A multicentre prospective study of Guillain-Barré syndrome in Japan: a focus on the incidence of subtypes.

OBJECTIVE: Guillain-Barré Syndrome (GBS) is classified into the two major subtypes; acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Previous studies have suggested that AIDP is predominant and AMAN is rare in Western countries, whereas AMAN is not always uncommon in East Asia. We aimed to clarify the incidence of the subtypes of GBS in Japan. METHODS: We performed a prospective multicentre survey over 3 years (2007-2010). Clinical and electrophysiological findings were collected from 184 patients with GBS in 23 tertiary neurology institutes. Anti-ganglioside antibodies were measured by ELISA. We also surveyed the incidence of Fisher syndrome (FS). RESULTS: By electrodiagnostic criteria of Ho et al, patients were classified as having AIDP (40%), or AMAN (22%), or unclassified (38%). Anti-GM1 IgG antibodies were found for 47% of AMAN patients, and 18% of AIDP patients (p<0.001). There were no specific regional trends of the electrodiagnosis and anti-GM1 positivity. During the same study period, 79 patients with FS were identified; the percentage of FS cases out of all cases (FS/(GBS+FS)) was 26%. CONCLUSIONS: The frequency of GBS patients with the electrodiagnosis of AMAN by single nerve conduction studies is approximately 20% in Japan, and the AMAN pattern is closely associated with anti-GM1 antibodies. The incidence of FS appears to be much higher in Japan than in Western countries.

A case of thymoma-associated myasthenia gravis accompanied with myositis showing the clusters of histiocyte along the fascicles in perimysium.

Patients with myasthenia gravis (MG) often have other autoimmune disorders. However, the coexistence of MG and myositis is rare. Here, we report a case of a 77-year-old woman who developed mild fatigable muscle weakness and diplopia in 3 months. Serum creatine kinase was elevated to 1385 IU/L. Antibodies to acetylcholine receptor (AChR), titin and voltage-gated potassium channel 1.4 (Kv 1.4) were all positive while all tested myositis-specific autoantibodies were negative. Standard needle electromyography showed fibrillation potential and early recruitment of motor units. The repetitive nerve stimulations were consistent with a disorder of the neuromuscular junction. Muscle biopsy showed that the clusters of histiocyte were present along the fascicles in perimysium and some of them invaded into endomysium.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

Task-specific dystonia in hairdressers: a questionnaire survey and review of the literature.

Hairdresser dystonia is one of the occupational dystonias and task-specific movement disorders occurring as a result of long-term repetitive cutting with scissors. The task-specific dystonia manifests itself as a loss of voluntary motor control during extensive practice of cutting requiring a high level of technical proficiency. The prevalence rate of hairdresser dystonia is not well-known worldwide. A questionnaire regarding dystonia was prepared for hairdressers. After sending the questionnaires to 800 hairdressers by direct mail, 134 answers were received by mail. Five of the 134 were suspected to have hairdresser-associated focal dystonia. Thus, 3.7% of hairdressers might have task-specific dystonia. This report was limited because of the small number of participants. However, this research is valuable because it was difficult to find a patient with suspected dystonia due to concerns related to job security.

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases.

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.

[Dramatic improvement in two cases of anti-NMDA receptor encephalitis after immunomodulating therapy].

We report two patients with encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor that showed dramatic improvement after immunomodulating therapies. A 38-year old woman (case 1) suddenly developed seizures and short term memory loss. Brain MRI appeared almost normal except for a small number of high intensity spots of white matter on T(2) weighted images. Cerebrospinal fluid examination (CFS) disclosed lymphocytic pleocytosis (61/µl) and Qualitative analysis of NR1-NR2 antibodies in both CFS and serum were positive. Although an initial treatment with high-dose methylprednisolone was not beneficial for clinical improvement, intravenous immunoglobulin (IVIg) therapy led to complete recovery from her neurological problems. Repeated general surveys showed no evidence of tumors including ovarian teratoma. A 71-year old man (case 2) suddenly developed seizures and short-term memory loss three days after receiving an influenza vaccination. Brain MRI appeared normal. CSF analysis revealed no pleocytosis and a slight elevation of protein value accompanying oligoclonal IgG band. Qualitative analysis of NR1-NR2 antibodies in both CFS and serum were positive. Intravenous high-dose methylprednisolone caused dramatic improvement and his neurological problems immediately disappeared. Repeated general surveys showed no evidence of tumors, as in case 1. These two cases showed relatively benign clinical courses with no evidence of tumors and were quite different from the well-known encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor. Our clinical experience in these two cases suggests that the disease spectrum of anti-NMDA-receptor associated encephalitis might be broader than was once considered.

