Yu-Hsiang Su

Six novel NPC1 mutations in Chinese patients with Niemann–Pick disease type C

In patients with Niemann–Pick disease type C (NPC), an autosomal recessive lipid storage disorder, neurodegeneration can occur in early life. Vertical ophthalmoplegia and extrapyramidal signs may be seen. Cholestatic jaundice and hepatosplenomegaly occur frequently in patients with early onset disease, with bone marrow biopsies showing diffuse infiltration of foamy histiocytes. Cholesterol esterification in skin fibroblasts is reduced, resulting in intracellular accumulation of cholesterol. NPC1 mutations are responsible for the disease in ∼95% of patients. NPC1 encodes a 1278 amino acid protein which contains 13 transmembrane domains. Over 130 mutations have been identified in NPC1, with over a third present within an NPC1 specific cysteine-rich domain positioned in a large extracellular loop. It has been proposed that the defect in cholesterol homoeostasis is the cause of neuronal apoptosis, but the precise role of the NPC1 protein and the functional implications of its mutations remain unknown. Although NPC is routinely diagnosed by biochemical analysis, identification of molecular defects helps confirm the diagnosis and enables family studies, and rapid, accurate prenatal diagnosis. This report describe the analysis of the NPC1 gene in five Taiwanese/Chinese patients with NPC. Six novel NPC1 mutations (N968S, G1015V, G1034R, V1212L, S738Stop, and I635fs) were identified of which three are missense mutations located in the cysteine-rich domain. These are the first NPC1 mutations reported from Chinese patients with NPC.

Increased Use of Thrombolytic Therapy and Shortening of In-Hospital Delays Following Acute Ischemic Stroke: Experience on the Establishment of a Primary Stroke Center at a Community Hospital

PURPOSE To improve and standardize stroke care, the establishment of primary stroke centers (PSCs) has been advised. Thrombolytic therapy has been proved to improve the outcome of acute ischemic stroke (AIS). We assessed the use of thrombolytic therapy before and after setting up a PSC at a community hospital. METHODS In November 2007, a PSC was established at our hospital. Following guidelines based on national recommendations, we administered intravenous tissue plasminogen activator (tPA) to patients who met the criteria. To study the effects of the establishment of the PSC on tPA treatment rates, we examined our database of stroke patients dating back to January 2004. RESULTS Before the establishment of the PSC, there have been 2,420 patients admitted to our hospital diagnosed with AIS. Only 1.2% of these patients were treated with intravenous tPA. Following the establishment of the PSC, 2.8% of 1151 AIS patients were treated with tPA. Time of patient arrival to patient treatment was also diminished. CONCLUSION The establishment of the PSC significantly increases the usage of tPA treatment. Furthermore, response time to patient cases was also quicker. However, for maximum effectiveness, the public still needs to be made more aware of the risks of stroke and the importance of seeking medical care at the first signs of stroke.

Intravenous thrombolytic therapy for acute ischemic stroke: the experience of a community hospital.

BACKGROUND AND PURPOSE Tissue plasminogen activator (tPA) is a standard therapy for acute ischemic stroke (AIS) but only limited data are noted in Taiwan. The purpose of this study was to assess the safety, feasibility, and efficacy of treatment in a community hospital setting. METHODS We retrospectively reviewed the medical records of all patients who had received intravenous tPA therapy from 1998 to 2007 in our hospital. We compared the characteristics, complications, and outcomes in our patients with those of patients in the National Institute of Neurological Disorders and Stroke (NINDS) trial. RESULTS A total of 43 patients were reviewed with a mean age of 63 years and a male predominance (64%). The median pretreatment National Institutes of Health Stroke Scale score was 18. In our patients, cardioembolism was the leading course of the strokes. The mean time from stroke onset to treatment was 134 minutes, and the mean door-to-computed tomography-time was 34 minutes while the mean door-to-needle time was 93 minutes. Within 36 hours symptomatic intracerebral hemorrhage occurred in two patients (4.7%). Four patients (9.3%) developed brain herniation with fatality. At follow-up, fourteen patients (33%) had a favorable outcome on the modified Rankin Scale (0-1). Patient outcome was not significantly different from that in the NINDS trial. CONCLUSION Although the number of patients with AIS receiving tPA in this study was small, thrombolytic therapy can be performed safely and effectively by physicians in the community hospital setting.

