Epilepsy & Behavior 1, 219-227 (2000)
doi:10.1006/ebeh.2000.0090, available online at http://www.idealibrary.com on IDEAL

REVIEW

Psychosis of Epilepsy: A Neurologist's
Perspective

Andres M. Kanner, M.D.1

Department of Neurological Sciences, Rush Medical College, and Rush Epilepsy Center, Rush–Presbyterian Saint Luke's Medical Center, Chicago Illinois 60612

Received July 21, 2000; revised July 22, 2000; accepted for publication July 22, 2000


Psychosis of epilepsy (POE) comprises a group of disorders that are closely associated with epileptic seizures. These include interictal POE, postictal psychosis, and alternative psychosis (also known as "forced normalization"). Neurologists have, in general, played a limited role in the evaluation and management of patients with POE. Yet, as reviewed in this paper, a good understanding of electrophysiologic, neuroradiologic, and neuropathologic variables associated with POE can yield valuable data in the evaluation of the seizure disorder of these patients. The purpose of this review article is to highlight the clinical, neuroradiologic, neurophysiologic, and neuropathologic aspects of POE that can assist in the evaluation and management of the associated seizure disorder and to identify the circumstances in which a timely therapeutic intervention by neurologists can avert or minimize the occurrence of a psychotic episode. Specifically, the clinical characteristics of interictal POE and ictal, postictal, and alternative psychotic episodes are highlighted together with their potential pathogenic mechanisms and the associated treatment issues. Finally, discussions of psychotic disorders following epilepsy surgery and the pharmacotherapy of psychotic disorders in patients with epilepsy are presented. © 2000 Academic Press
Key Words: psychosis; epilepsy; schizophrenia; postictal psychosis; hamartomas; focal dysplasias; neuroleptic medication; forced normalization; electroconvulsive therapy.

INTRODUCTION

Psychosis of epilepsy (POE) is a term applied to a group of psychotic disorders with a distinct phenomenology in which potential etiopathogenic mechanisms are believed to be closely related to the seizure disorder (1). For example, several studies have suggested that the recurrence of some forms of POE may be closely linked to seizure exacerbation. In a recent review of the topic, Ferguson and Rayport described how episodic POE results from seizure recurrence and remits with seizure control (2). Further, small hamar-

1 To whom all correspondence should be sent at Rush Epilepsy Center, Rush–Presbyterian Saint Luke’s Medical Center, 1653 West Congress Parkway, Chicago, IL 60612. Fax: (312) 942-2238. E-mail: akanner@rush.edu.

tomas and dysplasias in the temporal lobe have been identified in patients with intractable temporal lobe epilepsy (TLE) and are more commonly found in patients with POE than without (3).

Up to the present, neurologists and epileptologists have played a very limited role (if any at all) in the evaluation and treatment of POE. Yet the close relationship between some forms of POE and seizure disorders may directly bear on the neurologic evaluation and seizure management of these patients. The purpose of this paper is to identify the clinical, neuroradiologic, neurophysiologic, and neuropathologic aspects of POE that can assist neurologists in their evaluation and management of the associated seizure disorder and to identify the circumstances in which a timely therapeutic intervention can avert or minimize the occurrence of a psychotic episode.

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220 Andres M. Kanner

The association between epilepsy and insanity has been recognized since antiquity (4). However it was not until the 19th century when the close relationship between these two conditions was studied in a systematic manner (5). Several treatises by Esquirol in 1827 (6), Morel in 1850 (7), Farlet in 1864 (8), and others stressed the close links between epilepsy and insanity and suggested that psychopathologic phenomena could be considered the "equivalent of epileptic activity." This concept was illustrated by terminology of that era like "epilepsie larvee" that referred to psychotic phenomena in the patient with epilepsy (7).

In the 1950s, several investigators recognized that patients with epilepsy, in particular those with TLE, suffered from a psychotic disorder that differed in many ways from the schizophrenias. Hill in 1953 (9) and Pond in 1957 (10) noted that such patients did not display the lack of affect and "asocial or withdrawn attitude" that were typical of the schizophrenic patient. In their classic paper, Slater et al. (11) further highlighted the differences described by Hill and Pond and coined the term "schizophrenia-like psychosis" in recognition of the similarities between these two disorders, noting that these patients’ psychotic episodes included paranoid delusions with visual and auditory hallucinations. Yet, further systematic analyses of psychiatric phenomena by others continued to depict a psychotic disorder that, while sharing pivotal symptoms, differed in important ways from the psychotic disorders affecting the nonepileptic patient.

