[Show abstract][Hide abstract] ABSTRACT: Objective In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.
Methods 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.
Results Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179).
Conclusions Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients.
Trial registration The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.
Full-text · Article · Sep 2013 · Journal of neurology, neurosurgery, and psychiatry
[Show abstract][Hide abstract] ABSTRACT: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
Full-text · Article · Mar 2012 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis.
We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging.
Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%).
In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.).
Oral laquinimod for multiple sclerosis. [N Engl J Med. 2012]
New and old: notable drug developments for clinical practice. [J Neurol. 2012]
Full-text · Article · Jan 2012 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: We report an unusual case of juvenile ischaemic stroke syndrome associated with the A8344G mutation in tRNA(Lys) gene of mitochondrial DNA. The clinical phenotype of patient was typical for MELAS (mitochondrial ecephalomyapathy with lactate acidosis and stroke like episodes). The MELAS has been related to mutation A3243G in most cases, but some other mitochondrial DNA mutations were described in the background of this syndrome as well. A 22-years-old man and his family were investigated. Throughout clinical investigation as well as Doppler sonography, neuroradiological, and immunserological examinations were performed. Molecular studies included the analysis of the Leiden, prothrombin G20210A and the most common mitochondrial DNA mutations. The DNA analysis of the proband revealed a heteroplasmic A8344G substitution in the T-loop of the tRNALYS gene. The mutation could not been detected in her mother blood. We can conclude that A8344G mutation of the mitochondrial DNA resulted in juvenile ischemic stroke, which is associated only rarely to this genetic alteration. In young age onset of a stroke-like episode with undetermined etiology the mtDNA alterations always have to be excluded.
Full-text · Article · Nov 2011 · Ideggyógyászati szemle
[Show abstract][Hide abstract] ABSTRACT: High stroke mortality in central-eastern European countries might be due to higher stroke incidence, more severe strokes or less effective acute care than in countries with lower mortality rate. Hospital databases usually yield more detailed information on risk factors, stroke severity and short-term outcome than population-based registries.
The Debrecen Stroke Database, data of 8088 consecutively hospitalised patients with acute cerebrovascular disease in a single stroke centre in East Hungary between October 1994 and December 2006, is analysed. Risk factors were recorded and stroke severity on admission was scored by the Mathew stroke scale. The modified Glasgow outcome scale was used to describe patient condition at discharge.
Mean age was 68+/-13 years, 11.4% had haemorrhagic stroke. The rate of hypertension on admission was 79% in men, and 84% in women, 40.3% of men and 19.8% of women were smokers, and 34% of all patients had a previous cerebrovascular disease in their history. Case fatality was 14.9%, and 43% had some disability at discharge. Outcome at discharge was worse with higher age, higher glucose, higher blood pressure, higher white cell count and erythrocyte sedimentation rate and more severe clinical signs on admission. In multivariate analysis admission blood pressure lost its significance in predicting outcome.
In this large Hungarian stroke unit database hypertension on admission, smoking and previous cerebrovascular disease were more frequent than in most western databases. These findings indicate major opportunities for more efficient stroke prevention in this and probably other eastern European countries.
No preview · Article · Oct 2009 · International Journal of Stroke
[Show abstract][Hide abstract] ABSTRACT: The A3243G mutation in the mitochondrial tRNALeu (UUR) gene is one of the most common causes of mitochondrial DNA related disorders. Originally it was described in MELAS syndrome
(Mitochondrial Encephalomyopathy, Lactic acidosis, Stroke-like episodes), later it had been found to be associated with various
phenotypes. In our study the mutation frequency of the A3243G mtDNA mutation was investigated in patients with maternal sensoneural
hearing loss, stroke-like episodes, ataxia and myopathy with undetermined etiology. We screened 631 Hungarian patients in
North-East, South-West and Central Hungary between 1999 and 2008 for this mutation. The mtDNA analysis was performed from
blood and/or muscle tissue. The A3243G substitution was present in 6 patients in heteroplasmic form. The segregation analysis
detected 8 further cases. The frequency of the A3243G mutation was 2.22% in the investigated patients. The A3243G mutation
frequency in Hungary does not differ significantly from other countries using similar patient selection criteria, however
in Finland a higher mutation rate was found. In studies investigated the mutation frequency of this mutation in diabetes mellitus
similarly wide variety was detected as well. We conclude that the study design has a huge impact on the result of the genetic
epidemiological investigation analyzing the mutation frequency of the A3243G mutation due to the broad clinical phenotype
and the different mutation load in different tissues.
No preview · Article · Jun 2009 · Central European Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis.
Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA.
In the whole study population we found a negative correlation between PON1 activity and IMT (r = -0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = -0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = -0.28, p = 0.008; r = -0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly.
The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.
No preview · Article · Feb 2008 · Cerebrovascular Diseases
[Show abstract][Hide abstract] ABSTRACT: We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (beta = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (beta = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (beta = 1.39; 95% CI, -5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory processes have importance in atherosclerosis. We evaluated if subjects below 55 years of age with occlusive carotid artery disease have higher serum levels of antibodies against oxidized LDL and endothelial cells and the chemokines MCP-1 and RANTES than age matched subjects without atherosclerosis.
Sixty patients with occlusive carotid artery disease (stenosis or occlusion) and 30 age-matched controls participated in the study. We measured the degree of carotid artery stenosis and intima-media thickness (IMT) by duplex ultrasound. White blood cell count (WBC), C-reactive protein (CRP), and fibrinogen levels were significantly higher in patients (means+/-SD: 7.5+/-1.8 vs. 6.1+/-1.1 G/L, p<0.001; 7.7+/-20.7 vs. 2.5+/-1.9 mg/L, p=0.015; and 3.7+/-0.9 vs. 3.1+/-0.5 g/L, p<0.001, respectively). Antibody levels against oxidized LDL and endothelial cells (21.1+/-22.9 and 19.9+/-15.3 EU/mL, p=0.6; and 19+/-15 vs. 20+/-9 U/mL, p=0.07) and RANTES and MCP-1 levels (72.4+/-32.3 vs. 73.8+/-27.3 ng/mL, p=0.7; and 468+/-1041 vs. 318+/-131 pg/mL, p=0.7) did not differ significantly between patients and controls and did not correlate with IMT.
Higher levels of WBC, CRP, and fibrinogen suggest an ongoing inflammation in early-onset carotid atherosclerosis, but increased IMT is not associated by the elevation of serum levels of chemokines and antibodies evaluated in this study.
[Show abstract][Hide abstract] ABSTRACT: Asymmetric dimethylarginine (ADMA) assumes a significant role in atherosclerosis by inhibiting the endothelial nitric oxide synthase (eNOS). Moreover, ADMA inhibits the inducible NOS (iNOS), the isoform that triggers atherosclerosis via peroxynitrite formation. Therefore, we investigated whether ADMA is a risk or protective factor in the atherosclerotic process. Intima-media thickness (IMT) of the common carotid artery, a surrogate for vascular diseases, was chosen as the outcome variable of interest.
Sixty patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and gender-matched controls were recruited at a community-based neurosonological laboratory. We investigated relatively young patients to circumvent the confounding effect age has in the development of atherosclerosis.
The IMT showed a negative correlation with ADMA upon analysis of the pooled data (Spearman correlation coefficient -0.300, p = 0.0041) and the atherosclerotic stratum (Spearman correlation coefficient -0.323, p = 0.012). A multiple linear regression model containing all determinant factors of IMT previously identified by simple regression was used to further quantify the relationship between IMT and ADMA. The negative association between IMT and ADMA remained statistically significant (beta: -0.510, CI: -0.894, -0.127; p = 0.010), furthermore it was even stronger in the atherosclerotic stratum (beta: -0.67, CI: -1.16, -0.18; p = 0.008).
A minimal increase in ADMA concentration may be protective by inhibiting iNOS but not eNOS in states where iNOS is induced, e.g. inflammation accompanying atherosclerosis.
No preview · Article · Feb 2007 · Cerebrovascular Diseases
[Show abstract][Hide abstract] ABSTRACT: Soluble CD40 ligand (sCD40L) has been suggested as a key mediator between inflammation and atherosclerosis, and the CD40-CD40L interaction has a role in atherosclerotic lesion progression. We evaluated if platelet released serum sCD40L and sCD40 levels differ between patients with early onset occlusive carotid artery disease and age-matched controls.
sCD40L and sCD40 levels were measured in serum samples of 60 patients with occlusive carotid artery disease and 30 age-matched controls using ELISA. Degree of stenosis of the internal carotid artery (ICA), and intima-media thickness (IMT) in the common carotid artery were measured by high resolution ultrasound. Values are given as mean +/- SD.
