Provoked seizures are usually contrasted with “spontaneous” seizures. In reality, no seizures are truly spontaneous, as all result from the interaction of any number of intrinsic and external excitatory and inhibitory factors. The dynamic interaction of these factors determines when a seizure occurs. Yet in most cases, our knowledge of these factors is so limited that it is impossible to predict, with any reasonable degree of reliability, when a seizure will or will not occur. Thus, most seizures occur randomly but not spontaneously. In a tertiary care epilepsy center, 62% of patients identified at least one specific precipitant for their seizures.¹⁴ In order of prevalence, those precipitants were stress, sleep deprivation, sleep, fever or illness, and fatigue. In some cases, however, one or (rarely) more consistent factors can be discerned preceding a seizure with a sufficiently short latency that a direct cause-and-effect relationship can be assumed. In certain cases, the seizure follows the provocative factor with such fixed latency and response rate that many have spoken of the “reflex epilepsies.” In these cases, the provocative agent is a more or less specific sensory stimulus interacting with established epilepsy. These susceptible subjects almost always have “spontaneous” seizures as well. In other cases, the latency is longer and variable, and the provoking “stimulus” is not always followed by the “response” (seizure). Seizures in catamenial epilepsy and seizures after hyperventilation would be examples. Nevertheless, in either case, the relation is close enough that few would have difficulty in categorizing these seizures as being provoked. On occasion, provocative factors may be of sufficient intensity to bring on seizures in subjects who do not have epilepsy. Fever in young children and sleep deprivation in young adults are the two most frequent examples.

Provoked seizures are indistinguishable, once they have begun, from “spontaneously” occurring seizures. All major types of seizures can be provoked. The electro-clinical manifestations for each type of seizure are the same whether provoked or spontaneous. Thus, it is only the setting in which seizures occur that gives a clue to whether they are provoked or not. One should be suspicious of the presence of provoking factors in any patient who does not respond well to standard treatment or in whom the history suggests that seizures occur in characteristic circumstances, that is, at the same time of day, in the same phases of the diurnal cycle, or in specific psychosocial settings. Although this may also be true for pseudoepileptic seizures, the history usually fails to reveal any “secondary gain,” as is so often seen in psychogenic pseudoepileptic seizures.

Provocative factors are both intrinsic and extrinsic. Common intrinsic factors include sleep deprivation,⁶ sleep itself, the menstrual cycle, and any number of abnormal systemic toxic–metabolic states. Extrinsic factors include a large array of specific psychophysiologic stimuli (e.g., stroboscopic stimulation) and many less specific states, such as arousal, stress, and mood.

The significance of recognizing provoked seizures is that recognition offers another therapeutic option—that is, attempts to eliminate or avoid the provoking stimulus. Although simple in principle, this is often difficult in practice. Environmental stimuli are ubiquitous. A specific environmental stimulus may be difficult to recognize as the triggering factor. Emotional status is complex and often requires a multifaceted treatment regimen. Many patients require both short-term and long-term efforts to alter habits, behavior, and emotional status. Some patients report the ability to self-control their epilepsy by consciously avoiding high-risk situations and seeking low-risk situations. Further, some patients with aura or warnings can at times abort their habitual seizure.⁴² Optimal medical and psychological therapy must be pursued aggressively in those who have coexistent epilepsy, as this is the primary treatment modality.

Isolated or single seizures occurring in nonepileptic subjects are found, on careful inquiry, to have been provoked in the majority of such cases. Identification of the provocative factor must be made with circumspection. Many of these seizures are related to commonly prescribed drugs. It becomes important to appreciate additional factors, such as severity of illness, neurologic status, renal clearance, hepatic elimination, drug dosing and administration route, polypharmacy, and physiochemical and toxicologic properties of the drugs. These factors modify pharmacotherapeutic and toxicologic responses, making their recognition and understanding vital for treatment.

