Introduction

Psychotic disorders are an uncommon psychiatric comorbidity in patients with epilepsy, but their prevalence is higher than in the general population. An association between psychotic phenomena and epilepsy was described in ancient Greek and Roman literature. For example, Hippocrates and Aristotle considered Hercules to have suffered from epilepsy and to have killed his children in the midst of a “fit of madness.”¹ Until the 19th century, epilepsy continued to be associated with “madness” in one form or another to the point where various authors considered psychotic episodes to be an “epileptic equivalent.”² Indeed, Falret in 1854 and Morel in 1873 referred to psychotic disorders in patients with epilepsy as larval epilepsy, epileptic mania, and grands maux intellectuels.^3,⁴ Kraepelin described the temporal relation between seizure occurrence and the development of psychotic episodes, such as postictal psychosis, and also recognized their occurrence independent of seizures (interictal psychotic episodes).⁵

In the 1950s, several investigators recognized that patients with epilepsy, especially those with temporal lobe epilepsy (TLE), could have a psychotic disorder that differed in many ways from the schizophrenias. Hill in 1953 ⁶ and Pond in 1957⁷ observed that these patients did not display the lack of affect and the “asocial or withdrawn attitude” that was typical of patients with schizophrenia. In their classic paper, Slater et al.⁸ also emphasized the differences described by Hill and Pond. Because the psychotic episodes in these patients included paranoid delusions with visual and auditory hallucinations Slater et al. introduced the term “schizophrenia-like psychosis.” Further systematic analyses of psychiatric phenomena by others continued to depict a unique psychotic disorder that, while sharing pivotal symptoms, differed in important ways from the psychoses that affected nonepileptic patients.

Today, psychotic disorders identified in patients with epilepsy are commonly referred in the medical literature as psychosis of epilepsy (POE). This is a term applied to a group of psychotic disorders with distinct phenomenology and etiopathogenic mechanisms that are likely to be closely related to the seizure disorder.⁹ For example, in a review of the literature, Ferguson and Rayport described how episodic psychosis of epilepsy is related to seizure recurrence and remits when seizures are controlled.^9,¹⁰ The purpose of this chapter is to review the clinical manifestations of the various forms of POE, their potential pathogenic mechanisms, and current management.

EPIDEMIOLOGIC ASPECTS

The prevalence rates of primary schizophreniform disorders in the general population range between 0.4 and 1%. In contrast, the prevalence of POE has been estimated to be between 7 and 10%.² Unfortunately, data about POE derived from population-based studies are limited. In a retrospective study from a tertiary center, Mendez et al found psychotic disorders to be prevalent in 9% of patients with epilepsy and in 1% in migraneurs.¹¹ In a study by Matsuura et al. carried out in Japan, psychotic disorders were found in 6% of patients with epilepsy.¹² Overall, the incidence of schizophrenia-like psychosis is believed to be 6 to 12 times higher in patients with epilepsy than in the general population.

The relation between psychotic disorders and epilepsy has long attracted considerable interest. At the beginning of the last century, von Meduna described an inverse relationship between the occurrence of psychotic episodes and seizures.² Such observations ultimately led to the use of iatrogenic convulsions, initially with camphor and later with electroconvulsive therapy (ECT), for the treatment of serious psychotic disorders. In a case-control study of new-onset epilepsy in older adults, Hesdorffer et al. concluded that a prior diagnosis of schizophrenia was protective against developing epilepsy.^13,¹⁴ However, this does not appear to be the case in pediatric populations. For example, Jablinsky et al. found that epilepsy in children increased the risk of schizophrenia by a factor of 2 in a case-control study of psychiatric illness in developing countries.¹⁵ The relation between febrile seizures and the risk of schizophrenia is disputed: A Danish study found a positive correlation,¹⁶ whereas no association was found in a ten-country study by the WHO.

