PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

A case of Parkinson's disease following dystonia.

Parkinsonism and dystonia are both disorders of the extrapyramidal motor system, and some patients exhibit a complex of the two symptoms. Although several reports have referred to the coexistence of these disorders as parkinsonian disorders with dystonia, in the majority of cases, dystonia appeared after parkinsonism. DAT-scan is useful for the early diagnosis of Parkinson's disease (PD) and other types of parkinsonism such as dementia with Lewy bodies. This case report describes a 67-year old woman diagnosed with axial dystonia without parkinsonism 6 years previously, which had worsened despite treatment with Botulinum toxin injections, and hindered the patient's gait. The patient visited the hospital because of gait disturbances and DAT-scan showed a levodopa transducer decrease in the putamen. A few weeks later, she was re-admitted to hospital and exhibited Parkinsonism. Levodopa improved the gait disturbances but axial dystonia was unchanged, and a clinical diagnosis of PD was made. In the authors' opinion, this was a rare case of parkinsonian disorders with dystonia, characterized by the development of PD after dystonia. DAT-scan may be helpful for the diagnosis of patients with parkinsonian disorders with dystonia.

Zebra sign of precentral gyri in amyotrophic lateral sclerosis: A novel finding using phase difference enhanced (PADRE) imaging-initial results.

OBJECTIVE: We compared the precentral gyri (PG) on the PADRE of patients with amyotrophic lateral sclerosis (ALS) and healthy subjects (HSs) in order to determine whether it is possible to discriminate between ALS patients and HSs on an individual basis. METHODS: First, two radiologists reviewed the appearance of the normal PG and that of ALS patients on PADRE in a non-blinded manner, and deviations from the appearance of the normal PG were recorded. Next, based on the presence of PG abnormalities on PADRE, we performed an observer performance study using 16 ALS patients and 16 HSs. RESULTS: The radiologists were able to consensually define the PG as abnormal on PADRE when a low-signal-intensity layer was observed in the gray matter of the PG; a three- or four-layer organization (zebra sign) was characterized by the low-signal-intensity layer. The observer performance study demonstrated that the sensitivity, specificity, and accuracy of PG abnormalities on PADRE for discriminating ALS patients from HSs were 94 %, 94 %, and 94 %, respectively, for reviewers 1 and 2. CONCLUSIONS: It was possible to discriminate between ALS patients and HSs based on the presence of PG abnormalities on PADRE, which may reflect upper motor neuron impairment in ALS. KEY POINTS: • PADRE reveals low-signal-intensity layer in the PG of ALS • By PADRE findings on PG, we can discriminate ALS from HSs • PADRE may be a useful method for detecting UMN impairment in ALS.

Improved Detection of Cortical Gray Matter Involvement in Multiple Sclerosis with Quantitative Susceptibility Mapping.

RATIONALE AND OBJECTIVES: Quantitative susceptibility mapping (QSM) is a novel technique which allows determining the bulk magnetic susceptibility distribution of tissue in vivo from gradient echo magnetic resonance (MR) phase images. Our purpose was to evaluate if there is additional diagnostic value of QSM images in detecting the cortical gray matter involvement in multiple sclerosis (MS) patients. MATERIALS AND METHODS: Our institutional review board approved this study. Conventional MR imaging, including T2-weighted imaging and two- or three-dimensional fluid-attenuated inversion recovery images, and QSM imaging examinations were performed in 27 patients (19 male and eight female) with MS. Two radiologists (radiologists 1 and 2) assessed the MS lesions in the following 3 anatomic regions: intracortical, mixed white matter-gray matter (WM-GM), and juxtacortical regions. The numbers of lesions per region category were compared between conventional MR images with and without QSM images. RESULTS: For radiologists 1 and 2, QSM images identified 6 (50.0%) and 7 (50.0%) additional lesions that were not seen in the conventional MR images, respectively. In a lesion-by-lesion analysis, the substantial fraction (20 [25.3%] of 79 at radiologist 1, 22 [29.7%] of 74 at radiologist 2) of juxtacortical white matter lesions on the conventional MR images were scored as mixed WM-GM lesions with QSM images. CONCLUSIONS: Our preliminary results suggest that the MR imaging with QSM may increase the sensitivity in cortical lesion detection in the MS brain and improved distinction between juxtacortical and mixed WM-GM lesions.

