Challenges in Diagnosing Lamotrigine-induced DRESS: A Unique Case of Acalculous Cholecystitis in Epilepsy

Case History 
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a fatal and complex hypersensitivity condition (Bocquet et al., 1996; González et al., 2024). In this syndrome, multiple organ systems, including the hematological, lymphatic, hepatic, and others, can be involved (Bonyadian & Kordi, 2020). Lamotrigine is an anti-epileptic medication that has an acceptable safety profile with mild central nervous system adverse effects (Richens, 1994; Vrhovski et al., 2022). Lamotrigine-associated skin rash occurs in 5% of patients but rarely requires hospitalization. DRESS is more common with other anticonvulsants, and levetiracetam is a rare cause of DRESS (Descamps et al., 2003; Seishima et al., 2006; Shiohara et al., 2007). To the best of our knowledge, acalculous cholecystitis in lamotrigine-induced DRESS has not yet been reported. In this study, we present a case of a patient on two anti-epileptic medications levetiracetam and lamotrigine that can cause DRESS syndrome. This was a great challenge to know the inciting drug, which was the second drug that introduced lamotrigine. 

Clinical Presentation 
A 29-year-old female was diagnosed with generalized epilepsy of myoclonus type and complex partial seizures. Initial treatment involved levetiracetam at a dosage of 500 mg, administered as half a tablet twice daily for the first week, followed by an escalation to 500 mg twice daily. Despite one month of continuous treatment, seizure control remained elusive. Subsequently, lamotrigine, a second anti-epileptic medication, was introduced into the therapeutic regimen (Komatsuda et al., 2008; Eshki et al., 2009; Brüning et al., 2024).
The initiation of lamotrigine involved a starting dose of 25 mg twice daily for 10 days, followed by an increment to 50 mg twice daily. Approximately, three weeks following the commencement of lamotrigine, the patient manifested symptoms, including low-grade fever (38-38.5 °C), painful enlargement of cervical and auricular lymph nodes, bone pain, headache, and a decrease in seizure control. This clinical state persisted for 10 days, during which the fever escalated to a high grade of 40-41 °C, accompanied by rigor and chills, partially responsive to antipyretic therapy.
Concurrently, the patient reported upper abdominal pain, nausea, vomiting, and decreased appetite. Physical examination revealed generalized lymphadenopathy, affecting cervical, auricular, axillary, inguinal, popliteal, and epitrochlear lymph nodes. The progression of symptoms included the development of an erythematous papillomacular rash on the arms, gradually extending to involve the abdomen, lower limbs, neck, and face. The rash was accompanied by severe pruritus.
Upon examination, the patient presented with a temperature of 40.5 °C, blood pressure of 110/60 mm Hg, oxygen saturation of 97%, a regular pulse rate of 118 beats per min with high volume, puffy face with jaundice, and non-pitting edema of the hands and feet. Comprehensive documentation of the rash on different parts of the body is provided in Figures 1, 2, 3 and 4. The abdominal examination revealed right upper quadrant tenderness with a positive Murphy sign.

Diagnostic Testing
Full laboratory investigations were done for the patient and the results are shown in Table 1. The blood film exhibited mild hypochromic red blood cells, with occasional oval cells and target cells; however, no malignant cells were identified. These findings were indicative of a presentation consistent with infectious mononucleosis. The blood culture demonstrated no bacterial growth.

Abdominal ultrasound revealed grade 1 fatty liver, with a gallbladder of normal size and shape, a thickened wall measuring 4 mm, and the absence of stones. The common bile duct appeared normal without the presence of stones, consistent with a diagnosis of acalculous cholecystitis, as illustrated in Figures 5 and 6.

Given the systemic manifestations, including a generalized erythematous rash emerging approximately three weeks after the initiation of lamotrigine (the second anti-epileptic medication in this case), suspicion arose regarding lamotrigine-induced DRESS (Shear & Spielberg, 1988; Fiszenson-Albala et al., 2003; Krivda et al., 2022). Immediate cessation of lamotrigine was instituted. The patient received an oral steroid regimen comprising prednisolone at 10 mg twice daily, along with silymarin which has an antioxidant property and is used as a protective drug in prophylaxis and treatment of drug-induced hepatotoxicity. To manage the rash and itching, desloratadine was used as needed, as clobetasol skin ointment, and as a skin lotion (Saltzstein & Ackerman, 1959; Doan et al., 2023).

The patient exhibited significant improvement in fever the day following lamotrigine discontinuation. Over the subsequent days, her overall condition, including the rash, edema, and lymphadenopathy, gradually resolved. Liver function showed progressive improvement, reaching complete recovery a few weeks after the onset, as detailed in Table 2.

