level of depolarisation. Other drugs used were clomipramine, imipramine, taurine, nifedipine, diazepam and prednisone. It is hypothesised that tricyclics (imipramine and clomipramine) act on the sympathetic nerve terminals to increase levels of norepinephrine, which exerts an inhibitory influence on skeletal muscle membranes by ß2-adrenoreceptor stimulation.64, 94 Taurine, an amino-acid, may affect cellular hyperexcitability by increasing membrane conductance of potassium and chloride.63, 71 All these types of drugs seem to act as membrane-stabilisers.
The outcome measures used differed between trials. The most frequently used outcome measure was the clinical relaxation time in seconds. It was measured after three seconds 62, two to three seconds 64, five seconds 66 and three minutes 93 of maximum voluntary contraction (MVC). Others did not specify the length of maximum voluntary contraction.45, 65 The EMG relaxation time (after-discharge) in seconds after MVC was also used.45, 63 Additional ways of measuring relaxation time were used such as the use of EEG surface electrodes or an ergographic device.66 Two trials used a mean score of three relaxation times and one used a mean score of five relaxation times after MVC.64-66 Another trial used a mean score of six measurements consisting of three clinical relaxation times and three EMG relaxation times.46 Other outcome measurements were occurrence of percussion myotonia 63, percussion myotonia in seconds 64, lid myotonia in seconds after firm closure 45, occurrence of myotonic discharge induced by electrical stimulation of the median nerve 63, potassium chloride (KCl) loading test in mmol/litre for occurrence of myotonia 63, time to climb ten stairs (stair test) 45 and subjective responses.45, 93
All trials were analysed on a per protocol basis instead of an intention-to-treat basis (withdrawals were not included in the analysis).
Methodological quality of included studies
See Additional Table 01. The methodological quality assessment took into account allocation concealment, patient blinding, observer blinding, explicit inclusion and exclusion criteria and explicit outcome measures. We graded these items as: A: adequate, B: unclear, C: inadequate, D: not done. If the information was not available the item was graded as unclear. The scores of each trial are included in Table 01. In all nine trials participants were randomised for crossover studies to either active treatment or placebo (or another active drug treatment). The allocation concealment was considered adequate in the study of Leyburn ; a statistician randomised trial participants.46 For the study of Lewis the allocation concealment was inadequate; the procedure was described as "arbitrary by secretary".66 The other allocation concealments were unclear, because the method of randomisation was not explained. Patient blinding was intended in at least eight trials. In only three trials the blinding was considered adequate.45, 47, 63 In five trials the blinding was unclear because it was not described 46, 62, 64-66 and in Finlay et al. the patient blinding was inadequate because participants could recognise the side effects having used the medication previously in a clinical setting.93 Observer blinding was also intended in at least eight trials. Four trials were considered adequate for observer blinding.63, 64, 66, 93 In one trial the observer could recognize the origin of the medication by the kind of adverse events.47 Another single trial did not have observer blinding 45 and the study of Grant et al. was designed as a randomised single-blind crossover study but it was unclear if the participants or the observers were blinded.65 The other two studies were unclear. None of the trials recorded effectiveness of blinding. We also graded the inclusion and exclusion criteria. This item is discussed under participants in the Description of studies section. As expected there was no uniform outcome measurement. The explicit outcome measurements were considered adequate in eight trials. We considered the outcome measure of Leyburn et al. as inadequate only because it was the mean value of six measurements in which three were EMG relaxation times and three were clinical relaxation times.46 It is difficult to give an explanation of the meaning of these values. Moreover, some studies took the mean of three to five relaxation times. It is likely that these times are shortened by the warming-up phenomenon.
