INTRODUCTION:

An uncommon immune-mediated life-threatening reaction known as toxic epidermal necrolysis (TEN) is a severe form of Stevens-Johnson syndrome (SJS), with more than 30% involvement of body surface area (BSA).^1,2,3 When epidermal detachment impacts less than 10% of BSA, it is referred to as SJS; when it affects over 30% of the BSA, it is referred to as TEN; and when it affects between 10% and 30% of the BSA, it is referred to as SJS-TEN overlap.^4,5

SJS/TEN is an uncommon illness that affects 1-2 persons out of every million annually.⁶ Various medications have been associated with causing SJS and TEN, including Allopurinol, Lamotrigine, Valproic acid, Sulfonamides, Minocycline antibiotics, Non-Steroidal Anti-inflammatory Drugs and medicines used in the treatment of HIV and tuberculosis.^7,8 A recent study shows the elevated occurrence of SJS/TEN for the patients co-administered with Lamotrigine and Valproate.^9,10The current case demonstrates, TEN induced by medications in a 45-year-old female patient with the history of seizure treated with antiepileptics.

A notable genetic component linked to SJS/TEN is the existence of particular Human Leukocyte Antigen (HLA) alleles, specifically HLA-B*1502.^11,12 Although the HLA-B*1502 allele is most commonly associated with carbamazepine-induced reactions, some evidence suggests that it may also predispose to Lamotrigine-induced SJS/TEN.^13,14 The HLA-B*1502 allele is strongly associated with vigorous cutaneous reactions including epidermal detachment such as SJS and TEN, particularly in individuals of Asian descent who are prescribed aromatic antiepileptics (Carbamazepine, Phenytoin and Lamotrigine).^15,16,17 In Asian populations, it ranges from 0.2% to 36%, with the highest frequencies in the Philippines (22% to 36%), Thailand (8.5% to 27.5%), and Indonesia (16%). The allele is absent in European and African populations. In East Indians, it can be found in ≤6% of individuals.^18,19,20

Apart from HLA alleles, differences in the genes that code for drug-metabolizing enzymes, like Cytochrome P450 (CYP) family, could also influence the risk of adverse drug reactions. Lamotrigine is primarily metabolized by uridine diphosphate-glucuronosyl transferase (UGT), particularly UGT1A4 and UGT2B7.^21,22,23 Genetic polymorphisms in these enzymes can lead to altered drug metabolism, affecting Lamotrigine plasma levels and potentially increasing the risk of hypersensitivity reactions like TEN.²⁴

CASE REPORT:

Around 45-year-oldfemale patient with a known case of seizure for the past 12 years was on Tab. Sodium valproate and Valproic acid 500mg BD. The patient had a family history of seizure. But her condition was worsened so Tab. Lamotrigine was added to her treatment regimen. Later, within a week, the patient experienced painful sores, blisters all over the upper surface of her body, H/O red raised lesions all over the body for one week, H/O fluid-filled lesions all over the body, and oral lesions for past three days. These symptoms prompted her admission to heathcare centre. At admission, the patient's vitals were observed as Blood Pressure-120/70mm/Hg, Pulse Rate- 93/min, Respiratory Rate- 17 breaths/min, Temperature- 100.2°F and Spo2- 96%. Upon admission, the Offending drugs were stopped. A punch biopsy was done over the left leg and sent for examination; an eye examination to determine ocular involvement and necessary blood tests, such as an erythrocyte sedimentation rate and total blood count, to indicate systemic inflammation were all part of our diagnostic workup. The punch biopsy results were consistent with toxic epidermal necrolysis syndrome, and the results of the HBsAg and Anti-HCV tests were confirmed to be negative. On examination, the rashes involved around 60-70% of the body surface area, peeling skin all over the body, conjunctival congestion and Nikolsky's sign was positive. The report shows the result of blood glucose-115mg/dL, Urea-34mg/dL, sodium bicarbonate- 25mEq/L, Total Leucocyte Count-2700 cells/mcL, Erythrocyte sedimentation rate- 20 mm/hr. Based on these findings, the clinical presentation, and considering the percentage of epidermal detachment, the patient was diagnosed with TEN. The SCORTEN score is used to assess the severity and predict the mortality risk in patients with SJS and TEN.²⁵ Her SCORTEN score result was 3, indicating a significant mortality risk of 35.3%, as in Table 1. The challenge here was identifying the culprit drug, given that the patient had been on Sodium Valproate for 12 years without adverse effects, and Lamotrigine had been newly introduced. The time frame of the reaction (within one week of starting Lamotrigine) helped narrow down the causative agent. By considering the subjective and objective evidence, the final diagnosis was made as TEN secondary to Lamotrigine use. Unfortunately, in this case, a genetic polymorphism test was not performed due to the patient's refusal. The Adverse Drug Reaction Probability Scale or Naranjo Algorithm was applied to determine the casuality assessment and was found "probable”.^26,27 Figure1 depicts the Timeline of Lamotrigine-induced TEN on sodium valproate and valproic acid.

