Transient ischemic attacks characterized by RNA profiles in blood.

OBJECTIVE: Transient ischemic attacks (TIA) are common. Though systemic inflammation and thrombosis are associated with TIA, further study may provide insight into TIA pathophysiology and possibly lead to the development of treatments specifically targeted to TIA. We sought to determine whether gene expression profiles in blood could better characterize the proinflammatory and procoagulant states in TIA patients. METHODS: RNA expression in blood of TIA patients (n = 26) was compared to vascular risk factor control subjects without symptomatic cardiovascular disease (n = 26) using Affymetrix U133 Plus 2.0 microarrays. Differentially expressed genes in TIA were identified by analysis of covariance and evaluated with cross-validation and functional analyses. RESULTS: Patients with TIA had different patterns of gene expression compared to controls. There were 480 probe sets, corresponding to 449 genes, differentially expressed between TIA and controls (false discovery rate correction for multiple comparisons, p ≤ 0.05, absolute fold change ≥1.2). These genes were associated with systemic inflammation, platelet activation, and prothrombin activation. Hierarchical cluster analysis of the identified genes suggested the presence of 2 patterns of RNA expression in patients with TIA. Prediction analysis identified a set of 34 genes that discriminated TIA from controls with 100% sensitivity and 100% specificity. CONCLUSION: Patients with recent TIA have differences of gene expression in blood compared to controls. The 2 gene expression profiles associated with TIA suggests heterogeneous responses between subjects with TIA that may provide insight into cause, risk of stroke, and other TIA pathophysiology.

Secondary preventive medication persistence and adherence 1 year after stroke.

OBJECTIVE: Data on long-term use of secondary prevention medications following stroke are limited. The Adherence eValuation After Ischemic stroke-Longitudinal (AVAIL) Registry assessed patient, provider, and system-level factors influencing continuation of prevention medications for 1 year following stroke hospitalization discharge. METHODS: Patients with ischemic stroke or TIA discharged from 106 hospitals participating in the American Heart Association Get With The Guidelines-Stroke program were surveyed to determine their use of warfarin, antiplatelet, antihypertensive, lipid-lowering, and diabetes medications from discharge to 12 months. Reasons for stopping medications were ascertained. Persistence was defined as continuation of all secondary preventive medications prescribed at hospital discharge, and adherence as continuation of prescribed medications except those stopped according to health care provider instructions. RESULTS: Of the 2,880 patients enrolled in AVAIL, 88.4% (2,457 patients) completed 1-year interviews. Of these, 65.9% were regimen persistent and 86.6% were regimen adherent. Independent predictors of 1-year medication persistence included fewer medications prescribed at discharge, having an adequate income, having an appointment with a primary care provider, and greater understanding of why medications were prescribed and their side effects. Independent predictors of adherence were similar to those for persistence. CONCLUSIONS: Although up to one-third of stroke patients discontinued one or more secondary prevention medications within 1 year of hospital discharge, self-discontinuation of these medications is uncommon. Several potentially modifiable patient, provider, and system-level factors associated with persistence and adherence may be targets for future interventions.

Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome.

OBJECTIVE: To describe the frequency, risk factors, and outcome of intracerebral hemorrhage (ICH) in pregnancy and the postpartum period using a large database of US inpatient hospitalizations. METHODS: The authors obtained data from an administrative dataset, the Nationwide Inpatient Sample, which includes approximately 20% of all discharges from non-Federal hospitals, for the years 1993 through 2002. Women aged 15 to 44 years with a diagnosis of ICH were selected from the database for analysis, and within this group patients coded as pregnant or postpartum were identified. Using US Census data, estimates were made of the rates of ICH in pregnant/postpartum and non-pregnant women. Rates of various comorbidities in patients with pregnancy-related ICH were compared to the rates found in the general population of delivering patients using multivariate logistic regression to identify independent risk factors for pregnancy-related ICH. RESULTS: The authors identified 423 patients with pregnancy-related ICH, which corresponded to 6.1 pregnancy-related ICH per 100,000 deliveries and 7.1 pregnancy-related ICH per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for non-pregnant women in the age range considered). The increased risk of ICH associated with pregnancy was largely attributable to ICH occurring in the postpartum period. The in-hospital mortality rate for pregnancy-related ICH was 20.3%. ICH accounted for 7.1% of all pregnancy-related mortality recorded in this database. Significant independent risk factors for pregnancy-related ICH included advanced maternal age (OR 2.11, 95% CI 1.69 to 2.64), African American race (OR 1.83, 95% CI 1.39 to 2.41), preexisting hypertension (OR 2.61, 95% CI 1.34 to 5.07), gestational hypertension (OR 2.41, 95% CI 1.62 to 3.59), preeclampsia/eclampsia (OR 10.39, 95% CI 8.32 to 12.98), preexisting hypertension with superimposed preeclampsia/eclampsia (OR 9.23, 95% CI 5.26 to 16.19), coagulopathy (OR 20.66, 95% CI 13.67 to 31.23), and tobacco abuse (OR 1.95, 95% CI 1.11 to 3.42). CONCLUSION: Intracerebral hemorrhage (ICH) accounts for a substantial portion of pregnancy-related mortality. The risk of ICH associated with pregnancy is greatest in the postpartum period. Advanced maternal age, African American race, hypertensive diseases, coagulopathy, and tobacco abuse were all independent risk factors for pregnancy-related ICH.