A total of nine single centre trials were included, in which 137 patients with myotonia were randomised in a single-blind or double-blind crossover study with a treatment period ranging from two weeks to six months. Twelve different drugs were used in those nine trials. Participants could be divided into 109 patients with myotonic dystrophy type 1 and 28 patients with myotonia congenita. Three studies were performed in the 1960s, five in the 1980s and one in the 1990s. In general the trials were small, with the participant numbers ranging from nine to thirty, and the methodological quality was poor. All nine included randomised crossover trials were based on a per protocol analysis which could result in an attrition bias. The data for an intention-to-treat analysis were not available. The data analysis of Finlay et al. was inadequate.93 The study only presented descriptive results. The individual continuous data were not stated and no statistical analysis was performed. Lewis had a large placebo effect.66 Research into the placebo tablets identified that they contained 0.5 mg quinine sulphate per tablet. This substance could be an effective treatment for myotonia, resulting in performance bias. For these reasons we were unable to use the data from these two trials. Furthermore, the study of Durelli et al could officially not be included because we defined a maximum duration of treatment of 12 weeks in our protocol and Durelli used a treatment period of six months.63 Despite this criterion, we will present the data of this single study with taurine. Six studies were of crossover design without washout intervals.45-47, 63-65 Data were inappropriately presented in the form of combined results of both active treatment arms and both placebo arms. Since a washout interval was not incorporated there is a strong possibility of a carry-over effect. Data from the first arms were not presented and four studies did not present data individually.45-47, 65 From these four studies three included both participants with myotonic dystrophy as well as myotonia congenita, without defining subgroups. For these reasons we were unable to use data from those four trials. We tried to contact the authors of the trials but have not yet been successful in obtaining the raw data. Two single studies gave data for some of our specified outcome measures and in spite of a carry over effect we will present these data.63, 64 For one study we can provide the results for the treatment of myotonia without any restrictions.62 Because most trials included different diseases in the same trial without giving the individual data and used different drug treatments, meta-analysis was not possible. Thus it is only possible to present the data of three single studies for the treatment of myotonia in myotonic dystrophy.62-64 We could not present potentially valuable data for the treatment of myotonia in myotonia congenita. For the study Durelli et al. with a treatment period of six months it is only possible to present the data for our secondary outcome measure, the EMG relaxation time.63 The EMG relaxation time after treatment with taurine was lower (average 0.58 seconds; SD 0.24) than both the baseline (average 1.33 seconds; SD 0.71) and after placebo (average 1.02 seconds; SD 0.36) (P value < 0.01; Student's t test). Taurine had no side effects. Gascon et al. measured both left and right-hand relaxation times after imipramine and placebo.64 Our primary outcome with the McNemar's test was significant for the right hand with an infinity odds ratio (95% CIs from binomial distribution 0.92 to infinity) (P value = 0.025) and also significant for the left hand with an infinity odds ratio (95% CIs from binomial distribution 0.66 to infinity) (P value = 0.046). The relaxation time was measured as a secondary outcome. Repeated measures of analysis of variance (ANOVAs) of these data revealed significant improvement of myotonia as measured by right grip (F(2.20) = 11.14, P value < 0.001) and left grip (F(2.20) = 6.65, P value < 0.01). The most important side effects of imipramine were dry mouth (8 out of 12 participants; 67%), dizziness (four out of 12; 33%), increased sweating (four out of 12; 33%), constipation (four out of 12; 33%), tremor (three out of 12; 25%), blurred vision (three out of 12, 23%) and diarrhoea (three out of 12, 23%). The trial of Antonini et al. used clomipramine and had two washout intervals of thirty days so the risk of carry-over effect was reduced.62 They stated that there were no differences between patients receiving clomipramine in the first or second treatment period. The primary outcome measure of improvement of myotonia with the McNemar's test was not significant and showed an odds ratio of 3.00 (95% CIs 0.25 to 157.49) (P value = 0.32). The analysis of a secondary outcome measure with a paired t-test (crossover study) demonstrated that the mean relaxation time after clomipramine (average 15.85 seconds, SD 9.44) was significantly shorter (P value = 0.02) than after placebo (average 22.54 seconds, SD 16.47). The study has no electromyographic relaxation time, stair test or presence of percussion myotonia as outcome measures. Minor side effects were drowsiness (six out of 15 participants; 40%), dry mouth (two out of 15; 13%), tiredness (two out of 15; 13%), hyperhydrosis (one of 15; 7%) and dizziness (one of 15; 7%). In conclusion, it was only possible to calculate our primary outcome measure in this review for two studies.62, 64 This outcome was only significant for treatment with imipramine for myotonia in myotonic dystrophy.64 Our secondary outcome measure of relaxation time could be calculated in the same two studies. Both imipramine and clomipramine showed a significant result in relieving myotonia in myotonic dystrophy. We could only provide data for the EMG relaxation time from the study with the treatment of taurine for myotonia in myotonic dystrophy.63 This result was also significant. Meta-analysis was not possible. The side effects of the other active drug treatments taken from the included trials were:
Mexiletine: 8% (2 of 24) epigastric distress prevented by taking the drug with food.
