Antiepileptic Drug Concentrations Research Articles

Enzyme-Inducing Antiepileptic Drugs in Pregnancy and the Risk of Bleeding in the Neonate

Most epileptic women continue taking antiepileptic drugs (AEDs) throughout pregnancy despite their teratogenic potential and the possibility that they may pose a risk of neonatal bleeding. In the past four decades more than 40 cases of such bleeding have been reported in connection with maternal AED treatment. The presumed mechanism is altered vitamin K metabolism by drugs that induce hepatic enzymes. Phenobarbital, phenytoin, and carbamazepine are among the AEDs that cross the placenta and promote oxidative degradation of vitamin K in the fetus. This study examined the risk of bleeding in a prospective series of 662 pregnancies where the women took enzyme-inducing AEDs, most frequently carbamazepine and phenytoin. The control group included 1324 nonepileptic pregnancies totalling 1334 infants. The groups were matched for maternal age, parity, and delivery date. No mother received vitamin K 1 during pregnancy, but all infants received 1 mg intramuscularly at the time of birth. Serum AED concentrations were estimated every 2 months, and ultrasonography was performed at 16 to 20 weeks' gestation. The epileptic women abused alcohol more often than control women. They more often had cesarean delivery, and their infants more often had low Apgar scores. There were no significant differences in mean gestational week at delivery, birth weight, or perinatal deaths. Grand mal seizures occurred during 18% of pregnancies. Five infants exposed to AEDs (0.7%) had intracranial bleeding. Three of them were born before 34 weeks' gestation, and the other two had complications known to increase the risk of such bleeding. None of these mothers had grand mal seizures or supranormal serum AED levels during late pregnancy. Five control infants (0.4%) also had intracranial bleeding-not a significantly lower rate than for infants exposed to AEDs. In neither univariate nor multiple logistic regression analysis was exposure to material AEDs associated with neonatal bleeding. The findings from this study give no indication that the use of enzyme-inducing AEDs throughout pregnancy makes intracranial bleeding more likely in the newborn infant. Nevertheless, selected mothers may require antenatal vitamin K treatment.

Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis.

Concerns over teratogenicity of antiepileptic drugs (AEDs) during pregnancy must be balanced against the risks of seizures to the mother and developing fetus. Pharmacokinetic changes and vomiting may alter drug levels, but more important may be the patient's decision to stop medication before or during pregnancy. Compliance assessment traditionally relies either on self-reporting or on AED plasma level monitoring; neither provides reliable information on drug-taking behaviour over an extended interval (e.g., before, during, and after pregnancy). We have used hair analysis to assess AED-taking behavior in pregnant women compared with nonpregnant female controls. Twenty-six pregnant women [mean age, 27.5 +/- 6.7 (SD) years] and 13 nonpregnant female epilepsy outpatients (mean age, 31.9 +/- 8.3 years) were studied. Carbamazepine (CBZ) or lamotrigine (LTG) concentrations were measured in 1-cm hair segments, and the within-subject variance in segmental hair concentrations of these drugs was calculated for each group. The variances of each group were then compared by using a variance ratio test. The variance of AED concentration in hair differed significantly between the pregnant and nonpregnant groups [variance ratio, 1.59 (p < 0.01)]. Four (15%) of the 26 pregnant patients had little or no AED in their proximal hair segments compared with more distal segments, apparently having discontinued their medication during pregnancy. Only one of these later disclosed having stopped her medication. One pregnant woman whose hair profile was similar to controls died suddenly at 30 weeks of gestation. This study confirms the perception that pregnant women with epilepsy frequently stop or greatly reduce their prescribed medication, usually without reference or acknowledgement to their clinician.

Limbic Seizures Induce P-Glycoprotein in Rodent Brain: Functional Implications for Pharmacoresistance

The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect anticonvulsant drug concentrations in the brain.MdrmRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3–24 hr after kainic acid-induced limbic seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of phenytoin or carbamazepine for 7 d did not changemdrmRNA expression in the mouse hippocampus 1–72 hr after the last drug administration. Six hours after seizures, the brain/plasma ratio of phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b −/−) lacking P-gp protein showed a 46% increase in phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr. Carbamazepine concentrations were measurable in the hippocampus at 3 hr inmdr1a/b −/− mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus,mdr1mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect antiepileptic drugs concentrations in the brain, suggesting that seizure-inducedmdrmRNA expression contributes to MDR in epilepsy.

Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance.

The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect anticonvulsant drug concentrations in the brain. Mdr mRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3-24 hr after kainic acid-induced limbic seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of phenytoin or carbamazepine for 7 d did not change mdr mRNA expression in the mouse hippocampus 1-72 hr after the last drug administration. Six hours after seizures, the brain/plasma ratio of phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b -/-) lacking P-gp protein showed a 46% increase in phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr. Carbamazepine concentrations were measurable in the hippocampus at 3 hr in mdr1a/b -/- mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect antiepileptic drugs concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy.

Synergistic Effect of Valproate Coadministration and Hypoalbuminemia on the Serum-Free Phenytoin Concentration in Patients With Severe Motor and Intellectual Disabilities

We investigated whether a combination of risk factors affects the free phenytoin (PHT) fraction by multiple regression analyses in 30 patients with severe motor and intellectual disabilities (SMID) with epilepsy. The risk factors analyzed were gender, age, total PHT concentration, albumin concentration, aspartate aminotransferase, alanin aminotransferase, serum creatinine, blood urea nitrogen, and antiepileptic drug concentrations. Serum levels of total and free PHT were measured by fluorescence polarization immunoassay. Free PHT fractions were between 7.2% and 17.3% (average 10.9%). Two factors, hypoalbuminemia and valproate (VPA) coadministratation with PHT, increased free PHT fraction, and a combination of these two markedly increased free PHT fraction. Patients with these double risk factors have a high risk of exceeding the therapeutic range of serum-free PHT concentration even if their total PHT concentration does not. Therefore, we should monitor free PHT concentration, especially in SMID patients with epilepsy, because they may have hypoalbuminemia and are treated with antiepileptic drug polytherapy and, moreover, cannot report adverse effects of the drugs.

An Evaluation of the Effects of Methylphenidate on Outcomes in Adult Epilepsy Patients

Purpose. To determine if methylphenidate (MPH) therapy can improve cognition in adult epilepsy patients on multiple antiepileptic drugs (AEDs), we assessed the impact of MPH on seizure activity, quality of life, cognition, and fatigue in patients with a primary diagnosis of localization-related epilepsy. Methods. This was an open-label, nonrandomized 3-month study. MPH (Ritalin) was added to patients' current antiepileptic drug regimens. Outcome measures included seizure activity, select AED serum concentrations, quality of life (via Quality of Life in Epilepsy—89 questions (QOLIE-89)), cognition (via Microcog), and fatigue (via a visual analog scale) at baseline and at monthly intervals for the treatment phase. Results. Eleven patients were enrolled and eight completed this pilot study. Of the eight completing the study, five were seizure-free at baseline and throughout the study. One patient had an increase, one a decrease, and one no change in seizure activity. No serious adverse events were observed. On average, serum AED concentrations changed <10% from baseline to the end of the study. Mean overall QOLIE-89 scores and select domains improved significantly from baseline. All Microcog domains improved from baseline. Fatigue also improved significantly. Conclusions. Adult epilepsy patients received relief from sedation with MPH and showed an improved quality of life, without significant alteration of seizure control.

Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.

Epilepsy is resistant to drug treatment in about one-third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resistance proteins, such as multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 may also be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurones, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumours (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases) and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumour nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression was also noted in dysplastic neurones. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein-positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 may also do so. The overexpression of these drug resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs.

Simultaneous determination of four antiepileptic drugs in serum by high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin. After protein precipitation by acetonitrile, the supernatant was analysed on a C18 reversed-phase HPLC column. Antiepileptic drugs and oxazepam (internal standard) were detected by ultraviolet absorbance at 240 nm. Linearity was established for the whole concentration range for each compound. Quantitation limits of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin were 0.58, 3.5, 2.35, 0.66, 1.02 and 3.13 microg/mL, respectively, and mean recoveries added to serum were 105.15, 84.76, 94, 45, 96.52, 98.62 and 95.08%, respectively. This method has been used for the simultaneous determination of steady-state serum concentration of antiepileptic drugs in patients treated by one or more anticonvulsive treatment.

