Reacciones cutáneas severas inducidas por lamotrigina. Reporte de dos casos

Lamotrigine-induced severe cutaneous reactions: a two-case report

Resumen

Introducción. Las reacciones cutáneas adversas graves a medicamentos (RCAG) constituyen un grupo heterogéneo de entidades potencialmente mortales que incluyen el síndrome de Steven Johnson (SSJ) y la Necrólisis epidérmica tóxica (NET), el síndrome de hipersensibilidad inducido por fármacos (DRESS por sus siglas en inglés) y la pustulosis exantemática generalizada aguda (AGEP por sus siglas en inglés). SSJ/NET son un espectro de la misma afectación cutánea grave que se caracterizan por necrólisis epidérmica mucocutánea y desprendimiento de la epidermis.

Presentación de casos. Caso 1: mujer de 46 años quien el 09 de noviembre de 2023 consultó al servicio de urgencias de una institución de cuarto nivel de atención de la ciudad de Bogotá (Colombia) por fiebre, rash en cara, tronco y extremidades, odinofagia, edema en labios, y aftas en lengua y paladar durante los últimos 5 días. La paciente había iniciado manejo con lamortrigina 15 días antes para el tratamiento de episodios de manía en el marco del diagnóstico de trastorno bipolar. En la valoración inicial el servicio de dermatología documentó mucosa oral con erosiones extensas y dolorosas, costras hemáticas en labios, ulceraciones en mucosa lingual y eritrodermia en más del 90% de la superficie corporal. Los paraclínicos mostraron transaminasa glutámico oxalacética (TGO) en 184 U/L y transaminasa glutámico pirúvica (TGP) en 212 U/L, por lo que inicialmente se consideró diagnóstico de SSJ incipiente versus una posible reacción cutánea adversa grave secundaria al uso de lamotrigina. Se suspendió la lamotrigina y se inició manejo con metilprednisolona 500mg/día en pulsos intravenosos, con lo cual tuvo una evolución satisfactoria.

Caso 2: mujer de 26 años quien el 27 de octubre de 2023 consultó al servicio de urgencias de una institución de cuarto nivel de atención de la ciudad de Bogotá (Colombia) por exantema maculopapular no descamativo y pruriginoso que inició 15 días y que afectaba al 95% de la superficie corporal, incluyendo mucosas orales y regiones vaginal y anal. La paciente había iniciado manejo con lamortrigina un mes antes para manejo de trastorno depresivo. La biopsia cutánea mostró hiperqueratosis, acantosis con espongiosis, disqueratosis focal y exocitosis linfocitaria, sin necrosis epidérmica de espesor completo. Inicialmente, fue interpretado como un eritema multiforme mayor severo; sin embargo, tras la integración de los hallazgos clínicos, analíticos e histopatológicos, se reclasificó como una reacción cutánea adversa grave. Se suspendió el fármaco y se administró metilprednisolona intravenosa 500 mg/día en pulsos y tres dosis de inmunoglobulina humana (0,5 g/kg/día), con recuperación clínica completa.

Conclusión. Las reacciones cutáneas adversas graves (RCAG) son entidades poco frecuentes, pero potencialmente mortales que deben sospecharse en pacientes con trastornos mentales tratados con psicofármacos. Estas reacciones suelen estar relacionadas con el uso de anticonvulsivantes —especialmente lamotrigina, carbamazepina, fenitoína y fenobarbital— y antipsicóticos empleados para el manejo sintomático de estas enfermedades. El reconocimiento temprano, la suspensión inmediata del fármaco implicado y el manejo multidisciplinario son determinantes para reducir la morbimortalidad asociada.

Abstract

Introduction: Severe cutaneous adverse drug reactions (SCARs) comprise a heterogeneous group of potentially life-threatening conditions, including Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and erythema multiforme major. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of the same severe mucocutaneous disorder, characterized by mucocutaneous epidermal necrolysis and detachment of the epidermis.