Tocainine: 6% (1 of 18) lymphadenopathy and 11% (2 of 18) dizziness, anxiety and tremor.
Diphantoin: 10% (3 of 30) skin rash, somnolence and mild ataxia.
Disopyramide: 32% (7 of 22) dry mouth and blurred vision while taking high doses.
Nifedipine: 20% (2 of 10) headache and lethargy while taking 3 doses of 20 mg and 10% (1 of 10) light T wave flattening or T wave inversion on the ECG.
Procainamide: 39% (15 of 39) gastro-intestinal complaints.
Quinine: 45% (9 of 20) mild and tolerable tinnitus, 30% (6 of 20) some degree of deafness and 5% (1 of 20) dull head without tinnitus.
Prednisone: no side effects in three weeks. This is of course of little value in judging safety of steroid therapy as a long-term measure.
Diazepam: 64% (7 of 11) sedation and 27% (3 of 11) of dizziness.
The tested drug treatments in this review varied in costs from EUR 2.29 per month (phenytoin) to EUR 23.67 per month (quinine).95
Despite the fact that different drug treatments have been used to reduce symptoms of myotonia since 1936, very few good randomised crossover trials have been performed to study the effect of these treatments. Overall, the methodological quality of the studies considered was poor. Most methods reported in original papers were not described in sufficient detail. Only one crossover trial had a washout interval and reported data from each treatment period. Clomipramine, studied in this small trial, demonstrated a significant effect on the relaxation time in participants with myotonic dystrophy. For more reliable results it is necessary to perform studies with a larger cohort. The other crossover trials did not have a washout interval and did not report data from each (or at least the first) treatment period separately. Four studies included participants with myotonic dystrophy as well as myotonia congenita without defining subgroups. For these reasons it was not possible to estimate the treatment effect of four studies. Two other small studies indicated, despite a carry-over effect, a short-term effect of imipramine and a long-term effect of taurine on myotonia in myotonic dystrophy. In spite of the evidence (admittedly limited) for these three drugs reducing myotonia, they are probably not used very often in medical practice. Expert opinion on the base of clinical experience still favours mexiletine, particularly in myotonia congenita. This is despite the lack of randomised controlled trials with mexiletine although one is awaiting assessment.92 In conclusion, better randomised crossover studies with a proper washout interval and clearly presented data from both arms and with clear separation of the different diseases associated with myotonia are necessary for further determination of an effective and safe treatment for myotonia. The adverse events from randomised data are given in the results. Non-randomised data suggest serious side effects for tocainide and procainamide such as agranulocytosis and pancytopenia.96-100 These serious side effects are a contraindication for their use in myotonia. Other side effects of tocainide are diplopia, dizziness, nausea, tremor and anxiety.48, 73, 77 For procainamide more than 50% of the patients had gastro-intestinal side effects and 33% complained of insomnia.83 Three patients with myotonic dystrophy and treated with phenytoin or carbamazepine had cardiac side effects (ventricular tachycardia and atrioventricular block grade 1).101 Reported side effects of acetazolamide were paraesthesias, anorexia, weight loss, renal failure, renal calculi, osteoporosis, and haematological and hepatic dysfunction.54, 71 In a non-randomised study of amitriptyline for myotonia six from the eight patients complained of a dry mouth and two had drowsiness. One participant had supraventricular tachycardia due to an adrenergic effect.74 Verapamil for myotonia was tested in a non-randomised study in five people. One participant complained of dizziness with a first-degree heart block, another had transient nausea.81 The lack of appropriate trials and data is not the only difficulty in determining the treatment effect in myotonia. Difficulty also exists in the clinical assessment of myotonia. Although many outcome measures have been developed, until now no validated scale has been used with unanimous consent. Sansone et al. wrote an experimental protocol but also reported some unsolved problems.56 One of the main problems is the inter- and intra-variability of myotonia under the same conditions and the inter rater variability. Furthermore, myotonia can be dependent on temperature, physical effort, rest, food intake, pregnancy, phenotype and genotype. Therefore, it is difficult to standardize outcome measures for myotonia. A technique to overcome some of these problems in measuring relaxation