The use of NMDA antagonist memantine in drug-resistant dyskinesias resulting from L-dopa.
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Adult↗
Biomedical subjects
M Emre
Publications and source records attributed to M Emre.
Diagnosis and management of Alzheimer's disease and other disorders associated with dementia. The role of neurologists in Europe. European Federation of Neurological Societies.
In 1998 a task force to develop guidelines for diagnostic evaluation and treatment of dementia was initiated by the European Federation of Neurological Societies (EFNS) scientist panel on dementia. The aims of the task force were to provide evidence-based recommendations and to highlight the role of the neurologist in the management of patients with Alzheimer's disease and other disorders associated with dementia. We based our recommendations on a review of available evidence-based guidelines supplemented with further literature reviews. The recommendations were derived from consensus meetings and relate to individual patient management, as there are inadequate data on the cost-effectiveness of different diagnostic evaluations and treatments for dementia. Their specific applications will depend upon available resources. The particular contributions of the neurologist include: early identification and differential diagnosis of rare and common brain disorders causing cognitive and behavioural symptoms, referral for and interpretation of ancillary investigations, and identification and treatment of vascular and other concurrent diseases. A review of the management of dementia in Europe revealed considerable variation. In some countries neurologists have taken the lead in the management of patients with dementia, while in other countries the neurologist is rarely involved. We recommend that neurologists should have a clear role in the management of dementia in the whole of Europe. They should be involved in the diagnostic evaluation of dementia and facilitate the development of multidisciplinary teams for evaluation and management of patients with cognitive disturbances. The increasing role of neurology in the management of patients with dementia has important implications for training and education.
Alzheimer Disease↗
Evidence-based pharmacological treatment of dementia.
The current literature on the pharmacological treatment of dementia was reviewed and the strength of evidence for the efficacy of each drug was categorized using an evidence-based approach. Acetylcholinesterase-inhibitors represent the only category of drugs with consistently demonstrable efficacy in well-designed studies of Alzheimer's disease, although the effect is not large. There is a lack of prospective, controlled, randomized studies for most of the nootropics. Epidemiological evidence suggests prophylactic effects of oestrogens and anti-inflammatory agents, and a single large-scale trial suggests that long-term administration of vitamin E or selegiline may be associated with improved outcome in patients with Alzheimer's disease. A number of drugs were reported to be effective in the treatment of non-cognitive symptoms of dementia including classical and atypical neuroleptics, antidepressants and anticonvulsants. The evidence for efficacy, however, is not strong for the majority of these compounds.
Cognition↗
Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans.
Effects of the novel competitive N-methyl-D-aspartate (NMDA)-receptor antagonist SDZ EAA 494 were investigated on memory and attention in humans. SDZ EAA 494 was administered either as single doses at a dose range of 1-50 mg, or as multiple doses over the course of 1 week at doses of 25 mg once or twice daily. Selected cognitive functions were assessed at baseline, 2 and 4 h after single dose administration, and at baseline, 2, 4 and 8 h on days 1 and 7 of multiple dose administration. The assessments included simple and complex reaction time tests to assess attention, and verbal, non-verbal and spatial memory tests with immediate and late recall. Verbal and non-verbal memory test performance was significantly impaired at a dose level of 50 mg after single administration, and of 25 mg twice daily after multiple administration, without concomitant significant impairment of reaction time. Spatial memory test performance was not significantly affected. The maximum effect occurred 2 h postmedication and was more pronounced after repeated administration. These results suggest that the inhibition of NMDA-receptors in humans may impair memory processes.
Adult↗
The pharmacology of SDZ EAA 494, a competitive NMDA antagonist.
SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.
Animals↗
Correlations between dose, plasma concentrations, and antispastic action of tizanidine (Sirdalud).
In a double blind, placebo controlled, cross over study the correlations between single doses (2, 4, and 8 mg), plasma concentrations, and antispastic action of tizanidine were investigated in 16 patients with extensor spasticity of the legs due to multiple sclerosis. An electrogoniometer was used to assess muscle tone at knee extensors, applying Wartenberg's pendulum test. Blood samples, a clinical assessment of muscle tone by the Ashworth scale, and muscle strength by the British Medical Research Council scale were obtained concomitantly. Confirmatory analysis using the change in the relaxation index (R2 value) 1.5 hours after each treatment, showed a statistically significant (p = 0.0123) linear dose-response relation between single doses and antispastic action of tizanidine. Further statistical analysis showed a strong within patient linear correlation between plasma concentrations and antispastic action at 4 and 8 mg doses (p = 0.014 and 0.004 respectively), but only weak between patient correlations. The analysis of the dose-plasma concentration relation showed results consistent with linear pharmacokinetics. The comparison of changes in the R2 ratio with concomitant Ashworth scores showed a significant correlation between the two. It is concluded that there are linear correlations between single doses, plasma concentrations, and antispastic action of tizanidine. Because of the strong within patient but weak between patient correlation between plasma concentrations and antispastic action of tizanidine the effective doses should be determined individually.
