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Background and Purpose: Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease in young patients presenting with cerebrovascular disease in Belgium., Methods: In this national, prospective, multicenter study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar dolichoectasia. In male patients, we measured alpha-galactosidase A (alpha-GAL A) activity in dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the alpha-GAL A gene., Results: alpha-GAL A activity was deficient in 19 men (3.5%), although all had normal alpha-GAL A gene sequences. Enzymatic deficiency was confirmed on repeat assessment in 2 male patients (0.4%). We identified missense mutations in 8 unrelated female patients (1.8%): Asp313Tyr (n=5), Ala143Thr (n=2), and Ser126Gly (n=1). The pathogenicity of the 2 former missense mutations is controversial. Ser126Gly is a novel mutation that can be linked to late-onset Fabry disease., Conclusions: alpha-GAL A deficiency may play a role in up to 1% of young patients presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all cases.

Background and Purpose: Matrix metalloproteinases (MMP) may play a role in blood-brain barrier (BBB) disruption after ischemic stroke. We hypothesized that plasma concentrations of MMP-9 are associated with a marker of BBB disruption in patients evaluated for acute stroke., Methods: Patients underwent MRI on presentation and approximately 24 hours later. The MRI marker, termed hyperintense acute reperfusion injury marker (HARM), is gadolinium enhancement of cerebrospinal fluid on fluid-attenuated inversion recovery MRI. Plasma MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were measured by enzyme-linked immunosorbent assay. Logistic regression models tested for predictors of HARM on 24-hour follow-up scans separately for MMP-9 and the ratio of MMP-9 to TIMP-1., Results: For the 41 patients enrolled, diagnoses were: acute ischemic cerebrovascular syndrome, 33 (80.6%); intracerebral hemorrhage, 6 (14.6%); stroke mimic, 1 (2.4%); and no stroke, 1 (2.4%). HARM was present in 17 (41.5%) patients. In model 1, HARM was associated with baseline plasma MMP-9 concentration (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.001-1.019; P=0.033). In model 2, HARM was associated with the ratio of MMP-9 to tissue inhibitor of matrix metalloproteinase-1 (OR, 4.94; 95% CI, 1.27-19.14; P=0.021)., Conclusions: Baseline MMP-9 was a significant predictor of HARM at 24-hour follow-up, supporting the hypothesis that MMP-9 is associated with BBB disruption. If the association between MMP-9 and BBB disruption is confirmed in future studies, HARM may be a useful imaging marker to evaluate MMP-9 inhibition in ischemic stroke and other populations with BBB disruption.

Background and Purpose: The small G protein rhoA and its downstream effector rho-kinase are both expressed in vascular cells and are involved in several cellular processes. One of these processes is the regulation of the phosphorylation state of myosin light chain in vascular muscle and thus, the development of force. Recently, considerable evidence for increased activity of this pathway in cerebral and noncerebral vessels has been reported in several cardiovascular diseases associated with increased vascular tone., Summary of Review: The main aim of this brief review is to summarize current evidence for the involvement of rhoA/rho-kinase signaling in dysfunction of the cerebral circulation in disease states, such as cerebral vasospasm, hypertension, diabetes, and ischemic brain injury. We will also briefly consider the novel hypothesis that augmented activity of endothelial rho-kinase decreases nitric oxide production and contributes to increased vascular tone in disease and the possibility of this action being a key therapeutic target of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) in cerebral and noncerebral arteries., Conclusions: Considerable evidence indicates that rhoA/rho-kinase activity is commonly increased in cerebral vascular disease, not only in vascular muscle, but also in the endothelium and possibly in inflammatory cells and neurons.

