Automated three-dimensional signature model for assessing brain injury in emergent stroke.

This presentation will focus on the value of established and newer MR methods that can be applied to the diagnosis and management of ischemic stroke with emphasis on future applications of MR to provide previously unmet needs of the treating clinician and clinical trials. Time alone is an inadequate indicator of the therapeutic window, especially when the time of stroke onset is uncertain. Thus, there is a need to predict the evolution of stroke in a way that more precisely and with greater resolution identifies the progression of cellular damage at the moment of investigation. This also would be of value for thrombolysis when knowledge of the degree and extent of tissue necrosis and the consequent potential for brain hemorrhage is of the utmost importance. To provide this, we perform postprocessing of diffusion-, T(1)- and T(2)-weighted images to produce the apparent diffusion coefficient of water, and T(1) and T(2) maps that are then further processed to provide maps and quantitation of the tissue signatures of ischemic histopathology. By these means, we can accomplish objective volumetric analysis of infarct size and of the proportions of potentially viable and salvageable tissue. We will show how this has the potential to predict long-term stroke outcome and facilitate decision-making in terms of safety of reperfusion strategies and the appropriateness of cytoprotective treatment. The value of our approach is to replace time as the therapeutic window and extend the opportunity of treatment to those patients presenting beyond the stringent time limits employed in current investigative clinical trials. Further, used as a surrogate marker of clinical outcome, this form of stroke analysis may speed proof of principle clinical trials in small numbers of stroke patients.

Tissue plasminogen activator for acute ischemic stroke in patients with unruptured cerebral aneurysms.

Intracranial hemorrhage (ICH) is the most feared complication of thrombolytic therapy for acute ischemic stroke. There are limited data on the risks of thrombolysis in patients with asymptomatic intracranial aneurysm. We report 2 adults with signs of hemispheric ischemia who were successfully treated with intravenous tissue plasminogen activator (t-PA), despite the presence of asymptomatic intracranial aneurysm. The presence of an asymptomatic intracranial aneurysm may not necessarily preclude a good outcome from acute ischemic stroke treated with rt-PA. Selected patients harboring incidental, unruptured intracranial aneurysm may benefit from thrombolytics.

Anticardiolipin antibodies and their associations with cerebrovascular risk factors.

OBJECTIVE: To investigate associations between cerebrovascular risk factors and anticardiolipin (aCL) immunoreactivity. BACKGROUND: High titers of aCL immunoreactivity, mainly the immunoglobulin (Ig) G isotype, were shown to predict aCL-related thrombo-occlusive complications. METHODS: aCL antibodies, and IgG and IgM isotypes were measured by a validated assay in a single laboratory, run in duplicate, in 749 individuals with first ischemic stroke (n = 300) and patients with other CNS disease or undergoing diagnostic procedures. RESULTS: Age varied according to aCL categories, with a mean of 61.8 years among patients with negative aCL (< 10 IgG phospholipid units [GPL]) to 62.3, 64.9, and 69.9 years in patients with immunoreactivity 10 to 20, 20 to 40, and >40 GPL respectively (p = 0.02). History of atrial fibrillation, congestive heart failure, or valvular heart disease was associated with significantly higher rates of positive IgG aCL (>10 GPL) and with higher immunoreactivity. IgG aCL immunoreactivity increased significantly, in a dose-response manner, as a function of the number of cerebrovascular risk factors present. In patients with first ischemic stroke, rates of 10 to 20, 20 to 40, and >40 GPL were 14%, 7%, and 0% among those with no risk factors versus 20%, 12%, and 12% respectively among patients with four or more risk factors (p = 0.007). No significant associations were identified, however, between IgM isotype aCL and any of the risk factors or increasing number of risk factors. CONCLUSION: The presence of multiple cerebrovascular risk factors is associated with substantially higher rates of positive IgG isotype aCL, and with higher immunoreactivity. These findings should caution against overdiagnosis of the antiphospholipid syndrome, and consequent changes in management among patients with multiple cerebrovascular risk factors.

Moyamoya syndrome associated with Sneddon's syndrome and antiphospholipid-protein antibodies.

