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Biomedical subjects

D M Treiman

Publications and source records attributed to D M Treiman.

At least 19 recordsLinked to original sources
PubMed1995

Functional mapping of the early stages of status epilepticus: a 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat.

Continuous convulsive activity in status epilepticus generally does not occur suddenly in response to the inciting epileptogenic agent, but is rather the culmination of a stereotyped sequence of stages. Initially seizures are discrete, then undergo waxing-and-waning of convulsive/electroencephalographic severity. Following a transitional EEG-recorded fast-and-slow spiking phase, continuous fast spiking with invariant convulsive behavior ensues. We sought to map the seizure anatomic substrates corresponding to these stages, utilizing the 14C-2-deoxyglucose technique, in order to make inferences about underlying mechanisms. The lithium-pilocarpine status epilepticus model in rat was employed. Cerebral autoradiographs associated with discrete seizures revealed non-uniform cerebral metabolic activation, with rostral cortical and olfactory areas especially involved. Portions of basal ganglia were also activated, consistent with projections from seizure-activated areas. Successive stages of status entry displayed additional limbic and cortical activation, along with subcortical projection sites, so that by fast-and-slow spiking most forebrain areas were recruited. Based on these results, a model is proposed whereby cyclical seizure-attenuating mechanisms cause, in the initial stages of status entry, fluxing of seizure anatomic extents between small and large cerebral domains, with corresponding cycling of convulsive severity. In the later stages of status entry, these mechanisms become ineffective, resulting in steady-state maximal forebrain recruitment, associated with continuous and invariant convulsive behavior and electrographic fast spiking.

Animals↗
PubMed1995

Functional mapping of the late stages of status epilepticus in the lithium-pilocarpine model in rat: a 14C-2-deoxyglucose study.

Pilocarpine administration to lithium chloride-pretreated rats results initially in discrete convulsive seizures, each behaviorally and electroencephalographically terminated, which then progress to convulsive activity with waxing-and-waning behavioral and electrographic severity; finally, a continuous convulsive state ensues, associated electrographically with continuous fast spiking. This stage does not last indefinitely but is followed by a dramatic electrographic change to periodic epileptiform discharges. The purpose of the present study was to determine with the 14C-2-deoxyglucose functional mapping technique what changes occur in the seizure anatomic substrate during and after this transition, in order to enable inferences about underlying mechanisms. Behavior associated with early and late continuous fast spiking consisted of head twitching; corresponding deoxyglucose autoradiographs displayed seizure-induced intense glucose utilization in most forebrain areas; extranigral brainstem was normal. At 2-3 h of status, fast spiking became interrupted by flat periods; periodic complexes soon dominated the electroencephalogram. Behaviorally, convulsive severity increased. Despite this dramatic electrographic evolution, little change in generalized forebrain metabolic hyperactivation occurred, except that the zona incerta/pretectal/superior colliculus complex displayed markedly increased activity. Deoxyglucose studies in late stages of periodic epileptiform discharges established a sequence of further changes. In late periodic discharges with clonic jerks, at 4 h after status entry, generalized forebrain hyperactivation still prevailed, but to a lesser degree than in early periodic discharges with clonic jerks. At a still later stage, late periodic discharges, subtle convulsive, autoradiographs revealed constriction of the seizure-activated anatomic substrate: hyperactivation was lost in most of neocortex and thalamus, and in caudal olfactory structures, cortical amygdala, and entorhinal areas, but retained in deep occipital cortex and many limbic areas. In the last stage, late periodic discharges, electrical, not associated with convulsive behavior, autoradiographs revealed residual activation in only Ammon's horn; in contrast, much of the forebrain displayed below-normal glucose utilization. These results demonstrate that in the later stages of status epilepticus, the transition from fast spiking to periodic complexes is not associated with a reduction in the seizure anatomic substrate. The electrographic entity of periodic epileptiform discharges is not anatomically or behaviorally homogeneous, but proceeds through successive stages characterized initially by a reduction of glucose utilization within generalized seizure-activated forebrain, then a contraction of the seizure anatomic substrate. Possible mechanisms underlying the transition to periodic complexes are discussed.

Animals↗
PubMed1995

Cardiac hypertrophy secondary to status epilepticus in the rat.

