Alpha-bungarotoxin binding to the myotome and choline acetyltransferase activity in the rabbit embryo.

We have previously found incomplete sarcomeres and acetylcholinesterase activity in the myoblasts of the myotome of the rabbit at day 13 of gestation. We now report that an acetylcholine (ACh)-synthesizing enzyme and the nicotinic receptor are present at this stage as well. A study of the myotome using [125I]alpha-bungarotoxin shows that the mononucleated myoblasts have alpha-bungarotoxin binding sites before they migrate away to form multinucleated myotubes. Choline acetylcholinesterase activity and/or a different ACh-synthesizing enzyme are found at early stages of development, even before the spinal nerve has formed. An ACh-synthesizing enzyme is present in the notochord, a neural tube-dorsal root ganglion preparation, as well as in rows of myotomes separated from the latter preparation. Assays of isolated myotomes with very little adherent mesenchyme indicate that the enzyme is located either within the myotome or in its immediate vicinity. Cholinergic components, therefore, are associated with the mononucleated myoblasts of the myotome before they fuse to form myotubes and before they receive their permanent innervation.

Severe dystonia and myoglobinuria.

Myoglobinuria may follow extreme muscular exertion or disorders that cause muscle necrosis. Dystonia has not been implicated previously. We studied an 8-year-old boy of non-Jewish, Mexican-American descent with autosomal-dominant dystonia musculorum deformans who developed rapidly progressive and severe generalized dystonia, hyperpyrexia, myoglobinuria, and renal failure. Curarization was required. Transient improvement was achieved with tetrabenazine and baclofen, but bilateral thalamotomy was then performed. Patients with severe dystonia should be observed for evidence of myoglobinuria.

Myasthenia gravis: determinants for independent ventilation after transsternal thymectomy.

We evaluated the respiratory function of 32 patients with myasthenia gravis who had transsternal thymectomy. Preoperative clinical, pulmonary function, and respiratory muscle pressure data were submitted to stepwise logistic regression analysis to identify preoperative factors that correlated with duration of supported ventilation after surgery. Ten patients (31%) had postoperative supported ventilation for more than 3 days. The duration of ventilatory support correlated most closely with maximal static expiratory pressure (r = 0.714, p less than 0.001). Expiratory weakness, by reducing cough efficacy, seems to be the main determinant that predicts need for longer postoperative supported ventilation.

Isolation of influenza virus from muscle in myoglobinuric polymyositis.

We report the first isolation of influenza virus from muscle in a man with myoglobinuria and acute polymyositis. Influenza virus was isolated from cultures of Madin Darby bovine kidney and primary rhesus monkey kidney cells inoculated with muscle homogenates in the presence of trypsin; the virus was identified by neutralization and hemagglutination inhibition studies using influenza B/Lee antiserum. Viral plaque assay was performed with Madin Darby canine cells. Viral antigen was also detected by specific immunofluorescence in muscle, and myxovirus-like particles were seen in subsarcolemmal vacuoles by electronmicroscopy. The pathologic findings were similar to those of childhood dermatomyositis, except for a large proportion of necrotic muscle fibers. The evidence suggests that the pathogenesis of influenzal polymyositis in this patient involved direct viral infection of muscle.

Heterozygous C2-deficiency and myasthenia gravis.

Complement deficiency states in myasthenia gravis (MG) have not been reported previously. We describe a 19-year-old woman with typical MG and heterozygous C2 deficiency, along with HLA typing of the patient and her immediate family.

Penicillamine-induced myasthenia gravis: effects of penicillamine on acetylcholine receptor.

Autoimmune diseases, including myasthenia gravis, occur in patients treated with D-penicillamine. Because D-penicillamine might induce autoantibodies by the mechanism of antigenic alteration, we studied the reaction of D-penicillamine with purified acetylcholine receptor from Torpedo californica. We found that brief exposure to D-penicillamine resulted in its covalent attachment to two receptor subunits, alpha (40,000 daltons) and gamma (59,000 daltons), presumably by reduction and formation of mixed disulfides. Furthermore, D-penicillamine treatment resulted in a dramatic modification of the equilibrium acetylcholine binding properties of both purified receptor and receptor-rich membrane fragments.

HLA typing and Guillain-Barré syndrome.

In an effort to determine if there might be an association between Guillain-Barré syndrome and specific antigens of the HLA system, 18 patients with Guillain-Barré syndrome were typed for HLA-A, B, and D antigens. No statistically significant relationship was established by this study.

