Footnotes

• Contributors JS: idea for the guidelines and editing manuscript. All contributors attended initial guideline drafting meeting. All authors contributed to modifying guidelines until final version achieved.

• Competing interests None declared.

• Provenance and peer review Commissioned. Externally peer reviewed. This paper was reviewed by Jon Walters, Swansea, UK.

• ↵i There are remarkably few studies comparing treatments in myasthenia gravis. Some were established before the era of evidence-based medicine. Some pivotal positive treatment studies used only small numbers, and their flawed design may account for studies suggesting that a commonly used medication (mycophenolate mofetil) lacks efficacy. For these reasons, these guidelines provide practical advice on starting standard treatment but avoid giving authority to non-evidence-based opinion by suggesting that expert opinion is sought where evidence is lacking, such as in the choice of immunosuppressive agents.

• ↵ii Myaware. College Business Centre, Uttoxeter New Road, Derby, UK DE22 3WZ tel: +44 1332 290219. Website at http://www.myaware.org/ (accessed 23 Mar 2015).

• ↵iii The same errors in myasthenia management occur repeatedly. These include a misplaced faith in the benefits of pyridostigmine, and reluctance to use sufficient doses of prednisolone to induce remission.1 ,2

• ↵iv Other autoimmune diseases are more common in patients with myasthenia gravis; thyroid dysfunction that may otherwise be occult may exacerbate myasthenia. B₁₂ deficiency is more common in patients with myasthenia gravis and may cause changes in the full blood count, including a rising mean corpuscular volume and falling white count (mimicking the effect of azathioprine). For practical management of myasthenia gravis, measuring B₁₂ can help.

• ↵v Single-fibre electromyography lacks specificity. It helps in the clinical setting of myasthenia but may be positive in a wide range of other settings, such as denervation and myopathic disorders. It should therefore be carried out only by neurophysiologists with experience in neuromuscular transmission disorders.

• ↵vi The edrophonium test may be difficult to interpret. Conditions that mimic myasthenia may produce a positive result and there are potential cardiac complications. If serology and neurophysiology still give no diagnosis, seek a specialist opinion.

• ↵vii Thymic hyperplasia is a pathological diagnosis and cannot be evaluated by scanning. The scan is done solely to exclude thymoma.

• ↵viii Note that most patients with ocular myasthenia develop generalised myasthenia within about two years.

• ↵ix The recently published EFNS/ENS Guidelines3 offer identical advice.

• ↵x There is little evidence for the pyridostigmine and prednisolone dose schedules recommended here; there are no studies comparing treatment regimens. These guidelines are based on the practice of experts in the field. The emphasis is on identifying the optimum dose for each patient. Undertreatment, particularly with corticosteroids, is the commonest cause of persisting symptoms.

• ↵xi Around 50% of patients with ocular myasthenia develop generalised myasthenia within 2 years and up to 75% do so within 3 years or so of disease onset. This is more likely in the seropositive group.

• ↵xii Many experts consider thymectomy, and particularly the less traumatic and scar-minimising video-assisted thoracoscopic thymectomy in a young person with seropositive generalised myasthenia gravis. Some experts consider video-assisted thoracoscopic thymectomy in purely ocular myasthenia gravis. Thymectomy is probably most effective if carried out early on, say 2 years after symptom onset. Thymectomy probably does not help established ocular myasthenia gravis where there is little risk of generalisation.

• ↵xiii Offering video-assisted thoracoscopic thymectomy even before starting corticosteroids may be an option for some patients. As thymectomy produces benefit slowly, this is appropriate only for patients with mild disease.

• ↵xiv An alternate day corticosteroid regimen probably reduces side effects. Daily corticosteroids may be suitable in some patients, such as those with diabetes mellitus.

• ↵xv In principle, immunosuppression is only started following relapse induced by corticosteroid withdrawal. In some patients with complex medical problems, higher doses of corticosteroids may be preferable to immunosuppression, or vice versa. It is impossible to provide absolute guidance on the target corticosteroid dose. In some patients, even low-dose corticosteroids cause side effects; these might be treated with immunosuppression. Exceptional cases should be discussed with a myasthenia expert.

