Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Impact of HIV on inpatient mortality and complications in stroke in Thailand: a National Database Study.

The co-existence of stroke and HIV has increased in recent years, but the impact of HIV on post-stroke outcomes is poorly understood. We examined the impact of HIV on inpatient mortality, length of acute hospital stay and complications (pneumonia, respiratory failure, sepsis and convulsions), in hospitalized strokes in Thailand. All hospitalized strokes between 1 October 2004 and 31 January 2013 were included. Data were obtained from a National Insurance Database. Characteristics and outcomes for non-HIV and HIV patients were compared and multivariate logistic and linear regression models were constructed to assess the above outcomes. Of 610 688 patients (mean age 63·4 years, 45·4% female), 0·14% (866) had HIV infection. HIV patients were younger, a higher proportion were male and had higher prevalence of anaemia (P < 0·001) compared to non-HIV patients. Traditional cardiovascular risk factors, hypertension and diabetes, were more common in the non-HIV group (P < 0·001). After adjusting for age, sex, stroke type and co-morbidities, HIV infection was significantly associated with higher odds of sepsis [odds ratio (OR) 1·75, 95% confidence interval (CI) 1·29-2·4], and inpatient mortality (OR 2·15, 95% CI 1·8-2·56) compared to patients without HIV infection. The latter did not attenuate after controlling for complications (OR 2·20, 95% CI 1·83-2·64). HIV infection is associated with increased odds of sepsis and inpatient mortality after acute stroke.

Safety of withholding anticoagulation in patients with mechanical prosthetic valves and intracranial haemorrhage.

Patients with prosthetic heart valves require lifelong anticoagulation to prevent thromboembolism. When they have intracranial haemorrhage, anticoagulation has to be withheld. This study was aimed to identify safety duration and complications of anticoagulation withholding in patients with prosthetic heart valves and intracranial haemorrhage. This was a retrospective descriptive study in 26 prosthetic heart valve patients hospitalised in Srinagarind Hospital, Khon Kaen University because of intracranial haemorrhage from 2003 to 2008. Range of anticoagulation withholding was 1 to 26 days with mean 8.5 ± 7.7 days. Most patients (84.6%) were withheld anticoagulation for less than 14 days. There were five in-hospital deaths mostly within 3 days of admission from severe intracranial haemorrhage. No data of reintroduction of anticoagulation was found in three patients because they were lost to follow up. One patient had right basal ganglia infarction after 7 days of anticoagulation withholding. Prosthetic heart valve dysfunction was suspected in one patient who withheld anticoagulant for 76 days. Discontinuation of anticoagulation in patients with prosthetic heart valves and intracranial haemorrhage for less than 7 days was associated with low thromboembolic risk and there was no clinical evidence of prosthetic heart valve dysfunction when anticoagulation was withheld for less than 14 days.

Bioequivalence study of two meloxicam tablet formulations after single-dose administration in healthy Thai male volunteers.

OBJECTIVES: To compare the bioavailability of two meloxicam tablet formulations (MEL-OD, Zydus Cadila Healthcare Limited, India, as a test formulation and Mobic, Boehringer Ingelheim International GmbH, Germany, as a reference formulation) in healthy Thai male volunteers under fasting condition. MATERIALS AND METHODS: A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 26 healthy Thai male volunteers. Blood samples were collected 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 24, 36, 48, 72 and 96 h post dose. Plasma concentrations of meloxicam were determined using a validated HPLC method. The pharmacokinetic parameters of meloxicam were determined using a non-compartmental model. RESULTS: The mean Cmax was 1,027.32 +/- 251.91 and 1,151.89 +/- 282.58 ng/ml while the mean AUC0-t was 34,024.31 +/- 11,811.68 and 35,137.66 +/- 11,970.47 ng x h/ml for the test and reference formulation, respectively. In addition, the mean AUC0-infinity for test formulation was 37,241.44 +/- 14,888.85 ng x h/ml and for the reference formulation was 39,541.04 +/- 16,624.64 ng x h/ml. The median tmax for the test and reference formulation was 4.50 (range 2.00 - 12.00) and 4.50 (range 3.00 - 10.00), respectively. The geometric means (90% confidence intervals) of the ratio for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf were 0.8919 (82.58 - 96.32%), 0.9697 (89.46 - 105.10%) and 0.9525 (87.68 - 103.47%), respectively. CONCLUSIONS: It can be concluded that two meloxicam tablet formulations are bioequivalent both in term of rate and extent of absorption after single-dose administration under fasting condition.

