Stevens Johnson Syndrome is a rare but life-threatening skin disease and Carbamazepine is considered as one of the most common cause. The reported frequency of serious Carbamazepine hypersensitivity reaction is between 1/1000 and 1/10000 new exposures to the drug. Here, we report a case of a 40 year old female patient, who developed multiple ulcerative lesions all over the body three days after starting treatment with Carbamazepine for Trigeminal Neuralgia. (Worldwide Unique Number- 2017-58502 and AMC Report Number- BJGMC-Pune/Nov-2017/BBG-1860) Stevens Johnson Syndrome was diagnosed. Carbamazepine was withdrawn, and the patient was treated with topical and intravenous antibiotics. A biopsy was done which confirmed the diagnosis of Stevens Johnson Syndrome

Gadhade, Jyoti B.

Ghongane, Balasaheb B.

Hiray, Rajesh S.

English

International Journal of Basic & Clinical Pharmacology

 www.ijbcp.com                                  International Journal of Basic & Clinical Pharmacology | August 2018 | Vol 7 | Issue 8    Page 1654 IJBCP    International Journal of Basic & Clinical Pharmacology Print ISSN: 2319-2003 | Online ISSN: 2279-0780 Case Report Carbamazepine induced Stevens Johnson Syndrome: a case report from a tertiary care hospital  Jyoti B. Gadhade, Rajesh S. Hiray*, Balasaheb B. Ghongane                INTRODUCTION Stevens Johnson Syndrome (SJS) is characterised by blisters arising in macules or flat atypical target shaped lesions and that has a potentially lethal outcome.1 The most common cause is the use of medications. Among the drugs, most commonly involved are anti-epileptics, allopurinol, antibiotics and non-steroidal anti-inflammatory drugs.2 Anti-epileptics are one of the main triggers, causing Stevens Johnson Syndrome, among which Carbamazepine is responsible for maximum number of cases.3 Cutaneous drug reactions are most-common type of adverse drug reactions.4 They form 2-3% of hospitalized patients. The percentage of potentially serious reactions is around 2%.5 Clinically, Stevens Johnson Syndrome presents as erythema, necrosis and extensive sloughing of the epidermis, mucosal involvement and appearance of systemic symptoms. The pathogenesis of this syndrome has not yet been established. The death of keratinocytes due to apoptosis is believed to play a key role in the mechanism.6 It is very difficult to diagnose Stevens Johnson Syndrome because drug hypersensitivity reactions occur in a very unpredictable way. The incidence of SJS/TEN has been reported to be 1.5-1.8/per million persons per year.7 Carbamazepine, an iminostilbene is widely used to treat seizure disorder, bipolar disorder, trigeminal neuralgia and chronic pain and is the most common cause of drug hypersensitivity reactions.7 The reported frequency of ABSTRACT Stevens Johnson Syndrome is a rare but life-threatening skin disease and Carbamazepine is considered as one of the most common cause. The reported frequency of serious Carbamazepine hypersensitivity reaction is between 1/1000 and 1/10000 new exposures to the drug. Here, we report a case of a 40 year old female patient, who developed multiple ulcerative lesions all over the body three days after starting treatment with Carbamazepine for Trigeminal Neuralgia. (Worldwide Unique Number- 2017-58502 and AMC Report Number- BJGMC-Pune/Nov-2017/BBG-1860) Stevens Johnson Syndrome was diagnosed. Carbamazepine was withdrawn, and the patient was treated with topical and intravenous antibiotics. A biopsy was done which confirmed the diagnosis of Stevens Johnson Syndrome.  Keywords: Adverse drug reaction, Carbamazepine, Stevens Johnson Syndrome DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20183039    Department of Pharmacology, Byramjee Jeejeebhoy Government Medical College, Pune, Maharashtra, India  Received: 22 May 2018 Accepted: 26 June 2018  *Correspondence to: Dr. Rajesh S. Hiray, Email: rajesh.hiray@gmail.com  Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Gadhade JB et al. Int J Basic Clin Pharmacol. 