Ken-ya Murata

Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan

AbstractStatins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG.We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies.We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients’ serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy.Anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.

Clinical Features of Autoimmune Autonomic Ganglionopathy and the Detection of Subunit-Specific Autoantibodies to the Ganglionic Acetylcholine Receptor in Japanese Patients

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and β4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -β4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG.

Methylmercury exposure and neurological outcomes in Taiji residents accustomed to consuming whale meat

Methylmercury (MeHg) is a major environmental neurotoxicant that causes damage to the central nervous system. In Japan, industrial emission of MeHg has resulted in MeHg intoxication in Minamata and Niigata, the so-called Minamata disease. Humans are exposed to MeHg derived from natural sources, primarily fish and fish predators. Therefore, MeHg continues to be an environmental risk to human health, particularly in susceptible populations that frequently consume substantial amounts of fish or fish predators such as whale. This study aimed to investigate the health effects of MeHg exposure in adults. The subjects were 194 residents (117 males, 77 females; age 20-85 years) who resided in the coastal town of Taiji, the birthplace of traditional whaling in Japan. We analyzed hair for mercury content and performed detailed neurological examinations and dietary surveys. Audiometry, magnetic resonance imaging, and electromyography were performed to diagnose neurological defects. Whole blood mercury and selenium (Se) levels were measured in 23 subjects. The geometric mean of the hair mercury levels was 14.9 μg/g. Twelve subjects revealed hair mercury levels >50 μg/g (NOAEL) set by WHO. Hair mercury levels significantly correlated with daily whale meat intake. These results suggested that residents in Taiji were highly exposed to MeHg by ingesting MeHg-contaminated whale meat. Multivariate regression analysis demonstrated no significant correlations between hair mercury levels and neurological outcomes, whereas some of the findings significantly correlated with age. A significantly positive correlation between whole blood mercury and Se levels was observed and the whole blood mercury/Se molar ratios of all subjects were <1. These findings suggested that sufficient Se intake might be one of causes of the absence of adverse effects of MeHg exposure in this study.

A dysphagia study in patients with sporadic inclusion body myositis (s-IBM)

The nature of the swallowing impairment in patients with sporadic inclusion body myositis (s-IBM) has not been well characterized. In this study, we examined ten consecutive s-IBM patients using videofluoroscopy (VF) and computed pharyngoesophageal manometry (CPM). The patients were divided into two groups: patients with complaint and without complaint of dysphagia. VF results indicated pharyngeal muscle propulsion (PP) at the hypopharyngeal and upper esophagus sphincter (UES) in all s-IBM patients. Patients without complaint of dysphagia showed a mild degree of PP, whereas a severe form of PP was observed in patients with complaint of dysphagia. CPM revealed that negative pressure during UES opening was not observed in the s-IBM patients with complaint of dysphagia. Incomplete opening and PP at the UES were observed in all s-IBM patients. These results indicate that the dysphagic processes occur subclinically in s-IBM patients who may not report swallowing impairments.

POLYNEURITIS CRANIALIS CAUSED BY VARICELLA ZOSTER VIRUS IN THE ABSENCE OF RASH

A 21-year-old man presented with acute hoarseness, pharyngeal pain, and dysphagia on December 24, 2008. He was able to drink water only and his condition did not improve; therefore, he was admitted to our hospital on January 5, 2009. On admission, his body temperature was 38.5°C, and he had mild headache and tenderness of the left external auditory meatus. There was no evidence of a skin rash around his ears or face, and no rash was observed in the oral cavity. No lymphadenopathy or hepatosplenomegaly was observed. On neurologic examination, there was paralysis of the left soft palate and the constrictor muscles of the pharynx and hypoesthesia of the left soft palate and pharynx. The remainder of the neurologic examination was normal. Meningeal signs, long tract signs, and autonomic dysfunction were not observed. These findings were consistent with acute isolated left hemilateral glossopharyngeal and vagus nerve palsy. CSF examination revealed a cell count of 218/mm3 (mononuclear cells: polynuclear cells was 216:2), and a protein concentration of 56 mg/dL. Antibody titers …

Balloon Dilation in sporadic Inclusion Body Myositis patients with Dysphagia

Here, we describe balloon catheter dilation at the upper esophageal sphincter (UES) in three sporadic inclusion body myositis (s-IBM) patients with dysphagia. Initially, we performed IVIg therapy, and, three months later, switched to balloon dilation therapy. A 12-Fr balloon catheter was inserted from the mouth under fluoroscopy and the balloon inflated at the UES. The catheter was pulled back and re-inserted several times. We examined videofluoroscopy (VF) and pressure at the oropharynx, hypopharynx and UES using computed pharyngoesophageal manometry (CPM). Before both therapies, the VF study revealed a very small amount of barium paste passing through the UES. After balloon dilation therapy, as well as IVIg, subjective complaints of dysphagia disappeared and the VF study revealed an increased amount of barium paste passing through the UES. We conclude that balloon dilation therapy is a complementary method for conventional dysphagia therapies in s-IBM patients with dysphagia.

