Rhabdomyolysis: a rare adverse effect of levetiracetam

Abstract

A 62-year-old previously healthy male was admitted with new onset generalised tonic-clonic seizures. Treatment was initiated with the antiepileptic levetiracetam and he had no further episodes of seizures. Creatine kinase (CPK) level was 1812 IU/L 12-hour postadmission. Despite good hydration, his CPK levels continued to rise dramatically and reached a level of 19 000 IU/L on day 5. This rise was unexplained as he did not have any further seizures and had a normal renal function. In the absence of other risk factors, the rare possibility of levetiracetam being responsible for the disproportionately high CPK was considered. Within 12 hours of withdrawal of levetiracetam, there was a downward trend in the CPK levels, with a 10-fold decrease in CPK levels over the next 4 days. This is only the ninth case reported in literature regarding this rare and potentially serious adverse effect of levetiracetam.

Background

Seizures involving muscular activity are known to cause a rise in the creatine kinase (CPK) levels and possible rhabdomyolysis. However, when there is an unexplained rise in CPK disproportionate to the seizure activity and level of renal impairment other causes should be sought, including a drug review. In the absence of common inciting factors the side-effect profile of medications, including rare side effects should be carefully considered. Levetiracetam is a commonly used broad-spectrum antiepileptic with a relatively innocuous side-effect profile. However, there have been a few cases reported in literature regarding this serious adverse effect. The case described here shows a parallel trend in the level of the CPK levels corresponding to the use of levetiracetam, thereby demonstrating its probable causal role. It adds to the existing evidence that levetiracetam can induce rhabdomyolysis and the possibility should be considered in cases where the rise in CPK is unexplained or disproportionate to the presumed underlying inciting cause.

Case presentation

A 62-year-old previously healthy Frenchman, was admitted to the hospital on 1 January 2019 with a history of being found confused and agitated in his room by his wife 2 hours prior to presentation. There was no witnessed seizure and he did not lose consciousness. He was well prior to this episode. There was no history of fever, influenza symptoms, vomiting, headache, head injury or excessive alcohol consumption. He had no known medical illness and was not on any regular medications. He was a non-smoker and a social alcohol consumer.

While he was being seen in the emergency department he had an attack of generalised tonic-clonic seizure, followed by postictal confusion. He was admitted under the neurology team as a case of seizure for evaluation and given a loading dose of levetiracetam of 1 g, followed by 500 mg two times per day. He had no more episodes of seizure and his neurological examination was unremarkable. No significant lab abnormality was found except a high CPK level (1812 IU/L). He was started on intravenous hydration. However, despite adequate hydration his CPK levels continued to rise dramatically.

In view of rising CPK level which was not improving despite adequate hydration, he was referred to the medical team for further workup and management of rhabdomyolysis. He complained of myalgia and back pain, which improved in 2 days. There was no change in colour of his urine and he had good urine output. On day 6 of admission, his CPK levels reached a maximum of 19 518 IU/L. There was no apparent cause for this extreme increase. There had been no further seizures and his renal function was normal. Common causes like trauma, viral illness, alcohol and dyselectrolytemia were easily excluded. The possibility of levetiracetam-induced rhabdomyolysis, though rare was considered. Levetiracetam was discontinued and substituted with phenytoin. CPK levels began to fall within the next 24 hours.

Relevant investigations

CT brain (1 January 2019)

• Normal.

• No evidence of acute/chronic haemorrhage, ischaemia or mass.

CT angio cerebral (1 January 2019)

Normal multiphase CT angiogram of cerebral vessels with no evidence of any occlusion of the major arteries neither any delay in the opacification of peripheral cortical cerebral vessels.

EEG (3 January 2019)

• Abnormal.

• Intermittent bitemporal slowing without any epileptiform activities.

Repeat EEG (8 January 2019)

• Abnormal.

• Evidence for the interictal expression of focal epilepsy with two independent epileptogenic foci in the right and left temporal regions. In addition, the appearance of some of the epileptiform discharges in both temporal region bisynchronously, may be suggestive of tendency for generalised epilepsy.

MRI brain (7 January 2019)

Non-specific white matter changes.

Thyroid function test (5 January 2019)

• Normal.

• T4: 15.3 pmol/L, T3: 4.0 pmol/L, thyroid stimualting hormone (TSH): 3.500 uIU/mL.

Treatment

Prompt discontinuation of levetiracetam results in improvement of symptoms, CPK levels and renal impairment if any.