Intraocular angiostrongyliasis: clinical findings, treatments and outcomes.

Ocular angiostrongyliasis, diagnosed by identification of Angiostrongylus cantonensis in any part of the eye, is a very rare manifestation. We report seven cases of intraocular angiostrongyliasis in Srinagarind Hospital, Khon Kaen University, Thailand. From a total of 654 cases of angiostrongyliasis diagnosed between January 1995 and April 2005, 7 cases (1.1%) with ocular manifestations were found. Four men and three women were diagnosed, with a mean age of 32.1 years (range 21-46 years). All of the patients lived in the northeast of Thailand and acquired the infection by eating raw Pila spp. snails, the intermediate host of A. cantonensis. The incubation period lasted from 2 weeks to 2 months. The most common symptom, blurred vision without eosinophilic meningitis, occurred as a presenting symptom in five cases. The other two cases presented with eosinophilic meningitis prior to development of poor visual acuity. Both cases had papilloedema, neck stiffness and eosinophilia without fever. The visual acuity of the patient was mostly lower than 2/60 and, evidently, visual impairment in all patients was caused by retinal pigment epithelial defects. All cases had only one immature A. cantonensis worm in the eye, with the most common site being the intravitreous area. Several treatments, including oral prednisolone, topical prednisolone, argon laser, diode laser, Nd:YAG laser, surgical removal of the parasite and combination therapy, were used. There is no evidence that surgical and laser interventions improve the course of the disease, and both have associated risks. Visual outcome depends on the initial visual defects.

Seizure-related injury in an adult tertiary epilepsy clinic.

OBJECTIVE: To assess the frequency, characteristics, and risk of injury during seizure attacks. DESIGN: Questionnaire survey. SETTING: Epilepsy out-patient clinic of the National Hospital for Neurology and Neurosurgery, Institute of Neurology, London. PATIENTS: One hundred consecutive epileptic patients and their caretakers or relatives, who attended the hospital between 1 May and 30 June 2000. MAIN OUTCOME MEASURES: Details of epilepsy including the age of onset, causes, types, and number of seizures during the previous 12 months; injuries incurred as a result of seizures; and treatment required. RESULTS: The mean age of the 100 patients (38 male, 62 female) was 39 years (range, 16-78 years). Generalised tonic-clonic seizures occurred in 51% of patients and complex partial seizures in 40%. Hippocampal sclerosis was found in 12% of patients. Twenty-seven patients reported 222 seizure-related injuries. The total number of seizures per year was 4459 (mean, 45), of which 1094 (mean, 11) were with a fall (24.5%). Soft-tissue injury was the most common (61%), followed by burns (17%), head injury (14%), orthopaedic injury (5%), and injuries in water (3%). The most common site of soft-tissue injury and burns were to the face: 49% and 38% respectively. Burns occurred during cooking in 78% of cases. Two patients had skull fractures. Orthopaedic injuries usually occurred at home (73%). In cases of seizures in water, five of six occurred while swimming. Injury occurred once in every 20 seizures, every 11 generalised tonic-clonic seizures, and every five seizures with a fall. The significant risk factors for injury were generalised tonic-clonic seizures, high frequency of seizures, and seizures with a fall. CONCLUSION: Soft-tissue injury was the most common seizure-related injury. Injury occurred once in every 20 seizures. The risk factors were generalised tonic-clonic seizures, high frequency of seizures, and seizures with a fall.

Myasthenia gravis accompanied with hypokalemic periodic paralysis.

