Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

Siriraj Acute Stroke Unit: 10 years experience.

BACKGROUND: Stroke is the second most common cause of death and leading cause of adult disability worldwide. The recent publication guidelines suggest that there are treatment strategies for optimizing the management of acute stroke patients including thrombolytic therapy, antiplatelet drugs and the establishment of a stroke unit. In Thailand, the first stroke unit has been established since May 1997 and was named Siriraj Acute Stroke Unit (SASU). MATERIAL AND METHOD: The authors retrospectively analyzed the data of stroke patients who were admitted in the SASU from May 1997 to May 2007, as well as hyper acute stroke (within 3 hours after onset). The statistical analysis was performed by using SPSS 11.0. RESULTS: There were 2,109 patients admitted to the SASU during 10 year-period. The mean age of all patients was 65.35 years (range 14-94 years, median 69.2 years). Stroke subtypes were classified as infarction (including transient ischemic attack) in 1799 patients (86.7%) and hemorrhage in 310 patients (13.26%). The most common stroke mechanism was small vessel disease (38.97%). The mainly ischemic stroke distribution was middle cerebral artery territory (77.14%). Risk factors of stroke were as follow: hypertension (61.79%), diabetes mellitus (35.47%), hyperlipidaemia (46.58%), smoking (21.02%) and prior stroke or coronary heart disease (23.74%). Mortality rate was 3.4% mainly due septicemia (26 patients). The mean total hospital stay of stroke patients at the SASU was 13.81 days (ranging from 1-120 days). There were thirty hyper-acute ischemic stroke patients who received intravenous thrombolytic therapy (between August 2005 and May 2007) for which the mean age was 70.7 years (ranges 48-88 years, median 74.5 years). Mean initial National Institutes of Health Stroke Scale (NIHSS) was 14.27. Intracranial hemorrhage after intravenous thrombolytic therapy was found in 8 patients which include 3 patients with symptomatic hemorrhage. CONCLUSION: The standard of care in SASU is not inferior to other stroke unit worldwide. Admission of acute stroke patient to the SASU provides a better chance of survival as well as a shorter length of hospital stay.

Optimal Use of Perampanel in Elderly Asian Patients with Epilepsy: Expert Opinion.

Managing epilepsy in the elderly remains complicated largely due to factors related to aging. In this population, management practices are increasingly shifting towards the use of newer-generation anti-seizure medications (ASMs) as they are generally associated with better tolerability and safety profiles than older ones. Perampanel is a new ASM with broad-spectrum efficacy and a favorable safety profile. However, because of the lack of information and experience in its use, the prescription of perampanel has not been optimized in the elderly in the real-world setting in Asia. A group of epilepsy experts across the region convened at a series of virtual meetings to share their experience and discuss recommendations on perampanel use in elderly patients, including dose optimization, considerations with treatment initiation, and strategies to manage adverse events and maximize tolerability. This article summarizes key clinical and real-world evidence for perampanel in the elderly and consolidates the experts' opinions on optimizing perampanel use in elderly Asian patients with epilepsy, providing practical guidance for clinicians to address challenges related to treatment initiation and tolerance.

Can we predict final outcome of internal medicine residents with in-training evaluation.

OBJECTIVE: To assess the predictive value of in-training evaluation for determining future success in the internal medicine board certifying examination. MATERIAL AND METHOD: Ninety-seven internal medicine residents from Faculty of Medicine Siriraj Hospital who undertake the Thai Board examination during the academic year 2006-2008 were enrolled. Correlation between the scores during internal medicine rotation and final scores in board examination were then examined. RESULTS: Significant positive linear correlation was found between scores from both written and clinical parts of board certifying examination and scores from the first-year summative written and clinical examinations and also the second-year formative written examination (r = 0.43-0.68, p < 0.001). Monthly evaluation by attending staffs was less well correlated (r = 0.29-0.36) and the evaluation by nurses or medical students demonstrated inverse relationship (r = -0.2, p = 0.27 and r = -0.13, p = 0.48). CONCLUSION: Some methods of in-training evaluation can predict successful outcome of board certifying examination. Multisource assessments cannot well extrapolate some aspects of professional competences and qualities.

