Hospital Medicine

Myasthenia-Gravis

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Myasthenia gravis

I. What every physician needs to know.

Myasthenia gravis (MG) is a well-characterized autoimmune disorder, serving as a case study in diagnosis and therapy. In the bulk of cases, antibodies are formed that act against acetylcholine receptors, thereby blocking transmission at the post-synaptic neuromuscular junction. Hospitalists may encounter cases that are complicated to manage, but this is typically due to other comorbidities or complications of therapy. At times, a hospitalist may be the one to make an initial diagnosis. Given the protean manifestations of the disease, a working understanding of the basics of presentation and evaluation are important.

II. Diagnostic Confirmation: Are you sure your patient has Myasthenia gravis?

A combination of history, physical examination and laboratory confirmation is typically adequate for confirming the diagnosis of myasthenia gravis.

A. History Part I: Pattern Recognition:

Patients usually present with weakness that worsens with activity and improves with rest. Symptoms fluctuate widely in severity. In the inpatient setting, patients may come to attention with weakness noted after surgery, during active infection, or following administration of specific medications. Another common presentation is diplopia or lid weakness at times, accompanied by difficulty speaking or lack of neck strength.

Uncommonly, patients may present with respiratory difficulty due to diaphragmatic weakness. This can result in primary respiratory failure, or can manifest as difficulty in weaning from mechanical ventilation in a patient intubated for other reasons.

B. History Part 2: Prevalence:

MG has a bimodal presentation, commonly affecting women in their twenties and men in their fifties. Estimates of prevalence in the United States is approximately 60 cases per million, with an annual incidence of about three to four cases per million.

C. History Part 3: Competing diagnoses that can mimic Myasthenia gravis.

Because MG can present in a multitude of ways, the differential diagnosis is very broad.

One of the most common initial complaints is diplopia, for which potential diagnoses include trauma, paraneoplastic syndromes, and brain stem ischemia. Even more subtle than diplopia is ptosis which, again, is non-specific and could indicate facial nerve palsy, orbital fracture, preseptal or orbital cellulitis, or any number of other conditions.

Perhaps the disease most easily confused with MG is Lamber Eaton Myasthenic Syndrome (LEMS). LEMS is also an autoimmune disease of the neuromuscular junction, that can occur either as a paraneoplastic disorder or as a general autoimmune disease. While both MG and LEMS present with gradual onset of fatigue and weakness, patients with LEMS are more likely to have initial improvement of symptoms with activity. Lower extremity weakness is also a more prominent feature in LEMS than in MG.

D. Physical Examination Findings.

Physical examination findings in myasthenia are quite variable, but are primarily due to fatigability. In order to elicit findings on exam, patients can be asked to focus their gaze on a point above their head, resulting in ptosis as the muscles of the eyelids become fatigued. Patients may also be asked to hold an arm out in front of them or do a series of deep knee bends. In either of these exercises, the patient will become progressively less able to perform the maneuvers due to muscle weakness.

E. What diagnostic tests should be performed?

At the bedside, the ice test has largely supplanted the Tensilon (edrophonium) test due to its safety and comparable sensitivity and specificity. In the ice test, the patient holds ice (in an exam glove) against the ptotic eyelid for several minutes. The amount of ptosis is measured before and after the application. If the degree of ptosis decreases by two millimeters, the test is considered positive. While the ice test has utility as a fast, inexpensive, and benign test, it has relatively low sensitivity. Thus, laboratory evaluation follows in order to more definitely diagnose the patient.

Electrodiagnostics are a valuable resource in the diagnosis as well. However, testing is not necessarily straightforward and therefore an experienced practitioner should be sought. Repetitive nerve stimulation typically shows a decremental muscular response. The more technically difficult single fiber EMG may show evidence of increased jitter and blocking which is said to be positive in 90% of patients with MG but is not 100% specific.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

With the advent of laboratory testing, the diagnosis of myasthenia gravis has dramatically improved. Approximately 80% of patients with generalized MG will test positive for autoantibodies against the muscle acetylcholine receptor (AChR) in the serum. Patients with ocular myasthenia will test positive about 50-70% of the time as well. The patients that do not have these antibodies have been referred to as "seronegative." AChR testing is nearly 100% specific, though false positives have been reported in patients with thymoma, LEMS, and small cell lung cancer, as well as in patients with rheumatoid arthritis who are being treated with penicillamine.

In patients for whom the clinical suspicion for MG is high, but AChR antibody testing is negative, further testing can be performed for the presence of muscle-specific tyrosine kinase (MuSK) antibodies. These are present in approximately 50% of seronegative patients.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Patients newly diagnosed with MG should have a plain chest radiograph and/or chest computed tomography performed in order to determine the presence/absence of thymic hyperplasia or thymoma, which has implications for their treatment. Typically, neuroimaging is not necessary in MG. Ocular MG and cases which affect predominantly the bulbar musculature may be an exception if the diagnosis is in doubt.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A thorough history and physical exam, using maneuvers as described above, can prevent overutilizing laboratory testing for MG.

