Acetylcholinesterase inhibitor treatment for myasthenia gravis

Abstract

Background

In myasthenia gravis, antibody‐mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring ‘safety factor’ of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness but there is controversy about their long‐term efficacy, dosage and side effects. This is the second update of a review published in The Cochrane Library Issue 2, 2011.

Objectives

To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis.

Search methods

On 8 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE for randomised controlled trials and quasi‐randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data and searched clinical trials registries for ongoing trials.

Selection criteria

The types of studies were randomised or quasi‐randomised trials. Participants were myasthenia gravis patients diagnosed by an internationally accepted definition. The intervention was treatment with any form of acetylcholinesterase inhibitor.

Types of outcome measures

Primary outcome measure

Improvement in the presenting symptoms within one to 14 days of the start of treatment.

Secondary outcome measures

(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.

(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score, within one to 14 days and more than 14 days after the start of treatment.

(3) Myasthenia Gravis Association of America post‐intervention status more than 14 days after start of treatment.

(4) Adverse events including muscarinic side effects.

Data collection and analysis

One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials.

Main results

We did not find any large randomised or quasi‐randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis either for the first version of this review or this update. One cross‐over randomised trial using intranasal neostigmine in a total of 10 participants was only available as an abstract. It included three participants with ocular myasthenia gravis and seven with generalised myasthenia gravis. Symptoms of myasthenia gravis (measured as improvement in at least one muscle function) improved in nine of the 10 participants after the two‐week neostigmine treatment phase. No participant improved after the placebo phase. Lack of detail in the report meant that the risk of bias was unclear. Adverse events were minor.

Authors' conclusions

Except for one small and inconclusive trial of intranasal neostigmine, no other randomised controlled trials have been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. The response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in a placebo arm of treatment would be difficult to justify.

Plain language summary

Acetylcholinesterase inhibitor treatment for myasthenia gravis

Review question

We reviewed the evidence about the effect of aceytlcholinesterase inhibitor drugs in people with myasthenia gravis.

Background

Myasthenia gravis is a rare autoimmune condition in which antibodies produced by the immune system attack the connection between nerves and muscles (the neuromuscular junction). Nerve impulses become blocked, causing muscles to become weak and easily tired. Symptoms fluctuate in severity. Acetylcholine is a chemical messenger that carries signals between nerve and muscle. An enzyme called acetylcholinesterase breaks down acetylcholine. Some drugs that are used to treat myasthenia gravis act on acetylcholinesterase to stop the breakdown of acetylcholine. These acetylcholinesterase inhibitors increase the amount of acetylcholine available and so help muscle activation and contraction.

Study characteristics

We only included evidence from randomised controlled trials (RCTs) in the review. In RCTs, participants are assigned to groups by chance. This makes it more likely that any changes seen can be attributed to the treatments under study rather than to other possible causes.

We found only one RCT for the treatment of myasthenia gravis. The participants received either the study drug or placebo for the first period of the trial. They then received the other treatment for the second period of the trial. For example, if a person had study drug in the first period they received placebo for the second period. If they had placebo for the first period, they received study drug for the second period. This type of study is called a 'cross‐over' trial.

The trial included 10 people with myasthenia gravis. In three people the condition affected only their eyes. In seven people it affected the body more widely. The trial compared neostigmine (an acetylcholinesterase inhibitor) given via the nose, with placebo. Each treatment was given for two weeks.

Key results and quality of the evidence

After the two‐week neostigmine treatment phase, symptoms of myasthenia gravis (measured as improvement in at least one muscle function) improved in nine of the 10 participants. No participant improved after the placebo phase. We were unable to assess how well the trial had been designed and run because of lack of information. Adverse events were minor.

Several observational (non‐randomised) studies, case reports, case series and daily clinical experience favour the use of acetylcholinesterase inhibitors. This means that placebo‐controlled trials to confirm the effectiveness of the drug are probably not ethical and are unlikely to be performed. At present, the best dose and duration of treatment with acetylcholinesterase inhibitors is determined by the balance between improvement in symptoms and adverse effects. This varies over time and depends on other types of treatment that are given at the same time to switch off the underlying autoimmune response.

This is the second update of this review, which was first published in 2011. The evidence is current to July 2014.

Summary of findings

Summary of findings for the main comparison. Intranasal neostigmine compared with placebo for myasthenia gravis.

