Somsak Tiamkao

Strong association between hla-b * 5801 and allopurinol-induced Stevens–johnson syndrome and toxic epidermal necrolysis in a Thai population

Objectives Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B*5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B*5801 in a Thai population that has a high allelic frequency of this allele. Methods Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively. Results All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B*5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B*5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2–6336.9, P = 1.6×10−13). The sensitivity and specificity of the HLA-B*5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B*5801 allele was 1.52 and 100%, respectively. Conclusion A strong association of allopurinol-induced SJS/TEN with the HLA-B*5801 allele was observed in a Thai population. The results suggest that HLA-B*5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.

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 × 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.

Long term results of botulinum toxin type A (Dysport) in the treatment of hemifacial spasm: a report of 175 cases

OBJECTIVE To describe the long term efficacy and side effects of the treatment of hemifacial spasm with Dysport and to evaluate two different sites of injection to hopefully reduce side effects. METHODS This study was designed as a prospective descriptive study. Injections were made subcutaneously around the eye. Peak improvement was subjectively assessed by using a visual analogue scale and reported in percentages (0–100%). Duration of improvement was assessed subjectively and reported in months. RESULTS Of 175 cases, 17 were lost to follow up and were excluded. 855 treatments were injected in the remaining 158 patients with a median of 4 treatments. The response rate was 97%. Of 855 treatments, the adjusted mean peak and duration of improvement was 77.2 (95% confidence interval (95%CI) 74.7–79.4)% and 3.4 (95%CI 3.2–3.6) months respectively. In 158 patients (complete group), the long term results from the first to the 12th treatment showed that the mean peak improvement ranged from 72.70 to 80.10% and the duration of improvement was 2.60 to 3.71 months. It remained constant throughout (p=0.40, p=0.87 respectively). The most common side effect was ptosis. Of the 158 patients, 21 completed 12 treatments (subgroup). A separate analysis of this group disclosed a mean peak and duration of improvement from the first to 12th treatments ranging from 70.00 to 78.10% and 2.65 to 4.31 months respectively. Analysis of variance with repeated measures showed no significant variation of peak and duration of improvement over the first to the 12th treatments (p=0.38, p=0.38 respectively). Only 3% of the treatments were unsuccessful but responded to subsequent treatments. The incidence of ptosis was reduced from 27.17% to 9.68% by moving the injection site to the lateral part of orbital orbicularis oculi without any loss of efficacy. The yearly cost of Dysport is considerably less than Botox. CONCLUSION This study is the first to show, in detail, the long term results of treatments of hemifacial spasm with Dysport. The efficacy is constant throughout the first to 12th treatments in both the complete group and subgroup. Ptosis can be reduced by moving the injection site further up to the lateral part of the orbital orbicularis oculi. The efficacy of Dysport is comparable with Botox® in long term follow up.

HLA-B*1502 Strongly Predicts Carbamazepine-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Thai Patients with Neuropathic Pain

Background:  Carbamazepine (CBZ) is one of the standard pharmacological treatments for neuropathic pain. However, its serious adverse drug reactions include Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, HLA‐B*1502 allele was implicated as a genetic marker of CBZ‐induced SJS/TEN in some Asian epilepsy populations.

