Yoshimichi Miyazaki

Which target is best for patients with Parkinson's disease? A meta-analysis of pallidal and subthalamic stimulation

Background There is a growing body of evidence demonstrating that deep brain stimulation (DBS) of globus pallidus internus (GPi DBS) and subthalamic nucleus (STN DBS) are effective treatment for patients with Parkinsons disease (PD). However, it remains controversial whether the best stimulation target for a PD patient is GPi or STN. Methods A computer literature search of PubMed was carried out. We included randomised studies with direct comparison between targets. The outcome of unified PD rating scale (UPDRS) III was expressed as the standardised mean difference (SMD) between targets in baseline to endpoint change. Pooled risk ratio (RR) between targets was also used to assess adverse events. Results Four studies, comprising a total sample size of 502 PD patients (254 GPi DBS, 248 STN DBS), were included in this meta-analysis. The overall effect of GPi DBS on UPDRS III was not significantly different from STN DBS (SMD=0.19, 95% CI −0.2 to 0.58, p=0.34, four studies, n=448). This result was heterogeneous (p=0.03, I2=66%). In terms of adverse events, depression was significantly less frequent in patients with GPi DBS than STN DBS with homogeneous studies (pooled RR=0.53, 95% CI 0.31 to 0.90, p=0.02, three studies, n=479, I2=48%). Conclusions The effect of GPi DBS was similar to STN DBS except for depression, however, only three studies described depression as adverse events. We need additional randomised trials with direct comparison between targets based on unified scoring of adverse events.

Efficacy of zolpidem for dystonia: a study among different subtypes

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor.

Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome

OBJECTIVE Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K(+) channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. METHODS Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. RESULTS Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K(+) current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. CONCLUSIONS This study showed that patients with CFS might have abnormal kinetics in a slow K(+) current. SIGNIFICANCE Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K(+) channel openers.

Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia

Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.

Imaging-based differential diagnosis between multiple system atrophy and Parkinson's disease

There are many tools for differentiating between multiple system atrophy with predominant parkinsonian features (MSA-P) and Parkinsons disease (PD). These include middle cerebellar peduncle (MCP) width, apparent diffusion coefficient (ADC) value of the putamen and cerebellum, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy images. We aimed to directly compare the above-mentioned methods, and to determine the optimal tool for differential diagnosis. Eleven patients with MSA-P and 36 patients with PD were enrolled. Of these, 7 patients with MSA-P and 14 patients with PD were chosen as background-matched subjects. We measured MCP width, ADC value of the putamen and cerebellum, and MIBG myocardial scintigraphy images. Area under curve (AUC) of receiver operating characteristic (ROC) was assessed to compare the above-mentioned methods. MCP width and ADC value of the putamen may be helpful for differentiating between MSA-P and PD relative to other methods in background-matched patients (MCP, AUC=0.95; putamen ADC, AUC=0.88; cerebellar ADC, AUC=0.70; MIBG, AUC=0.78). Similar AUCs were seen in all patients with different backgrounds. Our findings suggested that MCP width and ADC value of the putamen could be superior to ADC value of the cerebellum and MIBG uptake for differentiating between MSA-P and PD.

The effect of tremor onset on middle cerebellar peduncle of Parkinson's disease

The majority of studies of Parkinsons disease (PD) focused on basal ganglia initially; however, accumulating evidence suggests cerebellar involvement in pathophysiology. We aimed to investigate the effects of tremor onset on middle cerebellar peduncle (MCP) width of PD patients and of disease duration on differential diagnosis. We measured MCP width of 81 PD, 34 multiple system atrophy (MSA) and 16 normal controls, using MRI. A meta-analysis was performed including two previous and the present studies. We carried out correlation analysis between disease duration and MCP width separately in subgroup of PD with or without tremor onset. Receiver operating characteristic curves were analyzed. Our meta-analysis indicated that MCP width was significantly smaller in MSA relative to PD with homogeneous studies. There was significant correlation between disease duration and MCP width in PD without tremor onset. In contrast, there was no correlation observed in PD with tremor onset. Subclassification according to disease duration showed improved area under curve of PD vs. MSA with predominant parkinsonian features. MCP width could be a valuable tool for differential diagnosis. Our finding suggested that MCP was impaired in advanced stage of PD without tremor onset as part of the abnormality of the cerebellar system.