The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case.

Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. RESULTS: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.

"Prominent ear sign" on diffusion-weighted magnetic resonance imaging in relapsing polychondritis.

Relapsing polychondritis is a rare autoimmune disease characterized by recurrent inflammation of cartilage in multiple sites of the body, including the auricles. Central nervous system involvement appears rare. We encountered a case of relapsing polychondritis with encephalitis that could be diagnosed by the unique appearance of the auricle with signal hyperintensity on diffusion-weighted magnetic resonance imaging.

[Case of Gerstmann-Sträussler-Scheinker syndrome (GSS-P102L) mimicking variant Creurtzfeldt-Jakob disease in clinical manifestation and MRI findings].

We reported a 51-year-old woman with Gerstmann-Sträussler-Scheinker syndrome (GSS P102L) manifesting characteristic MRI findings. At the age of 45, She developed gait disturbance with muscle atrophy in the lower limbs and positive plantar flexor sign. Subsequently, sensory disturbance such as refractory pain in the lower limbs and ataxic gait were developed at the age of 49. Following these clinical symptoms, she finally demonstrated rapid progressive cognitive dysfunction. Just after presenting cognitive dysfunction, cranial MRI was performed. Cranial MRI with diffusion-weighted imaging and FLAIR imaging demonstrated abnormal high intensity lesions in the bilateral pulvinar, caudate nuclei and cerebral cortex. The degree of high signal at the pulvinar was less than those of the cortex and caudate nuclei. A proline-for-leucine substitution at codon 102 of the prion protein gene was demonstrated. These results allowed the diagnosis of GSS (P102L). This is a rare case of GSS (P102L) presenting with high intensity lesions in the bilateral pulvinar on MRI.

Diagnosis of Parkinson's disease and the level of oxidized DJ-1 protein.

Parkinson's disease (PD) is difficult to distinguish from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA); in addition, biomarker studies in PD mostly focused on those found in the cerebrospinal fluid, and there are few reports of simple biomarkers identified by blood analysis. Previously, the DJ-1 gene was identified as a causative gene of familial PD. Oxidized DJ-1 protein (oxDJ-1) levels were reported to increase in the blood of patients with unmedicated PD. Therefore, we determined the levels of oxDJ-1 in the erythrocytes of patients with PD, PSP, and MSA using ELISA. The oxDJ-1 levels were 165±117, 96±78, and 69±40ng/mg protein in the PD, PSP, and MSA groups, respectively. The mean level in disease control group was 66±31, revealing significant differences between the PD and PSP groups, the PD and MSA groups, and the PD and disease control groups. Our results indicated that oxDJ-1 levels in erythrocytes can be used as a marker for the differential diagnosis of PD.

[Clinical report of hereditary motor and sensory neuropathy with proximal dominance in Shiga prefecture].

We followed eight hereditary motor and sensory neuropathy patients with proximal dominance (HMSN-P) in Shiga prefecture from 1984 to 2007. There were 4 men and 4 women from two families showing autosomal and dominant prepotency. These families were related by marriage. The average onset of disease was at 53.4 +/- 8.9 (40-68) years-old. Initial symptoms were difficulty of standing up, difficulty elevating their arms, limping, or numbness. The main feature was neurogenic muscular atrophy with proximal dominance. All deep tendon reflexes were decreased or nonexistent. Paresthesia in the hands and feet and/or decreased vibratory sense in the legs were found in six patients. High CK blood levels were recognized in three patients. EMG in four patients revealed neurogenic pattern. Nerve conduction study was conducted in two patients. MCV of the median nerve and of the tibial posterior nerve, also SCV of the median nerve and of the sural nerve were within normal range in all nerves. Amplitudes of sensory action potential or of M wave were decreased or nonexistent in five of eight nerves, and distal latency of M waves was delayed in three of four nerves. These data suggests dysfunction of distal parts of the peripheral nerve fibers and axonal degeneration of the nerve trunk. Seven patients have died, and their average death age was 69.1 +/- 8.2 (52-77) years-old. Their average affected period was 16.6 (4-30) years. Their clinical history resembles Okinawa-type HMSN-P, but without the painful muscle cramps which are distinctive Okinawa-type signs.

