Yuko Nemoto

Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis

Objectives: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features. Methods: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays. Results: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 μs in seropositive patients, 36 μs in MuSK positive patients, and 30 μs in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients. Conclusions: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitation-contraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.

Anti-ryanodine receptor antibodies and FK506 in myasthenia gravis

Anti-ryanodine receptor (RyR) antibodies were measured in sera from 33 myasthenia gravis (MG) patients using three peptides from the human RyR1 sequence, two C-terminal peptides included in the functional calcium release channel, and an N-terminal peptide implicated in ion-conduction. Antibodies were more frequently positive against the two C-terminal peptides, particularly in thymoma-associated MG. In a preliminary open trial with FK506, immunosuppressant and enhancer of RyR-related sarcoplasmic calcium release, the authors observed the sustained benefits in anti-RyR-positive MG patients.

Treatment and outcome of myasthenia gravis: retrospective multi-center analysis of 470 Japanese patients, 1999-2000.

To clarify the current status of treatments and outcomes of patients with myasthenia gravis (MG) in Japan, a total of 470 patients (164 men and 306 women; mean age 41 years) were recruited from 19 Japanese tertiary medical centers in 1999-2000. Thymectomy was performed in 319 (68%) of the patients. Patients who received thymectomy were younger (p = 0.01) and had more severe disabilities (p < 0.01) than patients without thymectomy. Irrespective of receiving thymectomy, most of the patients were administered corticosteroids (64%), other immunosuppressive agents (10%), or cholinesterase inhibitors (86%). Of 395 patients followed up for more than 12 months after treatment (mean 8.0 years), 30% (34% of thymectomized and 21% of non-thymectomized patients) were in remission (no symptoms with/without medication), 34% had only ocular symptoms, and the remaining 35% still had weakness of bulbar or limb muscles at the end of follow-up. The prognosis of MG in Japan was generally favorable, but despite the frequent use of thymectomy and immunosuppressive treatments, approximately one-third of patients still had generalized weakness. More effective or intensive treatments are required to improve the prognosis.

Low-dose tacrolimus treatment in thymectomised and steroid- dependent myasthenia gravis

SUMMARY Objectives: The effects of tacrolimus, a new immunosuppressive drug, which inhibits calcineurin pathway and also might enhance corticosteroid (CS) receptor-mediated gene expressions, on clinical outcome and biochemical data were evaluated in thymectomised and steroid-dependent myasthenia gravis (MG) patients. Patients and Methods: We administrated low-dose tacrolimus (3 mg/day orally) to 17 steroid-dependent thymectomised mg patients. They were followed for 4 to 58 months, average 19.2 months. The mg activities of daily living (MGADL) scores and the dosage of prednisolone (PSL) were assessed at baseline and 4 months later. Results: The average MGADL scores improved from 6.8 to 5.0 ( p < 0.01) at 4 months; to 3.5 at the last visit ( p < 0.01) as well as the average dosage of PSL reducing from 31.6 to 24.1 mg/alternate day ( p < 0.01) at 4 months; 14.6 mg at the last visit ( p < 0.01). Conclusions: The additional low dose tacrolimus therapy for steroid-dependent thymectomised mg is effective in improving symptoms as well as allowing the tapering of CSs.

Effects of thymectomy on late-onset myasthenia gravis without thymoma

OBJECTIVES This study aims to investigate whether thymectomy is beneficial for late-onset (>50 years) myasthenia gravis patients with no thymoma, particularly for those with mild generalized weakness. PATIENTS AND METHODS A total of 34 patients were included in the study. The clinical course and long-term outcomes over 2 years were reviewed in 20 patients who underwent thymectomy and in 14 without thymectomy. RESULTS Of the 34 patients, 20 (59%) underwent thymectomy. Thymectomized patients had more severe disability at entry than non-thymectomized patients, but outcome measures did not significantly differ between the two patient groups. Moreover, subgroup analyses including 22 patients with mild generalized weakness at entry showed that the thymectomized group (n=10) showed a greater percentage of clinical remission (no symptoms; 50% versus 17%; p=0.11) and a lower frequency of the presence of generalized symptoms (30% versus 75%; p<0.05) than the non-thymectomized group (n=12) at the end of follow-up (means 9.6 years after onset). CONCLUSIONS Thymectomy is a potentially effective treatment for late onset, non-thymomatous patients with mild generalized myasthenia gravis.

