CT angiography in an acute stroke protocol: correlation between occlusion site and outcome of intravenous thrombolysis.

Thrombolysis with intravenous rt-PA is the current therapy for acute ischemic stroke. Unlike other outcome factors, relatively little is known about the prognostic value of the occlusion site on treatment outcome. We compared the effectiveness and safety of intravenous thrombolysis in patients with different levels of occlusion identified by CT angiography (CTA) in anterior circulation stroke, and analyzed the influence of the occlusion site on treatment outcome in relation to other outcome factors. We selected 71 patients from a stroke database collected between June 2007 and December 2011 at our hospital. All of the studied patients had anterior circulation stroke with intracranial occlusion detected by CTA and were treated with intravenous rt-PA. They were divided into two groups according to the site of occlusion along the middle cerebral artery course: proximal (carotid "T", complete M1 and mild M1 occlusions) and distal (M2/M3 occlusions). Treatment effectiveness was assessed by modified Rankin Scale (mRS) at three months, considering a positive outcome a mRS value ≤ 2. Treatment safety was assessed by evaluating the rate of hemorrhagic complications seen on unenhanced CT at 24 hours. Binary logistic regression was performed to evaluate the interaction between occlusion site and other variables such as sex, age, ASPECT score on admission and baseline NIHSS value in determining treatment outcome. The degree of effectiveness and safety differed when considering patients with proximal and distal occlusions. The percentage of successfully treated cases was 28.6% in the first group compared to 72% in the second, and the rate of hemorrhagic complications was 28.6% and 6% respectively. After adjustment for sex, age, ASPECT score on admission and baseline NIHSS value, occlusion site was the only variable significantly influencing treatment safety and, together with baseline NIHSS value, the only valid predictor of treatment effectiveness. We demonstrated a correlation between the site of arterial occlusion and outcome of intravenous thrombolysis. By helping the choice of the best therapeutic strategy depending on the identified occlusion site, CTA could be usefully added to the examinations included in the Stroke Protocol for the baseline evaluation of patients with suspected acute stroke.

Status epilepticus in acute ischemic stroke.

Stroke is one of the most frequent causes of acute symptomatic status epilepticus. The aim of this study was to investigate the electroclinical features of status epilepticus in acute ischemic stroke. Nine consecutively admitted patients with status epilepticus during ischemic stroke were examined: five of them had convulsive unilateral or generalized status epilepticus for from 24 hours to 9 days after a large hemispheric infarction, always associated with EEG epileptiform abnormalities; the remaining four had focal motor status epilepticus during the first 24 hours after a small cortical or subcortical infarction, and showed no clear EEG changes. Status epilepticus in acute ischemic stroke may have two distinct electroclinical patterns of different prognostic significance.

Combined levodopa-anticholinergic therapy in the treatment of Parkinson's disease. Effect on levodopa bioavailability.

The effect of chronic intake of the anticholinergic drug orphenadrine on the bioavailability of levodopa was studied in six patients with Parkinson's disease. Plasma levodopa profiles and corresponding motor response to a standard dose of levodopa plus an inhibitor of peripheral L-aromatic aminoacid decarboxylase (benserazide) were followed, over a 5-h period, on two different sessions, with and without anticholinergic cotherapy. Six control patients were also included in the study for assessment of intrasubject variability in levodopa absorption under identical conditions. A considerable delay in levodopa absorption was found in one patient, and decreased absorption in an additional two patients while on anticholinergic. Patients' clinical performance corresponded well to plasma levodopa profiles. A significant impairment of basal clinical state was observed in two cases on anticholinergic withdrawal, probably as a result of pharmacodynamic interactions. Our observations suggest that chronic anticholinergic intake may contribute to a less predictable pattern of levodopa absorption and related therapeutic response in some subjects.

Familial hypomelanosis of Ito.

Two siblings presented the typical skin changes of hypomelanosis of Ito (HI) associated with mental and cerebellar signs. Their mother showed only the skin changes of HI but no neurological disturbances. HI is a hereditary disorder, in which familiarity may go unnoticed because of the different expressions of neural and cutaneous features.

Cognitive effects of valproate.