Impact of Silent Infarction on the Outcome of Stroke Patients

BACKGROUND/PURPOSE Silent infarcts (SIs) are commonly found on brain computed tomography (CT) or magnetic resonance imaging (MRI) among elderly subjects, but their risk factors and impact on outcome in stroke patients are unknown. We evaluated the prevalence, risk factors and impact of SIs on the outcome of patients admitted with first-ever ischemic stroke or transient ischemic attack (TIA). METHODS A prospective study of 446 patients admitted consecutively to the neurology service with a diagnosis of TIA or stroke between July 2003 and June 2005, including 226 without any history of prior TIA or stroke. All patients underwent brain CT on the day of admission to the hospital. Risk factors analyzed included age, history of hypertension, diabetes mellitus, cardiovascular disease or stroke, smoking habit and alcohol use. Cholesterol and triglyceride levels were measured on the second day of admission. We monitored these patients for 24 months after stroke onset. RESULTS The frequency of SIs among the 226 patients with first-ever stroke or TIA was 20%. Most of the SIs were small and deep. Small-artery disease was more frequently observed in patients with SIs. Age, hypertension, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, alcohol use, smoking habits and atrial fibrillation did not significantly differ between patients with SIs and those without SIs. During the 24-month follow-up period, the frequency of recurrent stroke was higher in patients with SIs than those without SIs. The mortality rate was higher in patients without SIs than those with SIs. The interval from stroke onset to rehospitalization was shorter in patients without SIs than in those with SIs. CONCLUSION The study showed a higher frequency of small artery disease in patients with SIs. First-ever stroke patients with SIs should be considered at high risk for recurrent stroke.

Early neurological improvement after intravenous tissue plasminogen activator infusion in patients with ischemic stroke aged 80 years or older.

Background: Early neurological improvement has been observed in patients with stroke receiving treatment with standard intravenous recombinant tissue plasminogen activator. However, the effectiveness of thrombolytic treatment and the risk of hemorrhagic transformation are not well understood in patients aged ≥80 years. In this study, we investigated the influence of age on early neurological improvement and hemorrhagic transformation rates in patients with stroke aged ≥80 years and receiving recombinant tissue plasminogen activator. Methods: The study included 157 patients who received recombinant tissue plasminogen activator infusion at a teaching hospital. The National Institutes of Health Stroke Scale was used to evaluate stroke severity. Early neurological improvement was defined as an improvement of 8 or more points on this scale (compared with baseline) 24 hours after thrombolytic treatment. Neurological improvement was defined as an improvement of 8 or more points (compared with baseline) at discharge. Neurological deterioration was defined as an increase of 4 or more points (compared with baseline). Multivariate analysis was used to evaluate the associations among age, neurological improvement, and hemorrhagic transformation. Results: The rate of early neurological improvement was 36.9% (58/157 patients) and the rate of hemorrhagic transformation was 22.3% (35/157 patients). At discharge, the rate of neurological improvement was 50.9% (80/157 patients) and the rate of neurological deterioration was 13.4% (21/157 patients). There was no statistically significant difference between patients aged ≥80 years and those <80 years of age with respect to rates of early neurological improvement, neurological deterioration, or hemorrhagic transformation. Among patients ≥80 years, the rate of neurological improvement in those receiving thrombolytic treatment was higher than the rate in those patients not receiving thrombolytic treatment (58.8% vs. 14.1%, p < 0.01). We concluded that thrombolysis increases the rate of neurological improvement in patients aged ≥80 years. Conclusion: In older patients, thrombolytic treatment increased the rate of neurological improvement compared with patients not receiving the treatment. The study showed that thrombolytic treatment may be beneficial for patients ≥80 years, but should be performed with extreme care.

Underestimated Rate of Status Epilepticus according to the Traditional Definition of Status Epilepticus

Purpose. Status epilepticus (SE) is an important neurological emergency. Early diagnosis could improve outcomes. Traditionally, SE is defined as seizures lasting at least 30 min or repeated seizures over 30 min without recovery of consciousness. Some specialists argued that the duration of seizures qualifying as SE should be shorter and the operational definition of SE was suggested. It is unclear whether physicians follow the operational definition. The objective of this study was to investigate whether the incidence of SE was underestimated and to investigate the underestimate rate. Methods. This retrospective study evaluates the difference in diagnosis of SE between operational definition and traditional definition of status epilepticus. Between July 1, 2012, and June 30, 2014, patients discharged with ICD-9 codes for epilepsy (345.X) in Chia-Yi Christian Hospital were included in the study. A seizure lasting at least 30 min or repeated seizures over 30 min without recovery of consciousness were considered SE according to the traditional definition of SE (TDSE). A seizure lasting between 5 and 30 min was considered SE according to the operational definition of SE (ODSE); it was defined as underestimated status epilepticus (UESE). Results. During a 2-year period, there were 256 episodes of seizures requiring hospital admission. Among the 256 episodes, 99 episodes lasted longer than 5 min, out of which 61 (61.6%) episodes persisted over 30 min (TDSE) and 38 (38.4%) episodes continued between 5 and 30 min (UESE). In the 38 episodes of seizure lasting 5 to 30 minutes, only one episode was previously discharged as SE (ICD-9-CM 345.3). Conclusion. We underestimated 37.4% of SE. Continuing education regarding the diagnosis and treatment of epilepsy is important for physicians.