Seronegative myasthenia gravis.

Of 221 patients with myasthenia gravis, 18.5% had no detectable antibodies to acetylcholine receptor. Seven of 14 patients (50%) with only ocular symptoms for more than 2 years were seronegative, and 25 of 145 (17%) patients with generalized myasthenia were seronegative. The clinical characteristics of seronegative patients did not differ from patients with high antibody titers. No seronegative patient had a thymoma, but that difference did not reach statistical significance. Lack of serum antibodies did not preclude favorable response to thymectomy or plasmapheresis.

Complement-fixing antiperipheral nerve myelin antibodies in patients with inflammatory polyneuritis and with polyneuropathy and paraproteinemia.

Serum from patients with peripheral neuropathies was tested for antiperipheral nerve myelin antibodies by complement fixation. Antibody activity was detected in 5 of 20 patients with acute or chronic remitting polyneuritis and in 4 of 20 patients with polyneuropathy and paraproteinemia but not in patients with other types of neuropathy, neurologic disease, or immunologic disease. In three patients with IgM paraproteinemia, the complement-fixing activity resided in the IgM fraction; in one patient with chronic inflammatory polyneuritis, antibody activity resided in the IgG fraction. In the inflammatory polyneuropathies, antibody titers did not always correlate with disease activity. Sera from patients with remitting polyneuropathies reacted with either human or rabbit peripheral nerve myelin, but sera from patients with paraproteinemia reacted only with human myelin.

Potentially fatal cardiac dysrhythmia and hyperkalemic periodic paralysis.

An 11-year-old boy was evaluated for mild periodic muscular weakness exacerbated on separate occasions by disopyramide phosphate and procainamide. He and his mother both had bidirectional ventricular tachydysrhythmia (BVT), short stature, microcephaly, and clinodactyly. The mother, but not the child, had lingual myotonia. The two antiarrhythmic drugs worsened the muscular weakness without benefiting the cardiac dysrhythmia. Potassium loading produced skeletal muscle weakness and transient conversion of the BVT to normal sinus rhythm. Hypokalemia aggravated the BVT without causing weakness. Acetazolamide had no effect. The patient suffered a nonfatal cardiac arrest after several days of increased carbohydrate intake. Imipramine controlled the dysrhythmia without inducing weakness. Periodic paralysis should be considered as the diagnosis in children with BVT, a potentially fatal condition.

"Maximal" thymectomy for myasthenia gravis. Results.

Thymectomy has been shown to be effective in the treatment of myasthenia gravis. The logical goal of operation has been complete removal of the thymus, but there has been controversy about the surgical technique and its relation to results. Surgical-anatomic studies have shown gross and microscopic thymus widely distributed in the neck and mediastinum. We believe that an en bloc transcervical-transsternal "maximal" thymectomy is required to remove all thymic tissue predictably. Ninety-five patients with generalized myasthenia gravis underwent "maximal" thymectomy consecutively between 1977 and 1985 and were evaluated 6 months to 89 months after operation. In Group A (N = 72), myasthenia gravis without thymoma, the uncorrected data revealed that 96% (69) had benefited from operation: 79% (57) had no symptoms; 46% (33) were in remission; 33% (24) were symptom free when receiving minimal doses of pyridostigmine; and none were worse. Life table analysis yielded a remission rate of 81% at 89 months. In group B (N = 8), myasthenia gravis without thymoma for which patients underwent reexploration for incapacitating weakness after earlier transcervical or transsternal operations, residual thymus was found in all. One patient was in remission, two were symptom free when receiving medication, one was unchanged, and none were worse. In group C (N 15), myasthenia gravis and thymoma, two patients were in remission and nine were symptom free when receiving medication. Two patients in this group died 2 and 4 years postoperatively in crisis. Response to thymectomy in group A was greater in patients with mild myasthenia gravis and may have been better in patients who had symptoms for less than 60 months preoperatively, but the response did not depend on age, sex, presence or absence of thymic hyperplasia or involution, or titers of acetylcholine receptor antibodies. The response to thymectomy in group B was striking but slower than in group A, perhaps because symptoms were more severe and of longer duration. The response in group C was also less good than in group A and proportionately fewer benefited. These results support the recommendation for thymectomy in the treatment of patients with generalized myasthenia gravis and indicate the desirability of a maximal procedure. For persistent or recurrent severe symptoms after previous transcervical or submaximal transsternal resections, reoperation by this technique is also recommended.