The effects of valproate on cognition are usually considered to be minimal, but few formal neuropsychological studies are available. We studied the psychomotor performances of 20 seizure-free epileptics during fixed valproate monotherapy and after its withdrawal. Our findings suggest some adverse effects of valproate which appear to be completely reversible after withdrawal.

Response to a standard oral levodopa test in parkinsonian patients with and without motor fluctuations.

The acute dose-response profile of a standard oral levodopa dose was followed, over a maximum 8-h period, in 13 patients with and 10 patients without motor fluctuations using a battery of motor quantitative tests (tapping and walking speed, and multiple choice reaction and movement times). Thirteen age-matched normal controls performed tapping and psychomotor tests, at the same time intervals, over a 4-h period. Tapping test and movement times proved significantly impaired in all patients and were the best indicator of levodopa effect, while walking speed and reaction times were apparently of less value, except in severely affected patients. The duration of the levodopa antiparkinsonian effect differed markedly between the two groups, since fluctuating patients returned to prelevodopa dose values within 4 h (mean +/- SEM: 203 +/- 16 min), while in the stable group motor scores remained significantly higher than baseline values up to at least 7 h postdose. The magnitude of the effect was similar in the two groups, but response was complicated by mild to severe dyskinesias in 9 of 13 fluctuating subjects. The pharmacokinetic parameters of levodopa were almost identical in the two groups. Our data add further weight to the hypothesis that cerebral pharmacokinetic or pharmacodynamic factors are responsible for motor fluctuations. Oral levodopa doses coupled with objective tests of motor performance may prove a practical clinical tool to assess and optimize the relationship between drug dose and therapeutic effect.

Diurnal variability in cranial dystonia.

Eleven patients with cranial dystonia were investigated for diurnal variations in disability by means of video recordings. Disability increased significantly from morning to evening. The increase was not related to changes in vigilance levels assessed by dynamic electroencephalogram. Cranial movement disorders display diurnal fluctuations that are probably related to endogenous circadian rhythms.

Increased dosage of carbidopa in parkinsonian patients on low carbidopa-levodopa regimen. Effect on levodopa bioavailability.

The effect of a 2.5-fold increase in daily carbidopa intake on the bioavailability of levodopa was studied in six patients with Parkinson's disease on a low chronic regimen of carbidopa-levodopa (Sinemet) at the fixed ratio of 1:10. The extent of levodopa absorption, expressed as the area under the 11-h plasma levodopa concentration-time curve (AUC0-11 h), was not enhanced by the higher carbidopa dose. A significant increase in the AUC was found for the levodopa metabolite 3-O-methyldopa at the higher carbidopa intake. Clinical performances of individual patients were identical with both carbidopa-levodopa ratios. From these data, an adequate inhibition of peripheral decarboxylation and hence a good bioavailability of levodopa may be expected in patients taking low doses of carbidopa-levodopa, using currently available commercial preparations.

Carbamazepine and phenytoin. Comparison of cognitive effects in epileptic patients during monotherapy and withdrawal.

We compared the cognitive effects of carbamazepine and phenytoin with neuropsychological tests exploring intelligence, vigilance, attention, memory, and visuomotor performances in 25 epileptics (13 receiving carbamazepine and 12 receiving phenytoin) and 26 matched normal controls. Patients were seizure free for at least two years and taking prolonged monotherapy. We also evaluated the effects of drug withdrawal by retesting patients three months after reduction at half drug dose and three months and one year after complete withdrawal. Our findings suggest that phenytoin affects the cognitive functions more than carbamazepine does, although the negative effects of both drugs are reversible by complete therapy withdrawal.

Influence of meal ingestion time on pharmacokinetics of orally administered levodopa in parkinsonian patients.

The influence of meal ingestion time on rate and extent of oral levodopa absorption was evaluated in a group of 17 patients, after administration of their usual second daily dose of levodopa plus carbidopa (Sinemet 10:1) or benserazide (Madopar 4:1). Standard meals were consumed by the patients after they had fasted 15-17 h, on one occasion 30 min before ingestion of the levodopa "study dose" and, at another time, 2 h after ingestion of the same dose. This study dose, ranging from 50 to 250 mg levodopa, was given to the patients at 11 a.m., 4 h after their first morning dose. Time to peak plasma levodopa concentration increased threefold (from 45 +/- 23 to 134 +/- 76 min, p less than 0.001), when levodopa was administered after meals. Area under the 6-h plasma concentration-time curve for levodopa was decreased in 10 subjects, unchanged in three and higher in four after ingestion of meals, the latter finding probably resulting from an erratic absorption even at fasting. On the whole, levodopa absorption proved significantly lower (p less than 0.01), on the average 15%. Similarly, peak plasma levodopa concentrations were lower in 12 patients, unchanged in two, and higher in three, with an overall significant decrease (p less than 0.001) of 30% on the average. The data confirm the importance of meal ingestion time in relation to levodopa dose as a determinant of drug absorption.

