Psychiatric Complications of Epilepsy in the Geriatric Patient: Diagnostic and Treatment Considerations

Marlis Frey

Demographical trends document the significant increase in the number of older adults in our population. People aged 65 years and older currently represent 13% of the population (1). By 2030, this group is expected to increase to 20% of the population. Not only is the population getting older in general, but also the older population itself is getting older. The age-group 85 years and older comprises the fastest growing segment of the older population.

These statistics are astounding by themselves, but they gain new significance when one considers the epidemiology of seizure disorders in the elderly. Recent studies demonstrated that epilepsy, typically thought of as a disorder or syndrome starting early in life, is the third most common neurological disorder in the elderly, following stroke and Alzheimer’s disease (2). The incidence of epilepsy increases sharply after the age of 50 and by the age of 80 exceeds that of children. The highest incidence has been reported in the oldest age-group, those older than 75 years of age (139/100,000) (3). This represents a significant increase from the younger cohorts (100/100,000) and from the age-group up to the age of 50 (15/100,000). Because of the combined effects of increasing age in the population and the high incidence of seizures in the oldest old, the clinical significance of epilepsy is highlighted.

Although seizures in the elderly are generally related to secondary factors, the etiology of the largest group of new onset of seizure disorders remains idiopathic (2). Acute symptomatic seizures, which are seizures secondary to a toxic, metabolic, traumatic, or vascular event, are very frequent in the elderly, with an incidence of 100 per 100,000 after the age of 60 (4). These seizures often present in the form of status epilepticus or as clusters of seizures. Stroke is the most frequent cause, followed by low anticonvulsant levels, alcohol-related causes (5), systemic metabolic disorders, acute brain trauma, central nervous system infection, and toxic insults (2). Mortality rates of 38%, up to 50% for patients older than 80 years have been reported with status epilepticus (6,7). Litt et al. (8) reported a sample of 25 critically ill elderly patients with a 52% mortality rate associated with nonconvulsive status epilepticus. Clinical outcome was correlated to the number of life-threatening medical problems at the time of initial presentation.

The relationship between epilepsy and psychiatric disorders has received increased attention over the last few decades. Most studies and reviews have explored mood, anxiety, personality, and psychotic disorders in the general epilepsy population. A review of the literature reveals little information on the psychiatric aspects of geriatric patients with epilepsy. Epidemiological studies have shown that the second highest incidence of epilepsy occurs in the geriatric population, and only recently has this age-group received specific attention as to psychiatric manifestations associated with seizures. Although many of the observations made in younger patient groups with epilepsy will apply to their geriatric counterparts, some do not. For example, as discussed in other chapters of this book, psychopathology is more likely to occur among patients with poorly controlled partial epilepsy. Yet, in 80% to 90% of geriatric patients, seizure disorders beginning after the age of 60 have a very benign course. Therefore, do geriatric patients with epilepsy have a lower incidence of psychopathology related to the epileptic disorder than younger patients? This supposition is just beginning to be investigated.

This chapter will review the epidemiology, symptomatology, and assessment of the three major psychiatric disorders: anxiety disorder, depressive disorder, and psychosis, in the elderly in general and in the elderly with epilepsy specifically. Current treatment recommendations for these disorders in the elderly and their specific implications for the subgroup with seizures will be discussed.

Anxiety Disorders

Epidemiology

In comparison with the studies of depressive disorders in the aged, little formal research investigating anxiety disorders in the elderly is available. (There is even less information available about anxiety symptoms in elderly patients with epilepsy.) This is somewhat surprising, given that the prevalence of anxiety disorders in the elderly is greater than that of depressive disorders (9). Indeed, anxiety disorders are the most prevalent psychiatric disorders in the elderly. The age-adjusted prevalence rates range from 10% to 20% (10), with even higher rates among those older than 75 (11). Incidence data suggest a lower rate of development of new cases of anxiety in the elderly. Larkin et al. (12) reported an incidence rate of 4.4/1,000/year of anxiety disorders in the elderly. Kramer et al. (13) reported a higher incidence of 10.1% in the elderly older than 75 years. These studies show that new onset of anxiety disorders occurs at a much lower rate in the elderly than in the younger population.