The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments

Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimers disease (AD) are primarily composed of hyper‐phosphorylated tau protein. Recently, several other molecules, including flotillin‐1, phosphatidylinositol‐4,5‐bisphosphate [PtdIns(4,5)P2] and cyclin‐dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin‐1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs.

Guillain−Barré syndrome in a local area in Japan, 2006-2015: an epidemiological and clinical study of 108 patients

Many epidemiological studies of Guillain−Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends.

Late-onset myasthenia gravis is predisposed to become generalized in the elderly

Objective The continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG. Methods We retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50–64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status. Results Elderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course. Conclusions Our study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.

On-period unified Parkinson’s disease rating scale before surgery correlates with differences in outcomes between pallidal and subthalamic stimulation: a meta-analysis

The updated meta-analysis demonstrated that neurostimulation for treating Parkinson’s disease (PD) resulted in more improvement in quality of life compared with medication alone [1]. However, the target of deep brain stimulation has been a controversial matter. In this context, we performed a meta-analysis of pallidal and subthalamic stimulation for PD, and found that depression occurred more frequently after deep brain stimulation of the subthalamic nucleus (STN DBS) than after DBS of the globus pallidus internus (GPi DBS) with homogeneous studies [2]. By contrast, similar extent of improvement on the unified Parkinson’s disease rating scale (UPDRS) III was observed after surgery with heterogeneous studies [2]. The main cause of the heterogeneity remains unknown. Here, we updated a meta-analysis with randomized studies that directly compared pallidal stimulation with subthalamic stimulation, and performed subgroup and meta-regression analyses to determine the cause of heterogeneity. The detailed method for a meta-analysis and the characteristics of the included studies were described elsewhere [2]. We searched the PubMed database using the same terms as described previously [2]. This search was performed in January 2015 and yielded 9 papers in addition to previous search in 2013. However, none of the papers satisfied our inclusion criteria for the following reasons: GPi DBS and STN DBS were compared with medication (1 paper), PD animal models were analyzed (2 papers), unilateral DBS was performed (1 paper), subjects overlapped with those of previous reports (1 paper), and four papers were reviews and/or meta-analysis studies. Four studies same as a previous meta-analysis (254 GPi DBS, 248 STN DBS) were finally included in the present study [2]. For UPDRS III in the off medication/on stimulation, standardized mean difference (SMD) was employed to combine each effect (Hedge’s g). A random-effect model was used to calculate the pooled mean effect size. We carried out subgroup analysis and meta-regression analysis according to disease duration, on-period or off-period UPDRS III at baseline. Furthermore, publication bias was assessed by the asymmetry of the funnel plot using the Egger’s linear regression test, and there was no significant deviation of the intercept from zero (P = 0.6). All analyses were performed using the library of ‘‘meta’’ and ‘‘metaphor’’ in R software (http://www.r-project.org/), and Review Manager (RevMan 5.2) for Windows (http://ims. cochrane.org/revman). There was a significant subgroup difference between more than and less than 21 of on-period UPDRS III score at baseline with homogeneous studies in each subgroup (P = 0.003; Fig. 1a). Furthermore, meta-regression analysis indicated significant correlation between on-period UPDRS III score before surgery and SMD (P = 0.003; Fig. 1b), though there was no correlation between SMD and off-period UPDRS III score or disease duration (P[ 0.1). These findings suggested that outcome after DBS was influenced by the on-period UPDRS III score at baseline. That said, patients with a low UPDRS III score could be good candidates for STN DBS to improve their motor & Wataru Sako dwsako@yahoo.co.jp