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Levodopa-carbidopa intestinal gel (LCIG) therapy has been established as a device-aided treatment for advanced Parkinson's disease. We retrospectively investigated the issues related to LCIG therapy in patients with Parkinson's disease at our hospital from March 2014 to July 2018. The subjects were 18 patients including nine men and nine women. The mean duration of PD symptoms and motor fluctuation was 14.5 ± 5.9 and 7.2 ± 4.5 years, respectively. The mean age at initiation of LCIG was 60.1 ± 9.4 years and the mean treatment period was 21.1 ± 19.5 months. One hundred and sixteen LCIG-associated issues were observed, including pain at the gastrostomy site (23 cases), hypergranulation tissue (14 cases), skin redness and/or erosions (11 cases), cutaneous infections at the gastrostomy site (eight cases), percutaneous endoscopic gastrojejunostomy (PEG-J) tube occlusion in the gastrointestinal tract (19 cases), irremovable PEG-J tube (13 cases), dislocation of the PEG-J tube (six cases), and breakage of the connector (eight cases). The majority of these issues were easily diagnosed and could be managed by neurologists who are familiar with LCIG therapy.

We conducted a questionnaire survey to collect epidemiological information on patients with Scans Without Evidence of Dopaminergic Deficit (SWEDD). We sent questionnaires to 4,970 neurology specialists in Japan in July 2015 and received responses from 933 of them. The total number of patients reported to have Parkinson's disease was 39,532, which included 237 cases of SWEDD in patients (111 males, 125 females, and 1 case without a gender description). The disease duration in patients with SWEDD was short; 127 cases (53.6%) had a duration less than 3 years, and 78 cases (32.9%) had a duration of 3 years or more but less than 7 years. By age, 59 cases (24.9%) occurred in individuals in their 60s, and 106 cases (44.7%) occurred in individuals in their 70s. Sixty-three neurologists stated that they performed dopamine transporter single photon emission computed tomography (DaT SPECT) on almost all patients with Parkinson's disease. They treated a total of 3,600 patients with Parkinson's disease which included 107 cases of SWEDD; therefore, approximately 3.0% of Parkinson's patients were estimated have SWEDD. The causes of SWEDD were unknown (101 cases), essential tremor (22 cases), vascular Parkinsonism (14 cases), and drug-induced Parkinsonism (14 cases). The majority of neurologists had doubts about the diagnosis of Parkinson's disease prior to confirming the diagnosis using DaT SPECT for reasons such as: normal findings on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, poor responses to anti-Parkinson drugs, lack of true akinesia, unchanged symptoms, and atypical symptoms. Two hundred and nineteen cases included reports on treatment paradigms following the SWEDD diagnosis. Of those cases, patients in 159 cases were maintained on the same treatment following diagnosis.

Documentation of the current status of specialty training to become a neurologist in Japan would represent an important basis for constructing better neurology training program in the planned reform of the specialty training system in Japan. The committee for future neurology specialty system of Japanese Society of Neurology (JSN) conducted a questionnaire survey on the process of specialty training of each trainee for neurology in board-certified educational facilities and semi-educational facilities throughout Japan. The response rate was 46.2% in all facilities and 87.5% in medical universities. The training process of 905 trainees over 5 grades was clarified, which was estimated to be about 80% of all the relevant subjects. Specialty training dedicated to neurology was started at the 3rd year of residency in 87.8% of subjects. During the 3 years following junior residency, 51.3% of subjects ran the rotation training between university and city hospital, whereas 36.5% was trained within the same institution throughout the 3 years of training period.

