IJCRI – International Journal of Case Reports and Images, Vol. 2 No. 1 2, December 2011 . ISSN – [0976-31 98]

Lamotrigine is said to be safe but be cautious:A case reportShri Niwash Jangir, Rajeshwari Suthar,AK Singhal, Smita N Deshpande

ABSTRACTIntroduction: Severe hypersensitivity reactionsof lamotrigine are very uncommon conditions.We present this case of rapid development oftoxic epidermal necrolysis. Case Report: A 37­year­old female of bipolar affective disorder onlamotrigine presented with acute skin eruptionswith fever which involved almost whole body innext 7­10 days. There was massive peeling of theskin involving more than 50% of the bodysurface. Discussion: The case was diagnosed aslamotrigine induced toxic epidermal necrolysisand treated conservatively. Conclusion:Watchfulness of the clinicians and educating thepatient about the doses schedule and adversereaction of lamotrigine is key to prevent severecutaneous reactions.Keywords: Lamotrigine, Bipolar affectivedisorder, Stevens ­ Johnson syndrome, Toxicepidermal necrolysis.

*********

Jangir SN, Suthar R, Singhal AK, Deshpande SN.Lamotrigine is said to be safe but be cautious: A casereport. International Journal of Case Reports andImages 2011;2(12):19­22.*********

doi:10.5348/ijcri­2011­12­75­CR­5

INTRODUCTIONLamotrigine is being widely used in the treatment ofpartial seizures and generalized tonic­clonic seizures,either as monotherapy or as adjunctive treatment. It hasa distinct place in the management of bipolar disorder,with the potential to treat and prevent bipolardepression. The strongest evidence for its efficacy lies inthe prevention of bipolar depression [1].Of all the adverse events associated with lamotrigine,rash has been the greatest concern. Indeed, before itslaunch in the United States in 1994, lamotrigine trialswere complicated by severe rashes, presenting asStevens–Johnson syndrome, toxic epidermal necrolysisor severe hypersensitivity syndrome. This led to theinclusion of a black­box warning in the prescribinginformation. The relatively high incidence of seriousrash was attributed to a high initial dose and rapidescalation, which compelled the manufacturer torecommend the policy of start with low and go slow.Thus, the starting dose of lamotrigine was cut from 50mg/day to 12.5 mg/day, when used as adjunct therapywith valproic acid, and from 100 mg/day to 50 mg/day,when added to a regimen of enzyme­inducingantiepileptic drugs [2].

CASE REPORTA 37­year­old, illiterate female with bipolardepressive disorder was admitted in the emergencydepartment with an acute skin eruption over legs and

CASE REPORT OPEN ACCESS

Shri Niwash Jangir1 , Rajeshwari Suthar2, AK Singhal3,Smita N Deshpande4

Affi l iations: 1Senior Research Associate, Department ofPsychiatry, PGIMER-Dr. RML Hospital, New Delhi, India;2Senior Resident, Department of Obstetric & Gynecology,ESIC Hospital, Government of India, New Delhi, India;3Head, Department of Psychiatry, SP Medical College &AG Hospital, Bikaner, Rajasthan, India; 4Head, Departmentof Psychiatry, PGIMER-Dr. R.M.L. Hospital, New Delhi,India.Corresponding Author: Dr. Shri Niwash Jangir, Flat no. 5,Plot no. 42, Lake View Apartment, sector 9, Rohini, NewDelhi (India). Pin No.11 0085; Ph: +91 -9968236021 , +91 -941 43081 21 ; Fax no: +91 -011 233421 22; Email :dr_snjangir@yahoo.co. in

Received: 24 May 2011Accepted: 05 September 2011Published: 31 December 2011

IJCRI 2011 ;2(1 2):1 9-22.www.ijcasereportsandimages.com Jangir et al. 1 9

IJCRI – International Journal of Case Reports and Images, Vol. 2 No. 1 2, December 2011 . ISSN – [0976-31 98]