Intranasal neostigmine compared with placebo for myasthenia gravis
Patient or population: people with myasthenia gravis Settings: not specified Intervention: intranasal neostigmine Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Intranasal neostigmine
Improved muscle function various methods1 Follow up: 2 weeks	See comment	See comment	Not estimable	10 (1 cross‐over study)2	+OOO very low3,4,5	Abstract only. See text for details. 9 of the 10 participants improved in either ocular, bulbar, breathing or strength symptoms on intranasal neostigmine and 0 of the 10 participants improved on placebo.
Adverse events Follow up: 2 weeks	See comment	See comment	Not estimable	20 (1 study)2	+OOO very low	One participant developed borborygmi and fasciculations after using intranasal neostigmine
Change in impairment 1 to 14 days after the start of treatment ‐ not reported	See comment	See comment	Not estimable	_	See comment	No data available
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Primary outcome not stated.
 ² Number of participants refers to 10 participants in a cross‐over trial, so 20 measurements.
 ³Abstract only available so that it is difficult to assess quality.
 ⁴Small sample size reduces confidence in result.
 ⁵Large effect size: 9 of 10 participants improved in at least one muscle function with neostigmine and 0 of 10 with placebo.

Background

Myasthenia gravis (MG) is caused by antibody‐mediated autoimmunity against the nicotinic acetylcholine (ACh) receptor (AChR) at the neuromuscular junction (NMJ) (Drachman 1994a; Vincent 2001). MG has a reported annual incidence of about three to four cases per million, and the prevalence is about 60 cases per million (Punga 2009). Treatments for MG include acetylcholinesterase (AChE) inhibitors (AChEIs), corticosteroids, immunosuppressants, intravenous immunoglobulin, plasma exchange and thymectomy. In the literature the terms anticholinesterase and acetylcholinesterase inhibitor have been used interchangeably. We shall use the term acetylcholinesterase inhibitor in this review. Immunosuppressive agents used for generalised MG and medical and surgical treatment for ocular myasthenia have been the subjects of five Cochrane reviews (Gajdos 2002; Schneider‐Gold 2005; Benatar 2006b; Hart 2007; Gajdos 2009).
 
 Antibody‐mediated blockade of NMJ receptors abolishes the naturally occurring ‘safety factor’ of synaptic transmission. The antibodies bind to AChR molecules and speed up breakdown of acetylcholine, possibly through a complement mediated effect on the membrane. These mechanisms in turn lead to reduced activation of voltage‐gated sodium channels. These channels normally help in the process of depolarisation and facilitate the end plate potential to create the muscle action potential (Conti‐Fine 2006). Approximately 85% of people with MG have measurable antibody levels against AChRs (Vincent 1985). A significant proportion of people with MG who are 'seronegative' for AChR antibodies have antibodies directed against muscle specific kinase (MuSK). MuSK is a NMJ protein that is associated with the AChR and helps in its assembly (Vincent 2003; Conti‐Fine 2006; Newsom‐Davis 2007).

Jolly noted that symptoms of MG were similar to those of curare poisoning in animals and suggested that physostigmine might be of therapeutic value, but did not use it (Taylor 1996). Mary B Walker was the first physician to report a MG patient with a rapid response to the AChEI physostigmine (Walker 1934; Walker 1935). Edrophonium chloride (Tensilon) is a short‐acting AChEI used for diagnostic purposes in the 'Tensilon test'. In a positive test, edrophonium improves the function of a weak muscle group (Osserman 1952; Nicholson 1983; Daroff 1986; Benatar 2006a). The longer acting AChEIs neostigmine and pyridostigmine are used for symptomatic treatment (Drachman 1994a; Engel 2004; Conti‐Fine 2006; Skeie 2006).

In patients with MG, the required dose of AChEI and the interval between doses may vary from day to day because the natural history of MG is characterised by exacerbations and remissions (Richman 2003). The most disabling phase may occur years after onset (Grob 1981). About 10% of people with MG experience spontaneous remissions in the 10 years after disease onset, but these are often temporary (Oosterhuis 1981). MG patients rarely experience complete amelioration of weakness when treated with AChEIs, but in some instances weakness may improve enough for normal activity to be regained. However, corticosteroids appear more effective, particularly in ocular MG (Benatar 2006a; Bhanushali 2008). Bhanushali et al recruited 35 participants with ocular MG from a database of 83 people. Eight participants received AChEI only, six were initially treated with AChEI followed by steroids, and 21 received steroids alone. Improvement was seen in 70% of participants in the steroid treatment group and in 29% of participants in the AChEI treatment group. When people with MG require more than the recommended dose of AChEI to achieve adequate relief of their symptoms, they are often judged to be candidates for other modalities of treatment.

