Tetsuro Konishi

Antibodies against Muscle-Specific Kinase Impair Both Presynaptic and Postsynaptic Functions in a Murine Model of Myasthenia Gravis

Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.

Clinical study of FK506 in patients with myasthenia gravis

To investigate the usefulness of low‐dose FK506 for the treatment of myasthenia gravis (MG), we treated 19 patients with generalized MG in a 16‐week open clinical trial of FK506 (3–5 mg/day). At the end of the trial, total MG scores (range: 0–27 points) improved by 3 points or more in 7 of 19 patients (37%), and activities of daily living (ADL) scores (range: 0–6 points) also improved by 1 point or more in 8 of 19 patients (42%). Nine of 19 patients (47%) showed improvement in either MG or ADL scores. Significant reduction of anti‐acetylcholine receptor antibody titers and interleukin 2 production were observed at the end of this study. Minor but commonly observed side effects were an increase in neutrophil count and a decrease in lymphocyte count. No serious adverse events such as renal toxicity or diabetes mellitus were observed during the 16‐week treatment period. FK506 could safely serve as an adjunct to steroid therapy for MG at low dosage. Muscle Nerve 28: 570–574 2003

Clinical and experimental features of MuSK antibody positive MG in Japan.

We investigated the presence of antibodies (Abs) against muscle‐specific tyrosine kinase (MuSK) in Japanese myasthenia gravis (MG) patients. MuSK Abs were found in 23 (27%) of 85 generalized seronegative MG (SNMG) patients but not in any of the ocular MG patients. MuSK Ab‐positive patients were characterized as having female dominance (M:F, 5:18), age range at onset 18 to 72 (median 45) years old, and prominent oculobulbar symptoms (100%) with neck (57%) or respiratory (35%) muscle weakness. Limb muscle weakness was comparatively less severe (52%), thymoma absent. Most patients had good responses to simple plasma exchange and steroid therapy. MuSK IgG from all 18 patients was exclusively the IgG 4 subclass and bound mainly with the MuSK Ig 1–2 domain. Serial studies of 12 individuals showed a close correlation between the variation in MuSK Ab titers and MG clinical severity (P = 0.01 by Kruskal–Wallis). MuSK Ab titers were sharply decreased in patients who had a good response to early steroid therapy or simple plasma exchange, but there was no change, or a rapid increase on exacerbation after thymectomy. Measurement of MuSK Ab titers aids in the diagnosis of MG and the monitoring of clinical courses after treatment.

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

3,4-Diaminopyridine improves neuromuscular transmission in a MuSK antibody-induced mouse model of myasthenia gravis

This study investigated the effect of 3,4-diaminopyridine (3,4-DAP), a potent potentiator of transmitter release, on neuromuscular transmission in vivo in a mouse model of myasthenia gravis (MG) caused by antibodies against muscle-specific kinase (MuSK; MuSK-MG) and ex vivo in diaphragm muscle from these mice. 3,4-DAP significantly improved neuromuscular transmission, predominantly by increasing acetylcholine (ACh) release, supporting presynaptic potentiation as an effective treatment strategy for MuSK-MG patients who have defective transmitter release. In MuSK-MG, we suggest that only low-dose acetylcholinesterase (AChE) inhibitors be used to avoid side effects, and we propose that 3,4-DAP may be effective as a symptomatic therapy.

Myasthenia gravis: Relation between jitter in single‐fiber EMG and antibody to acetylcholine receptor

In 39 patients with myasthenia gravis, we measured jitter in the extensor digitorum communis muscle, using a single-fiber electrode (SFEMG) and the serum titer of antiacetylcholine receptor antibody. Clinical severity was correlated more closely with jitter, especially the percentage of abnormal jitter pairs with blocking, than with antibody titer. In patients who responded fairly well clinically after certain treatments, both the SFEMG abnormalities and antibody titer tended to improve in parallel with clinical improvement. After the plasma exchange, there was a time lag between the recovery from the defective neuromuscular transmission and the rapid decrease in antibody titer. The percentage of abnormal jitter pairs with blocking and the mean jitter value reflect defective neuromuscular transmission in generalized myasthenia gravis.