Electroencephalographic features of benign adult familial myoclonic epilepsy.

OBJECTIVE: To investigate electroencephalographic (EEG) features of benign adult familial myoclonic epilepsy (BAFME). METHODS: We reviewed interictal EEG features in patients with BAFME treated between April 2005 and November 2012 at a tertiary referral center. The diagnostic criteria for BAFME were the presence of infrequent generalized tonic-clonic seizures, myoclonus or myoclonic seizures, and autosomal dominant inheritance. Interictal EEG findings of epilepsy with generalized tonic-clonic seizure only (EGTCS) were reviewed for comparison. We randomly selected 10 generalized spike/polyspike and wave complexes (GSW) for each BAFME patient and measured the duration of them. Photic stimulation and hyperventilation were performed in all. RESULTS: Nineteen (eight men, 11 women) patients with BAFME were included in this study. The mean frequency of GSW was 4.3±1.0Hz (mean±SD, n=14) in BAFME and 3.2±0.8Hz (n=10) in EGTCS. There was a statistically significant difference (p=0.008) between the two. Photoparoxysmal responses (PPR) were noted in 18 (95%) patients with BAFME but 1 (10%) with EGTCS. CONCLUSION: Faster frequency of GSW, compared with that in EGTCS, accompanied by PPR may be characteristic EEG features of BAFME. SIGNIFICANCE: These findings may lead the diagnosis of BAFME.

Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: a randomized, multicenter, double-blind, crossover, sham-controlled trial.

There is little evidence for multisession repetitive transcranial magnetic stimulation (rTMS) on pain relief in patients with neuropathic pain (NP), although single-session rTMS was suggested to provide transient pain relief in NP patients. We aimed to assess the efficacy and safety of 10 daily rTMS in NP patients. We conducted a randomized, double-blind, sham-controlled, crossover study at 7 centers. Seventy NP patients were randomly assigned to 2 groups. A series of 10 daily 5-Hz rTMS (500 pulses/session) of primary motor cortex (M1) or sham stimulation was applied to each patient with a follow-up of 17days. The primary outcome was short-term pain relief assessed using a visual analogue scale (VAS). The secondary outcomes were short-term change in the short form of the McGill pain questionnaire (SF-MPQ), cumulative changes in the following scores (VAS, SF-MPQ, the Patient Global Impression of Change scale [PGIC], and the Beck Depression Inventory [BDI]), and the incidence of adverse events. Analysis was by intention to treat. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry. Sixty-four NP patients were included in the intention-to-treat analysis. The real rTMS, compared with the sham, showed significant short-term improvements in VAS and SF-MPQ scores without a carry-over effect. PGIC scores were significantly better in real rTMS compared with sham during the period with daily rTMS. There were no significant cumulative improvements in VAS, SF-MPQ, and BDI. No serious adverse events were observed. Our findings demonstrate that daily high-frequency rTMS of M1 is tolerable and transiently provides modest pain relief in NP patients.

Parkinson's disease: diagnostic potential of high-resolution phase difference enhanced MR imaging at 3 T.

OBJECTIVES: To determine whether it is possible to diagnose patients with Parkinson's disease (PD) on an individual basis using magnetic resonance imaging with phase difference enhanced imaging (PADRE). METHODS: PADRE delineated the crural fibres as a layer of low signal intensity and the substantia nigra as a layer of medium signal intensity in a healthy volunteer, and showed a clear boundary between the crural fibres and the substantia nigra (BCS). Twenty-four PD patients and 24 control subjects were enrolled. Contrast ratios between the substantia nigra and occipital white matter were calculated, and two radiologists independently reviewed the PADRE findings regarding BCS obscuration. RESULTS: Mean contrast ratio in PD patients was significantly higher than in control subjects (0.56 vs 0.39, P < 0.01). The BCS on PADRE was obscured significantly more frequently in any subgroups with PD patients compared with control subjects (P < 0.01). The observation of BCS obscuration had a sensitivity, specificity and accuracy for the diagnosis of PD of 92 %, 88 % and 90 % for radiologist 1 and 83 %, 88 % and 85 % for radiologist 2, respectively. CONCLUSION: PADRE is able to identify PD in patients as a loss of delineation between the crural fibres and the substantia nigra on an individual basis.