Treatment advances over the past 50 years have markedly reduced MG mortality and morbidity (Oosterhuis 1988). The current management of ocular and generalised MG includes AChEIs for temporary improvement, removal of anti‐AChR antibodies and nonspecific immunomodulation or immunosuppression (Drachman 1994a; Drachman 1994b; Richman 2003). Thymoma (tumour of the thymus gland) is an indication for thymectomy (removal of the thymus gland).

The side effects of AChEIs include muscarinic overactivity symptoms such as nausea, vomiting, abdominal cramping, diarrhoea, diaphoresis, increased lacrimation, salivation, tearing and bronchial secretions, bradycardia and atrioventricular block. Bradycardia may cause light‐headedness or syncope (Gehi 2008). Some nicotinic side effects have also been reported, such as muscle cramps and fasciculations (involuntary muscle twitches). Higher than recommended doses of AChEIs desensitise AChRs and increase weakness resulting in ‘cholinergic crisis’ (Munsat 1984; Richman 2003).

Rarely, people with a polymorphism in the promoter region of the gene that encodes the catalytic subunit of AChE show acutely exaggerated sensitivity to conventional doses of AChEI (Shapira 2003). Punga et al reported cholinergic adverse effects in the majority of people with MG examined after oral pyridostigmine treatment (Punga 2008). In addition, experimentally, long‐term high‐dose exposure to AChEIs causes degeneration of the junctional folds, loss of post‐synaptic AChRs, and decreased motor end plate potential amplitudes (Engel 1973).

The immediate effects of AChEIs can be so dramatic in MG that some authors consider a therapeutic response part of the definition of the disease. For instance, Simpson et al (Simpson 1966) excluded participants from their study of 295 people with MG when there was a failure of their symptoms to respond to therapeutic doses of neostigmine or pyridostigmine. Rowland et al (Rowland 1980) stated that "There is no need for a controlled trial when ptosis disappears before your very eyes or ophthalmoplegia melts into normal motion". However, some MG patients, such as those with MuSK antibodies, may show poor tolerance to AChEI agents or a lack of improvement (Sanders 2003).

In clinical practice, these AChEI agents are often prescribed for people with MG and the impression is that their usefulness has been adequately established. However, the methodological quality of therapeutic studies has been low (Benatar 2006a) and so far the studies have failed to establish, for example, the optimal dosage and duration of treatment with these drugs (Rowland 1980).

This is the second update of a review published in The Cochrane Library Issue 2, 2011.

Objectives

To evaluate the efficacy of AChEI therapy in all forms of MG.

Methods

Criteria for considering studies for this review

Types of studies

We searched for randomised controlled trials (RCTs) or quasi‐RCTs of any form of AChEI for generalised MG compared with placebo, no treatment or any other form of treatment.

Quasi‐RCTs are studies in which treatment allocation is organised in a way which is intended to have the effect of randomisation but which might nevertheless be biased (for example alternate allocation).

Types of participants

Participants of any age with any type and severity of MG, regardless of concomitant use of glucocorticosteroids or immunomodulatory therapies or thymectomy.

Types of interventions

We included studies which compared AChEIs with no treatment, placebo or another treatment. We considered any AChEI agent used in the treatment of MG. We examined any randomised or quasi‐RCT or a branch of a trial evaluating the efficacy of one of these AChEI drugs versus placebo or glucocorticosteroids, or both.

We did not include studies of AChEI treatment in congenital myasthenic syndromes because the response to AChEIs can vary greatly, being beneficial in one type but harmful in another, such as in congenital myasthenic syndromes with end plate AChE deficiency (Engel 2007).

Types of outcome measures

Primary outcomes

Improvement in the presenting symptoms within one to 14 days of the start of treatment.

Secondary outcomes

(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.

(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score within one to 14 days and more than 14 days after the start of treatment (Bedlack 2005).

(3) Myasthenia Gravis Association of America post‐intervention status (Jaretzki 2000) more than 14 days after the start of treatment.

(4) Adverse events: we planned to record muscarinic side effects such as abdominal pain, diarrhoea, bronchorrhoea, excessive sweating, bradycardia and cholinergic crisis.

