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.[1,2] Encephalopathy resulting from LEV administration is a rare occurrence and has been reported previously in a patient with renal failure and in another patient when the drug was added to valproate. 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partialis continua (EPC), following which he developed encephalopathy and showed complete recovery after the drug was withdrawn.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.
Figure 1: Computed tomography brain shows gliotic scar in the left frontal region ex-vacuo dilatation of left frontal horn of third ventricle
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. 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. Various studies have shown its efficacy in idiopathic generalized epilepsies (IGE), benign focal epilepsies, epileptic encephalopathies and difficult to treat or refractory seizures.[6,7] 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. Eggers et al., reported a patient in whom EPC was controlled after bolus administration of 2000 mg intravenous LEV. Similar observation was made by Haase and Hopmann. It is considered relatively safe and probable first choice AED in elderly. 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. [12-14] Increased seizure frequency was reported by Callenbach et al., in 12.2% (4/33) children receiving LEV. 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. 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. LEV undergoes minimum metabolism in blood via hydrolysis and excreted through kidneys; 66% unchanged and 24% as an inactive metabolite. 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. This is important as reduction in creatinine clearance may not be reflected by serum creatinine levels, especially in elderly patients.
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
Letters to the Editor
b 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
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.
Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh, India
For correspondence: Prof. Rajesh Verma, Department of Neurology,
King George Medical University,
Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: Results of a double-blind, randomized clinical trial. Neurology 2000;55:236-42. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: A multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000;41:1276-83. Vulliemoz S, Iwanowski P, Landis T, Jallon P. Levetiracetam accumulation in renal failure causing myoclonic encephalopathy with triphasic waves. Seizure 2009;18:376-8. Bauer J. Encephalopathy induced by levetiracetam added to valproate. Acta Neurol Scand 2008;117:374-6. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861-6.
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8. 9. 10. 11. 12. 13. 14.
Letters to the Editor Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 2008;70:607-16. Huber B, Bömmel W, Hauser I, Horstmann V, Liem S, May T, et al. Efficacy and tolerability of levetiracetam in patients with therapy-resistant epilepsy and learning disabilities. Seizure 2004;13:168-75. Rösche J, Pohley I, Rantsch K, Walter U, Benecke R. Experience with levetiracetam in the treatment of status epilepticus. Fortschr Neurol Psychiatr 2013;81:21-7. Eggers C, Burghaus L, Fink GR, Dohmen C. Epilepsia partialis continua responsive to intravenous levetiracetam. Seizure 2009;18:716-8. Haase CG, Hopmann B. Epilepsia partialis continua successfully treated with levetiracetam. J Neurol 2009;256:1020-1. Alsaadi TM, Koopmans S, Apperson M, Farias S. Levetiracetam monotherapy for elderly patients with epilepsy. Seizure 2004;13:58-60. Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat 2008;4:507-23. Nakken KO, Eriksson AS, Lossius R, Johannessen SI. A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 2003;12:42-6. Trinka E, Marson AG, Van Paesschen W, Kälviäinen R, Marovac J, Duncan B, et al. KOMET: An unblinded, randomised, two parallelgroup, stratified trial comparing the effectiveness of levetiracetam
with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2012. [Epub ahead of print] 15. Callenbach PM, Arts WF, ten Houten R, Augustijn P, Gunning WB, Peeters EA, et al. Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study. Eur J Paediatr Neurol 2008;12:321-7. 16. Szucs A, Clemens Z, Jakus R, Rásonyi G, Fabó D, Holló A, et al. The risk of paradoxical levetiracetam effect is increased in mentally retarded patients. Epilepsia 2008;49:1174-9. 17. Cormier J, Chu CJ. Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age. Neuropsychiatr Dis Treat 2013;9:295-306.
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Bilateral facial nerve palsy: A rare association with hepatitis A Sir, A 17-year-old female presented with a history of sudden onset of inability to close eyes, epiphora as well as inability to drink fluids from cup associated with drooling of fluids along the corners of the mouth bilaterally of 2 days duration. There was no associated history of taste disturbances or hearing abnormalities in either of the ears. No other associated cranial nerve disturbances or long tract symptoms were present. No associated fever, cough, headache, vomiting or other relevant systemic symptoms. Examination was unremarkable except for bilateral lower motor neuron type of facial nerve palsies with sparing of taste sensation and without hyperacusis. A clinical diagnosis of bilateral lower motor neuron facial palsy was made with the possible anatomical site distal to the origin of nerve to stapedius muscle. On detailed assessment, she revealed to have been convalescing from an episode of jaundice, which she had acquired 1 month prior to the onset of the present focal deficit. Work-up was carried out to find out the etiology of bilateral facial palsy. Hemogram parameters were within normal limits including erythrocyte sedimentation rate. (hemoglobin –11.9 g/dl [10-12], total leucocyte count –4580 cells/cumm [4000-11,000], differential count [P –62%, L –30%, M –2%, E –6%] platelet count - 1,89,000 [1,50,000-4,00,000]). Liver function parameters had normalized (S. bilirubin - 0.4 mg/dl [0-1.3], conjugated bilirubin - 0.2 mg/dl, serum glutamic axaloacetic transaminas –16 U/L [0-36], serum glutamic pyruvic transaminas –31 U/L [0-52], alkaline phosphatase –59 U/L [38-126], total protein –7.8 g/dl [6.0-8.2], S. albumin –4.5 g/dl
[3.5-5.0]). Metabolic parameters were normal: S. calcium –9.1 mg/dl (8.4-10.2), S. phosphorous –3.5 mg/dl (2.5-4.5) and S. creatinine –0.8 mg/dl (0.7-1.2). Viral markers were assessed: Human immunodeficiency virus - non-reactive by enzymelinked immunosorbent assay (ELISA), herpes simplex 1, 2 immunoglobulin (Ig)M and IgG antibody (ELISA): Negative, hepatitis B surface antigen (ELISA)-negative, anti-hepatitis C virus-negative, anti-hepatitis E virus IgM (ELISA)-negative, anti-hepatitis A virus (HAV) IgM (ELISA)-positive; 2.66 EU/ ml (cut-off value: 0.600 EU/ml). Serum angiotensin converting enzyme levels were 102.0 IU/L (8-65). Nerve conduction studies revealed bilateral facial nerve axonopathy only. Neuroimaging study [gadolinium contrast enhanced magnetic resonance imaging brain with constructive interference in steady state (CISS) sequences] did not reveal any structural pathology. High resolution computerised tomography scan of the chest did not reveal any structural pathology. Mantoux test was borderline positive (8 mm induration at 72 h). Cerebrospinal fluid evaluation was not performed in view of lack of any clue towards meningeal based pathology. As the dedicated work up for etiology of bilateral lower motor neuron type facial palsy was negative, we postulated it to be probably an immune phenomenon as a consequence to the recent HAV infection from, which she was convalescing. With conservative neurorehabilitative measures and facial nerve stimulation procedures our patient had significant improvement in her neurological status over duration of 8 weeks.
Annals of Indian Academy of Neurology, October-December 2013, Vol 16, Issue 4
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