Status epilepticus was induced in rats by sequential injections of lithium and pilocarpine. Seizure activity was aborted by a combination of MK-801 and diazepam, with status duration ranging from 3 to 180 min. When the hearts were examined 8-12 days later, rats that had experienced an episode of status epilepticus had significantly heavier hearts than did controls. The nature of the cardiac tissue changes was not examined, and deserves further study.

Animals↗
PubMed1995

Electroclinical features of status epilepticus.

Status epilepticus (SE) is a condition wherein epileptic seizure discharges are sufficiently prolonged or repetitive so as to produce persistent alterations in neurologic function and in the underlying physiologic and neurochemical activities of the brain. Thus, the definition of SE now includes any disorder in which there is sustained and prolonged excitation of neurons. Electroencephalographic (EEG) patterns associated with specific types of SE are important components in their classification. Like epileptic seizures, SE can be divided into partial onset SE and primarily generalized SE. Partial onset SE includes secondarily generalized convulsive SE (GCSE), complex partial SE (CPSE), simple partial SE (SPSE), and the syndromes of epilepsia partialis continua (EPC) and rolandic SE (RSE). Primarily generalized SE includes primarily GCSE, absence SE, atypical absence SE, generalized myoclonic SE, generalized clonic SE, generalized tonic SE, atonic SE, and the syndromes of electrical SE of sleep (ESES) and minor epileptic SE of Brett. SE is a dynamic disorder. Behavioral and electrical manifestations change over time if seizure activity is allowed to persist without successful treatment A progression from overt to subtle convulsive activity occurs in secondarily GCSE and there is also a progression of predictable EEG changes in prolonged GCSE. CPSE begins as discrete complex partial seizures but also progresses behaviorally and electrically through a sequence similar to that observed in GCSE. Progressive behavioral and electrical changes have not been reported in primarily generalized forms of SE. EEG is an important tool for verifying successful treatment of SE if the patient does not immediately recover neurologic function. EEG recordings also contribute substantially to understanding the mechanisms of, and development of better treatments for, human SE through their use in the study of experimental SE in the laboratory.

Animals↗
PubMed1994

Interictal spiking increases 2-deoxy[14C]glucose uptake and c-fos-like reactivity.

Although interictal spikes are thought to share pathophysiological mechanisms with partial-onset seizure discharges, positron emission tomographic studies of the interictal state have paradoxically shown focal hypometabolism whereas seizures produce hypermetabolism. To address this question, we performed functional mapping studies in an interictal spiking model in the rat. Recording screw electrodes were inserted through the skull bone so as to depress underlying cortex. Interictal spiking was subsequently induced by systemic administration of bicuculline methiodide. 2-deoxy[14C]glucose studies revealed increased glucose utilization in superficial and middle cortical layers at spiking screw sites. Nonspiking screw sites in the same animals and in controls did not show increased uptake. Convulsive seizures caused additional 2-deoxy[14C]glucose uptake at screw sites and in widespread forebrain areas. c-fos immunoreactivity occurred in superficial cortex at interictal spiking, but not nonspiking, sites. Convulsive seizures induced widespread forebrain c-fos immunoreactivity. These data suggest interictal epileptiform activity occurs in cells adjacent to cortical injury; these activate deeper layers via local connections. Interictal and ictal epileptiform states share common mechanisms, as both induce glucose hypermetabolism and immediate-early gene product activation. Possible reasons for failure to detect hypermetabolism in interictal human subjects are discussed.

Animals↗
PubMed1994

Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus.

Adenosine is an endogenous neuromodulator that suppresses excitatory neurotransmission. We postulated that adenosine-mediated mechanisms resist status epilepticus (SE) entry and limit SE severity. In the first experiment rats were given an adenosine agonist (2-chloroadenosine), an adenosine antagonist (aminophylline), or saline vehicle, prior to SE induction with pulsed-train current delivered to amygdala in successive 5-min current-on sessions. Saline-treated animals entered limbic SE, with predominantly exploratory behavior, after 6.0 +/- 0.9 current-on sessions. Aminophylline increased major convulsive activity during stimulation and resulted in entry into convulsive SE after only 2.1 +/- 0.1 sessions. 2-Chloroadenosine, in contrast, suppressed major convulsive activity during stimulation, and blocked (in 3/7) or delayed (4/7) SE entry, with successes requiring 12.8 +/- 0.9 stimulation sessions. In a second experiment, animals already in exploratory SE were administered a single injection of saline vehicle, aminophylline, or 2-chloroadenosine. Aminophylline converted exploratory SE into lethally severe convulsive SE. 2-Chloroadenosine suppressed SE behaviorally and electrographically, and protected recipients from the seizure-associated cerebral damage seen in saline-administered SE controls. These results support the hypothesis that endogenous adenosine mechanisms resist SE entry, modulate the severity of ongoing SE, and limit the anatomic spread of seizure activity.