Outcome and follow-up

With discontinuation of levetiracetam, the CPK showed a downward trend in 12 hours falling to 15 198 from 19 518 IU/L. It continued to show an exponential decrease till the day of discharge when it was 1200 IU/L which was 4 days after stopping levetiracetam. He had no further seizure episodes during his stay. Further workup was done to evaluate cause of his seizure. MRI brain was normal. Initial EEG showed bitemporal slowing without any epileptiform focus but a repeat EEG showed two independent epileptogenic foci in the right and left temporal regions. His antiepileptic medication was changed to oxcarbemezipine.

He was discharged with advice to keep himself well hydrated and follow-up with neurologist in his home country. He was also educated regarding his risk of rhabdomyolysis with levetiracetam and advised to inform his neurologist regarding this in order to avoid future inadvertent use of levetiracetam for his epilepsy.

Discussion

The first case of probable levetiracetam-induced rhabdomyolysis was reported in 2014 in a 29-year-old woman hospitalised for generalised tonic-clonic seizures.¹ Since then there have been only a handful of case reports linking this antiepileptic medication to the elevated CPK levels and rhabdomyolysis, a rare and potentially life-threatening adverse effect.

Rhabdomyolysis literally meaning lysis or rupture of striated muscle is a common clinical syndrome most commonly due to direct muscle injury or trauma and other causes such as drugs, toxins, viral or bacterial infections, heatstroke, endocrinopathies, malignant hyperthermia, neuroleptic malignant syndrome, electrolyte alterations and connective tissue disorders. An accepted definition is elevation of serum CPK activity of at least 10 times the upper limit of normal.² Muscle damage due to any of the various causes listed can lead to raised CPK levels which may be asymptomatic, associated with mild symptoms, or severe with electrolyte imbalance, myoglobinuria, renal failure and disseminated intravascular coagulation. Symptoms can range from non-specific malaise, fatigue, nausea and vomiting to the classically described triad of myalgia, weakness and dark urine which is present in <10% of patients.^{3 4}

Levetiracetam is a broad-spectrum antiepileptic medication with mild side effects mainly reported to be nasopharyngitis, somnolence, headache, fatigue, dizziness, vomiting and behavioural alterations.⁵

Rhabdomyolysis has rarely been reported as an adverse effect of levetiracetam and until only eight cases have been reported, all in the setting of seizures- generalised tonic-clonic seizures or partial seizures with secondary generalisation.^{1 6–12} Details of these eight cases including our case are summarised in table 1. The average time of onset of symptoms and rising CPK was from 24 to 72 hours. In the case reported by Kubota et al,¹¹ the time of onset of rhabdomyolysis is reported as 15 days. But this patient had severe intellectual impairment and it is likely that milder symptoms may have been present before rhabdomyolysis was eventually detected. In all cases except one the CPK showed a downward trend within 24 hours except in the case reported by Di Lorenzo and Li where the CPK peaked at 48 hours after stopping levetiracetam before showing a tendency to improve.⁷ Though the downward trend of CPK and resolution of symptoms started early, CPK values took around 7–14 days to return to normal range. Once again, in the case described by Di Lorenzo and Li it took 40 days for CPK to normalise.⁷ He did not have renal impairment and was not on any other antiepileptic. Possibly, this was because he was a muscular young male and had the highest CPK level (49 539 IU/L) among these reported cases. Three of the patients had renal impairment and their time to recovery of CPK and renal function ranged from 7 to 12 days which was not significantly more than those who had renal impairment. The youngest patient was a 13-year-old girl and the oldest case reported was in a 42-year-old man. Symptoms were mostly myalgia, but three out of the eight patients had no symptoms. Discontinuation of levetiracetam resulted in resolution of sympktoms and normalisation of CPK values in all cases.

Table 1.

