Does myasthenia gravis affect the brain?

Associations between myasthenia gravis (MG) and CNS functions have been made for over 80 years. An increased incidence of psychiatric disorders, epilepsy and multiple sclerosis as well as electroencephalographic (EEG) abnormalities and abnormal evoked responses have been noted in patients with MG. Descriptions of sleep and memory disturbances in MG patients appeared as knowledge accumulated about the role of brain cholinergic systems in sleep and memory. The inference of many of these studies has been that the alleged central cholinergic effects in MG were caused either by the anticholinesterases used to treat MG or by antibodies to muscle nicotinic acetylcholine receptor (nAchR) present in the serum and cerebrospinal fluid (CSF) of MG patients. The antigenic differences between muscle nAchR and neuronal nAchRs, together with the very low concentrations of muscle nAchR antibodies in the CSF, make highly unlikely the claims that CNS cholinergic systems are affected by these muscle antibodies in MG patients. Evoked response abnormalities, if indeed present, are more likely caused by peripheral than central mechanisms, and sleep abnormalities in MG also probably originate in the periphery rather than in the CNS, the result of hypoxia caused by oropharyngeal, intercostal and diaphragmatic muscle weakness which may worsen during sleep, especially during REM sleep. Such hypoxia may account for some of the EEG abnormalities noted in MG patients, but the association of MG with epilepsy appears to be either coincidental or the result of uncontrolled MG. Significant excessive daytime sleepiness resulting from sleep disturbances can also impair memory and the performance of MG patients on neuropsychological tests, as can the presence of mental depression. The psychological aspects of MG can be attributed to the expected consequences of a chronic but unpredictable neuromuscular disease involving weakness of breathing, swallowing, talking, limb and eye movement. Considering the number and variety of claims for direct CNS involvement in MG, the evidence for this is remarkably unconvincing. The quality of MG treatment, both physical and psychological, is a presently undefined variable which might help explain the diametrically opposed results which have been obtained in some of the studies reviewed. Adequate respiratory muscle strength during sleep is an often overlooked peripheral influence upon mental functioning and general well-being of MG patients.

Contemporary opinions about Mary Walker: a shy pioneer of therapeutic neurology.

OBJECTIVE: To contribute to a better understanding of a poorly appreciated pioneer of therapeutic neurology, Mary Broadfoot Walker, MD. BACKGROUND: At a time when the treatment of myasthenia gravis (MG) was "a source of discouragement to the patient and a cause of nightmare for the physician," Mary Walker demonstrated that temporary relief of myasthenic symptoms could be produced by subcutaneous injection of physostigmine or neostigmine (Prostigmin; Roche, Basel, Switzerland). She also pioneered the concept of a circulating factor as the etiology of myasthenia and was the first to report hypokalemia in familial periodic paralysis. Throughout her career she was dependent on her salaried jobs as a medical officer in several large London hospitals and was thus forced to turn down an offer of an honorary staff position with research beds. DESIGN/METHODS: Previously unpublished material written by persons who lived at the same time as Mary Walker is incorporated with the published record into an account of Mary Walker's accomplishments as assessed by her contemporaries. RESULTS: 1) Although Mary Walker's 1934 report on physostigmine for MG was ignored by most of those in clinical medicine at the time, those responsible for the financing of British medical research vainly hoped that it could be used as an example of the practical outcome of basic research. 2) Her 1935 demonstration of the beneficial effect of neostigmine (Prostigmin) was greeted with general skepticism because of the rapidity with which the patient's symptoms of myasthenic weakness improved, but she was soon vindicated by published confirmatory reports from several contemporaries. 3) Her 1938 demonstrations of what came to be known as "the Mary Walker effect" may have helped her reputation because subsequent published opinions of her contributions were generally favorable, although some people continue to disparage her even today. CONCLUSION: Mary Walker, with her brief case reports and her frequent demonstrations, not only offered symptomatic treatment for MG that has stood the test of time, but also provided the most convincing evidence at the time that the neuromuscular junction was the focus of the disease.

AAEE Minimonograph #33: electrodiagnostic approach to defects of neuromuscular transmission.

Clinical testing for neuromuscular dysfunction is supported by an extensive amount of excellent basic information about normal and abnormal subcellular physiology and ultrastructure. This information provides an essential frame of reference for describing the rationale of single-fiber electromyography (SFEMG). SFEMG in turn helps to explain the more conventional clinical testing of neuromuscular function by repetitive nerve stimulation (RNS). Electrical findings in myasthenia gravis, Lambert-Eaton myasthenic syndrome, and botulinum intoxication are discussed from the subcellular level via the cellular level (SFEMG) to the integrated responses of whole muscle (RNS) as a rational means of understanding the technique of clinical repetitive nerve stimulation.

Myasthenia gravis--current concepts.