Myasthenia gravis and hypokalemic periodic paralysis are commonly related with hyperthyroidism but rarely occur together. Here, the authors reported a case of hypokalemic periodic paralysis in a Northeastern Thai woman accompanied with myasthenia gravis. She had motor weakness despite a normal level of serum potassium. Prostigmine test was positive. She dramatically improved after pyridostigmine treatment. Autoantibodies to nicotinic AchR-Ab and dihydropyridine receptor or L-type voltage gated calcium channel were postulated to explain these associated diseases.

Levodopa induced motor complications in Thai Parkinson's disease patients.

BACKGROUND: Long-term levodopa usage in Parkinson's disease (PD) patients is known to cause several motor complications. It may be related to several factors such as levodopa dosage, duration of treatment and severity of disease. OBJECTIVE: To study the prevalence of levodopa motor complications and associated factors in Thai Parkinson's disease patients. MATERIAL AND METHOD: The authors prospectively collected baseline characteristics of PD patients, details of treatment and complications from 3 hospitals in various parts of Thailand. These patients were diagnosed by UK PD Brain Bank criteria. RESULTS: A total of 154 patients aged 68.1 +/- 9.5 years were recruited. Age of onset was 61.2 +/- 9.8 years. Most patients were in Hoehn-Yahr stage 1-3. The common clinical features were bradykinesia, rigidity and resting tremor Treatments were levodopa (98.1 per cent), anticholinergic (29.9 per cent), dopamine agonists (26 per cent) and COMT inhibitor (9.1 per cent). Eighty-five per cent of the patients had excellent response to levodopa. However, 25 per cent of patients developed motor complications, which were wearing off (79 per cent), on-off fluctuation (45 per cent), freezing (42 per cent), morning dyskinesia (10.5 per cent) and permanent dyskinesia (23.7 per cent). Twelve patients developed severe levodopa induced chorea. Factors associated with levodopa side effects were earlier age of onset, long duration of disease, advanced stage, higher levodopa dosage and long duration of levodopa treatment. In the present study, age of onset was inversely correlated with H-Y stage, while dosage of levodopa was positively correlated with H-Y stage but inversely correlated with lower ADL score, which may be due to advanced disease state. CONCLUSION: Levodopa motor complications are common in Thai PD patients. Wearing off on-off fluctuation and freezing are common forms of motor complications.

Seizure presenting to the emergency department, Srinagarind Hospital.

The authors would like to evaluate the incidence, clinical manifestation, the appropriateness of treatment, and outcome of seizure at the emergency department (ED). All charts of patients who visited the ED of Srinagarind Hospital from 1 January 2003 to 31 December 2003 were reviewed. The profiles of patients and management at the ED were recorded. There were 33,508 cases who visited the ED with 104 cases (0.31%) presenting with seizure. Four cases (3.9%) were diagnosed as status epilepticus. Generalized tonic-clonic seizure was the most common type. Poor antiepileptic drug (AED) compliance with the low AED level was the main precipitating factor. The normal physical examination and routine laboratory tests were normal in the majority of patients. Phenytoin intravenous loading was the commonest initial treatment even in patients with non-status epilepticus. Fourteen patients (13.5%) were treated with intravenous diazepam even though seizures were discontinued. Sixty patients (57.7%) were discharged after seizure was controlled. The advice in seizure control was recorded in only 11 cases (10.6%). From this review, 12 patients presented at the ED for continuing medication without any seizures. In conclusion, seizure at the ED should be treated more appropriately with both laboratory investigation and drug treatment. Futhermore, patient education should be implemented.

Seizure-related injuries in northeast Thailand.