A novel tract imaging technique of the brainstem using phase difference enhanced imaging: normal anatomy and initial experience in multiple system atrophy.

OBJECTIVES: To develop a new tract imaging technique for visualising small fibre tracts of the brainstem and for detecting the abnormalities in multiple system atrophy of the cerebellar type (MSA-C) using a phase difference enhanced (PADRE) imaging technique, in which the phase difference between the target and surrounding tissue is selectively enhanced. METHODS: Two neuroradiologists compared the high-spatial-resolution PADRE imaging, which was acquired from six healthy volunteers, three patients with MSA-C, and 7 patients with other types of neurodegenerative diseases involving the brainstem or cerebellum. RESULTS: Various fine fibre tracts in the brainstem, the superior and inferior cerebellar peduncles, medial lemniscus, spinothalamic tract, medial longitudinal fasciculus, central tegmental tract, corticospinal tract and transverse pontine fibres, were identified on PADRE imaging. PADRE imaging from MSA-C demonstrated the disappearance of transverse pontine fibres and significant atrophy of the inferior cerebellar peduncles, while the superior cerebellar peduncles were intact. PADRE imaging also demonstrated that the transverse pontine fibres and inferior cerebellar peduncle were not involved in the other neurodegenerative diseases. CONCLUSION: PADRE imaging can offer a new form of tract imaging of the brainstem and may have the potential to reinforce the clinical utility of MRI in differentiating MSA from other conditions.

[Quality of life and burden in caregivers for ALS patients in Japan].

The present study was conducted with 20 ALS patients and their caregivers with the aim of examining whether caregiver burden and the caregiver's quality of life were correlated to the patient's degree of functional impairment. Patients were divided into a relatively mild functional impairment group (score of 14-18 on the ALS Functional Rating Scale (ALSFRS)) and a severe ALS group (score of 0-3 on ALSFRS). For those in the high-score ALSFRS group, caregiver burden increased as the patient's degree of functional impairment progressed, but there was no correlation in the low-score group. Furthermore, caregivers in the high-score ALSFRS group had significantly more mental health problems. These findings suggest the need for mental health care and reduction of caregiver burden due to progression of functional impairment for caregivers of ALS patients still at a relatively early stage of the disease.

[Case of sporadic hemiplegic migraine with cerebellar ataxia].

A 34-year-old man was admitted with his unsteady gait, difficulty in speech and a paroxysmal severe headache accompanied with sensori-motor disturbance of the right extremities and aphasic symptom. His family history was unremarkable. His unsteadiness has progressed very slowly from childhood. He noted to be inarticulate at the age of 18 years. At the age of 33 years, he suddenly had an attack of severe throbbing headache, which was mainly left parietal, with nausea and photophobia. During the headache, his right extremities were paralyzed and he became aphasic. He had lost a partial memory of the event All these symptoms had gone within 24 hours. Thereafter, the same headache occurred about once a month. Neurological examination revealed a mild truncal ataxia and ataxic dysarthria. Electroencephalography (EEG) showed intermittent delta waves restricted over the left fronto-temporal region. Brain MRI showed a moderate atrophy of superior cerebellar vermis and anterior cerebellar lobe. The diagnosis of sporadic hemiplegic migraine (SHM) with cerebellar ataxia was made. Our case was very similar to familial hemiplegic migraine (FHM) 1, of which some families are accompanied with transient amnesia, cerebellar ataxia and EEG abnormality. Although we did not detect any mutations in CACNA1A gene previously reported in FHM1, our case might share same pathogenesis with FHM1.

