Predicting antiepileptic drug response in children with epilepsy

In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy--focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy--up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood.     

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 The drugs had a different profile of side-effects but topiramate (42%) was the most common drug to be withdrawn due to side-effects as compared with tiagabine (26%), vigabatrin (16%), gabapentin (16%), and lamotrigine (15%).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.     

Discontinuing antiepileptic drugs in children with epilepsy: A prospective study

In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RR] = 1.81). On multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3.1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children.     

Pregabalin: a new antiepileptic drug for refractory epilepsy.

Pregabalin is a recently licensed and marketed antiepileptic drug for use as adjunctive treatment of partial epilepsy. It acts at presynaptic calcium channels, modulating neurotransmitter release in the CNS, properties it shares with gabapentin. Its clinical development over the past decade has included its use in the treatment of neuropathic pain, and generalized anxiety disorder, in addition to epilepsy. Three multi-centre randomised, double-blind, placebo-controlled trials enrolling patients with refractory partial epilepsy have demonstrated an antiepileptic effect of pregabalin against placebo, as adjunctive therapy, with 31-51% of patients showing a 50% reduction in seizure frequency. Adverse effects were dose related, the commonest being somnolence, dizziness, and ataxia. Weight gain was seen in 14% of patients on the highest dose of 600 mg/day. Around 9000 people have been exposed to pregabalin in its development for all indications. No idiosyncratic reactions have been described to date. Pregabalin may be a useful addition in the treatment of refractory partial epilepsy. As with all new AEDs long-term follow up and post marketing surveillance is required.     

Nonepileptic uses of antiepileptic drugs in children and adolescents

Antiepileptic drugs are often prescribed for nonepileptic neurologic and psychiatric conditions. The United States Food and Drug Administration has approved several antiepileptic drugs for the treatment of neuropathic pain, migraine, and mania in adults. For pediatric patients, use of antiepileptic drugs for non-seizure-related purposes is supported mainly by adult studies, open-label trials, and case reports. Summarized here is the published literature for or against the use of antiepileptic drugs for neuropathic pain, migraine, movement disorders, bipolar disorder, aggressive behavior, and pervasive developmental disorders in children and adolescents. Using the American Academy of Neurology's four-tiered classification scheme for a therapeutic article and translation to a recommendation rating, there are no nonepileptic disorders for which antiepileptic drugs have been established as effective for pediatric patients. Valproate and carbamazepine are "possibly effective" in the treatment of Sydenham chorea, and valproate is "probably effective" in decreasing aggressive behavior. Carbamazepine is "probably ineffective" in the treatment of aggression, and lamotrigine is "possibly ineffective" in improving the core symptom of pervasive developmental disorders. Despite the frequent use of antiepileptic drugs in the treatment of juvenile bipolar disorder, migraine, and neuropathic pain, the data are insufficient to make recommendations regarding the efficacy of antiepileptics in these conditions in children and adolescents.     

Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet

This study was performed to evaluate carnitine deficiency in a large series of epilepsy children and adolescents treated with old and new antiepileptic drugs with or without ketogenic diet. Plasma free carnitine was determined in 164 epilepsy patients aged between 7 months and 30 years (mean 10.8 years) treated for a mean period of 7.5 years (range 1 month-26 years) with old and new antiepileptic drugs as mono or add-on therapy. In 16 patients on topiramate or lamotrigine and in 11 on ketogenic diet, plasma free carnitine was prospectively evaluated before starting treatment and after 3 and 12 months, respectively. Overall, low plasma levels of free carnitine were found in 41 patients (25%); by single subgroups, 32 out of 84 patients (38%) taking valproic acid and 13 of 54 (24%) on carbamazepine, both as monotherapy or in combination, showed low free carnitine levels. A higher though not statistically significant risk of hypocarnitinemia resulted to be linked to polytherapy (31.5%) versus monotherapy (17.3%) (P=.0573). Female sex, psychomotor or mental retardation and abnormal neurological examination appeared to be significantly related with hypocarnitinemia, as well. As to monotherapy, valproic acid was associated with a higher risk of hypocarnitinemia (27.3%) compared with carbamazepine group (14.3%). Neither one of the patients on topiramate (10), lamotrigine (5) or ketogenic diet (11) developed hypocarnitinemia during the first 12 months of treatment. Carnitine deficiency is not uncommon among epilepsy children and adolescents and is mainly linked to valproate therapy; further studies are needed to better understand the clinical significance of serum carnitine decline.     

Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs

Antiepileptic drugs (AEDs) are commonly prescribed for long periods, up to a lifetime, and many patients will require treatment with other agents for the management of concomitant or intercurrent conditions. When two or more drugs are prescribed together, clinically important interactions can occur. Among old-generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of hepatic enzymes, and decrease the plasma concentration of many psychotropic, immunosuppressant, antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral contraceptive steroids. Most new generation AEDs do not have clinically important enzyme inducing effects. Other drugs can affect the pharmacokinetics of AEDs; examples include the stimulation of lamotrigine metabolism by oral contraceptive steroids and the inhibition of carbamazepine metabolism by certain macrolide antibiotics, antifungals, verapamil, diltiazem, and isoniazid. Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.     

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study

Objectives – We evaluated long‐term retention rates of newer antiepileptic drugs (AED) in adults with localization‐related epilepsy retrospectively. Methods – We estimated retention rates by Kaplan–Meier method in all 222 patients (age ≥ 16) with localization‐related epilepsy exposed to new AED at the Tampere University Hospital. Results – There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three‐year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. Conclusions – Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.     

Art therapy focus groups for children and adolescents with epilepsy

Children with epilepsy are at risk for numerous psychological and social challenges. We hypothesized that art therapy focus groups would enhance the self-image of children and adolescents with epilepsy. Sixteen children with epilepsy, ages 7-18 years, were recruited from pediatric neurology clinics at the University of Wisconsin to participate in four art therapy sessions. Pre-group assessments included psychological screens (Piers-Harris Children's Self-Concept Scale; Childhood Attitude Toward Illness Scale; Impact of Childhood Neurologic Disability Scale) and art therapy instruments (Formal Elements Art Therapy Scale; Seizure Drawing Task; Levick Emotional and Cognitive Art Therapy Assessment). Developmental levels of drawings were significantly below age-expected standards. Following completion of focus groups, a repeat Childhood Attitude Toward Illness Scale showed no differences between pre- and post-test scores on any measure of this scale. However, subjects and parents were uniformly positive about their group experiences, suggesting a qualitative benefit from participation in art therapy focus groups.     

Effects of antiepileptic medications on psychiatric and behavioral comorbidities in children and adolescents with epilepsy

The three goals of this article are (1) to delineate the limitations in determining the actual incidence of antiepileptic drug (AED) psychiatric and behavioral side effects; (2) to summarize existing data on the direct effects of AEDs on psychiatric and behavioral comorbidities and examine the relationship between these direct effects and specific AED mechanisms of action; and (3) to recognize the indirect effects of AEDs on psychiatric and behavioral medications that can result in aggravation of these comorbidities through drug-drug interactions. All of these data are then combined and formatted into a practical algorithm useful in many clinical situations.     

Effects of antiepileptic drug therapy on heart rate variability in children with epilepsy

Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy. Heart rate variability (HRV) is a useful tool for the detection of sympathetic-parasympathetic balance of autonomic nervous system. In the present study, epilepsy patients who had never received antiepileptic medication and those whose seizures have been successfully controlled with antiepileptic drugs were compared with each other and a control group in order to investigate the effects of epilepsy and various antiepileptic drugs on HRV. HRV were tested via 5 min ECG monitoring in 92 patients and 83 controls. Time domain parameters including SDNN, RMSSD and the frequency domain parameters including HF (reflects parasympathetic activity) and LF (reflects sympathetic activity) were assessed. In this group, 78 patients were using antiepileptic drugs including valproic acid (n=33), oxcarbazepine (n=19), phenobarbital (n=11), combined regimens (n=10) and other drugs (n=5), while 14 patients had never received antiepileptic medication. For both of the epilepsy patients groups with or without treatment, time domain parameters were found to be significantly suppressed. In addition, parasympathetic activity was found to be decreased (HF was decreased, LF/HF ratio was increased) in epilepsy patients without antiepileptic drug therapy. Our results indicate that seizure control with antiepileptic drugs may help to improve the cardiac autonomic function impairment in epilepsy patients.