Generalised tonic–clonic seizures on the subtherapeutic dose of olanzapine

Abstract

Olanzapine is a second-generation antipsychotic. Incidence of olanzapine-induced seizures (OIS) is low with monotherapy. Combination therapy with another antipsychotic, drug metabolism and old age are risk factors for OIS. Our patient was a 71-year-old man, admitted to the psychiatry unit. He was managed on the lines of bipolar affective disorder current episode depression and dementia. He was started on olanzapine 1.25 mg two times/day. The patient developed generalised tonic–clonic seizure that lasted for around two and a half minutes within 24 hours of olanzapine treatment. His electroencephalogram showed findings that were suggestive of mild slowing. Our case discusses the incidence of OIS on the subtherapeutic dose. This presentation involves multiple risk factors for OIS: a history of stroke, poststroke seizure, old age and cognitive impairment. Due to scarcity of evidence of OIS; mostly with recommended therapeutic dose range physicians may underestimate seizure risk at subtherapeutic doses.

Background

The propensity of antipsychotics (APs) to lower the epileptogenic threshold and cause seizures is dose-dependent.¹ History of seizures, use of other drugs that increase seizure risk, dementia, rapid dose escalation or slow drug metabolism may further worsen the risk of APs induced seizures.^{2 3} Clozapine and chlorpromazine are commonly associated with seizures whereas olanzapine has a safer profile.²

Olanzapine is a second-generation antipsychotic (SGA). It is a thienobenzodiazepine derivative with a similar structural profile as clozapine. The dose ranges from 5 to 20 mg/day. Olanzapine causes relatively fewer adverse effects as compared with other SGAs.⁴ Incidence of olanzapine-induced seizures (OIS) is low with monotherapy. Nevertheless, changes in electroencephalogram (EEG) are seen in the patients using olanzapine.⁵ During phase II and III clinical trials, the incidence of OIS has been reported to be 0.9%.⁶ Combination therapy with another AP, drug metabolism and old age are risk factors for OIS.⁷

We describe a case of an elderly patient who developed GTCS after starting a subtherapeutic dose of olanzapine.

Case presentation

A 71-year-old man, divorced, living with his elderly sisters, was brought to the emergency room by a neighbour with decline in daily activities, memory disturbances, social isolation, low mood, decreased appetite and increased sleep. He had been diagnosed with bipolar affective disorder 20 years ago. His other medical comorbidities included: hypertension and ischaemic heart disease.

At the time of presentation, the mental state examination showed signs of poor personal hygiene, grooming and malnourishment. On Mini-Mental State Examination, the patient had difficulty in attention, calculation, orientation and recall; total score 21/30. Body mass index (BMI) was 16. Prior medical history revealed a history of stroke and poststroke seizures 1 year ago. Levetiracetam 500 mg two times per day was advised. Medication compliance was questionable and difficult to ascertain. However, attendant did not report a witnessed seizures in the last 1 year.

The patient was admitted to the psychiatry unit. Management was started on the lines of bipolar affective disorder current episode depression and dementia. Baseline blood workup was within normal limits. The vitamin B₁₂ levels were low (table 1). With prior history of manic episodes and current state of malnourishment team opted for olanzapine. The starting dose was 1.25 mg two times per day. His other medications included: aspirin 75 mg/day, perindopril 2 mg/day, atorvastatin 10 mg/day and vitamin B₁₂ replacement regimen. After receiving two doses of olanzapine 1.25 mg, the patient developed generalised tonic–clonic seizure that lasted for around two and a half minutes. After initial seizure management, neurology consult was called for seizures workup. Olanzapine was stopped till then. EEG showed findings that were suggestive of mild slowing (table 2).

Table 1.

Investigations

Investigations	Results	Reference range
Haemoglobin	140 g/L	137–165 g/L
Total leucocyte count	8.8×109/L	4.0–10.0×109/L
Platelets	357×109/L	150–400×109/L
Total bilirubin	0.2 mg/dL	0.1–1.2 mg/dL
Direct bilirubin	0.1 mg/dL	0–0.2 mg/dL
Indirect bilirubin	0.1 mg/dL	0.1–0.8 mg/dL
Gamma-glutamyl transferase (GGT)	16 IU/L	Males: <55 IU/L
Alanine aminotransferase (ALT)	13 IU/L	Males: <45 IU/L
Aspartate aminotransferase (AST)	25 IU/L	Males: <35 IU/L
Alkaline phosphatase (AP)	103 IU/L	45–129 IU/L
Blood urea nitrogen	17 mg/dL	6–20 mg/dL
Creatinine	1.0 mg/dL	0.8–1.3 mg/dL
Sodium	135 mmol/L	136–145 mmol/L
Potassium	4.3 mmol/L	3.5–5.1 mmol/L
Chloride	100 mmol/L	98–107 mmol/L
Bicarbonate	20.7 mmol/L	20–31 mmol/L
Urine detailed report	Within normal limits
Vitamin B12	167 pg/mL	>201 pg/mL acceptable

Table 2.

Electroencephalogram

Electroencephalogram (EEG)

The posterior head region showed 8–9 Hz alpha activity of 40–44 uV bilaterally symmetrical, which attenuated on eye opening. The anterior head regions showed 16–18 Hz beta activity of 7–8 uV bilaterally symmetrical. The findings are suggestive of mild slowing.