We included a 'Summary of findings' table using GRADEprofiler software (GRADEpro 2008). The table summarises the quality of evidence and magnitude of effect of interventions for the following outcomes: improvement in muscle function; adverse events; and change in impairment 14 days after the start of treatment.

Search methods for identification of studies

We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 July 2014), CENTRAL (2014, Issue 7 in The Cochrane Library), MEDLINE (January 1966 to June 2014) and EMBASE (January 1980 to June 2014) for RCTs and quasi‐RCTs regarding usage of AChEIs in myasthenia gravis. This review also identified observational (case‐control or cohort) studies that report use of AChEI agents for symptomatic treatment of MG. We only used case‐control and cohort studies that were found using the RCT filters; we did not specifically search for these.

We scanned the references of all manuscripts included in the review to identify additional articles of relevance and contacted experts in the field to identify published and unpublished data. We contacted three authors and received a reply from one. We searched clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing studies on 17 July 2014, using the search terms acetylcholinesterase inhibitor treatment for myasthenia gravis, acetylcholinesterase inhibitor in myasthenia gravis, treatment of myasthenia gravis.

Electronic searches

For the search strategies see: Appendix 1 (MEDLINE), Appendix 2 (EMBASE), Appendix 3 (CENTRAL) and Appendix 4 Cochrane Neuromuscular Disease Group Specialized Register.

Data collection and analysis

Selection of studies

Two authors (MMM and SP) read the titles and abstracts of all articles accessed and reviewed the full text of all articles that were of possible relevance. They independently decided which trials fitted the inclusion criteria and graded their methodological quality. The authors resolved disagreements about inclusion by discussion.

Data extraction and management

One author (MMM) extracted the data, which were checked by a second author. We extracted data on study type, interventions, methodological quality, participants, outcomes and adverse events, in a tabular form. We attempted to obtain missing data by contacting authors. In the discussion, we supplemented evidence concerning adverse events obtained from RCTs with information on adverse events reported in the non‐randomised studies. At a minimum, we took into consideration side effects reported in Meyler’s Side Effects of Drugs (Dukes 2006). In the absence of formal studies of cost‐effectiveness, we planned to collect evidence from non‐randomised studies.

Assessment of risk of bias in included studies

We completed an assessment of the risk of bias of the included study (to the extent it was possible) according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008, updated Higgins 2011). Two authors (MMM and SP) independently assessed randomisation, sequence generation, allocation concealment, blinding (participants, personnel and outcome assessors), incomplete outcome data, selective outcome reporting and other sources of bias.

We made a judgement on each of these criteria relating to the risk of bias, assessing them as 'High risk of bias', 'Low risk of bias' or 'Unclear risk of bias'.

Measures of treatment effect

With only one included study no meta‐analysis was possible. If, in the future, we identify further studies we will use risk ratios and mean differences to assess outcomes.

Unit of analysis issues

Meta‐analysis could not be performed as we identified only a single RCT that was available only in abstract form.

Dealing with missing data

Attempts were made to obtain missing data by contacting authors.

Assessment of heterogeneity

We planned to note whether the meta‐analyses showed evidence of heterogeneity. If they did, we planned to investigate its source by repeating the analysis after elimination of trials with a high risk of bias, paying particular attention to allocation concealment. If there was still heterogeneity, we planned to repeat the analysis using a random‐effects model.

Assessment of reporting biases

Since only one trial was found, further assessment of bias was not possible beyond that described above. Had sufficient studies been available, we would have looked for evidence of reporting bias by inspecting forest plots and producing funnel plots.

Data synthesis

Not possible due to lack of data.

Subgroup analysis and investigation of heterogeneity

Not possible due to lack of data.

Sensitivity analysis

Not possible due to lack of data.

Results

Description of studies

The number of articles found by the current strategies were: MEDLINE 929, EMBASE 109, Cochrane Neuromuscular Disease Group Specialized Register 18 and CENTRAL 208. From the results of the search, we examined seven studies more closely for potential inclusion but six were ineligible (see Characteristics of excluded studies). Our search revealed only one eligible randomised placebo‐controlled, double‐blind cross‐over trial (Badrising 1996). No additional included or excluded studies were identified for either update. We identified no ongoing trials.

