Carbamazepine: The Common Antiepileptic Which Induces Stevens Johnson Syndrome - A Case Series

Introduction

The acute life-threatening dermatoses Stevens Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are associated with severe epidermal sloughing at the dermo-epidermal interface as a result of keratinocyte apoptosis and they share the identical pathophysiology.^1,2 Only epidermal detachment enables them to be distinguished from each other on the body surface area. Thirty percent of epidermal detachment has three major categories: SJS, SJS/TEN, and TEN.2 SJS is estimated to occur in 1-6 cases per million individuals annually on average.³ In a retrospective study, Carbamazepine was identified as the most common complication of SJS/TEN. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0. SJS/TEN is classified as a category ‘B’ adverse effect with a genetic and immunological predisposition under the World Health Organization's (WHO) classification of carbamazepine adverse drug reactions (ADR).⁴ Here, we cover a set of case reports of patients from different age groups who presented with SJS secondary to carbamazepine.

Case Report-1

A 42-year-old female patient with no underlying comorbidity had presented with a complaint of left-sided headache with blurred vision and burning sensation of the left upper and lower limb following which the patient had undergone MRI brain for further evaluation. The investigation revealed the presence of an intracranial space-occupying lesion (ICSOL) and was diagnosed as cavernoma, following which the patient was initiated on tablet carbamazepine 200 mg BD for the prevention of neuralgic pain. Two months later during the follow-up, dose of tablet carbamazepine was increased to tablet carbamazepine 200 mg TID. One-month post-treatment with increased dose of tablet carbamazepine the patient presented with facial puffiness with discharge from the eyes and a history of dryness of the lips for the past 3 days. On physical examination, bullous lesions in the ear lobe, crusting over the lips, and maculopapular rash over the cheeks, oral mucosal ulcers, and conjunctivitis were seen. Vitals were found to be within normal limits. Because of the above symptoms, the patient was clinically diagnosed as carbamazepine-induced SJS, following which she was withheld on carbamazepine. ANA screening was negative. Blood culture had no growth. Dermatology and Ophthalmology consult was sought. She was advised to be on steroids (Tablet prednisolone 10 mg BD tapering dose). She improved symptomatically and the lesions were healing.

During the hospital stay, she developed a headache which was radiating to the neck and had a burning sensation. A neurology consult was sought and the patient was started on tablet amitriptyline 25mg bed time for 15 days.

During the hospital stay, she developed cough with expectoration. On auscultation B/L crepitations were present. Chest X-Ray (CXR) was normal. She was started on IV empirical antibiotics (Injection ceftriaxone 1gm BD and injection azithromycin 500 mg OD). Sputum culture had grown Pseudomonas and non-group A beta-hemolytic Streptococci. Further, she was diagnosed with Lower Respiratory Tract Infection (LRTI) yet was symptomatically improved after initiation of antibiotics. There was no further worsening of respiratory symptoms or fever spikes. During the hospital stay, she had hypokalemia (Potassium level: 3.3mmol/L) which was resolved and was discharged on oral antibiotics.

On follow-up, the patient’s symptoms in relation to carbamazepine-induced SJS were found to be resolved after the drug was withheld. Oral mucosa was cleared up and dry peeling of the skin was presented.

Case Report 2

A 43-year-old female patient presented with complaints of high-grade intermittent fever for 4 days. She was admitted to a local hospital and she developed rashes all over her body, initially around her right ear, and face and then gradually it spread all over the body. Her outside investigations revealed low platelets. Her investigations showed rashes present all over the body, angular stomatitis with crusting, and B/L lower limb petechiae. USG Abdomen and pelvis showed Grade 1 fatty liver. She was admitted to the ICU. In the ICU, the tropical fever workup was negative. Blood and urine cultures were sent and she was started on empirical antibiotics.

A complete blood count (CBC) showed normal platelet count after a few tests had been done. A dermatology consult was sought, and a diagnosis of Steven Johnson Syndrome was made as well as she was k/c/o right facial tics. Further probing of the history revealed that she was on tablet carbamazepine 200 mg BD for tics and was initiated 20 days back. Patient developed tiredness after starting gabapentin-100 mg HS in another hospital as an alternative to tablet carbamazepine for tics. Steven Johnson Syndrome was attributed to an allergy to carbamazepine/cephalosporins. She improved with treatment. Physiotherapy was initiated and she was mobilized well. She was symptomatically better, hemodynamically stable, and discharged. On follow-up, there had been no new complaints or lesions yet only had peeling of the skin.