Clinical Features

The traditional classification of POE has been based on the temporal relationship between the psychotic episode and occurrence of seizures. Psychotic episodes are divided into ictal (e.g., the psychotic symptoms are the clinical expression of the seizure), postictal (e.g., episodes occurring up to 120 hours after the seizure); and interictal (e.g., episodes that are independent of seizures).¹⁷ A fourth manifestation of POE is the alternative psychotic episode (APE), also known as forced normalization, in which psychotic episodes occur in patients who become seizure free after having had persistent seizures for many years.^18,¹⁹ Rayport and Ferguson proposed that POE be grouped into two categories ^9,¹⁰: 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, are closely linked to the effectiveness of seizure control. Episodic psychotic episodes last from a few days to several weeks. They can have a prolonged course and carry a guarded prognosis. Rayport and Ferguson also pointed out that episodic exacerbations can occur in patients with nonepisodic disorders if the seizures worsen. Thus, Rayport and Ferguson’s episodic psychosis of epilepsy corresponds to postictal psychotic episodes (PIPE) and APE, whereas the nonepisodic psychoses are equivalent to the interictal psychosis of epilepsy (IPE). Finally, in addition to IPE, PIPE, and APE, any classification should also include psychotic processes resulting from iatrogenic effects of antiepileptic drugs (AEDs) or surgical treatment.

Interictal Psychosis of Epilepsy

Persons with epilepsy can have interictal psychotic disorders that are clinically indistinguishable from primary schizophreniform disorders.²⁰ However, these patients are older at onset of psychotic symptoms than people without epilepsy. According to the Diagnostic and Statistical Manual of Mental Disorders,²¹ a diagnosis of schizophrenia requires symptoms from at least two of the following five categories to have been present for a minimum period of 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms (i.e., affective flattening, alogia, avolition). In addition, patients have to display dysfunction in social and occupational domains or in self-care for a minimum of 6 months (including at least 1 month of negative symptoms or at least two of the symptom categories listed earlier), but of lesser severity.

However, as already mentioned, POE is remarkable for the absence of negative symptoms as well as a better premorbid condition. It is also only rarely accompanied by deterioration of a patient’s personality.⁸ 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).”⁸ There is general agreement about the lesser severity and also that better response to therapy can be anticipated in POE.²²

Postictal Psychotic Episodes

In the past, IPE was thought to be the most frequent POE. Since the advent of video-electroencephalogram (V-EEG), however, PIPE have been recognized with increasing frequency, and some investigators are now suggesting that their prevalence is greater than IPE. Furthermore, several studies have now demonstrated that PIPE can progress to chronic IPE ^23,²⁴ (see discussion later in chapter).

Although PIPE are of limited duration and remit following treatment with low doses of antipsychotic drugs or, sometimes, even benzodiazepines, they must nonetheless be taken seriously as they are associated with increased mortality, which results from an elevated incidence of suicide. In addition, PIPE are associated with more severe forms of epilepsy that are often not amenable to surgical treatment (see discussion later in chapter). Postictal psychotic phenomena can present as isolated symptoms or as fully developed psychotic episodes.

POSTICTAL PSYCHOTIC SYMPTOMS

Kanner et al. investigated the prevalence of postictal psychiatric symptoms in 100 consecutive patients with pharmaco-resistant focal epilepsy during a 3-month period.²⁵ The postictal period was defined as the 72 hours that followed recovery from the last seizure. Questions were asked about the frequency of occurrence of each symptom. Only symptoms that were identified after more than 50% of seizures were included in this study to reflect a “habitual” occurrence. To ensure that patients were reporting postictal psychiatric symptoms, each question in the survey also asked about occurrence of the same symptoms during the interictal period. When similar symptoms were identified during both interictal and postictal periods, the only symptoms considered to be postictal were those that were significantly more severe during the postictal period. These were then classified as a postictal exacerbation of interictal psychiatric symptoms. Among the 100 patients, 79 patients had seizures of temporal origin, and 21 had seizures of extratemporal origin. Half of the patients had only complex partial seizures (CPS); the other half had both CPS and generalized tonic-clonic (GTC) seizures. Fifty-two patients had a history of psychiatric conditions: depression, anxiety disorders, and attention deficit disorders. Seven patients experienced postictal psychotic symptoms after more than 50% of their seizures; the duration of the postictal psychotic symptoms, ranged between 1 and 108 hours (median: 15 hours). Such symptoms always occurred together with postictal symptoms of depression and anxiety.