Background and Purpose: Few admission variables adequately predict neuronal damage and prognosis in individual patients after stroke. Therefore, there is a need for a reliable non-invasive surrogate measure of clinical outcome., Methods: We have developed a surrogate measure of stroke outcome using the ratio of serum neuron-specific enolase (NSE) to human serum carnosinase (HSC) in 124 patients with acute ischemic or hemorrhagic stroke and 61 matched control subjects. Serum NSE is known to rise and HSC to fall after neuronal injury such as cerebral ischemia., Results: Serum NSE levels were significantly higher and HSC levels lower in the patient group. The NSE/HSC ratio was elevated in patients with stroke: median (semiquartile) hemorrhages, 0.072 (0.033); infarcts, 0.039 (0.026); and control subjects, 0.019 (0.014), P = .0001. Patients with a primary intracerebral hemorrhage had nonsignificantly higher ratios than those with an infarct (P = .082). The NSE/HSC ratio was significantly associated with 90-day outcome measured in two out of three disability and handicap scales: modified Barthel Index (rs = -.34, P = .001), modified Rankin Scale (rs = .30, P = .002), and Lindley Score (rs = .19, P = .057). Patients who died or were institutionalized had higher ratios than those who were discharged home: 0.069 (0.043) versus 0.038 (0.024), P = .011. Correlations between the NSE/HSC ratio and outcome were comparable to those between patient age or consciousness level on admission and clinical outcome., Conclusions: We believe that measurement of NSE, HSC, or their ratio may be useful in the assessment of patients with acute stroke with respect to diagnosis and prediction of clinical outcome.

Background and Purpose: There is evidence that an allelic variation in the angiotensin-converting enzyme (ACE) gene may confer an increased risk of vascular disease. The roles of the ACE insertion/deletion polymorphism and circulating ACE levels are unknown in cerebrovascular disease., Methods: We studied an insertion/deletion polymorphism within intron 16 of the ACE gene by polymerase chain reaction and plasma ACE activity in 467 cases of stroke, the pathological type of which was established by cranial CT, and 231 control subjects. ACE genotype and activity were related to stroke type and mortality at 4 weeks and 3 months., Results: No difference in genotype frequency was observed between all subjects with stroke and control subjects or between control subjects and subjects with cerebral infarction or cerebral hemorrhage. Plasma ACE activity was significantly lower in stroke patients at presentation (64.1 IU/L) than in control subjects (79.6 IU/L; P<.0001). Twenty-one patients (4.5%) with cerebral infarction died within 4 weeks and 56 patients (12%) within 3 months. These patients had significantly lower plasma ACE activity than patients who survived. There was some evidence that risk of death within 4 weeks increased with the number of D alleles (P=.02). Among survivors, plasma ACE activity showed a mean increase of 6.9 IU/L (95% confidence interval, 3.0 to 10.8) between levels at presentation and at 3 months (73.6 IU/L), the latter being similar to ACE activity in control subjects., Conclusions: Low ACE activity at sroke presentation and possession of the D allele may be associated with increased risk of early death from acute cerebral infarction.

Background and Purpose: Nitric oxide-mediated cerebral vasodilation is altered in spontaneously hypertensive stroke-prone rats. Stroke predisposition in this strain could be related to a genetic defect of brain nitric oxide synthase, the enzyme responsible for nitric oxide production. We tested the hypothesis that brain nitric oxide synthase activity is altered in spontaneously hypertensive stroke-prone rats compared with spontaneously hypertensive or Wistar-Kyoto rats., Methods: A colony of spontaneously hypertensive stroke-prone rats was bred, in which the rate of neurological events under salt load was assessed. In a separate cohort of animals brain nitric oxide synthase activity was measured in spontaneously hypertensive stroke-prone rats (n = 6) and in spontaneously hypertensive (n = 6) and genetically related Wistar-Kyoto rats (n = 6). Calcium dependency of nitric oxide synthase was also assessed in cortical brain samples from the three rat strains to determine if altered calcium-dependent activation of nitric oxide synthase was present., Results: Brain nitric oxide synthase activity was highest in the cerebellum (eg, spontaneously hypertensive stroke-prone rats: cerebral cortex, 10.6 +/- 0.9; cerebellum, 50.1 +/- 12.0; brain stem, 14.7 +/- 10.3 pmol/mg protein per minute); however, there was no difference among the three rat strains in any region (eg, cerebral cortex: spontaneously hypertensive stroke-prone, 10.6 +/- 0.9; spontaneously hypertensive, 10.8 +/- 0.5; Wistar-Kyoto, 10.9 +/- 0.7 pmol/mg protein per minute) or at any calcium concentration tested., Conclusions: A genetic defect of brain nitric oxide synthase is unlikely to be the cause of stroke predisposition in spontaneously hypertensive stroke-prone rats.