Primary Sjogren's syndrome presenting with generalized autonomic failure

A 64 year‐old woman developed Raynauds phenomenon and dry eyes/mouth. Laboratory examination revealed positive Schirmers test, rheumatoid factor and anti‐nuclear antibody, and lymphocytic sialoadenitis on salivary gland biopsy. These features strongly suggested the diagnosis of primary Sjogrens syndrome. Three years later, she gradually developed generalized autonomic failure without apparent sensory neuropathy on nerve conduction study. She had systolic pressure fall of 51 mmHg on head‐up tilt test, cardiovascular supersensitivity to diluted norepinephrine infusion, cardiac denervation in [123I]‐MIBG scintigraphy, impaired R‐R variability, decreased sweating and prolonged colonic transit time. Autoimmune autonomic ganglionopathy was mostly responsible for her autonomic failure.

High-dose intravenous immunoglobulin for the treatment of MuSK antibody-positive seronegative myasthenia gravis.

We treated two patients with anti-muscle specific tyrosine kinase (MuSK)-antibody positive seronegative myasthenia gravis (MG) with high-dose intravenous gammaglobulin (IVIg) and evaluated their clinical courses. Both patients were Japanese women, MuSK-positive seronegative MG, and were unresponsive to conventional treatments, including thymectomy, steroids, and tacrolimus. The patients required frequent hospitalization for plasmapheresis. In case 1, a 45-year-old woman, it was difficult to obtain blood access for plasmapheresis. High-dose IVIg, 400 mg/kg per day for 5 days, was administered in cases 1 and 2. In both cases, clinical improvement was observed 3 days after the start of IVIg therapy and lasted for 2 to 3 months. We propose that IVIg therapy is an effective treatment for MuSK-positive seronegative MG, when conventional treatments have failed.

Anti-MuSK-positive myasthenia gravis: neuromuscular transmission failure in facial and limb muscles

The presence of antibodies against muscle‐specific receptor tyrosine kinase (MuSK) appears to define a subgroup of patients with myasthenia gravis (MG) characterized by weakness predominant in bulbar, facial and neck muscles compared with anti‐acetylcholine receptor (AChR) antibody‐positive MG. To investigate the patterns and severity of neuromuscular transmission failure in different muscles in MuSK‐positive MG, we performed single fiber electromyography (SFEMG) in the facial (frontalis) and limb (extensor digitorum communis, EDC) muscles in three anti‐Musk‐positive patients, and compared results with those of 11 anti‐AChR‐positive patients. Only one of the three MuSK‐positive patients had abnormal jitter in EDC, but all the three showed clearly increased jitter in the frontalis. By contrast, the AChR‐positive patients showed similarly abnormal jitter for the two muscles. These results suggest that when the diagnosis of anti‐MuSK‐positive MG is suspected, SFEMG should be performed in most prominently affected muscles.

Concomitant chronic inflammatory demyelinating polyneuropathy and myasthenia gravis following cytomegalovirus infection

We describe a patient who concomitantly developed chronic inflammatory demyelinating polyneuropathy (CIDP) and myasthenia gravis (MG) following cytomegalovirus (CMV) infection. Whereas CIDP and MG presumably have different immunopathogeneses, a number of reports presented cases with CIDP and MG, some of which were concomitant cases. Several reports described association between CIDP or MG, and CMV infection, although the association is still a matter of controversy. This is the first report of patients with concomitant CIDP and MG following CMV infection. The association may be coincidental, but the possibility that CMV infection triggered development of both CIDP and MG simultaneously cannot be excluded.

Is tongue atrophy reversible in anti-MuSK myasthenia gravis? Six-year observation

Approximately 15% of myasthenia gravis (MG) patients do not have any detectable antiacetylcholine receptor (AChR) antibodies and are referred to as ‘seronegative.’ Of these, antibodies against muscle-specific tyrosine kinase (MuSK) are positive in 30–50%.1 2 Tongue muscle atrophy is frequent in MuSK-positive MG.3 The pathophysiology of muscle atrophy is unclear, and it has not yet been reported whether tongue muscle atrophy in MuSK-MG is reversible or not. We herein report a 6-year observation of tongue muscle atrophy with its MRI evaluation in a MuSK-MG patient. In 2002, a 46-year-old woman was admitted with an 8-month history of progressive neck weakness, hoarseness and dysphagia. These symptoms did not fluctuate throughout the day. The patient had lost her body weight by 14 kg over 8 months. Neurological examination showed equivocal blepharoptosis on the right, prominent nasal voice and dysphagia, and mild atrophy of the tongue. There was moderate weakness in the neck muscles and mild weakness in the limbs. No fasciculations were observed. Tendon reflexes were active in all four limbs. Serum anti-AChR antibodies were negative. The patients percentage vital capacity (%VC) was decreased to 62%. An edrophonium test was negative. A repetitive nerve stimulation test showed no significant decremental responses in …