A Case of Psychosis in Epilepsy: Forced Normalization?

Case Vignette

“Mark” is a 36-year-old man with a past medical history of left-sided, focal epilepsy with hippocampal sclerosis that was diagnosed when he was aged 21 years. Mark then underwent temporal lobectomy with amygdalohippocampectomy aged 24 years. Since these surgeries, he has been seizure-free and doing well. However, for the past 3 months, he has been increasingly preoccupied with his cousins and worries that they are spying on him. Mark has been looking out of his windows throughout the day and is convinced that his phone is tapped. As time goes on, he believes that his spying cousins have a “vibration machine” and are sending vibrations to his body day and night. He has stopped showering because he thinks that the cousins are watching him with cameras. He is afraid to eat because he says things “taste poisoned.” His mother asked the important question: “Is this forced normalization?”

Forced Normalization

Psychosis and epilepsy have a controversial and convoluted history. Forced normalization was initially described by Hans Heinrich Landolt in 1953 as the disappearance of epileptic discharges and the subsequent development of psychosis.¹ The concept was based on the work of Laszlo Von Meduna, who hypothesized an antagonism between epileptic discharges and dopamine.² Von Meduna’s hypothesis led to his work with convulsive therapy (a predecessor of today’s electroconvulsive therapy) for the treatment of acute psychosis.¹

Landolt later clarified his diagnosis, specifying that forced normalization was an acute or subacute behavioral change after a week without clonic seizures or with a marked reduction in epileptic activity.¹ Yamile Calle-Lopez expanded on this and described an association with forced normalization and antiepileptics and/or surgery.¹ Ethosuximide has historically been associated with forced normalization, with literature estimating that 2% of children and 8% of adults taking ethosuximide develop psychosis.³ Interestingly, the literature indicates cessation of psychosis with the termination of ethosuximide and the resumption of seizures.⁴ Some hypothesize that the blockade of ethosuximide on the T-type calcium channels leads to forced normalization.⁴ However, other antiepileptics, including lacosamide, lamotrigine, levetiracetam, phenobarbital, vigabatrin, and zonisamide, have been associated with forced normalization.⁴ Vagal nerve stimulation and epilepsy surgery have also been associated with psychosis.¹

Aura, Ictal, Postictal, and Interictal Psychosis

Epidemiological data appear to disagree with the supposition of an antithetical relationship between psychosis and epilepsy. Psychosis occurs in 2% to 7% of patients with epilepsy, compared to the lifetime prevalence of 3% in the general population.⁵ This prevalence increases in patients with temporal lobe epilepsy, where the prevalence is between 10 and 15%.⁵ Data also indicate a 2.5 times greater incidence of psychosis in the epileptic population compared with the general population.⁶ Patients with a family history of psychosis or epilepsy appear to be at higher risk for psychotic symptoms.⁶ In addition, the evidence suggests that left temporal lobe epilepsy, history of status epilepticus, and hippocampal sclerosis also pose risk factors for psychotic symptoms.⁵

The literature hypothesizes that psychosis is related to decreases in prefrontal cortical dopamine and increases in mesolimbic dopamine.⁵ Interestingly, in both epilepsy and psychosis, individuals develop changes in dopamine binding on D2 and D3 receptors, disinhibiting thalamocortical circuits and leading to both psychotic and epileptic presentations.⁵ In addition, D1 receptor agonism appears to be associated with lowering the seizure threshold.⁵ Stimulation of N-methyl-D-aspartate (NMDA) receptors and excitation of the neurons also appears to be a shared pathway of both psychosis and epilepsy.⁵ Mesial dysplasia and hippocampal sclerosis appeared to be a shared pathological finding as well.⁷ Differences in the onset of timing (often psychosis following epilepsy) are thought to be related to remodeling axonal networks.⁷

Current investigators classify psychosis with epilepsy into different categories depending on the temporal relationship of the psychosis to the ictal event.⁵ The types of psychosis are described as aura, ictal psychosis, postictal, and interictal.⁵ Ictal psychosis is difficult to quantify or describe, given the brief period of seizure and the limited history of the patient. Typically, ictal psychosis occurs as the seizure is ending and results in bizarre behaviors and disorientation.⁵ A short course of psychosis with symptoms of delusions, hallucinations, and psychomotor agitation may be a clinical symptom of nonconvulsive status epilepticus.⁸ Postictal psychosis occurs hours to days after an epileptic event and lasts days to weeks.⁹ Typically, symptoms are positive in nature—consisting of hallucinations, delusions, and affective disruption.⁹ Postictal psychosis also appears to have higher proportions of visual hallucinations and grandiose or religious delusions.⁸

