Therapy for Neurobehavioral Disorders in Epilepsy
Address correspondence and reprint requests to Dr. O. Devinsky at NYU Epilepsy Center, 403 E. 34th St, Rivergate 4th Floor, New York, NY 10016, U.S.A. E-mail: email@example.com
Summary: Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.
Therapy for cognitive and behavioral disorders in patients with epilepsy remains unsatisfactory. Encompassing neurology, psychiatry, and psychology, neurobehavioral therapies usually treat symptoms, not the disease process. In caring for patients with epilepsy, we often confuse seizure control with treatment of the underlying process. While controlling seizures and minimizing the antiepileptic drug (AED) burden are critical to improving cognition and behavior, cessation or reversal of the epileptogenic process may offer the greatest long-term benefits. However, we are very far from this goal, which could normalize the seizure threshold and improve cognition and behavior. Our symptom-based therapies reflect the limits of our understanding of epilepsy pathogenesis and progression, of ways to translate known mechanisms into therapy, and of strategies to reverse the physiological or structural changes that underlie the epilepsies.
Therapy for cognitive and neurobehavioral symptoms is similar across neurologic disorders. Anxiety, depression, aggression, and psychosis appear to respond to the same pharmacotherapies regardless of whether the patient has epilepsy, stroke, or multiple sclerosis. Clinical features, such as the patient's age, comorbid disorders (e.g., cardiac arrhythmia, migraine), concurrent medications, and response to prior therapies, may be more important therapeutic guides than the specific neurologic disorder. Adverse-effect profiles are very relevant, with concerns regarding the effects of psychotropic drugs on seizure threshold and interactions with AEDs.
Neurobehavioral disorders often remain undiagnosed. A patient may offer a complaint that is dismissed, and even when the complaint is noted, its significance may remain unappreciated. A problem noted by a nurse or a diagnosis buried at the end of a neuropsychological report is often not followed. The patient's complaint that he “has nothing to live for” may be written off as “something I hear a lot from old people,” and a disabling depression may be left untreated. Effective therapy depends on the correct diagnosis. Cognitive and behavioral disorders are diagnosed by identifying symptoms, classifying the syndrome, discovering the etiology, and localizing the brain area of dysfunction, without losing sight of the person behind the disorder. Effective therapies may require sensitive communication and exploration of the person and his or her world. Problems with compliance are often discovered by this approach. Although psychopharmacotherapy is often underutilized in epilepsy patients, caring should not stop there. For example, in addition to prescribing a selective serotonin reuptake inhibitor (SSRI) for a depressed patient, emotional stressors should be explored and other factors considered (e.g., side effects of antihypertensive drugs, such as thyroid dysfunction).
Omissions and misconceptions limit the diagnosis and treatment of behavioral disorders. A central element of behavioral medicine is simply asking a patient how he or she really feels. Look the patient in the eye as he or she speaks; assess eye contact, comfort, hesitation, directness, and body language, and the ease of the patient's own answer. One must listen to a patient's story, but listen hard, beyond the superficial layer, and try to feel what the patient is feeling. Many psychological and neurologic disorders cause the patient to neglect or deny his or her feelings and problems. Family members, friends, and caregivers must also be interviewed.
Therapy for neurobehavioral disorders in epilepsy favors a biological approach. Behavioral, humanistic, and practical approaches are relatively neglected. Stress aggravates most neurologic and neurobehavioral disorders, including epilepsy and the commonly associated depression, anxiety, and psychotic disorders. Physicians often underestimate the impact of patients' stressors, environment, family, and fears. Therapeutic opportunities are thereby missed. Diagnosis and therapy must be balanced, with emphasis on the patient and his mental world, as well as his neurobiology.
Patients with epilepsy often suffer from cognitive and behavioral disorders that range from subtle to lethal. Behavioral changes occur during and immediately after most seizures. In some cases, cognition and behavior also change for prolonged periods after individual seizures or throughout the long interictal gaps. Aggressive control of seizures, and possibly reduction of interictal epileptiform activity and epileptogenesis, may help prevent interictal cognitive and behavioral disorders. The late 19th century view of epilepsy as a progressive disorder—in terms of both seizures and cognitive-behavioral disorders—is finding support from modern studies (1). Our best therapy for cognitive and behavioral disorders may be prevention, but there is little systematic study of the phenomenon either retrospectively or prospectively.