Clobazam in therapy-resistant patients with partial epilepsy: a double-blind placebo-controlled crossover study.

Clobazam was compared with placebo as antiepileptic adjunct medication in 129 therapy-resistant epileptic patients who were mainly suffering from complex partial seizures. The study was performed in five European countries according to a double-blind crossover design lasting 7 months. Two treatment periods of 3 months (1 month adjustment and 2 months maintenance medication) were separated by one medication switch-over month. The difference in seizure reduction between clobazam and placebo was significant (p less than 0.05). Nineteen percent of patients receiving clobazam became seizure-free during the maintenance dose period. In contrast, freedom from seizures was not observed in any placebo patient. Electroencephalogram (EEG) signs, mood ratings, and global impressions also indicated therapeutic effects of clobazam in epilepsy. The most frequent adverse reactions to clobazam were drowsiness and dizziness. However, the sedative effects of clobazam seemed to be less pronounced in comparison with other benzodiazepines. The study gives evidence of the therapeutic value of clobazam as adjunct medication in therapy-resistant partial seizures. The use of clobazam as monotherapy and long-term treatment, as well as the particular seizure response pattern to clobazam, has to be further investigated.

Cognitive effects of phenytoin during monotherapy and after withdrawal.

We studied the psychomotor performance of 10 seizure-free epileptics during a fixed monotherapy with phenytoin and after its withdrawal. Our findings suggests some adverse effects of phenytoin which seem reversible after withdrawal.

Withdrawal of phenobarbital and carbamazepine in epileptic patients: a preliminary neuropsychological report.

We systematically investigated the neuropsychological effects of controlled withdrawal of antiepileptic therapy with a battery of tests exploring intelligence, vigilance, attention, memory and sensori-motor performance. 16 patients without seizures for at least 2 years, 9 on therapy with phenobarbital (PB) and 7 with carbamazepine (CBZ), were examined 4 times over a period of 21 months. No significant correlation was found between drug levels and performance in the tests. The slight differences found between the PB and CBZ groups at full doses disappeared completely one year after withdrawal.

Free concentration of carbamazepine and carbamazepine-10,11-epoxide in children and adults. Influence of age and phenobarbitone co-medication.

Total and free plasma concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) were determined in 39 children (aged 3 to 10 years) and 79 adults (aged 15 to 65 years) receiving long term treatment with CBZ alone or in combination with phenobarbitone (PB). Compared with the corresponding age groups treated with CBZ alone, adults and children receiving PB co-medication showed lower total and free CBZ concentrations, similar CBZ-E concentrations and higher CBZ-E/CBZ ratios. Among patients on CBZ alone, children had at any given dose lower total and free CBZ and CBZ-E concentrations than adults. Lower CBZ levels in children than in adults were also found among patients receiving phenobarbitone in combination. CBZ-E/CBZ ratios did not differ significantly between children and adults. These data provide evidence that children show an elevated free CBZ clearance with a metabolic pattern different from that observed during phenobarbitone induction.

Time-dependent interaction between phenytoin and valproic acid.

The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.

Lateral gaze nystagmus in carbamazepine-treated epileptic patients: correlation with total and free plasma concentrations of parent drug and its 10,11-epoxide metabolite.