SW2-year outcomes of subthalamic deep brain stimulation for idiopathic Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is the recent surgical treatment of choice for patients with idiopathic Parkinson's disease (PD) complicated by motor fluctuation and disabling dyskinesia. OBJECTIVE: To study 2 years clinical outcomes, changes of medication and complications following STN-DBS in patients with advanced PD. MATERIAL AND METHOD: Twenty-seven patients with 2-year follow-up and complete data were enrolled for retrospective evaluation of Unified Parkinson's Disease Rating Scale (UPDRS) and levodopa equivalent dose (LED). Postoperative UPDRS at 6-month, 1-year and 2-years were compared with the preoperative corresponding UPDRS. Postoperative LED at 2 years was compared with the preoperative baseline. Statistical analysis was performed with paired t-test. Additionally, 62 patients with STN-DBS were enrolled for evaluation of treatment complications. RESULTS: Of 27 patients with complete 2-years follow-up, preoperative dopamine challenge test showed 50.6% improvement of motor score (UPDRS axis III). Mentation, behavior and mood (UPDRS axis I) were not significantly improved in each subscore, but significantly improved in the total score. Marked improvement of activities of daily living (UPDRS axis II) and complications of therapy (UPDRS IV) was found. Two-year postoperative motor score (UPDRS axis III) during "off medication-on stimulator" showed progressive and dramatic improvement by mean of 59.83%. The present study also revealed significant improvement of motor score (UPDRS axis III) during "on medication-on stimulator" in some items. A significant 33.4% reduction of LED was noted. Of 62 patients with bilateral STN-DBS, there was 1 asymptomatic intracerebral hemorrhage (0.8% per side), 2 speech difficulty (3.2%), 1 transient confusion (1.6%), 2 transient hypomania (3.2%), 1 stimulation induced hemiballism (1.6%), 1 wound infection (1.6%) and 1 lead malposition (0.8% per side). CONCLUSION: STN-DBS is a safe and effective treatment for PD complicated by motor fluctuation or dyskinesia. The operative outcomes show long-term improvement of activities of daily living, motor function and reduction of medication and drug-related complications.

Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations.

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718-1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations.

Efficacy and economic evaluation of delivery of care with tele-continuous EEG in critically ill patients: a multicentre, randomised controlled trial (Tele-cRCT) study protocol.

INTRODUCTION: Some critically ill patients are confirmed by continuous electroencephalography (cEEG) monitoring that non-convulsive seizure (NCS) and/or non-convulsive status epilepticus (NCSE) are causes of their depressed level of consciousness. Shortage of epilepsy specialists, especially in developing countries, is a major limiting factor in implementing cEEG in general practice. Delivery of care with tele-continous EEG (tele-cEEG) may be a potential solution as this allows specialists from a central facility to remotely assist local neurologists from distant areas in interpreting EEG findings and suggest proper treatment. No tele-cEEG programme has been implemented to help improve quality of care. Therefore, this study is conducted to assess the efficacy and cost utility of implementing tele-cEEG in critical care. METHODS AND ANALYSIS: The Tele-cRCT study is a 3-year prospective, randomised, controlled, parallel, multicentre, superiority trial comparing delivery of care through 'Tele-cEEG' intervention with 'Tele-routine EEG (Tele-rEEG)' in patients with clinical suspicion of NCS/NCSE. A group of EEG specialists and a tele-EEG system were set up to remotely interpret EEG findings in six regional government hospitals across Thailand. The primary outcomes are functional neurological outcome (modified Rankin Scale, mRS), mortality rate and incidence of seizures. The secondary outcomes are cost utility, length of stay, emergency visit/readmission, impact on changing medical decisions and health professionals' perceptions about tele-cEEG implementation. Functional outcome (mRS) will be assessed at 3 and 7 days after recruitment, and again at time of hospital discharge, and at 90 days, 6 months, 9 months and 1 year. Costs and health-related quality of life will be assessed using the Thai version of the EuroQol-five dimensions-five levels (EQ-5D-5L) at hospital discharge, and at 90 days, 6 months, 9 months and 1 year. ETHICS AND DISSEMINATION: This study has been approved by the ethics committees of the Faculty of Medicine, Chulalongkorn University, and of Ramathibodi Hospital, Mahidol University, and registered on Thai Clinical Trials Registry. The results will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: TCTR20181022002; preresults.

From international guidelines to real-world practice consensus on investigations and management of status epilepticus in adults: A modified Delphi approach.

