Late side-effects of valproate and lamotrigine

Efeitos adversos tardios no uso de valproate e lamotrigina

BRIEF COMMUNICATIONS

Late side-effects of valproate and lamotrigine

Efeitos adversos tardios no uso de valproate e lamotrigina

Bernardo Moreira; Sigride Thomé-Souza; Kette Valente

Laboratório de Neurofisiologia Clínica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

^{Corresponding Author}

ABSTRACT

Lamotrigine (LTG) is a generally well-tolerated antiepileptic drug with broad-spectrum efficacy in several forms of partial and generalized epilepsy. Adverse effects of lamotrigine are usually associated with introduction and titration. This risk increases in children and in the co-medication with valproate. Herein, we report four patients with late adverse-effects, under the co-medication valproate and LTG, not related to drug introduction or titration. This study demonstrates that late side-effects without apparent etiology in children, adolescents and adults in chronic use of LTG, especially when associated to VPA, led to a diagnostic investigation, sometimes invasive. It must be emphasized that, due to the excellent seizure control, the authors opted for drug decrease instead of drug withdrawal, as previously done. Studies on late adverse effects are scarce, but physicians must be aware of these risks.

Key words: lamotrigine, side-effects, epilepsy, anti-epileptic drugs.

RESUMO

Lamotrigina (LTG) é uma droga antiepiléptica bem tolerada com eficácia em diferentes formas de epilepsia, parcial e generalizada. Os efeitos adversos da lamotrigina estão freqüentemente associados com a sua introdução e a sua titulação. Este risco encontra-se aumentado em crianças e quando a LTG é usada em associação com o valproato. Nós relatamos quatro pacientes que apresentaram efeitos adversos tardios com a co-administração de LTG e valproato, não relacionados à introdução ou o escalonamento das drogas antiepilépticas. Este estudo demonstra que efeitos adversos tardios sem etiologia aparente nas crianças, adolescentes e adultos em uso crônico de LTG, especialmente quando associados ao valproato, levou à investigação diagnóstica, por vezes invasiva. Os autores enfatizam que, devido ao bom controle de crises, os autores optaram pela redução da dose ao invés da suspensão da medicação, como previamente realizado. Embora os estudos sobre efeitos adversos tardios das drogas antiepilépticas sejam escassos, os clínicos devem estar cientes deste risco.

Unitermos: lamotrigine, efeitos adversos, epilepsia, drogas antiepilépticas.

INTRODUCTION

Lamotrigine (LTG) is a newer anti-epileptic drug (AED), well-tolerated by children and adults¹ with a wide-spectrum efficacy, in either monotherapy or polytherapy.^2,3 Its mechanism of action is determined by its action blocking Na+ channels⁴ and a possible action on NMDA receptors.^4,5

The pharmacokinetic profile of LTG demonstrates good absorption after oral administration, a linear relation between dose and plasma concentrations, ~55% protein binding, and an elimination half-life of 25-30 h with monotherapy.⁶ The elimination half-life is reduced to ~15 h during combination therapy with hepatic enzyme-inducing AEDs [e.g., carbamazepine (CBZ), phenytoin (PHT)]^7-10 and more than doubled to ~60 h when combined with valproate (VPA) a microsomal enzyme inhibitor.^7,8

Tolerability and long-term safety studies have shown a relatively low incidence of neurotoxicity (e.g., asthenia, dizziness, somnolence, ataxia, trembling) in add-on studies and when compared with CBZ and PHT in monotherapy trials.^6-11 Several studies have reported a tendency to improve mental function, especially in children.^12-16

The most common adverse effect leading to discontinuation of LTG is rash, which was severe enough to require discontinuation in 3% of adults in early clinical trials.¹⁷ This risk increases in children and with the co-medication VPA-LTG.

There is scarce data on long-term late adverse effects on tissues or organs or on cognitive function. Herein, we report four patients with late adverse-effects, under the co-medication VPA-LTG, not related to drug introduction or titration.

CASE REPORT

CASE 1. A 6 year-old girl, with partial epilepsy characterized by partial motor seizures, occurring predominantly during sleep with onset at 2 years and 6 months. EEG revealed epileptiform discharges over the centroparietal region. MRI displayed a polymicrogyria over the right opercular region. The child evolved with refractory epilepsy and medical control was obtained with association of LTG to VPA and nitrazepam. LTG was slowly introduced, according to Guberman et al. guidelines.¹ Nine months after the last dose adjustment, the child presented sporadic episodes of vomiting every 15 days. A pediatrician ruled out infection or other acute causes, such as metabolic disturbances. At the same time, the patient started presenting trembling and dizziness. One month later, the patient evolved with a sudden opsoclonus, ataxia, vomiting, headache and vertigo. Ancillary exams were conducted including lumbar puncture, CT and MRI in order to rule out infection or tumors. A slow decrease of LTG dose of 50 mg led to remission of these signs and symptoms without worsening of seizures.