Background and Purpose: To investigate the clinical relevance of plasma concentrations of neuron-specific enolase (NSE) in patients with severe cerebrovascular diseases, serial analyses were performed during the first 10 days after the acute event., Methods: Plasma samples taken from 61 patients (30 with brain infarction, 13 with intracerebral hemorrhage, 11 with cardiogenic hypoxia-ischemia, and 7 with myocardial infarction [as control group]) were analyzed for NSE concentration using an enzyme immunoassay. The time course of plasma NSE was correlated with clinical findings, clinical outcome, cranial computed tomography, intracranial pressure, and other laboratory data., Results: In cases of hypoxia-ischemia there was close correlation between plasma NSE values during the first 72 hours and the clinical outcome. In brain infarction and intracerebral hemorrhage, high plasma NSE mostly indicated an unfavorable outcome, but low values did not permit a reliable prognostic estimation. In cases of cerebral infarction and intracerebral hemorrhage with secondary neuronal destruction (for example, due to malignant edema), increasing NSE concentrations in plasma preceded the change of clinical or other diagnostic parameters., Conclusions: The course of plasma NSE levels is seen as a relevant parameter for assessing the prognosis of cerebral hypoxia-ischemia. Additionally, it may prove to be a useful tool for monitoring space-occupying brain infarctions and intracerebral hemorrhages and therefore may contribute to improved therapeutic management of severe cerebrovascular diseases.

Background and Purpose: Platelet-activating factor is a potent bioactive phospholipid and may play an important role in occlusive vascular diseases. To assess the inactivation of this autacoid in plasma, we measured platelet-activating factor acetylhydrolase activity in plasma low density and high density lipoproteins from patients with ischemic stroke., Methods: Low density and high density lipoproteins were separated by ultracentrifugation from plasma of 33 patients with cerebral thrombosis and 31 age-matched healthy control subjects, and platelet-activating factor acetylhydrolase activity in each fraction was assayed., Results: The average values of platelet-activating factor acetylhydrolase activity in low density lipoprotein from patients and control subjects were 41 +/- 18 and 29 +/- 17 nmol/ml per minute, respectively, and the difference was statistically significant (p less than 0.01 U test). There was no difference in activity in high density lipoprotein between the two groups (16 +/- 11 versus 14 +/- 9 nmol/ml per minute, respectively)., Conclusions: The increased plasma platelet-activating factor acetylhydrolase activity in stroke patients is primarily attributable to the increased binding to low density lipoprotein, and this increase may be an adaptation to the augmented generation of platelet-activating factor in ischemic stroke.

We examined the concentrations of lactate dehydrogenase in the cerebrospinal fluid of 25 patients with strokes and 15 patients with transient ischemic attacks less than or equal to 8 hours after the onset of the vascular event and in a control group of 21 patients. We found significantly higher concentrations in the stroke patients (40.9 +/- 14.5 units/l) than in the transient ischemic attack patients (11.8 +/- 2.9 units/l, p less than 0.001) and the controls (11.2 +/- 6.7 units/l, p less than 0.001). Among the stroke patients, we found a significantly higher lactate dehydrogenase concentration in those with cortical strokes (n = 12, 50 +/- 12.3 units/l) than in those with lacunar white matter infarcts (n = 5, 26.4 +/- 6.5 units/l; p less than 0.001) and those with basal ganglia infarcts (n = 8, 36.37 +/- 11.7 units/l; p less than 0.05). Our study offers a supplementary examination for diagnosing cortical or subcortical infarction during the early stage of the event, with the possibility of distinguishing precisely stroke from transient ischemic attack during the first hours after onset of the event.

Cerebrospinal fluid enzyme levels of creatine kinase (CK), lactate dehydrogenase (LDH), glutamate oxaloacetate transaminase (GOT) and angiotensin converting enzyme (ACE) were studied in 40 acute stroke patients comprising 20 lacunar strokes and 20 cortical strokes. A marked elevation of at least one of the enzymes CK, GOT or LDH was seen in 80% of cases of cortical strokes. No elevation was seen in lacunar stroke with CK, GOT or ACE and only a slight elevation with LDH. Within the cortical group, there was a correlation between the site, size of infarction seen on CT scan and enzyme level. These findings may help to explain the previously noted unpredictability of rises in CSF enzymes in stroke patients. In certain instances, a study of CSF enzymes may be of use to distinguish cortical from lacunar stroke. A precise diagnosis of lacunar infarction is important for management purposes, entry into stroke treatment trials or description of new syndrome types.

