Clinical manifestations

Presentation and course

The epileptic patient who presents with a psychotic disorder is evaluated by focusing on the relationship of the psychiatric disorder to the onset of seizure activity. The appropriateness of surgical treatment of refractory epilepsy in the presence of a psychosis of epilepsy has also been controversial and will be discussed.

Preictal. Psychiatric symptoms noted prior to seizure onset have been noted in 9 out of 143 patients by Mula and colleagues and in 22 out of 27 patients in a study by Blanchet and Frommer (01; 27). Patients often note a change in mood state that crescendos to an ictal event. These symptoms may result from a simple partial seizure with secondary generalization.

Ictal psychosis. Ictal psychosis represents 10% of all psychoses in people with epilepsy (33). Ictal psychiatric symptoms often involve fear (60%) or mood complaints (15%) (15). Both symptoms are characteristically brief and stereotyped, which allows distinction from idiopathic psychiatric disorders. More infrequently, psychiatric manifestations may be the most prominent feature of nonconvulsive status epilepticus. They may include affective, autonomic, and psychic phenomena (31). Patients may be alert and functional with mild alterations of consciousness. Visual and auditory hallucinations can also be found in patients with epilepsy experiencing simple partial status but are often recognizable by the patient as not real (15). The major focus of epileptic discharge appears to be in the limbic and temporal lobes but may be extratemporal in 30% (31). Aura continua can also be found in people with epilepsy and simple partial status epilepticus, with symptoms lasting for hours to days (15).

Postictal psychosis (PIP). Postictal psychosis represents 25% to 50% of all psychoses in people with epilepsy (33). The postictal period has 2 phases. The first is the immediate phase occurring minutes to several hours after an event. It is characterized by postictal confusion or delirium. The second often takes place after a quiescent interval. Symptoms often materialize after a flurry of seizure activity. Although not essential characteristic of postictal psychosis, a lucid period from the termination of seizure activity to psychiatric symptoms usually occurs and is the differentiating factor from postictal confusion. Postictal psychosis can manifest as delusions, hallucinations, and/or hypomania with clear consciousness. Aggression, if it occurs as a result of a seizure, often appears in the postictal period. If directed violence instigated by seizure activity occurs, it is usually postictal and appears in up to 22.8% of postictal psychosis patients; this is in contrast to 4.8% in the interictal phase and 0.7% with postictal confusion (14).

Rates of postictal psychosis vary from 1.7% to 3.8%, depending on the population being evaluated. In tertiary care monitoring units the frequency has been documented from 6.4% to 10% (31). Abnormal mood and delusions are common with grandiosity and religiosity, and command hallucinations may be present and result in violence. The level of consciousness may vary. Psychotic symptoms may remit in days or weeks but sometimes evolve into a chronic interictal psychosis after repeated episodes of postictal psychosis with decreasing symptom free periods (33). Resolution of symptoms is often by 1 month. Predisposing factors include partial complex seizures with secondary generalization, epilepsy of more than 10 years duration, and the increasing severity of the epilepsy. In addition, frequent bitemporal disease and structural lesions like hamartomas and gangliogliomas and resistant mesial temporal sclerosis of left hemisphere origin may be associative factors (23).

Interictal psychosis. Interictal psychosis is often termed schizophrenia-like psychosis of epilepsy and represents approximately 20% of psychoses in people with epilepsy (33). Interictal psychosis refers to psychotic symptoms that happen without an apparent relationship to seizure activity and are often severe and long-lasting. Debate has always occurred regarding the difference between idiopathic schizophrenia and the schizophrenic-like disorder of epilepsy. This issue was reviewed by Kanner and Barry in 2001 (16). The risk factors for interictal psychosis are similar to those in postictal psychosis with the addition of a history of status epilepticus. Slater and colleagues were the first to describe this phenomenon (34). The similarities between the 2 disorders, interictal psychosis and idiopathic schizophrenia, were noted, and interictal psychosis featured a preservation of affect (warm schizophrenics) coupled with increased frequency of Schneiderian first- rank symptoms. This is in contrast with studies completed by Matsuura and Trimble who reviewed the Japanese literature on people with epilepsy and noted several studies where interictal psychosis was almost identical to schizophrenia (25). Mendez and colleagues had similar findings, but some studies noted differences (07). It has been proposed that interictal psychosis may present as a subcategory of schizophrenia (ie, psychosis associated with AEDs), or an alternative psychosis may be differentiated from nuclear schizophrenia (16). Others have observed the lack of negative symptoms and catatonic states in interictal psychosis and the improved response to medication (32). Many authors have noted the progression of postictal psychosis evolving into an interictal psychosis (12). The outcome of interictal psychosis may be similar to those with schizophrenia, with 64% having a chronic course (08).