Mean age was 50.9 +/- 3.5 and 50.1 +/- 3.5 years in the patient and control groups. IMT was significantly thicker in patients than in controls (0.89 +/- 0.14 vs. 0.78 +/-0.12 mm, p=0.0003). Serum levels of sCD40L were significantly higher (6.9 +/- 5 vs. 4.5 +/- 3.0 ng/mL, p=0.038) in patients, whereas sCD40 did not differ significantly between patients and controls (85 +/- 56.9 vs. 79.3 +/- 18.7 pg/mL, p=0.34). IMT did not correlate with sCD40L or sCD40 levels (R=-0.03, p=0.77; and R=0.109, p=0.308, respectively).
sCD40L but not sCD40 levels are significantly higher in patients with occlusive carotid artery disease. Platelet derived sCD40L may be a key mediator among inflammation, thrombosis and atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Previously, 30 untreated hypertensive patients were investigated by transcranial Doppler (TCD) monitoring during physical exercise, and changes of hemodynamic parameters were compared with those of age matched healthy subjects. After 3-year antihypertensive (AHT) treatment, these hypertensives were investigated again. The aim of this study was to compare the cerebral hemodynamic changes in the regularly treated and noncompliant (untreated) hypertensives during ergometer cycling.
Nineteen of 30 previously untreated hypertensive patients could be investigated again using the same method as before. Eleven were regularly treated (treated hypertensive [T-HT] group), and 8 did not take their AHT medications due to lack of compliance (noncompliant hypertensive [NC-HT] group). Blood pressure, heart rate, end-tidal CO2 (etCO2; Capnogard capnograph), and bilateral middle cerebral artery mean blood flow velocity (MV) were continuously monitored during ergometer cycling according to the World Health Organization protocol. Values of 2-minute loading were analyzed.
Median loading time did not differ significantly between the T-HT and NC-HT groups. After 2 minutes of cycling in treated patients, the ratio of MV and etCO changes (DeltaMV/DeltaetCO2) showed similar values as before therapy (P = .38), whereas in noncompliant patients, a further worsening of the ratio of DeltaMV/DeltaetCO2 could be observed (P = .04).
The decrease of arteriolar vasodilation (ie, the ratio of DeltaMV/DeltaetCO2) could be demonstrated in the NC-HT group after 3 years. TCD combined with ergometer cycling is a useful method for evaluation of cerebral hemodynamic changes after AHT therapy.
No preview · Article · Feb 2005 · Journal of Neuroimaging
[Show abstract][Hide abstract] ABSTRACT: The role of serum cholesterol and triglycerides in carotid artery atherosclerosis is controversial. We measured carotid artery intima-media thickness (IMT), a marker of atherosclerosis in subjects younger than 55 years of age with a 6-fold range of serum cholesterol levels (3.93-25.03 mmol/L) and a 200-fold range of triglyceride levels (0.36-75.97 mmol/L).
Eighty-six patients with increased serum lipid values and 30 subjects with normal lipid values were included. Serum lipids were measured after an overnight fast. High-resolution sonographic investigations of the carotid arteries of all patients were videotaped. Intima-media thickness was measured offline at 1-mm increments in the distal 10-mm segments of both common carotid arteries by a reader blinded to patient characteristics. First, IMT was compared among groups defined by their cholesterol and triglyceride levels with the use of traditional cutoff values. Next, all subjects were pooled, and general regression analysis was performed to identify significant predictors of IMT with age, body mass index, lipid values, sex, diabetes, hypertension, and smoking status as independent variables.
Intima-media thickness was larger in patient groups with high cholesterol levels (ie, the hypercholesterolemic and combined hyperlipidemic groups) than in the control, borderline, and isolated hypertriglyceridemic groups (P < .01). In the general multiple regression model, IMT correlated positively with total cholesterol level (beta = 0.343; P = .002) and age (beta = 0.3; P = .006) but not with triglyceride level.
Both the group comparisons and the general regression analysis of the pooled data suggest that hypercholesterolemia has an important role in early onset IMT changes in the common carotid artery, whereas hypertriglyceridemia does not have an appreciable role.
No preview · Article · Sep 2004 · Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine
[Show abstract][Hide abstract] ABSTRACT: Several factors have been held responsible for the development of atherosclerosis. To avoid the masking effect of age, we evaluated correlates of carotid atherosclerosis in patients <55 years of age.
Plasma lipids, oxidative resistance of low-density lipoprotein, homocysteine, inflammatory markers, plasma viscosity, and red cell deformability were measured in fasting blood samples of 100 subjects: 45 patients with >30% stenosis of the internal carotid artery, 20 patients with carotid occlusion, and 35 control subjects. Stenosis and intima-media thickness (IMT) of the carotid artery were evaluated by duplex ultrasound.
