Richard F. Mayer

Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy

Fifteen patients with chronic inflammatory demyelinating neuropathy (CIDP) were treated with pulse intravenous cyclophosphamide (IVCY) monthly for up to 6 months. Eleven patients reached a complete remission; only one patient worsened. Complications included nausea, vomiting, anemia, and hair loss. This case series suggests that monthly IVCY is beneficial in the treatment of CIDP and warrants a controlled study.

Physiological alterations of motor units in hemiplegia

Isometric contractions of single motor units in the first dorsal interosseous muscle were recorded with an intramuscular microstimulation technique in patients with short- or long-term hemiplegia and compared with controls. In the hemiplegic patients motor units could be classified as in controls, utilizing twitch contraction time and fatigue sensitivity, as FF (fast fatigable), FR (fast fatigue resistant) and S (slow fatigable). The mean twitch contraction time of fast-twitch but not slow-twitch units was slightly prolonged in patients with spastic hemiplegia and motor units, especially type S, tended to generate larger twitch tensions. A fourth type of motor unit, characterized by slow-twitch contraction times and increased fatigability (SF units), was recorded in long-term hemiplegia. The data demonstrate that during long-term spastic hemiplegia in man some motor units develop increased fatigability and prolonged-twitch contraction times, reflecting the dynamic properties of muscle.

An electrophysiological and morphological study of the neuromuscular junction in patients with myasthenia gravis

Abstract Three types of neuromuscular junction were found in the surface fibers of internal and external intercostal muscles from patients with myasthenia gravis. One group (about 25% of the fibers) responded to nerve stimulation with an endplate potential (EPP) large enough to trigger an action potential and was associated with relatively mild morphological alterations in the postjunctional membrane. A second group had EPPs of markedly reduced amplitude and was associated with grossly altered postjunctional membrane structure and slight to moderate nerve degeneration. The spontaneous miniature endplate potentials (MEPPs) found in this group were markedly reduced in amplitude and frequency. In the third group of surface fibers neither EPPs nor spontaneous MEPPs were recorded at the endplate region. These endplates exhibited gross alteration of the cleft and folds and their nerves were absent or degenerating. Microiontophoretic application of acetylcholine (ACh) at the endplate region of all three groups of surface fibers disclosed low values of ACh sensitivity at the endplate region. No increase in extrajunctional sensitivity to ACh was detected in the myasthenic muscles. There was no significant difference in membrane potential between normal and myasthenic muscles. Electron microscopic analysis of fibers from each group revealed a continuum of alterations in the synaptic folds and the sequential destruction of nerve terminals. The appearance of “fuzzycoated” vesicular remnants of degenerating folds and the invasion of the endplate region by a variety of leucocytes suggest the occurrence of an immune response. Thus, in myasthenia gravis, alterations of the synaptic folds are associated with a decrease in ACh receptor density, thereby accounting for the marked reduction in the membrane response to endogenous or microiontophoretically-applied ACh at the endplate region.

Lysosomes and disuse atrophy of skeletal muscle.

The specific activities of the acid hydrolases β-glucosidase, β-galactosidase, β-N-acetylhexosaminidase, arylsulfatase, and acid phosphatase have been measured during the time course of disuse atrophy of rat gastrocnemius muscles. These enzymes are considered to be lysosomal in origin. The specific activity of β-glucosidase increased to 180% of the control level by the second day following the production of disuse, and to 400% of the control level by the 12th day. The specific activities of β-galactosidase, β-N-acetylhexosaminidase, arylsulfatase, and acid phosphatase were increased markedly by the 12th day. All enzyme activities returned to control levels by the 15th day. The early increase in the activity of β-glucosidase indicates that lysosomal enzymes may an important role in the etiology of disuse atrophy.

Autonomic dysfunction in Lambert-Eaton myasthenic syndrome

Autonomic symptoms were observed in 6 patients with clinically and electrophysiologically documented Lambert-Eaton myasthenic syndrome (LEMS). Of the 6 patients, 2 were extensively investigated in the laboratory. In contrast to previous reports which recognized only cholinergic dysautonomia, abnormalities of sympathetic as well as parasympathetic function were evident. Of the 6 patients, 4 had small cell lung cancer (SCLC). In one male patient, chemotherapy for SCLC resulted in an early improvement of autonomic dysfunction and the electrophysiological defect, documenting simultaneous regression of dysautonomia and LEMS. In addition, the patients with SCLC and LEMS had a survival thus far of 3-13 years suggesting that a subgroup of SCLC patients have a better prognosis.

Nerve conduction studies in the Twitcher mouse (murine globoid cell leukodystrophy)

Progression of the neuropathy in the Twitcher mouse (twi-C57BL/6J), an animal model of globoid cell leukodystrophy, was assessed with serial motor nerve conduction studies from just after birth until near death (day 45) and after hematopoietic cell transplantation (HCT). Under ether anesthesia, the tibial nerve was stimulated percutaneously at the sacral notch and at the ankle, and recordings were made from plantar foot muscles. Motor conduction velocity (MCV), distal latency, amplitude, duration and number of phases of compound muscle action potentials on proximal (pCMAP) and distal (dCMAP) stimulation were measured. In 15-19 day-old Twitcher, despite the absence of motor signs, MCV was significantly reduced, 12.8 +/- 2.8 (10) m/s (M +/- SD, No. of recordings), compared with unaffected siblings, 18.1 +/- 2.6 (21) m/s (P less than 0.01). The ratio of pCMAP to dCMAP amplitudes was reduced in the Twitcher, 0.39 +/- 0.13 (10), compared with controls 0.72 +/- 0.17 (21) and the ratio of pCMAP to dCMAP phases was increased (2.8 +/- 0.8 (10) vs 1.0 +/- 0.2 (21), P less than 0.01 for all). As neurologic signs progressed by 35-39 days, MCV became slower, 5.8 +/- 1.0 (11) m/s, pCMAP and dCMAP became smaller, but the ratio of pCMAP to dCMAP amplitudes in the Twitcher (0.55 +/- 0.36, 11) was similar to controls (0.71 +/- 1.0, 20) as was the ratio of pCMAP to dCMAP phases (1.0 +/- 0.4 vs 1.0 +/- 0.1). These results suggest that there is diffuse non-uniform slowing of nerve conduction with block especially in proximal nerve fibers initially. With HCT, mean MCV remained slow (6.7 +/- 1.2 (18) m/s, vs 34.5 +/- 3.9 (12) m/s) but motor function persisted.

