Myasthenia Gravis

Neurology

Myasthenia Gravis (MG) SX | LAB | DX | Diff-Dx | RX

It is a relatively rare autoimmune disorder in which

antibodies form against acetylcholine (ACh) nicotinic post-synaptic receptors at the myoneural junction, resulting in impaired muscle strength with
a characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest.
Female > Male (3:2). Children with MG plus associated disease: Female > Male (5:1)
Three peaks of onset: neonatal due to transfer of maternal autoantibodies, age 20-30 and over age 50.There are two peaks of onset in adults: age 20-30 (with a female predominance) and over age 50 (with a slight male predominance).
The role of the thymus: 75% of patients with MG have some degree of thymus abnormality (hyperplasia in 85%, thymoma in 15%). Given the immunologic function of the thymus and the improvement in the clinical condition of patients following thymectomy, it is suspected that this is the site of autoantibody formation.
Thyroid disorders may be seen in up to 4% of patients with MG and symptoms of hyperthyroidism or hypothyroidism may be present.

Symptoms & Signs of Myasthenia Gravis

Generalized weakness & fatigability with repeated activity, & reduced exercise tolerance that improves with rest or specific weakness of certain muscle groups, such as difficulty in climbing stairs.
Weakness of bulbar muscles, a prominent feature of MG, may lead to complaints of ptosis, diplopia, blurred vision, difficulty swallowing or dysarthria. MG may affect bulbar muscles alone in 20% of cases.
Dysarthria, Dysphagia , Neck and proximal limb weakness
Respiratory weakness with dyspnea, decreased tidal volume, vital capacity, & decreased voice volume.

Severe exacerbations of MG present dramatically.

The facial muscles may be slack and the face expressionless, the patient may be unable to support his head which will fall onto the chest while the patient is seated, the jaw is slack, the voice has a nasal quality and the body is limp.
The gag reflex is often absent and such patients are at risk for aspiration of oral secretions.

Respiratory Distress:

Of utmost concern in severe exacerbations of MG is the patient's ability to generate adequate ventilation and to clear bronchial secretions.
Inability to cough leads to an accumulation of secretions, such that rales, rhonchi and wheezes may be auscultated locally or diffusely. The patient may have evidence of pneumonia (i.e., fever, cough, dyspnea and consolidation).

Cholinergic Crisis:

One of the confusing factors in managing patients with MG is that insufficient medication (myasthenic crisis) and excessive medication (cholinergic crisis) can present in similar ways.
Cholinergic crisis results from an excess of cholinesterase inhibitors (i.e., neostigmine, pyridostigmine and physostigmine) and resembles organophosphate poisoning.
In this case, excessive ACh stimulation of striated muscle, at nicotinic junctions, produces flaccid muscle paralysis that is clinically indistinguishable from weakness due to MG.
The patient may also have bronchospasm with wheezing, bronchorrhea, respiratory failure, diaphoresis and cyanosis from either cause.
Cholinergic crisis may also be marked by miosis and the SLUDGE syndrome (i.e., salivation, lacrimation, urinary incontinence, diarrhea, GI upset, hypermotility and emesis). However, these findings are not inevitably present.

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Lab Studies:

There are no laboratory tests that are available in a time frame useful to confirm the emergency diagnosis of patients with MG.
CXR & Pulmonary function tests: as pulse oximetry, peak expiratory flow or FEV1 or vital capacity, and ABG sampling to determine pCO2. Evidence of hypoxemia, poor respiratory effort or CO2 retention is an indication for intubation and mechanical ventilation.
CXR is relatively insensitive in screening for thymoma as it misses up to 30%.
CT or MRI of the chest is highly accurate in detecting thymoma. Every MG patient should be screened for thymoma.
The Tensilon (edrophonium) challenge test
is useful in distinguishing myasthenic from cholinergic crisis. Once the patient's airway and ventilation are secured, an initial test dose of edrophonium (0.1 -0.2 mg IV) is given. Some patients may respond noticeably to even this small dose. If no adverse reaction occurs following the test dose, another dose of edrophonium (1-2 mg IV) should produce noticeable improvement in muscle strength within one minute. If there is no improvement, an additional dose of up to 8 mg IV can be administered to a total of 10 mg. The patient must be monitored carefully during this procedure as edrophonium can cause significant bradycardia, heart block and asystole.
(* Have atropine injection ready)
If muscle strength fails to improve following the maximum dose of edrophonium, the patient is having a cholinergic crisis or has another cause of weakness unrelated to myasthenia.
Patients with a cholinergic crisis may respond to edrophonuium challenge by increasing salivation and bronchopulmonary secretions, diaphoresis and gastric motility (i.e., SLUDGE syndrome).
These changes should be managed expectantly, as the half-life of edrophonium is short (approximately 10 minutes). Patients who respond, generally show dramatic improvement in muscle strength, regaining facial expression, posture and respiratory function within one minute.
The effects of edrophonium are brief and repeated doses may be required before oral anticholinesterase medication can take effect.
In patients with less severe exacerbations, the degree of improvement with edrophonium may be subtle.
Electromyography and assays of cholinesterase activity (myasthenia panel blood tests); however, these tests are usually not available on an emergent basis.
Ice pack test: In a myasthenic patient with ptosis, ice placed over an eyelid will lead to cooling of the lid; the ptosis may improve neuromuscular transmission leading to improvement of the ptosis.
Ice placed in a surgical glove or wrapped in a towel placed lightly over the eyelid will cool it within 2 minutes.
A positive test is clear resolution of the ptosis.
Thought to be positive in about 80% of patients with ocular myasthenia.