After most complex partial and all tonic-clonic seizures, memory is impaired. Is it coincidence that impaired anterograde memory is a common interictal cognitive disorder? Do postictal symptoms predict future interictal symptoms? Postictal psychosis may evolve into interictal psychosis (2). Personal observation also suggests that in some patients without prior psychiatric history, periods of postictal depression develop and are followed years later by severe interictal depression. Can treatment of seizures and postictal symptoms provide an opportunity for prevention?
A long-standing bias suggests that temporal lobe epilepsy (TLE) is the epilepsy syndrome most often complicated by interictal cognitive and behavioral problems. This may be true, but the available evidence does not clearly support this view. Few studies have controlled for seizure frequency and severity, medication burden, family history, and other relevant factors. We lack well-defined incidence and prevalence rates for cognitive and behavioral problems in community epilepsy samples. Patients with all forms of epilepsy—including benign rolandic, childhood absence, juvenile myoclonic, and frontal lobe epilepsies—have increased rates of cognitive and behavioral problems (3–5).
The interictal period comprises >99% of most patients' lives. Interictal cognitive and behavioral disorders profoundly impair the quality of life. These problems are continuous, unlike the seizures, which are intermittent. Encompassing a wide spectrum, these disorders often fit awkwardly into neuropsychiatric categories. Even when patients fit into Diagnostic and Statistical Manual of Mental Disorders (6) categories, they often remain untreated because physicians fear using medications that might lower the seizure threshold. Some of the most devastating neurobehavioral disorders that complicate epilepsy have neither a defined symptom-nor a syndrome-level diagnosis. For example, the ability to read social cues and respond appropriately in social settings is essential for successful social function. These skills are often deficient in patients with right hemisphere or frontal lobe seizure foci. We need to develop systematic approaches to define these disorders and to develop therapeutic interventions to reduce symptom severity.
Romberg (7) (1853) recognized that memory impairment was the most common interictal disorder. Patients complain of impaired recall for recently learned information, especially details and names. Left temporal seizure foci impair mainly verbal memory, and right temporal foci impair recently acquired visual, spatial, and geographic memory. Although patients with TLE show memory impairments on 30-min delayed-recall tests, longer delays demonstrate even greater impairment (8). As in other cognitive disorders, several factors contribute to interictal amnesia, including structural lesions (9), neuronal dysfunction or loss, interictal epileptiform discharges (10), recurrent seizures, and AEDs (11–13). Interictal hypometabolism marks hypofunction, correlating with impaired memory when it involves the medial temporal memory structures (14).
How do we treat interictal memory disorders? Improved seizure control, reduction or elimination of AEDs that adversely affect cognition [e.g., phenobarbital, topiramate (TPM)] (15,16), and improved sleep hygiene can improve memory in some patients. Pragmatic approaches include using visual imagery, lists, and schedules (displayed prominently); learning to take simple and clear notes; carrying small portable notepads organized by topic; carrying important telephone numbers and addresses; and using alarms as reminders. These strategies often fail to fulfill the needs of higher-functioning patients with demanding jobs.
No medications are proven to enhance memory in patients with epilepsy (17). The progressive loss of basal forebrain neurons that synthesize acetylcholine (ACh) in Alzheimer's disease produces a diffuse cortical and subcortical deficiency of ACh and led to the use of cholinesterase (ChE) inhibitors. Four ChE inhibitors (tacrine, donepezil, rivastigmine, galantamine) are approved to treat Alzheimer's disease, and all other uses of these agents are off label. Their main side effects are gastrointestinal, with nausea, cramping, diarrhea, and vomiting. In patients with epilepsy-related cognitive impairment, pilot study data suggest that donepezil improves memory without increasing the risk of seizures (18).
Phytomedicinal extracts from Ginkgo biloba leaves are used as dietary supplements. The main active compounds in the leaves are flavonoid glycosides and ginkgolides. The latter are antioxidants, platelet-activating factor inhibitors, and circulatory enhancers (19). Although uncontrolled studies show improved memory function in demented and elderly subjects, controlled studies do not demonstrate efficacy (20,21). The only safety concern with ginkgo is a possible increase in the risk of bleeding, especially in patients taking warfarin (22).