Case presentations: Case 1: A 46-year-old woman presented on November 9, 2023, to the emergency department of a tertiary care hospital in Bogotá, Colombia, with a 5-day history of fever, rash on the face, trunk, and extremities, odynophagia, lip edema, and oral ulcers on the tongue and palate. The patient had started treatment with lamotrigine 15 days earlier for management of manic episodes in the context of bipolar disorder. On initial dermatologic evaluation, the patient exhibited extensive and painful oral mucosal erosions, hemorrhagic crusts on the lips, ulcerations on the lingual mucosa, and erythroderma involving more than 90% of the body surface area. Laboratory findings showed aspartate aminotransferase (AST) 184 U/L and alanine aminotransferase (ALT) 212 U/L. A diagnosis of early-onset SJS versus drug – induced erythroderma secondary to lamotrigine use was considered. Lamotrigine was discontinued, and intravenous pulse therapy with methylprednisolone 500 mg/day was initiated, resulting in satisfactory clinical improvement.

Case 2: A 26-year-old woman presented on October 27, 2023, to the emergency department of a tertiary care hospital in Bogotá, Colombia, with a 15-day history of a pruritic, non-desquamative maculopapular rash involving 95% of the body surface area, including the oral, vaginal, and anal mucosae. The patient had started lamotrigine one month earlier for management of depressive disorder. Skin biopsy revealed hyperkeratosis, acanthosis with spongiosis, focal dyskeratosis, and lymphocytic exocytosis, without full-thickness epidermal necrosis. A diagnosis of severe cutaneous adverse reaction mimicking SJS/TEN secondary to lamotrigine use was made. The drug was discontinued, and intravenous pulse therapy with methylprednisolone 500 mg/day was administered along with three doses of intravenous immunoglobulin (0.5 g/kg/day), resulting in complete clinical recovery.

Conclusion: SCARs such as SJS/TEN are rare but potentially fatal conditions that should be considered in patients with psychiatric disorders, as they are often caused by adverse drug reactions to agents such as anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital) and antipsychotics used for the symptomatic management of these diseases.

https://doi.org/10.15446/cr.v11.120436

Lamotrigine-induced severe cutaneous reactions: a report of two cases

Keywords: Lamotrigine; Drug Eruptions; Bipolar Disorder;
Borderline Personality Disorder

Palabras clave: Lamotrigina; Erupciones por Medicamentos; Trastorno Bipolar; Trastorno de Personalidad Limítrofe

María Daniela Moreno-Zambrano

Silvana Michelsen-Gómez

Universidad de los Andes - Faculty of Medicine - Department of Psychiatry -
Bogotá D.C. - Colombia

Hospital Universitario Fundación Santa Fe de Bogotá - Psychiatry Service -
Bogotá D.C. - Colombia

Sergio Andrés Ardila-Pinzón

Álvaro Enrique Arenas-Borrero

María del Pilar Otero-Rueda

Pontificia Universidad Javeriana - Faculty of
Medicine - Department of Psychiatry -
Bogotá D.C. - Colombia

Hospital Universitario Fundación Santa Fe de Bogotá - Psychiatry Service -
Bogotá D.C. - Colombia

Corresponding author

María Daniela Moreno-Zambrano. Departamento de Psiquiatría, Hospital Universitario Fundación Santa Fe de Bogotá. Bogotá D.C. Colombia.
E-mail: md.moreno2259@uniandes.edu.co

Received: 17/05/2025 Accepted: 18/12/2025

Introduction: Severe cutaneous adverse drug reactions (SCARs) comprise a heterogeneous group of potentially life-threatening conditions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

Case presentation: Case 1: On November 9, 2023, a 46-year-old woman presented to the emergency department of a tertiary care institution in the city of Bogotá (Colombia) with a 5-day history of fever, rash involving the face, trunk and extremities, odynophagia, lip edema, and aphthous ulcers on the tongue and palate. The patient had started treatment with lamotrigine 15 days earlier for the management of manic episodes under a diagnosis of bipolar disorder. On initial evaluation, dermatological examination revealed extensive and painful oral mucosal erosions, hemorrhagic crusts on the lips, ulcerations of the lingual mucosa, and erythroderma involving more than 90% of the body surface area. Laboratory tests showed elevated aspartate aminotransferase (AST) at 184 U/L and alanine aminotransferase (ALT) at 212 U/L. An initial diagnosis of early SJS versus a severe cutaneous adverse drug reaction secondary to lamotrigine was considered. Lamotrigine was discontinued, and intravenous methylprednisolone pulses at
500 mg/day were initiated, resulting in satisfactory clinical improvement.