OBJECTIVE: To establish a consensus which is practical and ready-to-use on investigations (ISE) and for management of status epilepticus (MSE) in adults using a modified Delphi approach. PATIENTS AND METHODS: A 4-round modified Delphi approach was used. First and second rounds were conducted using Google® survey with structured statements and 6-point Likert scale response. Threshold agreement was set to ≥80%. Third round was a face-to-face meeting aimed to facilitate the development of approach algorithms for ISE and MSE. Fourth round was a final review asking participants to rate the algorithms post completion. RESULTS: The panel consisted of 8 board-certified epileptologists along with 6 neurologists from main regional hospitals across Thailand. Thirty-seven statements for ISE and 68 statements for MSE were used for the Round I survey, 17/37 (45.9%) and 49/68 (72.1%) reached threshold agreement (≥80%). The average absolute-agreement intraclass correlation coefficients for ISE and MSE were 0.82 (95% CI 0.71, 0.89) and 0.81 (95% CI 0.73, 0.87), respectively; indicating good extent of consensus among participants. Upon Round II, further 10/18 (55.6%) for ISE and 10/19 (52.6%) for MSE reached agreement. In Round III, face-to-face point-by-point discussion was performed to generate approach algorithms. All (100%) provided positive responses with the algorithms post completion in Round IV. CONCLUSION: A practical and ready-to-use consensus using modified Delphi approach on ISE and MSE was developed in a Thai regional hospital context. In real practice, this approach is more suitable and feasible for a localized setting when compared with totally adopting international guidelines.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS): An alternative treatment using cyclophosphamide-thalidomide-dexamethasone (CTD) regimen.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance is a rare subacute adult-onset myopathy. Without appropriate treatment, the prognosis is unfavorable and can be fatal. Various efficacious treatment options have been reported. High dose melphalan followed by autologous stem cell transplantation is the most used option with favorable outcome. Nevertheless, potentially safer alternative regimens await exploration. Here, we report the case of sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance in a 33-year-old man with significant clinical improvement and complete remission of monoclonal gammopathy after 5 cycles of cyclophosphamide, thalidomide, and dexamethasone regimen. The regimen may be considered as an alternative option for patients with sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance that are ineligible for upfront high-dose melphalan with autologous stem cell transplantation or that are being treated in resource-limited settings. Longer-term follow-up is needed to determine the long-term effectiveness of the cyclophosphamide, thalidomide, and dexamethasone regimen.

An outbreak of botulism in Thailand: clinical manifestations and management of severe respiratory failure.

BACKGROUND: Northern Thailand's biggest botulism outbreak to date occurred on 14 March 2006 and affected 209 people. Of these, 42 developed respiratory failure, and 25 of those who developed respiratory failure were referred to 9 high facility hospitals for treatment of severe respiratory failure and autonomic nervous system involvement. Among these patients, we aimed to assess the relationship between the rate of ventilator dependence and the occurrence of treatment by day 4 versus day 6 after exposure to bamboo shoots (the source of the botulism outbreak), as well as the relationship between ventilator dependence and negative inspiratory pressure. METHODS: We reviewed the circumstances and timing of symptoms following exposure. Mobile teams treated patients with botulinum antitoxin on day 4 or day 6 after exposure in Nan Hospital (Nan, Thailand). Eighteen patients (in 7 high facility hospitals) with severe respiratory failure received a low- and high-rate repetitive nerve stimulation test, and negative inspiratory pressure was measured. RESULTS: Within 1-65 h after exposure, 18 of the patients with severe respiratory failure had become ill. The typical clinical sequence was abdominal pain, nausea and/or vomiting, diarrhea, dysphagia and/or dysarthria, ptosis, diplopia, generalized weakness, urinary retention, and respiratory failure. Most patients exhibited fluctuating pulse and blood pressure. Repetitive nerve stimulation test showed no response in the most severe stage. In the moderately severe stage, there was a low-amplitude compound muscle action potential with a low-rate incremented/high-rate decremented response. In the early recovery phase, there was a low-amplitude compound muscle action potential with low- and high-rate incremented response. In the ventilator-weaning stage, there was a normal-amplitude compound muscle action potential. Negative inspiratory pressure variation among 14 patients undergoing weaning from mechanical ventilation was observed. Kaplan-Meier survival analysis identified a shorter period of ventilator dependency among patients receiving botulinum antitoxin on day 4 (P=.02). CONCLUSIONS: Patients receiving botulinum antitoxin on day 4 had decreased ventilator dependency. In addition, for patients with foodborne botulism, an effective referral system and team of specialists are needed.

A Novel Mutation of the GNE Gene in Distal Myopathy with Rimmed Vacuoles: A Case with Inflammation.

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive or sporadic early adult-onset myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase (GNE) gene. Characteristic pathologic features of DMRV are rimmed vacuoles on muscle biopsy and tubulofilamentous inclusion in ultrastructural study. Presence of inflammation in DMRV is unusual. We report a sporadic case of DMRV in a 40-year-old Thai man who presented with slowly progressive distal muscle weakness. Gene analysis revealed a compound heterozygous mutation of the GNE gene including a novel mutation c.1057A>G (p.K353E) and a known mutation c.2086G>A (p.V696M). The latter is the most common mutation in Thai DMRV patients. The muscle pathology was compatible with DMRV except for focal inflammation.

Novel DYSF mutations in Thai patients with distal myopathy.

