Daniel B. Drachman

Neuromuscular Junction in Myasthenia Gravis: Decreased Acetylcholine Receptors

The number of acetylcholine receptors was determined in the neuromuscular junctions of eight patients with typical myasthenia gravis and in five controls, by means of 1251-labeled α-bungarotoxin binding. The junctional acetylcholine receptors were reduced in the myasthenic muscles as compared with the controls. This reduction in receptors may account for the defect in neuromuscular transmission in myasthenia gravis.

Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice

To study the role of humoral factors in the pathogenesis of myasthenia gravis, we employed passive transfer of human serum fractions to mice. Immunoglobulins from 16 patients with myasthenia gravis were injected into mice daily for one to 14 days. Typical myasthenic features of reduction in amplitude of miniature end-plate potentials (mean change more than 50 per cent, P less than 0.005) or reduction in acetylcholine receptors at neuromuscular junctions (mean change more than 50 per cent, P less than 0.005) (or both) were produced by immunoglobulin from 15 of the 16 patients. Some mice showed weakness or decremental responses to repetitive nerve stimulation as well. The active fraction was identified as IgG by three different purification methods. Its effect was enhanced by the third component (C3) of the complement system, but the fifth component (C5) had no effect. These data suggest that the pathogenesis of myasthenia gravis often involves and antibody-mediated autoimmune attack on the acetylcholine receptors of the neuromuscular junction.

Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS.

The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate‐mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase‐2 in treating the disease. Cyclooxygenase‐2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase‐2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase‐2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase‐2 inhibition may benefit ALS patients. Ann Neurol 2002

Trial of celecoxib in amyotrophic lateral sclerosis

To determine whether chronic treatment with celecoxib, a cyclooxygenase‐2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS).

Effects of aging on nerve sprouting and regeneration

Abstract We examined the effects of aging on nerve terminal sprouting and regeneration in the peripheral nervous system. Motor end-plates were demonstrated in rat soleus muscles by means of a cholinesterase-silver stain which permitted measurement of end-plate length and nerve terminal branching. Terminal sprouting was elicited by “pharmacological denervation” brough about by botulinum toxin treatment. In the youngest (2-month-old) animals, the end-plates were small, and the terminals had simple branch patterns. Botulinum toxin treatment elicited a striking increase in end-plate length and terminal arborization. In the older (10- and 18-month-old) animals, the end-plate length was greater, and nerve terminal branching patterns were more complex. Botulinum toxin elicited a sprouting response that was less marked than in the youngest animals. In the oldest (28-month-old) animals, the end-plates were shorter and the terminals less complex. Botulinum failed to elicit any significant sprouting response. Regeneration of motor and sensory axons after a crush lesion of the sciatic nerve was measured using radiolabeled proteins carried by axonal transport as a marker of axonal outgrowth. Our results showed that the average rate of regeneration slowed with increasing age, although a small population of axons continued to regenerate rapidly regardless of age. Evidence implicating inherent defects in the ability of nerves to sprout and regenerate with increasing age is presented. Our findings in the peripheral nervous system may shed light on similar functional changes occurring in the central nervous system.

Mycophenolate mofetil: A safe and promising immunosuppressant in neuromuscular diseases

The authors report the use mycophenolate mofetil (MM) in the treatment of neuromuscular diseases. Thirty-eight patients (32 with MG, three with inflammatory myopathy, and three with chronic acquired demyelinating neuropathy) were treated with MM for an average duration of 12 months. All patients tolerated MM without major side effects. Twenty-four patients improved either in their functional status or in their ability to reduce corticosteroid dose. Mean time to improvement was 5 months.

Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment.