Prompt initiation of treatment was essential to manage the patient's symptoms and prevent complications, so the first day of treatment involved intravenous fluids- 1-pint normal saline, 1-pint ringer lactate, 1-pint dextrose, Inj. Dexamethasone 2cc IM OD, Inj. Piperacillin 4.5mg IV BD, Inj. Ranitidine 50 mg IV BD, Tab. Calcium 300mg BD, Tab. MVT OD, Tab. Ferrous sulphate 200mg OD, Tab. Paracetamol and saline soaks. The same treatment was continued for remaining days, and instead of Lamotrigine and sodium valproate and valproic acid, Tab. Levitiracetam 500mg BD and Inj. Lorazepam 2CC IV SOS was added because she experienced one episode of seizure after admission. The treatment was continued for 18 days, and Over the course of treatment, the patient's symptoms showed significant improvement, with progressive healing of the skin lesions, stabilization of vital signs, and resolution of mucosal involvement. By the end of hospitalization, the patient's body surface area (BSA) involvement decreased, and no further epidermal detachment was observed. With stable laboratory values and clinical condition, the patient was discharged. The discharge medications include Tab. Levetiracetam 500mg BD, Tab. Dexamethasone 4mg BD, Tab. Ranitidine 150mg BD, Tab. B Complex BD, Liquid paraffin TID and advised to follow up after 14 days.

DISCUSSION:

Despite being two of the rarest dermatological emergencies, SJS and TEN are well-documented and lack clear diagnostic criteria.²⁸The diagnosis was determined using clinical features identified during a comprehensive physical evaluation. In addition, a skin punch biopsy was performed to validate the diagnosis and evaluate the degree of skin affected.^29,30 The development of diffuse erythema, or mucocutaneous eruption, is typically accompanied by fever, malaise, and more considerable bulla formation. Later, skin detachment and macula formation may be linked to compromised mucous membrane integrity (systemic involvement).^31,32

A study by Kavitha S et al 2015, reported a case of SJS caused by co-administration of Lamotrigine and Valproic acid.^33,34 This holds well in our case, where the patient was on sodium valproate and valproic acid for past 12 years and later she was added with Lamotrigine. Valproic acid is known to interact with the metabolism of Lamotrigine. As a result, there is a decrease in the overall clearance, which raises the elimination half-life of Lamotrigine and serum concentrations.

In our study, Toxic Epidermal Necrolysis(TEN) management involves 1 pint of normal saline, 1 pint of Ringer lactate, and 1 pint of dextrose daily as intravenous fluids. Regarding steroid administration, our patient was treated with Inj. Dexamethasone 2CC IM OD. The study conducted by Serap Oflaz et al. in 2011 involved isotonic solution of 1000 cc/day, 5% dextrose solution, and 500 cc/day, indicating a preference for balanced electrolyte solutions in managing fluid loss in TEN and prednisolone, 60 mg/day.³⁵

This case emphasizes the crucial risk of severe adverse medication reactions, Toxic Epidermal Necrolysis (TEN), and a comprehensive treatment plan, including fluid resuscitation, corticosteroids, antibiotics, and seizure management, demonstrates effective multidisciplinary care for a complex condition. However, the single-patient focus and lack of long-term follow-up data highlight the need for further studies to enhance the generalizability and understanding of such severe adverse drug reactions.

