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Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder
Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 147 – 150 www.elsevier.com/locate/pnpbp
Case report
Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder Chuan-Chia Chang a, I-Shin Shiah a,b,*, Hsin-An Chang a, San-Yuan Huang a,b a
Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan b National Defense Medical Center, Taipei, Taiwan Accepted 26 August 2005 Available online 12 October 2005
Abstract Toxic epidermal necrolysis (TEN) is the most severe and potentially life-threatening cutaneous reaction associated with lamotrigine. The risk of developing TEN during lamotrigine therapy is low and previously reported cases most involved epileptic patients. However, the risk of TEN with combination lamotrigine and valproate is greater than with monotherapy. We present here the emergence of TEN in a 32-year-old bipolar woman who was concomitantly treated with lamotrigine and valproate. The patient developed high fever, pharyngitis, cervical lymphadenopathy, mucosal sloughing, generalized erythematous eruptions and more than 40% epidermal detachment of the total body surface area (TBSA) after we added lamotrigine to her medications of valproate and trazodone. The patient’s illness course was protracted and accompanied with hepatitis, pneumonitis and hematologic abnormalities. In the beginning of her illness course, our patient did not respond to antihistamine treatment. However, she made a full recovery without any sequela after she had received systemic corticosteroid and intensive resuscitation. Our case suggests that early use of systemic corticosteroid might be beneficial in treating TEN patients, if there is not any clinical contraindication. D 2005 Elsevier Inc. All rights reserved. Keywords: Anticonvulsants; Bipolar disorder; Lamotrigine; Toxic epidermal necrolysis; Valproate
1. Introduction Toxic epidermal necrolysis (TEN) is a rare, severe, and life-threatening exfoliative skin disorder, which is characterized by a high fever, malaise, skin blistering or crusting and extensive epidermal necrosis (Warnock and Morris, 2003). This disorder has been considered as a maximal variant of Stevens-Johnson syndrome (SJS), depending on the amount of epidermal detachment (Bastuji-Garin et al., 1993). In TEN, there is greater than 30% total body surface area (TBSA) involvement, whereas SJS is usually defined as having less than 30% TBSA involvement (Bastuji-Garin et al., 1993). The pathogeness of both disorders is still unclear; however,
Abbreviations: CRP, C-reactive protein; FDA, Food and Drug Administration; NSAIDs, non-steroidal anti-inflammatory drugs; SJS, Stevens-Johnson syndrome; TBSA, total body surface area; TEN, toxic epidermal necrolysis. * Corresponding author. Department of Psychiatry, Tri-Service General Hospital, No. 325, Sec. 2, Cheng-Kung RD., Neihu District, 114, Taipei, Taiwan. Tel.: +886 2 87927431; fax: +886 2 87912161. E-mail address: [email protected] (I.-S. Shiah). 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.08.025
over 80% of TEN cases are specific medication related, as opposed to 50% with SJS (Warnock and Morris, 2003). Over 100 drugs have been implicated in the development of TEN and SJS, most commonly anticonvulsants, antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs) (Clennett and Hosking, 2003). The estimated mortality rate for SJS is approximately 10% while that for TEN is as high as 45%, with death mainly due to sepsis and homodynamic failure (Warnock and Morris, 2003). Lamotrigine is a relatively new anticonvulsant. It is effective in treating and preventing bipolar depression, and has been recently approved by the U.S. Food and Drug Administration (FDA) as a maintenance treatment for bipolar disorder (Yatham, 2004). The frequency of SJS and TEN in patients treated with lamotrigine is estimated to be 1 : 1000 for adults and 3 : 1000 for children (Messenheimer, 1998; Guberman et al., 1999). However, most reported cases of lamotrigineassociated TEN involved epileptic patients (Wadelius et al., 1996; Schlienger et al., 1998; Rzany et al., 1999; Clennett and Hosking, 2003; Hashim et al., 2004). Furthermore, the risk of TEN with combination lamotrigine and valproate is greater