Flint (14) reviewed eight community-based survey studies investigating anxiety disorders in persons older than 60 years. The results of this review suggested that phobias and generalized anxiety disorders are the most prevalent for that age-group. However, prevalence rates are very low for obsessive-compulsive disorder (15) and panic disorders (16) in the elderly. Lindesay (16) found agoraphobia to be the only late-onset phobia in the elderly population. The onset of the agoraphobia most often was related to the occurrence of a new medical condition or a traumatic event. Matt et al. (9) analyzed data collected from 1,131 community elderly and found that the prevalence of phobias, such as social and simple phobias, was invariably higher in women than men, and that the prevalence of phobias increased with advancing age.

Lindesay (16) reported rates of up to 30% of comorbidity between anxieties and depression in a geriatric community sample. Even higher rates (over 75%) were reported more recently in a study of institutionalized patients (17). Some studies suggested that anxiety arises secondary to depressive episodes (10). In contrast to this suggestion, Coryell (18) argued that anxiety disorders and depressive disorders are two separate and distinct disorders. He based this position on a review of the literature investigating the relationship between anxiety and depressive disorders, from which
he concluded that genetic, epidemiological, and diagnostic evidence supported the lack of dependent comorbidity.

Medical conditions such as endocrine disorders, cardiovascular conditions, and pulmonary conditions may cause symptoms of anxiety in the elderly (19). Additionally, increased sensitivity to pharmacological agents and frequent use of polypharmacy cannot be underestimated as causative factors in the development of anxiety disorders in this patient population. Primarily, steroids, thyroid preparations, stimulants, anticholinergic medications, and antidepressants may produce anxiety-related physical and psychotic symptoms in elderly patients.

Symptomatology of Anxiety in the Elderly

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (20) sets forth extensive criteria for all mental disorders. Generalized anxiety disorder is defined as “at least 6 months of persistent and excessive anxiety and worry” (p. 393). It is the intensity, duration, and irrational proportion of the feeling that warrants the diagnosis of anxiety disorder. Individuals may report psychiatric or physiological symptoms as expressions of anxiety (21). Physiological symptoms may be either motor signs, such as restlessness and trembling, or autonomic signs, such as sweating and dizziness. Hypervigilance and irritability may be expressions of anxiety symptoms, and patients may report difficulties with concentration or trouble falling asleep because of anxiety (22). Elderly patients often do not meet all the criteria set forth for a diagnosis of anxiety, but their symptoms still cause functional impairment. This situation has been termed subsyndromal anxiety (21).

Assessment of Anxiety

Assessment of anxiety in the elderly can be complicated for various reasons. First, elderly patients often have an atypical presentation of physical and psychiatric conditions. Second, different psychological tools used in the assessment of anxiety are, in general, designed and validated for a younger population without seizures (23) and may not adequately assess unique social and medical conditions in the elderly. Wording of questions has also been found to be important in the assessment of anxiety in the elderly. Schramke (23) found that on further questioning, patients who initially reported feeling nervous and anxious were actually not referring to internal feelings of anxiety but rather to physiological tremors. To help control for some of these confounding effects, a complete assessment of anxiety in the elderly must include a review of medical and psychiatric illness, current drugs that can cause symptoms of anxiety, and the patient’s current psychosocial situation.

Differential diagnosis of anxiety in the elderly should include primary anxiety disorders, such as generalized anxiety disorder and panic disorder, versus anxiety secondary to medical illness or drugs. Once a diagnosis of primary anxiety disorder has been established, it is essential to distinguish between the various anxiety disorders (22).

