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Lamotrigine Intoxication Provoking Status Epilepticus in an Adult With Localization-Related Epilepsy FREE

Eric Dinnerstein, MD; Barbara C. Jobst, MD; Peter D. Williamson, MD
[+] Author Affiliations

Author Affiliation: Section of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Dr Dinnerstein is now with Maine Neurology, Scarborough.


Arch Neurol. 2007;64(9):1344-1346. doi:10.1001/archneur.64.9.1344.
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Published online

ABSTRACT

Background  Various anticonvulsant medications have been associated with paradoxical aggravation of epileptic seizures in therapeutic doses and toxic concentrations. Lamotrigine has been reported to exacerbate seizures and myoclonic seizures in generalized epilepsy in a child with localization-related epilepsy.

Objective  To describe lamotrigine intoxication paradoxically producing status epilepticus in an adult with localization-related epilepsy.

Design  Observational case report.

Setting  Neurology service, inpatient hospitalization, and outpatient follow-up in a neurology clinic.

Patient  A patient with known localization-related epilepsy who ingested an overdose of lamotrigine tablets in a suicide attempt.

Intervention  None.

Main Outcome Measure  Observation of the course of the patient's reaction to lamotrigine intoxication, monitoring of lamotrigine levels, and monitoring of ictal and postictal status.

Results  The patient developed a prolonged convulsive status epilepticus, which was eventually controlled with benzodiazepines. The patient also developed transient obtundation and severe ataxia, all of which resolved completely within 96 hours.

Conclusions  To our knowledge, in addition to being the first case report to describe convulsive status epilepticus after lamotrigine intoxication, this is the first report of the proconvulsant effect of lamotrigine in a case of localization-related epilepsy in an adult. The effects of accidental or suicidal ingestion of lamotrigine tablets seem to be reversible.

It has been recognized for more than 40 years that anticonvulsant medications may paradoxically exacerbate seizure activity.1 Carbamazepine (including oxcarbamazepine), phenytoin, gabapentin, and tiagabine have been reported to aggravate seizures in idiopathic generalized epilepsies, especially myoclonic jerks and absence seizures.25 The mechanisms leading to a paradoxical seizure are not fully understood, but they are thought to be due to an inverse pharmacodynamic effect, the development of tolerance or an acute idiosyncratic adverse effect, or poor compliance.5

Lamotrigine has been associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies.6,7 Although a case report described a paradoxical reaction to lamotrigine therapy in benign focal epilepsy of childhood with centrotemporal spikes,8 little is known of the association between lamotrigine intoxication and exacerbation of seizure activity in symptomatic localization-related epilepsies. We describe a case of lamotrigine intoxication provoking status epilepticus in an adult with symptomatic localization-related epilepsy.

REPORT OF A CASE

A 42-year-old woman, without identifiable epilepsy risk factors, had developed a seizure disorder at the age of 7 years. The seizures consisted of left-sided tonic seizures with a nocturnal preponderance, lasting 5 to 60 seconds. Consciousness was preserved. Seizures were brought under control during adolescence and early adulthood with the administration of carbamazepine therapy. Seizures then returned and gradually became more frequent. They were similar to her previous left-sided tonic seizures, but she also reported tingling in her left leg. The seizures were exacerbated by exercise and during the pregnancy of her first child. The seizures would cluster in periods, with a nocturnal preponderance. Owing to her desire to become pregnant, carbamazepine therapy was discontinued and lamotrigine therapy was initiated. Seizures persisted but at a reduced rate. She was referred to the Dartmouth-Hitchcock Epilepsy Center, Lebanon, New Hampshire. Magnetic resonance imaging of the brain demonstrated a right-sided subcortical mesial frontoparietal hyperintense signal on the fluid-attenuated inversion recovery sequences. The patient had a history of anxiety and depression, but was never severely depressed or suicidal.