White blood cell (WBC) count, plasma fibrinogen, C-reactive protein (CRP), and lipoprotein(a) levels were significantly higher in patients than in control subjects, and patients had increased IMT (P<0.01 for all comparisons). There was a tendency for higher homocysteine levels in patients. Smokers had higher WBC, fibrinogen, and CRP levels. After the effect of smoking was controlled for, WBC count, natural logarithmic transform of homocysteine, and online-measured IMT remained significantly higher in patients than in control subjects. WBC, fibrinogen, and CRP levels were highest in the highest IMT quartile (P=0.012, P=0.007, and P=0.036, respectively).
Inflammatory markers and homocysteine have a more important role than lipid factors in early-onset carotid atherosclerosis. We cannot recommend the measurement of low-density lipoprotein peroxidation as a routine screening test to identify high-risk patients for early-onset carotid atherosclerosis. The confounding effect of smoking on inflammatory markers should be considered in studies on atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Ischaemic stroke ranks among the most important causes of death and disability in developed countries. Abnormal lipid metabolism is among the several factors that have a role in the pathogenesis of atherosclerosis. We hypothesize that the decreased resistance of low-density lipoproteins against oxidative stress is an independent risk factor for cerebral atherosclerosis and suggest testing this hypothesis by ultrasonographic evaluation of the carotid artery and correlating this finding to plasma values of compounds that play a role in lipid metabolism. By measuring the oxidative resistance of low-density of lipoprotein the risk for ischaemic stroke can be predicted.
No preview · Article · Jul 2001 · Medical Hypotheses
[Show abstract][Hide abstract] ABSTRACT: To evaluate the diagnostic value of a combined method, i.e. ergometer cycling with continuous bilateral transcranial Doppler monitoring (TCD) to detect cerebral hemodynamic abnormalities in recently diagnosed hypertensive patients.
30 neurologically symptom-free, nontreated patients with essential hypertension and 30 age- and sex-matched controls were studied. Carotid ultrasound, resting ECG and blood parameters were investigated. Cycling ergometry was performed according to the WHO protocol. Blood pressure, heart rate, end-tidal CO2 (etCO2) and bilateral middle cerebral artery (MCA) blood flow velocity (MV) were monitored.
At rest, MV in the MCA did not differ significantly between controls and hypertensive subjects. MV continuously increased in controls until the end of loading whereas a plateau was reached at 4 min in hypertensive subjects. During 6 min of cycling, the time course of absolute values of MV in the MCA and that of the changes in the ratio of mean velocity/end-tidal CO2 (DeltaMV/DeltaetCO2) differed significantly between hypertensive subjects and controls (p = 0.03 and p = 0.02, respectively).
Ergometer cycling combined with TCD revealed altered vasoreactivity, therefore this may be a sensitive method for the detection of early hemodynamic impairment in nontreated hypertensive subjects.
No preview · Article · Feb 2001 · Cerebrovascular Diseases
[Show abstract][Hide abstract] ABSTRACT: Cisternal samples of cerebrospinal fluid (CSF) were analyzed for protein, albumin, sodium (Na), potassium (K), and calcium (Ca) content in 21 control subjects and 64 patients who had experienced acute stroke. A second cisternal CSF sample was taken in 37 of the stroke patients after 2-3 weeks treatment with the calcium antagonist nimodipine. Increased permeability of the blood-brain barrier was reflected by the significantly higher CSF/serum ratio of albumin in stroke patients than in control subjects (0.0046 vs. 0.0028,p = 0.0012). Serum and CSF concentrations of Na, K, and Ca did not differ between control subjects and stroke patients. In control subjects and in stroke patients, concentration of calcium in cisternal CSF ([Ca]) was smaller than values reported by others in lumbar samples. In stroke patients, the pH of CSF was lower than that of simultaneously taken blood (7.38 vs. 7.44, p < 0.001). No differences between stroke patients and control subjects were found for the cisternal CSF/serum ratios of Na (1.0 and 0.99), K (0.61 and 0.63), and Ca (0.25 and 0.24). When patients and controls were pooled together, CSF total [Ca] correlated weakly with serum total [Ca] (Spearman r = 0.28, p = 0.014) and with serum ionized [Ca] (Spearman r = 0.27, p = 0.016). After 2-3 weeks of nimodipine treatment, CSF [Ca] was significantly lower in the subgroup treated with 60 mg nimodipine four times daily (240 mg/d) than with 30 mg four times daily. A nimodipine dosage of 30 mg four times daily (120 mg/d) did not affect CSF [Ca]. A 240 mg daily dosage, but not a 120 mg daily dosage, of nimodipine may affect the Ca transport system in humans at the choroid plexus.
