Forced normalization: A systematic review

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.