2-Chloroadenosine↗
PubMed1994

Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine.

The potential clinical efficacy of tiagabine for control of status epilepticus was evaluated in an experimental model. Tiagabine was administered to cobalt-lesioned rats in which status epilepticus was induced by injection of homocysteine thiolactone. Tiagabine was effective in controlling status epilepticus in this model; the median effective dose for control of generalized tonic-clonic seizures in the model was 8.3 mg/kg. Tiagabine administration produced an abnormal, hypo-reactive behavioral state which was accompanied by an EEG pattern of high-amplitude, frontally dominant, rhythmic, 3-5-Hz spike-wave activity. This EEG and behavioral syndrome could be reproduced by administration of tiagabine to normal, non-epileptic rats. The exact nature of this syndrome remains unclear, but whether it is an epileptic or encephalopathic phenomenon, further study is clearly required before this drug should be considered for use in the treatment of human status epilepticus.

Animals↗
PubMed1994

A new, non-pharmacologic model of convulsive status epilepticus induced by electrical stimulation: behavioral/electroencephalographic observations and response to phenytoin and phenobarbital.

Much remains to be learned about mechanisms underlying entry into, and temporal progression of, status epilepticus (SE). This report describes a non-pharmacologic model of generalized convulsive SE in rat. Pulsed trains of suprathreshold electric current, were administered bilaterally to either of four rostral forebrain sites: orbital cortex, medial precentral cortex, deep prepiriform cortex, or rostral caudate-putamen (n = 8 per site). This induction method resulted in 30/32 animals attaining limb-clonic convulsive SE within a mean of 30-35 min for each forebrain site, with no differences between sites. Subsequent SE proceeded without further interventions, permitting observation of the natural course of progression. A stereotyped behavioral/electrographic sequence occurred, characterized by devolution. Behaviorally, animals progressed from predominantly limb clonus to head clonus, then to subtle twitching, and finally to electrical SE before cessation of spikes. The corresponding electrographic progression was from fast and slow spiking to periodic epileptiform discharges (PEDs). In 20 animals surviving to 48 h, pathologic damage affected mainly limbic sites; damage was related to total convulsive time rather than to clonic activity. High-dose phenobarbital but not phenytoin suppressed SE when given during orbital cortex-induced limb-clonic SE. These findings are compatible with human observations and indicate that this model will enable investigations of generalized SE mechanisms and evaluation of new therapeutic agents for refractory SE.

Animals↗
PubMed1994

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Adolescent↗
PubMed1994

Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Adult↗
PubMed1992

Valproic acid treatment of experimental status epilepticus.

The efficacy of valproic acid (VPA) in control of generalized convulsive status epilepticus was tested in a rat model. Rats with cortical cobalt lesions were injected with homocysteine thiolactone to induce secondarily generalized tonic-clonic seizures (GTCS). The median effective dose (ED50) for control of GTCS was 211.9 mg/kg (270 micrograms/ml in serum 30 min post dose) when treatment was given intraperitoneally after the second GTCS. VPA entered both serum and brain very rapidly after injection, with little change in concentration from 5 to 30 min post dose. In earlier experiments with phenytoin, phenobarbital, diazepam and lorazepam in this model, we found that the serum concentrations produced by the ED50s versus GTCS were very similar to those which have been reported to be effective in treating human status epilepticus. If this same relationship holds true for VPA, we would predict that a serum concentration of around 270 micrograms/ml VPA would be required for control of generalized convulsive status epilepticus in human patients. The safety of this high a concentration of VPA has not been tested.

Animals↗
PubMed1991

Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam.

