Learning Objectives
- MG is a weakness that varies with effort
- In many cases antibodies to the acetylcholine receptor are present
- The mainstay of treatment is immune suppression when symptoms are moderate to severe
History
DS, a 64 year old widow, is undergoing treatment for pneumonia at the hospital. While she undergoes treatment, the nurses observe that she has difficulty swallowing and she seems to be unable to keep her eyes open. She has developed these symptoms during the past two days. When questioned, she has felt fatigued for the past two months, and during the past week she has had trouble swallowing fluids. She has lost a few pounds since she last felt healthy. She denies a problem with her walking, or with weakness. She denies the symptom of diplopia.
She has a history of allergic reaction to trimethoprim/sulfamethoxazole. She uses aspirin and metoprolol every day. Her past medical history includes hypertension and hysterectomy.
She is a life-long nonsmoker, and she has 4-5 glasses of wine during the week. She works as an elementary school librarian.
Her father died of a heart attack at age 79 and her mother suffers from Alzheimers disease at age 90. She has a younger sister who has no illnesses.
Review of systems shows she has had a normal heart rhythm. She has recently had fevers, coughing and trouble breathing. Her vision is ok, except that she cannot open her eyes easily. She has had some weight loss and trouble swallowing. Her bowel and bladder function has been fine. She has not had problems with rashes, with bruising or bleeding, and her mood and sleep have been normal.
Examination
Her vital signs are temperature 99.7 F, pulse 84, and blood pressure 141/83. She is coughing, she has a nasal cannula for oxygen delivery, but she is alert and appears comfortable enough to talk. Her heart beat sounds are normal. She is able to say the alphabet without taking a breath. Her eyelids are weak on both sides, but when opened, her pupils appear normal. Her language and attention are normal. Her eye motions are full and conjugate in each direction. Although she has ptosis on both sides, the forced eye closure and smile movements are normal. There is normal movement of the tongue, palate, trapezius and sternocleidomastoid. She has normal facial sensation to pin and normal hearing to a tuning fork. Shoulder abduction and hip flexion seem mildly weak on both sides. The muscle tone is normal. Deep tendon reflexes and Babinski response are normal. Sensation in the arms, trunk and legs are normal to pinprick. She has normal finger-nose-finger and heel-knee-shin movements. She is able to stand, despite her hip flexion weakness, and she is able to tandem walk.
Localization and Neuroanatomy
The summary of this case is that DM has developed fatigue, ptosis and dysphagia, with proximal muscle weakness in the arms and legs, but normal sensation and reflexes. It is suspicious that her trouble swallowing resulted in choking, aspiration, and now clinical pneumonia. Perhaps the most remarkable finding in this case is the ptosis, or the weak, droopy eyelids. This is a typical feature of a neuromuscular illness, especially myasthenia gravis (MG). A clinician should suspect the neuromuscular junction when the patient shows signs of diffuse weakness, no sensory deficits, and normal reflexes on the exam.
Diagnosis
Myasthenia may cause ptosis, and sometimes proximal muscle weakness, diplopia, dysarthria, dysphagia, and / or fatigue. As with other illnesses, the symptoms and severity of this illness vary from person to person, and sometimes the exam findings are not clear enough to suspect this illness. The differential diagnosis of a cause of fatigue and muscle weakness includes myasthenia gravis, the rare Lambert Eaton syndrome, thyroid disorders, polymyositis, muscular dystrophy, and multiple sclerosis.
After the clinical exam, the assessment of these illnesses is continued by laboratory testing. In particular, thyroid function, CPK, ESR and a serum acetylcholine receptor antibody test should be considered. The latter would support the diagnosis of MG, and in a case where the symptoms affect muscles below the neck, it may be expected to be abnormal 80% of the time. For cases of ocular MG, affecting only eye movements or the eye lids, the antibody testing tends to be abnormal only 60% of the time. If the antibody is negative and the other tests are normal, there are neurophysiological tests that can help. These include repetitive nerve stimulation, single fiber EMG testing, and CT scan of the chest. In some cases, CT scan of the chest will reveal evidence of a thymoma. The gold standard test for Myasthenia is single fiber EMG.