We report a 62-year-old woman with a history of Basedow's disease and Sjogren's syndrome who presented with slowly progressive limb muscle weakness over the course of ten years. On physical examination, she had dry eye and mouth, but was otherwise normal. Neurological examination revealed symmetrical proximal dominant muscle weakness. Polymyositis was suspected at initial diagnosis due to her clinical course, physical examination, and autoimmune disease. However, the final diagnosis based on a muscle biopsy was the chronic myopathic type of sarcoid myopathy. Among 25 definite sarcoid myopathy cases in the National Center of Neurology and Psychiatry muscle repository from 2010 to 2015, 6/25 had autoimmune diseases. All 6 patients were female and had the chronic myopathic type of sarcoid myopathy. The number of patients with Sjogren's syndrome, thyroid disease, autoimmune hepatitis, and idiopathic thrombocytopenia were 4, 1, 1, and 1, respectively. Only the present case had both thyroid disease and Sjogren's syndrome. In conclusion, the chronic myopathic type of sarcoid myopathy is one possibility to consider in patients who present with progressive myopathy together with autoimmune diseases.

Sporadic late onset nemaline myopathy (SLONM) associated with monoclonal gammopathy of undetermined significance (MGUS) is an adult onset myopathy with poor clinical outcomes, requiring high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM-SCT). Here we report two cases of SLONM associated with MGUS in which improvements were achieved only with immunotherapy. A 39-year-old woman had a two-year history of dropped head syndrome and progressive proximal weakness. On admission, she was able to walk with assistance and had lordosis with camptocormia. Combination therapy with plasmapheresis and intravenous immunoglobulin in addition to intravenous methylprednisolone pulse therapy ameliorated camptocormia and proximal weakness after one year. A 51-year-old man had difficulty in raising his arms and required walking assistance prior to visiting our hospital. He had proximal weakness and atrophy, winged scapulae, and gait disturbance. After combination immunotherapy, no progression was observed for 13 years. In both cases, patients did not desire to undergo HDM-SCT, and IgG kappa monoclonal protein was positive, of which the levels were normalized after immunotherapy. Combination immunotherapy can be a possible alternative to HDM-SCT in patients with SLONM. Both patients showed myogenic changes with abundant fibrillation, and needle EMG revealed positive sharp waves. Case 1 showed high signal intensities in MRI STIR/T2WI in muscles showing weakness. These findings are commonly observed in patients with myositis, suggesting that, without muscle biopsy, SLONM may be misdiagnosed as myositis. Muscle biopsy revealed scattered fibers with nemaline bodies without type 2B deficiency, which are important pathological findings that differentiate SLONM from congenital nemaline myopathy.

We report a 26-year-old woman who had respiratory dysfunction and muscle weakness at birth and was diagnosed with facioscapulohumeral dystrophy at the age of 5. The extent of muscle weakness fluctuated daily or weekly and deteriorated in menstrual periods. At the age of 12, she noted improvements in symptoms when taking procaterol hydrochloride and began to take it regularly. After that, her condition stabilized. At the age of 26, she visited our hospital presenting with ptosis, muscle weakness in the face, trunk, and proximal limbs, and easy fatigability. Serum CK was normal; anti-acetylcholine receptor and anti-muscle specific tyrosine kinase antibodies were negative. A repetitive stimulation test in the trapezius muscle showed a waning phenomenon. Gene analysis for congenital myasthenic syndrome (CMS) revealed a new mutation in the DOK7 gene; the diagnosis of CMS was confirmed. Her symptoms worsened with ambenonium chloride but improved with 3,4-diaminopyridine. Our findings suggest that daily or weekly fluctuation and worsening with a menses in muscle weakness is an important diagnostic feature of CMS.