Motor excitability after the C reflex in cortical reflex myoclonus.

Twelve patients with cortical reflex myoclonus were electrophysiologically investigated. From the results of the recording of the C reflex during voluntary contraction, cortical reflex myoclonus was classified into three subtypes: type I; C reflex with recurrent C reflex (C'), type II; double C reflexes (C1, C2) and type III; C reflex with evident inhibition. The jerk-locked motor evoked potential (MEP) showed different mechanisms in the C' and C2 reflexes. The findings of cortical delay, facilitatory effect of peripheral stimulation on MEP and jerk-locked MEP indicate that both cortical reflex myoclonus and the silent period after the C reflex in patients with type III cortical reflex myoclonus might originate from a change of cortical excitability of the motor cortex.

[Nationwide questionnaire study in "the Model Core Curriculum" and current status for the undergraduate education in neurology].

To investigate the current state of education for undergraduates, the subcommittee of the Japanese Society of Neurology for undergraduate education sent a questionnaire on the 2001-version of Model Core Curriculum to the department of neurology in 80 medical universities and their 7 associate medical institutes throughout Japan. Answers were obtained from 56 out of those 87 institutes (64.4%). According to the answers, the Core Curriculum was introduced to the program of undergraduate education in 93% of those 56 universities. For the revision of neurology part in the current Core Curriculum, there are number of requests for improving the description on the neurological examination, list of common symptoms and disorders, and addition of therapeutics. Despite application of the Model Core Curriculum in medical education, the present study disclosed that there were considerable difference in the number and content of the lectures, and the duration of clinical clerkship in neurology ward. These differences of the curriculum and training program depends on not only the number of staffs, but also whether they are working as staffs in a department of neurology or as a small group of neurologists within a department other than neurology.

Severe symptoms of 16q-ADCA coexisting with SCA8 repeat expansion.

We report a family with 16q-ADCA(16q 22.1 linked autosomal dominant cerebellar ataxia) coexisting with SCA8 repeat expansion. The brothers in this family presented with pyramidal signs, tremor, myoclonus and mental retardation in addition to cerebellar symptom in childhood. They showed both C-to-T substitution puratrophin-1 gene and an expanded allele of the SCA8 gene in the brothers and their father. These siblings presented with atypical symptoms and early onset age as16q-ADCA. Although it remains controversial whether the expanded SCA8 allele is associated with cerebellar symptoms, the coexistence of SCA8 repeat expansion with SCA6 was reported previously. Pure or predominant cerebellar symptoms were found in patients with SCA8, SCA6 and 16q-ADCA. In addition, common findings in neuropathology of SCA8, SCA6 and 16q-ADCA have been reported. We suppose that coexistence of SCA8 repeat expansion with 16q-ADCA may be involved in the pathogenesis and severe symptoms in this family.

[Longitudinally extensive spinal cord lesion in a case of Neuro-Behçet disease].

A 56-year-old right-handed man with recurrent orogenital aphtoid ulcers and bilateral uveitis had presented with memory disturbance, dressing apraxia and constructional apraxia at age 53. Neuro-Behçet disease was diagnosed based on pathergy test results and positivity for HLA-B51. Four months after azathioprine was introduced, he presented with subacute spastic paraparesis and urinary retention at age 56. Neurological examination demonstrated hyperreflexia in the lower limbs without pathological reflexes. He also showed memory disturbance, dressing apraxia and constructional apraxia. Spinal cord MRI showed a longitudinally extensive spinal cord lesion (LESCL) from C1 to Th3 with partial gadolinium enhancement from C6 to C8. Brain MRI showed moderate atrophy of the right temporal and parietal lobes without contrast enhanced lesion. There were hyperintense lesions in the pons, bilateral periventricular white matter and right parietal subcortical white matter. Cerebrospinal fluid analysis showed mild lymphocytic pleocytosis. After intravenous methylprednisolone treatment, clinical symptoms largely resolved and the abnormal intensities with contrast enhancement of the cord disappeared. However, higher cortical dysfunctions were not changed. LESCL may reflect inflammatory venous vasculitis with edema extending along the neural fibers since the lesion shows excellent responses to steroid without neurological sequelae. Differential diagnosis of neurological diseases demonstrating LESCL should include Neuro-Behçet disease.