Finger flexor weakness in inclusion body myositis.

A 72-year-old woman with sporadic inclusion body myositis presented with slowly progressive weakness in her finger flexors and proximal lower limb. She was unable to flex her bilateral first digits and second digits at the proximal and distal interphalangeal joints, whereas the fourth and fifth digits were relatively spared (figure, A). Neither a sensory …

Methotrexate myelopathy after intrathecal chemotherapy: a case report

IntroductionMethotrexate is often administered intrathecally or into the cerebral ventricles, particularly in patients with central nervous system tumors. However, in addition to chemical arachnoiditis, methotrexate can induce severe myelopathy.Case presentationA 59-year-old Japanese man with diffuse B-cell lymphoma who underwent systemic chemotherapy including methotrexate and 20Gy of radiotherapy received intrathecal methotrexate for recurrence. Flaccid paresis of his lower limbs and fecal and urinary incontinence appeared 1 month later. All sensations were impaired below the Th10 dermatome level. Although the clinical symptoms were compatible with transverse myelitis, T2-weighted imaging of his thoracic spinal cord demonstrated signal hyperintensity localized to the posterior and lateral funiculi, which resembled subacute combined degeneration. His serum vitamin B12, folic acid, and total homocysteine levels were within normal limits, but total homocysteine levels in his cerebrospinal fluid were elevated, suggesting spinal cord demyelination.ConclusionsLittle is known of the pathogenesis of methotrexate myelopathy. A possible mechanism of methotrexate myelopathy with demyelination was suggested by the increased homocysteine levels in the cerebrospinal fluid.

A primigravida with very-long-chain acyl-CoA dehydrogenase deficiency

with contrast enhancement of the right long thoracic nerve, suggesting inflammation (Fig. 1). The patient was given oral prednisolone, 1 mg/kg daily for 21 days, with dose tapering over the next month. Three months later, her symptoms were stable, but electrophysiological follow-up showed a slight reduction of fibrillation potentials in right serratus anterior muscle. Scapular winging is caused by imbalanced action of scapular muscles. The clinical examination based on the muscle group affected (trapezius, rhomboids, serratus anterior) is still the first guide for interpretation both of “pure” and “complicated” phenotypes. Isolated scapular winging due to serratus anterior weakness is usually caused by traumatic or postsurgical long thoracic nerve injury, or it can occur as a manifestation of neuralgic amyotrophy, also known as Parsonage-Turner syndrome (PTS). PTS is a clinical syndrome characterized by attacks of extreme pain at onset, patchy weakness in the upper extremities, and atrophy of affected muscles. The available evidence suggests that PTS has a complex pathophysiology that includes an underlying predisposition, susceptibility to dysfunction of some peripheral nervous system structures, and an autoimmune trigger. Cases of PTS are described after an immune event, such as pregnancy, childbirth, vaccination, or infection. Our patient did not have a history of previous surgery or trauma involving the thoracic area. Other possible causes were excluded by the laboratory evaluation. Moreover, she did not experience acute pain at onset, but only subsequent musculoskeletal pain due to compensation for the deficit. Since childbirth, an immunological trigger, occurred 3 days before symptom onset and approximately 4% of patients with PTS do not experience pain, we made a diagnosis of post-partum PTS. Currently, neuralgic amyotrophy cannot be diagnosed confidently by a single test, and often the presence of extreme pain of the upper limb together with patchy paresis helps in the diagnosis. In PTS without pain at onset, neuroimaging studies can be very useful, because they can exclude other causes such as intervertebral disc disease, tumors, or entrapment neuropathies. Furthermore, the evidence of contrast enhancement on MRI suggests a possible inflammatory etiology, thus supporting early administration of corticosteroids even in absence of pain, to block further evolution of the clinical picture and to possibly speed up functional nerve recovery. In conclusion, contrast-enhanced MRI can provide crucial help in identifying different phenotypes of PTS and can guide therapy.

Paraneoplastic anti-3-hydroxy-3-methylglutary-coenzyme a reductase antibody-positive immune-mediated necrotizing myopathy in a patient with uterine cancer

We report the case of a 69-year-old woman with proximal limb muscle weakness, who received post-operative chemotherapy for uterine cancer. Her serum creatinine kinase level was high (10,779 mg/dL) and a muscle biopsy from her left biceps revealed various sizes of muscle fibers accompanied by necrotic and regenerating fibers. She was positive for anti-3 hydroxy-3-methylglutary-coenzyme A reductase (anti-HMGCR) antibodies, but negative for anti-signal recognition particle (anti-SRP) antibodies. She was diagnosed with immune-mediated necrotizing myopathy (IMNM) and treated with prednisolone. Our findings indicate that not only drug-induced myopathy but also paraneoplastic myopathy can be involved in the pathogenesis of IMNM.