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C.-C. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 147 – 150
than with monotherapy. To our knowledge, the only case of lamotrigine-associated TEN in bipolar patient was published in a non-psychiatric journal (Sladden et al., 2004). We report here the emergence of lamotrigine-associated TEN in a 32-year-old bipolar woman who was concomitantly treated with lamotrigine, valproic acid and trazodone. 2. Case report Mrs. L, a 32-year-old Taiwanese woman, had her first depressive episode in 2000. This depressive episode persisted for longer than one year and was followed by a hypomanic episode lasting for three months. Her second depressive episode occurred in January 2003, and she was admitted to our psychiatric ward on January 24, 2003 under the impression of bipolar II disorder, most recent depressive episode, recurrent. After admission, she was treated with valproic acid (1000 mg/day) and trazodone (100 mg/day). Her depression responded to the combined treatment and she was discharged on February 20, 2003. However, her depression recurred in September 2004 because of noncompliance to her medications. She also developed persistent suicidal ideas. Thus she was admitted for the second time to our psychiatric ward on October 1, 2004. Apart from her diagnosis of bipolar II disorder, the patient’s medical history was unremarkable. She has no previous history of drug or food allergy. There was no history of previous upper respiratory tract infection or viral illness, in the patient, her family, or close contacts. Laboratory tests after her hospitalization including complete blood cell counts, tests of liver, renal and thyroid function, and urinalysis all showed no abnormal findings. After admission, the patient was restarted on valproic acid (1000 mg/day) and trazodone (200 mg/day). However, her depression did not improve after 2 weeks of the combined treatment. We thus added lamotrigine 12.5 mg/day to her medications on October 15. She tolerated the medication well for the first two weeks. No side effect of lamotrigine was reported but the patient remained depressed. We further increased her dose of lamotrigine up to 25 mg/day on October 29. The patient developed high spike fever (39.2 -C), dysphagia and sore throat after the dose of lamotrigine was increased. At that time, her physical examination showed swollen tonsils with diffuse exudative appearance and cervical lymphadenopathy. Laboratory tests including complete blood cell count with differential, liver panel, and electrolytes were all within normal limits except that Creactive protein (CRP) was 1.85 mg/dl (normal range: 0 –0.5 mg/dl). The workup to rule out infectious conditions including blood, sputum and urine cultures, IgG and IgM, serum antibody for herpes simplex, antigen for chlamydia, and antibody for mycoplasma were all negative. Antinuclear antibody was negative and chest radiograph was normal. Her blood level of valproic acid was 105.4 ng/ml (therapeutic range: 50– 100 ng/ml). On October 30, the patient showed diffuse, reddish, and pruritic rashes over her face, neck, chest and upper
extremities. In light of these cutaneous adverse reactions, we discontinued lamotrigine and valproic acid immediately. However, the skin eruptions become generalized and confluent erythema covering more than 60% of the total body surface area (TBSA) on October 31. These dermatological lesions looked like large areas of burn-damaged skin. Extensive erosions over oral, conjunctival and genital mucosa were noticed. The patient was transferred to medical ward on November 1 and she was treated with oral antihistamines (cetirizine 10 mg/day and cyproheptadine 12 mg/day), intravenous fluid supplement and supportive medical care. At that time, her psychotropic medications were all stopped, and her laboratory tests including blood, urine, and sputum cultures were all within normal limits except CRP was 13.68 mg/dl. Over the following 24 h, the patient developed confluent bullae and her skin began to slough from her back, trunk and extremities that accounted for 15% TBSA epidermal loss. She was then transferred to our burn center on November 2, five days after the onset of her adverse cutaneous reactions. Skin biopsies and pathological examinations showed separation of the