A 59-year-old man (case 1) with multiple sclerosis (MS) presented with shortness of breath and general fatigue. He had been treated using interferon β-1b (IFNβ-1b) since he was 51 years of age. Laboratory test results showed hypoproteinemia and hypoalbuminemia, proteinuria, and absence of hematuria. He was diagnosed with nephrotic syndrome, and the administration of IFNβ-1b was stopped. Percutaneous renal biopsy was performed, and the histology revealed membranous nephropathy. A 33-year-old woman (case 2) with MS, who had been treated using IFNβ-1b for 7 years, was diagnosed with proteinuria during a medical checkup. She was referred to a nephrologist and was found to have hypoalbuminemia and proteinuria. A diagnosis of nephrotic syndrome was made, and IFNβ-1b therapy was stopped. The patient underwent percutaneous renal biopsy, and the histology revealed membranous nephropathy. Both patients were treated using intravenous methylprednisolone followed by oral prednisolone. Case 1 was administered ciclosporin orally, and his clinical symptoms and laboratory test results improved at first, but his laboratory test results subsequently showed recurrence of proteinuria. Case 2 was administered mizoribine orally, resulting in improvement in clinical symptoms and laboratory test results. Case 2 showed relapse of multiple sclerosis, but the symptoms were mild and were alleviated after steroid therapy. IFNβ therapy has several complications including nephropathy. Previously, several cases of nephrotic syndrome associated with IFNβ within 2 years of therapy were reported, but drug-induced nephropathy could appear after several years of the therapy as our cases. We should pay attention to nephrotic syndrome under using long-term IFNβ.

We found that zonisamide (ZNS), an antiepileptic agent, has beneficial effects on Parkinson disease. A 25mg once a day of ZNS significantly improves motor function of advanced patients with Parkinson disease. Its effects maintained at least one year even in patients with advanced stage. It was finally approved as an anti parkinsonian agent in Japan on March 2009. ZNS increases dopamine contents in the striatum by activating dopamine synthesis through increasing the levels of tyrosine hydroxylase (TH) mRNA and TH protein. It moderately inhibits monoamine oxydase (MAO) activity. The inhibitory effect of ZNS on T-type Ca(++)channel may also affect the anti-parkinsonian effects. ZNS also showed neuroprotective effects on several parkinsonian models through effecting both neuron and glia. We will verify the neuroprotective effects of ZNS on patients with Parkinson disease and study the factors responsible for the individual difference of the effects of zonisamide by using genome wide association study (GWAS) in the near feature.

We report a 29-year-old man with limb-girdle muscular dystrophy type 2M (LGMD2M) caused by a compound heterozygous mutation of 3-kb insertion in the 3'-untranslated region and c.1073A > C (p.Q358P) mutation in exon 9 in FKTN. He had been diagnosed since childhood as having Becker muscular dystrophy based on limb-girdle muscle weakness and calf muscle hypertrophy. Loss of ambulation occurred at age 26 years and cardiomyopathy was noted one year later. Muscle biopsy at age 29 revealed dystrophic changes with loss of immunoreactivity to alpha-dystroglycan (alpha-DG), which prompted us to analyze FKTN and subsequent establishment of the diagnosis of LGMD2M. Brain MRI revealed hypoplasia of the right cerebellar hemisphere and tonsil. Dysplastic part was present in the lower medial part of the hypoplastic hemisphare, which was bordered by a deep cleft. Previously reported LGMD2M patients had mild or minimal muscle weakness in addition to dilated cardiomyopathy. In contrast, our patient had more severe skeletal muscle weakness and loss of ambulation. Treatment with 3-blockers or angiotensin II converting enzyme blockers has been reported to be efficacious for cardiomyopathy in patients with muscular dystrophy. The precise diagnosis should be established early in patients with muscular dystrophy complicated with cardiomyopathy.

A 41-year-old man with multiple motor neuropathy developed weakness of the left hand at the age of 35 years. The weakness gradually progressed to his right hand. High-dose intravenous immunoglobulin (IVIg) therapy (0.4 g/kg for 5 consecutive days) improved the muscle weakness in the hands but led to the development of generalized severe pompholyx that spread to the skin over the entire body. Because muscle weakness of the hands worsened several months after IVIg therapy, we attempted another course of IVIg therapy. However, antiallergic agents and oral corticosteroids did not suppress the pompholyx induced by the high-dose IVIg. Hence, the treatment was switched to low-dose immunoglobulin therapy (0.4 g/kg for one day) once every month. After more than 8 months of low-dose therapy, only mild form of pompholyx remained and the muscle strength was maintained without further deterioration.