OBJECTIVE: The authors aimed to assess the frequency, characteristics, and risk of seizure-related injuries from traffic accidents, near-drowning, burns, fractures, head and soft tissue injuries. MATERIAL AND METHOD: Attending physicians assisted 300 consecutive seizure patients to complete a questionnaire. The types and frequency of injuries were then expressed in terms of the type of seizure and related activity. RESULTS: The male (154) and female (146) patients were between 13 and 91 years of age (mean, 36.27 +/- 14.55). The seizure types comprised of Generalized Tonic-Clonic (GTC) (26%), secondary GTCs (21%) and complex partials (19%). Secondary causes accounted for 34% of seizures, and post-stroke was the most common (25.5%). The total number of seizure events per year was 8,525 and of these 7,306 included a fall with soft tissue injury (70%), head injury (22%), near-drowning (3%), burns (3%) and fracture or dislocation (1%). The ranking of significant risk factors for injuries was: 1) GTC seizure; 2) seizure with a fall; and, 3) number of seizures. CONCLUSION: Seizure-related injuries are common among Thai epileptic patients; thus, consistent treatment and education about the risk of injury would protect patients.

MR findings of eosinophilic meningoencephalitis attributed to Angiostrongylus cantonensis.

Eosinophilic meningoencephalitis is prevalent and widely distributed in Thailand, especially in the northeastern and central parts of the country. Angiostrongylus cantonensis is one of the causative agents of fatal eosinophilic meningoencephalitis. The nematodes produce extensive tissue damage by moving through the brain and inducing an inflammatory reaction. We report the clinical features and the findings revealed by MR imaging and MR spectroscopy in six patients with eosinophilic meningoencephalitis. The clinical presentation included severe headache, clouded consciousness, and meningeal irritation. Abnormal findings on MR images included prominence of the Virchow-Robin spaces, subcortical enhancing lesions, and abnormal high T2 signal lesions in the periventricular regions. Proton brain MR spectroscopy was performed in three patients and was abnormal in one severe case, showing decreased choline in a lesion. Small hemorrhagic tracts were found in one case. Lesions thought to be due to microcavities and migratory tracts were found in only one case. We believe the MR imaging and MR spectroscopy findings are of diagnostic value and helpful in understanding the pathogenetic mechanisms of the disease.

Pseudotumor cerebri caused by all-trans-retinoic acid: a case report.

Pseudotumor cerebri is a condition characterized by increased intracranial pressure with normal cerebrospinal fluid composition. It is usually associated with many medical conditions and drugs. It has been reported that all-trans-retinoic acid can induce pseudotumor cerebri. The authors report a 35-year-old patient diagnosed with acute promyelocytic leukemia who developed pseudotumor cerebri after receiving all-trans-retinoic acid. The patient was treated with 60 mg/day of all-trans-retinoic acid. Two weeks later, she had severe headache and blurred vision. The neurological examination revealed papilledema and decreased visual acuity. Other physical examinations were unremarkable. Brain CT was normal. Additionally, lumbar puncture was performed and the CSF finding was normal except for high CSF pressure. According to modified Dandy criteria, the diagnosis was pseudotumor cerebri. The patient's symptoms disappeared after all-trans-retinoic acid was discontinued. To our knowledge, this is the first case report in Thailand.

Hallervorden-Spatz syndrome in two siblings diagnosed by clinical features and magnetic resonance imaging.

The Hallervorden-Spatz syndrome (HSS) is a rare condition characterized by extrapyramidal and pyramidal signs, dystonia, dysarthria, retinal degeneration, dementia and a progressive course. The development of magnetic resonance imaging (MRI) has increased the number of clinical and pathological reports of HSS. MRI pallidal abnormalities are called "eye of the tiger" signs. The combination of clinical features and MRI findings can be considered as highly suggestive of a diagnosis of HSS. Patient 1 was a 28 year old man who had been well until the age of 25 years. He developed dysarthria, difficulty with his gait and dystonia in his arms at the age of 28 years. Patient 2 was a 33 year old man who was the older brother of the first patient. He developed gait difficulty, tongue dystonia and dystonia of both arms at the age of 25 years. Each patient had spastic gait, dysarthria, dystonic posturing of both arms and generalized hyperreflexia, but no Kayser-Fleischer rings or retinitis pigmentosa. Blood chemistry, urine copper, serum copper and serum ceruloplasmin were all normal. MRI of the brain showed the "eye of the tiger" sign in the globus pallidus on T2 weighted images. These siblings had clinical features and MRI findings consistent with HSS. They are the first to be reported in Thailand.