Ten participants, seven with generalised MG and three with ocular MG, received 4.5 mg intranasal neostigmine or placebo three times a day for two consecutive weeks; preceded by a baseline observation week. All participants scored their ocular, bulbar and global muscle function separately by comparing their symptoms with those of the baseline week.

Risk of bias in included studies

The risk of bias was 'unclear' for all categories (Figure 1).

1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (red = high risk of bias; yellow (?) = unclear risk of bias; green = low risk of bias.

Effects of interventions

See: Table 1

Primary outcome

Improvement in generalised MG occurred with intranasal neostigmine in nine of the ten participants in the treatment phase and none in the placebo phase. Two of five participants with ocular symptoms improved with neostigmine, four of four with bulbar symptoms and four of seven participants with impaired muscle power. Dyspnoea improved in both the participants with this symptom. One participant experienced no effect. One of three participants with ocular MG had less ptosis with neostigmine. None of the participants showed improvement on placebo.

Secondary outcomes

The secondary outcomes (1) to (4) could not be assessed as there was no information available.

One participant developed borborygmi (audible intestinal sounds) and fasciculations (involuntary muscle twitches) after intranasal neostigmine.

No data on cost‐effectiveness were available.

Discussion

Summary of main results

We only identified one RCT. This compared the effects of intranasal neostigmine and placebo in MG. Its sample size was too small to permit robust conclusions regarding the efficacy of AChEI in MG, see Table 1. There is no large randomised trial of AChEIs in MG to determine whether or not these drugs are effective.

Overall completeness and applicability of evidence

This study is not of much clinical relevance as the intranasal route is not a commonly used method of treatment and the study duration was only two weeks. However, the results suggested efficacy of the drug over placebo. All the relevant types of participants, interventions and outcomes were not investigated. The efficacy of AChEIs by the oral route in the treatment of MG has not yet been evaluated in a RCT.

Quality of the evidence

The risk of bias in the included study was unclear (Figure 1). We have considered the observational studies discussed below, but the evidence is necessarily of very low quality.

Potential biases in the review process

It is impossible to perform a comprehensive review of observational studies.

Agreements and disagreements with other studies or reviews

This review also identified observational (case‐control or cohort) studies that report the use of AChEI agents for symptomatic treatment of MG. Herbert Schwarz (Schwarz 1956) was the first to use pyridostigmine, comparing pyridostigmine with neostigmine in 14 participants, and concluded that pyridostigmine was more effective over a follow‐up period of one year "because of its superior ability to control myasthenic phenomena and the absence of side‐effects after prolonged use". In three participants, the combination of pyridostigmine with neostigmine was more effective than either drug alone. In two participants, no difference was noted between the two drugs and, in another two, pyridostigmine was found to be inferior to neostigmine. The author concluded that pyridostigmine alone or in combination with neostigmine is the drug of choice in MG because of the excellent response and lower toxicity. Similar conclusions came from an analysis of 295 participants with MG by Simpson et al (Simpson 1966) who wrote, "the drug of choice was determined for those participants who have used more than one of the acetylcholinesterase inhibitor preparations. Of 69 participants who compared neostigmine with pyridostigmine, only 12 preferred neostigmine".

Reported in 1993, 95 participants with MG were followed for 10 years to evaluate the long‐term effects of prednisolone, thymectomy, or both, and these participants were compared with a group on AChEI (Seto 1993). Only 15% of the participants on AChEI alone (40 participants, most treated before 1975) had shown improvement 10 years after the onset of MG, but more than 60% of those treated with prednisolone, thymectomy, or both, showed improvement. The study was retrospective and no statistical analysis was performed. In a study of 100 people with MG, epidemiological characteristics, the evolution of early signs, delay in diagnosis, yield of diagnostic tests and effects of treatment were reported (Beekman 1997). At the end of the follow‐up period, 55% were using an AChEI, 22% prednisolone, 19% azathioprine and 1% cyclosporine. However, more participants had received these drugs during the course of their disease: 99% AChEI, 49% prednisolone, 28% azathioprine and 4% cyclosporine. Overall, 51% were treated with immunosuppressants at some time. No comparison between groups was performed but it was reported that 34% of the participants who received pyridostigmine had one or more side effects, which were mostly mild.

In another study on late onset MG, which included 113 people, the proportion treated with AChEIs was 41% at treatment onset and 16% five years later. Surprisingly, the authors assumed that participants on AChEIs "probably had a more benign course and hence were often lost to follow‐up" (Slesak 1998).