III. Default Management.

Treatment of MG should be done with the direct input of a neurologist. In general, therapy is aimed at relief of symptoms and modulating the autoimmune process.

Symptomatic relief is primarily achieved through inhibiting acetylcholine esterase at the neuromuscular junction, using drugs such as pyridostigmine or neostigmine. The latter acts more quickly, and should be on call at the bedside of any hospitalized patient with MG who has evidence of respiratory compromise.

The effects of immunoactive therapy take longer to become apparent, but tend to last for a longer period of time. First line immunoactive therapy in MG is prednisone, with many patients remaining on low dose prednisone therapy chronically. Other immunomodulators have also been used, including azathioprine, rituximab, and methotrexate.

Of patients with MG, approximately 10-15% will have a thymoma. All of these patients should have a thymectomy performed.

One must take care with other medications which are prescribed, as a number may exacerbate MG. Neuromuscular blockers, aminoglycosides, older antiarrhythmics, and phenytoin are a few of these. Many physicians will find placing a list of these on the patients chart a helpful way to avoid these interactions.

A. Immediate management.

The most urgent threat to a patient with myasthenic crisis is that of hypoventilation. Some of these patients will require mechanical ventilation while further management is initiated, often with plasmaphersis or IVIG.

B. Physical Examination Tips to Guide Management.

Treatment response is most often assessed through bedside testing of limb strength or by trying to elicit ptosis. Patients with MG should also have their forced vital capacity (FVC) and negative inspiratory force (NIF) measured regularly during hospitalization. FVC less than 20 milliliters/kilogram (mL/kg) or NIF less than 30 centimeters water (cmH2O) should incite consideration for elective intubation.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

D. Long-term management.

Long term management of MG includes minimizing steroids and finding the most effective immunosuppressants in addition to appropriate acetylcholinesterase inhibitors. Thymectomy may be appropriate in select cases.

E. Common Pitfalls and Side-Effects of Management.

One must be aware of the potential for a myasthenic patient to worsen with the initiation of steroids. Patients in the setting of crisis need to be monitored very closely given their potential for decompensation.

IV. Management with Co-Morbidities.

One must be aware that concomitant diagnoses such as pulmonary disease and diabetes may impact these patients due to respiratory muscle compromise and side effects of steroids. As in all patients on immunosuppressants, there is a heightened risk of infection.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management, with the exception of steroid use.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Immunosuppressants are commonly used in management of MG.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

N/A

B. Anticipated Length of Stay.

Length of stay is highly variable.

C. When is the Patient Ready for Discharge.

Ideally patients will be stabilized from a pulmonary and functional standpoint prior to discharge. One must take care in titrating steroid doses in the outpatient realm.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

Patients with MG should be followed by a neurologist. Given the high frequency of co-morbid autoimmune conditions, post-acute care should be carefully coordinated with a rheumatologist if indicated. Follow up appointments should be sought within one week of discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

The bulk of patients will achieve good functional improvement with close follow-up and medication management.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients should remain vigilant if they note signs of progressive weakness or overmedication (gastrointestinal distress, excess salivation).

VII. What’s the evidence?

Argov, Z. "Management of myasthenic conditions: nonimmune issues". Curr Opin Neurol. vol. 22. 2009. pp. 493-497.

Cortese, I, Chaudhry, V, So, Y.T. "Evidence-based guideline update: Plasmapheresis in neurologic disorders: Report of the Therapeutics and Technology Asseessment Subcommittee of the American Academy of Neurology". Neurology. vol. 76. 2011. pp. 294-300.

Gajdos, P, Chevret, S, Toyka, KV. "Intravenous immunoglobulin for myasthenia gravis". Cochrane Database of Systematic Reviews 2008.

Gilhus, NE. "Myasthenia and the neuromuscular junction". Curr Opin Neurol. vol. 25. 2012. pp. 523-529.

Gilhus, NE, Owe, JF, Hoff, JM. "Myasthenia gravis: a review of available treatment approaches". Autoimmune Dis. 2011. pp. 1-6.

Keogh, M, Sedehizadeh, S, Maddison, P. "Treatment for Lambert-Eaton myasthenic syndrome". Cochrane Database of Systematic Reviews 2011.

Kumar, V, Kaminski, HJ. "Treatment of Myasthenia Gravis". Curr Neurol Neurosci Rep. vol. 11. 2011 Feb. pp. 89-96.

Mehndiratta, MM, Pandey, S, Kuntzer, T. "Acetylcholinesterase inhibitor treatment for myasthenia gravis". Cochrane Database of Systematic Reviews 2011.

Pascuzzi, RM. "Medications and myasthenia gravis: a reference for health care professionals". Myasthenia Gravis Foundation of America. 2000.

Rodriguez, PM. "Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis". JAMA Neurology. vol. 72. 2015. pp. 642-649.

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