Abstract
We describe the case of a young man with treatment-resistant schizophrenia, who developed myoclonus during clozapine titration. This subsequently led to a full tonic–clonic seizure. Clozapine treatment can result in a range of seizure-like activity, the most well-known being tonic–clonic seizures. This case highlights the importance of recognizing and treating clozapine-induced myoclonus, as it can herald the onset of a full seizure, even at low serum clozapine levels. We highlight the variety of ways myoclonus can present clinically and suggest treatment options.
Introduction
Myoclonus refers to sudden, involuntary jerking of a muscle or group of muscles. As such, it describes a symptom rather than a diagnosis, as it can occur in a variety of neurodegenerative and systemic metabolic disorders and central nervous system (CNS) infections [Jiménez-Jiménez et al. 2004]. Myoclonus can also arise as an adverse effect to medications, including cyclic antidepressants, levodopa and bismuth salts [Jiménez-Jiménez et al. 2004].
Myoclonic jerks commonly occur in seizure disorders and it is in this context that we present a case of clozapine-induced myoclonus, leading to the development of a tonic–clonic seizure. Although jerking movements are typical of the clinical presentation of myoclonus, it can present with a range of other symptoms and signs, which can make diagnosis difficult. We discuss the clinical features of clozapine-induced myoclonus and suggest treatment options.
Case description
T.R, a 20-year-old black British man of Caribbean heritage, was transferred from a young offender’s institution to a hospital inpatient unit because of increasing concerns about his mental health. He was initially observed to be talking to himself and later reported experiencing distressing command auditory hallucinations. As his condition deteriorated in prison, he developed symptoms of catatonia and was immediately transferred to hospital under a section of the English and Welsh Mental Health Act. Following initial assessment, including normal physical examination and routine blood results, he was diagnosed with paranoid schizophrenia and treated initially with oral olanzapine, using an oro-dispersible preparation. This afforded a limited therapeutic response and was associated with rapid weight gain. A subsequent trial of risperidone, initially orally and then by depot, also failed to produce an adequate therapeutic response and resulted in significant hyperprolactinaemia. Each drug was given for at least 6 weeks at therapeutic doses. Compliance with olanzapine was considered likely because of the oro-dispersible preparation and rapid weight gain observed. Compliance was assured with risperidone by the use of a depot preparation.
Given the limited response to the two antipsychotics, the patient was considered to suffer from a treatment-resistant illness. With the agreement of the patient, clozapine was initiated and titrated over 2 weeks to a dose of 300 mg/day. Plasma concentration remained subtherapeutic, so the dose was gradually increased further. An improvement in mental state was observed at a dose of 400 mg/day, but levels remained subtherapeutic. Although the patient was a nonsmoker, he may have been a rapid metaboliser of clozapine.
A period of 4 weeks following commencement of clozapine, the patient complained of unpleasant ‘electric shock’ sensations, occurring approximately every week or two. After 4 months had passed, the patient also suffered a number of falls. After a further few months, he began to experience occasional jerking movements, mainly of his upper limbs. The patient had no prior history of seizures, head trauma or medical comorbidities. He was not taking other medication known to lower the seizure threshold. Given the nature of these ongoing symptoms, we completed a full physical review, including electroencephalography (EEG) and a magnetic resonance imaging (MRI) brain scan. No abnormalities were found in either. Plasma clozapine concentrations were measured and found to be 0.14 mg/l (norclozapine was 0.13 mg/l), well below the suggested therapeutic range of 0.35–0.5 mg/l [Taylor et al. 2015]. We decided to maintain the dose at 400 mg/day, despite the low plasma concentration, as therapeutic response was positive.