PSYCHOSIS OF EPILEPSY: HOW DOES IT DIFFER FROM A SCHIZOPHRENIC DISORDER?

According to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (12), the diagnosis of schizophrenia in the nonepileptic patient requires the presence of at least two of the following five symptom categories with a minimal duration of 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms (i.e., affective flattening, alogia, avolition). In addition to the above, patients must be dysfunctional in social and occupational domains or in selfcare for a minimum of 6 months, during which they may present with negative symptoms or with at least two of the symptoms outlined above, but of lesser severity.

In contrast, the description of cases with POE is remarkable for the absence of negative symptoms, better premorbid function, and rare deterioration of the patient’s personality (13). This point is illustrated in Slater’s observation that "the delusions and hallucinations of patients with POE were empathizable (the patient remains in our world)" (11). While others suggested that psychotic episodes in patients with epilepsy are indistinguishable from those of classic schizophrenics (14), there is a consensus of their lesser severity and better response to therapy.

Different classifications of POE have been proposed (5). In a recent review of the topic, Rayport and Ferguson (2) suggested that POE be classified into two categories: episodic psychosis of epilepsy and chronic or nonepisodic psychosis of epilepsy. The former has been identified primarily in patients with TLE and, according to these authors, is closely linked to the status of seizure control. Psychotic episodes last from a few days to several weeks. These authors described a prolonged course and a more guarded prognosis in nonepisodic psychosis of epilepsy. They pointed out that episodic exacerbations may take place within the nonepisodic disorders in the presence of seizure worsening.

Other classifications have suggested separating the psychotic disorders according to their temporal relationship with seizure occurrence. Thus, psychotic disorders are classified as ictal if they are an expression of the seizure activity, postictal when they occur within 7 days of a seizure or seizure cluster, and interictal when they occur independently of seizures. Alternative psychosis is a separate category in which the onset of psychotic symptoms follows the suppression of seizure activity (see below). The episodic psychosis of epilepsy of Rayport and Ferguson would correspond to the postictal and alternative psychotic disorders of this other classification scheme, while the nonepisodic psychosis would be equivalent to the interictal psychosis of epilepsy (5).

From a neurologist’s perspective, a more useful classification is one that distinguishes the psychotic disorders in which the occurrence is closely linked to seizure occurrence (i.e., postictal psychosis) or remission (i.e., alternative psychosis) from those with a more chronic and stable course. This classification should also include iatrogenic psychotic processes resulting from antiepileptic drugs (AEDs). These are, in fact, the psychotic episodes in which the neurologist’s intervention is most pivotal to the prevention and/or remission of psychotic symptoms.

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Psychosis of Epilepsy 221

POSTICTAL PSYCHOSIS

Postictal psychotic phenomena can present in the form of isolated symptoms or as a cluster of symptoms mimicking psychotic disorders. While postictal psychiatric symptoms were described in the medical literature from antiquity to the 19th century (4), they remain poorly understood, in particular with respect to their prevalence and pathogenic mechanisms.

Postictal Psychotic Symptoms

We recently concluded an evaluation on the prevalence of postictal psychiatric symptoms (PPS) in 100 consecutive patients with pharmacoresistant partial epilepsy who underwent video-EEG monitoring (VEEG) as part of a presurgical evaluation at the Rush Epilepsy Center in Chicago (15). Every patient was asked to complete a 42-item questionnaire (The Rush Postictal Psychiatric Symptoms Questionnaire) that is designed to identify 26 psychiatric and 5 cognitive postictal symptoms. We defined the postictal period as the 72 hours following recovery from the last seizure. Questions inquired about the frequency of occurrence of each symptom. Only symptoms that were identified after more than 50% of seizures were included in this study, so as to reflect a "habitual" phenomenon. To ensure that patients were reporting postictal psychiatric symptoms, we also inquired about the occurrence of each symptom during the interictal period. For symptoms identified during both interictal and postictal periods, we included symptoms as postictal only if they were reported to be significantly more severe during the postictal period and identified this process as postictal exacerbation of interictal psychiatric symptoms.