Zhou Shui‐Zhen et al (Zhou 2004) reported that in 77 children aged from three months to 16 years, the prognosis of MG was "good following treatment with acetylcholinesterase inhibitor drugs and steroid treatment", but no statistical analysis was available to assess the efficacy of the AChEI agents.

In a study of 102 participants with generalised MG, 73 were found to be AChR‐antibody positive and, out of the remaining 29, 14 were MuSK‐Ab positive and 22 were MuSK‐Ab negative (Hatanaka 2005). In comparison to MuSK‐Ab‐negative or seropositive groups, the proportion of positive edrophonium tests in the MuSK‐Ab positive group was significantly lower. The edrophonium test was positive in only five of 10 tested MuSK‐Ab positive participants. AChEI non‐responsiveness was noted in 10 of 14 MuSK‐Ab positive participants (71%), which was very high in comparison to MuSK‐Ab negative participants (4 of 22 non‐responsive (18%)) and seropositive generalised MG participants (13 of 73 non‐responsive (18%)). The chances of benefit with long‐term pyridostigmine were also significantly higher in MuSK‐Ab negative and seropositive groups in comparison to participants in the MuSK‐Ab positive group.

Sustained release pyridostigmine bromide has been available by prescription in Europe and USA but to date there are no randomised controlled trials on the therapeutic effectiveness, safety and tolerability of this formulation in the treatment of myasthenia gravis. An open label study involving 72 participants with a confirmed diagnosis of myasthenia gravis and who were stable on standard release pyridostigmine was conducted at 34 German centres over a six month period. Participants who had side effects, fluctuations in symptoms, or whose symptoms were not completely alleviated with pyridostigmine were switched over to the sustained release formulation of pyridostigmine bromide. The switch from the conventional to the sustained release formulation reduced the total quantified myasthenia gravis score from 0.9 ± 0.5 to 0.6 ± 0.4 (P < 0.001); Euro Quality of Life (QoL) improved from 0.626 ± 0.286 to 0.782 ± 0.186 (on a scale of ‐0.594 (worst) to 1 (best)), which was statistically significant (P < 0.001); and dosage frequency also reduced from 4.3 to 3.6 doses per day. The participants who received the sustained release preparation experienced significant relief in already existing side effects when they were shifted from the standard preparation. The sustained release formulation also caused some new side effects but these were mild (Sieb 2010).

In 2006, a Task force of the European Federation of Neurological Societies (EFNS) (Skeie 2006) reported that "there are no placebo controlled randomised studies of these drugs, but case reports, case series and daily clinical experience demonstrate an objective and marked clinical effect. Although there is inadequate evidence for a formal recommendation, the Task force agreed that acetylcholinesterase inhibitor drug should be the first‐line treatment of all forms of MG (class IV evidence, good practice point)".

However, it appears that some patients may not respond to AChEIs, and this may be a feature of MuSK‐Ab positive MG patients.

Acetylcholinesterase inhibitors used in people with MG may cause general and systemic side effects. General side effects include bradycardia, colicky pain, hypersalivation and headache. If administered as bromide salts, bromide rash may occur. Systemic adverse effects may be related to cardiovascular, nervous system, gastrointestinal, musculoskeletal or immunological systems (Dukes 2006). The most common systemic side effects are sweating, hypersalivation, lacrimation, bronchial constriction and nightmares. In a study of 100 people with MG, the most common side effects that were reported were gastrointestinal disorders (30%); infrequent side effects were hypersalivation (6%), increased perspiration (4%), urgency (3%), increased bronchial secretion (2%), rash (1%) and blurred vision (1%); 4% developed tingling sensations in fingers and toes. Only one patient had to stop taking pyridostigmine, because of stomach complaints (Beekman 1997).

Authors' conclusions

Implications for practice.

Except for one small and inconclusive trial of intranasal neostigmine, there is no evidence from randomised controlled trials to support the common practice of using acetylcholinesterase inhibitors to treat myasthenia gravis.

Implications for research.

No adequate randomised controlled trial has been performed but the evidence from observational studies is so strong that none is needed to establish that acetylcholinesterase inhibitors are efficacious.

What's new

Date	Event	Description
17 July 2014	New citation required but conclusions have not changed	Minor update with no new evidence to incorporate
17 July 2014	New search has been performed	Searches updated in July 2014. No new trials identified. The plain language summary has been simplified. See Published notes on future updates of this review.