Sex-related differences in the risk factors for in-hospital mortality and outcomes of ischemic stroke patients in rural areas of Taiwan

Background and purpose Sex-related differences in the clinical presentation and outcomes of stroke patients are issues that have attracted increased interest from the scientific community. The present study aimed to investigate sex-related differences in the risk factors for in-hospital mortality and outcome in ischemic stroke patients. Methods A total of 4278 acute ischemic stroke patients admitted to a stroke unit between January 1, 2007 and December 31, 2014 were included in the study. We considered demographic characteristics, clinical characteristics, co-morbidities, and complications, among others, as factors that may affect clinical presentation and in-hospital mortality. Good and poor outcomes were defined as modified Ranking Score (mRS)≦2 and mRS>2. Neurological deterioration (ND) was defined as an increase of National Institutes of Health Stroke Score (NIHSS) ≥ 4 points. Hemorrhagic transformation (HT) was defined as signs of hemorrhage in cranial CT or MRI scans. Transtentorial herniation was defined by brain edema, as seen in cranial CT or MRI scans, associated with the onset of acute unilateral or bilateral papillary dilation, loss of reactivity to light, and decline of ≥ 2 points in the Glasgow coma scale score. Results Of 4278 ischemic stroke patients (women 1757, 41.1%), 269 (6.3%) received thrombolytic therapy. The in hospital mortality rate was 3.35% (139/4278) [4.45% (80/1757) for women and 2.34% (59/2521) for men, p < 0.01]. At discharge, 41.2% (1761/4278) of the patients showed good outcomes [35.4% (622/1757) for women and 45.2% (1139/2521) for men]. Six months after stroke, 56.1% (1813/3231) showed good outcomes [47.4% (629/1328) for women and 62.2% (1184/1903) for men, p < 0.01]. Atrial fibrillation (AF), diabetes mellitus, stroke history, and old age were factors contributing to poor outcomes in men and women. Hypertension was associated with poor outcomes in women but not in men in comparison with patients without hypertension. Stroke severity and increased intracranial pressure were associated with increased in-hospital mortality in men and women. AF was associated with increased in-hospital mortality in women but not in men compared with patients without AF. Conclusion The in-hospital mortality rate was not significantly different between women and men. Functional outcomes at discharge and six months after stroke were poorer in women than in men. Hypertension is an independent factor causing poorer outcomes in women than in men. AF is an independent factor affecting sex differences in hospital mortality in women.

Outcome of stroke patients receiving different doses of recombinant tissue plasminogen activator