Seizures in nonketotic hyperglycaemia

Dear Sir, The association between focal seizures and hyperglycaemia was first reported in 19651. The disorder is characterized by hyperglycaemia, no ketoacidosis, full consciousness (or minimal depression of sensorium) and focal seizures. We report 21 patients, who presented with seizures and nonketotic hyperglycaemia (NKH). This is a large case series. The aim of this report is to study clinical and laboratory characteristics of seizures in NKH. A retrospective study was done in a teaching hospital. Inclusion criteria were (1) hyperglycaemia (plasma glucose more than 11.11 mmol/l), (2) seizures, and (3) seizure stopping after control of the hyperglycaemia. Patients with seizures explained by causes other than hyperglycaemia were excluded from the study. Of the 21 patients, 9 were men (43%) and 12 were women (57%) who developed seizures and NKH (23 events). One patient had three events. Six patients had a previous history of diabetes mellitus (DM). Fifteen patients had no previous history of DM. They presented with seizures and NKH, and were diagnosed with DM in the index admission. Of the 21 patients, 3 were DM type 1 (14.3%) and 18 were DM type 2 (85.7%). The average duration of seizures before admission was 5 days (range 1–14 days). The average duration of seizures in each episode was 3 minutes (range 1–5 minutes). Total of 22 events (95.65%) were partial seizures, and 1 event was an unclassified tonic-clonic seizure. Among the 22 partial onset seizures, 14 were epilepsia partialis continua, 6 became secondarily generalized tonic-clonic seizures, and 2 were complex partial seizures (CPS). In all 20 events of partial seizures without CPS, seizures started in one extremity or the face: 14 started in an upper extremity, 5 in the face, and 1 in a lower extremity. Partial seizures started slightly more often on the left side (12 cases) than the right side (8 cases). At the time of the seizure, the average plasma glucose value was 32.61 mmol/l (range 16.11–61.33 mmol/l). The average calculated serum osmolarity was 302 mOsm/l (range 288–323 mOsm/l). When the seizures stopped, the average plasma glucose value was 11.3 mmol/l (range 4.11–21.67 mmol/l). Neurologic manifestations, particularly seizures, may provide the first clinical clue to the presence of NKH. Focal motor seizures are the most common type2. However, seizures in NKH are still not fully appreciated by physician and patient. Our patients took an average of 5 days before they got the correct diagnosis and treatment. Knowledge of this condition may shorten the time to diagnosis and decrease the discomfort of patients. Every patient who presents with seizures especially focal seizures should have an immediate determination of plasma glucose levels. Seizures in NKH happen equally in both sexes. In 15 of the 21 patients (71.4%), seizures were the earliest manifestation of DM and led to discovery of DM in these patients. Most of patients had type 2 DM. Although 3 of the 21 patients had type 1 DM, none of them had ketoacidosis during the seizure. This finding may be explained by the fact that ketosis has an anticonvulsant action, due to intracellular acidosis increasing glutamic acid and decarboxylase activity leading to increased levels of GABA3. Epilepsia partialis continua was the most common type (60.87%) of seizure in our series, as previously reported2. Interestingly, we found 2 (8.7%) of our patients presented with CPS. Our finding confirmed previous reports of CPS induced by hyperglycaemia4. The mechanism of seizures in NKH is still debated. The possible mechanisms are hyperglycaemia or hyperosmolarity, a low level of gamma aminobutyric acid (GABA), and focal ischaemia. Each mechanism, considered alone, is unsatisfactory. Mean plasma glucose value in our report was 32.61 (16.11–61.33 mmol/l), and osmolarity ranged from normal to a moderate value (288–323 mOsm/l). Almost all of our seizures in NKH patients have plasma osmolarity less than the classical diagnostic level (320 mOsm/l) of NKH. In addition, mean plasma glucose ranged from normal to hyperglycaemia (4.11–21.67 mmol/l) when seizures stopped. So, the explanation of hyperglycaemia or hyperosmolarity alone is unsatisfactory. In addition, the Krebs cycle in NKH is inhibited, GABA metabolism is increased and the levels may be decreased, thus lowering the threshold for seizure activtiy3, 5.

Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.

Background Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. Materials and methods Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. Results Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41–13.09, P<0.05). Conclusion Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.

Clinical factors predictive of encephalitis caused by Angiostrongylus cantonensis.

Angiostrongylus cantonensis is mainly caused eosinophilic meningitis in humans, whereas a minority of patients develop encephalitic angiostrongyliasis (EA). EA is an extremely fatal condition, and the clinical factors predictive of EA have never been reported. A comparison study was conducted in a hospital situated in an endemic area of Thailand. We enrolled 14 and 80 angiostrongyliasis patients who developed encephalitis and meningitis, respectively. Logistic regression analysis was used to assess the clinical variables predictive of encephalitis. Age (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42), duration of headache (adjusted OR, 1.26; 95% CI, 1.03-1.55), and fever > 38.0 degrees C (adjusted OR, 37.05; 95% CI, 1.59-862.35) were identified as statistically significant factors for EA prediction. Elderly patients with angiostrongyliasis experiencing fever and prolonged headaches were at the highest risk of developing EA.

Neurologic manifestations of pandemic (H1N1) 2009 virus infection.