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DX of Myasthenia Gravis

Physical exam that shows fatigue and weakness on examination.
Diagnosis be confirmed by an edrophonium or neostigmine test.
Repetitive nerve stimulation studies demonstrate a rapid reduction (>12% ) in the amplitude of the MAP.
Single-fiber EMG demonstrates increased jitter and blocking in more than 90 percent of patients.
An MRI of the chest should be performed to search for thymic hyperplasia or thymoma.
The serologic diagnosis of MG is made by detecting AChR antibodies with a radioimmunoprecipitation assay. These antibodies are present in as many as 90 percent of patients with generalized MG and in as many as 70 percent of patients with ocular MG. Such antibodies are also found in as many as 30 percent of patients with autoimmune liver disease, in 10 percent of patients with pernicious anemia, and in as many as 13 percent of patients with LEMS. Generally, AChR antibody titers do not correlate with clinical severity.

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Differential diagnosis of Myasthenia Gravis

MG must be differentiated from other diseases or agent-induced disorders that present similar clinical pictures, such as botulism, organophosphate poisoning, d-penicillamine toxic reaction, mitochondrial myopathy, compressive lesion affecting cranial nerves, LEMS, and congenital myasthenic syndromes.

RX of Myasthenia Gravis
Patients with myasthenic crisis can develop apnea very suddenly and must be closely observed.

Myasthenia gravis is controllable with cholinesterase inhibiting medications. These include edrophonium, which is primarily used as a diagnostic tool because its half-life is so brief.
Pyridostigmine /Mestinon 60 mg po q4-6 hours is used for long term maintenance.
Depending on clinical response, the dosage can be increased, but incremental benefit is not to be expected in amounts greater than 120 mg every 2 hours. If patients have difficulty eating, doses can be taken about 30 minutes before a meal. If patients have special difficulty on waking in the morning, a prolonged-release 180-mg tablet of pyridostigmine (Timespan) can be taken at bedtime. Muscarinic symptoms can be ameliorated by preparations containing atropine, with each dose of pyridostigmine.
For NPO patients, it may be given IM or very slowly IV at dose 1/30th of PO dose. (Watch for cholinergic reactions)
Prednisone 40-100 mg/day for an initial period of three to four weeks. Then, over an eight-week period, the dose on alternate days is gradually reduced by 10 mg a week (more often if side effects are severe) until the lowest possible dose is reached that controls the disease.
Other immunosuppressive drugs, such as azathioprine 2-3 mg/kg/d or cyclosporine 5 mg/kg/d.
Bronchodilators may be useful in overcoming the bronchospasm associated with a cholinergic crisis.
Respiratory support: O2 supplement, sputum suction, respirator if needed.
Plasmapheresis has been found to be an effective short term treatment for acute exacerbations of MG.
Thymectomy is associated with clinical improvement in 85% of cases and 35% of patients appear to have complete remission.

Consultations: Emergent consultation with a neurologist is indicated. Patients with severe exacerbations requiring intubation and mechanical ventilation are managed in an intensive care setting with appropriate consultation.

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Exacerbation of MG Sx:

The activity of the disease fluctuates and adjustments in medication dosage must be made accordingly.
Non-compliance with medications may result in a fulminant exacerbation of the disease.

Many other factors influence cholinergic transmission, including drugs, temperature and emotional state.

Exacerbations may be provoked by adverse effects of many medications. Thus, a careful medication history is important. Some of the medications reported to cause exacerbations of MG include:

Antibiotics: macrolides, fluoroquinones, aminoglycosides, tetracycline and chloroquine
Antidysrhytmic agents: beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide and trimethaphan.
Miscellaneous: diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, ACTH and corticosteroids.

In case of endotracheal Intubation:

Rapid sequence intubation should be modified in that depolarizing paralytic agents, such as succinylcholine, have less predictable results in patients with myasthenia. The relative lack of ACh receptors makes these patients relatively resistant to succinylcholine; higher doses must be used to induce paralysis. Once paralysis is achieved, it may be prolonged. A rapid onset nondepolarizing agent (i.e., rocuronium or vecuronium), is the preferred paralytic agent in this circumstance. Although the onset is delayed compared with succinylcholine, these medications will not result in unwanted prolonged paralysis.

Infection:

Although MG patients can develop any common infection that can result in decompensation, the most likely source of infection is pulmonary.
Cultures of blood, sputum and urine may be indicated on an individual basis and chest x-ray is important in detecting pneumonia.
Appropriate broad spectrum antibiotics are indicated for sepsis and pneumonia.
It is important to consider that fluoroquinones and macrolide antibiotics may adversely affect cholinergic transmission in MG and these should be avoided, if possible.
Fever: Patients with MG are sensitive to high temperatures (core or ambient) and their muscle strength can improve when temperature is lowered with cooling measures or antipyretics.

REF:
SAM 8-1999
E-Medicine 8-1999 Edward Newton, M.D., Department of Emergency Medicine, LAC-USC Medical Center
Manual of Neurologic Therapeutics - Martin A. Samuels

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