Statin use and stroke outcomes in the Heart and Estrogen-Progestin Replacement Study (HERS).

The authors investigated the relationship between statin use and the risk of stroke in the Heart and Estrogen-Progestin Replacement Study (HERS). Despite large reductions in relative risk point estimates, statin use was not associated with differences in the risks of all fatal stroke (relative hazard [RH] 0.52, 95% CI 0.23 to 1.18, p = 0.12), fatal ischemic stroke (RH 0.51, 95% CI 0.18 to 1.45, p = 0.21), fatal hemorrhagic stroke (RH 0.18, 95% CI 0.02 to 1.46, p = 0.11), or TIA (RH 1.32, 95% CI 0.84 to 2.09, p = 0.23).

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.

Improving patient selection for coagulopathy testing in the setting of acute ischemic stroke.

To improve patient selection for specialized coagulation testing in the setting of ischemic stroke, the authors sought to identify factors associated with the presence of hypercoagulable states. Of 208 patients with ischemic stroke tested, undetermined stroke subtype was significantly associated with the presence of coagulopathy, but only 60% were treated with warfarin. The frequency of coagulopathy in selected patients with ischemic stroke (5%) is low, and establishing the diagnosis did not uniformly influence treatment.

Hormone replacement therapy and ischemic stroke severity in women: a case-control study.

OBJECTIVE: To investigate whether ischemic stroke severity differed among women who were receiving hormone replacement therapy (HRT) as compared with those who were not receiving these drugs. BACKGROUND: Estrogen has a neuroprotective effect in animal models of ischemic stroke, but data reflecting the impact of HRT on ischemic stroke severity in humans are lacking. METHODS: All women receiving HRT at the time of admission for acute ischemic stroke to an academic medical center over 3 years were identified by medical record review (n = 58). HRT users were matched with 116 HRT nonusers by age and number of stroke risk factors. Stroke severity was assessed retrospectively with the Canadian Neurological SCALE: Data were analyzed with nonparametric univariate tests (Spearman rank and chi(2) tests) and linear regression modeling using nonparametric matched-pair analysis. RESULTS: History of congestive heart failure or coronary artery disease (p = 0.01), atrial fibrillation (p = 0.02), and African American race (p = 0.04), were significantly associated with greater stroke severity in the univariate analysis. There was a nonsignificant trend toward lesser stroke severity in HRT users (median Canadian Neurological Scale score, 10, vs 9.5 in non-HRT users, p = 0.08). Multivariate analysis showed no independent effect of HRT use on stroke severity (F = 1.24, p = 0.17). CONCLUSIONS: There was no significant effect of HRT status on stroke severity. Because this was a retrospective analysis, prospective studies are also needed to further elucidate any potential neuroprotective effect of hormone replacement.

Retrospective assessment of initial stroke severity: comparison of the NIH Stroke Scale and the Canadian Neurological Scale.

BACKGROUND AND PURPOSE: The NIH Stroke Scale (NIHSS) and the Canadian Neurological Scale (CNS) have been reported to be useful for the retrospective assessment of initial stroke severity. However, unlike the CNS, the NIHSS requires detailed neurological assessments that may not be reflected in all patient records, potentially limiting its applicability. We assessed the reliability of the retrospective algorithms and the proportions of missing items for the NIHSS and CNS in stroke patients admitted to an academic medical center (AMC) and 2 community hospitals. METHODS: Randomly selected records of patients with ischemic stroke admitted to an AMC (n=20) and community hospitals with (CH1, n=19) and without (CH2, n=20) acute neurological consultative services were reviewed. NIHSS and CNS scores were assigned independently by 2 neurologists using published algorithms. Interrater reliability of the scores was determined with the intraclass correlation coefficient, and the numbers of missing items were tabulated. RESULTS: The intraclass correlation coefficient for NIHSS and CNS, respectively, were 0.93 (95% CI, 0.82 to 1.00) and 0.97 (95% CI, 0.90 to 1.00) for the AMC, 0.89 (95% CI, 0.75 to 1.00) and 0.88 (95%, 0.73 to 1.00) for the CH1, and 0.48 (95% CI, 0.26 to 0.70) and 0.78 (95% CI, 0.60 to 0.96) for the CH2. More NIHSS items were missing at the CH2 (62%) versus the AMC (27%) and the CH1 (23%, P:=0.0001). In comparison, 33%, 0%, and 8% of CNS items were missing from records from CH2, AMC, and CH1, respectively (P:=0.0001). CONCLUSIONS: The levels of interrater agreement were almost perfect for retrospectively assigned NIHSS and CNS scores for patients initially evaluated by a neurologist at both an AMC and a CH. Levels of agreement for the CNS were substantial at a CH2, but interrater agreement for the NIHSS was only moderate in this setting. The proportions of missing items are higher for the NIHSS than the CNS in each setting, particularly limiting its application in the hospital without acute neurological consultative services.

Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke.

OBJECTIVE: To investigate the use and appropriateness of specialized coagulation tests in the evaluation of patients with acute ischemic stroke and identify factors that influence test ordering. BACKGROUND: Coagulation abnormalities are a rare but recognized cause of ischemic stroke. METHODS: Patient demographics, stroke risk factors, history of venous thrombosis or miscarriage, family history of stroke, and the results of specialized tests for coagulation disorders were recorded for a consecutive series of ischemic stroke patients over age 18 admitted to an academic medical center over 3 years (n = 674). Factors associated with testing were identified with univariate analyses in a random sample of two-thirds of the patients (n = 450). Multivariate logistic regression modeling was then used to identify variables independently associated with testing and then validated in the remaining patients (n = 224). RESULTS: Of the 31% of patients (n = 208) tested for coagulopathies, 29% (n = 60) were tested when the result was unlikely to influence therapeutic decisions. Historical factors associated with an increased incidence of a coagulopathy, such as history of venous thrombosis or miscarriage, were not commonly documented. The absence of small-artery atherosclerosis (OR 0.36, 95% CI 0.17 to 0.76) and younger age (OR 0.89 per year, 95% CI 0.87 to 0.92) were independently related to the frequency of specialized coagulation testing. CONCLUSIONS: One-third of specialized coagulation tests were ordered when the test results were unlikely to affect therapeutic decisions. Age was the only clinical factor increasing the likelihood of a coagulopathy that appeared to influence ordering of specialized coagulation tests.

Cost implications of specialized coagulation testing for acute ischemic stroke.

BACKGROUND AND PURPOSE: Hypercoagulable states are a rare but recognized cause of ischemic stroke. Evaluation for these coagulation disorders is costly, but establishing a diagnosis may lead to a change in treatment. We estimated the incremental cost of specialized coagulation testing per additional ischemic stroke patient placed on a regimen of warfarin therapy. METHODS: The cost-effectiveness analysis was performed based on data from a consecutive series of 674 adult ischemic stroke patients admitted to an academic medical center over a 3-year period. Those with atrial fibrillation or warfarin contraindications were excluded. Specialized coagulation test costs (protein C, protein S, antithrombin III, plasminogen, activated protein C resistance/factor V Leiden mutation, lupus anticoagulant, and anticardiolipin antibodies) were based on Medicare reimbursement rates. Effectiveness was defined as the difference in proportions of patients tested for coagulation disorders (coagulopathy present, normal complete battery, or incomplete) and treated with warfarin versus those patients who were not tested and treated with warfarin (the comparator). The incremental cost-effectiveness ratio (ICER) was defined as the cost associated with changing 1 patient to warfarin therapy. RESULTS: The base case ICER was $1,102 per additional patient treated with warfarin. The only factor that led to a significant change in the ICER was the proportion of untested patients treated with warfarin. The results of 2-way sensitivity analyses revealed a minimum ICER of $496 and a maximum ICER of $2,959. CONCLUSIONS: Strategies optimizing the selection of patients for specialized coagulation testing are needed. Outcomes-based cost-effectiveness cannot be determined until the impact of secondary prevention with anticoagulation in patients with specific coagulopathies is known.

Diagnostic testing for coagulopathies in patients with ischemic stroke.

BACKGROUND: Hypercoagulable states are a recognized, albeit uncommon, etiology of ischemic stroke. It is unclear how often the results of specialized coagulation tests affect management. Using data compiled from a systematic review of available studies, we employed quantitative methodology to assess the diagnostic yield of coagulation tests for identification of coagulopathies in ischemic stroke patients. SUMMARY OF REVIEW: We performed a MEDLINE search to identify controlled studies published during 1966-1999 that reported the prevalence of deficiencies of protein C, protein S, antithrombin III, plasminogen, activated protein C resistance (APCR)/factor V Leiden mutation (FVL), anticardiolipin antibodies (ACL), or lupus anticoagulant (LA) in patients with ischemic stroke. The cumulative prevalence rates (pretest probabilities) and positive likelihood ratios for all studies and for those including only patients aged

Survival and outcome after endotracheal intubation for acute stroke.