2018 Aug;7(8):1654-1658                                                                                                          International Journal of Basic & Clinical Pharmacology | August 2018 | Vol 7 | Issue 8    Page 1655 serious Carbamazepine hypersensitivity reaction is between 1/1000 and 1/10000 new exposures to the drug.8 Here, we report a case of Stevens Johnson Syndrome secondary to Carbamazepine in a patient with trigeminal neuralgia. CASE REPORT A 40 year old female, presented with sharp, intermittent unilateral facial pain over the right mandibular area and tingling sensation over the right jaw in August 2017. She was prescribed Tablet Carbamazepine 100mg daily by a private practitioner from Nanded. Post single dose, the patient developed swelling over both the lips. The patient was further advised to continue the medication. On her 4th day of medication, the patient developed rashes over the body and fluid filled lesions. The patient was then referred to Hyderabad for further management where she was taken to the casualty and admitted. There were multiple, discrete ulcers of variable size with foul smelling discharge on trunk, bilateral extremities, buttocks along with the involvement of mouth (Figures 1, 2, 3).  Figure 1: Abscess of the lower jaw with destruction of the lips in a patient with Carbamazepine induced Stevens Johnson Syndrome. The total body surface area involved was 23%. On clinical examination, patient showed involvement of both epidermis and dermis. There was involvement of conjunctival mucosa, too. Lower lip showed destruction. This soon developed into abscess of the lower jaw (Figure 4). The patient was unable to swallow food and so was put on Ryle’s Tube feeding. Rest of the medical history was not significant.  Carbamazepine was immediately stopped, and the patient was started on intravenous antibiotic which was a combination of piperacillin and tazobactam; fucidic acid cream 2% and calamine lotion. She was also prescribed oral potassium permanganate (KMnO4) (1:10000) and 3% hydrogen peroxide (H2O2) gargles with candid mouth wash. The abscess of the lower jaw was debrided under local anaesthesia. Daily dressing was done for a month. During the course of treatment, patient went into septic shock for which she was shifted to intensive care unit and was started on intravenous imipenem, colistin and oral variconazole. After two weeks, she recovered and was shifted back to ward.   Figure 2: Ulcerative lesions over the leg in a patient with Carbamazepine induced                              Stevens Johnson syndrome.  Figure 3: Ulcerative lesions over the buttocks in a patient with Carbamazepine induced                             Stevens Johnson Syndrome. Gadhade JB et al. Int J Basic Clin Pharmacol. 2018 Aug;7(8):1654-1658                                                                                                          International Journal of Basic & Clinical Pharmacology | August 2018 | Vol 7 | Issue 8    Page 1656 Table 1: Laboratory investigations (as on 18th September 2017). Test name Result Reference range Complete blood count Haemoglobin(g/dl) 8.6 12-15 White Blood Count (per cumm) 2710 4500-11,000 Differential Leucocyte Count Neutrophils 50% 40-80% Lymphocytes 44% 20-40% Monocytes 06% 2-10% Eosinophils 0% 1-6% Basophils 0% <1-2% Platelet Count (lacs per cumm) 3.14 1.5-4.5 Liver function tests Total bilirubin (mg/dl) 2.0 0.2-1.2 Serum albumin (g/dl) 1.6 3.5-5.5 Serum globulin(g/dl)   Serum glutamic oxaloacetic transaminase(SGOT) (IU/L) 2.8 2-3.5 Serum glutamic pyruvic 133 5-40 Transaminase (SGPT) (IU/L) 281 7-56 Serum alkaline phosphatase (IU/L) 297 40-140 Total protein (g/dl) 4.4 6-8 Renal function tests Serum creatinine (g/dl) 2.4 0.5-1.5 Blood Urea Nitrogen (g/dl) 108 7-20 Urine-routine and microscopy Normal  Electrolyte levels Serum Sodium (mEq/L) 131 135-145 Serum Potassium (mEq/L) 5.5 3.5-5 Serum Chloride (mEq/L) 102 96-106 C-Reactive Protein (mg/dl) 96 0-3 Human immunodeficiency virus (HIV) Negative  Hepatitis B surface antigen (HBsAg) Negative  Anti Hepatitis C virus Negative  Due to financial constraints, the patient was referred to Sassoon General Hospital, Pune for further treatment and work-up where she was put on intravenous ceftriaxone (1gm twice daily), intravenous metronidazole (500mg thrice daily), amikacin (0.5g twice daily) and ondansetron (4mg twice daily). The patient was then discharged after three days. Though the neuralgia was completely treated, she was advised follow up after a month and a half for plastic surgery opinion. Laboratory Investigations revealed anaemia, leukopenia, elevated c-reactive protein levels and altered hepatic function tests and blood urea nitrogen levels (Table 1). Patient’s skin biopsy and immunofluorescence report was consistent with Stevens Johnson Syndrome.  Figure 4: Ulcerative lesions over the back in a patient with Carbamazepine induced                                           Stevens Johnson Syndrome. DISCUSSION Trigeminal neuralgia is characterised by severe excruciating stabbing pain triggered by nociceptive stimuli in the distribution of one or more divisions of trigeminal nerve. The primary drug given for its treatment is an anti epileptic Carbamazepine.9 In a seven year study conducted by Devi, et al, anti epileptics like Carbamazepine are the most common cause of Stevens Johnson Syndrome especially in the first eight weeks of treatment in 80% of the cases.3 Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) are severe idiosyncratic reactions characterised by fever, mucocutaneous lesions leading to necrosis and sloughing of the epidermis. Depending upon the basal surface (BSA) involved, three entities are recognized: • Stevens Johnson Syndrome- a minor form of Toxic Epidermal Necrolysis with less than 10% BSA involvement. • Overlapping SJS/TEN- 10 to 30% of BSA involvement. • TEN- more than 30% BSA involved.10 The mortality rate of SJS/TEN is high depending on the disease and its severity. It varies from 1-5% in SJS and 25-30% in TEN.11 The severity of illness score for TEN(SCORTEN) is used widely for predicting the mortality of patients with SJS/TEN. This score consists of seven variables: 1. Age> 40 years 2. Skin detachment > 10% of BSA 3. Heart rate > 120/minute 4. Presence of malignancy 5. Blood Urea Nitrogen > 28mg/dl Gadhade JB et al. Int J Basic Clin Pharmacol. 2018 Aug;7(8):1654-1658                                                                                                          International Journal of Basic & Clinical Pharmacology | August 2018 | Vol 7 | Issue 8    Page 1657 6. Blood glucose level > 252mg/dl 7. Blood sodium bicarbonate levels< 20mEq/dl Each variable gets 1 point if it is present. Higher the score of SCORTEN, higher is the mortality rate.12 Lactate dehydrogenase levels (LDH) may also be considered in evaluation of the severity of the disease.13 At present, the exact mechanism of SJS is not known. A strong genetic predisposition has been found to be associated with SJS. It is believed to be associated with Human Leucocyte Antigen alleles (HLA B*15:02).14,15 SJS usually occurs during the first course of drug ingestion without prior sensitization.16 Histopathological examination plays a crucial role in the diagnosis of SJS. Early histological finding in SJS is a perivascular mononuclear cell mainly T-lymphocytes which gathers around basal keratinocytes. In addition to medications, conditions such as malignancies, systemic lupus erythematous, viral infection, exposure to ultraviolet rays may trigger SJS.17 The main therapeutic action in SJS is early recognition of the drug reaction and withdrawal of the drug because if delayed it can lead to serious complications. As such, there is no definitive treatment for acute SJS other than supportive care.18 According to the World Health Organization (WHO) system of causality definitions, the adverse drug reaction in this report case is categorized as ‘Probable’ with Naranjo Algorithm score of five. The adverse drug reaction was reported in Vigiflow (Worldwide Unique Number- 2017-58502 and AMC Report Number- BJGMC-Pune/Nov-2017/BBG-1860) Rechallenge was not carried out due to inherent risk involved. This presentation of adverse reaction to Carbamazepine was thus seen in this case with fluid filled lesions and multiple discrete ulcers on the skin and thus involving both hepatic and renal systems. CONCLUSION We report this case to aware physicians regarding drug implicated Stevens Johnson Syndrome which is a life-threatening reaction. So, judicious use of Carbamazepine is must to reduce mortality and morbidity. ACKNOWLEDGEMENTS  Authors would like to thank the Department of Surgery, Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals, Pune, India Funding: No funding sources Conflict of interest: None declared Ethical approval: Not required  REFERENCES 1. Acquier DA, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC, et al. Correlations between clinical patterns and causes of erythema multiforme, Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: results of an international prospective study. Arch Dermatol. 2002;138:1019-24. 2. Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, foster CS. Stevens Johnson Syndrome and Toxic epidermal Necrolysis: A review of the literature. Ann Allergy asthma Immunol. 2005;94:419-36. 3. Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine- The commonest cause of Toxic Epidermal Necrolysis and Stevens Johnson Syndrome: A study of 7 years Indian J Dermatol Venereol Leprol. 2005;71:325-8. 4. Sharma VK, Sethuraman G, Minz A. Stevens Johnson Syndrome, Toxic Epidermal Necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome. Indian J Dermatol Venereol Leprol. 2008;74:238-40. 5. Sharma VK, Sethuraman G. Adverse cutaneous reactions to drugs: An overview. J Postgraduate Med. 1996;42:15-22. 6. Paul C, Wolkensten P, Adle H, Wechsler J, Garchon HJ, Revuz J, et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol. 1996;134:710-4. 7. Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Cli Epidemiol. 1996 Jul 1;49(7):769-73. 8. Leeder JS. Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs- Epilepsia. 1998;39(7):S8-16. 9. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology. 1997;49:542-6. 10. Larsen A, Piepgras D, Chyatte D, Rizzolo D. Trigeminal Neuralgia. diagnosis and medical and surgical management. JAAPA. 2011;24:20-5. 11. Harr T, French LE. Toxic Epidermal necrolysis and Stevens Johnson Syndrome. Orph J Rare Diseas. 2010;5(1):39. 12. Bastuji-Garin S, Fouchard N, Bertocchi M, Rocyeau JC, Revuz J, Wolkenstein P. SCORTEN of Investigative Dermatology. 2000;115(2):149-53. 13. Yun SJ, Choi MS, Piao MS, Lee JB, Kim SJ, Won VH, et al. Serum lactate dehydrogenase is a novel marker for the evaluation of disease severity in the early stage of Toxic Epidermal Necrolysis. Dermatology 2008;217:254-9. 14. Devi K. The association of HLA B*15:02 Allele and Stevens Johnson Syndrome/toxic epidermal necrolysis Gadhade JB et al. Int J Basic Clin Pharmacol. 2018 Aug;7(8):1654-1658                                                                                                          International Journal of Basic & Clinical Pharmacology | August 2018 | Vol 7 | Issue 8    Page 1658 induced by aromatic anti convulsant drugs in a South Indian Population. Int J Dermatol. 2018;57(1):70-3. 15. Ou GJ, Wang J, Ji X, Yu H, Jiang L, Li L, et al. A study of HLA‐B* 15: 02 in 9 different Chinese ethnics: Implications for carbamazepine related SJS/TEN. Hla. 2017 Apr;89(4):225-9. 16. Guleria. Oxcarbazepine induced toxic epidermal necrolysis. Ind J of Pharmacol. August 2015;47(4):459-61. 17. Wu Y, Sanderson JP, Farrell J, Drummond NS, Hanson A, Bowkett E, et al. Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol 2006;118:233-41. 18. Bae HM, Park YJ, Kim YH, Moon DE. Stevens-johnson syndrome induced by carbamazepine treatment in a patient who previously had carbamazepine induced pruritus-a case report. The Kore J Pain. 2013 Jan 1;26(1):80-3.          Cite this article as: Gadhade JB, Hiray RS, Ghongane BB. Carbamazepine induced Stevens Johnson Syndrome: a case report from a tertiary care hospital. Int J Basic Clin Pharmacol 2018;7:1654-8. 

Carbamazepine induced Stevens Johnson Syndrome: a case report from a tertiary care hospital

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Carbamazepine induced Stevens Johnson Syndrome: a case report from a tertiary care hospital

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