Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.

BACKGROUND: Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. DESIGN AND METHODS: In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. RESULTS AND CONCLUSIONS: We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

Bleeding risk, physical functioning and non-use of anticoagulation among patients with stroke and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is common among people with stroke. Anticoagulation medications can be used to manage the deleterious impact of AF after stroke, however, may not be prescribed due to concerns about post-stroke falls and decreased functioning. Thus, the purpose of this study was to identify, among people with stroke and AF, predictors of anticoagulation prescription at hospital discharge. METHODS: This is a secondary analysis of a retrospective cohort study of data retrieved via medical records, including National Institutes of Health Stroke Scale score, Functional Independence Measure (FIM) motor score (motor or physical function), ambulation on second day of hospitalization, Morse Falls Scale (fall risk) and HAS-BLED score (Hypertension; Abnormal renal and liver function; Stroke; Bleeding; Labile INRs; Elderly >65; and Drugs or alcohol). Data analyses included bivariate comparisons between people with and without anticoagulation at discharge. Logistic-regression modeling was used to assess predictors of discharge anticoagulation. RESULTS: There were 334 subjects included in the analyses, whose average age was 75 years old. Anticoagulation was prescribed at discharge for 235 (70%) of patients. In the adjusted regression analyses, only the FIM motor score (adjusted OR = 1.015, 95% CI 1.001-1.028) and the HAS-BLED score (adjusted OR = 0.36, 95% CI 0.22-0.58) were significantly associated with anticoagulation prescription at discharge. CONCLUSION: It appears that in this sample, post-stroke anticoagulation decisions appear to be made based on clinical factors associated with bleed risk and motor deficits or physical functioning. However, opportunities may exist for improving clinician documentation of specific reasoning for non-anticoagulation prescription.

Poststroke depression and treatment effects on functional outcomes.

BACKGROUND: Poststroke depression (PSD) is common after stroke; however, the relationship to poststroke function is inconclusive. Our objectives were to 1) determine the relationship between PSD at baseline (1 month poststroke) and function (12 weeks later) and 2) assess the impact of depression improvement on 12-week function among those with depression at baseline. METHODS: We completed a secondary analysis of data from a cohort study of participants with and without PSD. We used logistic regression to identify factors associated with 12-week functional dependence for 1) all 367 participants and 2) the 174 participants with PSD. RESULTS: In the PSD cohort, 3 characteristics were found to be independently associated with 12-week dependence: increased medical comorbidity (odds ratio [OR] 1.10, 95%confidence interval [CI] 1.02-1.22), increased stroke severity (OR 1.42, 95% CI 1.19-1.69), and increased baseline depression severity (OR 1.13, 95% CI 1.03-1.23). Depression severity was significantly different between those considered dependent and independent at 12 weeks (entire cohort, PHQ-9 7.31 vs 5.18, p = 0.008; depressed cohort, PHQ-9 9.94 vs 7.27, p = 0.019). CONCLUSION: Among study participants with PSD, the severity of depression symptoms at baseline was associated with dependence; however, our results are inconclusive as to whether improvement of depression is independently associated with functional recovery at 12 weeks. Even if the treatment and improvement of PSD does not directly influence functional recovery poststroke, it is essential for PSD to be identified and treated due to its high symptom burden and association with other negative health and social outcomes.

Racial/ethnic disparities in access to physician care and medications among US stroke survivors.

BACKGROUND: Mexican Americans and non-Hispanic blacks have higher stroke recurrence rates and lower rates of secondary stroke prevention than non-Hispanic whites. As a potential explanation for this disparity, we assessed racial/ethnic differences in access to physician care and medications in a national sample of US stroke survivors. METHODS: Among all 4,864 stroke survivors aged≥45 years who responded to the National Health Interview Survey years 2000-2006, we compared access to care within the last 12 months by race/ethnicity before and after stratification by age (45-64 years vs ≥65 years). With logistic regression, we adjusted associations between access measures and race/ethnicity for sex, comorbidity, neurologic disability, health status, year, income, and health insurance. RESULTS: Among stroke survivors aged 45-64 years, Mexican Americans, non-Hispanic blacks, and non-Hispanic whites reported similar rates of no generalist physician visit (approximately 15%) and inability to afford medications (approximately 20%). However, among stroke survivors aged≥65 years, Mexican Americans and blacks, compared with whites, reported greater frequency of no generalist visit (15%, 12%, 8%; p=0.02) and inability to afford medications (20%, 11%, 6%; p<0.001). Mexican Americans and blacks more frequently reported no medical specialist visit (54%, 49%, 40%; p<0.001) than did whites and rates did not differ by age. Full covariate adjustment did not fully explain these racial/ethnic differences. CONCLUSIONS: Among US stroke survivors at least 65 years old, Mexican Americans and blacks reported worse access to physician care and medications than whites. This reduced access may lead to inadequate risk factor modification and recurrent stroke in these high-risk minority groups.

Outcomes of newly referred neurology outpatients with depression and pain.

BACKGROUND: Although depression and pain are common in neurology outpatients, patient factors influencing chronicity are poorly understood. The authors sought to determine the predictors of persistent depression and pain symptoms at 3 and 12 months after an initial outpatient neurology clinic visit. METHODS: Consecutive new patients (n = 483) at three clinics completed the Patient Health Questionnaire nine-item depression scale and the Brief Pain Inventory at baseline and at 3- and 12-month follow-up. Multivariate analysis was used to model 3- and 12-month depression and pain severity. RESULTS: The prevalence of depression and pain at baseline/3/12 months was depression 33%/28%/27% and pain 66%/61%/62%. Independent predictors of depression severity at follow-up were more severe depression and pain at baseline and less improvement in pain (model r(2) = 0.53 to 0.56). Independent predictors of pain intensity at follow-up were more severe pain and depression at baseline and less improvement in depression (model r(2) = 0.44 to 0.46). Health care utilization and impairments in health status were greatest in patients with coexisting depression and pain and least in those with neither depression nor pain. CONCLUSIONS: Depression and pain symptoms in neurology outpatients often persist for at least 12 months and have long-term negative effects on patients' health status. Pain is more likely to persist in patients with depression, and depression is more likely to persist in those with coexistent pain.

Prevalence and impact of depression and pain in neurology outpatients.

BACKGROUND: We examined the prevalence and health related quality of life (HRQoL) of depression and/or pain in neurology outpatients. METHODS: Patients at outpatient clinics completed depression, pain, and HRQoL scales. Group comparisons between those with pain alone, depression alone, both conditions, and neither condition were done. RESULTS: Overall, pain was present in 2/3 and depression in 1/3 of patients. Pain with depression was present in 25%; 75% of depressed patients had pain. These conditions had significant negative impact on mental and physical health status scores. The odds ratio (OR) for having pain was significantly increased in women (OR 2.0), those with depression (OR 2.4), and those with neuropathy/neuromuscular (OR 3.8) or pain syndromes (OR 4.8). The odds of having depression were increased in those with pain (OR 2.4) and with cognitive (OR 4.8) or cerebrovascular (OR 3.3) diagnoses. Neurologists were more likely to recognise and treat pain than depression. CONCLUSIONS: Depression and pain are common in newly referred neurology outpatients and have substantial negative effects on patients' physical and mental health. Pain is more likely than depression to be recognised and treated by neurologists.

Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke.

BACKGROUND: Hyperglycemia at the time of acute ischemic stroke has been linked to worse outcome in both human and animal studies. OBJECTIVE: To describe the prevalence and severity of hyperglycemia on hospital admission among acute ischemic stroke patients, to examine the independent relationship of admission hyperglycemia to all-cause mortality, and to document the inpatient management of hyperglycemia. METHODS: Patients hospitalized with acute ischemic stroke at one hospital from July 1993 to June 1998 (n = 656) were identified. Demographic data, diagnoses, and blood glucose (BG) values were retrieved from the electronic medical record system. Admission stroke severity, fingerstick BG results, and new diabetes diagnoses were obtained by chart review. Hyperglycemia was defined as admitting random serum BG > or = 130 mg/dL. Hazard ratios (HR) for 30-day, 1-year, and 6-year mortality were calculated using multivariable Cox regression models. RESULTS: Hyperglycemia at admission to hospital was present in 40% of patients with acute stroke. Patients with hyperglycemia were more often women and more likely to have prior diagnoses of diabetes and heart failure. Almost all of these patients remained hyperglycemic during their hospital stay (mean BG = 206 mg/dL), and 43% received no inpatient hypoglycemic drugs. Hyperglycemic patients had longer hospital stay (7 vs 6 days, p = 0.015) and higher inpatient hospital charges ($6,611 vs $5,262, p < 0.001). Hyperglycemia independently increased the risk for death at 30 days (HR 1.87, p < or = 0.01), 1 year (HR 1.75, p < or = 0.01), and 6 years after stroke (HR 1.41, p

Validating the Questionnaire for Verifying Stroke-Free Status (QVSFS) by neurological history and examination.

