Forced normalization: A systematic review

Abstract

Objective Forced normalization (FN) is an intriguing phenomenon characterized by the emergence of psychiatric disturbances following the establishment of seizure control or reduction in the epileptic activity in a patient with previous uncontrolled epilepsy. We aim to describe the clinical characteristics of the condition. Methods We conducted a systematic review on MEDLINE, EMBASE, Cochrane, and Scielo from January 1953 to January 2018. Clinical, electrographic, and imaging data were gathered. We considered all outcomes in children and adults. We performed no meta‐analyses due to the limited available data. Results Of 2606 abstracts identified, 36 fulfilled the FN diagnostic criteria; 193 FN episodes were evaluated and 77 of them were analyzed extensively. Sixty percent of cases were female. Mean age ± standard deviation (SD) was 28.3 ± 14.2 years. The majority of patients had focal (80%) symptomatic (44%) epilepsy. Most patients reported a high ictal frequency (58%) and were on polytherapy (51%). Patients presented psychosis (86.4%), mood disorders (25.8%), and dissociation (4.5%) as the main manifestations. In the psychosis group, persecutory (52.6%) and reference (47.3%) delusions were frequent. FN was provoked by an antiepileptic drug (AED) (48.5%) mainly levetiracetam, epilepsy surgery (31.8%), or vagus nerve stimulation (13.6%). Treatment was homogeneous including anticonvulsant withdrawal (47%) or taper (25%); antipsychotics were initiated in the majority of cases (73%). Psychiatric symptoms were partially controlled in 35%, with complete resolution of symptoms in the remaining 65% of cases. The majority of patients (87%) with AED trigger and withdrawal presented complete resolution of symptoms in comparison to 28.5% of patients triggered by surgery. Significance Forced normalization is an entity whose pathophysiology remains uncertain. Antipsychotic drug use does not predict complete resolution of psychiatric symptoms in comparison with AED withdrawal. Although there is a positive response to treatment in patients with FN triggered by drugs, the prognosis is obscure in patients with surgery triggered FN.

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

“…Risk factors for the development of drug-induced AP/FN include a long-lasting focal epilepsy with phar-macoresistance, a history of status epilepticus, psychosis, psychiatric disturbances, mental retardation and unfavourable psychosocial factors (Fröscher and Steinert, 2001;Majkowski, 2005). FN/AP seem to be more frequent in patients with temporal lobe epilepsy (Calle-López et al, 2019). The most prominent risk factor is probably the anticonvulsant medication.…”

“…An association of AP/FN with gender was not confirmed in the older literature (Schmitz and Trimble, 2005); however, two recent reviews report a higher incidence in women (Calle-López et al, 2019;Fröscher and Steinert, 2019). In the cases reported by Fröscher and Steinert (2019), women were affected more than twice as often as men; as a cause of this gender discrepancy a higher dose of anticonvulsants on average per body weight has been considered.…”

“…In earlier studies on psychoses with epilepsy there was a significant correlation between generalized idiopathic epilepsies and psychoses with FN as a consequence of the high risk associated with a treatment with ethosuximide (Wolf, 1991). In recent years, more patients with a focal, particularly a temporal lobe focus, have been observed with the development of alternative psychiatric disturbances (Calle-López et al, 2019;Fröscher and Steinert, 2019;Krishnamoorthy and Trimble, 1999). In the review of Fröscher and Steinert (2019), 47 out of 60 patients had a focal epilepsy (41 focal, 6 focal and generalized).…”

“…In the study of Calle-López et al (2019), the triggering anticonvulsants were (with decreasing frequency): Levetiracetam, vigabatrin, carbamazepine, lamotrigine, ethosuximide, lacosamide, valproic acid and once topiramate and phenytoin. The cases reported in this study partly correspond to the cases of our review.…”

“…The cases reported in this study partly correspond to the cases of our review. Other than in our review (Fröscher and Steinert, 2019), Calle-López et al (2019) included cases reported since 1953 (the year of the first publication on FN by Landolt (1953); however, only papers were included that fulfilled the FN criteria established much later by Krishnamoorthy and Trimble (1999). As a result, pre-1999 publications are probably under-represented.…”