times, is the use of computerized protocols in which a computer program places cursors along the relaxation phase and calculates the relaxation times between these points.1, 57 Another problem in determining the treatment effect of myotonia is the intriguing warming-up phenomenon (diminishing of myotonia after repetitive contractions). In chloride channelopathies this is probably the result of an improvement of both myotonia and transient paresis 2 and in myotonic dystrophy and sodium channel myotonias it is only the improvement of myotonia. The exact pathophysiological mechanism of the warming-up phenomenon is unknown but the phenomenon could influence the degree of myotonia, especially when measuring repeated maximum voluntary contractions. The length and frequency of maximum voluntary contractions differed between studies which could influence the outcome measures. Furthermore paramyotonia can occur, which is a worsening of myotonia after repetitive contractions (paradoxical myotonia). Myotonia is thus a symptom in different diseases. We excluded the diseases with no true myotonia (see background and type of participants) but when these are excluded there are still three groups left: (1) myotonic dystrophy type I (and probably type II), (2) non-dystrophic chloride channel myotonias, and (3) non-dystrophic sodium channel myotonias. In general myotonia is a mild symptom in myotonic dystrophy and a much more serious symptom in myotonia congenita and the sodium channelopathies. Paradoxically in our review only 28 patients with myotonia congenita were studied and the majority had myotonic dystrophy perhaps reflecting the higher prevalence of myotonic dystrophy. However most patients with myotonic dystrophy do not seek treatment for their myotonia because it often is a relatively mild symptom compared to the other symptoms they suffer. They also may have an avoidant personality with "avoidance" of medical treatment as part of their disease. All studies which included patients with myotonia congenita included patients with myotonic dystrophy as well. This causes a mixture of different diseases with different pathophysiologies, but the outcome measures were not analysed for the two disorders separately. For all the reasons mentioned above it would seem appropriate to perform different RCTs for the different kinds of myotonic diseases. It is also unlikely that a single method of assessment is appropriate for each separate disease. Finally, there is the lack of functional outcome measures. The most used functional outcome measure is the stair test (see last part of background), but only one study used this test. We recommend this test as a secondary outcome measure in future RCTs. Another possible functional test for future studies could be the chair test (time needed to stand up from a chair, walk around the chair and sit down again). In conclusion the best evidence for the treatment of myotonia in myotonic dystrophy is from single small studies of clomipramine, imipramine and taurine. We could not present valuable separate data for the treatment of myotonia in myotonia congenita. Taurine did not have any side effects in nine people for six months. Clomipramine and imipramine have some side effects but seem to be safe treatments. Based on these three single small randomised trials and clinical observations (subjective responses of the patients and expert opinion) some drugs have a potential effect in decreasing myotonia. To prove this hypothesis double-blind randomised controlled (multi-centre) trials have to be properly designed and performed for the different types of myotonic disorders. In the case of crossover trials a washout interval is recommended. Moreover, intention-to-treat analysis and appropriate analysis and presentation of the results are required.
Implications for practice
The beneficial effect of active drug treatment for myotonia cannot be excluded and its use in certain patients with severe myotonia might be appropriate (for example in those in whom there is a clear impact on daily activities), however, there is a lack of randomised evidence to determine which if any drug therapy is safe and effective in the treatment of myotonia.
Implications for research
The clinical efficacy of drug treatment for myotonia has not yet been properly evaluated. Larger, well designed RCTs are needed to assess the efficacy and tolerability of drug treatment for myotonia.
We are grateful to FA Kessels and E van Raak for a critical look at the review and statistical advice, and to the Princess Beatrix Foundation for financial support (MAR04-0118).
Potential conflict of interest
Authors were supported by the Princess Beatrix Foundation (MAR04-0118).
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