Adult↗
Pharmacokinetics and pharmacodynamics of tizanidine.
The relationship among tizanidine dose, plasma concentration, and antispastic action is linear in nature. Response to a given dose of this agent varies among patients, and determining the appropriate clinical dose requires individual titration.
Clonidine↗
Comparative profile of tizanidine in the management of spasticity.
The therapeutic profile of a new antispastic drug cannot be defined solely on the basis of placebo-controlled studies. Its potential advantages must be evaluated in comparison with existing drugs. This review compares the efficacy and tolerability of tizanidine, a newer muscle relaxant, with that of baclofen and diazepam, the most widely used antispastic agents, for a variety of diagnoses and target symptoms associated with spasticity. More than 20 double-blind, comparative studies were conducted between 1977 and 1987. These included a total of 777 patients suffering from spasticity of various causes. The collected clinical data have been integrated into a combined analysis. Tizanidine emerges from this comparison as a valuable drug in the treatment of spasticity related to cerebral and spinal disorders.
Activities of Daily Living↗
Cholinergic innervation of the amygdaloid complex in the human brain and its alterations in old age and Alzheimer's disease.
The cholinergic innervation of the human amygdaloid complex was studied immunohistochemically with a choline acetyltransferase (ChAT) antibody in eight brains: five control and three with Alzheimer's disease (AD). All amygdaloid nuclei displayed ChAT-immunopositive axons and varicosities. The density of these axons reached levels that were higher than in any other part of the forebrain except for the striatum. The highest level of ChAT-immunopositive profiles was seen in the basolateral nucleus and the second highest in the lateral part of the central nucleus. The basomedial, accessory basal, and cortical nuclei, the amygdalohippocampal and cortico-amygdaloid transition areas, as well as the anterior amygdaloid area, showed a moderate density of ChAT-positive varicosities and fibers. The lateral nucleus displayed a relatively low density of cholinergic innervation, and there were only rare ChAT-positive fibers in the medial nucleus. Although the level of cholinergic innervation in the lateral nucleus was relatively lower than in many of the other amygdaloid nuclei, it was approximately equivalent to that of entorhinal cortex, a region that receives one of the heaviest cholinergic inputs in the cerebral cortex. The distribution of the cholinergic fibers as studied by ChAT immunohistochemistry was nearly identical to that observed with AChE histochemistry. Quantitative densitometry in control specimens showed that there was no decline of amygdaloid cholinergic input when middle-aged subjects were compared with senescent subjects. In AD there was a severe and regionally selective depletion of this innervation in the amygdaloid complex. The cortical, accessory basal, and lateral nuclei displayed the most severe loss of ChAT-positive profiles, whereas the basolateral, and especially the central, nuclei displayed relatively little change. There was no consistent relationship between the loss of cholinergic fibers and the density of amyloid plaques and neurofibrillary tangles in amygdaloid nuclei.
Aged↗
The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy.
The amino acids L-glutamate and L-aspartate have been shown to be excitatory neurotransmitters in mammalian central nervous systems. Antagonists acting selectively at excitatory amino acid receptors have shown antiepileptic properties in several animal models. We report the results of the first therapeutic trial of the competitive NMDA antagonist, D-CPP-ene (SDZ EAA-494), in eight patients with intractable complex partial seizures. All patients withdrew prematurely because of side-effects, including poor concentration (8), sedation (7), ataxia (6), depression (3), dysarthria (2), amnesia (2) and unilateral choreo-athetosis in a patient with contralateral Sturge-Weber syndrome. Seizures were unchanged in four patients and worse in three. A further patient with apparent improvement in seizures in the first week developed complex partial status epilepticus on withdrawal of DCPP-ene. EEG on treatment (5) or in the immediate post-treatment period (2) showed slowing of background activity and, in five cases, an increase in epileptiform activity. Serum concentrations of DCPP-ene were found to be unpredictable and higher than expected from pharmacokinetic data on normal subjects. There was no clear relationship between serum concentrations and the severity of side-effects. Preliminary experience with DCPP-ene in patients with refractory partial seizures is not promising. Evaluation of related compounds is warranted.