Emotional stress is likely the most prevalent provocative circumstance to precipitate seizures in patients with epilepsy. The actual prevalence of this relationship is not known, yet clinical experience and the available clinical studies²⁸ support its ubiquity and impact. Patients have identified fear, worry, frustration, and anger as common stressors. An immediate temporal relationship is not usually evident—that is, the seizure usually does not occur at the instant the patient senses the anger or other emotion. Nevertheless, the patient is at maximal risk for one or more seizures in close temporal proximity to such states. Patients with complex partial seizures are more susceptible.

It is now appreciated that depression is the most common comorbidity in patients with epilepsy.²⁰ In patients with treatment-resistant epilepsy, depression reached 54%.⁷ There is growing evidence that depressive disorders and epilepsy share an endogenous or biologic association.²⁰ The linkage of these two disorders and their basic mechanisms is inferred by epidemiologic studies and clinical observations, and supported by animal experimentation. It is apparent that depressive disorders in epilepsy patients may likely create a milieu for seizure provocation and must be appropriately treated.

Certain clinical neurophysiologic analyses are anecdotal yet elucidating.¹⁰ Several different and indirect provocative processes may occur as a consequence of emotional stress. Willful noncompliance with medication has been demonstrated. Hyperventilation can develop sufficiently to trigger electroencephalographic (EEG) changes and clinical seizures. Sleep deprivation can be a consequence of profound agitation and restlessness. These phenomena, which are associated with emotional stress, do modulate brain excitability. However, it is not clear from such clinical studies whether emotional stress modulates brain excitability through the kind of neuronal mechanisms implied by basic research studies or through other indirect mechanisms.

As emotional stress is ubiquitous and protean, evaluation for its presence should be a part of the initial assessment in every patient with epilepsy. Vigilance for changes in interpersonal relationships, in school or job performance, and in social circumstances should be a routine component of follow-up examinations. Clinical judgment is required to place the significance of this provocative factor in perspective for the individual patient. Failure to pursue this approach and to ameliorate problems often means an increased frequency of seizures regardless of the best attempts at medical therapy.

Treatment includes both medical and nonmedical therapy. Medical therapy may require not only antiepileptic drug treatment, but also use of tranquilizers, antidepressants, or neuroleptics. More specifically, long-term anxiolytics with antiepileptic properties can be helpful; these include clor-azepate and clonazepam. Antidepressants, mood stabilizers, or neuroleptics can be used concurrently with antiepileptic therapy if clinically indicated. However, there is minimal risk for exacerbation of seizures with some of these drugs. Further discussion follows in the section on drug-induced seizures.

More severely ill patients with paranoia, thought disorder, hallucinations, and extreme agitation require treatment with neuroleptics. As with antidepressants, therapeutic precautions apply. High doses of neuroleptics, rapid changes in their levels, and induction of drowsiness may worsen seizures in epileptic patients; some neuroleptics can provoke seizures by direct effect. However, the reduction in agitation, thought disorder, and hallucinations can exert a significant calming effect and restitution of normalcy, which in turn is associated with improved seizure control. Thus, the benefits warrant their use and treatment should not be delayed.

Nonmedical therapy is often the cornerstone in treating patients with emotionally induced seizures. Delineation of the areas of concern is often facilitated by an early consultation with the social worker. Creation of a treatment paradigm for problems in the family or interpersonal relationships or financial difficulties assists in targeting resources and efforts. Psychological methods include individual or group psychotherapy. Therapists who are knowledgeable about epilepsy can promote a more comfortable and effective therapeutic milieu. Other interesting strategies include reward management, self-control exercises,⁴² relaxation, desensitization, and biofeedback.¹⁰ Unfortunately, controlled trials that validate the benefits of these therapies are limited.