• ↵xvia Use pyridostigmine carefully in patients with obstructive respiratory disease, brady-dysrhythmias, impaired renal function and recent coronary occlusion.

• ↵xvib The drug information sheet specifies that propantheline is contraindicated in myasthenia gravis: this is not correct as it is a standard treatment for the side effects of pyridostigmine.

• ↵xvii The evidence suggests that the biggest error in managing myasthenia is the failure to induce remission in a timely manner using corticosteroids. There is a tendency to try to avoid using large doses of corticosteroids. If it is tolerated, the top dose is prednisolone 0.75 mg/kg for ocular disease. Corticosteroid-induced deterioration in myasthenia sometimes occurs. It is particularly associated with starting high-dose corticosteroids. It can occur in patients adhering to the dose regimen recommended in these guidelines, though it may also be confused with the deterioration in symptoms that continues until the benefit from corticosteroids becomes apparent, often within a week or two. If in doubt, seek expert advice.

• ↵xviii The side effects are probably minimised by using alternate day dosing.

• ↵xix Patients with known diabetes mellitus should be monitored following the introduction of corticosteroids. Experts are aware of non-diabetic patients who developed diabetes mellitus, sometimes months after starting prednisolone. It is beyond the scope of these guidelines to offer specific guidance in this area. Local guidelines should be used.

• ↵xx There is little hard evidence on the absolute safest long-term dose of corticosteroids. Since a component of the complications can be managed by bone protection, and blood pressure and lipid management, there may be individual cases with other health problems, in whom higher doses of maintenance corticosteroids would be better than immunosuppression. In principle, however, failure to control myasthenia symptoms with a ‘safe’ dose of corticosteroids is the main indication for starting immunosuppression.

• ↵xxi There is little evidence for the pyridostigmine and prednisolone dose schedules recommended here and there have been no studies comparing treatment regimens. These guidelines are based on the practice of experts in the field. The emphasis is on identifying the optimum dose for each patient. Undertreatment, particularly with corticosteroids, is the commonest cause of persisting symptoms.

• ↵xxii Many experts consider thymectomy, particularly the less traumatic and scar-minimising video-assisted thoracoscopic thymectomy in a young person with seropositive generalised myasthenia gravis. Thymectomy appears most effective if carried out early on, say 2 years after symptom onset.

• ↵xxiii An alternate day regimen is thought to reduce side effects. Daily corticosteroids may be suitable in some patients, such as those with diabetes mellitus.

• ↵xxiv In principle, other than in exceptional circumstances, immunosuppression is not started other than following relapse induced by corticosteroid withdrawal. Some patients with complex medical problems, higher doses of corticosteroids may be preferable to immunosuppression, or vice versa. Exceptional cases should be discussed with a myasthenia expert. 

• ↵xxv It is impossible to provide absolute guidance on minimum corticosteroid requirements. There will be some patients in whom even low-dose steroids cause side effects, and who might be treated with immunosuppression. There may be good reasons why other patients are treated with a slightly higher than recommended prednisolone dose in preference to immunosuppression. Exceptions should be discussed with a myasthenia expert.

• ↵xxvi Pyridostigmine should be used carefully in patients with obstructive respiratory disease, brady-dysrhythmias, impaired renal function and recent coronary occlusion. The drug information sheet specifies that propantheline is contraindicated in myasthenia gravis: this is incorrect as it is a standard treatment for the side effects of pyridostigmine.

• ↵xxvii The evidence suggests that the biggest error in managing myasthenia is not inducing remission in a timely manner using corticosteroids. Clinicians tend to try to avoid using large doses of corticosteroids. If the patient tolerates these, the top dose is prednisolone 0.75 mg/kg for ocular disease and 1.5 mg/kg for generalised myasthenia gravis.

  Corticosteroid-induced deterioration in myasthenia may sometimes occur. This can be confused with the ongoing deterioration in symptoms that continues until the corticosteroids start to help, often within a week or two. If in doubt, seek expert advice.

• ↵xxviii Alternate day dosing probably minimises side effects.

