Forensic antiepileptic drug levels in autopsy cases of epilepsy

A 1-year retrospective coroner-based forensic examination of causes of death among persons with a history of epilepsy was conducted at the Allegheny County Coroner's Office to evaluate the phenomenon of sudden unexplained/unexpected death in epilepsy (SUDEP), a diagnosis of exclusion. All cases at the Coroner's Office from January 1, 2001 through December 31, 2001, were examined. Review of a total of 1200 autopsied deaths revealed 12 cases with a past medical history of seizure disorder on the death certificate, which listed seizure disorder as the immediate cause of death or contributory cause of the death. Of the 7 men with seizure disorders, 5 were categorized as definite SUDEP and 2 as possible SUDEP. Of the 5 women with seizure disorders, 2 were listed as definite SUDEP, 2 as possible, and 1 as non-SUDEP because the convulsive seizures developed from a grade II glial tumor. Postmortem findings were evaluated for 11 cases; 1 body was decomposed. Toxicological screens were carried out on blood, bile, urine, and eye fluid for all 12. Antiepileptic drug (AED) levels detected in postmortem toxicological analysis were examined. AED levels were determined in 7 cases. Four of 7 had subtherapeutic AED levels, 2 had therapeutic levels, and only 1 victim of SUDEP had levels above the therapeutic range. Five cases had no detectable AED levels. AED levels at autopsy were either absent or subtherapeutic in 9 of 10 SUDEP cases, findings consistent with the likelihood of poor AED compliance. Subtherapeutic levels of AEDs may be a risk factor for SUDEP that could contribute to increased interictal and/or ictal epileptiform activity with associated autonomic dysfunction leading to disturbance of heart rate, heart rhythm, and/or blood pressure.     

Forensic antiepileptic drug levels in autopsy cases of epilepsy

A 1-year retrospective coroner-based forensic examination of causes of death among persons with a history of epilepsy was conducted at the Allegheny County Coroner's Office to evaluate the phenomenon of sudden unexplained/unexpected death in epilepsy (SUDEP), a diagnosis of exclusion. All cases at the Coroner's Office from January 1, 2001 through December 31, 2001, were examined. Review of a total of 1200 autopsied deaths revealed 12 cases with a past medical history of seizure disorder on the death certificate, which listed seizure disorder as the immediate cause of death or contributory cause of the death. Of the 7 men with seizure disorders, 5 were categorized as definite SUDEP and 2 as possible SUDEP. Of the 5 women with seizure disorders, 2 were listed as definite SUDEP, 2 as possible, and 1 as non-SUDEP because the convulsive seizures developed from a grade II glial tumor. Postmortem findings were evaluated for 11 cases; 1 body was decomposed. Toxicological screens were carried out on blood, bile, urine, and eye fluid for all 12. Antiepileptic drug (AED) levels detected in postmortem toxicological analysis were examined. AED levels were determined in 7 cases. Four of 7 had subtherapeutic AED levels, 2 had therapeutic levels, and only 1 victim of SUDEP had levels above the therapeutic range. Five cases had no detectable AED levels. AED levels at autopsy were either absent or subtherapeutic in 9 of 10 SUDEP cases, findings consistent with the likelihood of poor AED compliance. Subtherapeutic levels of AEDs may be a risk factor for SUDEP that could contribute to increased interictal and/or ictal epileptiform activity with associated autonomic dysfunction leading to disturbance of heart rate, heart rhythm, and/or blood pressure.     

Principles of antiepileptic drug treatment of epilepsy

For the successful treatment of epilepsy, accurate diagnosis of epilepsy and epileptic seizures, and proper selection of antiepileptic drugs (AED) according to the classification of epileptic syndromes are fundamentally important. Efficacy of AED treatment, however, depends not only on its pharmacological action but also on its efficient use, namely a rationally thinking tailor-made treatment considering the characteristics of each patients, i.e. individual differences in pharmacokinetics, factors influencing AED concentrations, AED interactions, and comprehensively their life style and psychosocial factors.     

Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy

BACKGROUND: In the face of availability of newer antiepileptic drugs (AEDs) such as lamotrigine and topiramate, there is need to reassess the role of older AEDs in the treatment of juvenile myoclonic epilepsy (JME). OBJECTIVES: To explore whether lamotrigine and topiramate monotherapy or polytherapy can be effective options in the treatment of JME, and to determine whether older AEDs, such as phenytoin and carbamazepine, have a role in the treatment of JME. DESIGN: A retrospective cohort study. SETTING: A large academic teaching hospital. PATIENTS: Seventy-two consecutive JME patients treated with valproic acid, lamotrigine, topiramate, phenytoin, or carbamazepine between April 1, 1991, and March 31, 2001. METHODS: We compared the efficacy of valproic acid, lamotrigine, and topiramate monotherapy or polytherapy in the control of different seizure types of JME, and compared their efficacy and tolerability with the efficacy and tolerability of phenytoin and carbamazepine. RESULTS: Seizure outcome did not differ when patients receiving valproic acid monotherapy (n = 36) were compared with those receiving lamotrigine monotherapy (n = 14), and when patients receiving valproic acid polytherapy (n = 22) were compared with those receiving lamotrigine polytherapy (n = 21) or topiramate polytherapy (n = 15) (P>.05 for all). The combined data of myoclonic seizure control by all 3 AEDs were poorer when compared with the combined data of generalized tonic-clonic seizure control by all 3 AEDs (P =.03), but not when compared with the combined data of absence seizure control by all 3 AEDs (P =.43). Valproic acid, lamotrigine, and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures (P<.01 for all), but not of generalized tonic-clonic seizures (P>.11 for all). CONCLUSIONS: Lamotrigine and topiramate are effective alternative options to valproic acid in the treatment of JME. Lamotrigine is an effective option as monotherapy and polytherapy. Topiramate is an effective option as polytherapy, but more data are needed to determine if it is an effective option as monotherapy. More effective therapy is needed to improve myoclonic seizure control. Older AEDs, such as phenytoin and carbamazepine, may not be indicated in JME patients.     

Plasma levels of antiepileptic drugs in children on the ketogenic diet

Influence of the ketogenic diet on plasma concentrations of antiepileptic drugs was investigated in an open clinical study of 51 children (mean age 6.6 years) with medically refractory epilepsy. The plasma levels of concomitantly used antiepileptic drugs were determined immediately before and 3 months after initiating the ketogenic diet. To compensate for adjustments in dosing, the plasma concentration in relation to the dose per kilogram of body weight per day, i.e. the level-to-dose ratio, was used for comparison; it was calculated as the plasma concentration (micromol/L) divided by the corresponding weight-normalized dose (mg/kg body weight/day) for each drug and child. The level-to-dose ratios of each drug before and during the diet were compared. No significant changes in these ratios could be found for valproic acid, lamotrigine, topiramate, clonazepam, or phenobarbital. In 16 children, the ratio of the free unbound concentration of valproic acid to its total plasma concentration was compared before and during the diet, but it did not change significantly. Thus, the ketogenic diet did not change the plasma concentrations of commonly used antiepileptic drugs in children in any significant way. Therefore, when initiating the diet, it does not seem necessary to adjust drug doses due to pharmacokinetic interactions.     

Considerations in the choice of an antiepileptic drug in the treatment of epilepsy

The advent of multiple new antiepileptic drugs (AEDs) in the past 15 years has provided new options for clinicians treating patients with epilepsy, but has also created a need for guidelines in AED use. For selection of the most appropriate AED, the neurologist must know the pharmacological properties of the AEDs and has to balance their benefits and potential risks for the individual patient. A key consideration in AED selection is spectrum of efficacy for seizure types and epileptic syndrome. Other factors in AED selection include safety and tolerability, ease of use and titration rate, potential interactions, and efficacy in coexisting nonepileptic conditions. Comorbid conditions may favor or exclude the use of certain AEDs in a particular patient. Special considerations apply in specific epilepsy populations, such as women of childbearing age, children, and the elderly. This article analyzes the various factors involved in choosing an AED.     

Clinical utility of unbound antiepileptic drug blood levels in the management of epilepsy.

We tabulated all unbound and total antiepileptic blood levels collected in 13 months. According to strict criteria, 24% of phenytoin and 15% of valproate unbound blood levels but none of the carbamazepine unbound levels had clinical significance in the management of seizures or side effects. These data support frequent use of unbound phenytoin or valproate blood levels in the management of epilepsy.     

