Persistence of hyperdense middle cerebral artery sign on follow-up CT scan after intravenous thrombolysis is associated with poor outcome.

BACKGROUND: The rates and extent of recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA) remain highly variable. Hyperdense middle cerebral artery sign (HMCAS) on pretreatment unenhanced computerized tomography (CT) of the brain represents the presence of thrombus, often associated with severe neurological deficits and poor clinical outcome at 3 months. However, HMCAS is reliable only in AIS patients managed conservatively. In patients treated with systemic thrombolysis, HMCAS may disappear (representing clot dissolution) or persist (persisting clot) on the follow-up CT scan of the brain. We aimed at evaluating whether disappearance or the persistence of HMCAS on follow-up CT scan of the brain can predict the final outcome at 3 months. METHODS: Data from consecutive AIS patients treated with IV-tPA, in a standardized protocol, from January 2007 to March 2010 were included in the prospective thrombolysis registry at our tertiary care center. For this evaluation, posterior circulation stroke was excluded. HMCAS was assessed on admission as well as follow-up CT by 2 independent stroke neurologists, blinded to the patient data or outcomes. Functional outcomes assessed by the modified Rankin Scale (mRS) at 3 months were dichotomized as good (mRS score 0-1) and poor (mRS score 2-6). The data were analyzed for the early predictors of poor functional outcome with SPSS version 19 for Windows. RESULTS: Of the total of 2,238 patients admitted during the study period, 226 (11%) with anterior circulation AIS treated with intravenous thrombolysis were included. Median age of the patients was 65 years (range 19-92), 63% were males and they had a median National Institutes of Health Stroke Scale (NIHSS) score of 16 points (range 4-32). HMCAS was observed on admission CT scan in 109 (48.2%) patients and persisted on follow-up CT in 52 (47.7%) of them. Overall, 108 (47.8%) patients achieved poor functional outcome at 3 months. Admission NIHSS score (OR per 1-point increase = 1.241; 95% CI = 1.151-1.337, p < 0.0005), lesser change in NIHSS score at 24 h (OR per 1-point reduction = 0.730; 95% CI = 0.666-0.800, p < 0.0005) and persistence of HMCAS on follow-up CT scan (OR = 3.352; 95% CI = 1.991-11.333, p = 0.039) were associated with poor outcome at 3 months. CONCLUSION: Persistence of HMCAS on the follow-up CT scan of the brain in acute ischemic stroke patients treated with IV-tPA can be used as an early predictor of poor functional outcome.

Stroke risk factors and outcomes among various Asian ethnic groups in Singapore.

Data on interethnic differences in the Asian stroke population are limited. We evaluated the relationships among various cardiovascular risk factors, stroke subtypes, and outcomes in a multiethnic Singaporean population comprising consecutive ischemic stroke patients presenting to our tertiary center over a 1-year period. Strokes were classified based on criteria used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Functional independence at hospital discharge was defined as a modified Rankin Scale (mRS) score of 0-2. The ethnic distribution of the study population (n = 481; mean age, 64.1 ± 11.9 years) was 74% Chinese, 17% Malay, and 9% Indian. The prevalence of risk factors was similar in the 3 ethnic groups except for diabetes (Chinese, 39.8%; Malay, 67.5%; Indian, 52.3%; P < .001). Hypertension and hypercholesterolemia were the most common cardiovascular risk factors. Lacunar stroke was the most frequent stroke subtype (47.9%). Large-artery atherosclerotic infarctions were more prevalent in Indians (25.0%), whereas lacunar infarctions occured more frequently in Chinese (51.8%; P < .01). No differences in in-hospital mortality and functional independence at discharge were seen among the 3 ethnic groups. Despite the differences in risk factors and in stroke subtypes classified by location or underlying etiology, short-term outcome measures were similar in the 3 different Asian ethnicities in Singapore.

Oxidative damage in ischemic stroke revealed using multiple biomarkers.

