Characteristics of falls in the epilepsy monitoring unit: a retrospective study.

Falls are an important adverse event in an epilepsy monitoring unit (EMU). We identified patterns of falls in an EMU and compared them with risk factors for inpatient falls. Twenty-six patients with 26 falls (2.3% of admissions) in the EMU were compared with 50 general neurology inpatients with 56 falls over a 4-year period. In the EMU, the majority (62%) of falls happened during the first 3 days of admission, mostly in the bathroom (74%), in patients with a normal mental status (77%). Most general inpatients fell after the third day (64%), inside their rooms (68%), and had an altered mental status before the fall (68%). All 26 EMU patients were identified as high risk at admission, in spite of which falls were not prevented. We outline these differences between EMU patients and general inpatients and highlight the practice gap in preventing falls in an EMU.

Brain dynamical disentrainment by anti-epileptic drugs in rat and human status epilepticus.

In this paper, we utilize a measure of brain dynamics, namely the short-term largest Lyapunov exponent (STLmax) to evaluate the efficacy of treatment in epileptic animals and humans with known antiepileptic drugs (AED) like diazepam and phenobarbital during status epilepticus (SE). This measure is estimated from analysis of electroencephalographic (EEG) recordings at multiple brain locations in both an SE patient and a cobalt/homocysteine thiolactone SE-induced animal. Techniques from optimization theory and statistics are applied to select optimal sets of brain sites, whose dynamics are then measured over time to study their entrainment/disentrainment. Results from such analysis indicate that the observed abnormal spatio-temporal dynamical entrainment in SE is reversed by AED administration (resetting of brain dynamics). These results may provide a potential use of nonlinear dynamical measures in the evaluation of the efficacy of AEDs and the development of new treatment strategies in epilepsy.

GABAergic mechanisms in epilepsy.

gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. When this balance is perturbed, seizures may ensue. GABA is formed within GABAergic axon terminals and released into the synapse, where it acts at one of two types of receptor: GABAA, which controls chloride entry into the cell, and GABAB, which increases potassium conductance, decreases calcium entry, and inhibits the presynaptic release of other transmitters. GABAA-receptor binding influences the early portion of the GABA-mediated inhibitory postsynaptic potential, whereas GABAB binding influences the late portion. GABA is rapidly removed by uptake into both glia and presynaptic nerve terminals and then catabolized by GABA transaminase. Experimental and clinical study evidence indicates that GABA has an important role in the mechanism and treatment of epilepsy: (a) Abnormalities of GABAergic function have been observed in genetic and acquired animal models of epilepsy; (b) Reductions of GABA-mediated inhibition, activity of glutamate decarboxylase, binding to GABAA and benzodiazepine sites, GABA in cerebrospinal fluid and brain tissue, and GABA detected during microdialysis studies have been reported in studies of human epileptic brain tissue; (c) GABA agonists suppress seizures, and GABA antagonists produce seizures; (d) Drugs that inhibit GABA synthesis cause seizures; and (e) Benzodiazepines and barbiturates work by enhancing GABA-mediated inhibition. Finally, drugs that increase synaptic GABA are potent anticonvulsants. Two recently developed antiepileptic drugs (AEDs), vigabatrin (VGB) and tiagabine (TGB), are examples of such agents. However, their mechanisms of action are quite different (VGB is an irreversible suicide inhibitor of GABA transaminase, whereas TGB blocks GABA reuptake into neurons and glia), which may account for observed differences in drug side-effect profile.

Status epilepticus and tiagabine therapy: review of safety data and epidemiologic comparisons.