The patient conceived, but the pregnancy terminated with a spontaneous abortion at 9 weeks' gestation. A week later, she ingested a total of 4.1 g of lamotrigine (41 tablets of 100 mg) in a suicide attempt. Approximately 1 to 2 hours after ingestion, the patient had a series of secondarily generalized tonic-clonic seizures over 3 hours without full recovery of consciousness between seizures. She was brought to the emergency department where seizures were ultimately controlled with benzodiazepines. The patient had significant tongue lacerations as a consequence of the prolonged seizure activity as well as multiple seizure-related orbital and body hematomas.

After control of convulsive activity, she remained obtunded for approximately 12 hours. The lamotrigine concentration on admission to the emergency department was 47.4 μg/mL. The patient's condition was monitored closely as lamotrigine levels gradually decreased during the course of the following days (lamotrigine levels were 47.4 μg/mL on hospital day 1, 15.8 μg/mL on hospital day 2, 3.2 μg/mL on hospital day 3, and 0.8 μg/mL on hospital day 4). The patient gradually regained consciousness and within 24 hours she was awake and alert. When further evaluated, she was found to be severely ataxic. There was gradual improvement to baseline neurological status over the course of 4 days. After discharge from the hospital, she had persistent and more frequent typical seizures. Lamotrigine therapy was replaced with levetiracetam therapy but the seizures continued nightly. Seizures also occurred more frequently during the day. An extensive presurgical workup included an intracranial electroencephalographic study. Seizure onset was localized to the supplementary motor area on the right side. She underwent resection of the supplementary motor area on the right side. She has remained seizure free during the 12 months following surgery. The results of pathologic studies disclosed cortical dysplasia.

COMMENT

Various anticonvulsant medications have been observed to be paradoxically proconvulsant for epileptic patients whose intake is at toxic levels. The proconvulsant effect of high doses of anticonvulsant medications was previously reported with carbamazepine3 (including oxcarbamazepine2) and phenytoin.1,4 A comprehensive review of the paradoxical aggravation of anticonvulsant medications was previously published by Genton.5 Aggravation of seizures with a certain medication does not necessitate discontinuation of the medication if it is used cautiously. A temporal relationship between the high levels and the exacerbation of seizures is crucial to identify a potential aggravation by antiepileptic medications.5 In our patient there was a clear temporal relationship between a lamotrigine overdose and status epilepticus.

Recent articles have demonstrated the proconvulsant effects of lamotrigine therapy, mostly in childhood conditions such as benign focal epilepsy of childhood with centrotemporal spikes,8 severe myoclonic epilepsy of infancy,9 Lennox-Gastaut syndrome,10 and juvenile myoclonic epilepsy.11 Although described less often in adults, the proconvulsant effects of lamotrigine therapy have been demonstrated in idiopathic generalized epilepsy alone12 and in idiopathic generalized epilepsy with myoclonic jerks.6 Moreover, nonconvulsive status epilepticus has been associated in 3 patients with idiopathic generalized epilepsy.12

To our knowledge, localization-related epilepsy exacerbated by toxic doses of lamotrigine has not been reported previously. Moreover, this is the first report of a case describing lamotrigine provoking status epilepticus in an adult with localization-related epilepsy. The patient, without history of secondarily generalized seizures, developed tonic-clonic status epilepticus with lamotrigine intoxication. Her seizures seemed to exacerbate after the acute intoxication, but no definite relationship between increased seizure frequency and the lamotrigine intoxication can be established, as her antiepileptic medication regimen was changed. The increase in seizure frequency may merely reflect medication changes.