We report a case of subcutaneous and mediastinal emphysema in a 39-year-old woman with late-onset Pompe disease who was undergoing non-invasive positive pressure ventilation (NPPV). Although the patient had a history of pneumothorax, she did not present with pneumothorax at the time of admission. She had not undergone adequate respiratory rehabilitation, which resulted in decreased respiratory compliance. We speculated that the emphysema had been caused by an increase in the airway pressure due to NPPV. Decrease in inspiratory pressure of NPPV from 14 cm H2O to 9 cm H2O made the patient dyspneic and hypoxic. Cuirass ventilation by itself resulted in dyspnea and hypoxia. By using a combination of cuirass ventilation (control mode) and NPPV (assist/control mode), we were able to decrease the inspiratory pressure to 7 cm H2O. After 26 days of treatment, the patient recovered from subcutaneous and mediastinal emphysema. After the treatment, her maximum inspiratory capacity was increased from 400 ml to 600 ml, which indicates increased thoracic compliance. Thus, a combination of cuirass ventilation and NPPV is beneficial in managing barotrauma that may occur during NPPV in a respirator-dependent patient.

We serendipitously found that zonisamide (ZNS), an antiepileptic agent, has beneficial effects on Parkinson disease. A 25 mg once a day of ZNS (200-600 mg/day for epilepsy), significantly improves motor function of advanced patients with Parkinson disease. Its effects maintained at least one year even in patients with advanced stage. It was finally approved as an anti parkinsonian agent in Japan on January 2009. As the mechanism of antiparkinsonian effects of ZNS, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis through increasing the levels of tyrosine hydroxylase (TH) mRNA and TH protein. It moderately inhibits monoamine oxydase (MAO) activity. ZNS shows significant inhibition on T-type Ca++ channel. It may also affect the beneficial effects of ZNS on Parkinson disease. ZNS also showed neuroprotective effects on several parkinsonian models. It markedly inhibited quinoprotein formation and increased the level of glutathione by enhancing the astroglial cystine transport system and/or astroglial proliferation through S100beta. We will verify the neuroprotective effects of ZNS on patients with Parkinson disease and study the factors responsible for the individual difference of the effects of ZNS by using genome wide association study (GWAS) in the near feature.

A 20 year-old woman with myotonic dystrophy type 1 (DM1) presented with fatigue, daytime somnolence, and sudden poor responsiveness. Blood glucose was measured before and after each meal for 4 days, and hypoglycemia was confirmed twice, although neither perspiration nor palpitations occurred in the hypoglycemic state. On a 75 g oral glucose tolerance test (OGTT), fasting blood glucose level was 83 mg/dl, and fasting blood immunoreactive insulin (IRI) level was 5.96 microIU/ml. However, IRI increased to 528 microIU/ml at 60 minutes and blood glucose decreased to 57 mg/dl at 120 minutes of the OGTT. The patient was diagnosed with reactive hypoglycemia due to excessive insulin secretion. Oral administration of pioglitazone improved the excessive insulin secretion as assessed by OGTT. After starting treatment, hypoglycemia was not detected either pre- or post-prandially. After 10 months of treatment, blood glucose level after glucose loading was higher than fasting blood glucose level during OGTT, and the IRI area under the curve of the OGTT decreased. We considered that hypoglycemia unawareness resulted from recurrent hypoglycemic episodes in this patient. Pioglitazone was effective in improving hyperinsulinemia and reactive hypoglycemia in nondiabetic DM1.