Thymic abnormalities: antigen or antibody? Response to thymectomy in myasthenia gravis.

The therapeutic value of thymectomy for myasthenia is still questioned although it retains an important place among management modalities that strive for sustained remission. Questions derive from uncertainty as to appropriate timing, variable extent of resection and quantitation of response. Forty-seven patients, followed one to seven years, underwent an extended transsternal or combined transcervical-transsternal procedure with anterior mediastinal exenteration. Sixteen have been in complete remission from six months to six years, four are asymptomatic on occasional pyridostigmine and eight are significantly improved. Evaluation of thymic pathology (hyperplasic, involuted areas, and thymoma) included a search for thymic myoid cells by fluorescence cytochemistry. Antibodies to acetylcholine receptor present in 38 of 43, decreased post-operatively to normal in four, by 50% to 80% in 14, by 20 to 50% in three and were unchanged in 14. Most remissions occurred in young women with noninvoluted hyperplastic glands and variably high anti-AChR titers which dropped toward normal in seven of 15. These results encourage us to utilize this procedure routinely.

Antibodies to acetylcholine receptors in rabbits: immunochemical and electrophysiological studies.

Acetylcholine receptors (AChR), purified from electric eel and Torpedo by affinity chromatography using a synthetic quaternary ammonium ligand, bound 10 nmole alpha-bungarotoxin (alpha-BuTx) per mg of protein and demonstrated a common subunit. Rabbits, immunized with either eel or Torpedo/AChR, developed flaccid paralysis barely altered by anticholinesterases and died 48 hours after the first sign of paralysis. In paralyzed animals, repetitive stimulation at low rates induced a 50% to 90% decrement of evoked potentials, temporarily reversed by edrophonium. Extracellular and introcellular MEPP amplitudes were 40% to 50% of controls. Serum and isolated IgG formed single immunoprecipitin lines against the antigens. AChR-antibody complexes did not bind alpha-BuTx, whereas alpha-BuTx-AChR complexes bound antibody if the antibody was specific for that AChR. Torpedo and eel AChR showed partial idenity with both antisera. Rat diaphragms and eel electroplax incubated with antisera to Torpedo and eel AChR showed a 50%-60% reduction in carbamylcholine depolarization. These studies demonstrate differences between eel and Torpedo AChR induce a block in neuromuscular transmission in rabbits with features of myasthenia gravis.

A rational approach to total thymectomy in the treatment of myasthenia gravis.

Thymectomy is important in the treatment of myasthenia gravis. Total removal of the gland is considered indicated. Although median sternotomy has been the accepted surgical procedure, the transcervical approach has been advocated as a safer method of achieving total thymectomy. A surgical-anatomical study of the thymus was made in 22 patients. A high incidence of surgically important variations in thymic anatomy was found in the neck and in the mediastinum. We believe wide exposure by way of median sternotomy with direct vision is required to remove all of the extracapsular mediastinal thymus in many patients, and good cervical exposure is required to remove the anomalous tissue in the neck. If a total thymectomy is to be achieved, we recommend a median sternotomy and a cervical incision, using the meticulous dissection described.

Myasthenia gravis in children: analysis of 18 patients.

Myasthenia gravis (MG) in childhood is rare comprising 10 to 20 % of all myasthenic patients. We studied 18 patients with MG whose first symptoms started from 1 to 12 years of age, followed at the Department of Neurology of the UNIFESP-EPM, from January 1983 to August 1997. There were 10 girls and 8 boys (1.2:1). Eleven patients (61%) presented moderate or severe generalized disease and 4 (22%) had at least one myasthenic crisis. EMG with supramaximal repetitive nerve stimulation was diagnostic in 8 (47%) out of 17 patients, and chest CT was normal in 14 patients. Seropositivity to acetylcholine receptor antibodies was found in 81.6% (9 out of 11 tested) and the levels had no relation to clinical severity. Nine out of 16 patients (56%) worsened with pyridostigmine alone and were treated with prednisone. Four out of those nine continued worsening despite steroids and were subjected to thymectomy (all showed thymic lymphoid follicular hyperplasia). Three patients (75%) improved markedly after thymectomy and one (25%) worsened, eventually getting better with intravenous immunoglobulin and oral azathioprine. MG treatment, using all resources available, has to be individualized for each child.