Myasthenia Gravis and Neuromuscular Respiratory Failure

 

 

 

General Issues Regarding Neuromuscular Respiratory Failure

 

Neuromuscular disorders may cause:

         weakness of the diaphragm (resulting in hypoventilation)

         weakness of the oropharyngeal and upper airway muscles (leading to aspiration or obstruction).

Patients may present with respiratory failure:

         due to progression of a chronic progressive neuromuscular condition such as ALS or muscular dystrophy.

         as an early or presenting manifestation of an acquired disorder as is the case with GBS, botulism, and myasthenia gravis.

Signs and Symptoms:

         Nocturnal or sleep associated hypoventilation (headaches upon awakening, daytime fatigue, daytime sleepiness, etc.)  C weakness of the diaphragm

         Slurry/ ̄nasal ̄ speech C weakness of the palate

         Dysphonia (raspy voice) C weakness of the larynx

         Weak cough C weakness of the epiglottis

         Accessory muscle usage

         Tachycardia 

Physical Exam:

         Ask pt to cough or ^sniff ̄

         Observe for paradoxical abdominal wall movement  

o        Normally, with inspiration as the diaphragm contracts, the abdomen is forced down leading to protrusion of the belly. In severe diaphragm weakness, inspiration may be more dependent on the intercostal and accessory muscles, in which case the weak diaphragm muscle may be drawn up into the chest with inspiration, leading to a sunken or scaphoid appearance to the abdomen.

         The Counting Test

o        take a huge breath and count aloud. Determine how high the patient can count in one breath. If the patient can count to "10" on one breath they likely have a forced vital capacity of about 1000 ml, if they can count to "25" then the vital capacity can be estimated at about 2000 ml.

Spirometry:

Forced vital capacity: 

         Respiratory failure is likely when FVC falls below 15-20 ml/kg. In an average size adult 15-20 ml/kg equals about 1000 ml.  

         In the acute setting the vital capacity should be monitored at least q4 hrs.

Peak inspiratory force:  

         < 25 cm/H20 is typically associated with impending respiratory failure.

ABG & O2 sat: 

         insensitive measure in the acute setting  

When To Intubate:

1) In the patient with acute or subacute progressive weakness, when the FVC < 15 ml/kg (about 1000 ml in the average size adult)

2) Poorly protected airway (oropharyngeal weakness)

         patient cannot handle oral secretion (choking)

         intermittent aspiration

         upper airway obstruction

3) Significant hypoxemia

4) If the patient just "looks bad" or appears to be struggling to breath

 

Myasthenia Gravis

 

         Autoimmune disorder of neuromuscular transmission involving autoantibodies against the nicotinic acetylcholine receptor.

         Acetylcholine receptor antibodies are detectable in 80-90% of patients with MG.

         One in 10,000 people. Women : Men = 2 : 1.

         Associated with other autoimmune diseases such as RA, lupus, and pernicious anemia in about 5% of patients.  

         Thyroid disease occurs in about 10%, often in association with antithyroid antibodies.

         10-15% of MG patients have a thymoma

         50-70% have thymic lymphoid hyperplasia

         Three iatrogenic causes:

o        D-penicillamine (used in the tx of Wilson disease and RA)

o        interferon alpha

o        bone marrow transplantation

         Clinical Features

o        fluctuating or fatigable weakness

o        Presenting symptoms

         Ocular (50%)  - diplopia, ptosis

         Bulbar (10%) C dysarthria, dysphagia

         leg weakness (10%)

         generalized weakness (10%)

         Respiratory failure (1%)

         Edrophnium (Tensilon) test

o        one or two weak muscles must be selected for monitoring. Eyelid ptosis, dysconjugate gaze, and other cranial deficits provide the most reliable endpoints.

o        Test should be run in a clinical setting where hypotension, syncope, or respiratory failure can be managed, as occasional patients decompensate during the test.

         Secure airway in pts with severe dyspnea.

         IV line

         Atropine 0.4 mg in case of bradycardia or extreme GI side effects.

o        Edrophonium 1 mg should be given as a test dose while checking the patient's heart rate. If no adverse side effects after 1 minute, another 3 mg is given. 

o        If after 1 minute there is no improvement, an give additional 3 mg is injected; if there is still no response, 1 minute later the final 3 mg is administered.

o        Improvement typically lasts about five minutes.  

o        Sensitivity of the test is 80- 90%.

o        The specificity is difficult to determine, as improvement following IV edrophonium has been reported in other neuromuscular diseases 

         Serological testing

o        AChR binding antibodies are present in about 80% of all MG patients.

o        Level of AChR antibodies does not predict the severity or clinical course.

         Electrophysiological testing

o        Repetitive stimulation testing is widely available and has variable sensitivity (usually about 50%).

o        Single fiber EMG is a highly specialized technique, usually available in major academic centers, with a sensitivity of about 90%.