A Prospective Evaluation of the Effects of a 12-Week Outpatient Exercise Program on Clinical and Behavioral Outcomes in Patients with Epilepsy

Purpose. We hypothesized that patients randomized to an exercise program would demonstrate a measurable improvement in behavioral outcomes with no adverse clinical outcomes, as compared with control patients. Methods. This randomized, prospective, parallel, and controlled study spanned 12 weeks. Twenty-eight patients were randomized either to participate in a supervised exercise program (Exercise) or to continue their current level of activity with no planned intervention (Control). The Exercise group worked with an exercise physiologist three times per week. At specific intervals, behavioral (QOLIE-89, POMS, PSDQ, Self-Esteem) and clinical (seizure activity, antiepileptic drug (AED) concentrations) outcomes were measured. Results. Twenty-three patients completed the study (Exercise n = 14, Control n = 9). Of the four patients in the Exercise group with active seizures, two had no change, one had an increase, and one had a decrease in seizure activity. Of the three patients in the Control group with active seizures, one had no change, one had an increase, and one had a decrease in seizure activity. In all patients, there was <26% coefficient of variation in AED concentrations over the 12-week study, suggesting little or no impact of the exercise intervention. The overall quality of life and two domain scores improved from baseline to Week 12 in the Exercise group ( P = 0.031), while the Control group score did not change ( P = 0.943). In the Exercise group, there were several measures of physical self-concept and vigor that improved and total mood disturbance decreased from the beginning to the end of the program. Conclusion. This is the first randomized, controlled study of exercise in patients with epilepsy. Behavioral outcomes are positively influenced by moderate exercise and there is no impact on seizure frequency. This suggests that exercise should not be discouraged in the care of epilepsy patients. The ability to offer an exercise program adds a health promotion component to the current plan of care provided by our comprehensive epilepsy program.

Therapeutic drug monitoring--antiepileptic drugs.

To provide a brief critical review of the basis and contemporary practice of monitoring the concentrations of antiepileptic drugs in biological fluids. The review is based on literature data and observations from clinical practice. As experience has accumulated, monitoring of antiepileptic drug concentrations has come to be applied mainly to certain of the drugs when present in whole plasma. For these drugs there is a reasonably established relationship between drug concentrations and biological effects, but attention still needs to be paid to issues such as the timing of the measurements in relation to drug intake, the presence or absence of steady-state conditions, the presence in plasma of active metabolites and possible nonlinear pharmacokinetics of particular agents, e.g. phenytoin. Plasma antiepileptic drug concentration monitoring is coming to be used in a more thoughtful and critical manner. Lack of adequate knowledge of matters such as the relationship between the plasma concentrations and antiepileptic and toxic effects of the drugs, not only the newer, but also the longer established ones, in particular clinical situations, remains more important than deficiencies in analytical methodology in limiting the clinical usefulness of antiepileptic drug concentration monitoring.

Sudden unexplained death in children with epilepsy.

Sudden unexplained death is a significant cause of mortality in people with epilepsy. Risk factors that have been identified include male sex, poor compliance with medications, and antiepileptic drug (AED) polypharmacy. However, these may not apply to the pediatric population in which the causes of epilepsy differ from the adult population. Therefore, risk factors for sudden unexplained death in epilepsy (SUDEP) in children must be evaluated independently from those in the adult population. Cases of SUDEP in children less than 18 years of age occurring over a 10-year period in the province of Ontario, Canada, were identified. Records were reviewed for demographic and clinical features and neuropathology findings. Twenty-seven cases of SUDEP in children were identified. Sixty-three percent were male. Age at death ranged from 8 months to 15 years. Fourteen children had symptomatic epilepsy (52%), five had cryptogenic epilepsy (18%), and eight had idiopathic epilepsy (30%). Twelve children were treated with one AED (46%), 10 were on two AED (38%), and three were on three AED (12%). At the time of death, seven children had one serum AED concentration below the therapeutic range (35%) and 12 children had AED levels within the therapeutic range (60%). This case series represents the largest series of sudden unexplained death in children with epilepsy. At least two previously described risk factors for SUDEP in adults, low serum AED levels at time of death and AED polytherapy, do not appear to be significant in children.