EFFECTS OF NORMAL AND MYASTHENIC SERUM FACTORS ON INNERVATED AND CHRONICALLY DENERVATED MAMMALIAN MUSCLES

Myasthenia gravis (MG) is a disease that is characterized by muscle weakness that becomes particularly apparent during repetitive motor unit activity. The mechanism underlying the progressive inability of the muscle to respond to repetitive neuronal discharge is still controversial. There is evidence that suggests that the amount of acetylcholine (ACh) released is insufficient and this insufficiency eventually results in the blockade of muscle contraction upon repetitive stimu1ation.l Using [1251]-a-bungarotoxin, Fambrough and associates have found that the density of cholinergic receptors in the postjunctional region was markedly reduced in muscles from myasthenic patients. This postsynaptic defect in receptor density was proposed to be of significant importance in explaining the decremental responses with repetitive stimulation. Recent studies suggest that an immunological defect related to the thymus may exist in myasthenic patients.3 The hypothesis of an immunological basis for myasthenia gravis was further supported by recent studies which demonstrated that sera and immunoglobulin G (IgG) fractions from diseased patients inhibited a-bungarotoxin (a-BuTx) binding to isolated extrajunctional receptor^.^ These findings prompted us to examine the effect of sera and immunoglobulin factors on membrane properties utilizing electrophysiological techniques. The results indicate that sera from myasthenic. patients do not directly influence the physiological activity of junctional or extrajunctional ACh receptors.

Contractile properties of rat fast-twitch skeletal muscle during reinnervation: Effects of testosterone and castration

The isometric contractile properties of skeletal muscle were examined after nerve crush to establish the temporal sequence of recovery during reinnervation of normal, castrated, and testosterone-treated rats. Extensor digitorum longus muscles of male rats were studied in vivo 8 to 21 days after crushing the peroneal nerve 1 cm from the muscle. The earliest signs of functional reinnervation in normal animals were observed 8 to 9 days after nerve crush when faint muscle twitches with markedly prolonged twitch contraction times were recorded. By days 10 and 11, twitch tension was 9 to 20% of control, twitch contraction time was 149 to 183% of control, and tetanic tension was 4 to 9% of control values. The optimal frequency of stimulation was 58 to 64 Hz, the twitch:tetanus ratio was three times control values, and little or no posttetanic potentiation of twitch tension was observed. During the next 9 days there was a gradual return of all experimentally measured contractile properties toward control values; the relative rate of return was twitch tension greater than twitch contraction time greater than twitch:tetanus ratio greater than tetanic tension greater than optimal frequency of stimulation greater than posttetanic potentiation. Neither testosterone nor castration significantly altered either the rate or extent of functional reinnervation 8 to 21 days after nerve crush (P greater than 0.05). During this period the twitch:tetanus ratio for any given animal was highly correlated (r = 0.83, P less than 0.001) with the extent of functional recovery of neurally evoked muscle tension and was determined to be the most reliable index of the degree of muscle reinnervation. These data provide valuable baseline information for future studies of reinnervation of skeletal muscle.

Predictable recovery from myasthenia gravis crisis with plasma exchange: thirty-six cases and review of current management.

Adult, acquired, idiopathic, autoimmune myasthenia gravis has a well‐characterized IgG anti‐acetylcholine striated‐muscle receptor antibody. Removal by plasma exchange is effective, established therapy to augment anti‐cholinesterase and immunosuppressive therapy and is the treatment of choice for myasthenia gravis crisis. We report 36 consecutive patients referred and accepted for plasma exchange, 32 of whom were in or entering myasthenia crisis, over a 10 year period. An average of 7.8 (range 1 to 16) plasma exchange procedures were done, with uniform, significant improvement, including extubation of 13 in myasthenic crisis and discharge from hospital in all. We conclude that this is the best treatment for myasthenia gravis crisis in hospital. From recent cases, most, if not all, crises can be prevented by IVIgG or plasma exchange as out‐patients with use of corticosteroid and or azathioprine. J. Clin. Apheresis 14:1–8, 1999.

Assessment of cellular and humoral immunity of myasthenics.

A close association of autoimmune diseases or autoimmune phenomena in myasthenia gravis is well known. A comprehensive immunological study of 22 patients with myasthenia gravis showed that changes in the immune system mainly involve the thymus-derived lymphocytes (T cells). Anti-thymus antibody was present in 90% of the patients, and it paralleled the frequency of thymic abnormality in myasthenia gravis. It is postulated that in myasthenia gravis the altered T cell functions caused by anti-thymus antibody result in the formation of an array of autoantibodies including the factor which blocks the neuromuscular transmission.