dermis and epidermis with full-thickness necrosis of the epidermis, broad areas of subepidermal blisters and a few inflammatory cells in the dermis. These presentations, together with a positive Nikolsky’s sign (shearing off of the epidermis with lateral pressure), were compatible with the diagnosis of TEN. Given the diagnosis of TEN, the patient was treated with oral antihistamines, aggressive hydration, parenteral analgesia, empiric antibiotics and porcine xenograft applications to all open skin lesions. On November 4, the patient’s medical condition including level of consciousness and oxygenation status deteriorated markedly despite intensive resuscitation. She continued to have spiking fever (38.7 -C). Her blood pressure was 113/58 mmHg, heart rate 92 beats/min, and respiration rate 26/min. All cultures were negative. Her maximum skin shedding involved 40% of the TBSA and hemorrhagic crusting of mucous membranes was noticed. Besides, her laboratory evaluations showed abnormalities including anemia, thrombocytopenia, impaired liver function, electrolyte imbalance, hypoalbuminea, and increased inflammatory parameters. Her chest radiograph revealed diffuse ground – glass opacity over both lung fields. Since the patient’s allergic reactions became more severe and involved multiple organ systems, she was given intravenous methylprednisolone 120 mg/day, ventilatory and circulatory support, broad spectrum antibiotics, special wound care, and pain control. With these treatments, her critical condition improved and was finally stabilized. One week after her use of parenteral corticosteroid, the patient’s skin showed regrowth of epidermis and islands of granulating tissue. After 14 days of hospitalization at the burn center, our patient was sent back to medical ward because of significant improvement in her medical condition. Her parenteral corticosteroid was tapered gradually and changed to oral prednisolone 30 mg/day. A follow-up chest radiograph revealed no more active lung disease and all her laboratory abnormalities returned to normal limits. She was discharged
C.-C. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 147 – 150
with a stable condition on November 16. Besides pigmentary changes over her lower extremities, she is doing well to date with lithium (600 mg/day) and clonazepam (2 mg/day) at our outpatient clinic. There was no any evidence of relapse of bipolar disorder or adverse drug reactions. 3. Discussion Previous reports on epileptic (Schlienger et al., 1998; Rzany et al., 1999) and bipolar patients (Calabrese et al., 2002) have suggested that the risk of lamotrigine-associated cutaneous reactions can be increased by co-administration with valproic acid, exceeding recommended initial dose, and exceeding the recommended dose escalation schedule. The international prescribing guideline (Guberman et al., 1999) recommended that adult patients taking concomitant valproate and lamotrigine should be initiated at dosage of 12.5 mg once daily for the first two weeks, followed by 25 mg once daily for the next two weeks, and increased thereafter by 25 mg every other week until a maintenance dosage of 100 –200 mg daily. Such a prudent titration schedule is especially important for patients with bipolar depression because most of them are difficult to treat and often need the combined treatment of valproate and lamotrigine. Our patient is an adult and has no history of allergies to other anticonvulsants. Her starting dose of lamotrigine and its rate of escalation were all based on the recommended dosing guideline. It appears that the only risk factor for our patient’s TEN is the concomitant use of valproate. Of note, the patient’s blood level of valproic acid (105.4 ug/dL) was higher than therapeutic range while she had been receiving lamotrigine add-on therapy. This is very likely to predispose the patient to the development of TEN because valproate can interact with lamotrigine and result in a decrease in the clearance of lamotrigine (Guberman et al., 1999). We thus suggest that if bipolar patients need concomitant valproic acid treatment in addition to their lamotrigine, blood level of valproic acid should be monitored closely and that the recommended dosing guideline should also be followed strictly. Management of patients with severe SJS or TEN should be performed in an intensive care or burn unit. General supportive measures should include immediate withdrawal of offending agents, careful fluid monitoring, nutritional support, antibacterial treatment, heat regulation, and pain control (Warnock and Morris, 2003). There is little evidence to support any specific therapeutic agent that is effective in treating patients with TEN. In this regard, the role of corticosteroids is still controversial. However, most clinicians would choose to try it if patient’s adverse reactions are severe (Knowles et al., 1999). Uncontrolled studies suggested that human intravenous immunoglobulin (Clennett and Hosking, 2003; Mayorga et al., 2003), cyclosporin (Hashim et al., 2004) and plasmaphresis (Sladden et al., 2004) may be efficacious in the treatment of TEN. These treatments need to be validated further for their effectiveness. In the beginning of her illness course, our patient did not respond to antihistamine treatment; however, she obtained a favorable outcome after
149
her having received systemic corticosteroid therapy. Thus our case might suggest that early use of systemic corticosteroid is beneficial in treating TEN patients, if there is not any clinical contraindication. Because it is impossible to predict which rash will be benign or severe, any patient who develops a rash associated with lamotrigine should discontinue it immediately. It is also imperative to know that early manifestations of TEN (e.g., fever, malaise, pharyngitis, lymphadenopathy) may be present even though a rash is not evident. Before initiation of treatment with lamotrigine, the patient should be instructed that a rash or other early constitutional symptoms may herald a serious adverse reaction such as SJS or TEN, and that the patient should report any such occurrences to their psychiatrist immediately within 24 h on an emergency basis (Faught et al., 1999; Guberman et al., 1999). If the clinical presentations are compatible with SJS or TEN, immediate hospitalization and consultations with a dermatologist and other specialists are recommended. Finally, although there are a couple of reports of successful rechallenge with slowly titrated lamotrigine after a mild rash (Besag et al., 2000; Manfredi et al., 2004), those patients who have had SJS or TEN should not be rechallenged with lamotrigine. 4. Conclusion In conclusion, we present the emergence of TEN in a patient with bipolar II depression who was concomitantly treated with lamotrigine and valproate. With systemic corticosteroid and intensive resuscitation, the patient made a full recovery without any sequela. Our case suggests that early use of systemic corticosteroid might be beneficial in treating TEN patients, if there is not any clinical contraindication. References Bastuji-Garin, S., Rzany, B., Stern, R.S., Shear, N.H., Naldi, L., Roujeau, J.C., 1993. Clinical classification of cases of toxic epidermal necrolysis, StevensJohnson syndrome, and erythema multiforme. Arch. Dermatol. 129, 92 – 96. Besag, F.M., Ng, G.Y., Pool, F., 2000. Successful re-introduction of lamotrigine after initial rash. Seizure 9, 282 – 286. Calabrese, J.R., Sullivan, J.R., Bowden, C.L., Suppes, T., Goldberg, J.F., Sachs, G.S., Shelton, M.D., Goodwin, F.K., Frye, M.A., Kusumakar, V., 2002. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J. Clin. Psychiatry 63, 1012 – 1019. Clennett, S., Hosking, G., 2003. Management of toxic epidermal necrolysis in a 15-year-old girl. J. Wound Care 12, 151 – 154. Faught, E., Morris, G., Jacobson, M., French, J., Harden, C., Montouris, G., Rosenfeld, W., 1999. Adding lamotrigine to valproate: incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group. Epilepsia 40, 1135 – 1140. Guberman, A.H., Besag, F.M., Brodie, M.J., Dooley, J.M., Duchowny, M.S., Pellock, J.M., Richens, A., Stern, R.S., Trevathan, E., 1999. Lamotrigineassociated rash: risk/benefit considerations in adults and children. Epilepsia 40, 985 – 991. Hashim, N., Bandara, D., Tan, E., Ilchyshyn, A., 2004. Early cyclosporine treatment of incipient toxic epidermal necrolysis induced by concomitant use of lamotrigine and sodium valproate. Acta Derm.-Venereol. 84, 90 – 91. Knowles, S.R., Shapiro, L.E., Shear, N.H., 1999. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 21, 489 – 501.
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Manfredi, G., Pacchiarotti, I., Kotzalidis, G.D., Ruberto, A., Girardi, P., Tatarelli, R., 2004. Successful rechallenge with slowly titrated lamotrigine after rash. Bipolar Disord. 6, 338 – 339. Mayorga, C., Torres, M.J., Corzo, J.L., Sanchez-Sabate, E., Alvarez, J., Vera, A., Posadas, S., Jurado, A., Blanca, M., 2003. Improvement of toxic epidermal necrolysis after the early administration of a single high dose of intravenous immunoglobulin. Ann. Allergy, Asthma, & Immun. 91, 86 – 91. Messenheimer, J.A., 1998. Rash in adult and pediatric patients treated with lamotrigine. Can. J. Neurol. Sci. 25, S14 – S18. Rzany, B., Correia, O., Kelly, J.P., Naldi, L., Auquier, A., Stern, R., 1999. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the
International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 353, 2190 – 2194. Schlienger, R.G., Shapiro, L.E., Shear, N.H., 1998. Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia 39 (Suppl 7), S22 – S26. Sladden, M., Mortimer, N., Chave, T., 2004. Toxic epidermal caused by lamotrigine. Aust. Fam. Physician 33, 829 – 830. Wadelius, M., Karlsson, T., Wadelius, C., Rane, A., 1996. Lamotrigine and toxic epidermal necrolysis. Lancet 348, 1041. Warnock, J.K., Morris, D.W., 2003. Adverse cutaneous reactions to mood stabilizers. Am. J. Clin. Dermatol. 4, 21 – 30. Yatham, L.N., 2004. Newer anticonvulsants in the treatment of bipolar disorder. J. Clin. Psychiatry 65 (Suppl. 10), 28 – 35.
Case report
Toxic epidermal necrolysis with combination lamotrigine and valproate in bipolar disorder Chuan-Chia Chang a, I-Shin Shiah a,b,*, Hsin-An Chang a, San-Yuan Huang a,b a
Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan b National Defense Medical Center, Taipei, Taiwan Accepted 26 August 2005 Available online 12 October 2005
Abstract Toxic epidermal necrolysis (TEN) is the most severe and potentially life-threatening cutaneous reaction associated with lamotrigine. The risk of developing TEN during lamotrigine therapy is low and previously reported cases most involved epileptic patients. However, the risk of TEN with combination lamotrigine and valproate is greater than with monotherapy. We present here the emergence of TEN in a 32-year-old bipolar woman who was concomitantly treated with lamotrigine and valproate. The patient developed high fever, pharyngitis, cervical lymphadenopathy, mucosal sloughing, generalized erythematous eruptions and more than 40% epidermal detachment of the total body surface area (TBSA) after we added lamotrigine to her medications of valproate and trazodone. The patient’s illness course was protracted and accompanied with hepatitis, pneumonitis and hematologic abnormalities. In the beginning of her illness course, our patient did not respond to antihistamine treatment. However, she made a full recovery without any sequela after she had received systemic corticosteroid and intensive resuscitation. Our case suggests that early use of systemic corticosteroid might be beneficial in treating TEN patients, if there is not any clinical contraindication. D 2005 Elsevier Inc. All rights reserved. Keywords: Anticonvulsants; Bipolar disorder; Lamotrigine; Toxic epidermal necrolysis; Valproate
1. Introduction Toxic epidermal necrolysis (TEN) is a rare, severe, and life-threatening exfoliative skin disorder, which is characterized by a high fever, malaise, skin blistering or crusting and extensive epidermal necrosis (Warnock and Morris, 2003). This disorder has been considered as a maximal variant of Stevens-Johnson syndrome (SJS), depending on the amount of epidermal detachment (Bastuji-Garin et al., 1993). In TEN, there is greater than 30% total body surface area (TBSA) involvement, whereas SJS is usually defined as having less than 30% TBSA involvement (Bastuji-Garin et al., 1993). The pathogeness of both disorders is still unclear; however,
Abbreviations: CRP, C-reactive protein; FDA, Food and Drug Administration; NSAIDs, non-steroidal anti-inflammatory drugs; SJS, Stevens-Johnson syndrome; TBSA, total body surface area; TEN, toxic epidermal necrolysis. * