John Keesey

Myasthenia gravis Recommendations for clinical research standards

The need for universally accepted classifications, grading systems, and methods of analysis for patients undergoing therapy for MG is widely recognized and is particularly needed for therapeutic research trials. The Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) formed a Task Force in May 1997 to address these issues. Initially, the Task Force planned to develop classifications and outcome measures pertaining only to standardizing thymectomy trials. However, it quickly became apparent that their efforts should apply to all therapeutic trials for MG, and thus the scope of the mission was expanded. During the development of these recommendations, the Task Force faced numerous dilemmas for which no universally satisfactory solution was available. Dilemmas were defined as “situations that require one to choose between two equally balanced alternatives or predicaments that seemingly defy satisfactory solutions.” The Task Force members agreed at the outset, however, that their primary goal was to develop a uniform set of classifications to be used in the comparative analysis of the various therapeutic interventions for MG. With this as the primary goal, a consensus was gradually developed. In developing a consensus, at least two meetings were held each year during a 3-year period. Between meetings there was exchange of all proposals by electronic and surface mail, consultation with national and international experts in the field, critical analysis of all proposals, and many revisions. All conflicts (both minor and major) were resolved by vote. Virtually all issues were eventually approved unanimously; a few received a plurality of six. This report presents the work of the Task Force and proposes classification systems and definitions of response to therapy designed to achieve more uniformity in recording and reporting clinical trials and outcomes research. Although designed primarily for research purposes, we think physicians may find some of …

Clinical evaluation and management of myasthenia gravis.

Myasthenia gravis (MG) is a syndrome of fluctuating skeletal muscle weakness that worsens with use and improves with rest. Eye, facial, oropharyngeal, axial, and limb muscles may be involved in varying combinations and degrees of severity. Its etiology is heterogeneous, divided initially between those rare congenital myasthenic syndromes, which are genetic, and the bulk of MG, which is acquired and autoimmune. The autoimmune conditions are divided in turn between those that possess measurable serum acetylcholine receptor (AChR) antibodies and a smaller group that does not. The latter group includes those MG patients who have serum antibodies to muscle‐specific tyrosine kinase (MuSK). Therapeutic considerations differ for early‐onset MG, late‐onset MG, and MG associated with the presence of a thymoma. Most MG patients can be treated effectively, but there is still a need for more specific immunological approaches. Muscle Nerve 29: 484–505, 2004

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.

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.

Thymectomy for myasthenia gravis

Abstract 1. 1. Myasthenia gravis appears to be related to an abnormality of the thymus. 2. 2. A significant number of patients with myasthenia gravis benefit from thymectomy. 3. 3. After thymectomy for myasthenia gravis, about one-third of patients are much improved, one-third somewhat improved and one-third unimproved. 4. 4. Young myasthenic women with a relatively short history of the disease, gradually losing ground, and without a tumor of the thymus benefit most from thymectomy. 5. 5. Patients with thymomas should have resection of the tumor regardless of the presence or absence of myasthenia. 6. 6. Thymectomy, with the patient under cyclopropane anesthesia, performed through a sternal-splitting approach in itself causes little risk. Deaths result after operation from pulmonary complications characteristic of myasthenia. 7. 7. The edrophonium test differentiates myasthenic crisis from cholinergic crisis, a dangerous and lethal complication of cholinergic treatment.

Detection of thymoma in myasthenia gravis

Twenty patients with myasthenia gravis had chest radiography, conventional tomography, and computed tomography (CT) of the thorax within 1 month of thymectomy. Four of the six macroscopic tumors were detected on routine chest radiography; conventional tomography provided no additional information. CT detected all six macroscopic tumors and provided additional information that was not available by other procedures. However, 18 patients (90%) had anterior mediastinum densities on CT, which could not be distinguished preoperatively from thymic tumors. All six patients with macroscopic tumors had serum antistriational muscle antibody titers; this test was negative in 10 of 11 patients (91%) without thymoma. Chest radiography, CT of the thorax, and antistriational antibodies are the tests recommended for detection of a thymoma in patients with myasthenia gravis.

Crisis in myasthenia gravis: an historical perspective.

