Allan L. Bernstein

Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack

BACKGROUND We aimed to validate two similar existing prognostic scores for early risk of stroke after transient ischaemic attack (TIA) and to derive and validate a unified score optimised for prediction of 2-day stroke risk to inform emergency management. METHODS The California and ABCD scores were validated in four independent groups of patients (n=2893) diagnosed with TIA in emergency departments and clinics in defined populations in the USA and UK. Prognostic value was quantified with c statistics. The two groups used to derive the original scores (n=1916) were used to derive a new unified score based on logistic regression. FINDINGS The two existing scores predicted the risk of stroke similarly in each of the four validation cohorts, for stroke risks at 2 days, 7 days, and 90 days (c statistics 0.60-0.81). In both derivation groups, c statistics were improved for a unified score based on five factors (age >or=60 years [1 point]; blood pressure >or=140/90 mm Hg [1]; clinical features: unilateral weakness [2], speech impairment without weakness [1]; duration >or=60 min [2] or 10-59 min [1]; and diabetes [1]). This score, ABCD(2), validated well (c statistics 0.62-0.83); overall, 1012 (21%) of patients were classified as high risk (score 6-7, 8.1% 2-day risk), 2169 (45%) as moderate risk (score 4-5, 4.1%), and 1628 (34%) as low risk (score 0-3, 1.0%). IMPLICATIONS Existing prognostic scores for stroke risk after TIA validate well on multiple independent cohorts, but the unified ABCD(2) score is likely to be most predictive. Patients at high risk need immediate evaluation to optimise stroke prevention.

Stroke in Users of Low-Dose Oral Contraceptives

BACKGROUND Previous studies have linked the use of oral contraceptive agents to an increased risk of stroke, but those studies have been limited to oral contraceptives containing more estrogen than is now generally used. METHODS In a population-based, case-control study, we identified fatal and nonfatal strokes in female members of the California Kaiser Permanente Medical Care Program and who were 15 through 44 years of age. Matched controls were randomly selected from female members who had not had strokes. Information about the use of oral contraceptives (essentially limited to low-estrogen preparations) was obtained in interviews. RESULTS A total of 408 confirmed strokes occurred in a total of 1.1 million women during 3.6 million woman-years of observation. The incidence of stroke was thus 11.3 per 100,000 woman-years. On the basis of data from 295 women with stroke who were interviewed and their controls, the odds ratio for ischemic stroke among current users of oral contraceptives, as compared with former users and women who had never used such drugs, was 1.18 (95 percent confidence interval, 0.54 to 2.59) after adjustment for other risk factors for stroke. The adjusted odds ratio for hemorrhagic stroke was 1.14 (95 percent confidence interval, 0.60 to 2.16). With respect to the risk of hemorrhagic stroke, there was a positive interaction between the current use of oral contraceptives and smoking (odds ratio for women with both these factors, 3.64; 95 percent confidence interval, 0.95 to 13.87). CONCLUSIONS Stroke is rare among women of childbearing age. Low-estrogen oral-contraceptive preparations do not appear to increase the risk of stroke.

Incidence of Stroke and Myocardial Infarction in Women of Reproductive Age

BACKGROUND AND PURPOSE Information on the incidence of vascular disease in women of reproductive age has been limited. These disease are rare in this age group, and a large population base is required for reliable estimation of incidence. METHODS For a case-control study of vascular disease and low-dose oral contraceptive use, we used emergency department logs and hospital admission and discharge records to ascertain fatal and nonfatal cases of first-ever stroke and myocardial infarction (MI) in women 15 to 44 years of age who were-members of a large California HMO. Incidence rates of stroke and MI were calculated on the basis of these data. RESULTS The incidence of MI not associated with pregnancy was 5.0 per 100,000 women-years. The incidence of stroke not associated with pregnancy was 10.7 per 100,000 women-years. MI was very rare until age 35 years. At every age, about half of hemorrhagic strokes were due to subarachnoid hemorrhage. CONCLUSIONS The incidence rates of stroke and MI are low in women of reproductive age in the United States.

Stroke and cocaine or amphetamine use.