Severity Assessment Scale:

Medical professionals in France developed the Scorten score to assess the severity of the ailment. The Scorten score comprises seven points, and the data included were Age, Malignancies, Heart Rate, Serum Urea, Serum Glucose, Bicarbonate, and Initial Epidermal Detachment.^36,37 Based on the patient criteria, each point will be allotted, and depending upon the end, the severity and mortality of the patient can be assumed (Table 1).

Table 1: SCORTEN Score to assess the severity

Criteria/s	Point
Initial Epidermal Detachment	1
Malignancy	1
Age >40 years old	1
Heart Rate >120 beats/minute	1
Bicarbonate	1
Serum Glucose	1
Serum Urea	1

Table 1. Demonstrates the criteria to depict the SCORTEN score to assess severity

Table 2: Interpretation of the SCORTEN score

Score	Predicted Mortality Rate
0-1	3.2%
2	12.1%
3	35.3%
4	54.3%
≥5	90%

Table 2. Demonstrates the interpretation of the SCORTEN score to predict the mortality rate

Pretreatment Assessments:

1. HLA Alleles and Risk of SJS/TEN:

Genetic screening, particularly for HLA-B*1502 in at-risk populations (such as those of Asian descent), can help identify patients with a genetic predisposition to vigorous cutaneous reactions including epidermal detachment such as SJS and TEN.

If Positive for HLA-B*1502: Avoid Lamotrigine and consider alternative treatments.

Negative for HLA-B*1502: Proceed with Lamotrigine therapy, starting with a low dose and titrating slowly. Monitor for early signs of hypersensitivity, particularly during the initial 2-8 weeks of treatment.

Inconclusive or Unknown Genetic Result: Proceed with caution, closely monitor for adverse reactions, and consider alternative treatments if other risk factors (such as concomitant medication like Valproate) are present.

2. Glucuronidation Deficiency:

Glucuronidation is a metabolic pathway where the enzyme UDP-glucuronosyltransferase (UGT) is responsible for detoxifying drugs like Lamotrigine. Deficiency in this pathway can increase the risk of drug toxicity. Test for UGT Enzyme Activity: Specifically assess for genetic polymorphisms in UGT1A4 and UGT2B7, which are key enzymes responsible for the glucuronidation of Lamotrigine.

Normal UGT Activity: Proceed with standard dosing of Lamotrigine and routine monitoring for adverse effects (rash, fever) is still necessary, but the risk of drug accumulation and toxicity is low.

Partial Deficiency: Reduce the initial dose of Lamotrigine, as these patients may metabolize the drug more slowly and Pay close attention to signs of toxicity (e.g., skin rash or flu-like symptoms) and adjust the dose as needed.

Complete Deficiency: Consider alternative treatments to avoid the high risk of Lamotrigine toxicity.

If Lamotrigine is necessary, start with a significantly reduced dose and extend the interval between doses.

Discontinue Lamotrigine immediately if early signs of toxicity or adverse reactions (such as skin rashes or flu-like symptoms) develop.

3. Baseline Blood Test:

Before initiating Lamotrigine therapy should focus on liver function, kidney function, and complete blood count (CBC) to assess any potential risk factors for adverse drug reactions like Toxic Epidermal Necrolysis (TEN).

Liver Function Tests (LFTs): Elevated ALT, AST, or bilirubin may indicate liver dysfunction, which can impair Lamotrigine metabolism, increasing the risk of toxicity. Consider dose reduction, alternative therapy, or frequent monitoring if abnormalities are present.