Anxiety and Epilepsy

Limited information can be found when investigating the relationship between anxiety and epilepsy. Betts (24) has provided a comprehensive description of the various relationships between anxiety and epilepsy. He argues that anxiety may occur as a reaction to the perceived psychosocial impact of having seizures or as a physical part of the peri-ictal experience. Accordingly, anxiety in the patient with epilepsy can reflect the adjustment the patient has to make to having this condition and the fear that one may have of experiencing a seizure. It can also be caused or exacerbated by the confusion experienced in a postictal state. This may be true especially for the elderly patient who is newly diagnosed and may feel frightened and overwhelmed with the diagnosis, especially when other chronic medical conditions already exist. At times, this anxiety may lead to a true phobic response that may prevent the patient from leaving the house.

Anxiety may also arise from the peri-ictal experience. A detailed description of the actual seizure will be necessary to determine whether the anxiety is physiological or psychological in nature. This may be particularly challenging in the geriatric patient who may have more than the usual age-related memory problems.

Anxiety in the elderly patient with epilepsy may be difficult to assess. Keeping in mind that anxiety is the most prevalent psychopathology in the elderly; the challenge for the clinician is to determine whether the anxiety is preexisting, part of the ictal event, or a psychological response to the seizures. A thorough seizure history, medical and psychiatric history, drug history, and psychosocial assessment are necessary to arrive at an accurate diagnosis.

Treatment of Anxiety in the Elderly

Before initiating any type of treatment for anxiety in the elderly patient with seizures, the clinician needs to spend time with the patient and family and discuss the natural course of seizures in the elderly, explaining treatment options and exploring the medical and psychosocial impact of the diagnosis on the patient. Should pharmacological treatment be indicated, clinicians need to consider the following pharmacokinetic and pharmacodynamic changes caused by the natural aging process: (i) pharmacokinetic changes in the elderly affect the absorption, distribution, metabolism, and excretion of the drug; and (ii) pharmacodynamic changes are poorly understood in the elderly (25) and will not be discussed in this chapter. It should be kept in mind, however, that elderly patients are more sensitive to negative psychotropic properties of antiepileptic drugs; therefore, attempts to use the lowest doses possible are of the essence.

The pharmacokinetic changes commonly identified in the elderly can be summarized as follows:

Absorption: Absorption of drugs in the elderly has generally been reported to be similar to that in younger individuals. Exceptions to this include reports of an increase in gastric acidity that may cause an increase or decrease in absorption of some drugs (26).
Distribution: Distribution is affected by the increase in lipid body mass and the decrease in water associated with age. Therefore, lipophilic drugs in the elderly may have an increased volume of distribution, whereas the volume of distribution for hydrophilic drugs may be decreased. Distribution of a drug is further affected by plasma protein levels. Plasma albumin levels have been reported to be decreased by approximately 20% in healthy elderly patients (26). For drugs that are highly protein bound, this can lead to an increase in the free fraction (unbound) of the drug. This can be of important clinical significance if the drug has a narrow therapeutic index.
Metabolism: There is a decrease in size of the liver and a 40% to 49% decrease in hepatic blood flow in aging. Phase I metabolism (such as oxidation, reduction, and hydroxylation) has been reported to decrease with age, whereas drug metabolism by conjugation (phase II metabolism) has been reported to remain stable with age (26).
Excretion: Renal blood flow and glomerular filtration rate decrease with age, leading to a decrease in elimination of drugs and drug metabolites (26). This may lead to an increase in a drug’s half-life for compounds depending on renal excretion.

Specific Treatment Options

Benzodiazepine

Schneider (22) found that most anxiolytics prescribed in the elderly were medications without active metabolites, such as lorazepam and oxazepam. The extensively metabolized alprazolam, which is usually the medication of choice for treatment of acute anxiety in younger patients, was relatively seldom prescribed in the elderly. The use of extensively metabolized, long-acting benzodiazepines in the elderly has been associated with an increase in hip fractures
(27) and motorist fatalities in older male drivers (28).