OBJECTIVE: To assess survival and functional outcome in patients endotracheally intubated after ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH). BACKGROUND: Endotracheal intubation is both a necessary life support intervention and a measure of severity in IS or ICH. Knowledge of associated clinical variables may improve the estimation of early prognosis and guide management in these patients. METHODS: We reviewed 131 charts of patients with IS or ICH who were admitted to the Neurosciences Intensive Care Unit at Duke University Medical Center between July 1994 and June 1997 and required endotracheal intubation. Stroke risk factors, stroke type (IS or ICH) and location (hemispheric, brainstem, or cerebellum), circumstances surrounding intubation, neurologic assessment (Glasgow Coma Score [GCS] and brainstem reflexes), comorbidities, and disposition at discharge were documented. Survivors were interviewed for Barthel Index (BI) scores. RESULTS: Survival was 51% at 30 days and 39% overall. Variables that significantly correlated with 30-day survival in multivariate analysis included GCS at intubation (p = 0.03) and absent pupillary light response (p = 0.008). Increase in the GCS also correlated with improved functional outcome measured by the BI (p = 0.0003). In patients with IS, age and GCS at intubation predicted survival, and in patients with ICH, absent pupillary light response predicted survival. CONCLUSIONS: Predictors for mortality differ between patients with IS and ICH; however, decreased level of consciousness is the most important determinant of increased mortality and poor functional outcome. Absent pupillary light responses also correspond with a poor prognosis for survival, but further validation of this finding is needed.

Temporal and qualitative properties of cold pain and heat pain: a psychophysical study.

Dorsal horn neurons that respond to noxious cold also respond to noxious heat, suggesting the hypothesis that pain evoked by temperature extremes, whether hot or cold, may be processed similarly in the CNS. In this study, we tested perceptual consequences of this hypothesis by comparing characteristics of heat and cold pain, as well as of innocuous warm and cool. Eight healthy subjects performed psychophysical tasks involving hot and cold cutaneous stimuli. Using a 9-cm2 contact thermode, temperatures from -5 degrees to 48 degrees C were each applied for 30 s to the thenar eminence. Subjects gave continuous ratings of perceived temperature and pain intensity, using an electronic VAS. After each stimulus, subjects also reported the maximum stimulus intensity and unpleasantness, and chose appropriate words from a list of qualitative verbal descriptors. We found that larger temperature differences were needed in the noxious cold than in the noxious heat range to produce equal perceptual differences. Further, in the heat range, stimulus-response functions were steeper for noxious than for innocuous temperatures, whereas in the cold range, the opposite held true. The relative unpleasantness of heat pain did not differ from that of cold pain, but subjects used a wider range of qualitative words to describe cold pain. Perceived stimulus intensity was compared to temperature recordings from intradermal and skin surface thermocouples. Heat pain, cool and warmth appeared to depend on surface temperature, whereas cold pain was related to subcutaneous temperature, suggesting different receptors for noxious heat and noxious cold. These data, combined with results of human brain imaging and primate electrophysiological studies, suggest that the unpleasantness associated with both heat pain and cold pain is processed similarly in the CNS, whereas differential information about stimulus quality is preserved in the cerebral cortex.

Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized females and intact males.

Variations in levels of estrogen receptor mRNA were investigated in the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus throughout the phases of the female estrous cycle and compared with those in ovariectomized female and intact male rats. Female Wistar rats were killed during estrus, metestrus, diestrus, or proestrus or 72 h after ovariectomy as were a group of intact male rats. Brains were removed and frozen, and 20-microns cryostat sections were thaw-mounted onto slides and hybridized with a 35S-labeled antisense estrogen receptor probe. Section-mounted slides were processed, apposed to x-ray film, then dipped in liquid emulsion, and quantified. After exposure, estrogen receptor mRNA was detected in several brain regions, including the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus. Estrogen receptor mRNA levels in the medial preoptic nucleus were highest during estrus and metestrus, attenuated at diestrus, and low during proestrus. In contrast, the hybridization signal in the arcuate and ventromedial nuclei was low during estrus and then gradually increased throughout the cycle until it peaked during proestrus. Ovariectomized females exhibited an elevated level of estrogen receptor mRNA in all brain regions investigated. Hybridization signal in male medial preoptic nucleus and ventromedial nucleus was reduced compared with those in both intact and ovariectomized females. Estrogen receptor mRNA levels in the arcuate nucleus were similar to those in intact females, but less than those in ovariectomized animals. The results of these studies demonstrate that estrogen receptor mRNA levels are sexually dimorphic, vary during the estrous cycle, and increase after ovariectomy. Furthermore, these results indicate that the magnitude and direction of change observed during the estrous cycle are region specific and suggest that factors other than endogenous estrogen levels differentially modulate estrogen receptor mRNA expression in the hypothalamus.