POSTICTAL PSYCHOTIC EPISODES

As mentioned previously, postictal psychiatric symptoms may cluster into PIPE, which correspond to approximately 25% of POE.²⁶ The prevalence of PIPE has been estimated to range between 6 and 10% among patients with pharmaco-resistant epilepsy.^27,²⁸ Since the advent of V-EEG monitoring more than four decades ago, recognition of PIPE has increased substantially. This is not surprising because the circumstances of V-EEG are such that the likelihood of psychiatric symptoms occurring is increased (due, for example, to the facilitation of frequent seizures over a short time period following discontinuation or dose reduction of AEDs). In a 1996 study, the yearly incidence of postictal psychiatric disorders among patients with focal epilepsy undergoing V-EEG was 7.9%.²⁷ The majority (6.4%) presented as PIPE. Among the 10 patients with PIPE, four patients had a delusional psychosis, one patient had a mixed manic depressive–like psychosis, two had psychotic depression, one had a hypomanic-like psychosis, and one had a manic-like psychosis. The tenth patient presented with bizarre behavior associated with a thought disorder. In every case, the onset of symptoms lagged the last seizure by a mean period of 24 hours (range 12 to 72 hours). The mean duration of the PIPE was 69.6 hours (range 24 to 144). In five patients, psychotic episodes remitted with low doses of a neuroleptic drug (2 to 5 mg/day of haloperidol), although one patient required high doses of haloperidol (40 mg/day), and remission occurred in four without pharmacotherapy. Six of the 10 patients had an average of 2.4 PIPE prior to V-EEG, whereas in the remaining four patients, it was the first one. Other authors have reported similar findings with respect to clinical characteristics, course, and response to pharmacotherapy.²⁹^–³⁴ Common findings among the different case series include (1) a symptom-free interval between the last seizure and onset of psychiatric symptoms; (2) a relatively short duration; (even shorter durations were noted among our patients, as only two had episodes lasting more than five days, while this was true in 5 of 9 patients in Savard’s³⁰ and in 7 of 14 patients in Logsdail’s series²⁹; (3) affect-laden symptoms; (4) clustering of symptoms into delusional and affective-like psychosis; (5) increased numbers of secondarily generalized tonic-clonic seizures before the onset of PIPE; (6) onset of PIPE after having had seizures for more than 10 years; and (7) a prompt response to low-dose neuroleptic medication or benzodiazepines.

Kanemoto et al. studied the clinical differences between PIPE and acute and chronic IPE.³³ They noted that patients with PIPE were more likely to experience grandiose and religious delusions in the presence of elevated moods as well as a sense of mystic fusion of the body with the universe. On the other hand, perceptual delusions or commenting voices were less frequent in PIPE, whereas feelings of impending death were common among patients with PIPE.

Various investigators have tried to identify the pathogenic mechanisms of PIPE. For example, Kanner and Ostrovskaya compared 18 consecutive adults with focal seizure disorders and PIPE, and 36 patients with focal epilepsy but without PIPE. Data analysis included the number and location of ictal foci recorded by V-EEG, seizure type, etiology, age at seizure onset, duration of seizure disorder, MRI abnormalities, and psychiatric history before the index V-EEG (other than PIPE).³⁵ Significant differences included the presence of bilateral independent ictal foci on V-EEG (these were identified as an independent predictor of the development of PIPE in univariate and multivariate analyses). The logistic regression model correctly classified 89% of patients. A second independent predictor of PIPE was the occurrence of only secondarily generalized tonic-clonic seizures. Conversely, the occurrence of PIPE and cryptogenic focal epilepsy were predictive of bilateral independent ictal foci in univariate analyses. In a recent study that included 59 consecutive patients with focal epilepsy and a history of PIPE, and 94 controls with focal epilepsy and no history of PIPE, Alper et al. found that predictors of PIPE included ambiguous or extratemporal localization, a family history of psychiatric disorders, abnormal interictal EEGs, and encephalitis.³⁶ Other investigators have also identified bilateral independent interictal³² and ictal³⁴ foci, as well as the presence of secondarily GTC.^29,^30,³⁴

Prompt recognition of PIPE has important clinical implications. First, its recurrence can be minimized by starting an atypical neuroleptic drug at a low dose at the first sign of PIPE (e.g., risperidone 1 to 2 mg). In most cases, insomnia is the initial presenting symptom. Family members need to be informed about early symptoms so that they can assist in the timely administration of the antipsychotic drug. Patients should be maintained on a dose of the drug for 2 to 5 days, after which it can be discontinued.

