Etiology of Dementia in Thai Patients.

INTRODUCTION: Molecular imaging has been developed and validated in Thai patients, comprising a portion of patients in the dementia registry. This should provide a more accurate diagnosis of the etiology of dementia, which was the focus of this study. METHODS: This was a multicenter dementia study. The baseline characteristics, main presenting symptoms, and results of investigations and cognitive tests of the patients were electronically collected in the registry. Functional imaging and/or molecular imaging were performed in patients with an equivocal diagnosis of the causes of dementia, especially in atypical dementia or young onset dementia (YOD). RESULTS: There were 454 patients in the study. The mean age of the patients was 78 years, with 60% female. Functional imaging and/or molecular imaging were performed in 57 patients (57/454 patients, 13%). The most common cause of dementia was Alzheimer's disease (AD; 50%), followed by vascular dementia (VAD; 24%), dementia with Lewy bodies (6%), Parkinson's disease dementia (6%), frontotemporal dementia (FTD; 2.6%), progressive supranuclear palsy (2%), multiple system atrophy (0.8%), and corticobasal syndrome (0.4%). YOD accounted for 17% (77/454 patients), with a mean age of 58 years. The causes of YOD were early onset amnestic AD (44%), VAD (16%), behavioral variant FTD (8%), posterior cortical atrophy (6.5%), and logopenic variant primary progressive aphasia (5.2%). CONCLUSION: AD was the most common cause of dementia in Thai patients and the distribution of other types of dementia and main presenting symptoms were similar to previous reports in Western patients; however, the proportion of YOD was higher.

Trinucleotide repeat expansion of TATA-binding protein gene associated with Parkinson's disease: A Thai multicenter study.

INTRODUCTION: Spinocerebellar ataxia type 17 (SCA17) is an inherited cerebellar degeneration associated with trinucleotide repeat expansions in the TATA-binding protein gene (TBP). Low-range expansions of TBP have recently been described in association with Parkinson's disease (PD). However, these low-range expansion alleles were also observed in healthy individuals. Prior distinct findings may result from reduced penetrance or age-dependent susceptibility, which may influence phenotypic expression. METHODS: A case-control study of 456 PD patients and 374 control subjects was conducted. Data and blood samples were collected during 2008-2013. Control subjects were individuals over 65 years old without parkinsonism. Sizes of TBP trinucleotide repeats were analyzed. All available carriers of the TBP repeat of ≥40 repeats were re-examined. RESULTS: A high prevalence of carriers of TBP repeat expansion ≥41 developed PD, mainly at an advanced age. Half of these carriers had onset after 70 years of age (range 34-84). Seven participants carried expansion alleles of ≥42, and all had PD. Fourteen participants (six patients and eight controls) carried a heterozygous 41-repeat allele. At the current mean age of 79 years and mean follow-up period of 4 years, three out of the eight control carriers of the 41-repeat allele developed PD, while none of the thirteen asymptomatic carriers of the 40-repeat allele did. CONCLUSIONS: A high prevalence of PD was observed in carriers of low-range expansions of TBP (41-45 repeats), especially in elderly. This finding suggests that cut-off value for pathological TBP repeat expansion appear to be 41.

Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 in patients with unknown spinocerebellar ataxia: a Thai multicentre study.

BACKGROUND: About 50 % of Thai patients with adult-onset spinocerebellar ataxia (SCA) was Machado-Joseph disease (MJD), SCA1, SCA2 and SCA6. The author investigated further on less common SCAs in the patients without any known mutations. METHODS: DNA samples of 82 index patients who were genetically excluded MJD, SCA1, SCA2, SCA6, SCA7 and dentatorubro-pallidoluysian atrophy (DRPLA) were examined. Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 genes were comprehensively performed. Normal range of trinucleotide repeat expansion sizes of TATA-box-binding protein gene (TBP) were also determined in 374 control subjects. RESULTS: Eight patients carried ≥42 CAG/CAA repeat allele in the TBP consistent with SCA17. The pathological repeat alleles ranged from 42 to 57 repeats. All patients had significant degree of cognitive dysfunction. Other non-ataxic phenotypes comprised of parkinsonism, chorea, dystonia and myoclonus. A sporadic patient carried a heterozygous 41-repeat allele developed chronic progressive cerebellar degeneration commenced at the age of 28 years. Whilst, 2 % of the control subjects (8/374) carried the 41-repeat allele. Five of the carriers were re-examined, and revealed that four of them had parkinsonism and/or cognitive impairment without cerebellar signs. Analysis of other types of SCAs was all negative. CONCLUSIONS: This is the first study of SCA8, SCA10, SCA12, SCA17 and SCA19 in Thais. SCA17 appears to be an important cause of ataxia in Thailand. Although, the pathological cut-off point of the TBP repeat allele remains unclear, the finding suggests that the 41-repeat may be a pathological allele resulting late-onset or mild phenotype. Apart from ataxia, cognitive impairment and parkinsonism may be clinical presentations in these carriers.

Confirmation of the association between LRRK2 R1628P variant and susceptibility to Parkinson's disease in the Thai population.

OBJECTIVE: LRRK2 p.R1628P (c.4883G > C) is associated with Parkinson's disease (PD) in Chinese and Thais. However, some studies in other East Asian ethnic groups did not observe this association. Carriers of p.R1628P are about 3-5% Chinese and Thais. In contrast, Japanese, Koreans and Malays are much less prevalent (0-<1%). The contradictory results may be caused by insufficient sample sizes especially studies in ethnic groups with low prevalence, which, theoretically need a much larger sample size. We conducted a case-control Thai PD study with appropriate size in order to support the role of p.R1628P related to susceptibility to PD. METHODS: Estimated total sample size of 958 Thai subjects was needed. 485 PD patients and 480 controls were recruited. The p.R1628P was screened by RFLP and confirmed by direct sequencing. Clinical characteristics were compared between PD patients with and without p.R1628P. RESULTS: 54 PD patients (11%) and 29 control subjects (6%) carried p.R1628P. Multiple logistic regression analysis showed that GC and CC genotypes were significantly higher in PD patients than in controls (OR = 1.81, 95%CI = 1.10-2.97). The PD patients carrying p.R1628P had earlier age at onset (56 ± 13 vs 60 ± 12; P = 0.021) and a more rapidly progressive course (P < 0.001) than the patients carrying wild-type nucleotide. CONCLUSIONS: We confirm the association between p.R1628P and risk of developing PD in the appropriated sample-sized cohort. Certain LRRK2 variants appear to be generally distributed among East Asians, however, in widely different frequencies. In order to study role of such variants in PD, it should be carefully estimated the appropriate sample size.

Glucocerebrosidase mutations in Thai patients with Parkinson's disease.

BACKGROUND: GBA mutations are an important risk factor in developing Parkinson's disease (PD) worldwide. The study aimed to determine the frequency and clinical characteristics of GBA mutations in a Thai PD cohort of 480 patients and 395 control subjects. METHODS: Direct sequencing of GBA was performed in all early-onset PD patients (EOPD: n = 108) and 100 PD patients with age at onset over 50 years (AAO > 50y-PD). The study subsequently screened all identified mutations in the remaining AAO > 50y-PD patients and all control subjects. Predictive factors associated with risk of developing PD were analyzed. Comparisons of clinical characteristics of PD patients with and without GBA mutations were also carried out. RESULTS: Heterozygous GBA mutations were identified in 24 patients (5%) and 2 controls (0.5%). Seven identified GBA point mutations comprised p.L444P, p.N386K, p.P428S, IVS2+1G > A, IVS9+3G > C, IVS10-9_10GT > AG and c.1309delG, of which five mutations were novel. Multiple logistic regression analysis revealed that GBA mutations were more frequent in EOPD than AAO > 50y-PD groups (OR = 4.64, P < 0.022). Patients with GBA mutations had mean age at onset (43.1 ± 10.2, mean ± standard deviation) earlier than patients without GBA mutations (54.4 ± 13.9, P = 0.002). The patients with GBA mutations also had a more rapid progressive course, in which they were more likely to have higher Hoehn and Yahr staging (OR = 4.20, P = 0.006) and slightly lower means of Schwab-England ADL score [74.1 ± 17.1 vs. 81.0 ± 18.08 (OR = 0.98, 95%CI = 0.96-1.01, P = 0.162)]. CONCLUSION: GBA mutations are an important risk of PD in the Thai population. Patients having the mutations are likely to have early onset and may exhibit more rapid motor progression.

Clinical analysis of adult-onset spinocerebellar ataxias in Thailand.