Unusual manifestation in a case of nocardial meningitis.

A case of subacute progressive painful external ophthalmoplegia of the right eye in a 55-year-old woman is reported. CT scan of the brain, paranasal sinuses and orbits revealed normal findings. Tolosa-Hunt syndrome was diagnosed and high dose prednisolone was given. The patient later developed fever, confusion and stiffneck. Lumbar puncture showed grossly purulent CSF with Gram-positive coccobacilli and rod organism. CSF culture grew Nocardia spp. The patient made a complete recovery with trimethoprim-sulfamethoxazole treatment.

Syringomyelia as a complication of tuberculous meningitis.

Tuberculous meningitis (TBM) is a common manifestation of extrapulmonary tuberculosis. Syringomyelia is a rare complication of TBM. We report a case of syringomyelia due to TBM. A 25 year old Thai male was admitted with a history of progressive paraparesis and loss of body sensation. He had a history of TBM in the previous year, and was treated with antituberculous drugs. Physical examination revealed a temperature of 37 degrees C. Motor power was grade 3/5 with generalized hyperreflexia. He had bilateral loss of pain, temperature and vibratory sensation below the T7 level. A magnetic resonance imaging of the spine demonstrated a long segment of syrinx from C4 to the conus medullaris region. A T12-L1 laminectomy and syringosubarachnoid shunt were done. His clinical symptoms improved after surgery.

Downbeating nystagmus and postural hypotension due to basilar invagination.

Downbeating nystagmus is an involuntary vertical rhythmic eye movement with the fast component in the downward direction. The sign indicates a craniocervical disorder. The most common cause is the Arnold-Chiari malformation, followed by cerebellar degeneration. Basilar invagination is a rare cause of downbeating nystagmus. However, with appropriate treatment its prognosis is good. Here, we report a case of basilar invagination which presented with downbeating nystagmus and postural hypotension. A 31 year-old Thai male patient had a 20 year history of postural hypotension. He had recurrent pneumonia and cough-induced syncope a year before admission. He complained of symptoms of an acute febrile illness and a productive cough. The physical examination showed high grade fever, postural hypotension and medium crepitation in the right upper lobe. The neurological examination showed downbeating nystagmus, atrophy and fasciculation of the right side of the tongue, atrophy of the right sternocleidomastoid muscle, mild weakness of the extremities and generalized hyperreflexia. The cervical spine X-ray revealed upward displacement of the vertebral bodies of C1 and C2, with a mild narrowing of the space between C1 and the occiput. The CT-myelogram and MRI showed upward displacement of C1 with overriding of the dens over the anterior lip of the foramen magnum; this also compressed the medulla. Syringomyelia was seen at the C1-C5 level. We report a patient who presented with postural hypotension, recurrent pneumonia and downbeating nystagmus due to basilar invagination. The symptoms were aggravated by cough which caused an increase in intracranial pressure. This resulted from medulla compression in the foramen magnum by the first cervical spine. The treatment of choice was surgical decompression.

Association between apolipoprotein E genotypes and Parkinson's disease.

Previous studies on the association between apolipoprotein E (APOE) alleles and Parkinson's disease (PD) have shown contradictory results. A recent study showed that APOE is involved in a molecular pathway of α-synuclein-induced neurodegeneration. We therefore conducted the first Thai study on APOE genotypes in patients with PD. We analysed the frequencies of APOE genotypes in our case-control study of 155 patients with sporadic PD and 158 control participants. We identified a higher frequency of the APOE-ε2 allele among patients with PD than among controls (odds ratio=2.309, 95% confidence interval=1.111-4.799). Genetic association is a powerful tool for detecting disease susceptibility alleles, but there are many pitfalls to consider before claiming any association. The discrepancy among the results of the genetic association studies of APOE genotypes as a risk of susceptibility to PD emphasises that this association merits clarification by the study of a single large homogeneous population.

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 orbicularis oculi. The efficacy of Dysport is comparable with Botox in long term follow up.