Drug Treatment in Adolescents

Eileen P. G. Vining

Introduction

In general, the incidence of epilepsy tends to decrease slightly in adolescence. It appears to range from 20 to 60 per 100,000 with a prevalence of 1.5% to 2%.⁴⁰ Certainly maturation itself, and specifically the effects of sexual maturation and menarche, may play a significant role in the development of seizures during this period of life. Trauma is an important cause of seizures in adolescents, and the idiopathic epilepsies appear to peak in this time frame. Mesial temporal sclerosis, causing temporal lobe epilepsy, frequently is recognized as intractable epilepsy during this period, and some of the rare progressive epilepsies (Unverricht-Lundborg disease, Lafora disease, ceroid lipofuscinosis, and some of the mitochondrial disorders) may also emerge in adolescence. The juvenile idiopathic epilepsies are very distinct entities that require accurate diagnosis and understanding for appropriate and comprehensive therapy. The drugs that are used for these epilepsies (juvenile absence, juvenile myoclonic epilepsy, and epilepsy with grand mal on awakening) are the focus of this chapter, as are issues that are of particular importance to adolescents. Unfortunately, treatment guidelines from the International League Against Epilepsy (ILAE),¹⁹ the American Academy of Neurology (AAN), and the American Epilepsy Society (AES)¹³^,¹⁴ routinely demonstrate how meager the evidence is for our choice of medications, particularly in younger patients. A review of the recent ILAE treatment guidelines indicates that no medication reaches the highest levels of evidence for efficacy in adults with generalized tonic–clonic (GTC) seizures. Carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM), and valproic acid (VPA) may be considered for initial therapy in adults with GTC. With the exceptions of LTG and OXC, the same statement can be made for children with GTC seizures. Ethosuximide (ESM), LTG, and VPA are possibly efficacious/effective for children with absence seizures. Finally, and of particular importance to this chapter, are the recommendations for juvenile myoclonic epilepsy. At a very low level of evidence (Class IV), clonazepam (CZP), LTG, levetiracetam (LEV), TPM, VPA, and zonisamide (ZNS) may have some efficacy for patients with newly diagnosed juvenile myoclonic epilepsy (JME).¹⁹ The AAN and AES note that TPM is recommended (Class A) for refractory generalized tonic–clonic seizures.¹⁴ In studies of mixed populations with both partial as well as generalized seizures, LTG, TPM, and OXC are effective, and LTG is effective in children with new-onset absence.¹³ Given the limitations of evidence-based recommendations, these medications are discussed based on clinical experience and reflect many of the observations made in a recent survey of treatment of pediatric epilepsies.³⁹ Medications that are particularly useful for the partial epilepsies are appropriately covered in the chapter on adult medications, although the issues that are critical to adolescents are addressed in this chapter.

Medications that are Useful in the Juvenile Generalized Epilepsies

Ethosuximide

Ethosuximide is an extremely effective medication for childhood absence epilepsy (CAE) and may play a role in controlling JAE and sometimes myoclonic seizures. However, since the majority of patients with JAE also have GTC seizures, ethosuximide is usually not considered a good therapy because it does not prevent the GTC events. Occasionally, when other medications are not controlling the absence and/or myoclonic seizures, ethosuximide can be effective when added to other regimens that are controlling the GTC seizures. It can be given once a day, and the side effect profile is acceptable: Gastrointestinal disturbance, headache, rarely rashes, and joint pain.

Valproic Acid, Sodium Valproate

Valproic acid was the first medication that successfully controlled the seizures in the majority of patients with juvenile myoclonic epilepsy.¹¹ It is effective in controlling myoclonic, absence, and GTC seizures. However, a number of side effects and the availability of alternative medications have diminished its use in the last decade. Weight gain has been recognized as a problem since the early 1980s.³⁰ When weight gain is going to occur, it usually occurs in the first 10 weeks of use and it persists.⁷ It may be more prevalent in those who are heavy to begin with.³⁰ Many explanations have been postulated, including an increase in serum leptin³⁷ that would stimulate appetite. VPA may also decrease the binding affinity of albumin for palmitate, leading to an increased availability of long-chain fatty acids. This increases insulin levels and lipogenesis, resulting in decreased lipolysis, and decreases glucose. This then may stimulate appetite via hypothalamic glucoreceptors.³⁸ VPA has also been associated with hair loss in about 10% to 12% of patients. This may be dose related and is generally mild, and hair tends to grow back well, perhaps with more curl.²²^,²⁸ Endocrine issues have cosmetic and general health importance for adolescents. VPA has been associated with hyperandrogenism, especially when started in adolescence,³⁵ and this may be related to polycystic ovary syndrome, which is reported in as many as 43% of women taking valproic acid.²¹ This syndrome can include obesity, menstrual disturbances, hyperandrogenism, and infertility, and may ultimately lead to dyslipedemia, diabetes mellitus, cardiovascular problems, and endometrial carcinoma. Another major concern to women in their childbearing years is a recognized association with neural tube defects and fetal malformations. This risk is typically considered to be 1% to 2%. However, some studies have found rates of adverse pregnancy
outcomes as high as 20%. Of growing concern is the possible association of the medication with an adverse impact on the cognitive development of the children of mothers exposed to the medication.¹⁸^,²⁷^,⁴⁴ These problems may be dose related, especially at doses >1,400 mg/d.³⁶ VPA has also been associated with hepatic dysfunction (even liver failure) and other gastrointestinal problems, as well as hematologic problems. On the positive side, VPA has mood-stabilizing effects and is important in migraine therapy.¹²^,³²

Lamotrigine

When LTG was introduced in 1994 it was quickly seen to be effective in the generalized seizures of Lennox-Gastaut syndrome and was soon adopted as a therapy in the juvenile generalized epilepsies because of perceived fewer side effects. Both VPA and LTG can be efficacious against absence seizures, although VPA shows a much faster onset of action, at least in part because of its shorter titration schedule.⁹ The American Academy of Neurology and the American Epilepsy Society also found evidence of its efficacy in absence epilepsy.¹³ Some studies suggested that LTG is as effective as VPA in JME, but most of these studies were retrospective in nature, and there is some evidence that myoclonic seizures may not be as well controlled with LTG as with other medications or combinations of medications; there is also some evidence that it can even worsen myoclonic seizures.²⁰^,³¹ Although LTG appears to have a generally good risk profile with respect to teratogenesis, further experience is required to understand the complete profile. The major disadvantage in using LTG is the slow titration (8–12 weeks) that is suggested to minimize the risk of developing a rash that might progress to Stevens-Johnson syndrome. This risk appears somewhat greater in children and if it is coadministered with VPA. The risk was virtually abolished when these guidelines were followed.⁴³ Other side effects that have been reported include dizziness, somnolence, nausea, tics or tremor, and sleep disturbances.

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