An 82 year-old woman with Parkinson's disease complained of a tendency to fall. She has had an extensive kyphosis since she was 66 years old. Over the last 6 months, she has repeatedly fallen. Even though she took anti-parkisonian drugs, she had also developed camptocormia. Her plasma levodopa concentration was analyzed for 4 hrs after administrating an oral dose of levodopa (200 mg) plus carbidopa (20 mg) at the time of fasting. The change in the plasma levodopa concentration showed bimodal peaks. The physical symptoms depended on the plasma concentration and improved twice. Esophageal tortuosity and esophageal hiatal hernia were detected by esophagography and upper gastric endoscopy. Such physical symptoms were speculated to have been caused by the transit disturbance of the drug in the gastrointestinal duct. During a second analysis of the plasma levodopa concentration, the patient was instructed to keep extending her back after consuming the same dose of drugs but with a greater amount of water than in the first analysis. A single and a higher peak were observed for the plasma levodopa concentration, and the physical symptoms, including camptocormia and parkinsonism, were improved. Hunched posture could influence the absorption of antiparkinsonian drugs.

The prognosis of Parkinson's disease (PD) has been improved with developing anti-parkinsonian agents. Recently the re-evaluation of L-dopa and dopamine agonists is the topic in the world based on focusing non motor side effects of dopamine agonists such as sudden uncontrollable somnolence and valvulopathy in place of motor complication. The development of anti-parkinsonian drugs based on the new mechanism has been progressed such as CEP-1347, AAV-neuturin, AAV-GAD, and AAV-DDC. The most reliable new drug is zonisamide which is originally synthesized in Japan for epilepsy. A nation-wide randomized double blind study showed that Zonisamide improves motor function of advanced PD patients. Long-term efficacy was also shown. The mechanism of zonisamide for PD is the increase of dopamine synthesis and moderate inhibition of monoamine oxydase B activity. Inhibitatory effects of sodium channel and T-type calcium channel may also affects. Zonisamide has neuroprotective effects though inhibition of quinoprotein and increasing the levels of GSH and Mn SOD. Up to now we have no agents with clinically evidenced neuroprotective effects for PD. Base on the results of ELLDOPA study and "delayed start" clinical trials the most important concept for neuroprotection may be the early dopaminergic support for the degenerating dopaminergic system.

A 64-year-old woman with myasthenia gravis (MG) presented with isolated bulbar symptoms. Two years earlier, she had developed neck weakness, diplopia, and ptosis and was diagnosed with MG. Extensive thymectomy was performed, and she was treated with predonisolone (PSL). The neck weakness, diplopia, and ptosis improved over a 2-year period. However, dysphagia developed, and her voice took on a nasal tone that did not improve subjectively even after administration of 10 mg of edrophonium chloride (EC). We then performed videofluorography (VF). After consumption of 10 ml of liquid barium and 8 g of corned beef hash, she attempted to swallow, but the residue remained in the valleculae and the piriform fossa. After the EC injection, her dysphagia on ingestion of corned beef hash improved; however, there was slight subjective improvement in swallowing. Drinking of liquid barium resulted in some residue with slight improvement of dysphagia. After treatment with 70 mg of PSL for 4 weeks, VF showed improvement of dysphagia. Thus, VF, particularly during consumption of solid food, with EC administration is helpful in evaluating bulbar symptoms in patients with MG.

We report a 73-year-old man who presented symptoms of low back pain and SIADH followed by weakness of all four limbs and sensory disturbance of the lower legs 2 month after the first symptoms. He was referred to our department because of the evolution of weakness. Neurological examination on admission revealed weakness of the arms and legs, areflexia, and hypoesthesia of the lower legs. The straight leg raising test induced prominent radiating pain bilaterally. The level of sodium was 114 mEq/l, the plasma osmolality was 239 mOsm/kg, and the level of plasma antidiuretic hormone was 3.45 pg/ml. Other blood chemical values were unremarkable. The urine osmolality was 527 mOsm/kg. T1-weighted MR image with gadolinium showed thickening and enhancement of the nerve root. Nerve conduction study revealed compromised conduction with demyelinating features, and somatosensory evoked potential study could not show any potentials. He was diagnosed as having CIDP complicating with SIADH. An association between SIADH and AIDP has been much reported previously. To our knowledge, however, there has been no report of SIADH complicating with CIDP.