TREATMENT OF GENERALIZED MYASTHENIA GRAVIS:

Start treatment with pyridostigmine. You can use pyridostigmine titration protocol as specified below.

• If the patient has positive anti- AChR and is under 50 years consider performing thymectomy.
• If symptoms persist despite treatment with Pyridostigmine add glucocorticoids (prednisone). It can be followed the protocol outlined below.
• If the patient present worsening or symptoms persist despite exceeding 15-20 mg / day of prednisone every other day introduce an immunosuppressant “glucocorticoid sparing” dose.
• If the patient has severe exacerbations or myasthenic crisis it is necessary admit patient in  a hospital,  provide ventilatory support and initiate necessary infusion of intravenous immunoglobulins or plasmapheresis.

– Protocol Pyridostigmine:

You can use the same pattern for both general and ocular MG.

– Start with 30 mg (1/2 tablet) each 4-6horas for 2-4 days.

– Continue with 60 mg (1 tablet) every 4-6 hours for 5 days and evaluate response.

– Increase to 90 mg every 4-6 hours a day for 1 week if required.

– If the Pyridostigmine not satisfactorily control symptoms start within weeks corticosteroids (prednisone).

– If the Pyridostigmine gets control symptoms use the lowest possible dose.

– If symptoms is corrected after start gradually lowering the dose corticosteroids Pyridostigmine to the lowest effective dose or to retirement.

– The dosage is most effective if the patient knows the drug and its effects well and flexible doses depending on their state of fatigability and schedules.

Extreme caution in patients with chronic obstructive pulmonary disease, bradycardia, recent coronary occlusion and impaired renal function. Muscarinic side effects: increased secretions, diarrhea, abdominal pain, sweating, nausea, bradycardia. Nicotinic adverse effects: twitching and cramps.

Acetylcholinesterase inhibitors have no effect on the spread of myasthenia gravis.

Care must be taken with the use of acetylcholinesterase inhibitors in patients with anti-MuSK antibodies because they usually have hypersensitivity.

The pediatric dose is 7 mg / kg / day.

– Protocol for the inciación and certification of glucocorticoids:

– Start at doses of 0.75-1 mg / kg day or on consecutive days starting dose 10-20 mg on alternate days and up to a recommended dose of 0.75-1 mg / kg to  days if MG eye (maximum dose 50 -60 mg on alternate days) or 1-1.5 mg / kg / day on alternate days if generalized MG (approximate dose of 100 mg every other day). You can make a pattern rising up 5-10 mg every 3 doses until symptoms improve. Some authors prefer the latter progressively increasing pattern to avoid worsening induced paroxysmal Prednisone that may occur in over one third of patients receiving corticosteroid begins first at high doses on consecutive days.

– If remission of symptoms titrate the dose to the lowest effective dose with a descending pattern of at least 2-3 months is achieved.

– In case of recurrence of the clinic, inability to lower the doses below 15-20 mg on alternate days or the presence of side effects should be considered inciar immunosuppressive treatment with intent to further reduce the doses of glucocorticoids.

– Intolerance to corticosteroids is an indication to enter a “thrifty glucocorticoid” immunosuppressive treatment.

Myasthenic symptoms usually subside after 4-6 weeks of treatment with steroids.

   It is controversial whether glucocorticoid treatment reduces the risk of generalization, although some retrospective studies suggest a lower rate of generalization in patients with ocular myasthenia treated with steroids.

   The pattern on alternate days is recommended to reduce the risk of side effects from the steroids. These side effects include obesity (moon face), hypertension, diabetes, opportunistic infections, glaucoma, cataracts, hirsutism, gastric ulcers. Some recommendations while on glucocorticoid treatment is a diet low in sodium and carbohydrates and manage VitD supplements and bisphosphonates to prevent osteoporosis.

– Immunosuppression:

   It is recommended to introduce an immunosuppressive treatment when the patient does not achieve remission with corticosteroid alone.
A dose of 15-20 mg of prednisone every other day is probably unacceptable long term.
Intolerance to corticosteroids or side effects are an indication to introduce an immunosuppressant.
Immunosuppression with a second drug should be considered early in patients with diabetes mellitus, osteoporosis or ischemic cardiopatís bulbar or clinic with respiratory compromise does not respond quickly to steroids.
The vaccines are less effective in immunosuppressed patient. Live attenuated vaccines are contraindicacdas in immunosuppressed patients because of their high risk of decompensation of the underlying disease or prevent the disease, compared with dead or inactivated vaccines. Patients requiring immunosuppression should have updated their immunization schedule. This will usually include the pneumococcal vaccine, Haemophilus influenzae, varicella. When possible, we recommend that clinicians plan to vaccinate patients before immunosuppression.
The high-dose corticosteroids reduce the immune response to vaccines, so they should be postponed at least a month after stopping steroids at high doses.