Attention is the foundation of cognitive function and is often impaired in patients with epilepsy. Attention-deficit/hyperactivity disorder (ADHD) is more frequent among children with epilepsy than in the general population (23), although the diagnosis is not straightforward. This is especially true in children with absence epilepsy, in whom the brief seizures and interictal epileptiform activity can impair both transient and sustained attention. However, attentional impairment affects children with all seizure types and of both sexes equally (23). Antiepileptic drugs can also impair attention. The use of central nervous system (CNS) stimulants appears to be safe in the large majority of patients with epilepsy (24). However, these drugs can cause new-onset seizures, especially in children with epileptiform activity (25), or exacerbate epilepsy, especially in children whose seizures are not fully controlled by AEDs (26). The safety and efficacy of other agents for ADHD, such as atomoxetine, have not been studied in epilepsy populations.
Subjective fatigue, with premature exhaustion during mental activity, weariness, and lack of energy, is common in patients with epilepsy. Fatigue is also commonly reported as a factor that can provoke seizures (27). Antiepileptic drugs and other drugs, such as β-blockers, often cause fatigue. In addition, seizures and, possibly, frequent interictal epileptiform activity, as well as depression, can contribute to fatigue. Therapy involves reducing or eliminating sedating medications, therapy for comorbid mood disorders, education about strategies to conserve energy, exercise, stress-management techniques, and, in some cases, stimulant medications (amantadine and CNS stimulants). Although amantdine (200–300 mg/day) and modafinil (200 mg/day) reduce fatigue in patients with multiple sclerosis (28), they have not been well studied in epilepsy.
Interictal depression (see the article by Gilliam in this supplement, pp. 28–33) is common, occurring in 25–55% of patients (29,30). Further, the suicide rate of persons with epilepsy is more than five times that of controls (29,31). Interictal depression has biological mechanisms (family history of depression, structural lesions, AEDs) and psychosocial-reactive mechanisms (29,30,32–34). The burden of suffering that depression causes is enormous. In one study of patients with medically refractory epilepsy, depression was by far the most significant predictor of poor quality of life, overshadowing seizure frequency and severity (35). Depression was common (54%), underdiagnosed, and largely untreated in this population (only 17% were taking antidepressants) (35). In two separate studies, use of tricyclic antidepressants or SSRIs by patients with epilepsy more frequently led to reduced seizure frequency than to exacerbation (36,37). If corroborated by larger, prospective studies, this finding may be secondary to improved sleep and mood, factors associated with reduction of seizure frequency.
Selective serotonin-reuptake inhibitors and related drugs (e.g., venlafaxine and nefazodone) are the first line of therapy for most patients with depression. However, the efficacy or safety of any specific SSRI has not been proved (38). Drug interactions are more likely with fluoxetine, fluvoxamine, and paroxetine than with escitalopram, citalopram, or sertraline. Fluoxetine's long half-life (>24 h) is an advantage during tapering off, since it reduces the frequency of withdrawal symptoms. However, a long half-life is a disadvantage if the patient cannot tolerate the drug or experiences an adverse drug interaction.
Anxiety, panic, and phobic symptoms can complicate interictal states in both limbic and idiopathic generalized epilepsies (39–42). Anxiety disorders may be more frequent in patients with left TLE than in those with right TLE (40). Supportive psychotherapy may help patients vent their feelings, dynamic (behavioral) therapy can identify provocative factors and help to target therapy, and cognitive behavioral therapies improve self-confidence and coping by reducing tension and avoidance. Meditation and biofeedback are also helpful.
Antianxiety agents that enhance serotonin activity (e.g., buspirone, SSRIs) are usually effective and well tolerated. A dangerous cycle can develop when a benzodiazepine (BZD) is used for the long-term treatment of anxiety or insomnia. Initially, the drug works well, but tolerance develops and the dose is increased. The cycle can repeat until a high dose is reached with cognitive and behavioral toxicity, but the role of the BZD may be overlooked because other factors also contribute.