Lamotrigine therapy is efficacious for most seizure types, and it is widely used in the treatment of partial and generalized epilepsies.13 It is considered a relatively safe medication, with rare central nervous system adverse effects such as anxiety, ataxia, confusion, depression, headache, insomnia, irritability, and concentration problems. The most significant adverse events are skin hypersensitivity reactions, which frequently lead to discontinuation of lamotrigine therapy, due to possible progression to Stevens-Johnson syndrome.14

Our patient became ataxic and somnolent with lamotrigine intoxication. All of those symptoms completely resolved. No skin eruptions occurred. Other articles have described ataxia and encephalopathy with accidental or suicidal lamotrigine ingestion at toxic concentrations.15,16 To our knowledge, no cases of fatal lamotrigine intoxication have been reported although, in a retrospective review of autopsies, death was associated with an intake of lamotrigine.17 However, those patients may have represented sudden unexplained death in epilepsy. Skin eruptions or Stevens-Johnson syndrome do not seem to be associated with lamotrigine intoxication per se.15 In summary, the aggravation of seizures with toxic concentrations of lamotrigine can occur not only in myoclonic seizures but also in localization-related epilepsy. Lamotrigine seems safe even after ingestion of high or toxic concentrations with reversible ataxia and encephalopathy.

ARTICLE INFORMATION

Correspondence: Eric Dinnerstein, MD, Section of Neurology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756 (ericdinnerstein@maineneurology.com).

Accepted for Publication: April 5, 2007.

Author Contributions:Study concept and design: Dinnerstein and Jobst. Acquisition of data: Dinnerstein and Jobst. Analysis and interpretation of data: Dinnerstein, Jobst, and Williamson. Drafting of the manuscript: Dinnerstein and Jobst. Critical revision of the manuscript for important intellectual content: Jobst and Williamson. Administrative, technical, and material support: Dinnerstein and Jobst. Study supervision: Jobst and Williamson.

Financial Disclosure: None reported.

REFERENCES

Levy  LLFenichel  GM Diphenylhydantoin activated seizures. Neurology 1965;15716- 722
PubMed Link to Article
Gelisse  PGenton  PKuate  CPesenti  ABaldy-Moulinier  MCrespel  A Worsening of seizures by oxcarbamazepine in juvenile idiopathic generalized epilepsies. Epilepsia 2004;45 (10) 1282- 1286
PubMed Link to Article
Dhuna  APascual-Leone  ATalwar  D Exacerbation of partial seizures and onset of nonepileptic myoclonus with carbamazepine. Epilepsia 1991;32 (2) 275- 278
PubMed Link to Article
Osorio  IBurnstine  THRemler  BManon-Espaillat  RReed  RC Phenytoin-induced seizures: a paradoxical effect at toxic concentrations in epileptic patients. Epilepsia 1989;30 (2) 230- 234
PubMed Link to Article
Genton  P When antiepileptic drugs aggravate seizures. Brain Dev 2000;22 (2) 75- 80
PubMed Link to Article
Crespel  AGenton  PBerramdane  M  et al.  Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology 2005;65 (5) 762- 764
PubMed Link to Article
Cerminara  CMontanaro  MLCuratolo  PSeri  S Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology 2004;63 (2) 373- 375
PubMed Link to Article
Catania  SCross  Hde Sousa  CBoyd  S Paradoxical reaction to lamotrigine in a child with benign focal epilepsy of childhood with centrotemporal spikes. Epilepsia 1999;40 (11) 1657- 1660
PubMed Link to Article
Genton  PGelisse  PCrespel  A Lack of efficacy and potential aggravation of myoclonus with lamotrigine in Unverricht-Lundborg disease. Epilepsia 2006;47 (12) 2083- 2085
PubMed Link to Article
Guerrini  RBelmonte  AParmeggiani  LPerucca  E Myoclonic status epilepticus following high-dose lamotrigine therapy. Brain Dev 1999;21 (6) 420- 424
PubMed Link to Article
Biraben  AAllain  HScarabin  JMSchück  SEdan  G Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology 2000;55 (11) 1758- 1759
PubMed Link to Article
Trinka  EDilitz  EUnterberger  I  et al.  Non convulsive status epilepticus after replacement of valproate with lamotrigine. J Neurol 2002;249 (10) 1417- 1422
PubMed Link to Article
Messenheimer  JA Lamotrigine. Epilepsia 1995;36(suppl 2)S87- S94
PubMed Link to Article
Richens  A Safety of lamotrigine. Epilepsia 1994;35(suppl 5)S37- S40
PubMed Link to Article
Sbei  MCampellone  JV Stupor from lamotrigine toxicity. Epilepsia 2001;42 (8) 1082- 1083
PubMed Link to Article
Lofton  ALKlein-Schwartz  W Evaluation of lamotrigine toxicity reported to poison centers [published online ahead of print September 7, 2004]. Ann Pharmacother 2004;38 (11) 1811- 1815
PubMed Link to Article
Pricone  MGKing  CVDrummer  OHOpeskin  KMcIntyre  IM Postmortem investigation of lamotrigine concentrations. J Forensic Sci 2000;45 (1) 11- 15
PubMed