BACKGROUND AND PURPOSE: We investigated changes in oxidative damage after ischemic stroke using multiple biomarkers. METHODS: Serial blood and urine samples of ischemic stroke subjects and age-matched control subjects were assayed for F2-isoprostanes, hydroxyeicosatetraenoic acid products, F4-neuroprostanes, 24-hydroxycholesterol, allantoin, and urate. RESULTS: Sixty-six stroke subjects (mean age, 65 years; median National Institutes of Health Stroke Scale 17) and 132 control subjects were recruited. A bimodal pattern of change was observed in plasma and urinary F2-isoprostanes and plasma 24-hydroxycholesterol. The rise in plasma hydroxyeicosatetraenoic acid products, F4-neuroprostanes, and allantoin was highest 6 to 12 hours after stroke onset, whereas plasma urate was significantly lower than controls on Days 1 to 3. After adjusting for age and baseline National Institutes of Health Stroke Scale, baseline plasma esterified hydroxyeicosatetraenoic acid products (OR, 1.01; 95% CI, 1.01 to 1.02), plasma urate (1.01; 1.00 to 1.01), and plasma free F4-neuroprostanes (2.73; 1.76 to 3.93) were associated with 90-day good functional recovery (modified Rankin Scale ≤1). CONCLUSIONS: Multiple markers of oxidative damage are increased immediately after stroke and remain elevated for several days. Recognition of these temporal changes may help design better antioxidant treatment trials for acute ischemic stroke.

Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore.

Treatment rates with intravenously administered tissue plasminogen activator (IV-tPA) in acute ischemic stroke (IS) remain low in Asian populations. Various logistic obstacles and higher anticipated bleeding risk in Asians are major concerns. We report on the feasibility and safety of IV-tPA therapy at our tertiary care center. Consecutive acute IS patients eligible for thrombolysis were treated with low-dose (maximum 50 mg) IV-tPA between January 2000 and September 2006 and with standard-dose (maximum 90 mg) IV-tPA between October 2006 and May 2008. The efficacy of IV-tPA was assessed by the modified Rankin Scale (mRS) score at 3 months and by absolute changes in the National Institute of Health Stroke Scale (NIHSS) score at hospital discharge and 3 months. The safety of IV-tPA was assessed by the rate of symptomatic intracranial hemorrhage (SICH). A total of 130 patients were included (mean age, 60±13 years; 60% males; median NIHSS score, 14). A total of 48 patients received low-dose IV-tPA, and 82 patients received standard-dose IV-tPA. The median onset to treatment time was 160 minutes. Some 59% of the patients achieved functional independence (mRS score 0-1) at 3 months with standard-dose tPA, compared with 35% in the low-dose group (P=.011). SICH occurred more frequently with the low dose (14.5%) than with the standard dose (1.2%; P=.004). In a multivariate logistic regression model, lower admission NIHSS score (odds ratio [OR]=0.78 per 1-point increase; 95% confidence interval [CI]=0.70-0.88), lower pretreatment blood glucose level (OR=0.76 per 1 mmol/L increase; 95% CI=0.60-0.95), shorter time from symptom onset to IV-tPA bolus (OR=0.97 per 1-minute increase; 95% CI=0.94-1.0), and standard-dose IV-tPA (OR=12.49; 95% CI=2.9-53.89) were associated with a higher likelihood for functional independence at 3 months. Our data indicate that standard-dose IV-tPA (0.9 mg/kg) was feasible and safe for treating acute IS in our multiethnic Asian population in Singapore.

Can demographic and admission laboratory variables be useful to identify long-stay patients with acute ischemic stroke? A hospital-based cohort study in Singapore.

The demographic and laboratory predictors of long-stay patients with ischemic stroke were sought in this retrospective hospital-based study. In the univariate and multivariate analysis, advanced age, male gender, leukocytosis, elevated creatinine, low-serum albumin, elevated alkaline transaminases, and lactate dehydrogenase were identified as independent predictors of "long" stayers. At an optimal probability cut-offs, the receiver operating curve incorporating these variables was 0.70, sensitivity 68%, specificity 80%, positive-predictive value 39% and negative-predictive value 95%. Application of this information may assist physicians to triage patients at risk of severe stroke for early therapy and care.

Novel chloride channel mutations leading to mild myotonia among Chinese.

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation.

The S218L CACNA1A mutation has been previously described in two families with familial hemiplegic migraine. We present three siblings with the mutation with the novel association of childhood seizures, and highlight the dynamic changes seen on electroencephalography during hemiplegic migraine attacks. Depressed activity contralateral to the hemiparesis was seen on electroencephalography during acute hemiplegic migraine attacks, which may be due to changes to calcium channels caused by the S218L mutation. Both parents were asymptomatic and did not carry the S218L mutation in their blood. This suggests the presence of mosaicism in the transmitting parent.

Computer-based testing of the modified essay question: the Singapore experience.