Psychosis encompasses a broad behavioral spectrum, including impaired content and coherence of thought, reduced connection to reality, hallucinations, delusions, disorganized speech and behavior, and extremes of affect and motivation. The diagnosis of psychosis can be difficult, as many patients willfully hide their signs and symptoms, such as delusional beliefs, and others are “quietly psychotic,” showing only quirky mannerisms. Psychotic symptoms may be categorized as positive and negative. Positive symptoms include tangential, incoherent speech and thought, hallucinations, delusions, and aggression, as well as exaggerated, bizarre, or disorganized behaviors. Negative symptoms include poverty of speech or speech content, flattened affect, social withdrawal, anhedonia, apathy, and impaired attention and self-monitoring.
Interictal psychosis occurs in ∼7% of all patients with epilepsy. These pleomorphic psychoses complicate both partial and generalized epilepsy syndromes (43–46). Chronic epilepsy probably contributes to the development of psychosis in some patients. Risk factors for interictal psychosis include early age at onset of epilepsy, female sex, severe epilepsy, left-sided temporal lobe focus, and a structural lesion (44).
Psychosis is treated primarily with dopamine receptor blockers, i.e., the conventional (e.g., chlorpromazine, haloperidol) and atypical (e.g., risperidone, olanzapine, quetiapine) antipsychotic (neuroleptic) drugs. Antipsychotic drugs are also divided into “low-potency” (e.g., chlorpromazine, thioridazine) and “high-potency” (e.g., fluphenazine, haloperidol) groups. Potency is determined mainly by therapeutic dosages and D2 receptor affinities. Among the conventional antipsychotic drugs, high-potency agents are less sedating, hypotensive, and anticholinergic, but have more acute extrapyramidal side effects.
The conventional antipsychotic drugs act mainly on D2 receptors, without selectivity between striatal and limbic/mesocortical sites. In contrast, the atypical antipsychotics are relatively selective for the limbic/mesocortical D2 site (47). In addition, their 5-HT2 receptor antagonist properties may account for their greater efficacy and lower extrapyramidal toxicity. The binding of atypical antipsychotics to D4 receptors, found in limbic and frontal but not striatal areas, may also contribute to their efficacy and toxicity profiles (48).
Tardive dyskinesia complicates antipsychotic therapy in 24% of patients overall and 50% of elderly patients receiving long-term treatment with conventional agents (49,50). The atypical antipsychotics have lower rates of acute and tardive extrapyramidal effects and cause less hyperprolactinemia than conventional agents. Except for clozapine, which can cause agranulocytosis in 1% of patients and is more likely to provoke seizures (usually with generalized spike-wave discharges), atypical antipsychotics are considered first-line therapy.
Blockade of striatal dopamine receptors can cause acute dystonic reactions, parkinsonism, rabbit syndrome (fine, rapid lip movements), and tardive dyskinesia. Among the atypical antipsychotics, extrapyramidal side effects are most common with risperidone. All antipsychotic drugs cause fatigue and impair motivation and drive, effects that can contribute to noncompliance. Other adverse effects include weight gain (ziprasidone appears to be the least and quetiapine the second least provocative of the atypical antipsychotics), diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, anticholinergic effects, hypotension, and, infrequently, seizures (clozapine is most potent).
All dopamine receptor blockers are most effective for positive symptoms, such as hallucinations and delusions. Atypical antipsychotic drugs are more effective than conventional agents for treating negative symptoms. Although blockade of D2 receptors occurs within hours, antipsychotic action takes days or weeks, suggesting that changes in dopamine receptor affinity or secondary effects are involved. The atypical antipsychotic agents, with the exception of clozapine, are safe for the large majority of patients with epilepsy and uncommonly increase seizure frequency or severity. When weighed against the morbidity and mortality (e.g., suicide) associated with chronic psychosis, use of antipsychotic agents is warranted. For acute and agitated psychosis (e.g., postictal psychosis), the combination of a high-potency antipsychotic agent and a BZD is often effective. In the long-term management of interictal psychosis, lack of insight, denial of illness, and disorganized thought often lead to noncompliance. Psychosocial intervention is critical, as stress can exacerbate the disorder. Social skills training, vocational training, and independent living skills foster a positive outcome.