Efficacy and tolerance of gastrostomy feeding in Japanese muscular dystrophy patients.

Although muscular dystrophy patients often have feeding difficulty and need long-term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26 years, range 13-47 years), 40 myotonic dystrophy (median age 54.5 years, range 13-70 years), 11 Fukuyama congenital muscular dystrophy (median age 22 years, range 13-29 years), 5 limb girdle muscular dystrophy (median age 62 years, range 43-78 years), and 5 facioscapulohumeral muscular dystrophy (median age 52 years, range 28-67 years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy.

Epileptic seizures in Japanese patients with multiple sclerosis and neuromyelitis optica

PURPOSE To examine the incidence and clinical features of epileptic seizures in Japanese patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS We reviewed medical records of all patients who visited the Neurology Clinic in Utano National Hospital between January and December, 2009, and enrolled 63 MS patients who fulfilled the McDonald criteria (2005) (mean age, 41.1 years) and 31 NMO patients who fulfilled the Wingerchuk criteria (2006) (mean age, 44.6 years). Patients with a history of epileptic seizures were selected and their clinical features were obtained. RESULTS Four MS patients (6.3%; 2 men and 2 women; mean age, 32.5 years) and 4 NMO patients (12.9%; 4 women; mean age, 36.0 years) had epileptic seizures. Disease onset age of MS patients with seizures was significantly younger than those without seizures by 13.1 years, and Expanded Disability Status Scale of NMO patient with seizures was significantly higher than those without seizures by 2.2. All 8 patients showed brain lesions on magnetic resonance imaging and 2 MS patients had tumefactive demyelinating lesions. Electroencephalography showed interictal epileptiform discharges in 5 patients. Seizure types of 6 patients were recognized as partial seizures based on clinical semiology. All patients responded to antiepileptic therapy well. In both MS and NMO, there were both seizures with and without concurrent relapse. CONCLUSIONS Similar to MS, NMO patients possibly have higher risk to develop epileptic seizures than general population.

The Aggravation of Depression with Aging in Japanese Patients with Subacute Myelo-optico-neuropathy (SMON)

Objective We attempted to clarify the factors related to the aggravation of depression in patients with subacute myelo-optico-neuropathy (SMON) caused by clioquinol intoxication more than 35 years previously. Methods We investigated changes in the depressive mental states that occurred with aging in 19 Japanese SMON patients (mean age, 78.3 years; range, 66-89 years) according to their scores on the Japanese version of the Zung Self-rating Depression Scale (SDS), which were obtained 3-10 years previously and their current scores. The depressive state was further evaluated using simultaneous semi-structured interviews. Results The depressive mental states of 6 patients, whose current total SDS scores had increased by ≥10% in comparison to the previous score, were considered to have been aggravated with aging. The mean current total SDS score of these six patients was significantly higher than the mean score of the 13 patients whose conditions were not aggravated. Among the 20 SDS questionnaires, the patients whose conditions were aggravated showed significantly higher scores in diurnal variation, sleep disturbance and weight loss. The semi-structured interviews revealed that physical disabilities due to the sequelae of SMON, a lack of acceptance of SMON, and a decline in social activities were important factors in the aggravation of their depressive mental states with aging. Conclusion The maintenance of social activities with public support was important for coping among Japanese SMON patients with a depressive mental state, especially those who could not walk independently or who could not go outside freely without assistance.

CD8+CD11ahigh Cells Decreased in Multiple Sclerosis but Not in Neuromyelitis Optica

In order to clarify the immunological characteristics of multiple sclerosis (MS) and neuromyelitis optica (NMO), we analyzed CD3, CD4, CD8, CD20, CD4⁺CD25⁺, CD4⁺CD29⁺, and CD8⁺CD11a^high cells in peripheral blood from patients with MS (16 stable, 6 active) and NMO (15 stable, 7 active), as well as 9 with NMO spectrum, 6 with clinically isolated syndrome (CIS), and 13 with other neurological diseases using flow cytometry. Significant decreases in the numbers of CD8⁺ CD11a^high cells were observed in stable and active MS and CIS. Our findings indicate that CD8⁺CD11a^high cells play different roles in MS and NMO, and their presence may be related to the pathogenesis of MS from the early stage.