DRESS syndrome is most commonly caused by anticonvulsants and antibiotics [8]. The reported incidence of this syndrome in the general population ranges from 0.9/100,000 to 10/1,000,000 [9], and the incidence of Lamotrigine-associated DRESS syndrome ranges from 1 to 1,000 to 1 in 10,000 drug exposures and has been less frequently reported since the introduction of a gradual titration schedule in the 1990s [10]. In fact, our case stands out as the only fatal instance we encountered in our literature review since the year 2000. However, we found other cases with life-threatening complications, primarily severe liver toxicity, and less frequently eosinophilic myocarditis, affecting children and adults from both genders, which are summarized in Table 2 [11,12,13,14]. In these cases, severe organ complications emerged while steroids were being tapered, highlighting the importance of close monitoring during this phase of the treatment.

The underlying mechanism of DRESS syndrome is not fully understood. It is believed to involve an idiosyncratic drug-specific immune response, genetic deficiencies in detoxifying enzymes leading to the accumulation of drug metabolites, and reactivation of viral infections, including human herpesviruses 6 and 7, Epstein Barr virus, and cytomegalovirus [1, 5, 8]. DRESS is a delayed hypersensitivity reaction mediated by T helper 2 (TH2) cells associated with increased production of IL-4, IL-5, and IL-13, leading to recruitment and activation of eosinophils [8, 9].

Myocarditis associated with DRESS syndrome can present as either non-necrotizing eosinophilic myocarditis (EM) or acute necrotizing eosinophilic myocarditis (ANEM). Both types are characterized by the presence of an inflammatory infiltrate rich in eosinophils in the myocardium, with or without necrosis. The mortality rate for EM and ANEM is 40 and 50%, respectively. In EM, mortality is often attributed to cardiac arrhythmias or sudden death, while in ANEM, it is typically due to cardiogenic shock and refractory heart failure, as in the present case [2,3,4,5]. Differential diagnoses for drug-associated EM and ANEM include conditions such as eosinophilic granulomatosis with polyangiitis, autoimmune endomyocarditis, infectious myocarditis caused by parasites, protozoa, or viruses, as well as clonal hypereosinophilic syndromes (Table 3). DRESS-associated EM/ANEM is typically preceded by eosinophil-rich cutaneous manifestations and has a temporal association with specific drug exposures. Vasculitis and autoimmune myocarditis can be identified through serologic testing, such as Antineutrophil Cytoplasmic Antibodies (ANCA), ANA, anti-dsDNA, or when a preexisting diagnosis (e.g., Eosinophilic granulomatosis with polyangiitis or systemic lupus erythematosus) exists. Parasitic and protozoal infections are often endemic, and viral myocarditis is usually preceded by viral infections or vaccination. Evaluation for idiopathic hypereosinophilic syndrome should be done in patients with persistent, steroid-refractory peripheral eosinophilia, and it requires bone marrow examination with conventional and molecular cytogenetic work-up [1, 4, 6, 9, 15].

Around half of the patients with EM/ANEM present with symptoms such as dyspnea, fever, and heart failure, while less than 25% experience nausea and vomiting [4, 5]. In our case, the patient’s young age, stable vital signs upon admission, and prominent gastrointestinal symptoms during relapse led to an extensive evaluation for gastrointestinal and biliary tract disease, while the signs of heart and hepatic failure were overlooked.

Liver injury is a prevalent manifestation of DRESS, affecting up to 90% of cases [16]. The initial presentation of liver injury can vary, encompassing cholestatic type (37.1%), hepatocellular type (19.4%), and mixed type (27.4%). Among older individuals, the cholestatic type is more commonly observed and is often associated with anticonvulsants [17]. The understanding of the mechanisms underlying liver injury in DRESS is limited and is attributed to TH2-induced, and primarily IL-5-mediated recruitment of eosinophils, leading to eosinophil degranulation and the release of various inflammatory mediators and cytotoxic molecules. These include cationic proteins (major basic protein 1, eosinophil peroxidase, eosinophil cationic protein, eosinophil-derived neurotoxin), matrix metalloproteinases, proinflammatory cytokines, chemokines, and leukotrienes, resulting in toxic hepatitis. Similar mechanisms have been proposed for interstitial nephritis, pneumonitis, myositis, eosinophilic myocarditis, pancreatitis, thyroiditis, and encephalitis [16, 17].

At autopsy, there was also evidence of thyroiditis characterized by sloughing of follicular cells and infiltration of the follicles by mononuclear cells, including numerous multinucleated giant cells. In our review of the literature, thyroid dysfunction is a common side effect of classical antiepileptic drugs, but it appears to be rare with lamotrigine [18, 19]. We did not find any other reports of lamotrigine-induced thyroiditis.

This case highlights the insidious life-threatening complications of DRESS syndrome, which has earned it the nickname of “the great clinical mimicker” [20]. A definitive diagnosis of DRESS-associated EM/ANEM can be obtained through endomyocardial biopsy, and biopsy is recommended when there is suspicion or uncertainty regarding the diagnosis.

Due to the rarity of EM/ANEM no standardized treatment guidelines are available. The management typically involves discontinuation of the offending medication and a combination of immunosuppression, mechanical circulatory support, and heart failure medications, provided in an intensive care unit setting, tailored to the specific needs of individual patients [1,2,3,4,5]. Immunosuppressive therapy often includes high-dose steroids, while other immunosuppressive agents such as cyclosporine, mycophenolate, intravenous immunoglobulins, and rituximab have also been used [10,11,12,13,14,15, 21]. Considering the crucial role of eosinophils in organ toxicity, the utilization of IL-5 blockers like mepolizumab seems reasonable and is supported by anecdotal reports [14]. Antiviral medications are employed in patients with viral reactivations [22].

In conclusion, we have presented a case of a fatal acute necrotizing eosinophilic myocarditis caused by lamotrigine, which occurred during steroid taper several weeks after reactivation of a previously recognized DRESS syndrome. In this patient, myocarditis was missed due to the atypical clinical presentation and lack of systematic cardiac work-up.

The case highlights the challenges associated with DRESS syndrome, including its low incidence/prevalence, variable clinical course, and unpredictable severe relapses which usually occur during or after steroid taper. As illustrated by this report, judicious regular assessments of organ function, including cardiac, liver, kidney, and lung evaluations, are necessary, as are the development of standardized guidelines to optimize the monitoring, follow-up, and prevention of complications in these patients.