ANTIEPILEPTIC DRUGS AS PSYCHOTROPIC AGENTS
Antiepileptic drugs are important psychotropic agents. The dramatic rise in AED use in psychopharmacology outpaces efficacy data. Large randomized, controlled trials on the behavioral effects of AEDs are few. Randomized, controlled trials have established the antimanic and mood-stabilizing properties of carbamazepine, valproate (VPA), and lamotrigine (LTG) in bipolar disorder (51). One controlled study found that gabapentin (GBP) was an effective treatment for social phobia (52). However, AEDs are used to treat a wide spectrum of other behavioral disorders, including unipolar depression, aggression, borderline personality disorder, and binge eating. Anecdotal reports, small uncontrolled series, and clinical trials with limited power can be misleading. For example, despite multiple reports that GBP improved both bipolar and unipolar depression, two randomized, controlled trials showed that GBP is not effective for these disorders (53,54). The use of AEDs to treat psychiatric disorders can be hazardous. The cognitive side effects of TPM were demonstrated in several randomized, controlled trials (55,56) and supported by systematic reviews of clinical experience in epilepsy centers (57,58). Depression can result from the use of this as well as other AEDs in patients without a past history of affective disorder. Although controlled data regarding TPM's efficacy for psychiatric disorders are restricted to bipolar disorder, its use in a wide spectrum of psychiatric disorders is growing steadily. Often, its appetite suppressant/weight loss effects are used to counterbalance the weight gain associated with many other psychotropic agents. Although weight gain carries substantial morbidity and mortality, the potential cognitive and behavioral risks of TPM must also be considered. Indeed, a general principle of treating epilepsy patients is to carefully consider the potential adverse cognitive and behavioral effects of AEDs. Otherwise, psychopharmacologic therapy may be unnecessarily layered on top of noxious AEDs, when a more effective approach would be to change the AED drug, dosage, or schedule.
The mechanisms by which AEDs affect behavior are not well understood. They may affect behavior through actions that suppress seizures, such as increased GABA activity, inhibition of fast-conducting sodium channels, or both. Sedative AEDs often possess anxiolytic, antimanic, and hypnotic efficacy, but can impair energy level and attention and depress mood (59). Agents that enhance GABA activity include barbiturates, BZDs, VPA, GBP, tiagabine, and vigabatrin (VGB). Activating AEDs (e.g., felbamate and LTG) paradoxically reduce excitatory neurotransmission. These drugs may possess antidepressant and attention-enhancing efficacy (60), but can cause anxiety, insomnia, and agitation. Some AEDs have both inhibitory and excitatory properties [e.g., TPM, levetiracetam (LEV), and zonisamide] and tend to be more sedating than activating, but can also cause anxiety, irritability, and depression. For all AEDs, side-effect profiles vary considerably between patients. For example, barbiturates, VPA, VGB, and LEV cause sedation and, in some patients, irritability and anxiety. Children often show very different behavioral reactions than adults. All AEDs can have positive or negative psychotropic properties in different patients. Atypical behavioral responses to AEDs and other medications are more frequent in children and the developmentally disabled. An individual's behavioral response to a specific AED is influenced by the neuropsychiatric disorder and drug interactions (Table 1), as well as genetic and environmental factors. While treatment concerns individual patients, studies identify group averages. We are limited in our ability to predict the behavioral changes associated with a specific AED in a specific patient.
Table 1. Interactions of psychotropic drugs and AEDs
| ||Fluvoxamine|| ||Olanzapine|
| ||Haloperidol|| ||Risperidone|
| ||Nefazodone|| ||Aripiprazole|
| ||Nortriptyline|| ||Clozapine|
|Lamotrigine||Sertraline|| || |
| ||Sertraline||Buprorpion|| ||Paroxetine|
| ||Buspirone|| ||Tricyclic|
| || antidepressants|
|Phenobarbital|| ||Buprorpion|| ||Haloperidol|
| ||Buspirone|| ||Antipsychotics|
| ||Clozapine|| ||Paroxetine|
| ||Molindone|| ||Tricyclic|
| ||Paroxetine|| || antidepressants|
| || antidepressants|