Case 2: On October 27, 2023, a 26-year-old woman presented to the emergency department of a tertiary care institution in Bogotá, Colombia, with a 15-day history of a pruritic, non-desquamative maculopapular rash affecting 95% of the body surface area, including the oral mucosa and vaginal and anal regions.
The patient had started treatment with lamotrigine one month earlier for depressive disorder. Histopathologic examination reported hyperkeratosis, acanthosis with spongiosis, focal dyskeratosis, and lymphocytic exocytosis, without full-thickness epidermal necrosis. Initially, severe erythema multiforme major was suspected; however, after integrating the clinical, laboratory, and histopathological findings, a diagnosis of lamotrigine-induced AGEP was established. The drug was discontinued, and intravenous methylprednisolone
at 500 mg/day and three doses of intravenous immunoglobulin (0.5 g/kg/day) were administered, achieving complete clinical recovery.

Conclusion: SCARs represent a spectrum of rare but potentially fatal conditions, most commonly associated with the use of anticonvulsants —especially lamotrigine, carbamazepine, phenytoin and phenobarbital— as well as antipsychotics. Early recognition, immediate discontinuation of the drug involved, and multidisciplinary management are crucial to reducing associated morbidity and mortality.

Introducción. Las reacciones cutáneas adversas graves a medicamentos (RCAG) constituyen un grupo heterogéneo de afecciones potencialmente mortales que incluyen el síndrome de Stevens-Johnson (SSJ), la necrólisis epidérmica tóxica (NET), el síndrome de hipersensibilidad inducido por fármacos (DRESS por sus siglas en inglés) y la pustulosis exantemática generalizada aguda (AGEP por sus siglas en inglés).

Presentación de los casos. Caso 1: mujer de 46 años quien el 9 de noviembre de 2023 consultó al servicio de urgencias de una institución de cuarto nivel de atención de la ciudad de Bogotá (Colombia) por fiebre, rash en cara, tronco y extremidades, odinofagia, edema en labios, y aftas en lengua y paladar durante los últimos 5 días. La paciente había iniciado manejo con lamortrigina 15 días antes para el tratamiento de episodios de manía en el marco del diagnóstico de trastorno bipolar. En la valoración inicial, el servicio de dermatología documentó mucosa oral con erosiones extensas y dolorosas, costras hemáticas en labios, ulceraciones en mucosa lingual y eritrodermia en más del 90% de la superficie corporal. Los paraclínicos mostraron transaminasa glutámico oxalacética (TGO) en 184 U/L y transaminasa glutámico pirúvica (TGP) en 212 U/L, por lo que inicialmente se consideró diagnóstico de SSJ incipiente versus una posible reacción cutánea adversa grave secundaria al uso de lamotrigina. Se suspendió la lamotrigina y se inició manejo con metilprednisolona 500mg/día en pulsos intravenosos, con lo cual tuvo una evolución satisfactoria.

Caso 2: mujer de 26 años quien el 27 de octubre de 2023 consultó al servicio de urgencias de una institución de cuarto nivel de atención, ubicada en la ciudad de Bogotá, por exantema maculopapular no descamativo y pruriginoso de 15 días de evolución, y que afectaba el 95% de su superficie corporal, incluyendo mucosas orales y regiones vaginal y anal. La paciente había iniciado manejo con lamortrigina un mes antes para manejo de trastorno depresivo. El estudio histopatológico informó hiperqueratosis, acantosis con espongiosis, disqueratosis focal y exocitosis linfocitaria, sin necrosis epidérmica de espesor completo. Inicialmente, se sospechó un eritema multiforme mayor severo, pero tras la integración de los hallazgos clínicos, paraclínicos e histopatológicos, se diagnosticó RACG secundaria al uso de lamotrigina. Se suspendió el fármaco y se administró metilprednisolona 500mg/día vía intravenosa y tres dosis de inmunoglobulina (0.5 g/kg/día), con lo cual se logró una recuperación clínica completa.