BACKGROUND AND PURPOSE: The Questionnaire for Verifying Stroke-Free Status (QVSFS) is an 8-item structured interview designed to identify stroke-free individuals. Previously, the QVSFS was validated with medical record review in a cohort with a low prevalence (7.1%) of stroke or transient ischemic attack (TIA). The objective of this study was to evaluate the validity of the QVSFS by comparing it with stroke status as determined by neurological history and examination in a population with a higher prevalence of stroke. METHODS: A research assistant administered the QVSFS to outpatients from Veterans Administration stroke and general medicine clinics. Subjects were defined as QVSFS negative if responses to all 8 questions were negative. Questions requiring rephrasing or clarification were noted. Neurologists, blinded to QVSFS scores, interviewed and examined all subjects to determine stroke-free status, defined as no history or examination findings of previous stroke and/or TIA. RESULTS: One hundred fifty-five subjects were examined; mean age was 70 years; 98.1% were male. Seventy-eight subjects were determined to be stroke free by the neurologist. The negative predictive value of the QVSFS was 0.96, with positive predictive value of 0.71. No question required rephrasing or clarification >5 times. Twenty-two subjects (14.2%) required rephrasing or clarification of at least 1 question. CONCLUSIONS: The QVSFS can effectively identify stroke-free individuals with a high degree of accuracy, even in a population with a large proportion of patients with prior stroke or TIA. Accuracy for identifying subjects with stroke and/or TIA is lower, but the QVSFS may still be useful as a screening tool in that regard.

Recurrence in pituitary adenomas in childhood and adolescence.

Pediatric pituitary adenomas are thought to behave more aggressively than their adult counterparts, and the ability to predict the degree of such behavior remains elusive. Proliferation marker Ki-67 and tumor suppressor gene p53 mutations have been used in adults to assist in the evaluation of invasiveness and recurrence; however, their use in childhood and adolescence remains anecdotal. Our study evaluates the proliferative potential in pituitary adenomas of five patients and its relationship with recurrence or persistence of endocrinologic or clinical abnormalities. For such assessment, tissues were stained with monoclonal antibodies BP53-12 forp53 tumor suppressor gene mutation and MIB-1, which binds to cell cycle-specific nuclear antigen Ki-67. In our series, one patient with recurrent adenoma demonstrated the highest (50%) p53 immunoreactivity. Ki-67-stained nuclei ranged from 0 to 2%, failing to identify the recurrent tumor. Therefore, p53 immunoreactivity, rather than Ki-67 nuclear stain, may be useful for identification of recurrent pituitary adenomas in childhood and adolescence.

Middle ear prosthesis displacement in high-strength magnetic fields.

HYPOTHESIS: Middle ear prostheses made from nonmagnetic, magnetic resonance (MR)-compatible metals reportedly displace ex vivo in the presence of high magnetic fields used in MR imaging (MRI). The authors postulate that the prosthesis displacement seen with "nonmagnetic" MR-compatible prostheses ex vivo may not be clinically significant in vivo. METHODS: Middle ear prostheses made from ferromagnetic (420F stainless steel) and nonmagnetic MR-compatible metals (316L stainless steel and platinum) were examined for magnetic field interactions at 4.7 Tesla (T). Ex vivo testing consisted of measurements of the translational and rotational motion of the prosthesis induced by the static magnetic field. In vivo testing was assessed by implanting prostheses in cadaveric temporal bones and performing clinical MRI sequences. Prosthesis displacement was measured semiquantitatively. RESULTS: Angular deflection was observed in all samples made from nonmagnetic stainless steel. The negative control (platinum) demonstrated no deflection, and the positive controls (ferromagnetic stainless steel) deflected >90 degrees. Torque analysis showed movement in five of five nonmagnetic stainless steel prostheses. Prostheses made from nonmagnetic stainless steel remained in place without appreciable loosening in vivo after MRI. Prostheses made with known ferromagnetic properties were displaced at 4.7 T but not at 1.5 T. CONCLUSION: Middle ear prostheses made from low-magnetic stainless steel do move in the presence of high magnetic fields ex vivo; however, this does not appear to be clinically or statistically significant in vivo at 4.7 T. Magnetic resonance imaging should be undertaken with caution in individuals with prostheses made from stainless steel with strong ferromagnetic properties.

Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.

Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis.

PURPOSE: To analyze the pretreatment imaging findings and outcome of patients with perineural spread of squamous or basal cell carcinoma of the face and scalp treated with radiotherapy, to determine whether CT (computed tomography) or MR (magnetic resonance) imaging can be effectively used to identify patients who would benefit from aggressive treatment, and to characterize the imaging features associated with cure. METHODS: Thirty-five patients had perineural spread of squamous and basal cell carcinoma along the divisions of the trigeminal and/or facial nerves based on clinical findings and/or histopathological proof. Perineural extension seen on imaging was divided into three zones of involvement. The volume of perineural disease was graded semiquanitatively. All patients received radiotherapy with curative intent. RESULTS: Eighteen of the 35 patients had imaging evidence of perineural spread of tumor, and the remaining 17 were imaging negative for perineural spread. The absolute 5-year survival of the imaging positive group was 50% compared with 86% in the imaging-negative group (p = 0.048). CONCLUSIONS: Imaging can be used to identify patients with advanced perineural spread who warrant aggressive radiotherapy. Imaging evidence of perineural invasion worsens prognosis; however, low-volume and peripheral perineural disease is radiocurable. Greater perineural tumor volume with more central disease was associated with an unfavorable outcome.

GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry.

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.

Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage.

BACKGROUND: Recombinant tissue plasminogen activator (rTPA) is an established treatment for acute ischemic stroke. The rate and type of protocol violations in rTPA use and their effect on patient outcomes in this setting are not well understood. OBJECTIVE: The objective of this study was to examine associations between protocol violations and outcomes in community-based rTPA use. METHODS: We reviewed medical records of stroke patients treated with rTPA in 10 acute-care hospitals in Indianapolis from July 1996 to February 1998 and assessed complications and outcome. Retrospective National Institute of Health Stroke Scale (on admission and discharge), Canadian Neurological Scale, and length of hospital stay were calculated. Appropriate use of rTPA was determined by the National Institute of Neurological Disorders and Stroke (NINDS) protocol. RESULTS: Fifty patients (mean age, 66 years; 76% white; 56% men) were treated by general neurologists (70%), stroke neurologists (24%), or emergency physicians (6%). Mean times to hospital arrival, brain CT, and start of rTPA infusion were 44, 86, and 141 minutes, respectively. In-hospital mortality rate was 10% (4 intracerebral hemorrhage [ICH], 1 cardiogenic shock). Complications were more frequent among patients with protocol violations (n=8) compared with those without all hemorrhages (75% versus 10%, P:<0.001), symptomatic ICH (38% versus 5%, P:<0.02), and ICH attributable to rTPA, occurring within 36 hours (38% versus 2.4%, P:<0.01), respectively. CONCLUSIONS: NINDS protocol violations are relatively common and are associated with symptomatic cerebral and systemic hemorrhages. When the NINDS protocol is strictly followed, hemorrhage rates in community-based rTPA use are similar to those in the NINDS trial.

Presentation, etiology, and outcome of stroke in pregnancy and puerperium.