BACKGROUND: Non-ataxic symptoms of spinocerebellar ataxias (SCAs) vary widely and often overlap with various types of SCAs. Duration and severity of the disease and genetic background may play a role in such phenotypic diversity. We conducted the study in order to study clinical characteristics of common SCAs in Thailand and the factors that may influence their phenotypes. METHODS: 131 (49.43%) out of 265 Thai ataxia families with cerebellar degeneration had positive tests for SCA1, SCA2, Machado-Joseph disease (MJD) or SCA6. The study evaluated 83 available families including SCA1 (21 patients), SCA2 (15), MJD (39) and SCA6 (8). Comparisons of frequency of each non-ataxic sign among different SCA subtypes were analysed. Multivariate logistic regression analyses were undertaken to analyze parameters in association with disease severity and size of CAG repeat. RESULTS: Mean ages at onset were not different among patients with different SCAs (40.31 ± 11.33 years, mean ± SD). Surprisingly, SCA6 patients often had age at onset and phenotypes indistinguishable from SCA1, SCA2 and MJD. Frequencies of ophthalmoparesis, nystagmus, hyperreflexia and areflexia were significantly different among the common SCAs, whilst frequency of slow saccade was not. In contrast to Caucasian patients, parkinsonism, dystonia, dementia, and facial fasciculation were uncommon in Thai patients. Multivariate logistic regression analysis demonstrated that ophthalmoparesis (p < 0.001) and sensory impairment (p = 0.025) were associated with the severity of the disease. CONCLUSIONS: We described clinical characteristics of the 4 most common SCAs in Thailand accounting for almost 90% of familial spinocerebellar ataxias. There were some different observations compared to Caucasian patients including earlier age at onset of SCA6 and the paucity of extrapyramidal features, cognitive impairment and facial fasciculation. Severity of the disease, size of the pathological CAG repeat allele, genetic background and somatic heterogeneity of pathological alleles may influence clinical expressions of these common SCAs.

Rivastigmine patch for treatment of Alzheimer's disease in clinical practice in Thailand.

BACKGROUND: Rivastigmine is a cholinesterase inhibitor for treatment of mild to moderate Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The new patch formulation was recently made available. We assessed the safety, tolerability, and cognitive outcome of rivastigmine patch in treatment of mild to moderate AD in clinical practice in Thailand. METHODS: A multicentre, hospital-based, prospective observational study was conducted in nine hospitals across Thailand. Patients with probable mild to moderate AD who received the rivastigmine patch were enrolled. Data were collected data at baseline, weeks 4-8 and after week16. RESULTS: A total of 116 AD patients were screened, and three were excluded. Of 113 patients, 62.8% were women with a mean age of 73.3 ± 9.2 years; 79.7% were newly diagnosed. One-third of all patients had been using antipsychotic or antidepressant medication. Common comorbidities were hypertension and dyslipidemia. The Thai Mental State Examination score significantly increased from 18.6 to 20.3 (weeks 4-8) and 20.4 (week 16+) (P < 0.001). Scores based on physicians' (Clinical Global Impression) and caregivers' (Patients' Caregiver Global Impression of Change) impressions of improvement suggested minimal improvement. Because of adverse events, seven patients's dosages were reduced 10 cm(2) to 5 cm(2) or from 5 cm(2) to nothing. Itching was the most common adverse symptom. CONCLUSIONS: During the first 16 weeks after initiation of rivastigmine patch therapy, patients with probable mild to moderate AD had statistically significant improvement in cognitive function, but clinically marginal benefit. Rivastigmine was safe and well tolerated.

Prevalence, clinical features and treatment outcomes of patients with myasthenia gravis positive for antibodies to muscle-specific kinase in Thailand.

A small but variable subgroup of patients with myasthenia gravis (MG) who have antibodies to muscle-specific kinase (MuSKAb-MG) can present with distinct phenotypes and are often treatment-resistant. The prevalence, clinical phenotypes and outcomes of treatment of patients with MuSKAb-MG in Thailand were determined. Eight (16.3%) of the 49 patients with generalized MG who were negative for acetylcholine receptor antibodies (AChRAb) were positive for muscle-specific kinase antibodies. Most patients had predominant oculobulbar features and respiratory failure occurred in three. At follow up, three out of the seven patients who underwent thymectomy were in complete stable remission and four had improved and were on reduced immunosuppression medication, suggesting a possible benefit of thymectomy.

Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population.

Carbamazepine (CBZ) has been reported as the most common culprit drug for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in several Asian countries including Thailand. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese but not in Caucasian and Japanese populations. A case-control study was conducted to determine whether HLA-B*1502 is a valid pharmacogenetic test for SJS/TEN caused by CBZ in a Thai population. Among 42 CBZ-induced patients with SJS/TEN, 37 (88.10%) patients carried the HLA-B*1502 while only 5 (11.90%) of the CBZ-tolerant controls had this allele. The risk of CBZ-induced SJS/TEN was significantly higher in the patients with HLA-B*1502, with an odds ratio (OR) of 54.76 [95% confidence interval (CI) 14.62-205.13, p = 2.89 x 10(-12)]. The sensitivity and specificity of HLA-B*1502 for prediction of CBZ-induced SJS/TEN were 88.10%. By assuming a 0.27% as a prevalence rate of CBZ-induced SJS/TEN in a Thai population, the positive predictive value (PPV) and negative predictive value (NPV) of the HLA-B*1502 were 1.92% and 99.96%. Results from this study suggest that HLA-B*1502 may be a useful pharmacogenetic test for screening Thai individuals who may be at risk for CBZ-induced SJS and TEN.

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.

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.