[A case of neuralgic amyotrophy with antiganglioside antibody].

A 54-year-old-man experienced pain from his left shoulder to his left arm and had difficulty in lifting his arm after a febrile episode. Three weeks after the onset, he was admitted to our hospital. Neurological examination demonstrated weakness and atrophy of the left deltoid muscle. Deep tendon reflexes were normal and no pathological reflexes were elicited. CSF total protein was slightly increased. The occurrence rate of F-waves was decreased in the left upper limb. Magnetic resonance imaging (MRI) study of the cervical cord and brachial plexus with and without Gadolinium infusion showed no abnormalities. Serological study showed that IgM anticytomegalovirus antibody was positive, and that serum IgM anti-GalNAc-GD1a antibody and IgM anti-GM2 antibody were positive. Symptoms were improved after treatment with mecobalamin, 1.5mg/day. This case was considered neuralgic amyotrophy after cytomegalovirus infection. The antiganglioside antibodies may play some role in its pathogenesis.

Electrophysiological assessment of Guillain-Barré syndrome with both Gal-C and ganglioside antibodies; tendency for demyelinating type.

Whether patients who have GBS with antibodies to galactocerebroside (Gal-C) and gangliosides (Gal-C-GS-GBS) more often have demyelinating or axonal neuropathy remains controversial. We assessed the electrophysiological data from 16 patients with Gal-C-GS-GBS based on the two established criteria to clarify this issue. In this largest cohort of Gal-C-GS-GBS, eight patients had demyelinating neuropathy and none exhibited axonal neuropathy on either criterion. These data indicated that antibodies to Gal-C, a myelin antigen, might predominantly be associated with demyelinating neuropathy, even in the presence of concomitant antibodies to gangliosides.

Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age ≥20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179. FINDINGS: Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0·39 (SD 0·34) in the thalidomide group compared with -0·02 (0·54) in the placebo group (adjusted mean difference 0·41, 95% CI 0·02-0·80; p=0·04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0·006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease. INTERPRETATION: Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk. FUNDING: Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals.

Behçet disease presenting with neurological complications immediately after conversion from conventional cyclosporin A to microemulsion formulation.

A 53-year-old man with Behçet disease was treated with conventional cyclosporin A (CyA), because of refractory bilateral uveitis. Immediately following the conversion from conventional CyA to a microemulsion formulation, he presented with neurological complications. The neurological findings, pleocytosis of the cerebrospinal fluid (CSF) and brainstem lesions revealed by brain magnetic resonance imaging (MRI) suggested neuro-Behçet disease. After discontinuing CyA and introducing oral prednisolone, the neurological symptoms, pleocytosis of CSF and brainstem lesions on MRI improved. Although the microemulsion formulation, which can maintain a stable level of blood CyA, is a useful agent for the control of ocular lesions in Behçet disease, the resulting abrupt increase in blood CyA level may have induced neuro-Behçet disease.

[A case of myasthenia gravis with anti-MuSK antibodies showing a dramatic improvement with plasma exchange].

A 49-year-old woman with seronegative myasthenia gravis (SNMG) was admitted to our hospital with severe respiratory failure, proximal muscle weakness and bulbar palsy. Permanent tracheostomy and continuous mechanical ventilation were performed. At a previous hospital, she was diagnosed as SNMG on the basis of the positive waning during 3 Hz repetitive stimulation of the ulnar nerve, although no acetylcholine receptor antibodies (Ab) were detected by serological examination. Before admission to our hospital, she was treated with corticosteroids, intravenous immunoglobulin and tryptophan column immuno-adsorption therapy without clinical improvement. At our hospital, serological examination detected muscle-specific receptor tyrosine kinase (MuSK) Ab and plasma exchange was performed as treatment. Plasma exchange and subsequent immunomodulating therapy with corticosteroids and tacrolimus showed a dramatic clinical improvement with a marked decline of MuSK Ab level in the serum. These results suggested that plasma exchange should be considered as first choice to treat patients with refractory MuSK Ab-positive MG.

[Vasospastic cerebral infarction induced by smoking: a case report].

