Levetiracetam induced encephalopathy in a patient with normal renal function: An unusual clinical encounter.

Sir,

Levetiracetam (LEV) is a relatively well-tolerated antiepileptic drug (AED) in both adults and children. The behavioral and psychiatric side-effects associated with LEV include irritability, nervousness, hostility, anxiety and depression.[12] Encephalopathy resulting from LEV administration is a rare occurrence and has been reported previously in a patient with renal failure[3] and in another patient when the drug was added to valproate.[4] We report here, a patient with normal renal function, who received LEV for epilepsia partialis continua (EPC), following which he developed encephalopathy and showed complete recovery after the drug was withdrawn.

A 56-year-old right handed man presented to our hospital with EPC involving the right upper limb and versive movements of head for last 18 h. Patient had a history of poorly controlled seizures for last 20 years following a head injury (Post-traumatic epilepsy). He used to have partial seizures with secondary generalization. Patient was irregularly taking phenytoin for last 20 years and he had completely stopped phenytoin for 3 months prior to admission. We administered intravenous LEV in loading dose (25 mg/kg) and subsequently started him on oral LEV (1.5 g/day). The seizures were controlled after initiating LEV, but after 2 days, he again started to have repeated focal seizures involving right arm and right half of the face and prolonged episodes of drowsiness and confusion for which he was added oxcarbazepine 450 mg twice a day. Subsequently, the seizures were controlled, but patient remained drowsy and confused. Computed tomography of brain showed gliosis in the left frontal region and periventricular ischemic demyelination [Figure 1]. Electroencephalogram (EEG) of the patient on day 7 after admission showed diffuse slowing with no focal or generalized epileptic discharges [Figure 2a]. Basic laboratories showed normal renal, liver and thyroid function tests. Patient's creatinine clearance was 72 ml/min. Serum ammonia and electrolyte levels (sodium, potassium, calcium and magnesium) were within normal limits. This led us to consider possibility of drug induced encephalopathy. Oxcarbazepine was stopped, but patient didn’t show any improvement for 3-4 days. Considering a possibility of LEV induced encephalopathy, we stopped it and switched patient to valproate (500 mg BD). He showed gradual improvement in the state of consciousness with normalization of EEG [Figure 2b] and he did not have any episodes of confusion or seizures. Patient was asymptomatic at discharge and at 3 months follow-up.

Figure 1

Computed tomography brain shows gliotic scar in the left frontal region ex-vacuo dilatation of left frontal horn of third ventricle

Figure 2

Electroencephalogram (EEG) (bipolar transverse montage, sensitivity 7.5 μV/mm, low frequency filter 1 Hz, high frequency filter 70 Hz, notch 50 Hz, speed 30 mm/s). (a) Abnormal background rhythm showing diffuse slowing (frequency 4-5 Hz). No focal epileptiform discharges or triphasic waves. (b) EEG after withdrawal of levetiracetam showing improvement in the form of background rhythm 7-8 Hz

LEV, a novel anti-epileptic, has a broad spectrum anti-seizure activity in generalized as well as focal onset seizures. It acts on synaptic vesicle protein SV2A and prevents vesicle exocytosis and presynaptic neurotransmitter release. Its unique mechanism, superior pharmacokinetics and lack of significant drug interactions make it a good choice not only as add on therapy, but also effective drug for monotherapy.[5] Various studies have shown its efficacy in idiopathic generalized epilepsies (IGE), benign focal epilepsies, epileptic encephalopathies and difficult to treat or refractory seizures.[67] Recently, the efficacy of LEV in treatment of EPC is being established by observational studies. Rösche et al., observed that LEV may be useful in treatment of status epilepticus and EPC.[8] Eggers et al., reported a patient in whom EPC was controlled after bolus administration of 2000 mg intravenous LEV.[9] Similar observation was made by Haase and Hopmann.[10] It is considered relatively safe and probable first choice AED in elderly.[11]

Adverse drug reactions (ADRs) due to AEDs are the “Achilles heel” in the management of the various forms of epilepsies. The most common ADR reported have been headache, somnolence, asthenia, drowsiness, behavioral disturbance, worsening of psychiatric symptoms and rarely paradoxical worsening of seizures have been reported, especially in mentally retarded children with refractory seizures.[121314] Increased seizure frequency was reported by Callenbach et al., in 12.2% (4/33) children receiving LEV.[15] Szucs et al., noted an increased paradoxical effect in 14% (30/207) of mentally retarded patients in the form of increased seizure frequency or the experience of more severe seizures including generalized tonic-clonic seizures within 1 month after starting LEV.[16] Drug induced encephalopathy has been reported due to many other AEDs but has been rarely seen with LEV. Bauer reported encephalopathy in young man with IGE who received oral LEV (3000 mg/day) as add on oral valproate (2000 mg/day) therapy.[4] LEV undergoes minimum metabolism in blood via hydrolysis and excreted through kidneys; 66% unchanged and 24% as an inactive metabolite.[17] As a result, accumulation of drug may occur in patients with renal failure. Vulliemoz et al., observed that administration of oral LEV (2000 mg/day) in a patient with renal failure resulted in LEV-induced encephalopathy.[3] This is important as reduction in creatinine clearance may not be reflected by serum creatinine levels, especially in elderly patients.

In our patient, etiology of localization related epilepsy was frontal lobe gliosis following trauma and EPC was precipitated by poor drug compliance. The seizures were controlled by LEV, but the drug lead to altered state of consciousness due to encephalopathy. Remarkable improvement in his state of consciousness along with normalization of EEG was seen after withdrawal of LEV and switching over to valproate. This case report demonstrates that drug induced encephalopathy is one of the unusual side effects of LEV and a high index of suspicion is needed for diagnosis of this condition.