Forced normalization. As noted previously, it was originally thought that there was an antagonism between epilepsy and psychosis. This concept was the driving force behind the development of electroconvulsive therapy (ECT). However, it was incorrect. In the 1950s, Landolt observed that symptoms of psychosis emerged with control of seizure activity and resolved with the reappearance of epileptic symptoms. This was termed alternative psychosis. From a clinical standpoint this phenomenon is uncommon but may represent up to 10% of psychosis in people with epilepsy (33). It is important to note that forced normalization may manifest as depression, irritability, and/or with conversion symptoms and usually occurs in patients with a long history of epilepsy. In addition, the role of AEDs has also been questioned as a potential etiology. Thus, medications like vigabatrin, topiramate, and levetiracetam may have an increased risk of developing an episode of forced normalization with psychotic symptoms (12).

Issues concerning epilepsy surgery and psychosis of epilepsy. One contentious topic that frequently arises clinically is whether the presence of preoperative psychosis in people with epilepsy is a contraindication to temporal lobectomy. The primary argument used against surgery in patients with psychosis is that seizure freedom rates are lower after surgery. One prospective cohort trial with 434 patients found that psychosis was a strong predictor of unfavorable seizure outcome, with only 16.7% achieving Engel 1A status versus 61.6% without a psychiatric disorder (20). New psychiatric disturbances can also occur following the procedure. For example, 1 study found that mental illness was a risk factor for anxiety, depression, and psychosis after surgery (10). In another study of 57 patients, 3.8% developed a new and 1.8% a probable new psychotic illness after surgery (22).

On the other hand, there are groups that argue that seizure freedom is unrelated to presurgical psychosis. For example, a publication professed that psychotic and nonpsychotic patients benefitted from the surgery (10). The authors concluded that preoperative psychosis was not a contraindication for epilepsy surgery, and in fact, this surgical group actually experienced greater benefit from the intervention. Similarly, another trial with 20 psychotic patients demonstrated that lobectomy had no significant effect on preoperative psychosis and concluded that it should not be a contraindication for surgery (11). Additionally, a prospective cohort study with 189 patients, 33 of whom presented with an epilepsy related psychosis, documented a reduction of psychotic symptoms from 17.5% to 4.2% following surgery. Interictal psychosis decreased from 5.3% to 0.5%. However, there were 4 new cases of interictal psychosis after surgery, underscoring the need for close psychiatric follow-up (02). Finally, in a review of 89 patients admitted for epilepsy surgery who were followed for 2 years, there were 14 patients presenting with psychoses. Only 3 had transient controllable psychotic symptoms after surgery, with 71% achieving an Engel class 1 to 2 status (D'Alessio et al 2014).

The power of temporal resective surgery for a select group of people with epilepsy with refractory disease has been well documented. Most groups recommend close psychiatric support immediately after the procedure to reduce the development or worsening of psychiatric conditions for the reasons noted previously. Koch-Stoecker and colleagues have proposed a 3-phase approach to treatment of psychiatric comorbidities postsurgically (19). Given the potential benefit of seizure control, evidence for improvement of psychiatric conditions, and the ability to reduce complications with close follow-up, the best solution is to remove psychiatric comorbidities as a contraindication for temporal lobectomy.

Clinical vignette

MR was a 30-year-old female who developed epilepsy as a young child after a prolonged episode of a febrile convulsion. MRs first seizure was at 2 years of age, and the semiology of the event consisted of a complex partial seizure with secondary generalization. MR also had a history of status epilepticus. MR was hospitalized after experiencing a flurry of seizure activity. She subsequently had phenytoin added to a regimen of lacosamide, carbamazepine, Lamictal, and Valium on a PRN basis. MR was discharged asymptomatic but subsequently returned to the emergency room 72 hours later after developing severe affective lability coupled with auditory and visual hallucinations. In the ER, the patient was treated with 1 mg of risperidone with some moderate response. The ER staff was concerned about lowering the seizure threshold with too much risperidone, and the patient was admitted to the neurology unit. In the middle of the night, MRs psychological state deteriorated; she became agitated, aggressive, and self-injurious, responding to command hallucination to kill herself. MR was treated with intravenous Haldol, and after becoming more controllable, risperidone was reintroduced but at a dosage of 6 mg/day, and a good clinical response was obtained. The event lasted a total of 9 days. Over the course of the next 3 years, seizures continued, and repeated episodes of postictal psychosis ensued with each episode lasting longer. Eventually, psychotic symptoms were continuous, requiring antipsychotic medication on an ongoing basis. Finally, MR was evaluated for surgery, a right anterior temporal lobe focus was found, and mesial temporal sclerosis was noted on an MRI. A discussion concerning the sagacity of an anterior temporal lobectomy in a patient with interictal psychosis was discussed. It was decided to proceed, and the patient underwent surgery with complete resolution of seizure activity. Her psychotic disorder was unchanged but was well controlled with medication.