Typically, fatigue and sleep deprivation appear in students who study long hours and try to meet early classes, grueling examinations, or a combination of these along with many social exercises. Compulsive workers are also subject to a similar degree of sleep deprivation and fatigue. The addition of alcohol consumption further raises the potential for seizures. It is not uncommon to find this phenomenon of seizure induction by a combination of fatigue, sleep deprivation, and alcohol in nonepileptic patients.¹³ Indeed, the revelation of such a circumstance in a particular patient should help dismiss the diagnosis of epilepsy in an otherwise healthy person. The frequency and extent of individual susceptibility to these factors is not known. Experience of the authors suggests that the occurrence of seizures associated with either fatigue or sleep deprivation is not unusual. Fatigue and sleep deprivation are often found to reflect emotional stress rather than isolated provocative stressors. Isolated fatigue may not influence seizures. At least in athletically conditioned epileptic patients, exercise may actually have a beneficial effect on seizure frequency.⁹

Treatment requires the determination of the cause of fatigue and sleep deprivation. Assessment of psychological problems can be revealing. Correction of those problems by counseling precludes the inappropriate addition or change of antiepileptic drugs. Appraisal of sleep deprivation or fatigue often reveals clinical depression or anxiety that warrants therapy with psy-chotropic medications or psychiatric intervention. Medical causes, such as sleep apnea,⁶ caffeine abuse, or excessive alcohol use, require specifically directed treatment and counseling.

Alcohol is well recognized as a cause of seizures in nonepileptic patients (see Chapter 268). Basic and clinical concepts about this phenomenon have been considered in detail.³⁷ Importantly, the constant use of alcohol may represent a predisposition for the evolution of epilepsy in the nonepileptic patient through various mechanisms, including head injury.

Alcohol may be a trigger for seizures in patients with epilepsy. Some patients appear exquisitely sensitive to the effects of alcohol, and seizures occur even with small exposure. Alcohol may provoke seizures in several different ways. The frequent use of alcohol results in induction of liver enzymes, which in turn lowers antiepileptic drug levels. A soporific effect may immediately follow alcohol consumption. Additionally, normal sleep cycles may be disrupted by alcohol. These derangements in wakefulness and sleep have the potential for provoking seizures. Forgetfulness as a consequence of alcohol use may also cause medication noncompliance.

Generally, alcohol is to be avoided. An exact measurement of alcohol consumption by a patient is typically unreliable. Yet in the responsible and stable patient, permission to have an occasional glass of wine or beer is not associated with adverse effects on seizure control. For some patients, it is important to allay feelings of exclusion, which may preclude social integration.

Seizures are not a common complication of drug therapy.^29,49 Most drug-induced seizures are self-limited and may be of limited consequence. On the other hand, even status epilepticus may occur as a consequence of drug induction. Failure to recognize that a specific drug is playing a role in causing seizures and continued administration of that drug will result in perpetuation of the seizure problem.

Drug-induced seizures cannot be predicted, but most are associated with excessively high brain concentrations of drugs or their metabolites. Awareness of general and specific circumstances for an individual patient will suggest predisposition. Those factors contributing to drug-induced seizures relate to the drug itself and have to do with the intrinsic epileptogenicity of a specific agent. The route of administration, dosing schedule, and plasma concentration are important. Factors that influence central nervous system levels include lipid solubility, molecular weight, ionization, and transport systems; however, practical knowledge of these drug properties is often missing at the bedside. Changes in protein binding can be inferred using clinical information regarding serum albumin concentrations, use of multiple drugs that might compete for binding sites, or the presence of azotemia. Patients with impaired renal function (azotemia) and decreased clearance or hepatic dysfunction (decreased protein production) will be exposed to high central nervous system concentrations of drugs that are administered in doses appropriate for healthy patients. The total serum concentrations will be within therapeutic range, but the alterations in drug binding create higher free concentrations. If clinical information is utilized, inferences about brain concentrations can be made at the bedside.

Predisposing factors related to the patient include specific illnesses. Patients who are extremely ill with multiple metabolic problems or multiple organ impairment and those with central nervous system infection are more likely at risk for drug-induced seizures. Additionally, patients with underlying neurologic abnormalities, including tumor, stroke, or degenerative diseases as well as epilepsy, have greater risk. Many of these conditions have in common an impaired blood–brain barrier. Another important point to consider about drug-induced seizures is that whereas such seizures reflect drug toxicity of the brain, drug toxicity may be affecting other organ systems concurrently. If this is suspected, prompt attention to medical management for cardiac, hepatic, or renal effects of drugs is warranted.