PURPOSE: To determine whether an increased risk of status epilepticus (SE) and complex partial status epilepticus (CPSE) is associated with tiagabine (TGB) therapy. METHODS: Thirteen cases in which an EEG, performed on patients with altered mental status taking TGB, was reported to demonstrate spike-and-wave discharges (SWDs) were reviewed by a panel of experts. In addition, all cases of suspected SE from TGB clinical trials were reviewed. The occurrence of SE in four epidemiologic cohorts from Rochester, Minnesota, Turku, Finland, Bronx, New York, and New Haven, Connecticut was analyzed as an external comparison. RESULTS: Review of the 13 cases with reported SWDs found that the majority had had prior EEGs with similar findings, and only three were thought to have electrographic evidence of SE. There was no difference in the frequency of SE or CPSE in the placebo-controlled clinical trials between the TGB-treated (1.0% SE, 0.8% CPSE) and placebo-treated (1.5% SE, 1.5% CPSE) groups. The 5% frequency of SE and 3% frequency of CPSE in the TGB-treated patients in the long-term safety studies, which included 2,248 patients, were very similar to the rates of occurrence of SE and CPSE in the four external cohorts. The major risk factor for the occurrence of SE and CPSE in all groups was a prior episode of SE (p < 0.0001). CONCLUSIONS: Over a 3-year period, SE will occur in 5-10% of patients with epilepsy not in remission. At highest risk are those who have had a prior episode of SE. Treatment with TGB in recommended doses does not increase the risk of SE in patients with partial seizures.

Therapy of status epilepticus in adults and children.

Clinical studies of the treatment of status epilepticus are extremely difficult to carry out, therefore a paucity of new clinical studies have been reported. Much of the progress regarding the therapy of status epilepticus has come from a better understanding of the epidemiology of status epilepticus and its consequences and from laboratory studies of experimental status. Status epilepticus has been used as an experimental tool to study epileptogenesis, but from such studies have come insights that can be applied to the therapy of status epilepticus itself. This review will focus on information from epidemiological, experimental, and clinical studies of status epilepticus, which may contribute to the improved treatment of this life-threatening disorder.

Violence and the epilepsy defense.

The essence of the epilepsy defense is the argument that a crime was committed as a result of the perpetrator having epilepsy, and thus that he or she should not be held responsible for a violent crime. Neurologists are frequently asked to pass judgment regarding whether an alleged act may have been the result of an epileptic condition; therefore, neurologists should be informed as to what criteria should be used to decide if a given act was, or could have been, the result of an epileptic seizure. This article discusses three cases where epilepsy is used as the defense argument. In addition, this article reviews types of epileptic seizures, syncopal events, and pseudoseizures.

Phenytoin penetration into brain after administration of phenytoin or fosphenytoin.

PURPOSE: This study was designed to measure the brain penetration of phenytoin (PHT) after intravenous (i.v.) administration of either standard PHT or fosphenytoin (FPHT), a PHT prodrug. The study was formulated to answer the question whether the time required for FPHT to be converted to PHT in the bloodstream would delay the accumulation of PHT in brain. METHODS: Four rats were sampled at various times after intravenous infusion of 30 mg/kg PHT i.v. or 30 mg/kg PHT equivalents of FPHT i.v. PHT was measured in serum, protein-free ultrafiltrate, and in brain, by using high-performance liquid chromatography. RESULTS: Although the initial PHT-free fraction was significantly higher for FPHT-treated rats than it was for PHT-treated rats, brain PHT levels were significantly reduced after infusion of FPHT. CONCLUSIONS: When FPHT is used for treatment of generalized status epilepticus, it should be anticipated that lower initial brain PHT levels will be achieved than are typically found with standard PHT.

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Effects of cholinergic deafferentation and NGF on brain electrical coherence.

Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with nerve growth factor (NGF) or vehicle. Electrocortical coherence was assessed at postoperative days 4, 7, 14, and 21 from all possible pairs of eight epidural electrodes in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta-1 (12-20 Hz), and beta-2 (20-28 Hz) bands. On day 21 choline acetyltransferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in losses of interhemispheric, as well as bilateral intrahemispheric coherence in the theta band (F1,21 = 28.61, p < 0.0001, F1,21 = 4.30, p < 0.05), with no significant differences seen in other bands. Changes were accentuated during immobility compared with walking and exploratory behavior. Intrahemispheric changes were greatest within the lesioned hemisphere (F1,21 = 6.97, p < 0.01) in long connections between electrode pairings connecting frontal to posterior brain regions. Nerve growth factor (NGF) attenuated losses in ChAT (F1,21 = 21.31, p < 0.0001) and intrahemispheric coherence (F1,21 = 9.66, p < 0.005), whereas interhemispheric coherence showed no significant response. Intact animals receiving NGF showed increases in intrahemispheric coherence, as well as modest increases in ChAT. Increases in coherence in response to NGF occurred within 4-7 days following brain lesions, with no significant change during the 2 weeks thereafter. Our results suggest that coherence is sensitive to cholinergic deafferentation, particularly of long corticocortical connections. NGF differentially restores coherence within hemispheres, as opposed to between hemispheres. Our study suggests that brain function in Alzheimer's disease related to damage of transcallosal fiber tracts may not be responsive to cholinergic treatments. Future studies may wish to evaluate the cognitive relevance of NGF's effects on intact brain.