Among the 100 patients, 79 had TLE and 21 had seizures of extratemporal origin. Half of the patients had only complex partial seizures (CPS) and the other half had CPS and generalized tonic– clonic (GTC) seizures. Seventy-eight patients had more than one seizure per month. Fifty-two patients had a past psychiatric history, consisting of depression, anxiety disorders, and attention deficit disorders, but none had a history of a psychotic disorder.

Ten of the one hundred patients experienced postictal psychotic symptoms after more than 50% of their seizures with a median duration of 15 hours (range: 1–108). A history of depression predicted the occurrence of postictal psychotic symptoms. These findings, however, cannot be generalized to all patients with

epilepsy, as our sample was restricted to patients with refractory partial epilepsy.

Postictal Psychotic Disorders

As previously mentioned, postictal psychiatric symptoms may cluster and mimic discrete psychiatric disorders. Postictal psychosis (PIP) corresponds to approximately 25% of POE (16). The prevalence of postictal psychiatric disorders in the general population of patients with epilepsy is yet to be established, however, but has been estimated to range between 6 and 10% (17, 18). The postictal psychiatric disorders reported in the literature have focused almost exclusively on PIP identified in the course of V-EEG. This is not surprising, since the circumstances around V-EEG are optimal to facilitate their occurrence and identification. These include the occurrence of frequent seizures over a short period, following the discontinuation or dose reduction of AEDs, under medical supervision and observation.

In a study published in 1996, we estimated the yearly incidence of postictal psychiatric disorders to be 7.9% among patients with partial epilepsy who are undergoing V-EEG (17). The majority (6.4%) presented with PIP. Among the 10 patients with PIP, four presented with a delusional psychosis, one had a mixed manic–depressive-like psychosis, two manifested a psychotic depression-like disorder, one had a hypomanic-like psychosis, and one other patient had a manic-like psychosis. The tenth patient presented with bizarre behavior associated with a thought disorder. In every case, the onset of symptoms began a mean period of 24 hours (range: 12–72 h) after the last seizure. The mean duration of the PIP was 69.6 hours (range: 24–144).

In five patients, the psychotic episode remitted with low doses of neuroleptic medication (2–5 mg/day haloperidol), while one patient required high doses (40 mg/day haloperidol), and in four, remission occurred without pharmacotherapy. Six of these ten patients had experienced an average of 2.4 PIP prior to V-EEG, while in the remaining four it was the first episode.

Other authors have reported similar findings with respect to clinical characteristics, course, and response to pharmacotherapy (18 –23). Kanemoto et al. studied the clinical differences between PIP and acute and chronic interictal psychosis of epilepsy (23). They noted that patients with PIP were more likely to experience grandiose and religious delusions in the presence of elevated moods and a feeling of mystic fusion of the body with the universe. On the other hand,

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222 Andres M. Kanner

perceptual delusions or commenting voices were less frequent in PIP, while feelings of impending death were common with PIP.

Similar findings among the different case series of PIP include: (1) delay between the onset of psychiatric symptoms and the time of the last seizure; (2) relatively short duration (a shorter duration, however, was noted among our patients, as only 2 patients had an episode lasting more than 5 days, while this was true in 5 of 9 patients in Savard and colleagues’ (20) and in 7 of 14 patients in Logsdail and Toone’s series (19)); (3) affect-laden symptomatology; (4) clustering of symptoms into delusional and affective-like psychosis; (5) increase in the frequency of secondarily generalized tonic–clonic seizures preceding the onset of PIP; (6) onset of PIP after having seizures for a mean period of more than 10 years; and (7) prompt response to low-dose neuroleptic medication or benzodiazepines.