Biological basis

Etiology and pathogenesis

Pathophysiology. The etiology of psychosis of epilepsy is multifactorial. Medication represents 1 of the most important causes of psychosis of epilepsy. AED-induced psychotic disorders were evaluated by Chen and colleagues (04). In a review of 2630 people with epilepsy, 98 had psychotic disorders, and 14 (14.3%) were diagnosed with AED-induced psychosis. Three factors were found to be pivotal: female gender, temporal lobe involvement, and current use of levetiracetam with a negative correlation with the use of carbamazepine (04). Levetiracetam-induced psychosis has also been observed in children as well (21). In a Cochrane report, it was noted that almost all AEDs have been implicated to some extent (08).

Other possible pathophysiological mechanisms include kindling, abnormal regeneration, and mis-wiring of mossy fibers from hippocampal structures associated with mesial temporal sclerosis, cortical dysgenesis, and diffuse brain damage. Similarities in the pathogenesis of schizophrenia and interictal psychosis of epilepsy have been postulated (16). Other contributing etiologies have also been proposed, including autoimmunity in 10% of refractory epilepsy patients often with psychiatric symptoms, usually psychosis. These autoantibodies may be directed against synaptic neurotransmitter receptors like N-Methyl-D-aspartate for example (29).

A unifying theory has been postulated by Sachdev whereby inhibitory excess in limbic structures follows seizure activity and determines whether alternating or postictal psychosis ensues (31). In addition, it appears that most patients who develop a psychosis associated with epilepsy do so after many years of seizure activity. It is hypothesized that modifications of the nervous system result in the development of a proclivity to psychosis. Kanner noted that the progressive development of bilateral ictal foci followed by the appearance of postictal psychosis may be an illustrative example of this progression (12; 15). In addition, semicontinuous and continuous ictal activity in limbic structures may also be associated with the development of psychosis (06). Butler and colleagues have also reviewed the results of PET scan studies, noting frontal hypoactivity and intermittent medial temporal hyperactivity as important in the evolution of psychosis in patients with and without epilepsy (03).

Differential diagnosis

The approach to a patient with a new onset of psychosis is complex. One method is to review all possibilities using the following mnemonic: I watch death, where I infectious (including limbic encephalitis, meningitis, etc.); W withdrawal; A acute metabolic states (electrolyte imbalance, etc.); T trauma; C CNS (strokes, tumor, etc.); H hypoxia; D deficiencies; E endocrinopathies; A acute vascular; T-toxins (substances, anticholinergics, etc.); H heavy metals (35). An excellent review with a recommended stepwise management paradigm has been published by Maguire and colleagues (24).

If the patient has a history of epilepsy and the aforementioned investigation is negative, then the development of psychosis may be related to the epileptic disorder itself. In that case, an initial investigation of medicationsthose that are new, increased in amount, or abruptly discontinuedshould be reviewed. Almost all AEDs have been implicated (08). Next, the association to seizure activity should be investigated; it should be determined if the psychotic complaints are ictal (subclinical status), postictal with the features noted previously, or interictal. Once a diagnosis is made, treatment can begin.

Management

Ictal hallucinations are treated by controlling seizure activity with an increase or change in AEDs. Postictal psychosis is treated by the use of benzodiazepines if the complaints are mild and especially if reality testing is maintained. If there is any question about safety, presence of command hallucinations, or suicidal or homicidal ideation, then antipsychotics are utilized. Very rarely, electroconvulsive therapy can also be utilized if symptoms are florid, acute, and nonresponsive to treatment. The use of antipsychotics in people with epilepsy and psychosis has been associated with a concern of decreasing the seizure threshold. This issue has been reviewed by several authors (06; 19; 26). All antipsychotics decrease the seizure threshold to some extent. Mild epileptogenic potential has been postulated for second generation antipsychotics (SGAP), but proconvulsant activity is low (from 0.3% for risperidone to 0.9% for olanzapine and quetiapine). Clozapine has the highest induction potential and appears to be dose dependent (1% with doses less than 300 mg/day to 2.7% with dosages 300 to 600 mg and 4.4% greater than 600 mg). However, in a study by Pacia and Devinsky involving 5629 patients, lower rates (1.3%) were found and without a dose effect (28). In general, fears of seizure induction appear to be exaggerated and certainly should not preclude or modulate their use in this clinical emergency. For patients with a brief episode of psychosis, rapid reconstitution treatment may be short, but for those with symptom remission taking more than 5 days, 1 to 2 months of treatment is recommended. A slow taper of medication can then take place. For those patients where a preictal warning is evident or frequent episodes of postictal psychosis occur, acute or chronic therapy may be useful. Those patients with an interictal psychosis disorder should be treated in a similar fashion to those with schizophrenia (18). Surgical interventions can be entertained for those patients with refractory epilepsy and psychosis who are felt to have a focus amenable to surgical intervention. As noted above, electroconvulsive therapy may also be useful (08). A review by Rossi and colleagues found that an admission for epilepsy has been associated with a subsequent readmission for a psychotic episode (30).

Outcomes

The outcome depends on the clinical situation. Ictal psychosis responds well to modulation of seizure activity, as do alternative and postictal psychosis. Generally, response to benzodiazepines and SGAP is good and should be the mainstays of intervention; however, a chronic course may be expected in 61% (16).