Assessment 
DRESS syndrome is a rare yet severe idiosyncratic drug reaction, with an estimated incidence ranging from 1 in 1000 to 1 in 10000 and a mortality rate of 10-20% (Chaabane et al., 2014; Mosallanejad et al., 2020). The spectrum of drugs capable of inducing DRESS is broad, with anticonvulsants and sulfonamides being the most commonly associated. This is particularly pertinent in the context of epileptic patients who may necessitate transitioning between medications following withdrawal of the causative drug (Vittorio & Muglia, 1995; Tas & Simonart, 2003; Kim et al., 2022).
Typically, the onset of DRESS occurs within two months of initiating the offending drug, with symptoms often manifesting between 2 to 6 weeks after its commencement. Thus, meticulous attention to the timing of drug administration and its correlation with symptom onset is critical, considering the variable susceptibility of different drugs to induce the syndrome (Sullivan & Shear, 2001; Eshki et al., 2009; Lin et al., 2021).
Clinical manifestations of DRESS encompass eosinophilia, skin rash, facial swelling, and lymphadenopathy, with the latter identified in nearly 75% of cases. Meanwhile, DRESS is characterized by the inflammation of visceral organs, notably the liver, kidneys, lungs, and heart (Naisbitt et al., 2003). Reactivation of herpesviruses, particularly human herpesvirus 6, has been frequently observed in DRESS cases, though cytomegalovirus, Epstein–Barr virus, and human herpesvirus 7 reactivation has been implicated in a minority of cases (Seishima et al., 2006; Shah et al., 2021). In this case, reactivation of EBV was noted.
A proposed hypothesis suggests that the reactivation of herpesviruses in DRESS may result from an allergic immune response to the triggering drug, stimulating latent T cells harboring the viruses. This immune stimulation leads to the reactivation of herpesviruses, a phenomenon potentially linked to the immunotropic properties of these viruses (Uetrecht, 1999).
Diagnosing DRESS poses challenges due to the heterogeneity of skin rashes and varied organ involvement among patients. In this case, the European registry of severe cutaneous adverse reactions (RegiSCAR) scoring system (Table 3) facilitated the diagnosis. RegiSCAR categorizes cases as “no,” “possible,” “probable,” or “definite,” with a score of 5 and above confirming the diagnosis (Knowles et al., 1999; Wang et al., 2024). Our patient’s RegiSCAR score was 7, incorporating various criteria, such as generalized lymphadenopathy, eosinophilia >10%, skin rash covering over 50% of the body surface area, and visceral organ involvement (liver and gallbladder) (Descamps et al., 2001; Naveen et al., 2012).

Also, this case introduces a unique aspect, acalculous cholecystitis associated with lamotrigine-induced DRESS. To the best of our knowledge, this report is the first of its kind linking lamotrigine-induced DRESS with cholecystitis (Shiohara & Kano, 2007; Oriolo et al., 2016). The presence of levetiracetam in the patient’s medication history posed a diagnostic challenge, but the gradual symptom development after three weeks from initiating lamotrigine strongly indicated lamotrigine as the inciting drug (Kano et al., 2010; Parsi & Daniel, 2020). Rapid improvement upon lamotrigine withdrawal, despite delayed normalization of laboratory results, further supported the diagnosis (Picard et al., 2010; Hamed et al., 2018; Al-Hasan et al., 2022).
With the patient’s improvement aligned with expectations after lamotrigine cessation, a cautious wait-and-watch approach was adopted as per the patient’s preference. Subsequently, she was initiated on valproate for epilepsy management, resulting in well-controlled seizures (Kardaun et al., 2013; Mansor et al., 2022). While DRESS syndrome is a rare occurrence, its significant mortality rate of 10-20% underscores its severity. Linked to a diverse array of drugs, its clinical presentation can vary widely, posing diagnostic challenges that are amplified by atypical manifestations, such as acalculous cholecystitis. The utility of the RegiSCAR score is evident, aiding in the classification of cases into distinct categories, and guiding clinicians in their diagnostic approach. Prompt identification of the inciting drug and immediate discontinuation remain the cornerstone of management, ensuring a swift and comprehensive recovery for affected individuals.

Ethical Considerations

Compliance with ethical guidelines
All ethical principles are considered in this article. The participants were informed of the purpose of the research and its implementation stages. They were also assured about the confidentiality of their information and were free to leave the study whenever they wished, and if desired, the research results would be available to them. A written consent has been obtained from the subjects. Principles of the Helsinki Convention was also observed.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
All authors contributed equally to the conception and design of the study, data collection and analysis, interpretation of the results, and drafting of the manuscript. Each author approved the final version of the manuscript for submission.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
The authors express their gratitude to all participants involved in this study, with special thanks to the dedicated medical staff in Iraqi hospitals.

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