Various investigators have tried to identify potential pathogenic mechanisms of PIP. In a study conducted at the Rush Epilepsy Center, we compared neuropsychometric studies, brain MRI, interictal and ictal data derived from V-EEG, and past psychiatric history among 17 patients with PIP, 20 patients with postictal depressive disorder (PID), and 20 controls (24; Kanner et al., submitted). A logistic regression model clearly demonstrated that bilateral independent ictal foci were strong predictors of PIP. Conversely, the presence of PIP predicted bilateral ictal foci with an 89% probability. Umbricht et al. (25) reported similar findings in a study comparing 8 patients with PIP, 7 patients with interictal psychosis, and 29 controls. In addition, they found that patients with PIP and interictal psychosis had a lower verbal IQ and the absence of mesial temporal sclerosis. Devinsky et al. (22) reported a higher frequency of bilateral independent interictal foci in 20 patients with PIP compared with 150 controls.

These observations suggest that the prompt recognition of PIP by neurologists has major diagnostic and therapeutic implications. First, neurologists can be alert to the possible development of PIP in the appropriate clinical situation and can potentially avert the episode by introducing low-dose neuroleptic medication at the first sign of PIP, which is usually insomnia. In patients with PIP, families need to be educated to recognize these symptoms so that timely administration of 1 to 2 mg of risperidone may avert the start of PIP. If PIP predictably occurs after most or all seizure clusters, then neuroleptic medication can be given at the time of the cluster rather than with the occurrence of insomnia to prophylax against PIP. We usually use

low-dose risperidone for 3 to 5 days in this situation and then discontinue it.

Patients undergoing a V-EEG monitoring study with the following clinical characteristics should be carefully watched for signs and symptoms of PIP: (1) occurrence of de novo cluster of secondarily GTC seizures (or CPS); (2) bilateral independent ictal foci; and (3) past psychiatric history of depression or psychosis. Patients, family members, and nursing staff should be on the lookout for insomnia or a mild thought disorder between 12 and 72 hours after the last seizure. If these symptoms are identified, low-dose risperidone can be administered as outlined above.

The occurrence of PIP also has important implications with respect to the localization of ictal foci; specifically, bilateral independent ictal foci should be suspected in patients who are being considered for epilepsy surgery who manifest PIP. These patients may therefore require longer V-EEG monitoring studies to record a greater number of seizures, and probably the use of intracranial electrodes, to be sure that a seizure focus is single. If recordings with depth or subdural electrodes are considered, prophylactic treatment with low-dose risperidone or haloperidol can avert the occurrence of PIP during the invasive V-EEG monitoring studies (17).

ICTAL PSYCHOSIS

This form of psychotic episode should always be considered in the differential diagnosis of PIP and POE. It is typically an expression of nonconvulsive status epilepticus, including simple partial status, complex partial status, and absence status (26). In the case of simple partial status, the diagnosis may be difficult to reach, as scalp electrographic recordings may not detect the ictal pattern (27). The presence of unresponsiveness and automatisms may facilitate the suspicion of the other two forms of status epilepticus. Yet, confirmation with EEG recordings is of the essence as certain non-seizure-related psychotic processes, such as catatonic states, are associated with unresponsiveness and mannerisms that mimic ictal automatisms.

ALTERNATIVE PSYCHOSIS OR FORCED NORMALIZATION

Landolt developed the concept of alternative psychosis in 1953 (28) from observations of an inverse

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Psychosis of Epilepsy 223

relationship between seizure control and the occurrence of psychotic symptoms. In fact, he described "normalization" of EEG recordings with the appearance of psychiatric symptoms and coined the term "forced normalization." Wolf and Trimble suggested the term "paradoxical normalization," while Tellenbach had proposed the term "alternative psychosis" (29). This opposite relationship between psychosis and epilepsy has been considered by some as the explanation for the therapeutic effect of electroconvulsive therapy (ECT) of psychotic disorders.

Alternative psychosis is not common. Landolt reported 47 cases between 1951 and 1958. Single case studies were reported by others (30) and Schmitz estimated the prevalence of alternative psychosis to be 1% among 697 patients followed at a university epilepsy center (31).

Forced normalization has been reported in patients with TLE and others with generalized epilepsies. As in other forms of POE, the psychotic manifestations of alternative psychosis were identified after a relatively long duration of the seizure disorder. Wolf noted a 15.2-year history of epilepsy in 23 patients with this type of POE (32). Both Landolt and Wolf reported a pleomorphic clinical presentation with paranoid psychosis without clouding of consciousness being the most frequent manifestation. As with other types of POE, a richness of affective symptoms is a characteristic finding.