A period of 9 months after starting clozapine, and approximately 1 month after experiencing jerking movements, the patient suffered a tonic–clonic seizure, which caused significant distress to him. He was admitted overnight to our local medical hospital for observation. At the time, the clozapine dose was 400 mg/day with a plasma concentration of 0.18 mg/l (norclozapine was 0.15 mg/l). Following the seizure, clozapine was withheld for one day and reintroduced at a lower dose of 350 mg/day. The patient was commenced on sodium valproate, titrated over 2 days to a dose of 1 g/day. Valproate steady-state plasma concentration of 85 mg/l was achieved and 1 g/day was continued as a maintenance dose for the prevention of secondary seizures. The patient was reviewed by a neurologist as an outpatient, but no additional findings or recommendations were made. Following the commencement of sodium valproate, all ‘electric shock’ sensations, myoclonic jerks and unexpected falls stopped. The dose of clozapine was increased tentatively over the following months to treat residual symptoms, using valproate for seizure prophylaxis. The patient has been seizure-free for over 6 months on the combination of these medicines. A recent clozapine plasma concentration was 0.23 mg/l (norclozapine 0.11 mg/l), on a dose of 475 mg/day. Although the levels remain below the suggested therapeutic range, the patient’s clinical response continues to improve.
Discussion
Clozapine-induced seizure activity
Clozapine has a well-documented pro-convulsive effect and carries a higher risk of seizures than other antipsychotics [Pisani et al. 2002]. Clozapine-induced EEG changes are strongly related to both the dose and plasma concentration of clozapine [Varma et al. 2011], but a clear relationship with actual seizures has not been found. It has been suggested that the speed of titration is related to the risk of clozapine-induced seizures [Devinsky et al. 1991] and slower titrations may be beneficial [Varma et al. 2011]. Seizure prophylaxis with anti-epileptic drugs is recommended for those with clozapine plasma concentrations over 0.5–0.6 mg/l [Taylor et al. 2015]. Fatalities as a result of clozapine-induced tonic–clonic seizures have been reported [Atkinson et al. 2007]. In general it has been shown that those at risk of seizures while on clozapine remain undertreated with anti-epileptic drugs [Sparshatt et al. 2008]. This may reflect the need for clearer guidance on when anti-epileptic drugs are indicated.
Clozapine-induced myoclonus
Clozapine-induced myoclonus is not well recognized or documented, but is part of a variety of seizure activity associated with clozapine, including atonic seizures and drop attacks, in additions to tonic–clonic seizures [Pacia and Devinsky, 1994]. Myoclonus associated with clozapine is less frequently documented in the literature than tonic–clonic seizures (see Table 1). This may reflect poor recognition or under-reporting in clinical practice, or be related to the generally less profound clinical consequence. However, as this case demonstrates, myoclonus can precede a full blown tonic–clonic seizure, which is unpleasant and frightening for the patient and may lead to complications [Wong and Delva, 2007]. Because of this, timely detection is valuable in determining when anti-epileptic drugs are indicated.
Summary of studies reporting the incidence of clozapine-induced myoclonus.
EEG, electroencephalography.
The incidence of clozapine-induced myoclonus has not been well defined. However, studies that record the occurrence of myoclonus in a clozapine-treated patient population have shown a 0.9% to 12.5% incidence (Table 1). The wide variation may reflect the difficulty of recognising and diagnosing myoclonus in clinical practice, as in this case. Clozapine-induced myoclonus tends to present during the titration phase of treatment [Taner et al. 1998] and has been followed by generalised seizures in a number of cases [Sajatovik and Meltzer, 1996; Meltzer and Ranjan, 1994; Berman et al. 1992].
We reviewed clinical features associated with clozapine-induced myoclonus described in previous case reports (Table 2) and summarise these in Table 3. Although jerking movements reflect so-called positive myoclonus [Kojovik et al. 2011], negative myoclonus can be characterised by sudden and brief interruptions of motor activity [Tassinari et al. 1995], resulting in unexpected falls or buckling at the knee. Case reports that document a clozapine-induced cataplexy [Desarkar et al. 2007; Chiles et al. 1990] may in fact reflect a clozapine-induced negative myoclonus [Butler, 2009].
Summary of case-reports/case-series of clozapine-induced myoclonus.