Dysferlinopathy refers to a variety of autosomal recessive, skeletal muscle disorders due to the mutations of dysferlin-encoding gene, DYSF. It encompasses limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), distal myopathy with anterior tibial onset (DMAT), isolated hyperCKemia, rigid spine syndrome and congenital muscular dystrophy. Herein, we report five Thai patients with distal myopathy due to dysferlinopathy including four MM and one DMAT patients. Muscle biopsy from one MM patient depicted numerous ring fibers which is an atypical finding in dysferlinopathy. Mutation analysis of DYSF revealed novel compound heterozygous mutations of p.Tyr309X and c.236+1G>T in two related MM patients, known homozygous mutations, p.Arg89X and p.Gln176X, in two MM patients and a heterozygous missense mutation, p.Arg555Trp, in a DMAT patient. Most of the previously reported DMAT patients were Hispanic. To the best of our knowledge, this is the first report of genetically confirmed patients with dysferlinopathy in Thailand.

Mutation analysis of the GNE gene in distal myopathy with rimmed vacuoles (DMRV) patients in Thailand.

Distal myopathy with rimmed vacuoles (DMRV) is an early-adult-onset, distal myopathy caused by a mutation of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE) gene. We herein report four Thai patients with DMRV who carried compound heterozygous mutations of the GNE gene including three novel (p.G89R, p.P511T, and p.I656N) and two known mutations (p.A524V and p.V696M). All patients shared p.V696M in one allele. Our study demonstrates the mutation spectrum of the GNE gene in Thai patients with DMRV.

Severe exacerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review.

Vasculitic neuropathy may occur in association with chronic hepatitis C infection. Interferon alpha (IFN(alpha)), an effective treatment for chronic hepatitis C, can precipitate or worsen autoimmune diseases. We report a patient with chronic hepatitis C and mild indolent vasculitic sensorimotor peripheral polyneuropathy, who developed severe mononeuropathy multiplex soon after IFN(alpha) was initiated, and review the literature on worsening vasculitic neuropathy after IFN(alpha) treatment for chronic hepatitis C. Care should be taken after starting patient with chronic hepatitis C-associated vasculitic neuropathy on IFN(alpha), as there is evidence that IFN(alpha) may exacerbate the neuropathy.

Lumbrical and interossei recording in severe carpal tunnel syndrome.

Patients with severe carpal tunnel syndrome (CTS) may occasionally have absent median motor and sensory responses; in these cases, it is not possible to accurately localize the median mononeuropathy to the wrist using standard electrodiagnostic tests. We prospectively investigated the use of comparing the median motor latency to the second lumbrical and the ulnar motor latency to the interossei muscles in 28 patient hands with severe CTS and absent median motor and sensory responses. We found a prolonged latency difference in 92.8%. Along with its use in mild CTS, study of the lumbrical-interossei latency difference is helpful in patients with severe CTS with absent median motor and sensory responses.

Epileptogenicity of focal malformations due to abnormal cortical development: direct electrocorticographic-histopathologic correlations.

PURPOSE: Malformations due to abnormal cortical development (MCDs) are common pathologic substrates of medically intractable epilepsy. The in situ epileptogenicity of these lesions as well as its relation to histopathologic changes remains unknown. The purpose of this study was to correlate the cellular patterns of MCDs with the expression of focal cortical epileptogenicity as assessed by direct extraoperative electrocorticographic (ECoG) recordings by using subdural grids. METHODS: Fifteen patients with drug-resistant focal epilepsy due to pathologically confirmed MCD who underwent subdural electrode placement for extraoperative seizure localization and cortical mapping between 1997 and 2000 were included in the study. Areas of interictal spiking and ictal-onset patterns were identified and separated during surgery for further pathologic characterization (cellular and architectural). Three pathologic groups were identified: type I; architectural disorganization with/without giant neurons, type IIA; architectural disorganization with dysmorphic neurons, and type IIB; architectural disorganization, dysmorphic neurons, and balloon cells (BCs). The focal histopathologic subtypes of MCDs in cortical tissue resected were then retrospectively correlated with in situ extraoperative ECoG patterns. RESULTS: Cortical areas with histopathologic subtype IIA showed significantly higher numbers of slow repetitive spike pattern in comparison with histopathologic type I (p = 0.007) and normal pathology (p = 0.002). The ictal onset came mainly from cortical areas with histopathologic type IIA (nine of 15 patients). None of the seizures originated from neocortical areas that showed BC-containing MCD (type IIB). CONCLUSIONS: This study shows that areas containing BCs are less epileptogenic than are closely located dysplastic regions. These results suggest a possible protective effect of BCs or a severe disruption in the neuronal networks in BCs containing dysplastic lesions. Further studies are needed to elucidate the nature and the potential role(s) of balloon cells in MCD-induced epileptogenicity.