No preview · Article · Oct 2000 · Clinical Neuropharmacology
[Show abstract][Hide abstract] ABSTRACT: To investigate cerebral metabolism by 2-[18F]fluorodeoxy-d-glucose (FDG) uptake using PET and cerebrovascular reverse capacity by transcranial Doppler sonography (TCD) in different mitochondrial diseases (mitochondrial myopathy; mitochondrial encephalopathy, lactacidosis, and stroke-like episodes [MELAS]; and chronic external ophthalmoplegia).
Previous studies on individual patients with mitochondriopathies revealed abnormal accumulations of mitochondria in endothelium, smooth muscle cells, and pericytes of blood vessels in different parts of the nervous system (cerebrum, cerebellum, sural nerve) and skeletal muscle. On this basis, some investigators suggested a pathogenic role of vascular involvement in the MELAS syndrome and other encephalopathies. smhd1
The authors investigated neuronal metabolism and cerebrovascular involvement with PET in 5 cases and with TCD with acetazolamide stimulation in 15 cases. The patients were divided into three groups: 1) interictal MELAS (n = 4); 2) progressive external ophthalmoplegia (n = 6); and 3) pure mitochondrial myopathy and neuropathy (n = 5). The results were compared with those from matched normal control subjects. The diagnoses were based on clinical phenotype as well as histopathologic and molecular analysis.
Cerebral glucose uptake was impaired in all patients, both with and without CNS symptoms, particularly in the occipital and temporal lobes. The vasoreactivity of the small arterioles to acetazolamide did not differ significantly between the patients and healthy control subjects or between the different groups of mitochondrial disorders.
MELAS does not appear to be a functional disturbance of arterioles leading to an ischemic vascular event. The clinical symptoms in MELAS are not the result of a mitochondrial angiopathy but are the consequences of a mitochondrial cytopathy affecting neurons or glia. There is no correlation between the decreased glucose metabolism and the duration of the disease.
[Show abstract][Hide abstract] ABSTRACT: Cerebrovascular reactivity, cerebrovascular reserve capacity, and velocity acceleration can be easily and reliably assessed by measuring acetazolamide-induced changes using transcranial Doppler. The authors' aim was to determine whether there are gender-related differences in these parameters. Fifty-six healthy subjects (27 males, 29 females) were examined using transcranial Doppler. Velocities in the middle cerebral artery on both sides were recorded before and at 5, 10, 15, and 20 minutes after intravenous administration of 1 g acetazolamide. The baseline mean flow velocity in the middle cerebral artery was significantly higher in women than in men (p < 0.02). After acetazolamide administration, significantly higher cerebrovascular reactivity, cerebrovascular reserve capacity, and velocity acceleration were observed in females than in males (p < 0.001 in all cases). Subgroup analysis showed that women before menopause responded with higher cerebrovascular reserve capacity and velocity acceleration than age-matched men (p < 0.01 and p < 0.001, respectively), but no significant difference was found between females after menopause and men of similar age.
No preview · Article · Aug 2000 · Journal of Neuroimaging
[Show abstract][Hide abstract] ABSTRACT: Because recent data are conflicting, it is not certain whether hyperlipidemia is an independent risk factor for cerebrovascular diseases. Decreased cerebrovascular reserve capacity refers to the decreased ability of the cerebral arterioles to adapt in critical conditions and probably predicts a higher risk of stroke. The aim of this study was to compare cerebrovascular reserve capacity in hyperlipidemic patients and healthy controls using transcranial Doppler sonography.
Thirty-four hyperlipidemic patients and 21 healthy controls were examined. With transcranial Doppler sonography, the mean blood flow velocity in the middle cerebral artery was registered at rest and at 5, 10, 15, and 20 minutes after intravenous administration of 1,000 mg acetazolamide. Cerebrovascular reactivity and reserve capacity were calculated from mean blood flow velocities. Various laboratory measurements were also made and assessed for correlation with resting cerebral blood flow velocity and cerebrovascular reserve capacity.
No significant differences could be observed between controls and hyperlipidemic patients in cerebrovascular reactivity or cerebrovascular reserve capacity. No correlation was found between various laboratory measurements and resting cerebral blood flow velocity or cerebrovascular reserve capacity.
We could not demonstrate any differences in cerebrovascular reserve capacity between hyperlipidemic patients and healthy controls. Thus, the vasodilatory ability of the cerebral arterioles seems to remain unchanged in this patient group and is not correlated with the severity of hyperlipidemia.
No preview · Article · Apr 2000 · Journal of Clinical Ultrasound