• ↵xxix We recommend monitoring patients with known diabetes mellitus after starting corticosteroids. Occasionally, non-diabetic patients develop diabetes mellitus, sometimes months after starting prednisolone. It is beyond the scope of these guidelines to offer specific guidance for blood glucose monitoring; local guidelines should be used.

• ↵xxx This is the typical rate of corticosteroid reduction. If there are other factors, such as serious side effects, the corticosteroids might be withdrawn more rapidly. Discuss with a myasthenia expert.

• ↵xxxi There is little hard evidence on the absolute safest long-term dose of steroids. Since a component of the complications can be managed by bone protection, and blood pressure and lipid management, there may be individual cases with other health problems, in whom higher doses of maintenance steroids would be preferable to immunosuppression. In principle, however, failure to control myasthenia symptoms with a ‘safe’ dose of corticosteroids is the primary indication for the initiation of immunosuppression.

• ↵xxxii A good source of ideas if things do not proceed according to plan is Hilton-Jones.2

• ↵xxxiii The pivotal paper that showed the corticosteroid-sparing effect of azathioprine4 has been interpreted as suggesting that all patients require immunosuppression to achieve a safe maintenance dose of prednisolone. However, many patients who achieve remission can be maintained on low-dose prednisolone without needing immunosuppression. There is no evidence-based way to identify patients who will fail to achieve remission on corticosteroid monotherapy, so it should be attempted in all.

• ↵xxxiv There is little hard evidence on the absolute safest long-term dose of corticosteroids. Since a component of the complications can be managed by bone protection, and blood pressure and lipid management, there may be individual cases with other health problems, in whom higher doses of maintenance steroids would be preferable to immunosuppression. In principle. however, failure to control myasthenia symptoms with a ‘safe’ dose of corticosteroids is the primary indication for the initiation of immunosuppression.

• ↵xxxv Local or national guidelines should be followed.

• ↵xxxvi There is a range of immunosuppressive agents that can be successfully used in myasthenia despite the lack of robust evidence for their use. All studies are underpowered or suffer from design faults. The criteria for selecting agents might include safety in pregnancy, time to onset of efficacy and risk of complications, although there is often a lack of evidence in these areas. In practice, we recommend that non-experts manage patients with corticosteroids to induce remission, and use azathioprine as a corticosteroid-sparing agent. If this fails, then the patient should be referred to a myasthenia expert to advise on alternative immunosuppressive agents.

• ↵xxxvii Note that TMPT levels will be modified in patients who have received blood products. Patients with low serum TMPT concentrations can be treated with lower doses of azathioprine. Some experts recommend using a dose of 25 mg once daily. In view of the evidence from other conditions that correlates efficacy with a rise in mean corpuscular volume and/or a drop in peripheral lymphocyte count, others titrate the dose up until there is a haematological response. 6-thioguanine nucleotides (6-TGN), which are incorporated into DNA, are the active metabolites of azathioprine. 6-TGN has started to be used to monitor compliance and toxicity. It is not widely available but can be used to guide dosing.

• ↵xxxviii In rheumatological and gastroenterology patients, azathioprine efficacy correlates with a drop in lymphocyte count and/or an elevation in mean corpuscular volume. In inflammatory bowel disease, macrocytosis appears to be the better marker. There is no evidence in myasthenia, but anecdotal observations suggest that a failure to respond to azathioprine is more common in patients without a change in these indices. We recommend treating using the initial mg/kg dosing, and following local shared-care protocols. A specialist opinion should be sought if difficulties arise.

• ↵xxxix The pivotal azathioprine study4 showed efficacy at 2 years but not at 1 year. It is likely that this varies between patients.

• ↵xl A patient taking 100 mg alternate day prednisolone would take 14 months to reduce to a safe maintenance dose.

• ↵xli Azathioprine is widely considered to be low risk in pregnancy and is the drug of choice in the UK. In the USA, it is considered high risk. This differing advice is based on a small number of animal studies and case reports. Other immunosuppressive agents pose more definite risks to the fetus. Studies, largely from patients with inflammatory bowel disease taking azathioprine, suggest a modestly increased risk of low birth weight or atrial or ventricular septal defects, though other studies suggest that these relate to disease activity rather than to azathioprine. A detailed discussion of these issues is beyond the scope of these guidelines. The risks and benefits should be discussed with individual patients.