Conclusión. Las RCAG representan un espectro de afecciones poco frecuentes, pero potencialmente mortales, que suelen estar relacionadas con el uso de anticonvulsivantes —especialmente lamotrigina, carbamazepina, fenitoína y fenobarbital— y antipsicóticos. Su reconocimiento temprano, la suspensión inmediata del fármaco implicado y el manejo multidisciplinario son determinantes para reducir la morbimortalidad asociada.

IntroducTIOn

Serious cutaneous adverse reactions (SCARs) are a group of rare but potentially fatal conditions that affect the skin and mucous membranes. They can lead to systemic involvement and require timely treatment due to their high morbidity and mortality (1,2).

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are SCARs characterized by epidermal detachment. They differ from each other in the extent of skin involvement: SJS involves 10% of the skin surface, while TEN involves more than 30% of the skin surface (3,4). Their incidence ranges between 2 and 7 cases per million inhabitants per year, being more frequent in women (5). Some genetic risk factors, such as certain alleles of the human leukocyte antigen (HLA), increase susceptibility to these reactions, especially in individuals exposed to aromatic anticonvulsants or allopurinol (5,6).

One of the main causes of SCARs is exposure to certain drugs, particularly anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital), allopurinol, sulfonamides, beta-lactam antibiotics, non-steroidal
anti-inflammatory drugs, antipsychotics, and antivirals such as nevirapine (1,5). This type of reaction usually occurs after administering the initial dose or when increasing the dose rapidly, so it is recommended to start with a low initial dose and adjust it gradually (7).

Lamotrigine, a drug of the phenyltriazine class indicated for the prevention of focal and generalized seizures in epileptic patients, as well as in monotherapy or adjunctive maintenance treatment for bipolar disorder (7), is one of the drugs most commonly associated with SCARs such as SJS/TEN. These reactions usually appear within the first 3 weeks of treatment, especially when administered concomitantly with valproate because this anticonvulsant inhibits lamotrigine degradation (1,7). In view of the foregoing, it is recommended to use slow titration schedules and to closely monitor the initiation of treatment (7).

The diagnosis of a SCAR is based on clinical presentation, but it must be confirmed with laboratory tests; in the case of SJS/TEN, it must be confirmed via skin biopsies and direct immunofluorescence studies of the skin with findings of full-thickness skin necrosis (6,7). The treatment for SCARs requires a multidisciplinary approach in a specialized hospital setting and must include immediate discontinuation of the drug involved, hemodynamic and nutritional support, infection control, pain management, and administration of immunomodulators such as systemic corticosteroids or intravenous immunoglobulin (1,2).

Below are two cases of patients with psychiatric disorders who developed SCARs associated with lamotrigine use, emphasizing the importance of timely identification and early intervention for these types of life-threatening reactions.

Case presentation

Case 1

46-year-old woman from Bogotá and living in Barranquilla, with a history of bipolar disorder type I diagnosed at the age of 33 years. Due to multiple manic episodes and symptom control difficulties, the patient required several hospitalizations and pharmacological treatment with valproic acid, lithium, and quetiapine.

In 2023, she was admitted to hospital twice, most recently in September, due to an episode of mania with psychotic symptoms characterized by delirious ideas of erotomanic content and disorganized thinking with lax association of ideas. After the last crisis, on October 25, 2023, she attended an outpatient appointment with the psychiatry service and received an indication to start treatment with lamotrigine 25 mg/day and gradually increase the dose to 50 mg/day.

On November 9, 2023, the patient presented to the emergency department of a tertiary care institution in Bogotá (Colombia) due to fever; rash on the face, trunk, and extremities (involving >90% of the body surface); odynophagia; edema of the lips; and aphthous ulcers on the tongue and palate during the last 5 days. In view of the symptomatology, on the same day of admission, the psychiatry service suspended the treatment with lamotrigine and started lithium carbonate at a dose of 300 mg every 12 hours as a mood stabilizer, as well as quetiapine at a dose of 25 mg every night to improve the sleep pattern.

On November 11, 2023, she was assessed by the dermatology service, which found oral mucosa with extensive and painful erosions, hematic crusts on the lips, ulcerations on the lingual mucosa, and erythroderma on more than 90% of the body surface. Laboratory tests showed aspartate aminotransferase (AST) at 184 U/L and alanine aminotransferase (ALT) at 212 U/L.

Given the findings, incipient SJS secondary to lamotrigine use was suspected. However, since there were no pathognomonic histopathological findings, the diagnosis was not confirmed and SCAR with mucositis secondary to the use of lamotrigine was diagnosed instead. In view of the above, on November 11, treatment with intravenous methylprednisolone 500 mg/day was started, achieving an adequate response with resolution of the skin lesions and a decrease in transaminase levels (AST: 33 U/L and ALT: 26 U/L) as shown by the follow-up laboratory tests performed 7 days after admission. Similarly, she responded well to management with lithium carbonate, with adequate affective modulation, and without decompensation of her mental illness during hospitalization.

Finally, the patient was discharged on November 17, 2023, 8 days after admission, with an indication for treatment with lithium carbonate 300 mg
every 12 hours and quetiapine 25 mg at night. Moreover, she was instructed not to restart lamotrigine therapy as part of her psychopharmacological plan and was advised to continue with outpatient psychiatry follow-ups.

Case 2

26-year-old woman, born in Bogotá and living in Cúcuta, with a history of unspecified epilepsy that required treatment with valproic acid until the age of 9, under psychiatric care since adolescence due to symptoms of depression and anxiety, and suspected diagnosis of attention deficit hyperactivity disorder (ADHD).

At the age of 23, she was diagnosed with recurrent depressive disorder in the context of borderline personality disorder, for which she was initially treated with bupropion at an initial dose of 150 mg/day, gradually increasing to 300 mg/day, and quetiapine 300 mg/day. Given the persistence of the affective symptoms and the report of non-suicidal self-harm, she received multiple psychopharmacological treatments, mainly with escitalopram 10 mg/day, lithium 900 mg/day, levomepromazine 10 drops every night, alprazolam 0.5 mg every 8 hours, and risperidone 2 mg/day.

On February 2, 2023, at the age of 25, she was admitted to the emergency department of a tertiary care hospital in Bogotá following an exogenous intoxication caused by the ingestion of quetiapine, escitalopram and pregabalin as a result of a suicide attempt. That same day, after being clinically stabilized, she was transferred to a mental health unit, with no changes in the treatment with quetiapine and bupropion. On September 20, 2023, during an outpatient follow-up appointment with the psychiatry service, she was prescribed lamotrigine with an initial dose of 50 mg and a gradual increase to 200 mg.

On October 27, 2023, she presented to the emergency department of the same institution due to a 15-day history of non desquamative and pruritic maculopapular exanthema affecting 95% of the body surface, including oral mucosa and vaginal and anal regions (Figures 1 and 2). She also had non-painful lymphadenopathies in the cervical and submandibular chain.

C

B

A

Figure 1. Maculopapular, erythematous, and diffuse lesions located on palms (a), thighs (b), and forearms (c).

Source: Images taken while conducting the study.

B

A

Figure 2. Symptom progression, with extensive skin involvement.

Source: Images taken while conducting the study.

On admission, complete blood count reported leukocytosis (11 800 x 103 cells/uL), neutrophilia (8 800 x 103 cells/uL), and eosinophilia (1 400 x 103 cells/uL). Arterial blood gas analysis showed respiratory acidosis and hyperlactatemia. A skin biopsy was also performed on the anterior aspect of the right thigh. Histopathology revealed hyperkeratosis, acanthosis with spongiosis, and presence of intraepithelial dyskeratotic cells (individual and in groups) in the upper dermis, as well as a perivascular and perianexial lymphohistiocytic infiltrate with exocytosis of lymphoid cells.

Based on the findings, severe erythema multiforme major was initially suspected. However, after the combined analysis of the clinical, laboratory, and histopathological findings, and given the extent of cutaneous involvement, mucosal involvement, the presence of eosinophilia and systemic manifestations, it was established that this was a SCAR compatible with drug reaction syndrome with eosinophilia and systemic symptoms (DRESS) induced by lamotrigine.

Accordingly, lamotrigine was suspended and treatment with intravenous methylprednisolone 500 mg/day and 3 doses of immunoglobulin 0.5 g/kg/day was started due to the risk of systemic involvement. Likewise, due to the high risk of hemodynamic instability, she was immediately transferred to the intensive care unit (ICU) for continuous monitoring.

On October 29, 2023, during her stay in the ICU, she presented a seizure episode lasting 90 seconds with bilateral tonic-clonic movements and altered consciousness, which was successfully treated with intravenous midazolam 5 mg.

As the skin lesions improved, on November 1, 2023, she was transferred to the general hospital ward. Five days later, upon achieving control of her baseline mental illness and normalization of laboratory parameters (blood count on November 5: leukocytes: 6 700 x 103 cell/uL, neutrophils: 2 410 x 103 cell/uL, lymphocytes : 3.390 x 103 cell/uL, and eosinophils 270 x 103 cell/uL), she was discharged with a plan to gradually taper methylprednisolone to 40 mg/day for 5 days, indication to discontinue bupropion due to the risk of decreased seizure threshold, and to continue quetiapine at a dose of 300 mg. She was also reminded of the importance of maintaining her psychotherapeutic treatment, attending outpatient psychiatric follow-ups, and refraining from reintroducing lamotrigine.

Discussion

In this report, we present the cases of two patients who developed SCARs associated with lamotrigine use: one case that was initially considered compatible with incipient SJS, which was subsequently ruled out due to the lack of the required histopathological findings, and another case of a SCAR compatible with drug reaction syndrome with eosinophilia and systemic symptoms. In both cases, the clinical presentation of SCAR is in line with what has been reported in the literature, which has documented that these reactions most frequently affect women and that drugs are the most common cause, especially anticonvulsants, nonsteroidal anti-inflammatory drugs, beta-lactam antibiotics, sulfonamides, and allopurinol (1,5,6).

SCARs include several pathophysiologically related conditions, such as
SJS/TEN, drug reaction syndrome with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. These diseases share certain characteristics such as immunological alterations, latency periods after drug exposure, and a potentially severe clinical course (1,2). In particular, SJS and TEN represent a continuum of severity characterized by extensive cutaneous necrolysis (3,4).

In the reported cases, the extent of skin involvement observed in both patients (>90%) posed a clinical challenge, as the morphology of the lesions did not strictly conform to SJS/TEN criteria. This clinical overlap, described in the literature, suggests that some SCARs may mimic SJS/TEN, especially in the presence of mucosal erosions or erythroderma. Consequently, the diagnostic approach requires an integration of clinical, physical, and histopathological findings, together with a rigorous exclusion of differential diagnoses, all of which makes the diagnosis and treatment of these conditions complex (8), as was the case of these patients.

The association between SCARs and the use of lamotrigine has been widely described in the literature. This drug acts by blocking voltage-gated sodium channels and inhibiting glutamate release (1,2,5,7). It is estimated that approximately 8% of treated patients present mild dermatological reactions, while between 0.01% and 0.04% develop severe symptoms, such as SJS/TEN. The risk of developing a SCAR increases significantly with high initial doses, a rapid increase in dosage, or coadministration with valproate (7).

