Book Review

Myasthenia Gravis: An Illustrated History

N Engl J Med 2003; 348:181-182January 9, 2003

Article

Myasthenia Gravis: An Illustrated History
By John C. Keesey. 113 pp., illustrated. Roseville, Calif., Publishers Design Group, 2002. (Distributed by the Myasthenia Gravis Foundation of America, Los Angeles.) $49.95. ISBN: 1-929170-04-1

The trajectory of discovery in science and medicine is rarely linear. On the contrary, it is nearly always erratic, with peaks of insight, troughs of wrong hypotheses, midcourse corrections, and ultimate enlightenment. In this profusely illustrated coffee-table book, John Keesey takes us on a journey through the history of myasthenia gravis, from the perceptive 17th-century clinical description of a woman afflicted with a “spurious palsy” to today's sophisticated molecular level of understanding.

Why should anyone other than a patient with myasthenia, a neurologist, or a researcher directly involved in work with myasthenia gravis be interested in this book, or in myasthenia gravis, for that matter? Although myasthenia gravis is admittedly uncommon, it involves many of the most fascinating biologic and pathologic processes in the fields of neurology, neurobiology, pathology, pharmacology, toxicology, and immunology. Indeed, acquired myasthenia gravis was the first clearly identified receptor disease and is the best understood of all human autoimmune diseases. In this beautifully designed and illustrated book, Keesey clearly explains how each of these subjects contributed to our present concepts of myasthenia gravis.

The initial recognition of myasthenia gravis was an intermittent process. Keesey attributes the earliest bona fide report of myasthenia gravis to Wilhelm Erb of Heidelberg, who presented three cases of “a new probably bulbar symptom-complex” in 1879. Erb distinguished these cases from “progressive bulbar palsy” (possibly bulbar-onset amyotrophic lateral sclerosis) because they did not follow the inexorable downhill course of bulbar palsy. Sixteen years later, Friedrich Jolly described the electrophysiological feature of myasthenic fatigue: the fading response of muscles to prolonged electrical stimulation. This painful examination was called the “Jolly test,” or, colloquially among neurology residents, the “not-so-jolly test.” Jolly also coined the term “myasthenia gravis pseudoparalytica,” the first two words of which have persisted to this day, despite its mixed etymology, which combines Greek (“myo,” meaning muscle, and “asthenia,” meaning weakness) and Latin (“gravis,” meaning serious). Early cases that were passed over initially have subsequently been unearthed, and it is my belief that the description by the great physiologist Sir Thomas Willis, in 1672, is probably the first authentic case in the medical literature.

During the 19th and early 20th centuries, autopsy studies revealed abnormalities of the thymus gland in many cases. These are now known to be related to the immune abnormality of myasthenia gravis. Muscle-like cells were also found in thymus glands, and the expression of acetylcholine receptors on their surface membranes, described much later, may play an important part in triggering myasthenia gravis. Mary Walker, a registrar at St. Alfege's Hospital in 1934, reported at that time that injection of the cholinesterase inhibitor physostigmine produced striking improvement in the muscle strength of a patient with myasthenia. This remarkable result, which was hailed as the “Miracle of St. Alfege's Hospital,” not only implicated the neuromuscular junction in myasthenia gravis but also provided the most effective treatment available for more than three decades. Keesey's admiration for Walker is evident in the number of pages devoted to her.

Once the neuromuscular junction had been identified as the site of the abnormality in myasthenia gravis, electrophysiological studies were carried out by several investigators to attempt to solve the riddle of whether the defect was presynaptic (at the motor-nerve ending) or postsynaptic (at the level of the muscle cell), but the results of these indirect tests were conflicting and controversial. Modern understanding of myasthenia gravis owes a great debt to the seminal studies of the Taiwanese pharmacologists C.-C. Chang, C.-Y. Lee, and L.F. Tseng. They found that the poisonous venoms of elapid snakes — cobras and kraits — contain toxins that bind with exquisite specificity to acetylcholine receptors. Using these toxins, a group at Johns Hopkins settled the presynaptic-versus-postsynaptic controversy by showing that acetylcholine receptors at neuromuscular junctions were reduced in myasthenia gravis and that a reduction of available acetylcholine receptors mimicked the characteristic weakness and fatigue of myasthenia gravis. Virtually simultaneously, workers at the Salk Institute immunized rabbits with acetylcholine receptors purified from electric eels' electric organs (which are homologous to neuromuscular junctions) and found that weakness and fatigue in the immunized rabbits responded dramatically to cholinesterase inhibitors. This finding was consistent with the idea that myasthenia gravis might be due to an autoimmune response, as postulated originally by John Simpson in 1960, and it further implicated acetylcholine receptors as the target of the abnormality. Antibodies to acetylcholine receptors, identified in serum samples from patients with myasthenia, caused typical features of the disease when injected into mice. The pathogenic role of these antibodies was confirmed by the improvement of patients with myasthenia after depletion of the antibodies by plasma exchange.

Since the time of these now-classic discoveries, where is the field of myasthenia gravis moving? Much important work has been done on the treatment of myasthenia gravis by a variety of immunosuppressive methods. Indeed, today, virtually all patients with myasthenia can be treated and lead fully functional lives. A chapter on the development of treatment for myasthenia gravis would have been a welcome addition to this book. Another important advance has been the description of several disorders that mimic myasthenia gravis. These are nicely summarized in Keesey's book. Among them, the Lambert–Eaton syndrome is a fascinating presynaptic counterpart. Like myasthenia gravis, it is due to an autoantibody-mediated attack at the neuromuscular junction. However, the targets of the antibodies in the Lambert–Eaton syndrome are the calcium channels at the nerve terminal. Disruption of these channels prevents the entry of calcium, triggering the release of the neurotransmitter acetylcholine. There are also genetic mimics of myasthenia gravis. Virtually every part of the neuromuscular junction is subject to genetic errors, and many of these “congenital myasthenic syndromes” have been elegantly described by Engel and colleagues at the Mayo Clinic.

Daniel B. Drachman, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21287-7519
dandrac@aol.com