The levels of lipid peroxides, determined as thiobarbituric acid reactive substances (TBARS), and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), were examined in the blood from stroke-prone spontaneously hypertensive rats (SHRSP), with and without cerebral lesions, and normotensive Wistar Kyoto (WK) rats. The levels of TBARS in the blood from healthy SHRSP were not significantly different from those of WK rats, while the values of SHRSP (male) with stroke were more than twice as high as those of healthy SHRSP. The activities of SOD and GSH-Px in stroke SHRSP were also statistically different from those of healthy SHRSP.

Serum dopamine-beta-hydroxylase (DBH) activity was measured in 34 patients with acute cerebrovascular disease. The serum level of DBH activity showed its highest value soon after the onset of stroke and then gradually decreased over the next few days. After reaching its lowest level, the DBH activity again showed a slight increase. There was no direct relationship between serum DBH activity and total serum protein, or blood pressure. In 8 of 12 patients, DBH activity in the cerebral venous blood was higher than that in the arterial blood. These results suggest that rapid release of DBH into the circulating blood occurred after stroke, presumably from sympathetic nerve endings in the vessels or organs, including the brain.

Adenylate cyclase activity was investigated in either homogenate or particulate fractions from the frontal cerebral cortex of the gerbil following five experimental conditions of bilateral ischemia. After periods of 15 min ischemia, 15 min ischemia plus 15 min of recirculation or 60 min ischemia the enzyme generally displayed enhanced responses to GTP, norepinephrine (NE), dopamine (DA), NE + GTP and DA + GTP. Pretreatment of the gerbils with methylprednisolone, allopurinol or indomethacin did not significantly influence the outcome of these findings. When the animals were subjected to 60 min ischemia plus 15 min of reflow, enzyme responses to the stimulatory agents including forskolin and NaF were all reduced. Pretreatment with methylprednisolone, allopurinol or indomethacin prevented the damage to adenylate cyclase in the 60 min ischemia plus 15 min reflow animals. When animals were made ischemic for 15 min followed by one week of recovery, enzyme sensitivity to GTP, calmodulin-Ca++, NE, combinations thereof and forskolin were reduced in only the particulate fractions. Enzyme damage was reversed following methylprednisolone. Enzyme damage may result from generation of free radicals during reflow and drugs that either inhibit synthesis pathways generating free radicals, stabilize cell membranes or act as free radical scavengers may be therapeutically beneficial under specific conditions of stroke.

Serum cardiac enzyme levels (CK, LDH, SGOT) were estimated and the ECG recorded for 4 days following admission of 288 patients (Group I) to a stroke intensive care unit. Sixty-four of these patients, subsequently found not to have strokes, served as controls. Mean serum levels of all 3 cardiac enzymes were elevated in 8% of the 224 patients with stroke. The mean serum enzyme levels in patients with transient ischemic attacks (TIA) did not differ from controls. In a second group of 230 patients with stroke (Group II) serum CK levels were measured and the isoenzyems were fractionated to determine the tissue source of the enzymes. One hundred and one patients had raised total CK values and 25 of these (11%) had raised CK-MB (heart) iso-enzyme, the remainder having CK-MM (skeletal muscle) fraction. No serum CK-BB (brain) iso-enzyme was detected in any patient. Patients with positive serum levels of CK-MB has more evidence of acute myocardial ischemia on ECG (p less than 0.05), and more cardiac arrhythmias (p less than 0.001) than those with normal CK levels. Scattered areas of myocytolysis were found in the myocardium at autopsy in one patient. The acute rise in serum cardiac enzymes which we have recorded in the initial stages of stroke suggest that acute myocardial involvement is a commoner complication than is generally recognized. Also, since the CK-MB rises were modest and progressive, it is more likely that this acute myocardial dysfunction is a consequence, rather than a cause, of the acute cerebrovascular lesion.