The properties of benzodiazepines make them very effective as hypnotics, anxiolytics, anticonvulsants, and muscle relaxants (29). Benzodiazepines are well known to cause sedation in the elderly patient. At toxic levels, which in the elderly may be reached at relatively low doses, benzodiazepines may cause cognitive impairment, confusion, and unsteadiness. One of the major disadvantages of benzodiazepines is that patients may develop physical and psychological tolerance. Benzodiazepines can have either a short half-life (oxazepam, lorazepam, and alprazolam) or a longer half-life (chlordiazepoxide, diazepam, and clorazepate). Lorazepam and oxazepam are the only benzodiazepines not extensively metabolized by the liver.

Buspirone

Buspirone belongs to a relatively new class of psychotropic medications called azapirones. This class of medication has both anxiolytic and antidepressant properties (30). Buspirone is considered an effective alternative to benzodiazepines because of its superior safety profile (31). Buspirone has been shown to be effective for treatment of generalized anxiety disorder and depression, either in conjunction with a Selective serotonin reuptake inhibitor (SSRI) or alone (32). However, buspirone is not effective against panic attacks (33). Buspirone has been used extensively in the treatment of anxiety and depression with anxiety in elderly patients (34). One of the drawbacks of using buspirone is that it may take several weeks before a therapeutic response is achieved. Cadieux (33) reported that patients can be switched safely from benzodiazepines to buspirone without causing benzodiazepine withdrawal symptoms by following these recommendations: an initial switch of the patient to a long-acting benzodiazepine if he or she is not already taking one. Next, start the patient on 5 mg of buspirone t.i.d. and increase the dose to 30 mg per day. Once this dose is reached, the taper of benzodiazepines can be started over 60 to 90 days.

β-Adrenergic Receptor Antagonists

These medications are mainly used to treat the physiological symptoms of anxiety, such as tremors and palpitations. One of the major limitations of using these medications in the elderly is their hypotensive effect.

Antihistamines

Antihistamines have a history of use for treatment of anxiety in elderly patients. They are far less effective than benzodiazepines and have anticholinergic effects, such as dry mouth, blurred vision, and cognitive impairment (34). For these reasons, they are not an ideal medication for the elderly and are rarely used.

Antidepressant Medications

Antidepressant medications have long been used in the treatment of anxiety (35). The drawback with older antidepressant medications, such as tricyclics, however, is that similar to buspirone, they may take several weeks before they become effective. In addition, their side effect profile is poorly tolerated in the elderly. Monoamine oxidase inhibitors (MAOIs), the classic treatment for phobic anxiety (36), are poorly tolerated in the elderly because of the postural hypotension associated with their use. Studies showing a propensity of antidepressant medications to lower the seizure threshold in the general population may lead to limiting their use in patients with epilepsy. A comparison of seizure risk between the general population, which is approximately 0.073% to 0.086% (37), versus the reported risk associated with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) at 0.1% to 0.2% (38), demonstrates the relative safety of these medications. Because possible lowering of seizure threshold has been linked to dose and rapid dose escalation (39), Kennedy recommends starting patients at half the standard dosage and titrating to the therapeutic dose at 2-week intervals. For example, start escitalopram at 5 mg per day and increase every 2 weeks by 5 mg to the therapeutic dose.

An important consideration when selecting an antidepressant for the elderly
patient with epilepsy is possible drug interactions. This is especially relevant for patients on first-generation anticonvulsants with liver enzyme–inducing properties such as phenytoin, carbamazepine, phenobarbital, and primidone. This increased metabolism may require an adjustment of the dosage of the antidepressant medication. The specific cytochrome P-450 liver enzyme pathway used by these older anticonvulsants is also used by fluvoxamine, fluoxetine, and paroxetine (40). The competing use of this pathway may inhibit the metabolism of anticonvulsant medications. Sertraline, citalopram, and escitalopram are less likely to have this interaction.