Renal Function Tests (RFTs): Elevated creatinine or BUN suggests impaired renal function, which can lead to drug accumulation. In this case, adjust the Lamotrigine dose or monitor closely to prevent toxicity.

Complete Blood Count (CBC): Eosinophilia (elevated eosinophils) can be an early marker of drug hypersensitivity. A low WBC count (leukopenia) or abnormal platelet levels may also indicate a predisposition to adverse reactions. In such cases, consider alternative medications or close monitoring during therapy.

4. Risk-Benefit Ratio:

When deciding whether to initiate Lamotrigine therapy, it is crucial to evaluate the risk-benefit ratio.

If the Risk is High (e.g., positive genetic markers, multiple risk factors): Consider alternative therapies or a different antiepileptic drug with a lower risk of causing severe reactions like SJS/TEN.

If the Benefit is High (e.g., Lamotrigine is the most effective option for seizure control or mood stabilization): Proceed cautiously with therapy, using the lowest effective dose and close monitoring.

CONCLUSION:

In conclusion, routine genetic screening for high-risk patients, particularly those of Asian descent or those receiving multiple anticonvulsants like Sodium Valproate, should be strongly considered. This would not only help prevent severe adverse reactions such as TEN but also guide personalized treatment strategies, ensuring patient safety and optimizing therapeutic outcomes. The main purpose for publishing this case report was to recommend the healthcare professionals to perform pre-treatment assessment, including genetic screening and careful consideration of the risk-benefit ratio, before initiating the therapy.

ABBREVIATIONS:

SJS - Stevens-Johnson Syndrome

TEN - Toxic Epidermal Necrosis

BSA – Body Surface Area

HIV – Human Immunodeficiency Viruses

TB - Tuberculosis

HLA – Human Leukocyte Antigens

CYP - Cytochrome

ADR – Adverse Drug Reaction

IV - Intravenous

IM - Intramuscular

UGT - Uridine Diphosphate-Glucuronosyltransferase

SCROTEN - Score for Toxic Epidermal Necrosis

BD - Twice a day

TID - Three times a day

Inj - Injection

Tab - Tablet.

ACKNOWLEDGEMENT:

The authors express their gratitude to the patients, and their family members, and to the JSS College of Pharmacy,Ooty for granting consent to utilize their valuable medical records for case reporting.

ETHICS STATEMENT:

The informed consent form was obtained from the patient for publishing his medical records.

CONFLICTS OF INTEREST:

All authors declared no conflicts of interest.

FUNDING:

No funding source is available.

REFERENCES:

1. Singh N, Phillips M. Toxic Epidermal Necrolysis: A Review of Past and Present Therapeutic Approaches. Skin Therapy Lett. 2022; Sep; 27(5): 7-13. PMID: 36469487.

2. Darshana Kumari Wankhede, Shalini Lokhande, Sonali Kolekar, Suvarna Gughare. Case report on Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). International Journal of Nursing Education and Research. 2024; 12(1): 67-0.

3. Mohammed Mustafa G, Chandana C, Feba Elizabeth Biju, Deepthi D J. A Case Report on Ciprofloxacin Induced SJS/TEN (Steven Johnson Syndrome/Toxic Epidermolysis Necrosis). Research Journal of Pharmacy and Technology. 2024; 17(6): 2707-9.

4. Marks ME, et al. Updates in SJS/TEN: collaboration, innovation, and community. Front Med (Lausanne). 2023; Oct 11; 10: 1213889. doi: 10.3389/fmed.2023.1213889. PMID: 37901413; PMCID: PMC10600400.

5. Vinod V. Bagilkar. Stevens - Johnson Syndrome / Toxic Epidermal Necrolysis in Pediatric . Int. J. Adv. Nur. Management 2015; 3(2): 155-160.

6. Zimmerman, D., and Dang, N. H. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): Immunologic reactions. In Oncologic Critical Care. 2020: 267–280.

