Toshiro Yoshimura

Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis

Muscle‐specific tyrosine kinase (MuSK) antibodies are found in some patients with “seronegative” myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)–positive end‐plates compared with AChR antibody–positive end‐plates, and C3 was detected in only two of eight MuSK Ab–positive patients. MuSK antibodies do not appear to cause substantial AChR loss, complement deposition, or morphological damage. Effects on MuSK function need to be explored. Ann Neurol 2005;57:289–293

Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome.

The aim of this study was to clarify whether autoimmunity against P/Q‐type voltage‐gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert‐Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD‐LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q‐type VGCC in these patients and controls for the amount and ratio of autoantibody‐channel complex using an 125I‐ω‐conotoxin MVIIC‐binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q‐type VGCC measured by Scatchard analysis were reduced in PCD‐LEMS patients (63.0 ± 7.0fmol/mg, n = 3), compared with the controls (297.8 ± 38.9fmol/mg, n = 6). The ratio of autoantibody‐VGCC complexes to total P/Q‐type VGCCs measured by immunoprecipitation assay were increased in PCD‐LEMS patients. We analysed cerebellar specimens by autoradiography using 125I‐ω‐conotoxin MVIIC, which specifically binds to P/Q‐type VGCCs. In PCD‐LEMS cerebellum, the toxin binding sites of P/Q‐type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q‐type VGCCs in the normal cerebellum. This suggests that P/Q‐type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD‐LEMS.

Seronegative Lambert-Eaton myasthenic syndrome Study of 110 Japanese patients

The authors characterized the clinical and immunologic features of 110 patients with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated calcium channels (VGCC) antibodies were detected in 85% of the patients (seropositive) but not in the rest (seronegative). Except for the indication that small cell lung carcinoma is less common in seronegative patients, no significant differences were found in the clinical characteristics of patients who had or did not have anti-P/Q-type VGCC antibodies. The results of passive transfer experiments suggest that seronegative LEMS is also an autoantibody-mediated disorder.

Low‐level laser irradiation promotes the recovery of atrophied gastrocnemius skeletal muscle in rats

Low‐level laser (LLL) irradiation promotes proliferation of muscle satellite cells, angiogenesis and expression of growth factors. Satellite cells, angiogenesis and growth factors play important roles in the regeneration of muscle. The objective of this study was to examine the effect of LLL irradiation on rat gastrocnemius muscle recovering from disuse muscle atrophy. Eight‐week‐old rats were subjected to hindlimb suspension for 2 weeks, after which they were released and recovered. During the recovery period, rats underwent daily LLL irradiation (Ga–Al–As laser; 830 nm; 60 mW; total, 180 s) to the right gastrocnemius muscle through the skin. The untreated left gastrocnemius muscle served as the control. In conjunction with LLL irradiation, 5‐bromo‐2′‐deoxyuridine (BrdU) was injected subcutaneously to label the nuclei of proliferating cells. After 2 weeks, myofibre diameters of irradiated muscle increased in comparison with those of untreated muscle, but did not recover back to normal levels. Additionally, in the superficial region of the irradiated muscle, the number of capillaries and fibroblast growth factor levels exhibited significant elevation relative to those of untreated muscle. In the deep region of irradiated muscle, BrdU‐positive nuclei of satellite cells and/or myofibres increased significantly relative to those of the untreated muscle. The results of this study suggest that LLL irradiation can promote recovery from disuse muscle atrophy in association with proliferation of satellite cells and angiogenesis.

Effects of reduced joint mobility on sarcomere length, collagen fibril arrangement in the endomysium, and hyaluronan in rat soleus muscle.

Immobilization is often associated with a decrease in muscle elasticity. This condition is called muscle contracture, but the mechanism is not yet clear. We examined changes in ankle joint mobility, sarcomere length, collagen fibril arrangement in the endomysium, and hyaluronic acid (HYA) in muscular tissue 1, 2, 4, 8, and 12 weeks after immobilization of rat soleus muscles in shortened position. Ankle joint mobility decreased with the duration of immobilization. Sarcomere length had shortened 1week after immobilization, but did not show further change 2, 4, 8, and 12 weeks after immobilization. Collagen fibril arrangement in the endomysium 1 and 2 weeks after immobilization was longitudinal to the axis of the muscle fibers, whereas 4, 8, and 12 weeks after immobilization it was circumferential. HYA in muscular tissue had increased 1 week after immobilization but remained at the same level at weeks 2, 4, 8, and 12. Histochemically, HYA in the endomysium of immobilized muscular tissue was stained more strongly and widely than that in the control tissue. Increased HYA in muscular tissue may induce muscle stiffness, but the significance of how HYA is related to the mechanism of muscle contracture was not clear. The findings suggest that muscle contracture started 1 week after immobilization and increased with the length of immobilization. Consequently, muscle contracture is affected by the shortening muscle fibers during the early stage of immobilization, after which the collagen adapts by the fibril arrangement in the endomysium becoming more circumferential. This change in collagen fibril arrangement may cause advanced muscle contracture in the late stage of immobilization.

Diagnostic significance of IgG, C3, and C9 at the limb muscle motor end‐plate in minimal myasthenia gravis

We detected deposits of IgG, C3, and C9 (immune complexes) at the limb muscle motor end-plates (biceps brachii muscle) in 16 of 19 patients who exhibited only ocular signs and symptoms of myasthenia gravis that were improved by intravenous injections of edrophonium chloride. Circulating anti-acetylcholine receptor (anti-AChR) antibodies were negative in 6 of the 16 patients, but the motor end-plate fine structure in the postsynaptic regions was abnormal in all 16. Single-fiber EMG revealed no abnormalities in 8 of 13 patients studied. Our results indicate that the detection of immune complexes at the limb muscle end-plate provides a highly sensitive and confirmative method for diagnosing patients with minimal or atypical myasthenia gravis who have no detectable anti-AChR antibodies in their serum.