One of the first books I bought when I went to medical school was Dorland’s Illustrated Medical Dictionary (1957). It had 32 examples of “crisis,” including “oculogyric crisis,” “tabetic crisis,” and even “clitoris crisis,” but “myasthenic crisis” and “cholinergic crisis” were not included. It defined “crisis” as “the turning point in the course of a disease for good or evil.” The definition in Webster’s New World Dictionary seems more appropriate for myasthenia gravis (MG): “A crucial situation whose outcome decides whether possible bad consequences will follow” (from the Greek, “to separate”). This “crucial situation” in MG is respiratory failure requiring mechanical ventilation. This may develop suddenly or insidiously in several ways: (1) oropharyngeal or neck muscles become so weak that the airway collapses; (2) weak vocal cord abductor muscles obstruct the larynx, leading to stridor; (3) repetitive coughing weakens the diaphragm to the extent that the airway cannot be kept clear of secretions; and (4) weak diaphragmatic, intercostal, and abdominal muscles fail to provide adequate inspiratory ventilation. Because of facial weakness, the MG patient may not be able to demonstrate the expressions of distress ordinarily seen in patients experiencing dyspnea. Inspiratory muscle fatigue, the end result of the aforementioned causes, can be detected by rapid shallow breathing, abdominal paradoxical motion, and alternation between rib cage and abdominal breathing. Treatment is straightforward standard emergency respiratory care: (1) establish an airway by endotracheal intubation; (2) suction secretions; and (3) mechanically assist respiration. Factors exacerbating the muscle weakness should be considered only after airway and ventilation are under control. Why is this special word, “crisis,” used for the MG patient with life-threatening respiratory insufficiency? Because of its use, clinicians not familiar with MG often think there must be something special or arcane about a “crisis” in MG, and as a result the aforementioned well-known standard emergency procedures are sometimes delayed. Among MG patients the word “crisis” is a source of considerable fear and anxiety. How did this special term come about? “Crisis” was not in the vocabulary of the early sad descriptions of respiratory failure in severely ill patients who had what we now recognize as MG. As their physicians stood by helplessly, these patients died of “attacks of dyspnea” (1900), “rapid exhaustion of the respiratory muscles” (1912), or “asphyxia due to choking” (1927). Because there was no treatment, these terminal events were probably not interpreted as a “turning point” or crisis. Brief manual attempts were made to support the failing respiration, but until Philip Drinker developed negative-pressure mechanical ventilation (the “iron lung”) in 1929, there was no effective treatment. The word “crisis” continued to be absent from the MG literature during the 1930s and early 1940s, perhaps until neostigmine (Prostigmin), introduced by Mary Walker in 1934, came into general use. The first use of the plural, “crises,” that I have been able to uncover occurs in a 1946 review by Viets: “As some patients, however, may have respiratory crises or difficulty in swallowing, all patients should be familiar with the parenteral use of the drug in the form of neostigmine methylsulfate.” The extraordinary enthusiasm for neostigmine in the 1940s seems to parallel an increasing familiarity with the concept of “crisis.” Viets, although he did not mention “crisis” at that time, claimed in 1945 that “neostigmine is a specific antidote for the curare-like symptomatology of myasthenia gravis,” and in 1946 he felt that “indeed, neostigmine should be considered a deficiency drug.” Eaton also used the plural, “crises,” in his 1947 review: “Theoretically at least, it may be possible to give the patient with MG too much neostigmine. I would agree with Viets, however, that in crises this is an error that is less

How electric fish became sources of acetylcholine receptor.

The purpose of this communication is to describe the historical steps by which fish electric organs were eventually determined to be modified motor endplates and therefore a plentiful source of acetylcholine receptor. A brief description of the early history of electric fish concerned with the nature of the discharge will provide the background for studies of the anatomy, embryology, and physiology of electric organs in the nineteenth century that suggested that electric organs were derived from modified muscles. In the twentieth century, transmission between nerve and electric organ was shown to be cholinergic, and because of their size and abundant cholinergic nerve supply, the electric organs of Torpedo and Electrophorus were chosen by biochemists and molecular biologists as possible rich sources of acetylcholine receptor.

Autoimmune neuromuscular disease induced by a preparation of choline acetyltransferase

Abstract An apparent fatal autoimmune disease was induced in guinea pigs by injection of a preparation of choline acetyltransferase in complete Freunds adjuvant. The animals probably died from respiratory failure based on the evidence from clinical, histological, and histochemical examination. At autopsy the pathogenic lesions were located at the neuromuscular junctions and near the nerves where choline actyltransferase was found. It is further proposed that this is a presynaptic autoimmune neuromuscular disease based on the finding of numerous target, as well as targetoid, fibers in muscle after histochemical staining. There was also denervation shown by electromyographic measurements in the form of positive sharp waves as well as fibrillation discharges.

The role of Herman Hoppe of Cincinnati in the initial clinical recognition of myasthenia gravis.

One of the earliest papers describing a case of what came to be known as myasthenia gravis was written in 1892 in the German language by an American, Herman Hoppe, who at the time was an assistant in the Berlin polyclinic of the prominent German neurologist, Hermann Oppenheim. At Oppenheim’s instigation, Hoppe published the pathology of a case that Oppenheim had diagnosed during life; he collected all the reported similar cases and tried to establish a symptom-complex, for which he was given credit in Oppenheim’s great neurology textbook of 1894. Upon his return to Cincinnati, Ohio, Hoppe’s European experience qualified him as a specialist in nervous and mental diseases. His private practice of “neuropsychiatry” was his main occupation, but he also volunteered to teach as Professor of Nervous and Mental Diseases at the University of Cincinnati. In 1901 Oppenheim published the first monograph about what he called “ Die Myasthenische Paralyse (Bulbarparalyse ohne anatomischen Befund) ”, summarizing 60 cases described in the medical literature up to that time. Hoppe, on the other hand, wrote on myasthenia gravis only once again, a review article in 1914 in a Cincinnati weekly, giving Oppenheim credit for the establishment of the disease as a clinical entity.