Myasthenia gravis
This patient presented with progressive bulbar dysfunction, manifesting as nasal speech, facial weakness, and dysphagia, as well as generalized weakness, fatigue and head drop. Interestingly, evidence of extraocular muscle dysfunction was minimal in this patient. Although the referral diagnosis was amyotrophic lateral sclerosis (ALS), several features raised concern about this diagnosis. The patient's history suggested a transient improvement early in his course, which would be unusual for ALS. No fasciculations were evident on clinical examination, again atypical for a diagnosis of ALS. Rather than the generalized tongue atrophy and fibrillations typical of ALS, the patient exhibited longitudinal furrowing of the tongue. This "tri-grooved" appearance of the tongue resembled that of patients with myasthenia gravis, as described in a number of classic texts. In addition, motor examination revealed triceps weakness substantially out of proportion to weakness of the biceps, as well as weakness of the neck extensors to a greater degree than weakness of neck flexors. This constellation of findings clinically suggested a diagnosis of myasthenia gravis, supported by demonstration of fatiguability on repetitive contractions of several muscle groups.
Additional evidence supporting a diagnosis of myasthenia gravis included: (1) a high titer of serum antibody specifically binding the skeletal muscle nicotinic acetylcholine receptor, (2) decrement of compound muscle action potential amplitude on low-frequency repetitive nerve stimulation in facial muscles (40%) as well as the trapezius (20%), and (3) a dramatic response to the edrophonium (Tensilon) test, and continued improvement with oral pyridostigmine. We note that the Tensilon test, which involves a potential risk to the patient, is not necessary in many patients with suspected myasthenia gravis; it was performed in this patient to confirm the diagnosis as his clinical status was declining, before the results of the acetylcholine-receptor antibody assay were available.
Several respondents suggested the possibility of a second disorder, in association with myasthenia gravis. Our clinical suspicion for Lambert-Eaton myasthenic syndrome (LEMS), a presynaptic disorder of the neuromuscular junction, was low, as the patient did not have facilitation of muscle strength on exam, and on electrodiagnostic screens he lacked significant facilitation of CMAP amplitude with exercise. Although we did note reduced amplitudes with stimulation of motor nerves of the right arm, these were not of a degree to raise high concern for LEMS, and other reported CMAP amplitudes were within normal range. The patient's complaints of dry eyes were felt to be related to his amitriptyline, and not to represent the autonomic dysfunction sometimes observed in LEMS. We also considered whether the patient might have concomitant motoneuron disease; however, the electromyographic studies did not show diffuse denervation, and fasciculations were noted on electromyography of only a couple of muscles, and no fasciculations were evident clinically to suggest a disorder of the lower motoneuron. The patient's generalized muscle atrophy was felt to result from reduced oral intake. We did not find evidence on muscle histopathology to suggest an inflammatory myopathy.
We did note evidence of early cognitive decline in this patient. However, the short-term memory deficit noted on the mental status assessment, predominantly cortical dysfunction on the neuropsychological tests, and MRI evidence of mild cerebral cortical volume loss, together with the patient's age, more strongly suggest an early dementia of the Alzheimer's type. In contrast, cognitive loss associated with motoneuron disease more typically presents as mild frontal-subcortical dysfunction in many patients with typical ALS, or as one of the frontotemporal dementia syndromes with supervening motoneuron degeneration.
Given the history of blood in the stool, we requested endoscopic evaluations to rule out an underlying malignancy; these were unrevealing. Chest CT with contrast did not suggest a pulmonary malignancy or an underlying thymoma.
The patient was treated with intravenous methylprednisolone and intravenous immunoglobulin, as well as oral pyridostigmine. Physical therapy and occupational therapy were continued throughout his hospitalization, and he was discharged home in improved condition, on an alternating-day prednisone regimen. At an opportune time, his gastrostomy tube was removed.
Myasthenia gravis, an autoimmune process usually associated with circulating antibodies to the post-synaptic acetylcholine receptor at the neuromuscular junction, has a bimodal incidence with an early peak between 20-30 years of age and a later peak between 60-70 years of age. Myasthenia gravis in older patients can be diagnostically challenging, particularly if symptoms and signs of extraocular muscle weakness are lacking at the time of presentation. Although extraocular muscle weakness is eventually present in over 90% of cases of myasthenia gravis, it is the initial symptom in only ~60% of cases. Weakness of lower cranial nerves may be the presenting symptom in 8-12% of cases of myasthenia gravis (7); a portion of these cases would be expected to lack significant extraocular muscle findings at presentation, as in the case presented. Isolated dysphagia from myasthenia gravis is uncommon (2), but dysphagia in association with dysarthria (particularly if speech has a nasal component) is highly suggestive of the possibility of myasthenia.
Diagnostic studies may show misleading results in cases of myasthenia gravis. About 10-15% of cases of myasthenia gravis are "seronegative" for antibodies against the skeletal muscle nicotinic acetylcholine receptor. Evidence of denervation may be present on electrodiagnostic studies or on muscle histopathology, attributed to a severe defect of neuromuscular transmission inducing a "functional" denervation of muscle. Myopathic changes on electromyography may be prominent in elderly patients with myasthenia gravis, and were seen in this patient. As highlighted by Maher et al. (5), typical decrementing of compound muscle action potential amplitude with repetitive nerve stimulation may be variable or absent, and initially low compound muscle action potential amplitudes may further complicate interpretation of repetitive stimulation studies. Fortunately, in this case, interpretation of diagnostic tests was straightforward.
Isolated bulbar forms of myasthenia gravis may be misdiagnosed initially as cerebrovascular disease affecting the brainstem, inflammatory myopathies, or motor neuron diseases including Kennedy's disease, or X-linked spinobulbar muscular atrophy (3). As shown in this case, bulbar myasthenia gravis is a well-accepted mimic of bulbar-onset amyotrophic lateral sclerosis. Demonstration of abnormal decrementing on repetitive stimulation studies may not suffice to distinguish myasthenia gravis from ALS in some cases, as ALS itself may be associated with decremental responses on repetitive stimulation (4, 8). For these reasons, a careful clinical and laboratory evaluation is mandatory in all patients with apparently isolated bulbar weakness of recent onset.
We believe that patients with suspected amyotrophic lateral sclerosis should have the diagnosis confirmed in an expedited fashion, to rule out mimic syndromes, minimize anxiety due to delays in definitive evaluation, and facilitate early entry into clinical trials.
Unfortunately, diagnosis is delayed by a mean of about 16-18 months from the onset of symptoms to confirmation of diagnosis (Gelinas, ref. 6). Complexities of the referral system, hesitancy associated with an undesirable diagnosis, inappropriate referrals based on early or nonspecific symptoms, and a number of other reasons have been discussed as causes of diagnostic delay (6).
Not only is the diagnosis of ALS commonly delayed, but increasing data suggest that actual misdiagnosis of ALS is common. In one e-mail survey, 27% of patients had received at least one prior misdiagnosis. By the time of referral to an ALS center, high false-positive rates are still encountered, accounting for 9.7% in the Scottish Motor Neuron Disease Register, and 7.3% in the Irish ALS Register (1). Disorders misdiagnosed as ALS include cervical spondylotic myelopathy, multifocal motor neuropathy, bulbar myasthenia gravis, Kennedy's disease, and inflammatory myopathies. Many of these disorders are treatable, or carry markedly different prognoses than typical ALS.
We thank Stanley H. Appel, M.D. (Neurology), and Cartrell Cross, M.D. (Pulmonary Medicine), for their assistance with this patient's case.
-- Dennis R. Mosier, M.D., Ph.D.
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