Jangir et al. 20

body, temperature 101° F and bilateral inguinal andsubmandibular lymphadenopathy. She was evaluatedand received one dose of sodium phosphatebetamethasone and dexchlorpheniramine maleate 5.3mg, intravenously along with oral antipyretics withpartial relief of her symptoms. A detailed history wastaken from the patient, her relatives and medical records.She had been prescribed lamotrigine for bipolardepression 25 mg every day; subsequently up titrated to200 mg/day during the next two months. Her depressionimproved and she discontinued the medications on herown. After a symptom free period of about four months,depressive symptoms reappeared and the patientresumed the old prescription ­ escitalopram 20 mg/dayand lamotrigine 200 mg/day in two divided doses. Theskin eruptions developed after 7­10 days of starting themedication.We discontinued the clinically suggested causativedrug lamotrigine immediately but the rash continued toprogress. We shifted the patient to dermatology care andtreated conservatively. The lesions disseminated veryrapidly all over the body including the palms and soleswith almost bilateral symmetry, in the form oferythematous papules, papulovesicles, bullae andnecrotic erosions. Even the oral mucosa and tongue werenot spared and developing erosions and aphthous ulcers.The lips had thick hemorrhagic crusting (figure 1). Thenasal mucosa was also affected. Her postnasal and oralsecretions were highly purulent. Both conjunctivas werehyperemic with purulent secretions. Ophthalmologicexamination revealed bilateral conjunctivitis with nocorneal involvement and epithelial detachment in theconjunctiva. The Nikolsky's sign was found positive.Erosions and erythematous papules also developed ongenitalia. The lesions lead to massive peeling of the skinaffecting face, neck, trunk and extremities. Theunderlying denuded skin was red and exquisitely tender(figure 2 A, B). The body surface area detachment wasapproximately 50%, as per estimation by rule of nine.Initially, the laboratory assessments suggested stronginflammatory reaction: leucocytosis, elevated erythrocytesedimentation rate and increased C­reactive protein levelwith peripheral blood eosinophilia, while otherinvestigations i.e. hepatic enzyme levels, renal function,and serum electrolyte levels were within normal limits.Urine, blood, and throat cultures were sterile. Later, abiopsy specimen from a lesion showed edema and scantymononuclear inflammatory cell infiltration in theperivascular region with total necrosis and completeseparation of the epidermis from the underlying dermis,suggestive of toxic epidermal necrolysis. Almost allepidermal structures were obliterated. The patientmanaged to survive with fluid replacement, nutritionalsupport, dressings and systemic as well as local culturespecified anti­infective treatment.

DISCUSSIONStevens­Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN) are rare life­threatening

mucocutaneous reactions of a continuous severityspectrum with incidence estimated to be 1­2 cases permillion population per year [3]. More than 70% of cases

Figure 1: Showing massive erosions and aphthous ulcers onoral mucosa and tongue and hemorrhagic crusting over thelips.

Figure 2: A, B) Large areas of epidermal shedding, and redand exquisitely tender underlying denuded skin over thetrunk, neck, face, ear and extremities.

IJCRI 2011 ;2(1 2):1 9-22.www.ijcasereportsandimages.com

IJCRI – International Journal of Case Reports and Images, Vol. 2 No. 1 2, December 2011 . ISSN – [0976-31 98]

Jangir et al. 21

of TEN are drug induced and the common culprit drugsare carbamazepine, phenytoin, phenobarbital,lamotrigine, sulfonamides, oxicam, nevirapine andallopurinol [4].Lamotrigine is said to be well­tolerated, having anadverse­event profile by and large comparable toplacebo [5]. Though, simple maculopapular rashes arecommon (3­15%) but the rare severe cutaneousreactions such as SJS and TEN have always been thegreatest concern and most frequent reason fordiscontinuation of the drug in clinical practice [6]. Therisk factors more commonly associated with adversereactions are: first eight weeks of treatment, exceedingthe recommended starting dose, rapid dose escalationand concomitant use of sodium valproate. However, theforecast of the progression of the rashes is difficult [7].SJS and TEN are often drug induced idiosyncraticcutaneous reactions of similar histology. It has beenproposed that they represent a spectrum of the samepathogenic mechanism. The pathogenesis of both thedisorders is still unclear; however, immunologicalhypersensitivity, particularly T­cell­dependent reactionssuch as cell­mediated cytotoxicity has been suggested[3]. Mechanisms for lamotrigine­inducedhypersensitivity reaction are less implicit than those forolder anti epileptics such as carbamazepine; however,they are structurally similar and are likely to sharemechanisms similar to sulphonamides, ie. they havedrug bio­activation that triggers clonal expansion of Tcells in skin, liver and other injury sites. HLA linkageshave not been performed for patients with lamotrigine­induced hypersensitivity. One patient with lamotrigine­induced hypersensitivity showed direct binding of T­cellreceptors with lamotrigine [8]. Lamotrigine binding of Tcells subsequently triggered clonal production of CD4+cells and some CD8+ cells in culture. It remainedunclear, however, whether direct T­cell–receptorbinding was the result of previous sensitization andwhether initial lamotrigine­induced hypersensitivityreactions are major histocompatibility complexdependent [9]. Most of the patients report the reactionwithin 14 days, which is also compatible with thedevelopment of immune sensitization [10].Another possible mechanism is altered drugmetabolism resulting in reactions mediated by toxicintermediate metabolites [10]. Lamotrigine ispredominantly metabolized by glucuronidation by liver.Valproate increases the half­life of this drug bydecreasing its glucuronidation through competition [11].Most reported cases of SJS or TEN due to lamotriginehave occurred in patients who were co­medicated withthese two drugs [8]. The findings suggest a possiblediversion of lamotrigine from glucuronidation to anoxidative elimination pathway, as found in rodents, withproduction of a reactive epoxide intermediate; however,this hypothesis remains to be demonstrated in humans[12]. This is why the combination of lamotrigine andvalproate may be toxic and a cautious use of thecombination, by adjusting the dosages, has beenrecommended by the manufacturer [2].