Evident difference in the excitability of the motoneuron pool between normal subjects and patients with spasticity assessed by a new method using H-reflex and M-response☆

The excitability of the motoneuron (MN) pool in the resting state was compared between normal control subjects and patients with spasticity resulting from HTLV-I-associated myelopathy, using a new parameter, Hslp/Mslp, and the conventional parameters Hmax/Mmax and Hth/Mth. Differences in the excitability of the MN pool between these two groups reached a high degree of statistical significance only when assessed with the new parameter. This suggests the methodological advantage of the Hslp/Mslp over both Hmax/Mmax and Hth/Mth for evaluation of the excitability of the MN pool in the resting state.

Effects of Therapeutic Ultrasound on Joint Mobility and Collagen Fibril Arrangement in the Endomysium of Immobilized Rat Soleus Muscle

This study examined effects of therapeutic ultrasound on joint mobility and collagen fibril arrangement in the endomysium of immobilized rat soleus muscle. Twenty-two male Wistar rats were divided randomly into control (n = 5) and experimental groups (n = 17). In the experimental group, bilateral ankle joints of each rat were fixed in full plantar flexion with a plaster cast over a 4-wk period. Five animals in the experimental group were immobilized throughout the 4-wk (immobilization group) period, whereas the remaining rats in the experimental group were randomly divided into the ultrasound (US, n = 6) and sham (n = 6) treatment groups. Under anesthesia, continuous ultrasonic energy (frequency, 1 MHz; intensity, 1.0 W/cm(2)) was delivered to the triceps surae muscle of the US group for 15 min per d, 6 d per wk over the 4-wk immobilization period. Ultrasonic energy was not delivered to the triceps surae muscle in sham animals; only the transducer head was moved. Ankle joint mobility on dorsiflexion in the immobilization, sham and US groups was significantly smaller than that of the control group, whereas in the US group, this parameter was significantly greater than in the immobilization and sham groups. Collagen fibril arrangement in the endomysium of the control and US groups was longitudinal to the axis of the muscle fibers; in contrast, it was circumferential in the immobilization and sham groups. Our findings revealed that joint immobilization induces decreased joint mobility and collagen fibril movement in the endomysium; furthermore, ultrasound treatment can prevent these changes. We hypothesized that therapeutic ultrasound during the immobilization process may inhibit deterioration of muscle contracture.

Extrapontine myelinolysis presenting with parkinsonism as a sequel of rapid correction of hyponatraemia.

acute psychotic illness after the removal of a normal appendix, when aged 18. The diagnosis of acute intermittent porphyria was confirmed by raised urinary porphobilinogen concentrations and reduced serum porphobilinogen deaminase activity. Her subsequent progress while ventilated was complicated by repeated chest infections and psychiatric problems. Soon after weaning from the ventilator, she developed hypercalcaemia (2-87 mmol/l, corrected value), that was refractory to simple lowering measures. An intravenous bolus of disodium pamidronate (15 mg) reduced calcium concentrations to 2-4 mmol/l but was associated with increasing weakness 36 hours later, necessitating ventilatory support for two days. Over the next four months she remained immobile and her calcium rose slowly to 3-19 mmol/l. On this occasion, oral bisphosphonate was prescribed which lowered the calcium to 2-78 mmol/l. Despite the lack of objective clinical deterioration, the patient complained of worsening weakness and discharged herself against advice. One year after her illness she is known to have moderate tetraparesis but is able to walk with supports. Although acute intermittent porphyria can cause various metabolic abnormalities, immobilisation hypercalcaemia is not widely recognised. It remains uncertain whether patients with acute intermittent porphyria are particularly prone to developing this complication as in other, more common, polyneuropathies with a potentially similar range of severity and duration such as Guillain-Barre syndrome, it is reported only rarely and with a male preponderance.3 Prolonged hypercalcaemia due to immobilisation and increased bone turnover is important to recognise and treat because of the potential for complications such as nephrocalcinosis, osteoporosis, and further axonal damage. In the context of severe acute intermittent porphyria, a strategy of early mobilisation is rarely possible and drug therapy is potentially hazardous. From our experience, repeated courses of steroids seem effective but are likely to have undesirable long term side effects such as reduced total body calcium. On the basis of a single injection of calcitonin, this also seems effective and safe. Bolus intravenous infusions of disodium pamidronate are likely to be the most efficient at lowering plasma calcium concentrations for prolonged periods but may not be safe at doses higher than 10 mg. If the drug is given, appropriate back up for ventilatory support needs to be readily available should clinical deterioration ensue. Pi READING PK NEWMAN Department of Neurology WF KELLY Department ofMedicine, Middlesborough General Hospital, Ayresome Green Lane, Middlesbrough TS5 5AZ, UK MC BATESON Department of General Medicine, Bishop Auckland General Hospital, County Durham DL14 6AD, UK P ROTHWELL Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK Immobilization-related hypercalcaemia-a possible novel mechanism and response to pamidronate. Postgrad Med J 1990;66: 918-22. 3 Walls TJ, Ashworth B, Saunders M. Immobilization hypercalcaemia complicating polyneuropathy in adolescent boys. J Neurol Neurosurg Psychiatry 1984;47:1232-5. 4 Carey DE, Raisz LG. Calcitonin therapy in prolonged immobilization-hypercalcaemia. Arch Phys Med Rehabil 1985;66:64-6.

CT demonstration of spinal epidural emphysema after strenuous exercise.

We report a case of spinal epidural emphysema after strenuous exercise. The emphysema was without clinical signs and disappeared after 2 weeks.