BACKGROUND: The modified essay question (MEQ), featuring an evolving case scenario, tests a candidate's problem-solving and reasoning ability, rather than mere factual recall. Although it is traditionally conducted as a pen-and-paper examination, our university has run the MEQ using computer-based testing (CBT) since 2003. AIMS: We describe our experience with running the MEQ examination using the IVLE, or integrated virtual learning environment (https://ivle.nus.edu.sg), provide a blueprint for universities intending to conduct computer-based testing of the MEQ, and detail how our MEQ examination has evolved since its inception. METHODS: An MEQ committee, comprising specialists in key disciplines from the departments of Medicine and Paediatrics, was formed. We utilized the IVLE, developed for our university in 1998, as the online platform on which we ran the MEQ. We calculated the number of man-hours (academic and support staff) required to run the MEQ examination, using either a computer-based or pen-and-paper format. RESULTS: With the support of our university's information technology (IT) specialists, we have successfully run the MEQ examination online, twice a year, since 2003. Initially, we conducted the examination with short-answer questions only, but have since expanded the MEQ examination to include multiple-choice and extended matching questions. A total of 1268 man-hours was spent in preparing for, and running, the MEQ examination using CBT, compared to 236.5 man-hours to run it using a pen-and-paper format. Despite being more labour-intensive, our students and staff prefer CBT to the pen-and-paper format. CONCLUSIONS: The MEQ can be conducted using a computer-based testing scenario, which offers several advantages over a pen-and-paper format. We hope to increase the number of questions and incorporate audio and video files, featuring clinical vignettes, to the MEQ examination in the near future.

Is there a place for placebo in management of psychogenic movement disorders?

INTRODUCTION: The management of psychogenic movement disorders is fraught with difficulties. Empathy and a non-judgmental manner are essential in dealing with patients, and a neurobiological explanation of the symptoms may help to foster trust, acceptance, understanding and recovery. CLINICAL PICTURE: We report a 17-year-old Chinese girl with psychogenic blepharospasm. Her parents refused psychotherapy and pharmacotherapy. TREATMENT AND OUTCOME: Placebo therapy (with parental consent) was prescribed with favourable results. CONCLUSION: We examine the ethical considerations for and against placebo therapy, and explore the role of placebo therapy in the management of psychogenic movement disorders.

POEMS syndrome--a case for more aggressive treatment.

INTRODUCTION: Patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal or M-protein and skin changes) syndrome exhibit a wide range of clinical manifestations and are often seen by a variety of specialists prior to diagnosis. CLINICAL PICTURE: We describe a case of POEMS syndrome that first presented with significant neuropathy but progressed to develop further manifestations of the condition, including marked gastrointestinal symptoms. TREATMENT: The patient was commenced on localised radiotherapy and chemotherapy in addition to immunomodulatory therapy for the neuropathy. CONCLUSION: We highlight several learning points that may benefit physicians from varied specialties. This case is also unique for its marked gastrointestinal manifestation. To our knowledge, this is the second reported case in the literature with this feature.

Botulinum toxin-A injections for spastic toe clawing.

Spastic toe clawing describes extension at the metatarsophalangeal joints of the feet, flexion at the proximal interphalangeal joints and flexion at the distal interphalangeal joints that results from upper motor neuron lesions, such as stroke, intracranial hemorrhage, cervical myelopathy and brain tumors. Even though toe clawing is often asymptomatic, it can be painful. Previous studies have described the efficacy of injections of botulinum toxin type-A (BTX-A) to the long flexors of the toes, but this is often unsatisfactory as high dosages (up to 175 units) have been required, and patients often report significant residual toe clawing. We performed an open label, prospective study to assess the efficacy of BTX-A injections, targeting the long and short flexors of the toes, performed with electrical (motor point) stimulation under electromyographic guidance. Outcome measures, which included timed walking over 20m, objective assessment of toe clawing (modified Ashworth scale and a visual analog scale rating) and patient assessment of functional disability, were assessed before injections and at six-weeks' follow-up. Seven patients (five male and two female) of mean age 51 (range 38-70) were recruited. Four had spasticity from underlying intracranial hemorrhage, the remaining three from cerebral infarct, astrocytoma and post-traumatic cervical myelopathy. The total dose of BTX-A injected for toe clawing ranged from 40 to 90 units. Improvements were observed in all outcome measures except timed walking. Injecting BTX-A to the long and short flexors of the toes, with electrical stimulation under electromyographic guidance, is well tolerated and efficacious in the treatment of toe clawing from spasticity, allowing for lower dosages to be used.

