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steroids in myasthenia gravis - General Practice Notebook
Myasthenia gravis MG is the most commonly occurring disorder of neuromuscular junction transmission and is characterized by weakness and fatigue of skeletal muscles. It is a T-cell dependent antibody-mediated autoimmune disease. The annual incidence of MG is approximately 10 to 20 new cases per million with a prevalence of about to per million. The age of onset is characterized by a bimodal distribution with an early incidence peak in the 2nd to 3rd decades affecting young women and a late peak in the 6th to 8th decades that is primarily seen in men.
Genetics also play a role as the pathogenesis and clinical manifestations of MG vary among different ethnic populations with distinct HLA associations. MG results from antibody mediated dysfunction of synaptic transmission. Two major components implicated in its pathogenesis are acetylcholine receptors AChR and muscle-specific tyrosine kinase receptors MuSK , both located on the postsynaptic membrane.
Antibody binding to AChR leads to complement activation and AChR cross-linking, which results in increased AChR internalization and degradation on the postsynaptic membrane. MG animal models deficient in MuSK function demonstrate significant reduction of AChR clusters and destructional changes in the neuromuscular junction.
The cardinal feature of MG is a fluctuating skeletal muscle weakness that worsens with repetitive movement. On bedside examination, ptosis can be induced or exacerbated by a sustained upgaze for more than 30 seconds, and diplopia can be induced or exacerbated by a sustained horizontal gaze for more than 30 seconds. Bulbar symptoms include dysarthria, dysphagia, and chewing difficulty.
Patients with facial muscle weakness experience difficulty in closing their eyes and mouth. Neck flexor weakness results in difficulty elevating the head up from a pillow while neck extensor weakness may present as "dropped head syndrome.
Muscles in arms tend to be more affected than legs. Respiratory muscle weakness leads to respiratory insufficiency and in severe cases, respiratory failure necessitating intubation, a life-threatening situation termed "myasthenic crisis.
Of all MG patients initially presenting with weakness restricted to the ocular region, two-thirds will develop weakness of other muscles and one-third will remain as purely ocular. Unique clinical phenotypes of MG-MuSK have been described, including profound atrophy of tongue and facial muscles, and restricted weakness of cervical and respiratory weakness.
MG-MuSK tends to occur in young female patients. Careful history taking and a thorough physical examination reveal fatigable weakness of specific muscle groups. Various bedside maneuvers, laboratory tests and electrodiagnostic tests are also helpful. Two easily performed bedside maneuvers include the ice pack test, which is performed by placing a small ice bag over the ptotic eye for 2 to 5 minutes and then assessing the degree of ptosis for noticeable improvement.
Edrophonium is a short-acting acetylcholinesterase inhibitor that may be administered intravenously after which the patient is observed immediately for objective improvement. There are three subtypes of AChR-Ab: Binding antibodies are the most sensitive and also highly specific for MG. AChR antibody titers correlate poorly with disease severity. Patients with low antibody titers may have more severe symptoms. MuSK-antibody testing should be considered for patients who exhibit specific phenotypes as discussed above, or who are negative for AChR antibodies.
Electrophysiological tests usually allow a confirmation of MG diagnosis in seronegative patients, seropositive patients with unusual clinical features or seriously ill patients who require immediate treatment decisions.
However, a decremental response on RNS is not specific for MG as this may be seen in other neuromuscular disorders, such as motor neuron disease or myopathy. The differential diagnosis for MG varies according to the clinical presentation. For example, differential diagnoses for patients with ocular weakness may include thyroid ophthalmopathy, oculopharyngeal muscular dystrophy and mitochondrial myopathy.
In general, a lack of fluctuation in the ocular symptoms distinguishes these disorders from MG. These disorders can usually be distinguished based on the clinical presentation, laboratory testing, e. Lambert-Eaton myasthenic syndrome LEMS is another autoimmune disorder of neuromuscular junction with several distinct clinical features. Its earliest presentation is usually difficulty in rising from a chair due to proximal leg weakness.
Symptoms in LEMS tend to improve with exercise. Autonomic symptoms such as erectile dysfunction or dry mouth are frequently observed. Brief exercise and RNS at high stimulation rate Hz produce a marked increase in motor nerve amplitudes otherwise known as an incremental response in LEMS patients in contrast with MG patients who demonstrate a decremental response.
Therapeutic strategies for MG are fairly effective and lead to sustained remission in most patients. Treatment goals in MG include symptomatic improvement, relapse reduction, and avoidance of medication side effects. The initial step in most patients with mild or moderate symptoms is the usage of Ach inhibitors. Ach inhibitors slow down the degradation of acetylcholine, prolong its effect at neuromuscular junction and improve MG symptoms.
Ptosis, dysphagia and dysarthria generally respond well to Ach inhibitors. Pyridostigmine mestinon is the usual choice of Ach inhibitors. It has a rapid onset minutes of action lasting for 3 to 4 hours. Its starting dosage is usually 60 mg three to four times daily. The dosage of pyridostigmine is limited by its muscarinic side effects, which include nausea, diarrhea, abdominal cramping, sweating, and bradycardia.
Patients with severe or rapidly worsening symptoms should be treated with rapid induction therapies such as intravenous immunoglobulin IVIg or plasmapheresis. The efficacy of both plasmapheresis and IVIg starts quickly within days and lasts for 3 to 6 weeks.