• ↵xlii Azathioprine is either undetectable in breast milk or is found in very low concentrations. The only concern would be that higher concentrations may occur in the breast milk of mothers with a low serum TMPT concentration. Asymptomatic low levels of neutrophils may develop in babies, leading some experts to recommend monitoring exclusively breastfed babies, though most feel that this is unnecessary. The concentration of azathioprine in breast milk drops significantly 4–6 h after taking the drug. A detailed discussion of these issues is beyond the scope of these guidelines.

• ↵xliii A comprehensive list of the causes of weakness is beyond the scope of these guidelines. Patients may describe tiredness, which may be hard to distinguish from fatigable muscular weakness. Steroid-induced muscle weakness is recognised. Neurological deterioration is common in patients with intercurrent infection. Other autoimmune conditions are more common in myasthenia, such as thyroid disorders and B12 deficiency, and may cause neurological symptoms. Degenerative spine disease resulting in myelopathy or lumbar canal stenosis may give rise to weakness. In most cases, the symptoms and signs are inconsistent with myasthenia and careful history and examination with targeted investigations should reveal the diagnosis. If in doubt, a neurological opinion should be sought or an expert in myasthenia should be asked to review.

• ↵xliv A range of medications may cause myasthenia or result in increased weakness in patients known to have myasthenia. Certain antibiotics are particularly implicated, such as aminoglycosides. Some medications are well recognised as having this effect while other agents are described in case reports. Clinical decisions must depend on circumstances. A list of medications can be found on the UK-based Myasthenia Gravis Association website (http://www.myaware.org/information-for-medical-professionals/39-xii-contraindications-of-drugs-that-can-make-myasthenia-worse). A more detailed review can be found on the Myasthenia Gravis Foundation of America website. (http://www.myasthenia.org/LinkClick.aspx?fileticket=JuFvZPPq2vg%3D).

• ↵xlv Sometimes, especially when a patient is slowly withdrawing prednisolone at the rate of 1 mg per month, the reversal of one or two of the previous reductions will bring the myasthenia under control. If not, revert to the initial steroid upward titration protocol.

• ↵xlvi In the presence of limb symptoms only, treatment should be with corticosteroids in the first instance. These can be slow to take effect, during which time the patient may continue to deteriorate. This should not be confused with corticosteroid-induced deterioration. Intravenous immunoglobulin has rare but life-threatening side effects and should not be used as first-line agent for all myasthenia patients. Corticosteroids are the primary treatment for moderate or severe myasthenia. Note: the duration of efficacy of intravenous immunoglobulin is 3–4 weeks, after which a stable patient may deteriorate if the patient is not established on an effective corticosteroid dose.

• ↵xlvii Intravenous immunoglobulin increases blood viscosity. Patients with known vascular occlusive disease might be given this over more rather than fewer days. Careful hydration might be a sensible precaution.

• ↵xlviii We prefer intravenous immunoglobulin as the treatment of choice as it is frequently easier and faster to give. Plasma exchange may be better if there are specific immunoglobulin risk factors (thrombotic tendency, unstable angina, recent stroke, IgA deficiency, etc).

• ↵xlix Note that antacids, laxatives and supplements may contain magnesium.

• ↵l A UK workshop in May 2011 discussed the practical clinical management issues relating to pregnancy in women with myasthenia gravis; this brief summary is based on its conclusions. For more detail, see Norwood et al.5

• ↵li Thymectomy for myasthenia in patients without thymoma is currently the subject of an international multicentre study; the results will be available after 2015. The trial examines thymectomy by sternotomy (not by video-assisted thoracoscopic thymectomy). Thymectomy may induce remission in some patients and reduce treatment requirements in others. Current recommendations should be followed.

• ↵lii Thymectomy has not been subject to assessment in modern studies; however, the benefits listed would be expected. The current thymectomy study will determine the steroid-sparing benefits of thymectomy.