A 31-year-old man was admitted to our hospital because of frequent transient ischemic attacks (TIAs). The first episode involved right amaurosis fugax and left hemiparesis at the age of 26. Treatment with aspirin did not reduce frequency of TIA. Cerebral angiography at the age of 29 showed a significant stenosis in the right internal carotid artery with a string-of-beads-like appearance. This pattern suggested fibromuscular dysplasia. TIAs persisted despite of prophylactic medication with ticlopidine. When cerebral angiography was repeated at age of 28, stenosis in the right internal carotid artery had almost disappeared. At the present admission, MR angiography showed stenoses of bilateral internal carotid arteries and middle cerebral arteries, which had disappeared when the study was repeated after 5 days. Vasospasm was suspected based on reversibility of changes in both conventional and MR angiographies. The patient was treated with a calcium antagonist to prevent vasospasm as well as cessations of smoking. The patient had a history of 20 cigarettes a day for 12 years and neurologic deficits often occurred after smoking. Therefore, smoking is considered to be a main trigger for TIAs in this patient.

[Internal ophthalmoplegia in acute oropharyngeal palsy with anti-GQ1b and anti-GT1a IgG antibodies].

A patient with acute oropharyngeal palsy associated with internal ophthalmoplegia was reported. A 13-year-old boy had fever and diarrhea for two days. Ten days after resolution of these symptoms, he noticed difficulty in speaking (day 1). Neurological findings on day 4 included bilateral mydriasis, right abducens nerve palsy, nasal voice with absent pharyngeal reflex. Although superficial sensation was preserved, vibratory sensation was reduced in distal limbs. Tendon reflexes were generally absent. Neither ataxia nor dysautonomia was seen. Serum anti-glycolipid antibody assay on day 4 disclosed elevated IgG antibodies to GQ1b and GT1a. His cerebrospinal fluid on day 21 contained 6 mononuclear cells/microl with 137 mg/dl of total protein. Nerve conduction study on day 5 showed minimal sensory nerve involvement. Quantitative sudomotor axon reflex test was normal in the lower extremities. Low dose pilocarpine eyedrops dilated his pupils. Although mild cerebellar-like ataxia appeared on day 5, intravenous immunoglobulin (0.4 g/kg/day for four days) rapidly improved his neurological abnormalities. IgG anti-GQ1b antibody might contribute not only oropharyngeal weakness but also internal ophthalmoplegia in this patient.

VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation.

Accumulating evidence has proven that mutations in the VCP gene encoding valosin-containing protein (VCP) cause inclusion body myopathy with Paget disease of the bone and frontotemporal dementia. This gene was later found to be causative for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, occurring typically in elderly persons. We thus sequenced the VCP gene in 75 Japanese patients with sporadic ALS negative for mutations in other genes causative for ALS and found a novel mutation, p.Arg487His, in 1 patient. The newly identified mutant as well as known mutants rendered neuronal cells susceptible to oxidative stress. The presence of the mutation in the Japanese population extends the geographic region for involvement of the VCP gene in sporadic ALS to East Asia.

Successful Combination of Pallidal and Thalamic Stimulation for Intractable Involuntary Movements in Patients with Neuroacanthocytosis.

OBJECTIVE: Neuroacanthocytosis (NA) is a rare neurodegenerative disease that involves severe involuntary movements including chorea, dystonia, and trunk spasms. Current treatments are not effective for these involuntary movements. Although there are a few reports on the use of deep brain stimulation to treat patients with NA, the optimal stimulation target is not yet definitive. Some authors have reported successful improvement of NA symptoms with stimulation of the globus pallidum interna, and others have reported a reduction in trunk spasm with stimulation of the ventralis oralis complex of the thalamus. We investigated whether the optimal target is well defined for NA. METHODS: We describe the effect of combination stimulation of the globus pallidum interna and the ventralis oralis complex of the thalamus in 2 patients with NA who presented with severe intractable involuntary movements. RESULTS: Gpi stimulation alone was an insufficient effect for trunk spasm and/or chorea. Vo complex stimulation given without Gpi stimulation resulted in improvement of trunk spasm after 2 weeks and might also have had an incomplete effect on involuntary movement including a chorea. The combination of Gpi and Vo complex stimulation reduced the trunk spasms and chorea. This improvement was maintained at 3 months after surgery. The Unified Huntington's Disease Rating Scale score at 1 year after surgery was lower than that before surgery. CONCLUSIONS: Gpi stimulation appears to be insufficient to control violent involuntary movements; therefore, combined GPi and Vo complex stimulation provided some moderate advantage over Gpi stimulation alone.