Acetylcholinesterase inhibitor treatment for myasthenia gravis

Review question

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


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.

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.

Read the full abstract...

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.


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

Search strategy: 

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.