Azathioprine

Azathioprine is an antagonist analogue purines and inhibits DNA synthesis in cell proliferation of T and B cells is immunosuppressive nonsteroidal most widely used in the treatment of MG, and can be used alone or as a ” saver steroids. ” It usually begins when low-dose glucocorticoids are insufficient to control the symptoms of patients required dose and unacceptable long-term (typically greater than 15 mg every other day). The onset of effect of azathioprine may take several months, between 3 and 10 months, although it can not be considered ineffective until you spend 18-24 months since its introduction. The initial dose is 50 mg / day weekly climb up to a dose of 2-3 mg / kg / day. If an idiosyncratic reaction appears as a flu-like syndrome the drug should be discontinued during the first two weeks. It has been associated with leucopenia, thrombocytopenia, nausea, vomiting, liver toxicity and risk of neoplasia, but it has been shown at high doses. They should perform analytical with liver function and blood count weekly for 4 weeks, then every 3 months the first year and then every 6 months. About 11% of the population are heterozygous and 0.3% homozygous for mutations in the thiopurine methyltransferase gene (TMPT) and have a higher induced myelosuppression having azathioprine risk. In case of low activity TMPT should modify the dose of Azathioprine.

Azathioprine has been linked to a lower rate of generalization in patients with ocular myasthenia being treated with azathioprine concomitantly with glucocorticoids.

It is the drug of choice in pregnant and breast-feeding.

There is no scientific evidence that azathioprine is contraindicated with intrauterine contraception.

* Mycophenolate mofetil

      Mycophenolate mofetil inhibits purine synthesis and inhibits replication of B and T lymphocytes can be used as “saving” of glucocorticoids, but is controversial rate decrease ocular myasthenia generalization in patients. Inciarse usually at doses of 1000 mg / day in case of ocular MG or 2000-2500 mg / day (maximum 3000 mg / day) divided into two doses if generalized MG. The beneficial effects are evident after a few weeks of their home employment. It has been linked with infections, myelosuppression and hepatotoxicity rarely. It should be performed weekly CBC analytical with the first 4 weeks, biweekly for two months, monthly during the first year and then every 6 months.

* Cyclosporine A and Tacrolimus

Cyclosporin A and tacrolimus are inhibitors “calcineurítics” causing blocking the synthesis of IL-2 and other proteins essential for the function of T Cyclosporin A (4-6 mg / kg day in two divided doses) and cells Tacrolimus (3-5 mg / day) are therapeutic options for patients where it has failed the first line of immunosuppression with azathioprine and mycophenolate mofetil. They should take into account their potential side effects, especially nephrotoxicity and hypertension in patients treated with cyclosporin A.

It has been reported with tacrolimus clear benefit in patients with MG and anti-receptor antibody positive Ryanodine.

* Methotrexate

A small study showed a similar efficacy and tolerability Azathioprine as “glucocorticoid sparing” agent.

* Other immunosuppressants

Cyclophosphamide, and Rituximab Etanercept have not been reported systematically to the treatment of ocular MG.

Cyclophosphamide (500 mg / m2 or 4 x 50 mg / kg) and Rituximab (1000 mg 2 doses separated by two weeks ev) are used in patients with severe and refractory to treatment MG.

Special mention Rituximab in patients with MG with anti-MuSK antibodies, which has become the drug of choice when remission is not achieved with corticosteroids.

– Immunoglobulins and plasmapheresis:

High doses of intravenous immunoglobulin (2g / kg in 2-5 days) and plasma (4-6 sessions) parts can be used in cases of exacerbation or myasthenic crisis, but its use is not recommended in patients with ocular myasthenia.

Some of the side effects of plasmapheresis are paresthesias, hypocalcemia induced citrate, infection, bleeding and thrombotic complications. The side effects of the infusion of immunoglobulins are headache, rash, aseptic meningitis, thrombotic risk in isolated cases and aplastic anemia.