Levetiracetam-related rhabdomyolysis—summary of case reports

Author	Age/sex	Underlying condition/seizure type	Noted time of onset	Peak time	Peak CPK value (IU/L)	Daily dose of LEV	Other AED	Time to improvement	Time to normalisation	Symptoms	Renal impairment
Akiyama et al 1	29/F	Idiopathic epilepsy GTCS	Day 4	Day 7	2410	1 g	Yes	24 hours	28 days	Myalgia, backache, lower limb weakness	No
Isaacson et al 10	19/M	Frontal AV malformation Complex partial seizure with secondary generalisation	Day 2	Day 7	29 136	2 g followed by 500 mg	OXC 1500 mg	24 hours	12 days	None	Yes
Lorenzo7	27/M	Moyamoya disease GTCS	Day 2	48 hours after stopping		1 g BD	No	After 48 hours	40 days	None	No
Incecik et al 9	13/F	Benign epilepsy with centrotemporal spikes Partial seizure with secondary generalisation	Day 7	Day 2	968	500 mg	No	24 hours		Myalgia, lower extremities	No
Rastogi et al6	42/M	Hyponatremia GTCS	24 hours	Day 3	30 000	1.5 g	No	24 hours	7 days	None	Yes
Singh et al 8	16/M	Idiopathic seizure GTCS	Day 2	Day 4	15 111	1.5 g	No	24 hours	10 days	Back pain day 2	Yes—day 2, normalisation day 7
Kuboto11	26/F	Syndromic epilepsy Partial secondary generalised	Day 15	Day 16	4396	500 mg	Phenytoin, CBZ	24 hours	11 days	Proximal weakness	No
Sung Yeon12	40/M	Idiopathic seizure GTCS	Day 3	Day 6	7800	1.5 g	No	24 hours	7 days	Headache, myalgia	No
Our case	62/M	Idiopathic seizure GTCS	Day 2	Day 6	19 518	1 g followed by 500 mg twice daily	No	24 hours	10 days	Back pain, myalgia	No

AED, antiepileptic drugs; AV, arteriovenous; CBZ, carbamazepine; CPK, creatinine kinase; GTCS, generalised tonic-clonic seizure; LEV, levetiracetam; OXC, oxcarbazepine.

The case reported by Sung Yeon et al is the only case in which a rechallenge with levetiracetam was done after 1 year and there was a repeat rise in the CPK observed.¹² They have calculated a ‘Naranjo adverse drug reaction score" suggesting levetiracetam as the ‘probable’ cause. In our case, rechallenge was not attempted because the improvement in CPK was so dramatic with stoppage of levetiracetam and an alternate antiepileptic was substituted immediately with well-controlled seizures. Our score on The Naranjo Adverse Drug Reaction Scale is 7, which translates into a ‘probable cause’.¹³

The mechanism by which levetiracetam induces rhabdomyolysis is uncertain. Levetiracetam acts as an antiepileptic by binding to synaptic vesicle 2A (SV2A), located mainly in the brain in the presynaptic terminals thereby modifying neurotransmission.¹⁴ The SVA2 receptor has also been found to be specifically located on the motor nerve terminals in slow muscle fibres. This could be a possible explanation for the muscle injury induced by levetiracetam.¹⁵ As proposed by Carnovale et al, it may act by potentiating cholinergic function thereby increasing neuromuscular stimulation and muscle stress.¹⁶ Other antiepileptic drugs like phenytoin, valproic acid, gabapentin and lamotrigine have been reported to cause rhabdomyolysis.¹⁷

Our patient was a previously healthy 62-year-old man. He had one episode of witnessed generalised tonic-clonic seizure which lasted for less than a minute. Following a seizure or muscle injury, the CPK usually rises within 2–12 hours of muscle injury, peaks around 24–72 hours and then declines over the next 3–5 days. More specifically in postictal CPK rise, as per a review by Brigo et al, CPK elevation is usually mild and peak levels are observed usually at 36–40 hours.¹⁸ Our patient had a rise in CPK which was disproportionate to the muscular activity and it continued to rise beyond 72 hours despite adequate hydration (figure 1). There was no renal impairment. There was no muscle trauma, other infectious, metabolic or endocrine causes which could explain this marked rise in CPK. Once levetiracetam was considered as the possible cause, it was promptly discontinued, and CPK started improving within the next 24 hours.

Figure 1.

Trend of CPK (creatine kinase) during hospitalisation. LEV, levetiracetam.

This is yet another case illustrating this rare side effect of levetiracetam and only the eighth reported case of levetiracetam-induced rhabdomyolysis. Levetiracetam-induced rhabdomyolysis should be considered in any patient who has recently been started on it and has no other apparent cause for rhabdomyolysis. It should be promptly discontinued and substituted with another antiepileptic medication to avoid the possible life-threatening complications of rhabdomyolysis.

Learning points.

• Levetiracetam - a broad-spectrum antiepileptic with a benign side-effect profile can cause rhabdomyolysis as a serious adverse effect.

• There are no known predisposing factors for levetiracetam-induced rhabdomyolysis.

• In patients newly initiated on levetiracetam, features of rhabdomyolysis in the absence of other apparent causes should prompt immediate discontinuation of levetiracetam.

• Withdrawal of levetiracetam results in rapid resolution of symptoms and normalisation of creatine kinase values.