Clinical characteristics of forced normalization and alternative psychosis with special consideration of the new anticonvulsants

Abstract

Background. In the case of an alternative psychosis (AP) or forced normalization (FN), the patient alternates between periods of clinically manifest seizures and normal behavior, and other periods of seizure freedom or significant seizure reduction accompanied by psychosis or behavioral disturbances. In clinical practice and in the literature, the terms AP and FN are mostly used synonymously despite small differences. FN of the EEG is not only common to interictal mental disturbances but may also occur in the case of pre-ictal and postictal mental disturbances. Aim. To update the 2007 review on "Alternative Psychoses of Epilepsy" in this journal with special consideration of the new anticonvulsants. Material and Methods. We conducted a literature research from 1987 (in this year a psychosis, triggered by the first "new "anticonvulsant vigabatrin in a patient with epilepsy was reported for the first time) up to September 2019. Discussion. AP/FN are rare events; only 10% of epileptic psychosis are AP/FN. AP/FN respectively occur with both generalized and focal epilepsy; in recent years, patients with focal epilepsy predominate. AP/FN generally present with behavioral disturbances of acute or subacute onset associated with thought disorder, delusions, hallucinations, significant mood change, or anxiety with depersonalization and derealization symptoms. The reports on EEG findings in patients with AP are inconsistent. In the case of FN, the EEG is by definition normal or substantially improved. The most prominent risk factor for the development of an AP/FN is the anticonvulsant medication. The following anticonvulsants have not been observed until now as triggers of an AP/FN in the literature reviewed by us: Acetazolamide and sulthiame ("old" anticonvulsants) and the "new" anticonvulsants brivaracetam, eslicarbazepine, pregabalin, retigabine, rufinamide, stiripentol. The treatment is based on 3 strategies: Reduction or complete cessation of anticonvulsants, change of anticonvulsants and administration of antipsychotic drugs. Conclusion. The risk of an AP/FN is probably different for the individual dugs. At the current level of experience, gabapentin, pregabalin, oxcarbazepine or eslicarbazepine can be the first alternative if an AP/FN was triggered by another anticonvulsant in a patient with focal epilepsy. In generalized epilepsy, especially in patients with absences, valproic acid remains the first alternative.

Forced normalization: case series from a Spanish epilepsy unit

“…We also find a 60 % of patients with focal epilepsies and 20 % with focal/generalized epilepsies. This is the most frequent type of epilepsy according to the data from previous studies [10,11]. We found focal seizures (with or without impaired awareness) were the most frequent (80 % of patients).…”

“…The fact that we did not find any case of forced normalization related to levetiracetam in our series is striking, despite it is the most frequently related antiepileptic drug, probably due to the fact that it is one of the most frequently prescribed antiepileptic drugs, according to Fröscher [10] and Calle-López [11]. Nevertheless, in these reviews forced normalization does not seem to be drug dependent.…”

“…In spite of this, the data available is mainly based in single case reports or small case series, although there are few larger trials published over three decades ago [8,9], which means that a contemporary case series would be of great interest. Two systematic reviews [10,11] have recently been published gathering the cases available in literature.…”

Effects of antiseizure medications on alternative psychosis and strategies for their application

“…This author believes that this was FN caused by VGB. To date, there have been more than 13 patients with FN caused by VGB[ 1 ].…”

“…FN is unique to the pharmacotherapy of epilepsy and often leads to the failure of epilepsy treatment. Although FN is still an entity with uncertain pathophysiology, it has received extensive clinical attention in recent years, and significant progress has been made regarding its pathogenesis and treatment strategies[ 1 - 5 ]. Recently, Calle-López et al [ 5 ] conducted a study on 193 FN episodes and found that the causes included antiseizure medications (ASMs), epilepsy surgery and vagus nerve stimulation (VNS), with ASMs being the most common cause.…”