Refractory epilepsy: treatment with new antiepileptic drugs.

Five antiepileptic drugs have been marketed in the last decade. We report here a retrospective study of patients attending our unit who were prescribed one of the new antiepileptic drugs. All these patients had refractory localization related epilepsy and had failed to respond to a first-line drug. The drugs had a different profile of side-effects but topiramate (42%) was the most common drug to be withdrawn due to side-effects as compared with tiagabine (26%), vigabatrin (16%), gabapentin (16%), and lamotrigine (15%). With regard to efficacy, 31% of the patients receiving gabapentin had a greater than 50% reduction in seizures compared with lamotrigine (25%), topiramate (20%), vigabatrin (19%) and tiagabine (11%). The number of patients remaining seizure free with gabapentin was 8% whilst for lamotrigine this was 5%, vigabatrin 5%, topiramate 1% and tiagabine 4%. In conclusion, all these five antiepileptic drugs are useful in treating refractory localization related epilepsy.     

Patient and physician reactions to generic antiepileptic substitution in the treatment of epilepsy

BACKGROUND: The clinical and economic consequences of generic antiepileptic drug (AED) substitution are not yet fully understood. This article provides a broad perspective of generic AED substitution in five countries. METHODS: Two cross-sectional telephone-based surveys (patient and physician) were undertaken in Canada, the United Kingdom, France, Germany, and Spain. A total of 1409 interviews, 974 patients and 435 physicians, were completed. RESULTS: Across all countries studied, patients and physicians alike have elevated concerns about the safety and efficacy of generic AEDs as compared with drugs for acute care. CONCLUSION: There is an opposition to generic substitution by both patients and physicians, especially with concern over increased breakthrough seizure risk. Further evidence is required to understand how costs and effects of generic AED substitution affect patient welfare.     

Use of antiepileptic drugs in the treatment of epilepsy in people with intellectual disability

The main principles of antiepileptic drug treatment of epilepsy in patients with intellectual disability are basically the same as for other patients with epilepsy. However, some specific issues need to be taken into account These are primarily associated with the diagnostic difficulties of epilepsy in this population. In addition, a number of other relevant issues, including the degree and location of brain lesion, the nature of the underlying disease, the higher frequency of difficult-to-treat epilepsies, the additional intellectual impairment caused by inappropriate antiepileptic medication, or by frequent and prolonged seizures, the appropriate use of monotherapy versus rational polytherapy, and the use of broad-spectrum antiepileptic drugs will be discussed in the present paper. Although the goals of treatment are to keep the patient seizure-free and alert while preventing possible mental deterioration, we have to accept compromises between these primary goals in many cases. Some people with epilepsy and intellectual disability are very vulnerable to insidious neurotoxic effects; for example, sedative effects caused by phenobarbital, or cognitive and/or cerebellar dysfunction caused by long-term phenytoin, especially together with other drugs. Because of the adverse effects of phenobarbital and phenytoin, these drugs are no longer recommended as a first-choice drugs when long-term antiepileptic medication is required. In primary generalized tonic-clonic seizures, valproate, oxcarbazepine/carbamazepine and lamotrigine are recommended in this order of preference. The corresponding recommendations are: in typical absences, valproate, ethosuximide and lamotrigine; in atypical absences, valproate and lamotrigine; in juvenile myoclonic epilepsy, valproate, lamotrigine and clobazam; in infantile spasms vigabatrin, ACTH and valproate; in Lennox-Gastaut syndrome, valproate, lamotrigine and vigabatrin; in atonic seizures, valproate and lamotrigine; in simple and complex partial seizures with or without secondary generalization, oxcarbazepine/carbamazepine, valproate/ vigabatrin and lamotrigine; and in status epilepticus lorazepam, diazepam and clonazepam together with phenytoin or fosphenytoin. In cases of poor response to the monotherapy recommended above, the following combinations may be indicated: in primary generalized tonic-clonic epilepsy, valproate and oxcarbazepine/ carbamazepine, or valproate and lamotrigine; in typical absences, valproate and lamotrigine, or valproate and ethosuximide; in juvenile myolonic epilepsy, valproate and lamotrigine, or valproate and clonazepam; and in partial epilepsies, add to the monotherapy one of the following drugs, vigabatrin, lamotrigine, gabapentin, tiagabine, topiramate, zonisamide or clobazam. So far, the order of preference of these new drugs remains undetermined. More data are needed on the efficacy and adverse effects of the new drugs based on controlled studies on patients with intellectual disability and epilepsy.     