History

Protocol first published: Issue 1, 2008
 Review first published: Issue 2, 2011

Date	Event	Description
4 July 2011	New search has been performed	Searches updated to May 2011. No new trials. Revisions to improve consistency of abstract, plain language summary and results sections and a note on use of current methodology added to 'Differences between protocol and review'. A paragraph on the sustained release pyridostigmine inserted in the Discussion section.

Notes

New evidence on this topic is slow to emerge. The next update of the review is scheduled to take place in four years, in July 2018, rather than the usual two years.

Appendices

Appendix 1. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to June Week 4 2014>
 Search Strategy:
 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
 1 randomized controlled trial.pt. (377908)
 2 controlled clinical trial.pt. (88775)
 3 randomized.ab. (275946)
 4 placebo.ab. (147416)
 5 drug therapy.fs. (1714581)
 6 randomly.ab. (195454)
 7 trial.ab. (286121)
 8 groups.ab. (1255003)
 9 or/1‐8 (3220367)
 10 exp animals/ not humans.sh. (3964775)
 11 9 not 10 (2741162)
 12 myastheni$.tw. (13614)
 13 exp myasthenia gravis/ (12940)
 14 Myasthenic Syndromes, Congenital/ (362)
 15 or/12‐14 (15715)
 16 Cholinesterase Inhibitors/ (16778)
 17 Cholinesterase inhibitor$.tw. (3708)
 18 (anticholinesterase$ or anti‐cholinesterase$1 or AChE).tw. (13150)
 19 (AChEI or AChE inhibitor$1).tw. (1296)
 20 (Acetylcholine‐esterase Inhibitor$1 or acetylcholineesterase inhibitor$1 or acetylcholinesterase inhibitor$1).tw. (2578)
 21 neostigmine/ (4220)
 22 pyridostigmine bromide/ (1442)
 23 (pyridostigmine or mestinon or neostigmine).tw. (4100)
 24 or/16‐23 (32147)
 25 11 and 15 and 24 (947)
 26 remove duplicates from 25 (929)

Appendix 2. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2014 Week 27>
 Search Strategy:
 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
 1 crossover‐procedure.sh. (39375)
 2 double‐blind procedure.sh. (114109)
 3 single‐blind procedure.sh. (18468)
 4 randomized controlled trial.sh. (344969)
 5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (1039063)
 6 trial.ti. (158684)
 7 or/1‐6 (1170836)
 8 (animal/ or nonhuman/ or animal experiment/) and human/ (1270616)
 9 animal/ or nonanimal/ or animal experiment/ (3226346)
 10 9 not 8 (2704065)
 11 7 not 10 (1075321)
 12 limit 11 to embase (890106)
 13 myastheni$.tw. (15714)
 14 exp myasthenia gravis/ (16849)
 15 Myasthenic Syndromes, Congenital/ (459)
 16 or/13‐15 (19834)
 17 Cholinesterase Inhibitor/ (16851)
 18 cholinesterase inhibitor$.tw. (5010)
 19 (anticholinesterase$ or anti‐cholinesterase$ or AChE).tw. (15465)
 20 (AChEI or AChE inhibitor$1).tw. (1749)
 21 (acetylcholine‐esterase inhibitor$1 or acetylcholineesterase inhibitor$1 or acetylcholinesterase inhibitor$1).tw. (3500)
 22 neostigmine/ (9787)
 23 pyridostigmine/ (4650)
 24 (pyridostigmine or mestinon or neostigmine).tw. (5070)
 25 or/17‐24 (43462)
 26 12 and 16 and 25 (109)
 27 remove duplicates from 26 (109)

Appendix 3. CENTRAL search strategy

#1MeSH descriptor Myasthenia Gravis, this term only
 #2MeSH descriptor Myasthenic Syndromes, Congenital, this term only
 #3(myastheni*)
 #4(#1 OR #2 OR #3)
 #5MeSH descriptor Cholinesterase Inhibitors, this term only
 #6(cholinesterase inhibitor*)
 #7(anticholinesterase* or anti‐cholinesterase* or AChE)
 #8AChEI or (ACHE inhibitor*)
 #9(acetylcholinesterase inhibitor*)
 #10(acetylcholine‐esterase inhibitor*)
 #11MeSH descriptor Neostigmine, this term only
 #12MeSH descriptor Pyridostigmine Bromide, this term only
 #13pyridostigmine or mestinon or neostigmine
 #14(#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
 #15(#4 AND #14)

