Abstract
A 15-year-old boy diagnosed with undifferentiated schizophrenia was treated with clozapine 350 mg/day and clomipramine 225 mg/day because of antipsychotic treatment resistance and persistent obsessive-compulsive symptoms. The clinical picture the parents consulted for initially was characterized by a subjective experience of corporal change and visual perceptual disturbances especially referred to the patient's skin (perception of dark spots appearing and color changes), associated with repetitive body checking behavior. These were followed by self-referentiality, hypochondriac worries, contamination fears, and a frequent need to spit. Increasingly frequent thought blocks and marked impoverishment of speech content then took place within a few months. Concurrently, his parents observed a clear progressive decline of academic performance. Initial medical workup, including electroencelphalogram (EEG) monitoring, revealed no abnormalities. Basal magnetic resonance imaging (MRI) examination showed moderately enlarged lateral ventricles and a single unspecific T2-weighted left cerebellar hyperintensity without apparent cortical atrophy or signs suggestive of hydrocephalus. The patient had no familial or personal history of epilepsy.
Three years after the introduction of combined pharmacotherapy, his family noted the onset of involuntary paroxysmal perioral movements, such as raising the lower lip, and facial tic-like movements. These were closely followed by sudden myoclonic jerks of the upper limbs, mostly triggered by action (e.g., grabbing game console pad), resulting in his dropping of objects. Myoclonic jerks were not associated with any particular circadian pattern or precipitated by sleep deprivation or fatigue. Along with these abnormal movements, the patient developed dysfluent speech characterized by stutter-like repetitions of syllables and transient accelerations of speech rate. Dystonic movements were absent on examination. Drug-induced tardive diskynesia was initially suspected and vitamin E was introduced without significant improvement. The motor symptoms persisted for a period of 5 months, after which he suffered a GTC seizure witnessed by his mother. Despite lowering the dose of clozapine to 300 mg/day, he suffered another GTC seizure soon afterward. No absence seizures were reported at any time. Total plasma level of clomipramine plus desmethylclomipramine was 283 ng/mL. A second MRI scan was unchanged from the previous examination. Scalp EEG at that time showed diffuse background slowing and frequent generalized and multifocal paroxysmal epileptiform discharges (spikes, polyspikes, and spike-and-wave complexes) without clinical correlates during monitoring. No EEG changes were observed during hyperventilation and intermittent photic stimulation. All motor symptoms were attributed to epileptic activity, and dyskinesia was thus ruled out. Valproic acid up to 500 mg/day was then initiated, achieving complete remission of the motor and speech disorders within days. The patient has remained seizure-free ever since then for over 2 years.
This report supplements previous evidence linking clozapine-induced stuttering to epileptic brain activity. Clinical observations in epileptic patients have suggested that at least some forms of acquired stuttering can be related to epileptic activity originating in brain areas that subserve linguistic functions (Michel et al. 2004). In addition, stuttering of possible epileptic origin, with or without concomitant myoclonic jerks, facial tic-like movements, or other speech disturbances, has been described in adult schizophrenic patients treated with clozapine, in some cases prior to GTC seizures (Thomas et al. 1994; Ebeling et al. 1997; Supprian et al. 1999; Duggal et al. 2002; Bär et al. 2004; Begum 2005; Krishnakanth et al. 2008).
Several features of the current case support the existence of a drug-induced encephalopathy with epileptic seizures, such as EEG findings consistent with a diffuse encephalopathy with epileptiform discharges and a previous normal EEG. Moreover, idiopathic generalized epilepsy was considered improbable because early morning myoclonus, absence seizures, and photosensitivity were absent. The additive effect of combined clozapine–clomipramine therapy could have induced this epileptic syndrome in a nonepileptic patient by markedly reducing the seizure threshold. Also, pharmacokinetic changes during adolescence (i.e., increasing serum levels of active metabolites due to drug metabolism changes) (Frazier et al. 2003) could additionally account for the lag between initiation of therapy and onset of symptoms, although we were not able to prove this. Such an interpretation is, however, open to debate.
This case suggests that the combination of dysfluent speech and myoclonic jerks can represent a particular form of clozapine-induced encephalopathy with epileptic activity. As such, the prompt identification of these phenomena could provide a therapeutic window to prevent further complications, including GCT seizures. In line with previous reports in adults, we suggest extending the recommendations of clozapine dose reduction or introduction of sodium valproate to an adolescent population whenever possible.
Footnotes
Disclosures
The authors have not conflicts of interest or financial ties to disclose.