CASE 2. An 18 year-old female adolescent with refractory epilepsy since the age of 8 months characterized by generalized seizures – myoclonic and tonic-clonic seizures. Later, these seizures were associated to atypical absence and atonic seizures. MRI revealed a diffuse malformation of cortical development characterized by band heterotopia (double cortex). After several drug trials, co-administration of VPA-LTG led to partial seizure control, abolishing disabling seizures that affected daily activities. In 2003, 1 year and 3 months after the last AED adjustment, with stable doses, the patient presented involuntary movements affecting the head and neck, characterizing tics. A LTG decrease in 25 mg led to the remission of these movements.

CASE 3. A 15 year-old female adolescent with epilepsy onset at the age of 4 years, which evolved with disabling seizures. EEG showed multifocal epileptiform discharges and MRI demonstrated band heterotopia. The patient evolved with refractory epilepsy and at the age of 11 years, LTG was associated to VPA with satisfactory seizure control. Two years after the last dose increase, the child presented an acute episode with nistagmus, ataxia, tremor and vertigo. Ancillary exams did not reveal an etiology for these signs and symptoms. Decrease of 50 mg in LTG dose led to remission of this clinical picture, without seizure worsening.

CASE 4. A 14 year-old male adolescent with refractory myoclonic epilepsy with onset at 1 year of age. This patient was referred at the age of 12 years with partial seizure control with a ketogenic diet that had to be with drawn after 5 years. Interruption of this treatment led to reiterated status epilepticus. The patient was admitted using VPA and clonazepam. LTG was introduced according to Guberman et al criteria.¹ The patient had total remission of generalized tonic-clonic events and partial control of myoclonic seizures (brief weekly events) with high doses of LTG (400 mg/day) and VPA (1.5 g/day). One year after the last adjustment of theses doses, patients began presenting speech and gait difficulties. The neurologic exam showed ataxia and disabling tremor. LTG reduction (50 mg) led to remission of the cerebellar signs and symptoms.

DISCUSSION

These four cases showed a common characteristic – a prolonged gap between the last dose adjustment and the onset of adverse effects. This period ranged from 9 months to 2 years. Other possible systemic triggering factors that could increase the blood level of LTG or VPA, or both, were ruled-out. Late side-effects without apparent etiology in children, adolescents and adults in chronic use of LTG, especially when associated to VPA, led to a diagnostic investigation, sometimes invasive, painful and stressful for both patients and their families.

The revision of La Roche and Helmers^18,19 demons trated that side-effects led to drug withdrawal in 10.2% of all patients under LTG therapy (n = 3501). Rash was the main reason for treatment discontinuation. It has been postulated that side-effects may be lessened by slow introduction and titration.^1,18,19

Rare studies have reported side-effects after chronic use of LTG (ex, 6 months).²⁰ The study of Mackay et al.²¹ evaluated adverse-effects six months after LTG introduction. Rash and Steven-Johnsons syndrome were earlier manifestations, observed during introduction. In the same study, other adverse-effects such as mood disorder, ataxia, visual blurring and diplopia were reported few months after treatment onset. Although the occurrence of these effects is rare (0.1-0.2%), it serves as a warning to possible late neurological and psychiatric signs and symptoms.

Patients described in this series presented heterogeneous signs and symptoms, such as ataxia, vertigo and headache, which are common adverse-effects.^1,22 On the other hand, tics, abnormal eye movements and movement disorders as observed in two patients are rare.^23-25 The mechanisms that cause abnormal eye movements and movement disorders are highly hypothetical. It has been postulated that AED may act on sodium channels causing such anomalies, by acting on dopaminergic metabolism with the inhibition of excitatory aminoacides (glutamine). Another hypothesis is that the increase in epileptiform discharges may cause these abnormal eye movements.²⁶ In disagreement with the latter, none of our patients had a worsening of epileptiform discharges or seizures during these events.

An important factor that must be stressed is that, due to the excellent seizure control obtained in these refractory cases, the authors opted for drug decrease instead of drug withdrawal, as usually done.^27-29

CONCLUSION

It is believed that after introduction of one AED, without dose increments, adverse-effects will not be observed. We corroborated the few cases in the literature that show serious adverse-effects with chronic use and stable doses of LTG and VPA. This must be kept in mind in order to avoid unnecessary exams. Additionally, we showed that a low dose decrease may lead to the remission of these serious adverse effects without consequences to the patient, such as seizure worsening.

Received Oct. 24, 2007; accepted Nov. 09, 2007.