Appendix 4. NMD Register (CRS) search strategy

#1 myastheni* [REFERENCE] [STANDARD]
 #2 "Cholinesterase Inhibitors" or "Cholinesterase Inhibitor" [REFERENCE] [STANDARD]
 #3 AChEI or "acetylcholine‐esterase inhibitor" or "acetylcholineesterase inhibitor" or "acetylcholinesterase inhibitor" [REFERENCE] [STANDARD]
 #4 "acetylcholine‐esterase inhibitors" or "acetylcholineesterase inhibitors" or "acetylcholinesterase inhibitors" [REFERENCE] [STANDARD]
 #5 neostigmine or pyridostigmine or mestinon [REFERENCE] [STANDARD]
 #6 #2 or #3 or #4 or #5 [REFERENCE] [STANDARD]
 #7 #1 and #6 [REFERENCE] [STANDARD]
 #8 (#1 and #6) AND (INREGISTER) [REFERENCE] [STANDARD]

Appendix 5. ClinicalTrials.gov and ICTRP

acetylcholinesterase inhibitor treatment for myasthenia gravis, acetylcholinesterase inhibitor in myasthenia gravis, treatment of myasthenia gravis.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Badrising 1996.

Methods	RCT single centre, cross‐over trial
Participants	10 participants, 7 with generalised MG and 3 with ocular MG were treated
Interventions	4.5 mg intranasal neostigmine or placebo three times a day for two consecutive weeks preceded by a baseline observation week
Outcomes	Improvement in generalised MG occurred in 2 of 5 participants with ocular symptoms, 4 of 4 with bulbar symptoms and 4 of 7 participants with impaired muscle power. Dyspnoea improved in both participants with this symptom. One participant experienced no effect. 1 of 3 participants with ocular MG had less ptosis with neostigmine. None of the participants showed improvement on placebo
Notes	One participant developed borborygmi and fasciculations after using intranasal neostigmine. The study could provide data for the primary outcome but only one of the secondary outcomes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study in abstract form. No information regarding sequence generation available
Allocation concealment (selection bias)	Unclear risk	Study in abstract form. No information regarding allocation concealment available
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Study in abstract form. Author mentions that the study was blinded but does not describe the method
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Study in abstract form. No information regarding outcome data available
Selective reporting (reporting bias)	Unclear risk	Study in abstract form. No information regarding selective reporting available
Other bias	Unclear risk	Study in abstract form. No information available whether the study was free of other bias

RCT: randomised controlled trial
 MG: myasthenia gravis

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Beekman 1997	Retrospective study. Thymectomy and immunosuppressive drugs mainly considered over and above AChEIs
Hatanaka 2005	Differential response to AChEIs in MuSK‐Ab participants
Schwarz 1956	Comparative study of prostigmine and neostigmine in different groups
Seto 1993	Comparative study of prednisolone, thymectomy and combination
Slesak 1998	Different immunosuppressive agents compared
Zhou 2004	Clinical progression and outcome analysed rather than effect of treatment

MG: myasthenia gravis
 AChEI: acetylcholinesterase inhibitor
 MuSK‐Ab: muscle specific kinase antibodies

Differences between protocol and review

In the protocol (Mehndiratta 2008) we stated that ocular myasthenia will not be included. Since the only RCT that was available regarding AChEIs included participants with ocular myasthenia, we included those cases of ocular myasthenia that were recruited in the trial in the review.

The sequence of authors has changed.

The 'Risk of bias' methods outlined in the protocol were revised according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008, updated Higgins 2011). We also added a 'Summary of findings' table.

For this update we searched clinical trials registries for ongoing studies.

Contributions of authors

First (Man Mohan Mehndiratta) and second (Sanjay Pandey) authors evaluated each paper. Man Mohan Mehndiratta extracted the data and Sanjay Pandey checked it. Both wrote the first draft of the review and sent it to third author (Thierry Kuntzer) who read and incorporated important changes. All the disagreements were resolved by mutual discussion.

Sources of support

Internal sources

• Man Mohan Mehndiratta, India.

  No financial grant received from any source for this review

• Sanjay Pandey, India.

  No financial grant received from any source for this review

• Thierry Kuntzer, Switzerland.

  No financial grant received from any source for this review

External sources

• No sources of support supplied

Declarations of interest

None known.

New search for studies and content updated (no change to conclusions)