7. Gronich, N., Maman, D., Stein, N. et al. Culprit Medications and Risk Factors Associated with Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Population-Based Nested Case–Control Study. Am J Clin Dermatol. 2022; 23: 257–266. https://doi.org/10.1007/s40257-021-00661-0

8. Prabhavalkar, K. S., Poovanpallil, N. B., and Bhatt, L. K . Management of bipolar depression with lamotrigine: an antiepileptic mood stabilizer. Frontiers in Pharmacology. 2015; 6. doi: https://doi.org/10.3389/fphar.2015.00242

9. Espinosa-Aguilar EJ, Piña-Ballantyne SA, Espinosa-Aguilar KL, Tun-Pisté JC, Calderón-Garcidueñas AL. Steven-Johnson Syndrome Induced by Lamotrigine and Valproic Acid in a Pediatric Patient: A Case Report. Cureus. 2023; 15(7): e41267. doi: 10.7759/cureus.41267. PMID: 37533620; PMCID: PMC10390704.

10. Reddy, S., and Puri, S. Lamotrigine-Induced Stevens–Johnson Syndrome: A Clinical Report. Ijcase reports and images.com. 2024; doi:11:101175Z01SR2020.

11. Ferrell, P. B., Jr, and McLeod, H. L. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics, 2008; 9(10): 1543–1546. doi: 10.2217/14622416.9.10.1543

12. HLA-B15:02 genotyping, carbamazepine hypersensitivity. Aruplab.com. Retrieved September. 18, 2024, from https://ltd.aruplab.com/Tests/Pub/2012049

13. Kwon, J. W., Park, J. W., and Kim, Y. S. HLA-B1502 and Lamotrigine-induced Severe Cutaneous Adverse Reactions. Allergy, Asthma and Immunology Research. 2013; 5(2): 110-112.

14. Remya Antony, Ashly Fernandez, Sandhya Lekshmi, Sreedevan Velayudhan, Sruthy Jose, Meenu Vijayan. Case report on Fluconazole Induced stevens - Johnson Syndrome. Research J. Pharm. and Tech. 2019; 12(8): 3735-3738.

15. Chung, W. H., Hung, S. I., et al. Medical genetics: A marker for Stevens-Johnson syndrome. Nature, 2004; 428(6982). 486.

16. Chen, P., Lin, J. J., et al. Carbamazepine-induced toxic effects and HLA-B1502 screening in Taiwan. New England Journal of Medicine. 2011; 364(12): 1126-1133.

17. Shaiji M J. Purple Glove Syndrome. Asian J. Nursing Education and Research. 2019; 9(4): 580-582.

18. Lim, K. S., Kwan, P., and Tan, C. T. Association of HLA-B1502 allele and carbamazepine-induced severe adverse cutaneous drug reaction among Asians, a review. Neurology Asia. 2008; 13: 15-21.

19. Zhou, Y., Krebs, K., Milani, L., and Lauschke, V. M. Global frequencies of clinically important HLA alleles and their implications for the cost-effectiveness of preemptive pharmacogenetic testing. Clinical Pharmacology and Therapeutics. 2020; 109(1): 160–174.

20. Yakaiah Vangoori, Naga Vishnu Kandra, Praveen Kumar Uppala, U. Upendrarao, S.V. Saibaba, Murali Krishna Balijepalli, Butti Lavanya, SK. M. Shabana. Case Reports of Stevens Johnson Syndrome (SJS) Induced by Chemically Unrelated Drugs. Research Journal of Pharmacy and Technology. 2023; 16(5): 2415-8.

21. Methaneethorn, J., and Leelakanok, N. Sources of lamotrigine pharmacokinetic variability: A systematic review of population pharmacokinetic analyses. Seizure: The Journal of the British Epilepsy Association. 2020; 82: 133–147.

22. Milosheska, D., Lorber, B., Vovk, T., Kastelic, M., Dolžan, V., and Grabnar, I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. British Journal of Clinical Pharmacology. 2016; 82(2): 399–411.

