Interictal Psychosis—A New Reason to Conduct Epilepsy Gene Testing?

Commentary

Although long-standing data indicate psychosis is much more prevalent in epilepsy than in the general population (nearly 8-fold odds compared to controls), ¹ this psychiatric comorbidity has been historically neglected in the epilepsy literature, especially in publications encouraging neurologist action to address psychiatric comorbidities. However, in the past decade-plus, data has been mounting to suggest a potential common underlying pathophysiology of epilepsy and psychosis, including epidemiologic data supporting a bidirectional relation between epilepsy and psychosis, ² and mounting support for a genetic mechanism including a genome-wide association study that estimated 97% of common risk variants for generalized epilepsy were shared with schizophrenia.^3,4

Most of the clinically oriented literature on psychosis of epilepsy has focused on postictal psychosis, with findings suggesting postictal psychosis is more common than interictal psychosis, and emphasizing that postictal psychosis must be recognized by epilepsy clinicians to initiate management and prevention efforts via improved control of seizures and seizure clusters.^5,6 Postictal psychosis is defined as onset of psychosis temporally related to a seizure or cluster of seizures, with psychotic symptoms appearing within 7 days of a seizure or seizure cluster, after a lucid interval of postictal recovery, and lasting from a few days to several weeks. ⁷ Interictal psychosis does not have a specific temporal relationship to seizure occurrence, and ictal psychosis is psychosis as a direct manifestation of seizure. While various publications provide resources for epilepsy clinicians to identify and manage postictal psychosis,^6,8 interictal psychosis is often considered entirely in the realm of psychiatry specialty care, and few clinical resources have been available for epilepsy clinicians on this topic until very recently. ⁹

The availability of clinical tools for identifying and managing interictal psychosis is timely in light of newly published research from 2 groups indicating that interictal psychosis may actually be more common than postictal psychosis, and elucidating risk factors and potentially clinically relevant genetic links between interictal psychosis and single gene causes of epilepsy.^10,11 These publications by Rayner et al and Shen et al add significantly to the literature on psychoses of epilepsy by highlighting Diagnostic and Statistical Manual of Mental Disorders (DSM)-based phenotypes of interictal psychoses, exploring genetic findings in psychoses of epilepsy, and identifying risk factors in a long-term multicenter cohort.

Rayner et al conducted an analysis of psychiatric and genetic characteristics of people with psychosis in epilepsy identified primarily from a large genetics research program database, characterizing psychosis as interictal, postictal, or related to a substance or antiseizure medication. ¹¹ Based on a review of medical charts that mostly contained psychiatric diagnostic assessments characterizing interictal psychoses according to the DSM-5 diagnostic criteria, individuals with interictal psychosis were categorized into DSM-5-based phenotype groups. The associations of psychosis phenotypes with epilepsy type, intellectual disability, presence of rare pathogenic variants in epilepsy-associated genes and schizophrenia-associated polygenic risk scores were evaluated.

Shen et al conducted a retrospective longitudinal cohort study over nearly 20 years among a multicenter epilepsy sample in which care procedures included detailed characterization of psychosis by a psychiatrist utilizing validated instruments, including instruments to quantify positive and negative psychotic symptoms. ¹⁰ Individuals were characterized as having pre-existing psychosis prior to epilepsy onset (pre-epilepsy psychosis), no psychosis, or psychosis of epilepsy divided into 3 main groups: interictal psychosis, postictal psychosis, and ictal psychosis. Clinical factors were analyzed in multivariable models to identify risk factors for each psychosis of epilepsy type.

Key findings across both studies were a notably higher prevalence of interictal psychosis than postictal psychosis (both studies showing nearly 3-fold higher prevalence of interictal psychosis than postictal psychosis), and association of interictal psychosis with earlier age of epilepsy onset compared to postictal psychosis (around 10 years earlier epilepsy onset for interictal psychosis than postictal psychosis, with a similar duration of epilepsy at psychosis onset). Rayner et al demonstrated that while postictal psychosis was found predominantly in individuals with focal epilepsy and normal intellectual capacity, interictal psychosis was present across a broad range of epilepsy types, including generalized epilepsies and developmental and epileptic encephalopathies, and interictal psychosis was often seen with intellectual disability. On the other hand, Shen et al identified temporal lobe epilepsy and hippocampal sclerosis to be risk factors for interictal psychosis (along with family history of schizophrenia, current seizure frequency of at least 1 per month, perampanel use, and taking at least 2 antiseizure medications). Shen et al also demonstrated that those who had pre-epilepsy psychosis had lower likelihood of drug-resistant epilepsy, less frequent and less severe seizures, and more positive symptoms of psychosis including hallucinations and delusions. Among those with interictal psychosis in the Rayner et al study, the most common DSM phenotypes were schizophrenia and schizophreniform disorders, and in these subgroups, nearly a quarter of individuals had a pathogenic variant identified, with the vast majority being in epilepsy genes. Further, schizophrenia-related common risk variants were enriched in the participants with psychosis of epilepsy compared to controls.

Collectively, these findings are interesting, as they may suggest interictal psychosis is more common than previously recognized and that systematic assessment may be beneficial for better identification, especially considering the intriguing link between interictal psychosis and presence of monogenic pathogenic epilepsy variants, especially among those with schizophrenia and schizophreniform phenotypes. The epilepsy distribution in interictal psychosis described by Rayner et al did not demonstrate a predominance of focal epilepsy, and this contrasts with Shen et al's finding that temporal lobe epilepsy was an independent risk factor for interictal psychosis. It is possible that generalized epilepsies, developmental and epileptic encephalopathies and intellectual disability were overrepresented in the Rayner et al study due to sampling bias since the sample was largely drawn from a genetics research database. Further research in less biased samples with systematic assessment would be beneficial to further clarify the associations and further investigate the relative prevalence of interictal and postictal psychosis. Despite the limitations, the findings in both studies support a genetic association of interictal psychosis and epilepsy which merits further mechanistic investigation. It is possible that additional research will provide mechanistic insights that may have treatment implications.

While further research is needed, the important investigations by Rayner et al and Shen et al do have potential immediate implications for clinical practice. It is prudent for clinicians to be on the lookout for interictal psychosis, especially delusions and auditory or visual hallucinations, across the full spectrum of patients with epilepsy, and perhaps especially among those with intellectual disability. It may be beneficial to collect family psychiatric history and ask specifically about schizophrenia, and to have enhanced awareness that individuals with epilepsy onset in childhood, teen years, or very early adulthood may be more at risk for interictal psychosis than those with later epilepsy onset. For patients in whom psychosis has already been identified, distinguishing whether psychosis onset was prior to epilepsy or whether a psychosis of epilepsy is present may have prognostic significance for seizure control, with pre-epilepsy psychosis being associated with less severe epilepsy, and interictal psychosis of epilepsy meriting further phenotyping and perhaps genetic testing for epilepsy pathogenic variants, especially if psychosis fits a schizophrenia or schizophreniform phenotype. These new clinical insights also highlight the importance of collaboration with mental health specialists, not only for management of interictal psychosis, but also to characterize psychosis given the potential clinical/genetic implications for epilepsy.