Adult↗
Effects of cigarette smoking on motor functions in patients with multiple sclerosis.
The acute effects of cigarette smoking on motor functions were examined in 21 patients with multiple sclerosis and 11 healthy control subjects. The motor function in the upper extremities was assessed by a simple test battery. Sixteen of 21 patients had a transient deterioration of their motor function immediately after smoking, lasting for 10 minutes. The mean decrease in motor performance score for all 21 patients was 14%. With the same tests performed without smoking only three of 14 patients had a deterioration and the group had a mean 8% improvement. The control group showed a steady improvement over time, both in smoking and in simulation experiments. We conclude that nicotine causes a transient worsening of motor functions in patients with multiple sclerosis, which can be due to its effects on the central nervous system or vegetative-vascular functions.
Adult↗
Effects of a selective partial D1 agonist, CY 208-243, in de novo patients with Parkinson disease.
A selective dopamine D1-receptor agonist, CY 208-243, was administered to 23 de novo patients who had had Parkinson disease (PD) for less than or equal to 3 months. The drug was first used as monotherapy and then in some patients in combination with a dopamine D2-receptor agonist, bromocriptine. Results showed that CY 208-243 exerted a mild antiparkinsonian action, and tremor was the main symptom that consistently improved. The addition of bromocriptine less than or equal to 15 mg to CY 208-243 did not result in additional improvement, but this might be due to the short duration of treatment and the low doses of bromocriptine. The study was prematurely discontinued for safety reasons. We conclude that D1-receptor stimulation may result in improvement of motor disability in PD.
Adult↗
Palatal myoclonus occurring during complex partial status epilepticus.
Palatal myoclonus is thought to occur after damage to certain brain-stem structures, and with a delay following the causative lesion. A case of palatal myoclonus, probably of epileptic nature, is described.
Electroencephalography↗
Antiparkinsonian activity of a non-ergot dopamine agonist, CV 205-502, in patients with fluctuating Parkinson's disease.
Six patients with fluctuating Parkinson's disease received single rising oral doses of the nonergot dopamine agonist CV 205-502 in an open experimental study. Doses of 0.5 mg produced antiparkinsonian effects of comparable intensity but longer duration than 200 mg of L-DOPA. CV 205-502, which combines structural features common to both ergolines and apomorphine, thus revealed interesting antiparkinsonian properties, but nausea and vomiting were dose-limiting side effects in all patients tested.
Administration, Oral↗
Somatostatin and heat sensitivity in multiple sclerosis.
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Hot Temperature↗
[Exertional dyspnea as the initial manifestation of amyotrophic lateral sclerosis].
In amyotrophic lateral sclerosis (ALS), respiratory problems are usually late complications. However, ALS may occasionally present with exertional dyspnea as the primary symptom, as was the case in the patient reported here. On the basis of this case and the literature, the diagnostic and therapeutic aspects of the neurologic causes of dyspnea are discussed. Where there is a discrepancy between severity of blood gas alterations, changes in lung volume determinations and severity of dyspnea, a neuromuscular disorder must be considered in differential diagnosis.
Aged↗
Somatosensory evoked potentials in comatose patients: correlation with outcome and neuropathological findings.
Subcortical and early cortical somatosensory evoked potentials (SEPs) were recorded in 63 comatose patients and classified into five salient SEP grades, which were defined as follows: grade 1, normal SEP; grade 2, SEPs with a clearly recognizable scalp component N20, normal central conduction time but clearly distorted wave N20-P25; grade 3, SEPs with a still recognizable N20 but delayed central conduction time and severely altered wave N20-P25; grade 4, SEPs with absence of N20 but with a more or less recognizable P15; grade 5, SEPs with absence of both N20 and P15. When these five patterns were compared with outcome, it was found that bilaterally normal SEPs or only unilaterally distorted SEPs were generally followed by good outcomes. Bilaterally altered SEPs (grade 2 or 3) were indicative of reduced chances of full recovery. The great majority of patients showing either grade 4 or 5 SEPs died within a few days after the recording session. In 31 patients, it was found post mortem that grade-2 SEPs reflected cortical brain damage, whereas grade-3 SEPs correlated well with subcortical lesions. In post-traumatic patients, this SEP pattern corresponded to diffuse subcortical shearing lesions. Patients with grade 4 or 5 SEPs were found to have severe brain oedema giving rise to transtentorial herniation, which was combined with secondary midbrain haemorrhage and tonsillar herniation in all patients with bilateral grade-5 SEPs.
Adolescent↗