The incidence of lateral gaze nystagmus and its correlation with free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine-10, 11-epoxide (CBZ-E) were examined in 97 epileptic patients receiving chronic treatment with CBZ alone (n = 54) or in combination with phenobarbital (PB) (n = 43). All patients had plasma CBZ concentrations within the clinically optimal range (less than 50 mumol/L). Nystagmus was seen in 26% of patients receiving monotherapy and in 33% receiving combination therapy. Within each group, however, nystagmus was much more frequent among patients with higher CBZ concentrations. For patients receiving PB in combination the CBZ levels above which nystagmus was particularly frequent appeared to be lower than in the monotherapy patients--a finding that could not be attributed to differences in plasma PB concentrations. The correlation of CBZ-E levels (or the sum of CBZ + CBZ-E) with the occurrence of nystagmus was no better than that observed with CBZ levels alone. Free drug levels did not appear to be superior to total levels in discriminating between patients with or without nystagmus. These results indicate that the occurrence of nystagmus is concentration-dependent within the therapeutic plasma CBZ concentration range and suggest that the threshold at which this neurological sign appears is reduced in the presence of PB, possibly as a result of a pharmacodynamic interaction.

Free and total plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients: diurnal fluctuations and relationship with side effects.

The diurnal fluctuations in free and total plasma levels of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) and their relationship with intermittent side effects were examined in 10 epileptic patients stabilized on chronic CBZ therapy alone or in combination with phenobarbital (PB). With a t.i.d. or q.i.d. dosing schedule, total plasma levels of CBZ and CBZ-E fluctuated to a similar extent (average 34% and 29%, respectively). The diurnal changes in free levels of both compounds mirrored closely those of the total levels. Free fraction values ranged from 13 to 26% for CBZ and from 24 to 66% for CBZ-E. Owing to the lower protein binding of the metabolite, CBZ-E/CBZ ratios were higher in plasma water (0.49) than in whole plasma (0.22). A good correlation was found between both total and free CBZ levels and dose-related side effects (diplopia, nystagmus). On the other hand, no apparent relationship was found between side effects and either total or free plasma CBZ-E. The correlation with the presence of neurological signs of toxicity for the sum of CBZ + CBZ-E levels was no better than that observed for CBZ levels alone. These data do not support the hypothesis that CBZ-E contributes significantly to the development of dose-related side effects in CBZ-treated patients.

Plasma concentrations of propranolol and 4-hydroxy-propranolol at steady-state in neurological patients: intersubject and intrasubject correlations with dose.

Plasma concentrations of propranolol (PROP) and its active 4-hydroxymetabolite were determined in neurological patients receiving chronic therapy with relatively low PROP doses (40-240 mg/day). Plasma PROP concentrations determined before the morning dose were much lower than, but significantly correlated (r = 0.91) with the drug level two hours after dosing. 4-hydroxypropranolol (4-OH-P) was often undetectable (less than 1 ng/ml) in the early morning samples. Plasma concentrations of both parent drug and metabolite determined two hours after the morning dose correlated weakly with the prescribed daily dose. The intrapatient dose-concentration relationship, on the other hand, was strong, particularly for the parent drug. The ratio between 4-OH-P and PROP in plasma was inversely related to the PROP concentration, at least over the lower PROP concentration range (0-100 ng/ml). The usefulness of determining the concentration of the metabolite in the evaluation of the pharmacological action of low doses of PROP is discussed.

Phenobarbital and propranolol in essential tremor: a double-blind controlled clinical trial.

In a double-blind study with Latin square design, phenobarbital (about 1.3 mg per kilogram), propranolol (about 1.7 mg per kilogram), and placebo were given orally for 1 month to 12 patients with essential tremor. By clinical evaluation, only propranolol appeared to be significantly more effective than placebo. As judged by tests of manual skill, none of the treatments significantly improved tremor. Patients' subjective evaluation and tremor amplitude measurement (by accelerometer) showed a significantly better effect of both propranolol and phenobarbital than placebo. These data suggest that phenobarbital may be a valuable alternative to propranolol in essential tremor.

Propranolol and acetylsalicylic acid in migraine prophylaxis. Double-blind crossover study.

The aim of this double-blind crossover study was to compare the prophylactic effect of acetylsalicylic acid (ASA) with that of propranolol (PRP) in the treatment of migraine. Plasma concentrations of the two drugs were measured in order to investigate a possible relationship to the clinical effect. Compared to the pretreatment period, PRP and ASA reduced migraine index, frequency, duration, severity of attacks and headache days. Due to the limited number of patients, our results should be cautiously interpreted, however relevant the clinical improvement seemed. Improvement of migraine index was not related to different plasma levels of the two drugs.