Altered residual ATP content in rat brain cortex subcellular fractions following status epilepticus induced by lithium and pilocarpine.

Changes in residual ATP concentrations were investigated following subcellular fractionation of rat brain cortex after a prolonged period of status epilepticus induced by sequential administration of lithium and pilocarpine. After 2 h of continuous high-amplitude rapid spiking on EEG, we found significantly decreased levels of residual ATP in the homogenate and mitochondria fractions from status epilepticus rat brains compared to matched controls. No difference in residual ATP level was observed in the synaptosomal preparations of status epilepticus animals compared to controls. Inorganic phosphate concentration in the status animals was higher than controls in the cytosolic fraction only. F1-ATPase activity, an enzymatic indicator of mitochondrial ATP synthesis rate, was significantly higher in the status brains, whereas other mitochondrial enzymes were not different in the status and control rat groups. These findings, together with our earlier report of reduced synaptosomal ecto-ATPase activity, suggest that either the corresponding in vivo ATP concentrations were reduced as a result of status epilepticus or other biochemical changes had occurred that facilitated the hydrolysis of ATP following decapitation. Controls for and measurement of such other changes failed to provide an explanation for the observed changes in residual ATP.

Changes in cortical EEG and cholinergic function in response to NGF in rats with nucleus basalis lesions.

We examined whether recovery of cholinergic function in response to nerve growth factor (NGF) results in restoration of electrocortical activity. Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with NGF or vehicle. Cortical electrical activity was assessed at postoperative days 4, 7, 14, and 21 from 8 epidural electrodes. On day 21, choline acetyl transferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in increases in slow-wave (delta) power and decreases in high-frequency (beta 2) power in the lesioned, as well as the non-lesioned hemisphere. Changes correlated topographically and in magnitude with losses of ChAT activity and suggested that regional electrocortical function was affected by cholinergic activity originating in the ipsilateral, as well as the contralateral hemisphere. NGF attenuated changes in cholinergic and electrocortical function bilaterally, though in the lesioned hemisphere, function did not return to control levels. Likewise, intact animals receiving NGF showed increases in beta 2-power, as well as modest increases in ChAT activity. Changes in brain electrical activity in response to NGF occurred within 4-7 days without significant changes during the 2 weeks thereafter. Our results suggest that outcomes of future animal and human trials-using unilateral i.c.v. infusions of NGF need to consider the reciprocal influences of hemispheric cholinergic function, as well as possible effects of NGF on intact brain.

Reduced cortical ecto-ATPase activity in rat brains during prolonged status epilepticus induced by sequential administration of lithium and pilocarpine.

Considerable evidence indicates that ATP, acting intracellularly of as a neurotransmitter, can influence nerve cell physiology in a variety of ways. Defects in the functioning of ATP-metabolizing enzymes could therefore lead to disturbances in neurotransmission and creation of sustained neuronal discharges characteristic of status epilepticus. In this study we investigated synaptosomal ATPase changes in rat brains during lithium/pilocarpine-induced status epilepticus. After 2 h of continuous electroencephalographic spiking, both Mg(2+)- and Ca(2+)-dependent ecto-ATPases were significantly decreased in freshly prepared synaptosomal preparations from the status rats. The intracellularly acting Ca2+Mg(2+)-ATPase (Ca-pump) was also decreased, but no changes occurred in synaptosomal Na+K(+)-ATPase activity. The difference between ecto-ATPase activities of the control and status rat brains was not affected by repeated freezing-thawing and lengthy storage. Possible involvement of reduced synaptosomal divalent cation-dependent ATPases in the pathophysiology of status epilepticus is discussed.