Assessment of teratogenic risk

Although the association between prenatal exposure to old generation antiepileptic drugs (AEDs) and major congenital malformations has been studied for many years, it is not clear whether any specific AED, or AED combination, is more harmful than others, or whether any pattern of malformations can be considered specific for any given drug. Relationships between dosage and plasma concentrations of AEDs and the risk of malformations also need to be clarified. The greatest limitation of all studies performed to date is the fact that none included a sufficiently large number of pregnancies. For newer generation AEDs the teratogenic risk, if any, is unknown. Large prospective studies are needed. The best approach is the establishment of registries through international collaboration. Inclusion of non-epileptic controls and untreated women is not strictly necessary to evaluate the comparative teratogenic risk of AEDs. The modalities of data collection should be pre-defined; common protocols, sufficiently exhaustive but at the same time easy to perform, should be shared from the beginning. Information on the presence or absence of major malformations or prenatal growth retardation, and on all major factors that may affect the teratogenic endpoints should be obtained. Study designs should ensure high quality data recording, and adequate quality assurance and auditing procedures. Further requisites are a clear definition of congenital malformation and prolonged follow-up to detect the occurrence of congenital malformations not detected at birth.

Neonatal Seizures.

Neonatal seizures are frequently manifested by subtle movements that are referable to brain stem structure, ie, nystagmus, conjugate eye movements, posturing, sucking movements, and so forth. Electroencephalogram (EEG) confirmation of abnormal movements is essential in diagnosing seizures in the neonate. Clinical seizure signs are often a clue to etiology. Metabolic abnormalities must always be considered, and blood gases, calcium, magnesium, glucose, and ammonia obtained. Neonatal seizures are an indication for cerebrospinal fluid examination. Specific metabolic abnormalities are treated with metabolic approaches, not conventional anticonvulsant drugs. Hypertensive encephalopathy is treated by controlling blood pressure, and not through anticonvulsant drugs. Critically ill infants bind anticonvulsants in an unpredictable fashion, and unbound or free anticonvulsant drug concentrations should be used to guide therapy. Phenobarbital is the most commonly used drug in treating nonmetabolic seizures. Doses to achieve free concentrations of at least 35 mg/L should be used. Use in vitro binding determinations with this formula to calculate loading doses. Dose is 25 mg/kg multiplied by volume and distribution (1 L/kg) divided by % free. Phenytoin is the second most commonly used agent, and doses should be calculated to achieve, but not exceed, 3 mg/L. Dose is 3 mg/kg multiplied by volume and distribution (1 L/kg) divided by % free. Benzodiazepines, notably lorazepam and diazepam are used at doses of 0.15 mg/kg and 0.3 mg/kg, respectively.

Treatment of status epilepticus in children.

Status epilepticus (SE) is a condition characterised by frequent and prolonged epileptic seizures which frequently develop in the immature brain. Fever, metabolic disorders and subtherapeutic concentrations of antiepileptic drugs are the most common factors precipitating SE in children. Progressive neuronal damage occurs if convulsive SE persists for more than 30 minutes, with neurological, epileptic and cognitive sequelae. Unfortunately, the immature brain is more predisposed to SE and its sequelae than the mature brain. SE may be categorised as convulsive, nonconvulsive or neonatal according to its responsiveness to antiepileptic drugs. Regardless of category, the main objective in the treatment of SE is to abort the seizures and treat the inciting condition. Treatment includes: (i) monitoring of hydration, electrolyte balance, and cardiocirculatory and pulmonary functions; and (ii) rapid intravenous administration of specific antiepileptic drugs. Benzodiazepines (usually diazepam, lorazepam or midazolam) are the most effective agents for the initial treatment of convulsive and nonconvulsive SE. In particular, midazolam infusion is an effective and well tolerated therapeutic approach for the management of childhood SE, including refractory SE. Phenytoin remains an excellent agent because of its long duration of action, but it is not active in nonconvulsive SE. Fosphenytoin, a phenytoin prodrug, represents a significant advance in the treatment of children with convulsive SE. Intravenous phenytoin and intramuscular phenobarbital (phenobarbitone) are generally used in neonatal SE; other agents are rarely used.

Chlormethiazole inhibits epileptiform activity by potentiating GABA A receptor function

Chlormethiazole has sedative, hypnotic, anticonvulsant and neuroprotective properties. Using in vitro grease-gap recordings, we show that it inhibits epileptiform activity in neocortical slices superfused with Mg 2+-free medium (IC 50∼200 μM). At an antiepileptic concentration (300 μM), chlormethiazole potentiated the action of exogenously applied GABA (1 mM) but did not affect responses to the glutamate receptor agonists N-methyl- d-aspartate (10 μM) or l-quisqualic acid (3 μM). The GABA A receptor antagonist N-methyl-bicuculline (50 μM) reduced chlormethiazole’s potency to inhibit the epileptiform activity. These results indicate that chlormethiazole’s anticonvulsant action is likely mediated by potentiating GABA Aergic inhibition rather than by antagonising glutamatergic excitation.