Figures

Tables

References

Levy  LLFenichel  GM Diphenylhydantoin activated seizures. Neurology 1965;15716- 722
PubMed Link to Article
Gelisse  PGenton  PKuate  CPesenti  ABaldy-Moulinier  MCrespel  A Worsening of seizures by oxcarbamazepine in juvenile idiopathic generalized epilepsies. Epilepsia 2004;45 (10) 1282- 1286
PubMed Link to Article
Dhuna  APascual-Leone  ATalwar  D Exacerbation of partial seizures and onset of nonepileptic myoclonus with carbamazepine. Epilepsia 1991;32 (2) 275- 278
PubMed Link to Article
Osorio  IBurnstine  THRemler  BManon-Espaillat  RReed  RC Phenytoin-induced seizures: a paradoxical effect at toxic concentrations in epileptic patients. Epilepsia 1989;30 (2) 230- 234
PubMed Link to Article
Genton  P When antiepileptic drugs aggravate seizures. Brain Dev 2000;22 (2) 75- 80
PubMed Link to Article
Crespel  AGenton  PBerramdane  M  et al.  Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology 2005;65 (5) 762- 764
PubMed Link to Article
Cerminara  CMontanaro  MLCuratolo  PSeri  S Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology 2004;63 (2) 373- 375
PubMed Link to Article
Catania  SCross  Hde Sousa  CBoyd  S Paradoxical reaction to lamotrigine in a child with benign focal epilepsy of childhood with centrotemporal spikes. Epilepsia 1999;40 (11) 1657- 1660
PubMed Link to Article
Genton  PGelisse  PCrespel  A Lack of efficacy and potential aggravation of myoclonus with lamotrigine in Unverricht-Lundborg disease. Epilepsia 2006;47 (12) 2083- 2085
PubMed Link to Article
Guerrini  RBelmonte  AParmeggiani  LPerucca  E Myoclonic status epilepticus following high-dose lamotrigine therapy. Brain Dev 1999;21 (6) 420- 424
PubMed Link to Article
Biraben  AAllain  HScarabin  JMSchück  SEdan  G Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology 2000;55 (11) 1758- 1759
PubMed Link to Article
Trinka  EDilitz  EUnterberger  I  et al.  Non convulsive status epilepticus after replacement of valproate with lamotrigine. J Neurol 2002;249 (10) 1417- 1422
PubMed Link to Article
Messenheimer  JA Lamotrigine. Epilepsia 1995;36(suppl 2)S87- S94
PubMed Link to Article
Richens  A Safety of lamotrigine. Epilepsia 1994;35(suppl 5)S37- S40
PubMed Link to Article
Sbei  MCampellone  JV Stupor from lamotrigine toxicity. Epilepsia 2001;42 (8) 1082- 1083
PubMed Link to Article
Lofton  ALKlein-Schwartz  W Evaluation of lamotrigine toxicity reported to poison centers [published online ahead of print September 7, 2004]. Ann Pharmacother 2004;38 (11) 1811- 1815
PubMed Link to Article
Pricone  MGKing  CVDrummer  OHOpeskin  KMcIntyre  IM Postmortem investigation of lamotrigine concentrations. J Forensic Sci 2000;45 (1) 11- 15
PubMed

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