• 1. Guberman AH, Besag FMC, Brodie MJ, Dooley JM, Duchowny MS, Pellock JM, Richens A, Stern RS, Trevathan E. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999; 40(7):985-91.
• 2. Matsuo F. Lamotrigine. Epilepsia. 1999; 40(Suppl 5):S30-S36.
• 3. Messenheimer JA, Giorgi L, Risner ME. The tolerability of lamotrigine in children. Drug Safety. 2000; 22(44):303-12.
• 4. Coulter DA. Antiepileptic drug cellular mechanisms of action: Where does lamotrigine fit in? J Child Neurol. 1997; 12(Suppl 1): S2-S9.
• 5. Brodie MJ. Lamotrigine: an update. Can J Neurol Sci. 1996; 23(4):S6-S9
• 6. Fitton A, Goa KL. Lamotrigine: an update of its pharmacology and therapeutic use in epilepsy. Drugs. 1995; 50:691-713.
• 7. Binnie CD. Van Emde Boas W, Kastelijn-Nolste-Trnite DGA, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia. 1986; 27:248-54.
• 8. Eriksson A-S, Hoppu K, NergDrdh A, Boreus L. Pharmacokinetics of lamotrigine in children with intractable epilepsy [Abstract]. J Epilepsy. 1994; 7:326.
• 9. Jawad S, Richens A, Goodwin G, Yuen WC. Controlled trial of lamotrigine (Lamictal) for refractory partial seizures. Epilepsia. 1989;30:356-63.
• 10. Ramsay RE, Pellock JM, Garnett WR, et al. Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy. Epilepsy Res. 1991; 10:191-200.
• 11. Chapman AA, Keane PE, Meldrum BS, Simiand J, Vernieres JC. Mechanism of anticonvulsant action of valproate. Prog Neurobiol. 1982; 19:315-59.
• 12. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol. 1992; 33:511-3.
• 13. Schachter S, Leppik I, Matsuo F, et al. for the US Lamotrigine Protocol 16 Clinical Study Group. A multicenter, placebo-controlled evaluation of the safety of lamotrigine (Lamictal) as add-on therapy in outpatients with partial seizures [Abstract]. Epilepsia. 1992; 33(Suppl 3):119.
• 14. Foletti G, Schmidt M, Delisle MC, Molleyres D, Volanschi D. An open study on effectiveness of lamotrigine in the treatment of secondary bilateral synchrony, unsatisfactorily controlled by conventional drugs [Abstract]. J Neurol. 1992; 239(Suppl 2):S71.
• 15. Oller LFV, Russi A, Oller Daurella L. Lamotrigine in the Lennox-Gastaut syndrome [Abstract]. Epilepsia. 1991; 32(Suppl 1):58.
• 16. Uvebrant P, Bauzien PR. Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics. 1994; 25:284-9.
• 17. Richens A. Safety of lamotrigine. Epilepsia. 1994; 35(Suppl 5): S37-S40.
• 18. LaRoche SM; Helmers SL. The new antiepileptic drugs: clinical applications.[Review]. JAMA. 2004; 291(5):615-20.
• 19. LaRoche SM; Helmers SL. The new antiepileptic drugs: clinical applications.[Review]. JAMA. 2004; 291(5):605-14.
• 20. Reutens DC, Duncan JS, Patsalos PN. Disabling tremor after lamotrigine with sodium valproate [letter]. Lancet. 1993 Jul; 342:185-6.
• 21. Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of Long-Term Lamotrigine in Epilepsy. Epilepsia. 1997;38(8): 881-6
• 22. Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia. 1994; 35(2): 359-67.
• 23. Lamictal product monograph (Burroughs Wellcome-Canada), Rev 12/15/94, Rec 4/18/95.
• 24. Matsuo F, Bergen D, Faught E, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology. 1993; 43:2284-91.
• 25. Leach MJ, Baxter MG, Critchley MAE. Neurochemical and behavioral aspects of lamotrigine. Epilepsia. 1991; 32(Suppl 2): S4-S8.
• 26. Cocito L, Maffini M, Loeb C. Long-term observations on the clinical use of lamotrigine as add-on drug in patients with epilepsy. Epilepsy Res. 1994; 19:123-7.
• 27. Das KB, Harris C, Smyth DPL, Cross JH. Unusual side effects of Lamotrigine therapy. J Child Neurol. 2003; 18(7):479-80.
• 28. Catania S, Cross JH, de Sousa C, et al. Paradoxic reaction to lamotrigine in a child with benign focal epilepsy of childhood with centrotemporal spikes. Epilepsia. 1999; 40:1657-60.
• 29. Neville BGR. Steroid responsive motor disorders associated with epilepsy. In: Guerrini R, Aicardi J, Andermann F, Hallet M, editors. Epilepsy and Movement Disorders. Cambridgde: Cambridge University Press; 2001. p. 511-6.

Publication Dates

• Publication in this collection
  28 Feb 2008
• Date of issue
  Dec 2007

History

• Received
  24 Oct 2007
• Accepted
  09 Nov 2007