Case Report-3

A 65-year-old female patient with no known comorbidity was diagnosed with Herpes Zoster infection and was started on treatment. Later, she was diagnosed as Post-Herpetic Neuralgia, for which she was started on acyclovir and carbamazepine. Post 15 days after treatment with the above medications, the patient presented with complaints of fever past 3 days-low grade, on/off type and not associated with chills or rigors and was seen to be reduced with medication. On the same evening, she developed rashes which were red in color, non- itchy, and macula- papular type, initially present over the abdomen and chest which gradually progressed to all over the body. She also had a history of oral ulcers past 2 days. In view of the above symptoms, the patient was diagnosed to have developed Steven-Johnson Syndrome and was abruptly discontinued on tablet acyclovir and tablet carbamazepine. She was admitted to HDU and relevant investigations were carried out. Her blood picture showed normocytic, normochromic with leukopenia. As she was found to have raised inflammatory markers, blood samples for culture were sent and she was started on empirical antibiotics, IV steroids, and other supportive measures. The blood culture was sterile. During the investigations, the patient’s urine sample reported 3-5 epithelial cells, 0-5 pus cells, and 0-2 RBCs and was thus treated conservatively. When she was symptomatically and hemodynamically stable, the patient was discharged and managed conservatively. During the follow-up visit, the symptoms were completely resolved, and the patient was stable.

Case Report-4

A 12-year-old male patient presented to the hospital with a history of falls while climbing a hill 1 year back with no loss of consciousness or seizure. The CT brain showed no abnormality, but the patient had sleep disturbance for 1 week after the fall. After a year, the patient complained of a recurrence of the above complaints. The patient was advised of EEG which showed activation of focal epileptiform abnormalities over the left frontal, rhythmic fast activity built during the episode, bilateral spread later. Events noted in the form of an immobile right hand touched the face with the left hand, then clonic jerking of the left upper limb and lower limb. Because of the above symptoms, the patient was diagnosed to have focal impaired awarenessmotor seizures under evaluation, following which the patient was initiated on tablet levetiracetam 500 mg BD for 15 days and tablet carbamazepine 100 mg BD. Two days after initiation of antiepileptic agents, the patient presented with complaints of swelling of the lip, throat pain, and was afebrile. On examination, lips were swollen, and the right eye had mild conjunctival congestion seen with no oral erosion. The patient was diagnosed as early SJS which was discontinued on tablet carbamazepine and was under observation. Following discontinuation, the patient presented with history of chapping of the lips and a burning sensation in the mouth and throat. No skin rash/ eye discharge or genital lesions were seen. On observation, cheilitis was seen, the tongue had whitish plaque, and minimal erosions along the sides of the tongue were seen. The patient was initiated on tablet prednisolone10 mg OD for 3 days, triamcinolone acetonide oral mucosal gel, BD for lip and oral lesions, and clotrimoxazole mouth paint for white patches over the tongue at bedtime. Fourteen days after treatment during a follow-up visit, the patient was symptomatically stable. The overview of all the cases who developed SJS due to carbamazepine are represented in Table 1.

Discussion

A severe mucocutaneous reaction brought on by an immune complex-mediated hypersensitivity reaction is known as Stevens-Johnson Syndrome (SJS). The use of antibacterial sulphonamides, anticonvulsants, oxicam NSAIDs, allopurinol, chlormezanone, and corticosteroids is associated with a sharp increase in the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis with Carbamazepine, the antiepileptic being most prominent causes of Stevens-Johnson syndrome.⁵ Carbamazepine belongs to a group of anticonvulsants that work by inhibiting activity in the thalamic nucleus ventralis, decreasing synaptic transmission, or reducing the summation of temporal stimulation leading to neural discharge, either by limiting the influx of sodium ions across cell membranes or by other as yet unidentified mechanisms.