Status epilepticus.

Status epilepticus is a condition in which multiple epileptic seizures occur without complete recovery from the physiological effects of one seizure before another seizure occurs. There are as many types of SE as there are kinds of epileptic seizures. Generalized convulsive status epilepticus initially presents with repeated generalized convulsions without full recovery of consciousness between seizures. If untreated or undertreated, the convulsive activity becomes progressively subtle and is accompanied by a predictable series of progressive EEG changes. Non-convulsive SE refers to complex partial SE or absence SE, both of which exhibit an epileptic twilight state of altered contact with the environment. In simple partial SE there is no impairment of consciousness, and the behavioural changes reflect focal ictal discharges confined to one area of the cortex. There are between 65,000 and 150,000 cases of the SE in the US each year. Both acute and remote cerebral insults can cause SE, as can severe systemic disease that causes SE secondary to a toxic-metabolic encephalopathy. Mortality is high, but is largely a reflection of underlying aetiology when SE is treated appropriately and aggressively. Treatment is focused on terminating ongoing seizure activity as quickly as possible, both because the longer SE persists the more likely permanent neuronal damage will ensure and also because of strong evidence that the longer SE persists the more refractory to treatment it will be. Currently the most commonly accepted treatment protocol involves rapid initiation of therapy with intravenous lorazepam (0.1 mg/kg), followed, if necessary, by 20 mg/kg of phenytoin, followed, if necessary, by 20 mg/kg of phenobarbital. However, some neurologists still use intravenous diazepam (because of its more rapid antistatus effect) followed by phenytoin. New experimental data in the rat suggest that phenytoin followed by diazepam may be more effective, but this order of administration still has to tested in properly designed clinical trials.

High-performance liquid chromatographic determination of midazolam in rat brain.

A high-performance liquid chromatography method for the determination of midazolam in rat brain is described. Midazolam and the internal standard halazepam were extracted with toluene and analyzed isocratically on a reversed-phase column with a mobile phase consisting of methanol, acetonitrile and potassium phosphate buffer. Detection was monitored by ultraviolet absorption at 240 nm. The standard curves were linear over the range of 25-350 ng midazolam per 50 mg brain tissue. The day-to-day coefficient of variation ranged from 1.7 to 6.9%. The limit of quantification was 80 ng/g brain tissue. The method is rapid, simple and reproducible for brain analysis.

Lamotrigine vs. phenytoin for treatment of status epilepticus: comparison in an experimental model.

The newly introduced antiepileptic drug, lamotrigine, has been reported to have a mechanism of action similar to that of phenytoin. Because phenytoin is a standard clinical treatment for convulsive status epilepticus, we compared the efficacy of lamotrigine to that of phenytoin in a model of secondarily generalized convulsive status epilepticus in rats that responds to drug concentrations similar to those that have been reported to be clinically useful for this purpose. Status epilepticus was induced in rats with actively epileptogenic cortical cobalt lesions by administration of homocysteine thiolactone. While phenytoin-controlled generalized tonic clonic seizures in this model with a median effective dose of 100.5 mg/kg (16.0 micrograms/ml in serum), lamotrigine was ineffective at doses ranging from 10 to 100 mg/kg, with serum drug concentrations (2.5-43.5 micrograms/ml) within or above the reported 'therapeutic' concentration for LTG treatment of chronic epilepsy. Lamotrigine also failed to prevent the onset of generalized tonic clonic seizures when given prior to homocysteine, while phenytoin was effective in this test. Studies of lamotrigine kinetics in serum and brain revealed that the drug was well-absorbed following i.p. injection and that it entered brain rapidly enough to have exerted an anti-status effect in these experiments. These results suggest that lamotrigine and phenytoin have differences in their mechanisms of anticonvulsant action, leading to very different abilities to control status epilepticus.

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.