An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles. The Director of Conferences is William M. Pardridge, MD, Associate Professor of Medicine. Current findings indicate that autoimmune myasthenia gravis is an acquired immune complex disorder of neuromuscular transmission in voluntary striated muscle. There is a break in immunologic tolerance leading to blocking and degradation of acetylcholine receptors, together with widening of the synaptic cleft associated with partial destruction, simplification and shortening of the postjunctional membrane. Thymic hyperplasia and thymoma may be present. A decremental response to nerve-muscle stimulation, blocking and jitter on single-fiber electromyography and circulating antibodies to acetylcholine receptor are detectable in most patients with generalized weakness. Although the cause of this abnormal immunologic mechanism remains to be discovered, anticholinesterases, corticosteroids, immunosuppressants, plasmapheresis or thymectomy (individually or in combination) provide control and better prognosis in most patients.

Computed tomography of the anterior mediastinum in myasthenia gravis. A radiologic-pathologic correlative study.

Chest radiographs and computed tomographic (CT) scans of the mediastinum were correlated with pathologic findings of the thymus following thymectomy in 57 patients with myasthenia gravis. Based on the patient's age and the overall morphology of the anterior mediastinum, CT scans were assigned one of four grades in an attempt to predict thymus pathologic findings. Using this grading, 14 of 16 cases of thymoma were suspected or definitely diagnosed. One of the two cases not diagnosed on CT was a microscopic tumor. There were no false-positive diagnoses in 11 cases graded as definitely thymoma. We conclude that thymoma can be sensitively diagnosed in patients older than 40 years of age. However, thymoma cannot be predicted with a high level of confidence in patients younger than 40 because of the difficulty in differentiating normal thymus or hyperplasia from thymoma. Recommendations for the use of CT in the preoperative evaluation of myasthenic patients are presented.

Moderator variables in life stress and illness relationship.

The relationship between life stress and physical illness was examined for the effects of potential moderator variables: The Sensation-Seeking Scale, health Locus of Control Scale, and Myers-Briggs Type Indicator. The Sensation-Seeking Scale proved to be a moderator with high sensation seekers (highest quartile) showing no significant correlations between life change and illness, while low sensation seekers (lowest quartile) showed a significant correlation. The Health Locus of Control Scale failed to differentiate between correlation levels for Internals and Externals. The Myers-Briggs provided several moderator variables. Introverts, Thinking and Sensing types showed larger correlations than their Extrovert, Feeling and Intuitive counterparts. The magnitudes and significance levels of these correlations suggest that the Myers-Briggs may have further usefulness in exploring the relationship between life change and illness.

Association of HLA-B8, DRw3, and anti-acetylcholine receptor antibodies in myasthenia gravis.

Twenty-eight patients with myasthenia gravis (MG), five with and 23 without thymoma, and 47 normal controls were typed for serologically defined HLA-A, B, C, and DRw antigens. Sera from all patients were titered for antibodies to acetylcholine receptors (AChR). The frequency of HLA-B8 and DRw3 in the non-thymoma MG patients was significantly higher than in the normal population. Most of the non-thymoma patients with AChR titers higher than the average level were positive for HLA-B8 and/or DRw3, while the majority of the HLA-B8(-) and/or DRw3(-) non-thymoma patients demonstrated AChR titers below average. These findings support the possibility of the existence of immune response genes in the HLA-B, DRw segment of the major histocompatibility complex which are concerned in the response to or recognition of autoantigens.

Saccade fatigue and response to edrophonium for the diagnosis of myasthenia gravis.

Maximum velocity and amplitude of repetitive ( 1-per-second) 30 degrees saccadic eye movements were quantitatively assessed for 4 minutes before and after intravenous edrophonium chloride as a diagnostic test for myasthenia gravis. Atropine was given initially to suppress muscarinic side effects. Eye movements were recorded by electrooculography and a digital computer identified saccadic eye movements and plotted amplitude-velocity relationships. When compared with control subjects, eleven of twelve patients with proven MG had a significant increase in saccade amplitude and/or maximum velocity after edrophonium chloride. Only three of twelve proven MG patients had clinically apparent extraocular muscle weakness. The initial period of fatigue improved the sensitivity of the test in those patients who began with normal saccade amplitude and maximum velocity. Two of the patients with positive saccade fatigue tests had no change in optokinetic nystagmus amplitude before and after edrophonium chloride. It is concluded that, quantitative assessment of repetitive large angle saccades before and after edrophonium chloride is a sensitive test for extraocular muscle involvement in MG.

Myasthenia gravis and invasive thymoma: a 20-year experience.

In 20 years, 19 patients with myasthenia gravis and invasive thymoma have been seen by the Neurology Service at the UCLA Center for Health Sciences. This represents 4 percent of 493 myasthenia gravis patients seen during the same time and 37 percent of myasthenic patients with thymomas. Eight are still alive and 11 have died. Fifteen patients had the onset of myasthenic symptoms before discovery of the thymoma, while only four patients had chest symptoms and/or radiographic evidence of an anterior mediastinal mass prior to the onset of weakness. Radical excision of the tumor, if possible, and the remaining thymus, high dosage alternate day prednisone, and radiation therapy, if indicated, seem the treatments of choice. Recurrences of tumor nodules may necessitate further local radiation or the use of cytotoxic agents.