Botulinum toxin: a novel therapeutic option for bronchial asthma?

Two components are essential for the development of an attack of bronchial asthma: inflammation and bronchoconstriction, the latter being mediated by smooth muscle contraction. Despite the efficacy of chronic therapy, many asthmatics relapse. Measures to inhibit contraction of the airway smooth muscle, such as vagotomy and thermoablation, may decrease the bronchoconstrictor component of the asthma attack and help to decrease morbidity and mortality from the disease. Botulinum toxin acts to weaken skeletal and smooth muscle by preventing the docking of the acetylcholine vesicle on the inner surface of the presynaptic membrane, thus causing chemical denervation and paresis of skeletal or smooth muscle. We explore the possibility that administration of botulinum toxin may achieve the same effect in bronchial asthma and examine the evidence to support this hypothesis.

Topical botulinum toxin to treat hyperhidrosis? No sweat!

Palmar, plantar and axillary hyperhidrosis, though benign, may be burdensome and occupationally restrictive, even hazardous. Treatment modalities range from topical antiperspirants, iontophoresis, systemic medications such as anticholinergics and benzodiazepines and injections of botulinum toxin, to thoracic sympathectomy. Intradermal injections of botulinum toxin (BTX), though effective, are painful especially when multiple injections are required. Iontophoretic administration of BTX has been described, the BTX entering the eccrine sweat glands via the sweat pores and through the sweat ducts. We postulate that BTX can be administered topically, either unassisted or assisted by application of an electrical gradient, low-frequency ultrasound or excipients such as dimethylsulfoxide. We examine the rationale and feasibility for such a treatment modality and route of administration.

Where has all the botox gone? (how) will we ever learn... using monoclonal antibodies to track botulinum toxin.

Botulinum toxin (BTX) is an important therapeutic tool in the treatment of overactive skeletal and smooth muscles, as well as hypersecretory and painful disorders. Despite advances in our understanding of how BTX works, much remains to be elucidated, such as how BTX ameliorates pain, how it produces weakness remote from the site of injection and the fate of the heavy and light chain components of the BTX molecule following endocytosis into the presynaptic membrane. BTX, conjugated to radionuclides, allows investigators to track the molecule both in vitro and in vivo. However, altering the BTX molecule may cause structural changes or pharmacokinetic and pharmacodynamic alterations, and disrupt its normal action. We propose instead to bind the biomarkers (appropriate dyes, radionuclides or MRI contrast agents) to monoclonal antibodies directed against either heavy or light chain components of BTX, thus allowing administration of native (i.e. unaltered) BTX.

Computer-based versus pen-and-paper testing: students' perception.

BACKGROUND: Computer-based testing (CBT) has become increasingly popular as a testing modality in under- and postgraduate medical education. Since 2004, our medical school has utilised CBT to conduct 2 papers for the third- and final-year assessments - Paper 3, with 30 multiple choice questions featuring clinical vignettes, and the modified essay question (MEQ) paper. AIMS: To obtain feedback from final-year students on their preferred mode of testing for Paper 3 and MEQ components of the Medicine track examination, and the reasons underlying their preferences. METHODS: An online survey was carried out on 213 final-year undergraduates, in which they were asked to provide feedback on Paper 3 and MEQ papers. Students were asked if they thought that the CBT format was preferable to the pen-and-paper (PNP) format for Paper 3 and the MEQ, and why. RESULTS: One hundred and fourteen out of 213 (53.5%) students completed the online survey. For Paper 3, 91 (79.8%) felt that CBT was preferable to PNP, 11 (9.6%) preferred the PNP format and 12 (10.5%) were unsure. For the MEQ, 62 (54.4%) preferred CBT over PNP, 30 (26.3%) preferred the PNP format and 22 (19.3%) were unsure. Reasons given to explain preference for CBT over PNP for Paper 3 included independence from seating position, better image quality (as images were shown on personal computer screens instead of projected onto a common screen) and the fact that CBT allowed them to proceed at their own pace. For the MEQ, better image quality, neater answer scripts and better indication of answer length in CBT format were cited as reasons for their preference. CONCLUSIONS: Our survey indicated that whereas the majority of students preferred CBT over PNP for Paper 3, a smaller margin had the same preference for the MEQ.

Computer calculated dose in paediatric prescribing.