In a systematic review that included 122 studies with a total of 18 698 patients receiving monotherapy lamotrigine, Bloom and Amber (9) found that adverse skin reactions occur in 8.3% of these patients, and that 0.04% develop SJS/TEN.
This is in line with what was reported by Calabrese et al. (10) in a study of lamotrigine-related rashes, with data from 12 multicenter studies (1 955 treated with lamotrigine in open settings, 1 198 treated with lamotrigine in controlled settings, and 1 056 given placebo), which found that, in the open setting, the rate of lamotrigine-related rashes was 13.1% (257 patients) and the rate of severe rashes was 0.1% (2 patients). Furthermore, no cases of TEN were reported, demonstrating that severe reactions are rare. This reflects the low rate of severe skin reactions induced by lamotrigine.

Similarly, Woo et al. (11), in a study conducted in South Korea in 237 patients with bipolar disorder type I treated with lamotrigine, reported an incidence of skin rash of 12.7%, as well as a severe reaction in 2 cases (0.8%), although none progressed to SJS/TEN. The mean time to rash onset was 16 days after initiation of treatment. In the cases reported here, the symptoms appeared within the usual latency period described in lamotrigine-induced SCARs; however, contrary to what has been reported in the literature, these patients did not exhibit a clear prodromal phase, which is typically characterized by malaise, fever, rash, conjunctivitis, and pharyngitis (1,5,8).

On the other hand, comparing the incidence of skin reactions when using lamotrigine with other mood stabilizers (valproate, carbamazepine, lithium), Pampaloni et al. (12), in a systematic review and meta-analysis (50 studies), studied the prevalence and types of adverse skin reactions associated with the use of mood stabilizers (lithium, valproate, carbamazepine, or lamotrigine). Lamotrigine was found to have the highest incidence of rash (9.2%), followed by carbamazepine (6.0%), valproate (2.9%), and lithium (1.3%).

Adequate drug titration was undertaken in both patients in this report. However, it should be noted that a history of psychiatric polypharmacy is an additional risk factor for the development of SCARs, since this increases the possibility of metabolic interactions and cross-reactions, and also makes it difficult to identify the suspected agent (13).

Regarding treatment, lamotrigine was immediately discontinued in both cases, with supportive measures being instituted. In case 1, the administration of intravenous methylprednisolone pulses resulted in a favorable clinical course, which is in line with the literature supporting the use of systemic corticosteroids as first-line therapy in selected SCARs (2,14). In case 2, in addition to corticosteroids, the patient required ICU care and the administration of intravenous immunoglobulin, a therapy that has been associated with a reduction in complications and a decrease in the mortality rate in severe SJS/TEN cases (6,15).

Strategies to reduce the risk of a SCAR include gradual dose titration, avoiding omissions that lead to abrupt reintroductions, and maintaining strict clinical surveillance during the first weeks of treatment (2,7,16). However, even with rigorous adherence to prescription protocols, there are no infallible preventive measures given the multifactorial nature of these reactions (1,7), as evidenced in the cases presented.

It was decided to avoid the reintroduction of lamotrigine in both patients, since evidence reports a failure rate of up to 50% after reexposure, especially in patients with severe symptoms or systemic manifestations (17). Upon resolution of skin lesions and clinical stabilization, the patients continued their psychiatric treatment with safe alternatives that had a lower risk profile for SCARs, such as lithium and quetiapine (18).

This report has some limitations to be considered. First, no biopsy was performed in case 1 to confirm the diagnosis, and not enough information on the patient’s psychopharmacologic history is available. Second, none of the patients underwent genetic studies, which could be useful in risk assessment.

Conclusions

SCARs represent a spectrum of rare but potentially fatal conditions. Although their etiology is multifactorial, exposure to certain drugs is the main triggering factor. Among these, anticonvulsants, especially lamotrigine, and some antipsychotics pose a higher risk of triggering these reactions, which emphasizes the need for rigorous clinical monitoring, mainly during the first weeks of treatment. Early detection, immediate suspension of the suspected agent, and a timely multidisciplinary approach are key to reducing morbidity and mortality rates and ensuring a favorable prognosis in patients affected by these dermatologic emergencies.

Ethical considerations

For the preparation of this case report, the patients’ data were kept anonymous, the confidentiality of the information was preserved, and informed consent was obtained.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgments

None stated by the authors.

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