Current evidence suggests that carbamazepineinduced SJS/TEN is a predictable, specific, delayed hypersensitivity immune reaction involving human leukocyte antigen (HLA) alleles specific for carbamazepine and other drugs in defined populations as opposed to the long-held belief that carbamazepine-induced SJS is an idiosyncratic, dose-independent, unpredictable adverse event specific to an individual.^1,2 TEN/SJS raises concerns beyond those related to the skin. According to Yip et al., 50% of patients develop late ocular problems, with dry eyes, trichiasis, symblepharon, distichiasis, vision loss, entropion, ankyloblepharon, lagophthalmos, and corneal ulcers occurring most frequently.³ Circulating cytotoxic T lymphocytes (CTLs) that are activated, multiply, and release cytotoxic proteins to cause keratinocyte death are what cause the lesion that developed with SJS.4 In one study, a 54-year-old man with SJS brought on by carbamazepine was examined. Prodromal symptoms like fever, headache, and polyarthralgia were reported in the patient, and they appeared 3 days before mucocutaneous lesions. Upon admission, physical examination revealed an asthenic male with a temperature of 37.2 ºC, generalised dermatitis, a positive Nikolsky sign, significant palm and sole erosions, onychomadesis, numerous oral erosions, and erosions along the vermilion border of the lips. Systemic steroid therapy was given to the patient, and carbamazepine dosage was gradually reduced before being substituted with valproic acid and valproate sodium. After three weeks of treatment, the patient's temperature returned to normal, and the skin lesions disappeared.⁶ 38-year-old lady with carbamazepine-induced SJS/TEN overlap was successfully treated with cyclosporine and supportive care, according to another study published in 2019. Being of Indian or Asian descent raises one's risk of anticonvulsant-induced SJS/TEN since a lot of people in these populations have the HLA-B*1502 trait. Unfortunately, technical and economical limitations disallowed sending for this patient's HLA phenotyping. In 2018, a meta-analysis of nine observational studies involving 256 SJS/TEN patients found that cyclosporine therapy significantly decreased the risk of death (standardised mortality ratio of 0.320; 95% confidence interval: 0.119-0.522; P = 0.002).⁷

In our case series, the first patient was a 42-year-old female with facial puffiness with discharge from the eyes and a history of dryness of the lips for the past 3 days. The second patient was a 43-year-old female who developed rashes all over her body, initially around her right ear, face, and then gradually it spread all over the body. The third patient was 65-year-old female who developed rashes which were red in color, non- itchy, and macula- papular type, initially present over the abdomen and chest which gradually progressed to all over the body. She also had a history of oral ulcers past 2 days. Fourth patient was 12-year-old male who had the H/O chapping of the lips and burning sensation in the mouth and throat. So, the series summarizes that carbamazepine being the most common anti-epileptic drug induces SJS/ TEN and may lead to mortality risk in patients if not withdrawal/withheld. The assessment of the adverse drug reaction developed by patients as per the standard scales: causality, severity, and preventability assessment scales have been represented in Table 2.

On average, the developed by different patients had almost similar scores with respect to causality, severity and preventability assessment The incidence of TEN was 0.6% in a prospective trial done on 335 children receiving carbamazepine therapy. The heterogeneity in the prescription pattern and genetic makeup of various populations may be the cause of the variety in the medicines that cause SJS/TEN.⁸ As an outcome; we discovered that carbamazepine was the medication most frequently cited as the cause of SJS/ TEN. The increased frequency of SJS/TEN caused by carbamazepine may be attributable to the rise in the number of prescriptions written for the drug for the treatment of pain.

Conclusion

Although carbamazepine is the most common antiepileptic in practice today, we should always be aware of the possible rare cutaneous adverse drug reactions that include Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) which appear to be variants of the same disease with different degrees of severity. Patients should therefore be monitored for the development of any complications following the use of carbamazepine. Thus, patients should be educated regarding the possible side effects and symptomatology and report accordingly. The treating physicians should be trained regarding the management of complications and the use of alternative regimens. Our case series also highlighted the safety and efficacy of carbamazepine along with the causality, severity, and preventability of the adverse drug reaction due to carbamazepine.

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