[Occupation and carpal tunnel syndrome].

Carpal tunnel syndrome (CTS), compression of the median nerve at the carpal tunnel of the wrist, is the most common of all entrapment syndromes. Diabetes, Rheumatoid arthritis, hypothyroidism and pregnancy are known to cause CTS. And certain occupations were been reported the risk factor of CTS. We report two patients with occupationally induced CTS, and discuss the relation between the development of CTS and occupation with reference to previous papers. Occupations that appear to promote CTS were classified in to three groups: jobs entailing the use of vibratory tools, assembly work and food processing and packing. These occupations involved repeated flexion and extension of the wrist. The prevalence of CTS was related to not only repetitive work but also forceful work involving the wrist. Both occupational and non-occupational factors (gender, age, body mass index, thyroid function and diabetes mellitus) were considered risk factors for CTS. The prevalence of CTS in Visual Display Terminal (VDT) workers was not high compared to that in control groups. If the cause of CTS is considered to be due to an occupational factor, the patient would be eligible workmen's compensation, and should be suspended from work as soon as possible. It has been reported that assembly line workers showed resolution of symptoms and normal nerve conduction studies after 2 years of a reduced work schedule. Treatment for CTS should begin early. When these workers return to work, the environment and the condition of work should be improved to prevent recurrence.

[Occupational dystonia associated with production line work and PC work].

It is considered that occupational dystonia is associated with fixed abnormal postures or repetitive skilled movements. In our country, occupational dystonia seems to be frequent to production line workers or visual display terminal (VDT) workers. Most of patients with occupational cervical dystonia start with symptoms of stiffness in the neck or shoulder portions. In the occupational health scene, dystonia is treated as cervicobrachial disorder. As for most occupational health staffs, dystonia is an unknown disorder, therefore the patients may not receive appropriate treatments.

Unilateral positive-negative myoclonus in Creutzfeldt-Jakob disease.

We report a patient with Creutzfeldt-Jakob disease who presented asymmetric myoclonus. Positive-negative myoclonus was seen only in the right extremities in association with periodic synchronous discharges (PSDs) on the electroencephalogram, although pure positive myoclonus was rarely seen in the left extremities, independently in PSDs. The duration of the silent period recorded in the right-hand muscle produced by transcranial magnetic stimulation was much longer than that in the left-hand muscle or that in normal subjects. Brain MRI diffusion-weighted images showed signal hyperintensities in the putamen and cerebral cortex, including the motor cortex, predominantly on the left side.

Rhythmic EMG and EEG activity during voluntary movement in posthypoxic cortical action myoclonus.

A patient with posthypoxic cortical action myoclonus was studied using polygraphic EEG-EMG recording techniques and transcranial magnetic stimulation. The myoclonic jerks were not stimulus-sensitive, and were not associated with enhancement of the somatosensory evoked potential (SEP). The most prominent electrophysiological finding was that rhythmic EMG activity was produced when the patient attempted rapid voluntary movement. EEG-EMG polygraph indicated that the rhythmic EMG activity was preceded by rhythmic activity in the EEG recorded overlying the contralateral central region. The frequency of both EEG and EMG activity was the same (approximately 50 Hz). Treatment using a combination of clonazepam, carbamazepine and primidone diminished the action myoclonus, concomitant with the disappearance of the rhythmic EEG and EMG activity. In the sensorimotor cortex of the normal monkey and humans, oscillatory activity ranging between 20-50 Hz has been recorded in the local field potential. Our findings suggest that cortical hyperoscillation may produce this characteristic rhythmic EEG and EMG activity and may, in turn, be related to cortical action myoclonus.