To the Editor: In April 2009, the outbreak of influenza A pandemic (H1N1) 2009 virus was reported. Subsequently, the disease spread throughout the world, and the pandemic alert level was raised to level 6 in June by the World Health Organization. Pandemic (H1N1) 2009 virus infection spread to Thailand and is now found throughout Thailand. Similar to the effects of other viruses, pandemic (H1N1) 2009 virus may cause neurologic complications. Associated neurologic symptoms were first reported from Dallas, Texas, USA: 4 children experienced unexplained seizures or had an alteration of consciousness level that was associated with this virus (1). We report an adult patient with pandemic (H1N1) 2009 infection who had neurologic complications. A 34-year-old man, previously healthy, was admitted to Chaiyaphum Hospital in Chaiyaphum, Thailand, on August 24, 2009, with influenza-like symptoms. Two days after admission, progressive quadriparesis with bilateral, symmetric paresthesia (glove-and-stocking pattern), and areflexia developed. His motor weakness (grades III/V) began in both legs and then involved both arms and hands. Other neurologic examinations showed limitation of extraocular movement in all directions, normal pupil size and light reflex, and facial diplegia. A lumbar puncture was performed, and cerebrospinal fluid (CSF) contained neither leukocytes nor erythrocytes, with a protein level of 19.5 mg/dL. On day 3 after the patient’s admission, acute respiratory failure developed. A nasopharyngeal aspirate specimen was positive for pandemic (H1N1) 2009 virus by PCR. The patient received oseltamivir, zanamivir, and ventilator support. His chest radiograph showed diffuse alveolar infiltration. On day 10, his motor weakness worsened to grade 0, and his consciousness level was diminished to a drowsy state. A computed tomography scan of the brain showed diffuse white matter lesions (Figure). Repeated lumbar punctures continued to show CSF findings within the reference range. An electrophysiologic study, electromyogram, and nerve conduction study showed polyneuropathy, axonopathy type. Guillain-Barre syndrome was suspected, and intravenous immunoglobulin was given for 5 days. Tests for GQ1b and GM1 antibodies were carried out at Oxford University; results were negative. Figure Computed tomography images of the brain of an adult patient with pandemic (H1N1) 2009 virus infection and neurologic signs. A noncontrast study showed hypodense lesions in both occipital lobes (A) and in both upper parietal lobes (B). Other laboratory tests showed mild transaminitis and negative results for syphilis testing and for serologic tests for HIV, hepatitis B virus, hepatitis C virus, Japanese encephalitis virus, herpes simplex virus, and Mycoplasma pneumoniae. A CSF antigen test was negative, and CSF culture was negative for bacteria. Meropenem was given to treat ventilator-associated pneumonia, which was caused by β-lactam–resistant Klebsiella pneumoniae. After a month of treatment, the patient regained consciousness, his motor strength improved considerably, and he was able to be gradually removed from the ventilator. After 3 months, he was discharged with self-assisted status. Our report shows neurologic manifestations associated with pandemic (H1N1) 2009 virus infection in an adult. The manifestation of progressive quadriplegia with diffuse sensory loss is compatible with a polyneuropathy. The neurologic signs developed 2 days after the respiratory tract signs. Although a diagnosis of Guillain-Barre syndrome was considered initially, according to the National Institute of Neurologic Disorders and Stroke criteria (2), some clinical features did not support this diagnosis. These included the lack of CSF albuminocytologic dissociation, the fact that the clinical signs occurred during the outbreak of pandemic (H1N1) 2009 virus infection rather than after it, and the fact that antibodies were not found in gangliosides. CSF albuminocytologic dissociation and serum ganglioside antibodies may be found in 85%–90% of Guillain-Barre syndrome patients (2). Alternatively, the patient might have had central nervous system complication from pandemic (H1N1) 2009 virus infection. Acute disseminated encephalomyelitis is a condition that might occur within 30 days after an infectious process (3). It can lead to quadriplegia and diffuse white matter lesions. The clinical feature that makes acute disseminated encephalomyelitis less likely in this patient was the CSF findings in the reference range. In summary, however, we believe that pandemic (H1N1) 2009 virus infection can cause neurologic complications affecting both the peripheral and central nervous systems in adult patients.

Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis

Objective: To perform a systematic review and pooled meta-analysis of published studies to assess whether the presence of leukoaraiosis on neuroimaging before treatment with thrombolysis (IV or intra-arterial) is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome. Methods: We included studies of patients with acute ischemic stroke, treated with IV or intra-arterial thrombolysis, which assessed functional outcome (3-month modified Rankin Scale [mRS]) or sICH in relation to leukoaraiosis on pretreatment neuroimaging (CT or MRI). We used random-effects models to calculate pooled relative risks (RR) of sICH and poor functional outcome (mRS ≥ 2) for any vs no leukoaraiosis (using any rating scale) and for no to mild vs moderate to severe leukoaraiosis (using the Van Swieten or Fazekas Schmidt scale). Results: We identified 15 studies (total n = 6,967). For sICH outcome, the RR was 1.65 (n = 5,551; 95% confidence interval [CI] 1.26–2.16, p = 0.001) with an absolute risk (AR) increase of 2.5% for any leukoaraiosis vs none. The RR was 2.4 (n = 4,192; 95% CI 1.83–3.14, p = 0.001) with an AR increase of 6.2% for moderate to severe vs no to mild leukoaraiosis. For poor functional outcome; the RR was 1.30 (n = 3,401; 95% CI 1.19–1.42, p = 0.001) with an AR increase of 15.4% for any leukoaraiosis vs none. The RR was 1.31 (n = 3,659; 95% CI 1.22–1.42, p = 0.001) with an AR increase of 17.5% for moderate to severe vs no to mild leukoaraiosis. No statistical heterogeneity was noted for any of the analyses. Conclusions: Leukoaraiosis presence and severity are consistently associated with an increased risk of sICH and poor functional outcome after IV or intra-arterial thrombolysis for acute ischemic stroke.

Glucocerebrosidase mutations in Thai patients with Parkinson's disease

BACKGROUND GBA mutations are an important risk factor in developing Parkinsons 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.