Abstract ACTH and adrenal corticosteroids are effective in the treatment of myasthenia gravis. However, increased weakness may occur early in treatment, posing a considerable risk for the patient. To determine whether the early weakening could be avoided by use of a gradually increasing dosage schedule, we started treatment with 25 mg of prednisone on alternate days, and gradually increased the dose to 100 mg on alternate days. Anticholinesterase medication was maintained. No increased weakness developed in any of 12 patients on this regimen. Seven patients had good to excellent improvement in strength, returning to normal activity. Four patients had moderate improvement, and one did not benefit. The greater safety of this treatment regimen extends the usefulness of steroid therapy to a larger group of myasthenic patients than would otherwise be feasible. (N Engl J Med 290:81–84, 1974)

Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis

We report the presence of serum antibodies directed against GM1 ganglioside, a defined neural antigen, in many patients with amyotrophic lateral sclerosis (ALS). We examined serum from a series of patients with well-documented clinical diagnoses. Serum antibodies to GM1 ganglioside were measured using ELIS A assays. Our results showed that polyclonal IgM anti-GM1 antibodies were present at dilutions of 1:25 to 1:2,000 in 42 of 74 (57%) patients with ALS. The anti-GM1 antibodies were especially frequent in patients with prominent lower motor neuron signs (41/59; 69%). Few normal controls (2/23) and motor-sensory neuropathy patients (3/27) had similar antibodies. Anti-GM1 antibodies did occur in patients with nonneural autoimmune disorders. However, the anti-GM1 antibodies in these patients tended to differ from those in ALS based on an analysis of their light chain types. Further examination of the role and spectrum of serum antiganglioside antibody activity in motor neuron syndromes is warranted.

Head drop and camptocormia

The spectrum of bent spine disorders Head ptosis (drop) results from weakness of the neck extensor, or increased tone of the flexor muscles. It is characterised by marked anterior curvature or angulation of the cervical spine and is associated with various neuromuscular (table 1) and extrapyramidal disorders.12–15 Camptocormia or the bent spine syndrome was first described in hysterical soldiers in 1915 by the French neurologist Souques.16 Typically there is marked anterior curvature of the thoracolumbar spine. In some patients the spine is angulated forward, the arms propped against the thigh for support. More cases, all among soldiers, were reported during the first and second world wars. These patients responded well to psychotherapy. Recently camptocormia arising as a result of weakness or abnormality in the tone of the paraspinal muscles has been described (table 2). In contrast with other skeletal disorders of the spine such as kyphosis, the deformity in head ptosis and camptocormia is not fixed and is corrected by passive extension or lying in the supine position. It is not possible to straighten the neck or back voluntarily. The evaluation of these disorders can indeed be challenging and often no definite diagnosis is made, as illustrated by four cases of head ptosis and camptocormia seen by us at the Johns Hopkins Hospital. View this table: Table 1 Neuromuscular causes for head ptosis View this table: Table 2 Causes of camptocormia An 80 year old man developed head ptosis insidiously over a period of few weeks. A week before this he had an upper respiratory tract infection and also experienced transient sharp pain over the left and then the right shoulder. He had no diplopia, dysarthria, dysphagia, limb weakness, or fatiguability. Examination showed severe neck extensor weakness, Medical Research Council (MRC) grade 2. Muscle strength was normal in all other cranial, proximal, and distal limb muscles. Serum …

Treatment of refractory myasthenia: “Rebooting” with high-dose cyclophosphamide

Patients with myasthenia gravis (MG) who do not respond to conventional immunotherapeutic agents, or cannot tolerate their side effects, are considered “refractory.” Ablation of the immune system followed by bone marrow transplant has been shown to cure experimental MG in rats. It is now known that immunoablative treatment with high‐dose cyclophosphamide does not damage hematopoietic “stem cells,” permitting repopulation of the immune system without bone marrow transplant. Recent evidence indicates that this treatment can induce durable remissions in autoimmune diseases. We treated three myasthenic patients, for whom treatment with thymectomy, plasmapheresis, and conventional immunotherapeutic agents failed, by using high‐dose cyclophosphamide (50mg/kg/day intravenously for 4 days) followed by granulocyte colony stimulating factor. All three patients tolerated the treatment well and have had marked improvement in myasthenic weakness, permitting reduction of immunosuppressive medication to minimal levels. Acetylcholine receptor (AChR) antibody levels decreased in two AChR antibody–positive patients, and anti–MuSK antibody levels decreased in one “AChR antibody–negative” patient. The patients have been followed for up to 3.5 years, with no recurrence of symptoms. High‐dose cyclophosphamide treatment appears to be an effective and safe treatment for selected patients with refractory MG. Further follow‐up of these and additional patients will be needed to determine whether the benefit is durable.