Forced Normalization Revisited: New Concepts About a Paradoxical Phenomenon

The phenomenon of Forced Normalization (FN) was first described by Landolt in 1953, who described the disappearance of epileptiform discharges in the EEG of patients with epilepsy, concomitant with the development of psychotic symptoms. Later, Tellenbach coined the term “alternative psychosis” referring specifically to the alternation between clinical phenomena. Finally, in 1991, Wolf observed a degenerative process involved in the phenomenon, which he called “paradoxical normalization.” Initially, FN was explained through experimental models in animals and the demonstration of the kindling phenomenon, in its electrical and pharmacological subdivisions. At this stage of research on the epileptic phenomenon, repetitive electrical stimuli applied to susceptible regions of the brain (hippocampus and amygdala) were considered to explain the pathophysiological basis of temporal lobe epileptogenesis. Likewise, through pharmacological manipulation, especially of dopaminergic circuits, psychiatric comorbidities began to find their basic mechanisms. With the development of new imaging techniques (EEG/fMRI), studies in the area started to focus on the functional connectivity (FC) of different brain regions with specific neuronal networks, which govern emotions. Thus, a series of evidence was produced relating the occurrence of epileptic discharges in the limbic system and their consequent coactivation and deactivation of these resting-state networks. However, there are still many controversies regarding the basic mechanisms of network alterations related to emotional control, which will need to be studied with a more homogeneous methodology, in order to try to explain this interesting neuropsychiatric phenomenon with greater accuracy.

Epilepsy and psychosis

This chapter reviews the important place that epilepsy has had in developing concepts of psychosis in general and for understanding some of the basic biological issues of schizophrenia and bipolar disorder. It starts out by offering a historical introduction noting important observations stemming from the nineteenth century. It reviews the complexity of classification in this area, highlighting in particular problems with Diagnostic and Statistical Manual, 5th edition (DSM-5). Epidemiology is followed by brief discussions of the relationship between seizures and psychosis, commenting on some paradoxes revealing why postictal psychoses are underdiagnosed, and the pitfalls of missing forced normalization, a concept that relates to the worsening of behavior with the cessation of seizures in people with intractable epilepsy. Finally, the chapter provides some guides to management of patients with epilepsy who have comorbid psychiatric disorders.

Mental disorders in children with intractable epilepsy as a manifestation of forced normalization of the electroencephalogram (Landolt syndrome)

The forced normalization of the electroencephalogram (Landolt syndrome) is a rapid normalization of the electroencephalogram (decrease in or disappearance of paroxysmal activity) under the influence of anticonvulsant treatment of epilepsy patients, corresponding to a decrease in frequency or complete disappearance of seizures with the appearance of neuropsychiatric disorders (dysphorias, the syndrome of hyperactivity and attention deficit, mysophobia etc). The authors present a review of the literature on the Landolt syndrome, and own data.

Treatment of psychoses in patients with epilepsy: an update

Psychotic disorders represent a relatively rare but serious comorbidity in epilepsy. Current epidemiological studies are showing a point prevalence of 5.6% in unselected samples of people with epilepsy going up to 7% in patients with temporal lobe epilepsy, with a pooled odds ratio of 7.8 as compared with the general population. This is a narrative review of the most recent updates in the management of psychotic disorders in epilepsy, taking into account the clinical scenarios where psychotic symptoms occur in epilepsy, interactions with antiepileptic drugs (AEDs) and the risk of seizures with antipsychotics. Psychotic symptoms in epilepsy can arise in a number of different clinical scenarios from peri-ictal symptoms, to chronic interictal psychoses, comorbid schizophrenia and related disorders to the so-called forced normalization phenomenon. Data on the treatment of psychotic disorders in epilepsy are still limited and the management of these problems is still based on individual clinical experience. For this reason, guidelines of treatment outside epilepsy should be adopted taking into account epilepsy-related issues including interactions with AEDs and seizure risk. Second-generation antipsychotics, especially risperidone, can represent a reasonable first-line option because of the low propensity for drug–drug interactions and the low risk of seizures. Quetiapine is burdened by a clinically significant pharmacokinetic interaction with enzyme-inducing drugs leading to undetectable levels of the antipsychotic, even for dosages up to 700 mg per day.