Inhibitory simple partial (non-convulsive) status epilepticus after intracranial surgery

OBJECTIVESTo report on five patients who developed, 2 to 4 days after an intracranial neurosurgical procedure, new, persistent, focal neurological deficits which were due to inhibitory simple partial (non-convulsive) status...

Sudden Unexpected Death In Patients with Epilepsy

Individuals with epilepsy have a mortality rate 2 to 3 times that of the general population, attributable both to any underlying disease that may be causing epilepsy and to the epilepsy itself. The commonest category of seizure-related death is sudden unexpected death in epilepsy (SUDEP). The epidemiology of SUDEP has been extensively studied and a number of such studies have taken anticonvulsant drug usage as an indicator of epilepsy, although obviously this may lead to inaccuracies. Epidemiological work has also yielded information about possible risk factors for SUDEP. At present there is no evidence that any particular anticonvulsant influences this risk, although there are anecdotal reports of sinus arrest and arrhythmias occurring in individuals receiving carbamazepine. A recent case-control study found that the risk of SUDEP increased with increasing number of concomitant anticonvulsants. In many cases of SUDEP, subtherapeutic anticonvulsant concentrations have been found at postmortem which may reflect noncompliance with medication, although the relationship between ante- and postmortem drug concentrations is unclear. The mechanism of SUDEP is unknown, although a possible role for anticonvulsants in its aetiology must be considered. Some anticonvulsants, by blocking sodium channels, have a direct effect on cardiac conduction, but studies examining the association between anticonvulsants and cardiac arrhythmia are lacking. As there is evidence to suggest an association between seizures and sudden death, the judicious use of anticonvulsants in optimising seizure control may be important in the prevention of these deaths.

Therapeutic monitoring of the new antiepileptic drugs.

To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed. The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM. TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration-effect relationships of the new antiepileptic drugs are urgently needed.

Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156 cases (1990–1995)

Objective To report clinical findings, treatments, and outcomes of dogs admitted to the hospital for status epilepticus or cluster seizures and evaluate factors associated with outcome. Design Retrospective study. Animals 156 dogs admitted for status epilepticus or cluster seizures. Procedure Medical records were reviewed for seizure and medication history, diagnostic test results, types of treatment, hospitalization costs, and outcome of hospital visits. Results Dogs were admitted for seizures on 194 occasions. Of 194 admissions, 128 (66%), 2 (1%), 32 (16.5%), 2 (1%), and 30 (15.5%) were of dogs with a history of clusters of generalized seizures, clusters of partial complex seizures, convulsive status epilepticus, partial status epilepticus, and &gt; 1 type of seizure, respectively. Underlying causes of seizures were primary epilepsy (26.8%; 52/194), secondary epilepsy (35.1%; 68), reactive epileptic seizures (6.7%; 13), primary or secondary epilepsy with low serum antiepileptic drug concentrations (5.7%; 11), and undetermined (25.8%; 50). One hundred and eighty-six hospital visits resulted in admission to the intensive care unit (ICU). Treatments with continuous IV infusions of diazepam or phenobarbital were initiated during 66.8% (124/186) and 18.7% (35) of ICU hospital stays for 22.3 ± 16.1 hours (mean ± SD) and 21.9 ± 15.4 hours, respectively. Of 194 admissions, 74.7% (145) resulted in discharge from the hospital, 2.1% (4) in death, and 23.2% (45) in euthanasia. A poor outcome (death or euthanasia) was significantly associated with granulomatous meningoencephalitis, loss of seizure control after 6 hours of hospitalization, and the development of partial status epilepticus. Conclusions and Clinical Relevance Granulomatous meningoencephalitis, loss of seizure control after 6 hours of hospitalization, or the development of partial status epilepticus may indicate a poor prognosis for dogs with seizures. (J Am Vet Med Assoc 1999;215:1463–1468)

Effect of maternal anticonvulsant treatment on neonatal blood coagulation

AIMSTo investigate the impact of maternal anticonvulsant use on the ability of cord blood to coagulate.METHODSCord blood prothrombin times were measured, over 15 years in a consecutive series of 137...