Few environmental risk factors for Alzheimers disease have been identified. This lack of information may reflect the fact that salient factors affect most of the population in developed countries. Furthermore, the critical period of exposure may be earlier than hitherto suspected, during the first years of life, as the brain differentiates and develops. Exposure to lead at levels lower than those associated with evident toxicity causes mild intellectual impairment in childhood. I hypothesize that this may be one of the childhood exposures that also confers an additional risk for the onset of Alzheimers disease.The association of cocaine and amphetamine use with hemorrhagic and ischemic stroke is based almost solely on data from case series. The limited number of epidemiologic studies of stroke and use of cocaine and/or amphetamine have been done in settings that serve mostly the poor and/or minorities. This case-control study was conducted in the defined population comprising members of Kaiser Permanente of Northern and Southern California. We attempted to identify all incident strokes in women ages 15–44 years during a 3-year period using hospital admission and discharge records, emergency department logs, and payment requests for out-of-plan hospitalizations. We selected controls, matched on age and facility of usual care, at random from healthy members of the health plan. We obtained information in face-to-face interviews. There were 347 confirmed stroke cases and 1,021 controls. The univariate matched odds ratio for stroke in women who admitted to using cocaine and/or amphetamine was 8.5 (95% confidence interval = 3.6–20.0). After further adjustment for potential confounders, the odds ratio in women who reported using cocaine and/or amphetamine was 7.0 (95% confidence interval = 2.8–17.9). The use of cocaine and/or amphetamine is a strong risk factor for stroke in this socioeconomically heterogeneous, insured urban population. (Epidemiology 1998; 9:596–600)

Ischemic Stroke and Use of Estrogen and Estrogen/Progestogen as Hormone Replacement Therapy

BACKGROUND AND PURPOSE Information about the risk of stroke in current postmenopausal hormone users is limited. METHODS In this case-control study, women aged 45 to 74 years hospitalized with a fatal or nonfatal stroke in any of 10 Northern California Kaiser Permanente facilities during the period November 1991 to November 1994 were identified as cases. Controls were selected at random from female Health Plan members. Data regarding use of estrogen plus progestogen or estrogen alone were obtained in interviews. RESULTS The analysis was based on nonproxy responses from 349 cases of ischemic stroke and 349 matched control subjects. After adjustment for confounders, the odds ratio for ischemic stroke in current hormone users was 1.03 (95% confidence interval, 0.65 to 1.65). The odds ratios for ischemic stroke in current hormone users showed no clear trend of increasing or decreasing risk in relation to duration of hormone use. The odds ratio for ischemic stroke in past hormone users was 0.84 (95% confidence interval, 0.54 to 1.32). CONCLUSIONS In this study postmenopausal hormone use was not associated with an increase or decrease in the risk of ischemic stroke, a finding that is consistent with the body of literature on this topic.

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease

Objective: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the associations of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. Methods: Incident cases (n = 178) and randomly selected age-matched controls (n = 189) who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. Results: The association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were observed with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was associated with reduction in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not associated with the risk of PD. Conclusion: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was observed.

A comparison of risk factors for recurrent TIA and stroke in patients diagnosed with TIA

Background: Some spells consistent with TIA may be benign, such as those produced by migraine or migraine accompaniments in the elderly. Distinguishing these from embolic or thrombotic events may be difficult. Methods: Emergency department physicians identified patients who presented with a presumed TIA at one of 16 hospitals in Northern California from March 1997 through February 1998. Recurrent TIAs and strokes were recorded for 90 days afterwards. Results: Of 1,707 patients in whom TIA had been diagnosed in the emergency department, 191 (11.2%) had a recurrent TIA and 180 (10.5%) had a stroke during 90-day followup. Independent risk factors for recurrent TIA were age >60 years (odds ratio 1.9; 95% CI 1.2 to 2.9; p = 0.003), history of multiple TIAs (odds ratio 2.9; 2.1 to 4.0; p < 0.001), duration of spell ≤10 minutes (odds ratio 2.3; 1.6 to 3.3; p < 0.001), and sensory abnormality associated with the spell (odds ratio 1.9; 1.4 to 2.6; p < 0.001). Independent risk factors for stroke from a previous analysis were age, duration >10 minutes, diabetes, weakness, and speech impairment. Among the 30 patients with isolated sensory symptoms lasting ≤10 minutes, the risk of recurrent TIA was 40% and none had a stroke. Conclusions: In patients in whom TIA has been diagnosed in the emergency department, risk factors for subsequent stroke and recurrent TIA are different. A subset of patients with presumed TIA has a benign short-term course with multiple brief TIAs more frequently characterized by sensory symptoms.