MRI brain was not ordered due to family’s financial constraints.

Treatment

Neurology team ordered Divalproex Sodium 1 g intravenous at once, followed by 500 mg two times per day/oral. The choice of Divalproex Sodium was made based on its efficacy as an antiepileptic and a mood stabiliser. The patient remained stable and showed remarkable improvement.

Outcome and follow-up

As initial and subsequent outpatient follow-ups till 6 months, the patient did not report any seizure. Patient’s mood symptoms were in remission at follow-ups. However, we do not have a longitudinal data of cognitive function of the patient.

Discussion

Our case discusses the incidence of OIS on the subtherapeutic dose. This presentation involves multiple risk factors for OIS: a history of stroke, poststroke seizure, old age and cognitive impairment.³

Evidence of OIS in patients is mainly limited to case reports (table 3). Most of the OIS cases have reported female patients. This can be explained by the lower drug metabolism of olanzapine in females.⁸ However, we postulate that in our case old age was the leading risk factor. Old age is a significant risk factor for OIS. Patients present with multiple comorbidities that warrant polypharmacy and a higher risk of drug–drug interactions.^{9 10} Similar results are seen in other reported cases.^11–14

Table 3.

Summary of available evidence on OIS

	Age of patient (years)	Gender of patient	Olanzapine dose/day	Type of seizure	Location of study	EEG findings
Current study	71	Male	2.5 mg/day	GTCS	Pakistan	The posterior head region showed 8–9 Hz alpha activity of 40–44 uV bilaterally symmetrical, which attenuated on eye opening. The anterior head regions showed 16–18 Hz beta activity of 7–8 uV bilaterally symmetrical. The findings are suggestive of mild slowing.
Shah et al 14	48	Female	2.5 mg/day	Status epilepticus	Nepal	Generalised epileptiform discharges
Uvais et al 17	23	Female	20 mg/day	GTCS	India	Intermittent generalised frontal-dominant slow wave activities
Anzellotti et al 21	47	Male	10–15 mg/day	Eyelid myoclonus, lingual dystonia and deviation of mouth towards right	Italy	Left frontotemporal focus with recruiting polyspikes, followed by generalised spikewave complexes at 4–5 Hz
Rosen et al 18	67	Female	2.5 mg/day	Generalised myoclonus	USA	Generalised slowing+spikes and sharp waves
Behere et al 16	25	Male	20 mg/day	GTCS	India	Generalised spikes+sharp and slow wave discharges
Spyridi et al 13	48	Female	30 mg/day	Status epilepticus	Greece	Status epilepticus
Camacho et al 11	54	Female	5 mg/day	Myoclonic status	Spain	High-amplitude generalised spikes, and spike/wave and polyspike/wave complexes
Wooley and Smith15	30	Male	10 mg/day	GTCS	UK	Multifocal and generalised epileptiform discharges
Lee et al 12	31	Female	10 mg/day	GTCS	USA	Not available
Wyderski et al 22	41	Female	Unknown	Status epilepticus	USA	Not available

EEG, electroencephalogram; OIS, olanzapine-induced seizure.

Another unique aspect of our case is the initiation of a subtherapeutic dose. In previous reports, generalised tonic–clonic seizures (GTCS) secondary to olanzapine have been associated with a dose range of 10–20 mg/day.^{12 15–17} Previously, a myoclonic seizure has been reported at a dose of 2.5 mg/day of olanzapine after 7 years on olanzapine treatment.¹⁸ Another case of status epilepticus in a patient with stroke is also reported. The patient had status epilepticus 4 hours after taking 2.5 mg of olanzapine once.¹⁴ In our case, OIS on the stated dose can be explained by patient’s low BMI, and age-related slowed metabolism. Elderly patients have decreased lean mass, increased body fat and pharmacokinetic changes which change drug absorption and metabolism.(9 Taken together, these studies provide initial support for a temporal association of olanzapine to the GTC but more research is needed to increase confidence in these conclusions.

The third aspect of our case is low levels of vitamin B₁₂. Previously, an association of seizure-like activity with vitamin B₁₂ deficiency has been reported. Interestingly, initiation of parental replacement therapy of vitamin B₁₂ has shown involuntary movement that may look like a seizure, further complicating the clinical picture.¹⁹ There is no consensus about management of OIS. In one of the reported cases of OIS, an antiepileptic drug was continued.¹⁷ Patients with poststroke seizure are at a high risk to have fatal status epilepticus.²⁰ Our patient was continued on antiepileptic drug to manage the risk of seizure recurrence and fatal status epilepticus which remained due to his medical comorbidities.

This case report highlights the importance of recognising the risk factors in deciding a treatment regime on elderly population. There was involvement of multiple risk factors that potentially primed the seizure threshold and acted as crucial mediators to the occurrence of a GTC. The direct causal relationship is difficult to establish due to complex interaction of various risk factors. There is a string possibility that our finding might be a coincidental occurrence. For this reason, the findings cannot be generalised to the broader community based on this study alone.

Patient’s perspective.

It was an opportunity for me to understand the importance of medication compliance which may have prevented the seizure episode altogether.

Learning points.

• Antipsychotics lower seizure threshold.¹

• Elderly patients are particularly susceptible to rare side-effects.

• The physicians may underestimate seizure risk at subtherapeutic doses.