PURPOSE: The purpose of this study was to evaluate the presentation, timing, etiology, and outcome of ischemic stroke (IS), hemorrhagic stroke (HS), and cerebral venous thrombosis (CVT) occurring during pregnancy and puerperium at 3 Indianapolis hospitals. METHODS: Medical records of patients with a stroke during pregnancy and the puerperium were identified by using International Classification of Diseases (ICD 9) codes and a computerized records database. The records were available from 1992 to 1999 at 2 of the hospitals and from 1994 to 1999 at the third hospital. The records were retrospectively reviewed for presentation, treatment, etiology, and outcome. The sample included all cases of IS, HS, and CVT occurring in our pregnant population and included events up to 12 weeks postpartum. RESULTS: Thirty-six patients were identified, including 21 with IS, 11 with HS, and 4 patients with CVT. The majority of events (89%) occurred in the third trimester and postpartum period, and 16 of 36 (44%) events occurred in postpartum week 1. Of the 8 African American patients in our study, 5 had HS (63%), whereas 18 of the 25 white patients (72%) had IS. A definable cause was identified in 72% of IS and 82% of HS. Some causes of IS include pre-eclampsia or eclampsia (13%), cardioembolism (23%), and a diverse array of other causes, include hypercoagulable states, thrombotic thrombocytopenic purpura (TTP), cerebral vasculitis, cerebrovascular mucormycosis, and migrainous infarction. Pre-eclampsia/eclampsia (37%) and ruptured atriovenous malformation (AVM) (36%) were the primary causes of HS. None of the cases of CVT had a clear etiology other than the pregnant or puerperal state, although risk factors included systemic lupus erythematosus (negative antiphospholipid antibodies and lupus anticoagulant) in 1 patient and dehydration in a second. Hypertensive disorders of pregnancy were the most common comorbid conditions in both IS and HS, affecting 45% of those with IS and 64% of patients with HS. IS presented with focal deficits (76%), whereas HS tended to present with an altered level of consciousness (73%) and headache (64%). All patients with CVT (4/4) presented with a headache, and 2 of 4 patients presented with an altered level of consciousness. The majority of patients with HS were discharged to nursing homes or rehabilitation centers (63%), whereas 73% of patients with IS and 3 of 4 patients with CVT were discharged home. Only 1 death occurred in our study, because of a brain herniation after a massive hemispheric IS. CONCLUSION: The etiology of stroke in pregnancy and the puerperium is diverse. Strokes are most likely to occur in the third trimester and postpartum period and cluster in the first postpartum week.

Spectrum of antiphospholipid antibodies (aPL) in patients with cerebrovascular disease.

BACKGROUND: The association of stroke and antiphospholipid antibodies (aPL) other than anticardiolipin antibodies (aCL) is not well documented. OBJECTIVE: To report the distribution of aCL, antiphosphatidylethanolamine (aPE), and antiphosphatidylserine (aPS) aPL among patients with symptomatic cerebrovascular disease evaluated by our Stroke Service at Indiana University Hospital from January 1997 to November 1999. METHODS: We retrospectively reviewed medical records from 1997 to 1999 at Indiana University Hospital for all patients with symptomatic cerebrovascular disease using the International Statistical Classification of Diseases, 9th Revision, (ICD-9) codes. We identified patients with elevated titers of aPL. Sera from these patients were obtained within the first 30 days of the index event. We included only those patients for whom the serum samples were tested in a single laboratory by an in-house enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) immunoglobulin A (IgA) and immunoglobulin M (IgM) aCL, aPE, and aPS. We examined the clinical presentation, stroke risk factors, associated rheumatologic disorders, and distribution of aPL specificity and isotype. RESULTS: Thirty-four of 185 patients, 26 women (76%), with a mean age of 46 years, and 8 men (24%) with a mean age of 46 years, had aPL. Nine patients had transient ischemic attacks (TIA), 25 suffered strokes, 23 had ischemic infarcts, and 2 had hemorrhagic infarcts (1 had a superior sagittal sinus thrombosis with bilateral hemispheric hemorrhagic infarcts, and one had bilateral hemorrhagic infarcts associated with systemic lupus erythematosus [SLE]). Six patients had SLE. The most common stroke risk factors were cigarette smoking (38%) and arterial hypertension (26%). Approximately two thirds (60%) of patients had a single positive aPL finding: aPE in 35%, aCL in 18%, and aPS in 6%. Multiple specificities were seen in 40%. IgA was the only aPL antibody isotype detected in 26% of the patients, IgG was the lone isotype in 24%, and IgM alone in 12%. Multiple aPL isotypes were detected in 38% of patients. Five patients (15%) presented with aPE IgA as the exclusive aPL. CONCLUSION: In our series, aPE was the most frequent finding in stroke patients who were suspected to have an associated aPL syndrome. These specific types of aPL may be present relatively often in stroke patients and are often not assessed. Further studies are needed to determine how specific these aPL are in stroke versus other acute illnesses and versus healthy controls, and how these aPL are associated with stroke risk.