SSRIs often have been thought to be too stimulating for patients with anxiety (22,41). Sadavoy and LeClair (41) reported that some of the SSRI side effects, such as gastrointestinal upset, anorexia, and insomnia, may be intolerable for the elderly. However, Lader and Ancill (34) considered SSRIs as the ideal treatment for generalized anxiety disorders, panic disorders, and obsessive-compulsive disorders in the elderly. They found that SSRIs in general are very well tolerated in the elderly, and that the feeling of anxiety experienced with their use generally is limited to the initial weeks of treatment. The authors were able to decrease the stimulating side effect by starting the patients on half-doses and then slowly titrating the dose upward.

Other Medications

Barbiturates and neuroleptics have been used for treatment of anxiety in the elderly. Given their unfavorable side effect profile in the elderly, their use should be limited in this patient population.

Anticonvulsants

The use of the anticonvulsant gabapentin for the long-term treatment of anxiety in psychiatric patients has been reported (42). Relatively low doses of 200 to 1,800 mg daily were found to have beneficial effects on anxiety-related symptoms, such as generalized anxiety, somatic complaints, panic, and obsessive-compulsive symptoms.

Several randomized, double-blind, placebo-controlled studies have looked at the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder. Pregabalin was found to be as efficacious as alprazolam 1.5 mg per day (43), venlafaxine 75 mg per day (44) or lorazepam 6 mg per day as measured by the Hamilton Anxiety Rating Scale, with improvement of symptoms noted as early as the first week of treatment. Somnolence, dizziness, and weight gain were the most frequently reported side effects reported with pregabalin at doses of 300 mg per day and 600 mg per day. Outcome measures of a 6-month pregabalin versus placebo-controlled, double-blind study demonstrated a statistically significant effect for prevention of relapse of generalized anxiety in the pregabalin-treated group.

Data on the use of pregabalin in the elderly is scarce at this time and appears to be limited to its use in the treatment of pain associated postherpetic neuralgia and diabetic peripheral neuropathy (45). As in younger patient populations, the most common side effects in the elderly patients were dizziness, somnolence, peripheral edema, and dry mouth. Age-related decreases in creatinine clearance and compromised renal function need to be taken into consideration when dosing the elderly.

Nonpharmacological Approaches

In discussing nonpharmacological approaches for treatment of anxiety in the elderly, Small (35) reported that both “… cognitive-behavioral and psychodynamic group therapy …” (p. 45) have proved beneficial for elderly patients with depression and anxiety. He goes on to stress the importance of educating elderly patients about the biological basis of anxiety, as these patients may be more reluctant to acknowledge psychological problems. Cognitive therapy, relaxation training, and teaching problem-solving skills have been reported to be beneficial in the treatment of anxiety disorders in the elderly (46). Often such interventions will take longer than medications for results to become evident, but in the long term the results may be more beneficial.

Treatment Recommendations for the Geriatric Patient with Anxiety and Seizures

From the review in the preceding text, several recommendations can be made. First, benzodiazepines are not the long-term drug of choice, despite their anticonvulsant efficacy. This class of drugs is used in epilepsy mainly for short-term management of seizure exacerbation; when used continuously, they lose their anticonvulsant efficacy. Therefore, epileptologists in general prefer patients to be treated with another class of drugs. If benzodiazepines need to be used on a short-term basis, oxazepam and lorazepam should be considered, given their short half-lives and absence of active metabolites. Second, buspirone and SSRIs are good choices for elderly patients with epilepsy because of their favorable side effect profiles. Buspirone has been well tolerated in the geriatric population when started at 5 mg three times a day, with gradual increases over 7 to 10 days to a total daily dose of 20 to 30 mg. Another advantage is buspirone’s minimal interactions with anticonvulsant medications. The pharmacokinetic interaction of some of the SSRIs with antiepileptic and other drugs demands caution in the use of these agents. The use of SSRIs in the elderly will be discussed under treatments for depression.

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