         Natural Course 

o        Half of all MG patients present with ocular symptoms and by one month 80% have eye findings.

o        Weakness remains restricted to the ocular muscles in about 15 to 20% (pure ocular MG).

o        Most patients with initial ocular involvement tend to develop generalized weakness within the first year of the disease.

o        Death is rare.

o        Spontaneous remission in about 10 to 15%, usually in the first year or two of the disease. 

         Treatment 

         Cholinesterase inhibitors (CEI)

o        First line therapy

o        reduces the hydrolysis of AC, increasing the accumulation of ACh at the post-synaptic membrane. The CEIs used in MG bind reversibly to AChE.

o        Side Effect Profile:

         Muscarinic autonomic side effects --  GI cramping, diarrhea, salivation, lacrimation, and diaphoresis

         Bradycardia C occasionally seen with usage of parenteral CEI

         Skeletal muscle weakness ("cholinergic weakness")  -- patients receiving parenteral CEI are at the greatest risk

o        Pyridostigmine (Mestinon) is the most widely used CEI for long-term oral therapy. Onset is within 15 to 30 min, with peak effect within 1 to 2 hours, and wearing off gradually at 3 to 4 hours post-dose. Of all the CEI preparations pyridostigmine has the least muscarinic side effects.

o        Pts with severe dysphagia or those undergoing surgical procedures may need parenteral CEI. IV mestinon should be given at about 1/30 of the oral dose.

o        For pts with intolerable muscarinic side effects, a concomitant anticholinergic drug such as atropine sulfate or glycopyrrolate (Robinul) on a PRN basis or with each dose of CEI may be helpful.

         Corticosteroids:

o        For patients with severe MG it is best to begin with high dose daily therapy of 60-80 mg/day orally.

o        Early exacerbation occurs in 50% of patients usually within the first few days of tx and typically lasting 3 or 4 days.

o        About 80% of patient show a favorable response to steroids

o        Improvement begins as early as 12 hours and as late as 60 days after beginning

o        Of those patients having a favorable response, most maintain their improvement with gradual taper at a rate of 10 mg every 1 to 2 months.

o        While many pts can eventually be weaned off corticosteroids and maintain their response, the majority cannot.

         Plasmapheresis

o        removes acetylcholine receptor antibodies and results in rapid clinical improvement.

o        The standard course is 3x/wk until the pt improves. Improvement begins after the first few exchanges and reaches maximum within 2 to 3 weeks.

o        improvement is moderate to marked in nearly all patients but usually wears off after 4 to 8 weeks due to the re-accumulation of antibodies.

         High dose IVIg

o        associated with rapid improvement in MG symptoms.

o        mechanism is unclear but may relate to down-regulation of acetylcholine receptor antibody production or to the effect of anti-idiotype antibodies.

o        2 g /kg over 5 consecutive days.

o        majority of MG pts improve usually within 1 wk of starting IVIg. The degree of response is variable and the duration of response is limited to about 4 to 8 wks.

o        botulinum toxin

o        d-penicillamine

o        interferon alpha

o        chloroquine

o        quinine

o        quinidine

o        procainamide

o        Aminoglycoside -- unless needed for a life threatening infection.

o        Neuromuscular blocking drugs such as pancuronium and vecuronium

o        Depolarizing drugs such as succinylcholine

o        Iodinated IV contrast C occasionally associated with exacerbation of MG and should be avoided unless absolutely necessary.

         Myasthenic crisis

o        a medical emergency

o        respiratory failure from diaphragm weakness or severe oropharyngeal weakness leading to aspiration.

o        Crisis can occur in the setting of

         surgery (post-op)

         acute infection

         following rapid withdrawal of corticosteroids

         sometimes no precipitating factors

o        Management

         Patients should be placed in an ICU setting

         FVC and FEV-1 should be checked q2 hours.

         low threshold for intubation and mechanical ventilation.

         If pt has been taking CEI the drug should be temporarily d/c¨d in order to r/o the possibility of "cholinergic crisis."

         Screen for and correct any underlying medical problems such as systemic infection, metabolic problems (like diabetes), and thyroid disease (hypo- or hyperthyroidism can exacerbate MG).

 

Myasthenic Crisis Cholinergic Crisis

Respiratory distress/arrest

Abdominal cramps
Cyanosis Diarrhea

Increased pulse and BP

Nausea/vomiting
Poor cough Miosis
dysphagia Fasciculations

Inability to handle oral secretions

Excessive secretions
Diaphoresis Diaphoresis
weakness weakness

Improves with edrophonium

Worse with edrophonium

 

Other Neuromuscular Disorders that can lead to respiratory failure

 

         botulism

         acute quadriplegic myopathy (critical illness myopathy)

         critical illness neuropathy 

         Acquired myopathies 

o        Hypokalemic periodic paralysis

o        Thyrotoxic periodic paralysis 

         Inflammatory Myopathies

o        Polymyositis

o        Dermatomyositis

o        Inclusion body myositis

o        Less common inflammatory myopathies

         Sarcoidosis

         Influenza myositis (viral myositis)

         Toxoplasmosis

         Cysticercosis

         Trichinosis

         Acute intermittent porphyria

         Tick Paralysis

         ALS


 

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