23. Mohathasim Billah A, Rajamohamed H, Mohamed Akram Ali S, Porkodi M, Vikashini S, Lida Sajimon. Statin-induced Rhabdomyolysis and its Management – A Case Report. Research Journal of Pharmacy and Technology. 2024; 17(7): 3241-5.

24. Yang, J., Wang, J., Ning, L., Wu, C., Liu, Y., Xia, J., Guan, Y., Liu, Q., and Zheng, J. Influence of UGT2B7, UGT1A4 and ABCG2 polymorphisms on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy. European Journal of Drug Metabolism and Pharmacokinetics. 2024; 49(4): 437–447.

25. Zhang L, Lavoie J, Annis K, et al. Glucuronidation of lamotrigine by UGT1A4 and UGT2B7. Biochem Pharmacol. 2007; 74(10): 1441-9. doi:10.1016/j.bcp.2007.07.005.

26. Dobry, A. S., Himed, S., Waters, M., and Kaffenberger, B. H. Scoring assessments in Stevens-Johnson syndrome and toxic epidermal necrolysis. Frontiers in Medicine. 2022; 9. https://doi.org/10.3389/fmed.2022.883121

27. Abdullahi Rabiu Abubakar, Nordin Bin Simbak, Mainul Haque. Adverse Drug Reactions: Predisposing Factors, Modern Classifications and Causality Assessment. Research J. Pharm. and Tech. 2014; 7(9): 1091-1098.

28. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. [Updated 2019 May 4]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548069/

29. Frantz, R., Huang, S., Are, A., and Motaparthi, K. Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: A review of diagnosis and management. Medicina (Kaunas, Lithuania), 2021; 57(9): 895. https://doi.org/10.3390/medicina57090895

30. Al-Shaqsi, S. Important Points in Toxic Epidermal Necrolysis Management. Oman Medical Journal. 2019; 34(4): 357–358. https://doi.org/10.5001/omj.2019.70

31. Toxic epidermal necrolysis (TEN). Cleveland Clinic. Retrieved July 15, 2024, from https://my.clevelandclinic.org/health/diseases/21616-toxic-epidermal-necrolysis-ten

32. Samantha P Jellinek-Cohen. Toxic epidermal necrolysis (TEN) clinical presentation. Medscape. Accessed on 05 october 2024. https://emedicine.medscape.com/article/229698-clinical

33. Estrella-Alonso, A., Aramburu, J. A., González-Ruiz, M. Y., Cachafeiro, L., Sánchez Sánchez, M., and Lorente, J. A. Toxic epidermal necrolysis: a paradigm of critical illness. Revista Brasileira de Terapia Intensiva. 2017; 29(4): 499. https://doi.org/10.5935/0103-507x.20170075

34. Oflaz, S., Kalkan, H. S., Gokce, E., Karsidag, C., and Gurel, M. S. Stevens Johnson syndrome—toxic epidermal necrolysis induced by A combination of lamotrigine and valproic acid: A case report. Klinik Psikofarmakoloji Bulteni [Bulletin of Clinical Psychopharmacology]. 2011; 21(2): 150–153. https://doi.org/10.5455/bcp.20110410031809

35. Dobry, A. S., Himed, S., Waters, M., and Kaffenberger, B. H. Scoring assessments in Stevens-Johnson syndrome and toxic epidermal necrolysis. Frontiers in Medicine. 2022; 9: 883121. https://doi.org/10.3389/fmed.2022.883121

36. Nimmy P S, Greeshma V R, Aiswaria S Pal. Lennox- Gastaut Syndrome (Childhood Epileptic Encephalopathy) – A Rare Case Report. International Journal of Nursing Education and Research. 2024; 12(3): 212-4.

37. N. Sangeetha, U.S. Mahadeva Rao.Hepatotoxic Effect of Sodium Valproate Therapy in Epileptic Children. Research J. Pharma. Dosage Forms and Tech. 2011; 3(4): 135-138.

Received on 09.10.2024 Revised on 07.02.2025

Accepted on 02.04.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):147-152.

DOI: 10.52711/0974-360X.2026.00023

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.