Higher ABCD2 Score Predicts Patients Most Likely to Have True Transient Ischemic Attack

Background and Purpose— Some patients diagnosed with transient ischemic attack (TIA) in the emergency department may actually have alternative diagnoses such as seizure, migraine, or other nonvascular spells. The ABCD2 score has been shown to predict subsequent risk of stroke in patients with TIA diagnosed by emergency physicians, but perhaps high ABCD2 scores simply separate those patients with true TIA from those with alternative diagnoses. We investigated this hypothesis in a cohort of patients with TIA identified in the emergency department whose records were reviewed by an expert neurologist. Methods— Among patients diagnosed by emergency physicians with TIA in 16 hospitals in the Kaiser-Permanente Medical Care Plan over a 1-year period ending February 1998 (before publication of prediction rules), an expert neurologist reviewed all records for those in which the diagnosis of TIA was considered questionable by a medical records analyst and determined whether the spell was likely to represent a true TIA. Subsequent strokes within 90 days were identified. ABCD2 scores were calculated for all patients and 2-sided Cochrane-Armitage trend tests were used to assess subsequent risk of stroke. Results— Of the 713 patients reviewed by the expert neurologist, 642 (90%) were judged to likely have experienced a true TIA. Ninety-day stroke risk was 24% (95% CI, 20% to 27%) in the group judged to have experienced a true TIA and 1.4% (0% to 7.6%) in the group judged to not have a true TIA (P<0.0001). ABCD2 scores were higher in those judged to have a true TIA compared with others (P=0.0001). In the group judged to have a true TIA, 90-day stroke risk increased as ABCD2 score increased (P<0.0001); there was no relationship between ABCD2 score and stroke risk in those judged unlikely to have had a TIA (P=0.73). Conclusions— Among patients diagnosed by emergency department physicians with TIA, higher ABCD2 score was associated with a greater likelihood that the diagnosis was confirmed on expert review. The predictive power of the ABCD2 model is therefore partially explained by identification of those patients likely to have experienced a true TIA, an important aspect of the score when used by nonneurologists. However, higher ABCD2 scores still remained predictive of 90-day stroke rate in the group of patients judged to have a true TIA by an expert neurologist.

Clinical Features in Early Parkinson Disease and Survival

OBJECTIVE To examine the association between demographic and clinical features in early Parkinson disease (PD) and length of survival in a multiethnic population. DESIGN Clinical features within 2 years of diagnosis were determined for an inception cohort established during 1994-1995. Vital status was determined through December 31, 2005. Predictor variables included age at diagnosis, sex, race/ethnicity, as well as clinical subtype (modified tremor dominant, postural instability gait difficulty), symmetry, cognitive impairment, depression, dysphagia, and hallucinations. Cox proportional hazards regression analysis was used to identify factors associated with shorter survival. SETTING Kaiser Permanente Medical Care Program, northern California. PATIENTS Five hundred seventy-three men and women with newly diagnosed PD. RESULTS Three hundred fifty-two participants in the PD cohort (61.4%) had died in the follow-up period. Older age at diagnosis (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.09-1.12), modified postural instability gait difficulty subtype (HR, 1.8; 95% CI, 1.3-2.7), symmetry of motor signs (HR, 2.0; 95% CI, 1.1-3.7), mild (HR, 1.7; 95% CI, 1.3-2.2) and severe (HR, 2.7; 95% CI, 1.9-3.9) cognitive impairment, dysphagia (HR, 1.4; 95% CI, 1.1-1.9), and hallucinations (HR, 2.1; 95% CI, 1.3-3.2) were associated with increased all-cause mortality, after adjusting for age, sex, and race/ethnicity. None of the other factors altered mortality risk. In an empirical predictive analysis, most previous significant predictors remained associated with shorter survival. CONCLUSIONS Both motor and nonmotor features in early PD predict increased mortality risk, particularly postural instability gait difficulty, cognitive impairment, and hallucinations. These predictors may be useful in clinical practice and when designing clinical trials.

Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors

OBJECTIVE To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. METHODS Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. RESULTS In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (p<0.01). Estimates trended in the same direction for males, but were not significant. BMI in 20s demonstrated a linear relationship with MS (p-trend=9.60×10(-4)), and a twofold risk of MS for females with a BMI≥30kg/m(2) was observed (OR=2.15, 95% CI 1.18, 3.92). Significant associations between BMI in 20s and MS in males were not observed. Multivariate modelling demonstrated that significant associations between BMI or body size with MS in females persisted after adjusting for history of infectious mononucleosis and genetic risk factors, including HLA-DRB1*15:01 and established non-HLA risk alleles. INTERPRETATION Results show that childhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors.