Mohamad Z. Koubeissi and Nabil J. Azar (eds.)Epilepsy Board Review10.1007/978-1-4939-6774-2_20

20. Epilepsy Management in Special Populations

Amir M. Arain¹

(1)

Vanderbilt University, A-0118 Medical Center North, Nashville, TN 37232, USA

Amir M. Arain

Keywords

EpilepsyEpilepsy managementPharmacokineticsPharmacodynamicsIntellectual and developmental disability (IDD)Mental retardation (MR)Generalized tonic-clonic (GTC)SeizuresEpilepsy in the elderlyWomen with epilepsyEstrogenAEDHormones

Epilepsy in Individuals with Intellectual and Developmental Disability

Individuals with intellectual disability, a lifelong condition, are dependent on others for their daily care needs. Intellectual and developmental disability (IDD) is defined by mental retardation (MR) and can be mild, moderate, or severe. Individuals with mild MR, with IQs between 50–55 and 70, are considered the educable mentally retarded and are placed in special classes. Individuals with moderate MR, with IQs between 35–40 and 50–55, are often institutionalized, and their training is focused on self-care rather than development of intellectual skills. Finally, those with severe MR, with IQs between 20–25 and 35–40, cannot care for themselves, have major problems with communication, and are often listless and inactive.

Individuals with IDD have higher incidence of epilepsy in comparison with those with normal intellect. Incidence of epilepsy increases with the severity of mental retardation, but it varies depending on epidemiological methodologies. In population-based studies, 21% of those with mild MR had epilepsy [1]. Another study reported epilepsy in 11% of subjects with mild MR and in 23% in those with severe MR [2]. On the other hand, in institution-based studies including patients with severe MR, the prevalence of epilepsy varies from 32–34% [3].

Regarding the seizure semiology in patients with IDD, a population-based study reported generalized tonic-clonic (GTC) seizures to be the most common type [2]. However, in institution-based studies, focal dyscognitive (complex partial) seizures with or without secondary generalization were reported to be the most common [3]. Other seizure types, such as tonic, atonic, myoclonic, and atypical absence seizures are also seen. Seizure types are also age-related with GTC and focal dyscognitive seizures becoming predominant at later ages. Only one-third of the individuals with IDD have seizures that can be classified per ILAE classification [3]. The reason for this is partly the fact that such individuals may have complex non-epileptic behaviors that are confused with epilepsy, and only video-EEG monitoring can discern the nature of such behaviors. This constitutes a major problem in these individuals because often antiseizure medications are added, or their dosages increased, to treat non-epileptic behaviors, impacting the patient’s quality of life.

About two-thirds of institutionalized patients with IDD have stereotypical behaviors, including head movements, rocking, and jerking [4]. Other motor behaviors may result from medication adverse events, including tardive dyskinesia, which may be confused with seizures. Video-EEG monitoring is often very helpful in confirming the diagnosis [5]. Caregivers can be advised to make a home video of the spells in question as a first screening tool. Several factors have an impact on the caring of individuals with intellectual disability such as maladaptive behavior of the patients [6], severity of intellectual disability, presence of multiple disabilities, and level of social support. Caregivers of individuals with IDD are at-risk of stress [7].

Seizure control is often brittle in this population. Seizure exacerbations occur with fever, infections, metabolic abnormalities [8, 9], or any stressful condition. At times, change in caregivers or environment may have detrimental effect on seizure control. Patients with IDD and epilepsy have risks of morbidity and mortality, including a higher incidence of vitamin D deficiency. Their limited mobility and the effects of antiepileptic drugs (AEDs), especially older generation ones, can worsen their bone health. Patients with epilepsy and IDD have a higher risk of fractures. The risk of mortality individuals with IDD and epilepsy exceeds that of individuals with epilepsy alone, which, in turn, exceeds that of the healthy population.

Treatment principle in the population is to improve their seizure control without compromising their quality of life. Excessive sedation is not an acceptable cost for seizure control. At times, patients may not like the color or taste of medicine. Caregivers should be astute enough to try different formulations. AEDs available as liquid, in soluble or granular form, or as powder may be useful. Caregivers of these patients are the most important liaison between the physician and the patient as often these patients are nonverbal. In these patients, assessment of treatment is often hampered by lack of communication. CNS side effects of AEDs may be masked. Caregivers should be tuned to assess any change in their behavior as drowsiness or mood changes may be a manifestation of side effects.

Patients with IDD and epilepsy who have been seizure-free for several years may undergo AED medication tapering trial. However, the risk of seizure recurrence is high. Predictors of successful discontinuation of AED include history of few documented seizures, no gross neurological abnormalities, and normal EEG before and after AED discontinuation [10].

Epilepsy in the Elderly

The incidence of epilepsy increases with age, with a steep rise after age 60 [11, 12]. Epilepsy has higher incidence (134/100,000 person-years) in the elderly than Alzheimer’s disease (123/100,000 person-years). Seizures may present with staring, disorientation, and subtle lip smacking. Atypical presentations are also common in the elderly, including altered mental status, memory lapses, and intermittent confusion. In addition, auras are less common while postictal states can be prolonged mimicking dementia.

The most common causes of seizures in the elderly are stroke, dementia, and head trauma [13]. Other risk factors for epilepsy include major depression, hypertension, and sleep apnea. Both ischemic and hemorrhagic cerebrovascular events increase the incidence of epilepsy [14, 15]. Epilepsy was a concomitant diagnosis in 10% of individuals with Alzheimer’s disease in an autopsy-verified study, and seizures can occur at any stage of Alzheimer’s disease [16]. In treating patients with dementia and epilepsy, it is important to keep in mind that acetylcholinesterase inhibitors may worsen seizures [17]. Hypertension is another independent risk factor for developing epilepsy in the elderly patients [18]. Aggressive treatment of hypertension in elderly patients, particularly with diuretics, may have a protective effect [19].

Depression in the elderly is associated with an increased risk of developing seizures. In a study of patients aged 55 or older, there was a sixfold increased risk of unprovoked seizures [20]. Similarly, sleep apnea can be a risk factor for new onset seizures or seizure exacerbations in the elderly. Treating comorbid sleep apnea in elderly patients with epilepsy may improve seizure control. In a study of elderly patients with epilepsy evaluated by polysomnography, patients with new onset or worsening seizures had significant high Apnea–Hypopnea Index compared to stable or seizure-free patients [21].

Diagnosis of epilepsy in elderly can be challenging because of higher percentage of partial seizures than generalized tonic-clonic seizures that can be readily diagnosed. Moreover, the extratemporal lobe seizures with subtle features and prominent postictal confusion are more common in elderly. Misdiagnosis may also result from difficulties in history taking, comorbidities, polypharmacy, and the fact that the EEG is less helpful for diagnosis than in younger individuals. Epilepsy in elderly can be delayed because of these factors. Physicians treating elderly patients should have epilepsy in their differential diagnosis.

Once the diagnosis of epilepsy is established, then the treatment should be started as the risk of recurrence after the first unprovoked seizure is ~80% [22]. Clinicians should have a low threshold in starting AEDs. Physiological changes of aging may affect AED pharmacokinetics. These include decreased albumin, decreased liver metabolism, and decreased glomerular filtration and excretion. These changes result in longer half-lives of the medication and greater risks of drug–drug interactions [23]. Several AEDs including carbamazepine, phenytoin, and valproate are highly protein bound and will compete with other medications, including digoxin, for adherence to serum proteins resulting in toxicity. Changes in protein binding result in misleading measurements of total AED concentration. Checking free levels of phenytoin and valproate is recommended to the elderly. Elderly patients are more sensitive to side effects of AEDs, including peak toxicity. Thus, extended release formulations can be helpful as they result in lower peaks.

Older generation AEDs have higher incidence of drug–drug interactions with other medications. Many AEDs induce liver enzymes, thus lowering the levels of other medications. Administration of carbamazepine, for example, can lower simvastatin level [24]. Newer AEDs have relatively better pharmacokinetics profile with less potential for drug–drug interactions. Grapefruit juice can increase the level of many medications, including carbamazepine, resulting in dizziness, lack of coordination, sedation, and other side effects.

It is recommended that newer AEDs be started in elderly patients with epilepsy because of their favorable pharmacokinetic profiles. Medications must be initiated at a low dose and slowly titrated up. Older AEDs with enzyme-inducing properties should be avoided, and newer generation AEDs with significant cognitive adverse events, including topiramate and zonisamide, should also be avoided [25]. Valproate may be a good choice in elderly, but one has to keep in mind the potential side effects of parkinsonism (which is usually reversible) and dementia [26]. Lamotrigine, gabapentin, and levetiracetam are appropriate medications to be started as monotherapy in elderly patients with epilepsy [27, 28]. Seizures in the elderly can often be well controlled with monotherapy. In patients with refractory epilepsy, epilepsy surgery must be considered.

Women with Epilepsy

Women with epilepsy have some unique characteristics that can significantly affect the course and management of epilepsy. Epilepsy and female hormones reciprocally influence one another. Similarly, AEDs and female hormones also influence one another. Such interactions can affect seizure control and medication adverse events. The specific issues in women with epilepsy warrant special attention to their menstrual cycle regularity, fertility and ovulatory function, sexuality, hormonal contraception, pregnancy and breast-feeding, and bone health. Unfortunately, the awareness to these issues is not prevalent among healthcare providers [29].

Estrogen and progesterone have different effects on epilepsy. Estrogen may be proconvulsant as it may reduce inhibition at the GABA_A receptor and also inhibits the synthesis of GABA. On the other hand, progesterone may be anticonvulsant as it enhances inhibition at the GABA_A receptor and increases the GABA synthesis [30]. Progesterone also may attenuate the action of the brain’s major excitatory neurotransmitter, glutamate, in the hippocampus. Thus, the hormonal fluctuations of the menstrual cycle may result in fluctuation in seizure frequency. This pattern is seen in catamenial epilepsy, which is present in approximately half of all women with epilepsy. In these patients, exacerbations of seizure frequency occur at certain points in the menstrual cycle, either before the start of their menstruation, during menses, or around the time of ovulation possibly because of higher estrogen-to-progesterone ratios [31].

Some AEDs may affect the female hormones and contraception. Enzyme-inducing AEDs, such as phenytoin, carbamazepine, phenobarbital, primidone (and at higher doses, oxcarbazepine >900 mg/day and topiramate >200/day), can reduce the levels of contraceptives [32, 33]. In such situations, alternative or supplementary contraceptive methods should be used. On the other hand, estrogen decreases lamotrigine level by about 50%. Dosage adjustments of lamotrigine may be necessary to maintain appropriate response when starting or stopping estrogen—containing oral contraceptives in these women.

Fertility issues are common in women with epilepsy. In epidemiologic studies, women with epilepsy are approximately two-thirds less likely to have children than women without epilepsy. Factors that may contribute to the lower fertility rates in women with epilepsy include decreased libido, reduced marriage rates, increased anovulatory menstrual cycles, menstrual disorders such as amenorrhea or oligomenorrhea, and increased early miscarriages. AEDs, specifically enzyme-inducing ones, may also have an effect on fetal survival. Moreover, women with epilepsy are more likely to have polycystic-ovary-syndrome-like ovulatory dysfunction with clinical evidence of hyperandrogenemia, a risk that is increased by valproic acid treatment [34].

Pregnancy can affect seizures, and although it is a high progesterone state, some women may have worsening of seizures during pregnancy. This worsening could be an effect of pregnancy itself or because of decreasing AED levels as the pregnancy progresses. The risk of congenital malformations may be increased by epilepsy. Teratogenicity can be worsened by AEDs, and the rates of major congenital malformations (ranging from 4.6% with carbamazepine to 10.7% with valproate monotherapy) are 2–3 times higher than in untreated women with epilepsy (~3%) [35]. Besides anatomical teratogenicity, there is a risk of cognitive teratogenicity with valproic acid. In a study that assessed cognition in 3- and 6-year-old children who were exposed in utero to AEDs, those who were exposed to valproate had significantly lower IQ scores than those exposed to other medications [36, 37]. Thus, valproate must be avoided in monotherapy or polytherapy during the first trimester of pregnancy. However, other authors suggest that if it is imperative to use valproate during pregnancy, then a low dose of the extended release formulation should be used, starting with 500 mg per day and not exceeding 1000 mg per day [38]. It is recommended to use AEDs in monotherapy rather than polytherapy as the risk of major congenital malformations is increased by polytherapy. Based on the data, the probable safest medications are lamotrigine, levetiracetam, oxcarbazepine, zonisamide, gabapentin followed by carbamazepine and phenytoin [39]. Folic acid supplementation is recommended to women with epilepsy prior to pregnancy. There is still controversy on the optimal dose of folic acid. For healthy women, a dose of 0.4 mg/day is optimal, while for high-risk patients, especially ones with the previous history of major congenital malformations, a dose of 4–5 mg/day is recommended [40]. Prenatal testing, at 14–20 weeks of gestation, should be considered in pregnant women with epilepsy. Since then by seizure medication levels drop during pregnancy, checking the levels on a monthly basis is recommended.

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