These therapeutic modalities are used in a variety of settings, including myasthenic crisis, preoperative prophylaxis, bridge therapy when initiating slower acting immunotherapies, or maintenance treatment in refractory MG patients who failed chronic immunosuppressive agents.
The most adverse events associated with plasmapheresis include line infection, thrombosis, air embolism, hypotension, cardiac arrhythmia, coagulopathy, and hypocalcaemia. IVIg may accelerate the catabolism of antibody, suppress antibody production, neutralize autoantibodies, and inhibit complement activation.
IVIg has been shown to improve muscle strength in patients with severe symptoms. Side effects of IVIg included nephrotoxicity, anaphylaxis, and thromboembolic events. Trials comparing the efficacy of IVIg and plasmapheresis in acute and severe MG did not reveal differences in efficacy. Since IVIg is easier to administer and associated with fewer adverse events than plasmapheresis, it is usually the preferred treatment.
A long-term immunosuppressive agent is usually required for patients who remain symptomatic on pyridostigmine, and virtually all patients with generalized MG. The long-acting immunosuppressive agents for MG include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, and others.
The choice of agents depends on comorbidities including diabetes relative contraindication to corticosteroids , liver disease precludes azathioprine usage , renal dysfunction precludes cyclosporine usage , or leukopenia restrictive for azathioprine and mycophenolate mofetil. The desired time of response onset and cost are also important considerations. The most commonly used immunosuppressive agent for the treatment of MG is prednisone.
The transient worsening usually occurs 5 to 10 days after dose initiation and lasts for about a week. For this reason, high-dose prednisone should be started in hospitalized patients receiving concurrent rapid induction immunotherapy.
In patients with mild to moderate MG symptoms, a lower dose of 20 to 40 mg per day is sufficient. There is no set approach for tapering prednisone in MG patients. In general, 2 to 3 months after patients have achieved maximal control of symptoms, a steroid taper should be considered due to the side effect profile of chronic steroid use. Patients should be maintained on the lowest possible dose of prednisone if the drug cannot be discontinued.
In those cases, other immunotherapeutic agents may be considered either in lieu of or in addition to corticosteroids as a "corticosteroid-sparing" agent.
The side effects of prednisone commonly include weight gain, cushingoid features, easy bruising, cataract, glaucoma, hypertension, diabetes, dyslipidemia, osteoporosis and rarely avascular necrosis of femoral or humeral head. For those most at risk for osteoporosis, treatment with bisphosphonate should be considered. The onset of beneficial effects from azathioprine is delayed at 6 to 12 months, with the maximal efficacy often appearing after 1 to 2 years of treatment.
Common side effects include fever, nausea, vomiting, and malaise, and less frequently hematological abnormalities, abnormal liver function, or pancreatitis. Blood cell counts and liver function tests should be monitored every week for the first 2 months then every month for at least the first year.
Some individuals are homozygous for a mutant allele in the thiopurine methyltransferase gene, and such patients should not receive azathioprine because of their inability to metabolize the medication leading to potential life-threatening bone marrow suppression. Mycophenolate mofetil inhibits purine synthesis and decreases the proliferation of B- and T- lymphocytes. The starting dose is mg twice daily and the usual maintenance dose is 1, to 1, mg twice daily.
It is a well-tolerated medication with fewer side effects and it has been increasingly used in MG management. A slow development of clinical benefit is observed after months of mycophenolate therapy, similarly to azathioprine.
Leukopenia can occur but rarely to the degree that leads to a discontinuation of mycophenolate. Similarly to azathioprine, a monthly complete blood count during the first 6 months of therapy is needed, and less frequently afterwards. As mycophenolate exposure in pregnancy results in a high incidence of major fetal malformation, its usage in pregnant patients is discouraged.
Cyclosporine inhibits the function of calcineurin and blocks synthesis of interleukin-2 and interferon by helper T-cells. Its onset of action appears faster and clinical benefit can often be appreciated as early as 1 to 2 months. However, the renal toxicity and interactions with other medications make cyclosporine a less favorable choice than other agents.
Tacrolimus has a similar action to cyclosporine but has the advantage of being less nephrotoxic. The reported dosage varies from 0. Side effects included hypomagnesemia, tremor, and paresthesia.
Rituximab is a monoclonal antibody that acts against the B cell membrane marker CD20 and leads to B lymphocyte depletion. A growing number of case series supports its usage in patients with severe generalized MG refractory to multiple immunosuppressive agents.
Rituximab is particularly effective for MG-MuSK, often resulting in a significant reduction of MuSK antibody titers and a long lasting treatment effect. Minimal infusion reactions, which include flushing, pruritis, chills, and rigors, are seen mostly with the initial infusion.
Patients may be more susceptible to certain infections such as reactivation of herpes zoster but overall rituximab is well tolerated.
Cyclophosphamide is an alkylating agent which interferes with DNA replication and in turn decreases the production of lymphocytes, monocytes and macrophages. Due to serious potential side effects, which include myelosuppression, hemorrhagic cystitis, skin, bladder and blood malignancies, cyclophosphamide is used sparingly and is usually reserved for severe cases that are refractory to other immunosuppressive agents. Patients with a thymoma should be considered for surgical removal of the thymus.
If it is not possible, chemoradiotherapy can be considered for both the relief of myasthenic symptoms and the prevention of local invasion. However, the need for thymectomy is less certain in MG patients without thymoma. A relatively low dose of corticosteroids is preferred to avoid postoperative problems with wound healing.