The dark horse diagnostically is interictal psychosis. Interictal psychosis is defined as psychosis occurring between seizure episodes that may evolve into a chronic psychotic presentation.⁵ The literature indicates this is associated with complex partial seizures, bitemporal seizure foci, and clustering of multiple seizures.⁹ There need not be a temporal relationship to seizures (unlike postictal psychosis), and interictal psychosis eventually may appear remarkably like a primary psychotic condition such as schizophrenia.^5,9 However, unlike schizophrenia, there appears to be a predominance of positive symptoms and less affective degeneration.⁸ “Schizophrenia-like psychosis,” coined by Slater et al, describes interictal psychosis with an intense paranoia.¹⁰ Interictal, similar to postictal psychosis, tends to consist of positive symptoms of hallucinations and delusions.⁵ The literature describes symptoms of delusions of paranoia, religious preoccupations, and visual hallucinations.⁸ The predominantly positive symptomatology and the age of onset are a few ways to differentiate this disorder from schizophrenia. However, the treatment remains the same, and patients appear to respond to antipsychotics, though the data are limited.⁸ See the Table for more information.

It is also worth mentioning that preictal or aura psychotic symptoms such as delusions of paranoia or auditory, olfactory, and somatosensory hallucinations may occur.¹⁰ These are limited to hours to days before the epileptic event and resolve once the seizure begins.¹¹ Interestingly, patients do retain some insight during these episodes and can demonstrate an improvement in symptoms following the ictal event.

Treatment for psychosis in epilepsy involves both management of the seizure activity and the psychotic symptoms. For ictal and postictal psychosis, managing seizures is essential. For interictal psychosis, patients may need antipsychotics (although the data are limited regarding efficacy) and a thorough review of iatrogenic causes of psychosis. While there is concern for lowering the seizure threshold with antipsychotics, careful monitoring and comanagement between psychiatry and neurology can mitigate risk.¹²

Case Concluded

Mark was placed on olanzapine, which was eventually titrated to 20 mg at bedtime. He began to report a decrease in tactile hallucinations and made statements such as, “I think I overthought about my cousins spying.” In addition, he had improved sleep and appetite, and began showering. A year after the remission of his psychotic symptoms, while considering a decrease in olanzapine, Mark had a sudden and unexpected tonic-clonic seizure.

Concluding Thoughts

The relationship between psychosis and epilepsy truly remains unclear. Is forced normalization a genuine condition? Or is it simply interictal psychosis by another name? While there may be pathological differences between interictal psychosis and schizophrenia, does it affect treatment and patient care? Finally, how do we safely treat psychosis while being mindful of a patient’s history of seizures? These controversies speak to the need for collaborative and holistic care for complex patients, including dual management by neurology and psychiatry.

Dr Shapiro-Krew is the director of epilepsy psychiatry at Cleveland Clinic's Neurological Institute.

References

1. Bragatti JA. Forced normalization revisited: new concepts about a paradoxical phenomenon. Front Integr Neurosci. 2021;15:736248.

2. Trimble MR. The Psychoses of Epilepsy. Raven Press; 1991.

3. Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia. 1999;40(suppl 10):S65-S70.

4. Apap Mangion S, Rugg-Gunn F. Development of forced normalisation psychosis with ethosuximide. BMJ Case Rep. 2017;2017:bcr2017220838.

5. Maguire M, Singh J, Marson A. Epilepsy and psychosis: a practical approach. Pract Neurol. 2018;18(2):106-114.

6. Qin P, Xu H, Laursen TM, et al. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ. 2005;331(7507):23.

7. Briellmann RS, Kalnins RM, Hopwood MJ, et al. TLE patients with postictal psychosis: mesial dysplasia and anterior hippocampal preservation. Neurology. 2000;55(7):1027-1030.

8. Adachi N, Akanuma N. Delusions and hallucinations. In: Mula M, ed. Neuropsychiatric Symptoms of Epilepsy. Springer International Publishing; 2016.

9. Tarulli A, Devinsky O, Alper K. Progression of postictal to interictal psychosis. Epilepsia. 2001;42(11):1468-1471.

10. Slater E, Beard AW, Glithero E. The schizophrenia-like psychoses of epilepsy: I. psychiatric aspects. Br J Psychiatry. 1963;109(458):95-112.

11. Mingot CG, Villar MG, Medel DC, et al. Epileptic peri-ictal psychosis, a reversible cause of psychosis. Neurología. 2013;28(2):81-87.

12. Ettinger AB, Kanner AM. Psychiatric Issues in Epilepsy: A Practical Guide to Diagnosis and Treatment. Lippincott Williams & Wilkins; 2001.