Changes in sex steroid levels in women with epilepsy on treatment: Relationship with antiepileptic therapies and seizure frequency

Purpose:   Reproductive dysfunction in epilepsy is attributed to the seizures themselves and also to antiepileptic drugs (AEDs), which affect steroid production, binding, and metabolism. In turn, neuroactive steroids may influence neuronal excitability. A previous study in this cohort of consecutive women with epilepsy showed that patients with more frequent seizures had higher cortisol and lower dehydroepiandrosterone sulfate levels than those with rare or absent seizures. The present study was aimed at evaluating, in these same women, the possible relationship between some clinical parameters, seizure frequency, AED therapies, and sex hormone levels.
Methods:   Estradiol (E2), progesterone (Pg), sex hormone-binding globulin (SHBG), and free estrogen index (FEI) were measured during the luteal phase in 113 consecutive females, 16–47 years old, with different epilepsy syndromes on enzyme-inducing AED (EIAED) and/or non–enzyme-inducing AED (NEIAED) treatments, and in 30 age-matched healthy women. Hormonal data were correlated with clinical parameters (age, epilepsy syndrome, disease onset, and duration), seizure frequency assessed on the basis of a seizure frequency score (SFS), and AED therapies.
Results:   E2, Pg, and FEI were lower, whereas SHBG levels were higher in the epilepsy patients than in the controls. However, sex steroid and SHBG levels were not different between groups of patients categorized according to SFS. Therapies with EIAEDs accounted for changes in E2 levels and FEI.
Conclusions:   Despite globally decreased sex steroid levels in serum, actual hormone titers were not significantly correlated with SFS in consecutive epilepsy women; rather, these hormonal changes were explained by AED treatments, mainly when EIAED polytherapies were given.     

New antiepileptic drugs in pediatric epilepsy

New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy.     

Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment

PURPOSE: Hormonal changes occur in epilepsy because of seizures themselves and of antiepileptic drug (AED) effects on steroid production, binding, and metabolism. Conversely, steroids may influence neuron activity and excitability by acting as neuroactive steroids. This cross-sectional observational study aimed to evaluating cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in female epilepsy patients with different disease severity, as assessed by a seizure frequency score (SFS). METHODS: Morning serum levels of cortisol and DHEAS were assayed in 113 consecutive women, aged 16 to 47 years, with varied epilepsy syndromes, receiving mono- or polytherapy with enzyme-inducing and/or noninducing antiepileptic drugs (AEDs). Hormonal data were correlated with clinical parameters (age, body mass index, epilepsy syndrome, disease onset and duration, SFS, AED therapy, and AED serum levels) and compared with those of 30 age-matched healthy women. RESULTS: In epilepsy patients, cortisol levels and cortisol-to-DHEAS ratios (C/Dr) were significantly higher, whereas DHEAS levels were significantly lower than those in controls. Patients with more frequent seizures showed higher cortisol and C/Dr values and lower DHEAS levels than did those with rarer or absent seizures during the previous 6 months. SFS mainly explained the increase of cortisol levels and C/Dr in patients with more active disease. Changes in DHEAS levels correlated with SFS and epilepsy syndrome, as well as with AED treatments and ages. CONCLUSIONS: Women with more frequent seizures had alterations of their adrenal steroids characterized by an increase of cortisol and a decrease of DHEAS levels. Such hormonal changes might be relevant in seizure control and in patient health.     