When rash develops during lamotrigine treatment,the drug should be stopped immediately. Unless therash can be clearly attributed to another cause,lamotrigine should be permanently withdrawn from theregimen. Also any other drug that may cause skinreactions, like ampicillin, should be avoided. If thepatient has fever or shows severe oral ulceration,lymphadenopathy, skin desquamation, blistering orother systemic signs, patient should be hospitalized.

In the above case, we had no doubt that lamotriginecaused the rash, because of the sudden resumption ofthe drug in relatively high doses. No other proximatereasons could be found. This case reiterates thatlamotrigine doses should not only be up titrated veryslowly, but patients and care givers should also becautioned not to resume the same regimen in case thedrug is discontinued for any reason.

CONCLUSIONWatchfulness of the clinicians and educating thepatient about the doses schedule and adverse reaction oflamotrigine is the key to prevent severe cutaneousreactions.

*********Author ContributionsShri Niwash Jangir – Conception and design,Acquisition of data, Analysis and interpretation of data,Drafting the article, Final approval of the version to bepublishedRajeshwari Suthar – Acquisition of data, Analysis andinterpretation of data, Critical revision of the article,Final approval of the version to be publishedA.K. Singhal – Analysis and interpretation of data,Critical revision of the article, Final approval of theversion to be publishedSmita N. Deshpande – Analysis and interpretation ofdata, Critical revision of the article, Final approval of theversion to be publishedGuarantorThe corresponding author is the guarantor ofsubmission.Conflict of InterestAuthors declare no conflict of interest.Copyright© Shri Niwash Jangir et al. 2011; This article isdistributed under the terms of Creative Commonsattribution 3.0 License which permits unrestricted use,distribution and reproduction in any means providedthe original authors and original publisher are properlycredited. (Please see www.ijcasereportsandimages.com/copyright­policy.php for more information.)

IJCRI 2011 ;2(1 2):1 9-22.www.ijcasereportsandimages.com

IJCRI – International Journal of Case Reports and Images, Vol. 2 No. 1 2, December 2011 . ISSN – [0976-31 98]

Jangir et al. 22

REFERENCES1. Ng Felicity, Hallam Karen, Lucas Nellie, BerkMichael. The role of lamotrigine in the managementof bipolar disorder. Neuropsychiatr Dis Treat2007;3(4):463­74.2. Messenheimer JA, Mullens EL, Giorgi L. Safetyreview of adult Clinical trial experience withlamotrigine. Drug Saf 1998;18:281–96.3. Roujeau J­C, Stern RS. Severe adverse cutaneousreactions to drugs. N Engl J Med 1994;331:1272–85.4. Auquier­Dunant A, Mockenhaupt M, Naldi L,Correia O, Schroder W, Roujeau JC. Correlationsbetween clinical patterns and causes of erythemamultiforme majus, Stevens­ Johnson syndrome, andtoxic epidermal necrolysis: results of aninternational prospective study. Arch Dermatol2002;138(8):1019–24.5. Bowden CL, Asnis GM, Ginsberg LD, Bentley B,Leadbetter R, White R. Safety and tolerability oflamotrigine for bipolar disorder. Drug Saf2004;27(3):173­84.6. Calabrese J. R., Sullivan J. R., Bowden C. L., SuppesT., Goldberg J. F., Sachs G. S. et al. Rash inmulticenter trials of lamotrigine in mood disorders:clinical relevance and management. J ClinPsychiatry 2002;63(11):1012­9.7. Schlienger RG, Shapiro LE, Shear NH. Lamotrigineinduced severe cutaneous adverse reactions.Epilepsia 1998;39(Suppl 7):S22–S26.8. Rahman M, Haider N. Anticonvulsanthypersensitivity syndrome from addition oflamotrigine to divalproex. Am J Psychiatry2005;162:1021.9. Pichler WJ. Delayed drug hypersensitivity reactions.Ann Intern Med 2003;139:683–93.10. Friedmann PS, Strickland I, Pirmohamed M, ParkBK. Investigation of mechanisms in toxic epidermalnecrolysis induced by carbamazepine. ArchDermatol 1994;130:598–604.11. Park BK, Kitteringham NR, Pirmohamed M, TuckerGT. Relevance of induction of human drug­metabolizing enzymes: pharmacological andtoxicological implications. Br J Clin Pharmacol1996;41:477–91.12. Maggs JL, Naisbitt DJ, Tettey JN, Pirmohamed M,Park BK. Metabolism of lamotrigine to a reactivearene oxide intermediate. Chem Res Toxicol2000;13:1075­81.

IJCRI 2011 ;2(1 2):1 9-22.www.ijcasereportsandimages.com