BACKGROUND AND OBJECTIVE: Medication errors are an important cause of hospital-based morbidity and mortality. However, only a few medication error studies have been conducted in children. These have mainly quantified errors in the inpatient setting; there is very little data available on paediatric outpatient and emergency department medication errors and none on discharge medication. This deficiency is of concern because medication errors are more common in children and it has been suggested that the risk of an adverse drug event as a consequence of a medication error is higher in children than in adults. OBJECTIVE: The aims of this study were to assess the rate of medication errors in predominantly ambulatory paediatric patients and the effect of computer calculated doses on medication error rates of two commonly prescribed drugs. METHODS: This was a prospective cohort study performed in a paediatric unit in a university teaching hospital between March 2003 and August 2003. The hospital's existing computer clinical decision support system was modified so that doctors could choose the traditional prescription method or the enhanced method of computer calculated dose when prescribing paracetamol (acetaminophen) or promethazine. All prescriptions issued to children (<16 years of age) at the outpatient clinic, emergency department and at discharge from the inpatient service were analysed. A medication error was defined as to have occurred if there was an underdose (below the agreed value), an overdose (above the agreed value), no frequency of administration specified, no dose given or excessive total daily dose. The medication error rates and the factors influencing medication error rates were determined using SPSS version 12. RESULTS: From March to August 2003, 4281 prescriptions were issued. Seven prescriptions (0.16%) were excluded, hence 4274 prescriptions were analysed. Most prescriptions were issued by paediatricians (including neonatologists and paediatric surgeons) and/or junior doctors. The error rate in the children's emergency department was 15.7%, for outpatients was 21.5% and for discharge medication was 23.6%. Most errors were the result of an underdose (64%; 536/833). The computer calculated dose error rate was 12.6% compared with the traditional prescription error rate of 28.2%. Logistical regression analysis showed that computer calculated dose was an important and independent variable influencing the error rate (adjusted relative risk = 0.436, 95% CI 0.336, 0.520, p < 0.001). Other important independent variables were seniority and paediatric training of the person prescribing and the type of drug prescribed. CONCLUSIONS: Medication error, especially underdose, is common in outpatient, emergency department and discharge prescriptions. Computer calculated doses can significantly reduce errors, but other risk factors have to be concurrently addressed to achieve maximum benefit.

Frequency of provocative factors in epileptic patients admitted for seizures: a prospective study in Singapore.

Intractable epilepsy is commonly believed to be the main cause of uncontrolled seizures and hospitalization in epileptic patients. We study frequency and types of potential provocative factors in epileptic patients admitted with seizures, and suggest methods to decrease seizure occurrence and hospitalization. Over 6 months we prospectively studied all epileptic patients hospitalized for seizures. A structured interview and laboratory investigations were used to determine type and number of potential seizure precipitants. Precipitants thought to be avoidable through actions taken by the patient or physicians were termed potentially preventable provocative factors (PPPF). Patients' awareness and knowledge of seizure precipitants were also assessed. Three quarters of all seizures leading to admission were associated with PPPF, the commonest being non-compliance (71%), sub-therapeutic doses of antiepileptic drugs (26%) and sleep deprivation (9%). Only one patient had intractable epilepsy. Patients' knowledge of seizure precipitants was poor. The majority of hospital admissions for seizures in epileptic patients are associated with potentially preventable causes amenable to education programmes. Patient education involving epilepsy nurse educators may play an important role in decreasing seizure occurrence and possibly unnecessary hospital admissions.

Generalised myoclonus evolving into epilepsia partialis continua due to a cingulate gyrus lesion: case report and review of the literature.

A young Chinese male was admitted for a generalised tonic-clonic seizure preceded by a week-long history of fever. Subsequently, he developed continuous myoclonic jerks in all four limbs, with clear left sided predominance, and no accompanying clouding of consciousness. Contrast MRI of the brain demonstrated a venous angioma in the right cingulate gyrus. Over the next few days, the clinical picture evolved, with focal motor status involving primarily the left lower limb and the abdomen. These movements resolved with anticonvulsant therapy. This case illustrates generalised myoclonus arising from a focal brain abnormality. The epileptiform aetiology became obvious only after evolution into the typical features of a focal motor seizure and supportive neuroimaging. This demonstrates the protean manifestations of epileptic seizures which have been ascribed to the cingulate gyrus. The lack of clear declarative clinical and EEG features highlights the melding of the fields of epileptology and movement disorders.