Pharmacologic control of refractory status epilepticus has been little-studied in experimental models. In this experiment, rats in status epilepticus induced by lithium and pilocarpine were treated with MK-801 alone, diazepam alone or MK-801 plus diazepam, with treatment begun at a time when this model of status is refractory to anticonvulsant drugs. EEG samples were digitized before and for two hours after treatment, and the digitized samples subjected to computerized frequency analysis. MK-801 plus diazepam halted all manifestations of status epilepticus. Although neither MK-801 alone nor diazepam alone stopped the ongoing electrographic status epilepticus, both drugs diminished motor seizures and total EEG power. MK-801 treatment prevented the progression of changes in EEG pattern which normally occurs in this model of status epilepticus, while diazepam did not. MK-801, with and without diazepam, allowed the rats to survive the episode of status epilepticus, but rats treated with MK-801 alone required several days to recover completely, while the MK-801 plus diazepam rats appeared normal the next day. MK-801 may be a useful agent for treatment of human refractory status epilepticus, because of its neuroprotective action as well as its ability to potentiate GABAergic drugs.

Animals↗
PubMed1991

Design of an individualized fixed-dose clinical trial to test the antiepileptic efficacy of a plasma flunarizine concentration.

Flunarizine (FLN) is a potential antiepileptic drug whose pharmacokinetic properties include a long half-life (2-7 weeks) and high interpatient variability in volume of distribution and clearance. The National Institutes of Health (NIH) is sponsoring a randomized, double-masked, multicenter, parallel-group, placebo-controlled clinical trial to demonstrate the antiepileptic activity of FLN. The design is based on the premise that plasma concentrations are more strongly related to drug response than are doses. For each patient, an estimate of the concentration-time curve following a single dose of FLN is used to determine a loading dose and maintenance dosage targeted at a specified plasma FLN concentration. After an inpatient, drug-loading period, the fixed maintenance dosage (of FLN or placebo) is prescribed for the entire 24-week outpatient treatment period unless a change is required for medical reasons. If the target concentration is well chosen and approximately achieved, this design has several potential advantages: (a) A fixed-dose design is simpler and less subject to bias than a design involving dosage adjustments; (b) the drug-loading period reduces from several weeks or months to 1 week the time required to achieve the target plasma FLN concentration; (c) compared with a design in which each patient receives the same dose, the decreased variability in FLN concentrations should result in fewer patients receiving subtherapeutic doses and fewer patients requiring dose reductions, as well as increased power to detect treatment effects in a population where such effects are generally small.

Data Interpretation, Statistical↗
PubMed1991

Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.

We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.

Aminocaproates↗
PubMed1991

Psychobiology of ictal aggression.

1. Aggression in animals has been classified into a number of stereotyped behavioral responses on the basis of the psychosocial environment in which it occurs. Many such responses can be either replicated or blocked by stimulation or ablation of selected sites in the brain, especially in the hypothalamus or amygdala. Stimulation of the amygdala or the hypothalamus in a limited number of humans has produced agitation, anger, or rage. Ablation of the amygdala has reduced aggression in violent patients. However, the ictal nature of episodic aggression in these patients has not been proven. 2. The diagnosis and classification of epileptic seizures is based on their characteristic clinical manifestations and electrical patterns. Independent objective markers of ictal events need to be identified. Epileptic seizures are characterized by stereotyped nondirected behavior, especially at onset. The more organized, directed, and modifiable by the environment the behavior is, the less likely it is epilepsy. 3. Ictal aggression can be classified into primary and secondary ictal aggression, resistive violence, and postictal psychosis. Few alleged cases of ictal violence or aggression fulfill criteria for ictal events; most which do are examples of resistive violence. 4. If animal models can be developed which exhibit spontaneous paroxysmal stereotypical aggression, they may be used to improve our understanding of the classification and pathophysiology of ictal aggression.

Aggression↗
PubMed1990

High-performance liquid chromatographic determination of selected amino acids in rat brain by precolumn derivatization with phenylisothiocyanate.

We describe here a simple, sensitive, selective and reproducible assay method for quantitative determination of aspartate, glutamate, serine, glutamine, glycine and gamma-aminobutyric acid in rat brain using reversed-phase high-performance liquid chromatography. The method is based upon formation of phenylthiocarbamyl derivatives of the amino acids. Good resolution of the six amino acids and the internal standard norvaline is achieved within 40 min. Other amino acids which have been reported to be present in rat brain do not interfere with the analysis. Standard curves for each of the amino acids exhibited good linearity (r greater than 0.9993) over the range 0.5-20 nmol. The coefficient of variation for the intra-day and inter-day determinations ranged from 0.4% at the highest to 11% at the lowest concentration limit. Storage of whole brains at -0 degrees C for up to 8 weeks did not affect mean concentrations of the six amino acids.

Amino Acids↗