Traditionally we are taught in medical school that the tensilon test, or edrophonium challenge, is the test of choice for diagnosing MG. Since MG affects acetylcholine signaling in the neuromuscular junction, it is helpful to remember this test when considering the disease mechanism. The tensilon test is often not available, it is fraught with error, and it is not used in actual practice.
Patients with generalized MG may have weakness of the diaphragm, causing respiratory insufficiency. Unlike conditions like COPD and restrictive lung disease, this cannot be compensated, and patients with this may rapidly decline. When they are struggling to breathe, they may have normal arterial blood gas parameters. After all, diffusion of gases is not the problem. A patient with dyspnea and neuromuscular illness should be monitored via respiratory parameters, such as the negative inspiratory force (NIF) and functional vital capacity (FVC). These are helpful measures of reserve and can help us decide if a patient needs noninvasive ventilation or mechanical ventilation for life support.
It may impress your colleagues to point out that MG has unique characteristics. In the case of eyelid ptosis, chilling the eyelids with an ice cube may result in inhibition of endogenous acetylcholinesterase, promoting an improvement in levator palpebrae muscle function. Patients may observe their symptoms improve in the morning, because after rest there may be a greater concentration of ACh in their neuromuscular junction. On repetitive nerve stimulation testing, sustained contraction of a muscle may overcome the deficit in motor amplitude decrement, for a similar reason. Patients with infections may feel their MG symptoms are worse. Treatment with antibiotics will treat a flare of symptoms that are caused by an infection.
Treatment
The mainstay of MG treatment is immune suppression. This may be accomplished with a moderate dose of prednisone, such as 20-30 milligrams daily. The function of prednisone is varied, but one of its roles here is to reduce lymphocyte populations and antibody production. The side effects of this medication are well-known: short term effects are GERD, insomnia, increased appetite, and hyperglycemia. Long term side effects may include osteoporosis, cataracts, and weight gain. Rapid tapering of this medicine in this condition is not recommended, as rebound exacerbation tends to occur.
Another important treatment of MG is acetylcholinesterase inhibitors, such as pyridostigmine. Interestingly, these are distinct from treatments for Alzheimers disease, there is not much cross reactivity of the drugs used for that disorder. This medication is normally administered as 60 milligrams three times daily. It may cause excess salivation, diarrhea, or abdominal cramping. Although we are often taught this is the key treatment of MG, it is really immune suppression that treats MG- acetylcholinesterase inhibition helps only to control the symptoms.
There are several other forms of immune suppression that may be helpful for MG, if the above treatments are not effective. These include cyclosporine, IVIG, plasma exchange, rituximab and surgical thymectomy. The latter should be done in cases of suspected thymoma, and it is occasionally done if the symptoms are severe and resistant to medical care.
A patient with MG may have symptoms that vary over time. At times, some patients may require no treatment at all. As with other autoimmune illnesses, some patients will appear to be very affected by their illness, and require a lot of attention, others may be easy to assist. Sometimes patients can develop chronic changes in the neuromuscular junction which do not respond to maximum cholinergic signaling or immune suppression.
Certain medications are known to worsen MG symptoms and should be avoided. These include penicillamine, vecuronium and curare agents, ciprofloxacin, aminoglycosides, quinine, beta blockers and calcium channel blockers.
Review Questions
- Myasthenia gravis is a disorder that causes weakness. The anatomical site of pathology in this disorder is the:
A. Brain
B. Spinal cord
C. Peripheral nerve
D. Neuromuscular junction
E. Muscle tissue - Typical symptoms of myasthenia gravis may include
A. Numbness
B. Ptosis (eyelid weakness)
C. Fatigue
D. Distal muscle weakness
E. Both b and c - A patient with trouble breathing and no prior history of a pulmonary disorder presents at the ER. Chest film and arterial blood gas appear normal, but the patient is clearly struggling. The respiratory therapy staff recommends noninvasive ventilation. This appears to help the patient feel more comfortable. A neuromuscular illness is considered as the diagnosis. In order to confirm that MG is the cause of the patient’s breathing disorder, which of the following tests would you recommend:
A. NIF / FVC respiratory parameter measurements
B. Acetylcholine receptor antibody testing
C. Acetylcholine esterase activity measurement
D. Single fiber EMG testing
E. Both b and d