When antiepileptic drugs aggravate epilepsy

Paradoxically, an antiepileptic drug (AED) may aggravate epilepsy. The number of AEDs is steadily increasing, and the occurrence of paradoxical aggravation will probably become a frequent problem. The overall status of the patient treated for epilepsy can be altered due to maladjustment to the diagnosis of epilepsy, to unwanted side-effects, to overdosage and to the occurrence of tolerance. However, the main mechanism of aggravation is the occurrence of an inverse pharmacodynamic effect. The specific effect of the AED is such that it controls epilepsy in most cases and increases seizures in other cases. Idiopathic generalised epilepsies (IGE) are particularly prone to pharmacodynamic aggravation: typical absences are constantly increased by carbamazepine (CBZ), vigabatrin, tiagabine, gabapentin, while phenytoin (PHT) is less aggravating. Juvenile myoclonic epilepsy is often aggravated by CBZ, less constantly by PHT and other AEDs. Generalised tonic-clonic seizures found in IGEs may respond to AEDs that aggravate the other seizure types. In symptomatic generalised epilepsies, patients have often several seizure types that respond differently to AEDs: myoclonias are generally aggravated by the same drugs that aggravated IGEs; tonic seizures in the Lennox-Gastaut syndrome respond to CBZ, which may however aggravate atypical absences. In severe myoclonic epilepsy of infancy, there is a nearly constant aggravating effect of lamotrigine. In some patients with benign rolandic epilepsy, a clear aggravation may be produced by CBZ, with occurrence of negative myoclonias, atypical absences, drop attacks, and at the maximum evolution into a state of electrical status epilepticus during sleep. It is much more difficult to pinpoint specific pharmacological sensitivity in other focal epilepsies, but aggravation clearly occurs. When treating epilepsy, the clinician should act according to seizure type, or, better, to epilepsy type. Patients are usually aware of aggravation before their doctors: we should listen carefully whenever they express a 'dislike' for an AED.     

Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy

ObjectiveTo study the effects of antiepileptic treatment on sleep parameters and video-polysomnography (VPSG) seizures in nocturnal frontal lobe epilepsy (NFLE).MethodsTwenty patients with a clinical and VPSG diagnosis of NFLE (baseline polysomnography [PSG]) underwent a clinical follow-up and performed a second VPSG after effective antiepileptic treatment lasting for at least 6 months. Conventional sleep measures, cyclic alternating pattern (CAP) parameters, and objective VPSG seizures were assessed in NFLE patients before and after treatment and were compared with the results of 20 age- and gender-matched control subjects.ResultsAntiepileptic treatment determined a partial reduction of objective VPSG seizures of approximately 25% compared to baseline condition. Alterations of most conventional sleep measures recovered normal values, but nonrapid eye movement (NREM) sleep instability remained pathologically enhanced (CAP rate, +26% compared to controls) and was associated with persistence of daytime sleepiness.ConclusionsResidual epileptic events and high levels of unstable NREM sleep can define a sort of objective resistance of both seizures and disturbed arousal system to the therapeutic purpose of the antiepileptic drugs in NFLE. This finding could determine the need for new therapeutic options in this particular form of epilepsy.     

抗癫痫药物长期控制特发性癫痫异常灌注灶的修复

Epileptic seizure control and the disappearance of epileptiform discharge are not indicative of the absence of abnormal perfusion foci.Perfusion abnormalities are a major cause of epileptic discharge,and the existence of abnormal perfusion foci implies possible relapse.Very little is known about perfusion abnormality repair in epilepsy.The present study selected 43 cases of idiopathic epilepsy under antiepileptic drug control for an average of 24 months.Comparisons between interictal single-photon emission CT(SPECT)images and long-term electroencephalogram(EEG)pre-and post-treatment showed that cases of normal SPECT increased by 48%(12/25)following treatment,with a total number of 15 reduced foci(36%,15/41).Perfusion foci,i.e.,region of interest,were altered following treatment.These changes included:normal to abnormal in 3 cases(7%,3/43;2 hyperperfusion and 1 hypoperfusion);abnormal to normal in 14 cases(32%,14/43;10 pre-treatment hypoperfusion and 4 hyperperfusion);abnormal to abnormal in 7 cases(16%,7/43;hyperperfusion to hypoperfusion in 5 cases,hypoperfusion to hyperperfusion in 2 cases).Long-term EEG revealed in an increase in the number of normal cases by 20(40%,20/39),and there were 25 fewer cases with epileptiform discharges(66%,25/38).These findings demonstrate that long-term control of anti-epileptic drugs partially repaired cerebral perfusion abnormalities and reduced epileptiform discharges in idiopathic epilepsy.