BACKGROUND: There are anecdotal reports of the rare combination of Sneddon's syndrome, lupus anticoagulant, and Moyamoya. To our knowledge, we now report the first case of anticardiolipin antibodies, Sneddon's syndrome, and Moyamoya. METHODS: Case-report and systematic literature review. RESULTS: A 37-year-old woman had 31/2 years of recurrent left-sided sensory-motor symptoms. More recently, she had experienced vertigo, diplopia, and imbalance. Medical history included headaches, labile hypertension, left arm venous thrombosis requiring anticoagulation, and cigarette smoking. On examination she had livedo reticularis, limited left eye abduction, and left hemiparesis. Magnetic resonance imaging (MRI) showed right frontal, left parieto-occipital and pontine high intensity lesions on T(2)-weighted images consistent with ischemia and abnormally increased flow-void in the basal ganglionic regions. Conventional cerebral angiography showed a Moyamoya pattern. Transesophageal echocardiography and electroencephalogram were normal. Serologic studies were remarkable for anticardiolipin antibodies immunoglobulin G isotype only. She responded favorably to carbamazepine as treatment of presumptive focal seizures, and long-term anticoagulation. Seven other cases reported in the literature were found and reviewed, with different combinations of Moyamoya, Sneddon's syndrome, and antiphospholipid-protein antibodies. The mean age was 37 (range 18-59, SD+/-16) years, male/female ratio 3/5; clinical features included cognitive changes (4 pts), ischemic stroke (6pts), seizures (1pt), and intracranial hemorrhage (2pts). Anticoagulation/steroids/anti-platelet agents were empirically associated with a favorable survival and functional outcome in 6 cases. CONCLUSION: This case expands the spectrum of associations with Moyamoya, and in conjunction with a review of the literature, suggests that evaluation for antiphospholipid-protein antibodies is recommended in cases of Moyamoya syndrome.

Specificity, isotype, and titer distribution of anticardiolipin antibodies in CNS diseases.

BACKGROUND AND PURPOSE: There is an association between anticardiolipin antibodies (aCL) and ischemic stroke. There are, however, also occasional reports linking aCL with other CNS diseases (OND), particularly with multiple sclerosis (MS). Hence, we studied the specificity of aCL for ischemic stroke. METHODS: Prospective, consecutively identified patients evaluated for aCL (immunoglobulin G [IgG] and immunoglobulin M [IgM] isotypes) were divided into two groups: ischemic stroke (first ever) and OND (stroke-free subjects affected by OND). RESULTS: The ischemic stroke group (n = 300) and the OND (n = 149) differed in the following risk factors: age (64 +/- 14 versus 58 +/- 15 years; p < 0.001) and proportions of African Americans (67% versus 29%; p < 0.001); current cigarette smoker (26% versus 17%; p = 0.028); hypertensive (69% versus 34%; p < 0.001); diabetic (18% versus 7%; p = 0.001); history of angina (16% versus 8%; p = 0.015) or myocardial infarction (15% versus 3%; p < 0.001). There were higher rates of aCL positivity (26% versus 17%; p = 0.050), IgG-aCL > 10 GPL (23% versus 11%; p = 0.003) or IgG aCL > 20 GPL (12% versus 4%; p = 0.012) among the stroke group than among the OND group. No differences in IgG-aCL positivity were found between the MS group and the rest of the OND group but the MS patients had a higher rate of IgM-aCL positivity than the other OND patients. CONCLUSION: IgG-aCL positivity does not appear to be a marker for CNS disease generally but of ischemic stroke.

Time course of ADCw changes in ischemic stroke: beyond the human eye!

BACKGROUND AND PURPOSE: Using newly developed computerized image analysis, we studied the heterogeneity of apparent diffusion coefficient of water (ADCw) values in human ischemic stroke within 10 hours of onset. METHODS: Echo-planar trace diffusion-weighted images from 9 patients with focal cortical ischemic stroke were obtained within 10 hours of symptom onset. An Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm was implemented to segment different tissue types with a series of DW images. ADCw maps were calculated from 4 DW images on a pixel-by-pixel basis. The segmented zones within the lesion were characterized as low, pseudonormal, or high, expressed as a ratio of the mean+/-SD of ADCw of contralateral noninvolved tissue. RESULTS: The average ADCW in the ischemic stroke region within 10 hours of onset was significantly depressed compared with homologous contralateral tissue (626.6+/-76.8 versus 842.9+/-60.4x10(-6) mm2/s; P<0.0001). Nevertheless, ISODATA segmentation yielded multiple zones within the stroke region that were characterized as low, pseudonormal, and high. The mean proportion of low:pseudonormal:high was 72%:20%:8%. CONCLUSIONS: Despite low average ADCW, computer-assisted segmentation of DW MRI detected heterogeneous zones within ischemic lesions corresponding to low, pseudonormal, and high ADCw not visible to the human eye. This supports acute elevation of ADCw in human ischemic stroke and, accordingly, different temporal rates of tissue evolution toward infarction.

Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study.

BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.

Preliminary clinical-radiological assessment of a MR tissue signature model in human stroke.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60

Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination.

OBJECTIVE: To analyse the natural history and survival of corticobasal degeneration by investigating the clinical features of 14 cases confirmed by postmortem examination. METHODS: Patients with definite corticobasal degeneration were selected from the research and clinical files of seven tertiary medical centres in Austria, the United Kingdom, and the United States. Clinical features were analysed in detail. RESULTS: The sample consisted of eight female and six male patients; mean age at symptom onset was 63 (SD 7.7) years, and mean disease duration was 7.9 (SD 2.6) years. The most commonly reported symptom at onset included asymmetric limb clumsiness with or without rigidity (50%) or tremor (21%). At the first neurological visit, on average 3.0 (SD 1.9) years after symptom onset, the most often encountered extrapyramidal features included unilateral limb rigidity (79%) or bradykinesia (71%), postural imbalance (45%), and unilateral limb dystonia (43%). Ideomotor apraxia (64%), and to a lesser extent cortical dementia (36%), were the most common cortical signs present at the first visit. During the course of the disease, virtually all patients developed asymmetric or unilateral akinetic rigid parkinsonism and a gait disorder. No patient had a dramatic response to levodopa therapy. Median survival time after onset of symptoms was 7.9 (SD 0.7) (range, 2.5-12.5) years, and, after the first clinic visit, 4.9 (SD 0.7) (range, 0.8-10) years. Early bilateral bradykinesia, frontal syndrome, or two out of tremor, rigidity, and bradykinesia, predicted a shorter survival. CONCLUSION: The results confirm that unilateral parkinsonism unresponsive to levodopa and limb ideomotor apraxia are the clinical hallmarks of corticobasal degeneration, and only a minority of patients with corticobasal degeneration present with dementia. The study also suggests that a focal cognitive and extrapyramidal motor syndrome is indicative of corticobasal degeneration. Survival in corticobasal degeneration was shortened by the early presence of (more) widespread parkinsonian features or frontal lobe syndrome.

Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis.

BACKGROUND AND PURPOSE: Studies of cerebral activation of motor function after ischemic stroke may enhance our understanding of the underlying mechanisms of motor functional recovery, including the role of the noninfarcted hemisphere. METHODS: Eight right-handed recovering hemiparetic or hemiplegic patients were studied using functional MRI. Results were evaluated for each patient to consider individual variability in original functional organization, neuroanatomy, infarct size and extent, treatment, age, and sex. The results were also pooled as a group for comparison with a control group of eight right-handed normal subjects. RESULTS: In six of eight stroke patients, extended activation in ipsilateral sensorimotor cortex was observed during paretic hand movements. Bilateral activation of the primary sensorimotor cortex was recorded in three of these six patients; ipsilateral activation alone was recorded in the remaining three patients. Only two patients had mild synkinesia. Furthermore, in two male patients, the paretic hand movements activated extended areas of ipsilateral premotor and dorsolateral prefrontal cortex, when compared with normal subjects. In two patients with left frontal infarction, profound activation in the right supramarginal gyrus and in the right premotor cortex was observed during the ipsilateral paretic hand movements. CONCLUSIONS: Synkinesia alone cannot explain the extent of ipsilateral activation in primary sensorimotor cortex. The explanation offered for our findings is that preexisting uncrossed motor neural pathways may be accessed or recruited to compensate for damage to the crossed motor pathways after ischemic stroke.

Transcranial magnetic stimulation as a prognostic tool in stroke.

Our aims were to evaluate the prognostic usefulness of magnetic motor evoked potentials (MMEPs) in ischemic stroke, to study the evolution of MMEP abnormalities and the relationships between MMEP abnormalities and infarction topography. We prospectively analyzed 50 consecutive ischemic stroke patients who were followed up to 1 year. MMEPs were recorded 1, 3, 30 and 90 days after stroke and we measured amplitudes and latencies/central motor conduction times (CMCTs) of MMEPs from hypothenar, biceps brachiallis, gastrocnemius and quadriceps. Univariate and multivariate analyses of the clinical and MMEPs data were performed. Patients with Rankin 0-3 at 1 year had had acutely MMEPs with shorter latencies and higher amplitudes than patients with Rankin 4-5 or deceased patients. Increased blood pressure correlated with increased survival, whereas increased heart rate and hyperglycemia correlated with increased mortality. The variables infarction size on second CT, age, and first day CMCT-S1 correctly classified 1 year outcome on discriminant analysis. The inclusion of MMEPs values increased the probability of correct classification from 76% to 84%. We conclude that in patients with nondisabling strokes MMEPs may have an independent value in the prediction of prognosis, increasing the accuracy of prognosis calculations made employing clinical and laboratory data. Topography of lesions should be considered when analyzing MMEP abnormalities after stroke.

Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? A clinicopathological study.

The difficulty in differentiating progressive supranuclear palsy (PSP, also called Steele-Richardson-Olszewski syndrome) from other related disorders was the incentive for a study to determine the clinical features that best distinguish PSP. Logistic regression and classification and regression tree analysis (CART) were used to analyse data obtained at the first visit from a sample of 83 patients with a clinical history of parkinsonism or dementia confirmed neuropathologically, including PSP (n = 24), corticobasal degeneration (n = 11), Parkinson's disease (PD, n = 11), diffuse Lewy body disease (n = 14). Pick's disease (n = 8) and multiple system atrophy (MSA, n = 15). Supranuclear vertical gaze palsy, moderate or severe postural instability and falls during the first year after onset of symptoms classified the sample with 9% error using logistic regression analysis. The CART identified similar features and was also helpful in identifying particular attributes that separate PSP from each of the other disorders. Unstable gait, absence of tremor-dominant disease and absence of a response to levodopa differentiated PSP from PD. Supranuclear vertical gaze palsy, gait instability and the absence of delusions distinguished PSP from diffuse Lewy body disease. Supranuclear vertical gaze palsy and increased age at symptom-onset distinguished PSP from MSA. Gait abnormality, severe upward gaze palsy, bilateral bradykinesia and absence of alien limb syndorme separated PSP from corticobasal degeneration. Postural instability successfully classified PSP from Pick's disease. The present study may help to minimize the difficulties neurologists experience when attempting to classify these disorders at early stages.

A reappraisal of reliability and validity studies in stroke.

BACKGROUND: The emergence of prophylactic and therapeutic interventions in stroke has been accompanied by the widespread use of stroke classifications and scales that measure deficit (stroke scales) or resulting long-term handicap (handicap and disability scales). Although the accuracy of some scales and classifications has been studied, there is no updated systematic review appraising all of them. REVIEW: We reviewed the literature and selected 21 studies on classifications and scales. The International Classification of Diseases, 10th revision, achieved the highest interobserver agreement among seven stroke classifications. The National Institutes of Health Stroke Scale, the Canadian Neurological Scale, and the European Stroke Scale had the highest reliability across items among nine stroke scales. The Barthel Index was the most reliable disability scale. CONCLUSIONS: The identification of the most reliable stroke classifications and scales should encourage their use in selection of homogeneous populations of patients for clinical research studies and to improve communication among scientists. Further research is needed to investigate neglected aspects of the neurological examination and the validity of stroke classifications.

Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study.

OBJECTIVE--To analyse the natural history of progressive supranuclear palsy (PSP or Steele-Richardson-Olszewski syndrome) and clinical predictors of survival in 24 patients with PSP confirmed by necropsy, who fulfilled the NINDS criteria for a neuropathological diagnosis of typical PSP. METHODS--Patients were selected from the research and clinical files of seven medical centres involving tertiary centres of Austria, England, France, and the United States. Clinical features were analysed in detail. The patients' mean age at onset of PSP was 63 (range 45-73) years. RESULTS--The most frequent clinical features (occurring in at least 75% of the patients) were early postural instability and falls, vertical supranuclear palsy, akinetic-rigid predominant parkinsonian disorder characterised by symmetric bradykinesia and axial rigidity unrelieved by levodopa, pseudobulbar palsy, and frontal release signs. Occasionally, segmental dystonia or myoclonus were described, but neither aphasia nor alien limb syndrome was reported. Fractures occurred in 25% of the patients but were unrelated to the severity of the gait or to the presence of falls. Median survival time was 5.6 (range 2-16.6) years. Onset of falls during the first year, early dysphagia, and incontinence predicted a shorter survival time. Age at onset, sex, early onset of dementia, vertical supranuclear palsy, or axial rigidity had no effect on prognosis of survival. Pneumonia was the most common immediate cause of death. PSP was most often clinically misdiagnosed as Parkinson's disease. Errors in diagnosis suggest that PSP is underdiagnosed. CONCLUSION--Progressive onset of early postural instability with falls or supranuclear vertical palsy in the fifth decade, should suggest the diagnosis of PSP. Onset of falls during the first year are emphasised, as they could lead to an early diagnosis and influence the prognosis of patients with PSP. Whether appropriate treatment of the dysphagia could prolong the survival of PSP patients needs to be explored.

Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome).

We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele-Richardson-Olszewski syndrome, rated 105 autopsy-proven cases of PSP (n = 24), Lewy body disease (n = 29), corticobasal ganglionic degeneration (n = 10), postencephalitic parkinsonism (n = 7), multiple system atrophy (n = 16), Pick's disease (n = 7), and other parkinsonian or dementia disorders (n = 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.

Movement disorders in ischemic stroke: clinical study of 22 patients.

Movement disorders (bemichorea-hemiballismus, hemidystonia and isolated tremor) are an uncommon clinical manifestation in ischemic stroke (IS), and their anatomical basis is poorly understood. We analyzed the clinical and neuroimaging characteristics of 22 consecutive patients who bad movement disorders associated with cerebral infarction (MDCI), studied at four institutions over 8 years. In one institution (from the La Alianza-Central Hospital of Barcelona Stroke Registry) nine patients with MDCI were identified among 1099 consecutive first ever stroke patients (0.8%) (908 with IS, 1%). Fifteen out of 22 patients (68%) had hemichorea-hemiballismus, five (23%) hemidystonia and two (9%) isolated tremor. MDCI were more often left sided (n = 15, 68%), being bilateral in one patient (4.5%). A lesion was found on neuroimaging (CT and/or MRI) in 15 patients (68%), in the territory of the posterior cerebral artery (n = 8) and middle cerebral artery (six deep and one superficial). The most commonly involved structure was the thalamus (n = 8, 36.5%). IS subtypes were; presumed lacunar infarcts in 14 patients (64%), atherothrombotic infarcts in two patients (9%), cardioembolic infarcts in two patients (9%) and infarcts of unknown etiology in four patients (18%). Hemichorea-hemiballismus was the most common type of MDCI in our study, usually being the result of a thalamic infarction. The thalamus was the most frequently damaged structure underlying all types of MDCI. There was a striking propensity of MDCI which resulted from nondominant deep hemispheric small vessel infarctions.

Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism.

BACKGROUND AND PURPOSE: The role of lipoprotein abnormalities in the development of ischemic cerebrovascular disease has not been sufficiently clarified. The aim of this study was to identify the lipoprotein profile in ischemic cerebrovascular disease and the possible role of apolipoprotein E polymorphism. METHODS: The relation between the concentrations of lipoprotein(a), intermediate density lipoproteins, apolipoprotein A-I, apolipoprotein B, apolipoprotein E, and other lipoproteins was studied in 100 men with ischemic cerebrovascular disease (48 atherothrombotic, 28 lacunar, and 24 of unknown type) and in 100 healthy age-matched men as a control group. RESULTS: Patients with ischemic cerebrovascular disease had significantly higher levels of lipoprotein(a), lipids carried by intermediate density lipoproteins, and low density lipoprotein cholesterol and lower levels of high density lipoproteins than control subjects. Patients with atherothrombotic infarction had higher total serum cholesterol and low density lipoprotein cholesterol concentrations than patients with lacunar infarction. To assess lipoprotein abnormalities in normolipidemic subjects, a subgroup of 38 patients with ischemic cerebrovascular disease and 53 control subjects, both with serum cholesterol levels < 5.2 mmol/l (200 mg/dl) and triglycerides < 2.3 mmol/l (200 mg/dl), was analyzed. Serum lipoprotein(a), lipids carried by very low density lipoproteins and intermediate density lipoproteins, and low density lipoprotein triglycerides were significantly higher in normolipidemic patients compared with normolipidemic control subjects, whereas high density lipoprotein cholesterol levels were lower. Apolipoprotein E polymorphism in our ischemic cerebrovascular patients differed from that of the control group, with the epsilon 4 allele being more prevalent. CONCLUSIONS: Increased serum lipoprotein(a) levels and intermediate density lipoprotein abnormalities together with decreased high density lipoprotein levels are major risk factors for ischemic cerebrovascular disease, even in normocholesterolemic and normotriglyceridemic subjects. Finally, the epsilon 4 allele could probably be a predisposing genetic marker for ischemic cerebrovascular disease.