Background and purpose Intravenous recombinant tissue plasminogen activator (tPA) at a dose of 0.9 mg/kg body weight is associated with a high hemorrhagic transformation (HT) rate. Low-dose tPA (0.6 mg/kg) may have a lower hemorrhage rate but the mortality and disability rates at 90 days cannot be confirmed as non-inferior to standard-dose tPA. Whether the doses 0.7 and 0.8 mg/kg have better efficacy and safety needs further investigation. Therefore, this study is to compare the efficacy and safety of each dose of tPA (0.6, 0.7, 0.8, and 0.9 mg/kg body weight) and to investigate the factors affecting early neurological improvement (ENI) and early neurological deterioration (END). Methods For this observational study, data were obtained from 274 patients who received tPA thrombolytic therapy in Chia-Yi Christian Hospital stroke unit. The tPA dose was given at the discretion of each physician. The definition of ENI was a >8 point improvement (compared with baseline) at 24 h following thrombolytic therapy or an improvement in the National Institutes of Health Stroke Score (NIHSS) to 0 or 1 toward the end of tPA infusion. The definition of END was a >4 point increase in NIHSS (compared with baseline) within 24 h of tPA infusion. The primary objective was to investigate whether 0.7 and 0.8 mg/kg of tPA have higher ENI rate, lower END rate, and better outcome at 6 months. Poor outcome was defined as having a modified Rankin Scale of 3 to 6 (range, 0 [no symptoms] to 6 [death]). The secondary objective was to investigate whether low-dose tPA has a lower risk of intracerebral HT than that with standard-dose tPA. We also investigated the factors affecting ENI, END, HT, and 6-month outcome. Results A total of 274 patients were included during the study period, of whom 260 were followed up for >6 months. There was a trend for the HT rate to increase as the dose increased (P=0.02). The symptomatic HT rate was not significantly different among the low-dose and standard-dose groups. The ENI and END (P=0.52) were not significantly different among the four dosage groups. The clinical functional outcome at 6 months after stroke onset was poorer in the standard-dose group (P=0.02). Stroke severity (P<0.01), stroke type (P=0.03), and diabetes mellitus (P=0.04) affected the functional outcome at 6 months. Conclusion Among the 274 patients receiving tPA thrombolytic therapy, the HT rate increased as dose increased. The symptomatic HT, ENI and END rates were not significantly different among the low-dose (0.6, 0.7, and 0.8 mg/kg) and standard-dose groups. Stroke severity (NIHSS >12), stroke type (cardioembolism and large artery atherosclerosis) and diabetes mellitus were associated with poor outcome at 6 months.

Atrial fibrillation is a predictor of in-hospital mortality in ischemic stroke patients

Background/purpose In-hospital mortality rate of acute ischemic stroke patients remains between 3% and 18%. For improving the quality of stroke care, we investigated the factors that contribute to the risk of in-hospital mortality in acute ischemic stroke patients. Materials and methods Between January 1, 2007, and December 31, 2011, 2,556 acute ischemic stroke patients admitted to a stroke unit were included in this study. Factors such as demographic characteristics, clinical characteristics, comorbidities, and complications related to in-hospital mortality were assessed. Results Of the 2,556 ischemic stroke patients, 157 received thrombolytic therapy. Eighty of the 2,556 patients (3.1%) died during hospitalization. Of the 157 patients who received thrombolytic therapy, 14 (8.9%) died during hospitalization. History of atrial fibrillation (AF, P<0.01) and stroke severity (P<0.01) were independent risk factors of in-hospital mortality. AF, stroke severity, cardioembolism stroke, and diabetes mellitus were independent risk factors of hemorrhagic transformation. Herniation and sepsis were the most common complications of stroke that were attributed to in-hospital mortality. Approximately 70% of in-hospital mortality was related to stroke severity (total middle cerebral artery occlusion with herniation, basilar artery occlusion, and hemorrhagic transformation). The other 30% of in-hospital mortality was related to sepsis, heart disease, and other complications. Conclusion AF is associated with higher in-hospital mortality rate than in patients without AF. For improving outcome of stroke patients, we also need to focus to reduce serious neurological or medical complications.

Applying natural language processing techniques to develop a task-specific EMR interface for timely stroke thrombolysis: A feasibility study

OBJECTIVE To reduce errors in determining eligibility for intravenous thrombolytic therapy (IVT) in stroke patients through use of an enhanced task-specific electronic medical record (EMR) interface powered by natural language processing (NLP) techniques. MATERIALS AND METHODS The information processing algorithm utilized MetaMap to extract medical concepts from IVT eligibility criteria and expanded the concepts using the Unified Medical Language System Metathesaurus. Concepts identified from clinical notes by MetaMap were compared to those from IVT eligibility criteria. The task-specific EMR interface displays IVT-relevant information by highlighting phrases that contain matched concepts. Clinical usability was assessed with clinicians staffing the acute stroke team by comparing user performance while using the task-specific and the current EMR interfaces. RESULTS The algorithm identified IVT-relevant concepts with micro-averaged precisions, recalls, and F1 measures of 0.998, 0.812, and 0.895 at the phrase level and of 1, 0.972, and 0.986 at the document level. Users using the task-specific interface achieved a higher accuracy score than those using the current interface (91% versus 80%, p = 0.016) in assessing the IVT eligibility criteria. The completion time between the interfaces was statistically similar (2.46 min versus 1.70 min, p = 0.754). DISCUSSION Although the information processing algorithm had room for improvement, the task-specific EMR interface significantly reduced errors in assessing IVT eligibility criteria. CONCLUSION The study findings provide evidence to support an NLP enhanced EMR system to facilitate IVT decision-making by presenting meaningful and timely information to clinicians, thereby offering a new avenue for improvements in acute stroke care.