BD, twice daily; EPSE, extrapyramidal side effects; IM, intramuscular.
Symptoms associated with clozapine-induced myoclonus, as described in case reports.
Myoclonus can be either cortical or subcortical in origin [Kojovik et al. 2011]. The origin of clozapine-induced myoclonus is not known. In this case report myoclonus was focal, distal and involved a synergistic group of muscles, which suggests a cortical origin [Pranzatelli, 2003]. In one case report, where an accidental ingestion of clozapine resulted in delayed myoclonus, EEG testing determined clozapine-induced myoclonus to be cortical in origin [Adam et al. 2015].
Symptoms of myoclonus can sometimes be misinterpreted in mental health settings, with jerking movements labelled as dyskinesia and unexplained falls incorrectly considered to be a result of clozapine-induced hypotension or sedation. As clozapine has a very low risk of inducing extrapyramidal side effects (EPSE) and dyskinesia, patients with movement abnormalities on clozapine should be closely assessed for the presence of positive myoclonus and treated accordingly. Although clozapine-induced hypotension is well documented, its presence should be objectively confirmed through blood pressure monitoring to exclude falls resulting from clozapine-induced negative myoclonus.
Management of clozapine-induced myoclonus
A reduction in clozapine plasma concentration may resolve myoclonus. For some patients, this may not be possible for clinical reasons, or may be insufficient in alleviating myoclonus. In these cases, an anti-epileptic drug should be considered to allow the safe continuation of clozapine therapy. Interestingly, many of the previous case reports indicated a discontinuation of clozapine. In our experience this is not usually necessary and may cause worsening psychiatric symptoms, given the treatment-resistant status of these patients.
Anti-epileptic drugs such as sodium valproate or lamotrigine are commonly used for the primary or secondary prevention of clozapine-induced seizures. Valproate has been recommended for those patients with associated mood disturbance, while lamotrigine is preferred for those with residual psychotic symptoms [Varma et al. 2011]. Both topiramate and lamotrigine are suggested as options for those with clozapine-induced weight gain [Varma et al. 2011]. However, as lamotrigine has been shown to occasionally worsen some types of myoclonic epilepsy [Guerrini et al. 1998], it is considered relatively contraindicated for the treatment of myoclonus [Gayatri and Livingston, 2006] and should be reserved for when valproate is not a suitable option. Valproate has a proven efficacy in treating clozapine-induced myoclonus and will prevent the onset of tonic–clonic seizures and allow the continued use of clozapine [Taner et al. 1998; Sajatovik and Meltzer, 1996; Meltzer and Ranjan, 1994; Malow et al. 1994]. As such, we suggest valproate as the first-line treatment for clozapine-induced myoclonus.
Conclusion
Clozapine-induced myoclonus can be difficult to diagnose with certainty in clinical practice and may present with either jerking movements or unexplained falls, or both. The onset of myoclonus in patients taking clozapine can be the harbinger of tonic–clonic seizures and, as such, represents a clear indication for the use of adjunctive anti-epileptic drugs for both the treatment of myoclonus and the prevention of seizures. The anti-epileptic drug of choice for patients with clozapine-induced myoclonus is valproate, because of its documented efficacy in the primary treatment of myoclonus and the secondary prevention of tonic–clonic seizures.
This case report highlights the need to remain vigilant for the varied signs of myoclonus for all patients on clozapine, regardless of clozapine plasma levels or whether or not patients are in the titration or maintenance phase of treatment.
Prescribers should remain alert to the varied presenting nature of clozapine-induced myoclonus (including unexplained falls, electric shock-like sensations) reported here and elsewhere.
Clozapine-induced myoclonus can occur at relatively low plasma levels.
Clozapine-induced myoclonus may precede a tonic–clonic seizure and treatment with an anti-epileptic is indicated to allow the continuation of clozapine.
Valproate is a suitable first line anti-epileptic for the primary treatment of patients with clozapine-induced myoclonus and the secondary prevention of tonic–clonic seizures.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.