Patients with a family history of psychiatric symptoms, who have a cluster of secondarily GTC seizures in the course of V-EEG monitoring, and who are found to have bilateral independent ictal foci should be watched carefully for development of PIPE. Symptoms typically become evident between 12 and 72 hours after the last seizure. Occurrence of PIPE has implications with respect to the localization of ictal foci. As suggested by the data cited earlier, development of PIPE should raise the possibility of bilateral independent ictal foci. This is especially important in patients who are being considered for epilepsy surgery. The consequence is that such patients may require longer V-EEG monitoring and, possibly, use of intracranial electrodes. If recordings with depth or subdural electrodes are undertaken, prophylactic treatment with low-dose atypical antipsychotic drugs can avert the occurrence of PIPE during the period of invasive V-EEG monitoring.²⁷

RELATION BETWEEN PIPE AND IPE

There appears to be a bidirectional relationship between PIPE and IPE. For example, in a retrospective study of 18 consecutive adults with focal seizure disorders and PIPE and 36 patients with focal seizure disorders not accompanied by PIPE, Kanner and Ostrovskaya found that seven patients with PIPE and one control patient went on to develop IPE.²⁴ Predictors of developing IPE in univariate logistic regression analyses included a history of PIPE, male gender and having bilateral ictal foci.

Whether preventing further PIPE protects patients from developing IPE has not been established. Such risk, however, supports the recommendation to consider epilepsy surgery whenever possible, even if it is only palliative.²⁴ Remission of IPE and PIPE has been reported after epilepsy surgery in a woman who had had temporal lobe epilepsy since the age of 15 years.³⁷ She developed recurrent PIPE at the age of 35, and this evolved to chronic refractory IPE. Presurgical evaluation demonstrated right hippocampal atrophy and a right mesial temporal epileptogenic focus. Following a right temporal lobe resection, she has been seizure free, and the IPE has remitted.

Although an association between a history of PIPE and development of IPE has been identified in nonsurgical case series,^23,³⁷ this has not been reported in studies of patients who have undergone epilepsy surgery. However, Kanemoto et al. found a significant risk of postsurgical mood disorders in patients with a history of presurgical PIPE.³⁸ Indeed, preoperative occurrence of PIPE was five times more frequent among patients with postoperative mood disorders (38%) than among those without (7%). The relation between mood disorders and PIPE was further established in a study by Alper et al. that found a higher prevalence of mood disorders among first- and second-degree relatives as the only psychiatric variable that predicted the development of PIPE on logistic regression analyses (odds ratio = 3.49, P = 0.001).³⁹

A bidirectional relationship between PIPE into IPE was also reported by Tarulli et al., who conducted a retrospective study of 43 patients with PIPE.²³ Five (13.9%) patients developed IPE after multiple documented PIPE, whereas in one patient IPE preceded PIPE. The length of time between PIPE and IPE ranged from 7 to 96 months. Adachi et al. also reported a bidirectional relationship between IPE and PIPE (which they called “bimodal psychosis”) in a study of 14 patients.⁴⁰ Ten patients who had PIPE went on to develop IPE, whereas four patients who had IPE that remitted later developed PIPE. Mean age at onset of epilepsy was 10.8 ± 4.3 years, at the time of the first IPE 24.4 ± 6.1 years, and at the time of the initial PIPE 33.8 ± 4.5 years. These patients did not differ with respect to the epilepsy-related characteristics found in patients with only PIPE: They had bilateral EEG abnormalities and borderline (or decreased) intellectual function.

In the study by Tarulli et al., the symptomatology of PIPE and IPE was similar or identical in five of six cases, and this was also true in our study. However, differences were found in other studies. For example, Kanemoto et al. compared the clinical semiology among 30 patients with PIPE, 33 patients with acute IPE, and 25 patients with chronic IPE.⁴¹ The most striking feature that distinguished PIPE from both acute interictal and chronic psychoses was “the relatively frequent occurrence of grandiose delusions as well as religious delusions in the setting of markedly elevated moods and feeling of mystic fusion of the body with the universe” in pipe. In addition, patients with PIPE exhibited few schizophreniform psychotic traits such as perceptual delusions or auditory hallucinations. Further studies are needed to clarify this point.

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