The phenomenon of forced normalization has been observed following the use of various AEDs, including phenacetylurea (33), phenytoin and primidone (34), valproate and carbamazepine (35), and, more recently, vigabatrin (35). In these cases, psychotic disorder was thought to result from the suppression of seizures rather than reflecting an adverse event of the AED (30). An iatrogenic effect of the AED has to be considered in the differential diagnosis of these patients, however (see below).

The pathogenic mechanisms mediating this phenomenon are yet to be established. The suggested hypotheses are of interest, however. Trimble postulated that an excess of dopamine effect is responsible for both the seizure cessation and the psychotic symptomatology (36). Rayport and Ferguson have suggested that forced normalization is not the expression of seizure cessation, but rather, of a "voltage depression or suppression" in neocortical derivations concurrent with ictal activity in amygdala or hippocampal structures (2). Depth electrode studies by Wieser (37) appear to lend support to this hypothesis. Neverthe-

less, to date it remains a hypothesis and further studies are required.

In their review, Reid and Mothersill (30) concluded that alternative psychotic episodes should be treated by reducing and/or discontinuing AEDs until overt seizure recurrence causes a remission of psychotic symptoms. The rapidity with which AEDs should be tapered is not clear. Tellenbach suggested rapid tapering under EEG monitoring, while Landolt advocated the use of ECT or Metrazol to induce seizures, if necessary. Following seizure recurrence and remission of psychotic symptoms, AEDs should be reintroduced slowly (30).

It is not rare that patients or parents of children with epilepsy report the occurrence of dysphoric symptoms, including increased irritability, mood liability, and overt symptoms of depression preceding their seizures, only to disappear the day after the ictus. Indeed, Blanchet and Frommer (38) reported a decline in mood ratings 3 days prior to the seizure occurrence, with a return to baseline ratings noted 1 day postictally. In my opinion, this phenomenon may be the expression of "alternative psychopathology" of significantly milder severity that occurs rather frequently, though its true prevalence is yet to be established.

AED-RELATED PSYCHOSIS

While AED-related psychotic episodes are, strictly speaking, not a form of POE, they are included in this discussion because they enter into the differential diagnosis with alternative psychosis. Psychosis has been reported as a side effect of most AEDs. These include standard AEDs such as ethosuximide (39), phenytoin (40), phenobarbital and primidone (41), as well as the newer AEDs, like vigabatrin (35), lamotrigine, topiramate, and levetiracetam (in my personal clinical experience). The clinical differentiation between alternative psychosis and a toxic reaction can be difficult if a seizure-free state followed the introduction of the AED. A toxic reaction can be suspected in the presence of neurologic symptoms like ataxia and tremor or in the absence of a seizure-free state.

Psychotic disorders can occasionally follow the discontinuation of AEDs, particularly those with moodstabilizing properties. Ketter et al. (42) reported the development of anxiety and depression, as well as psychosis, among 32 inpatients who were withdrawn from carbamazepine, phenytoin, and valproic acid. Acute withdrawal from benzodiazepines is well known to result in acute psychosis (43).

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224 Andres M. Kanner

HOW CAN THE PRESENCE OF INTERICTAL POE ASSIST IN THE NEUROLOGIC EVALUATION?

Interictal POE has been characteristically identified in patients with partial epilepsy. There has been an extensive debate regarding the possibility that POE is indicative of TLE (44). While older studies have favored this conclusion (11, 13, 33), a more recent study by Stevens has shown that the proportion of TLE among patients with POE is not higher than that in the general population (45). The presence of interictal POE does not suggest a lateralized seizure focus to either left or right hemisphere (44). On the other hand, POE should lead the neurologist to order high-resolution MRI studies in search of small gangliogliomas and hamartomas, which may be multiple (3). Such tumors may be difficult to identify on standard MRI studies and are often the cause of refractory epilepsy. If all seizures are localized by V-EEG monitoring studies to the same area as a single lesion identified on MRI, then epilepsy surgery can be considered.

The presence of interictal POE should also alert the neurologist to the presence of more diffuse central nervous system pathology, as described in the studies by Stevens (46) and Bruton et al. (47). These studies demonstrated the presence of larger ventricles, more periventricular gliosis, and white matter softening among patients with epilepsy and interictal POE more often than among nonpsychotic patients with epilepsy. On the other hand, the presence of mesial temporal sclerosis did not differ in occurrence between patients with and without POE. It is clear from the above discussion that the recognition of POE can suggest valuable diagnostic clues in the evaluation of seizure disorders. Conversely, the neurologists’ timely recognition of the specific POE may minimize and even avert their recurrence.

PSYCHOSIS FOLLOWING TEMPORAL LOBECTOMY

Temporal lobectomy has been associated with the development of de novo psychiatric complications, the most frequent of which consist of depressive disorders during the first year after surgery (48). Psychosis has also been reported after temporal lobectomy. In a series of 100 of Falconer’s patients, Taylor reported 7 with de novo postoperative psychosis (49). Jensen and Vaernet reported de novo psychotic disorders in 9 of 74

patients (50). Trimble (51) calculated that postoperative de novo psychoses ranged between 3.8 and 35.7% (mean, 7.6%) of patients and suggested that in at least some cases a causal relation based on forced normalization was possible. More recent studies of the psychiatric complications of temporal lobectomy confirmed psychosis as a potential complication. Compared with earlier studies, however, the reported incidence of postoperative psychosis was lower, ranging from 3 to 9% of patients (52–56). This lower incidence may reflect a difference in patient selection for epilepsy surgery. Many epilepsy centers currently do not consider patients with a preoperative history of psychosis as candidates for epilepsy surgery. Thus, more recent reports of postsurgical psychosis in patients are primarily de novo psychoses, which would be expected to be of lower incidence than postoperative exacerbations of preexisting psychosis.

A history of psychosis, however, should not be considered a contraindication to epilepsy surgery, provided that patients can cooperate during the presurgical evaluation and have a clear understanding of the nature of the surgical procedure, potential risks, and benefits that can allow them to give informed consent Reutens et al. (57) supports this recommendation: they reported five patients with medically intractable epilepsy and chronic psychosis who had temporal lobe resection for epilepsy. Postoperatively, all patients were seizure-free. Surgery had no apparent effect on the course or severity of the patients’ psychoses; however, seizure freedom allowed two of the five patients to return to work or a supervised workshop.

Although it is often difficult to predict which patients will develop psychiatric complications after epilepsy surgery, several studies have suggested potential risk factors for the development of psychosis. Among these are surgery over the age of 30 years (58) and family history of psychosis (52, 58). In addition, multiple studies have examined the issue of postoperative psychosis and the laterality of surgery. Several studies report psychosis to be more common in patients following right than left temporal lobectomy (53, 54, 59). The explanation for this correlation is yet to be established, however. Finally, as in the case of interictal POE, postoperative psychosis is reported to be more common in patients with hamartomas and cortical dysplasias in the temporal lobe (3). Among the patients with "alien tissue" on pathology, 23% developed psychosis postoperatively versus 5% of patients with mesial temporal sclerosis (3). Similarly, Andermann et al. recently reported 6 cases with postoperative psychosis, all of whom had either a ganglioglioma

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Psychosis of Epilepsy 225

or DNET on pathology (56). No patients from that series with different pathologic features in the temporal lobe developed a similar psychosis. These findings are intriguing, but as yet unexplained.

PHARMACOLOGIC TREATMENT OF POE

The treatment of PIP and alternative psychosis has already been discussed above and will not be further reviewed. We concentrate on the pharmacologic management of chronic interictal POE. In these patients, optimal seizure control is desirable as episodic psychotic exacerbations can accompany clusters of seizures (2). Nevertheless, the use of neuroleptic drugs (NDs) will be necessary, at times for a protracted period. Given the proconvulsant properties of NDs, clinicians have often displayed timidity with their use in patients with epilepsy for fear of causing or worsening seizures. While it is essential that the risk of seizure occurrence always be carefully considered when starting NDs, it should never be a reason not to treat a patient in need of antipsychotic medication.

The seizure rate associated with the use of NDs has ranged from 0.5 to 1.2% among nonepileptic patients (60). The risk is higher with certain drugs and in the presence of the following factors: (1) a history of epilepsy; (2) abnormal EEG recordings; (3) history of CNS disorder; (4) rapid titration of the ND dose; (5) high doses of NDs; and (6) the presence of other drugs that lower the seizure threshold (61). For example, when chlorpromazine is used at doses above 1000 mg/day, the incidence of seizures increases to 9% compared with 0.5% when lower doses are taken (62). Clozapine has been reported to cause seizures in 4.4% when dosed above 600 mg/day. At doses lower than 300 mg, the incidence of seizures is less than 1% (63). Other drugs in this class have been associated with seizure occurrence in the presence of the risk factors cited above. Thus these drugs should be started at low doses and should undergo slow dose increments to minimize the risk of seizures in patients with epilepsy.

The impact of NDs on seizure occurrence among patients with epilepsy has not been properly studied. Pacia and Devinsky (64) reviewed the incidence of seizures among 5629 patients treated with clozapine. Sixteen of these patients had epilepsy before the start of clozapine therapy and all patients experienced worsening of seizures while on the drug: 8 patients at doses lower than 300 mg/day, 3 patients at doses between 300 and 600 mg/day; and 5 at doses higher

than 600 mg/day. Thus clozapine should be avoided or used in exceptional circumstances with extreme caution in patients with epilepsy.

Most NDs can cause EEG changes consisting of slowing of the background activity when used at high doses. In addition, some of these drugs, particularly clozapine, can cause paroxysmal electrographic changes in the form of interictal sharp waves and spikes (63). This type of epileptiform activity, however, is not predictive of seizure occurrence. Data from studies by Tiihonen et al. (65) suggest that severe disorganization of EEG recordings is a more likely predictor of seizure occurrence.

The three NDs with the highest risk of seizure occurrence are clozapine, chlorpromazine, and loxepine. Those with a lower seizure risk include haloperidol, molindone, fluphenazine, perfenazine, and trifluoperazine (61), and risperidone, among the newer NDs. No data are available on olanzapine, quetiapine, and ziprasidone. Whether the presence of AEDs at adequate levels protects patients with epilepsy from breakthrough seizures on the introduction of NDs with proconvulasant properties is yet to be established.

In addition to the proconvulsant properties of NDs, clinicians must also consider the pharmacokinetic and pharmacodynamic interactions between NDs and AEDs. Hepatic enzyme induction from AEDs such as carbamazepine, phenytoin, phenobarbital, and primidone may increase the clearance of most NDs. This is, in fact, the most frequent and clinically relevant pharmacokinetic interaction encountered in clinical practice. It may potentially result in recurrence of psychotic symptoms previously controlled at higher serum concentrations of NDs. By the same token, discontinuation of an AED with enzyme-inducing properties may result in a decrease in the clearance of NDs, which in turn can lead to extrapyramidal adverse events caused by an increase of ND serum concentrations. Finally, certain AEDs, like valproic acid, can inhibit the metabolism (glucuronidation) of NDs like clozapine. Therefore, neurologists should be aware that adjustments of psychotropic drug dosages may be necessary with the addition or discontinuation of enzyme-inducing or enzyme-inhibiting AEDs.

McConnell and Duncan reviewed the pharmacodynamic interaction between NDs and AEDs (61). They highlighted the potential negative interaction between clozapine and carbamazepine, both of which are associated with leukopenia, and if combined, there is a potential synergistic effect on the white blood cell count. The combination of these two drugs has been

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226 Andres M. Kanner

also reported to increase the risk of neuroleptic malignant syndrome.

ECT IN EPILEPSY

ECT is not contraindicated in patients with severe POE, even though ECT is known to increase the seizure threshold (66). In 1997, Krystal and Coffey (61) suggested the use of unilateral ECT in the nondominant frontotemporal region. AEDs are held in the mornings before a treatment, but otherwise are kept at baseline doses.

CONCLUSIONS

POE comprises various psychotic disorders that are associated with poorly controlled seizure disorders. The role of neurologists and epileptologists in the evaluation and management of patients with POE is critical. An understanding of these psychotic disorders can, in turn, facilitate the evaluation and treatment of affected patients’ seizure disorders. Finally, treating neurologists are in a unique position to avert or minimize the occurrence of certain types of POE through timely intervention.

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All rights of reproduction in any form reserved.

Authored Date: 
11/2013
on: 
Wednesday, November 6, 2013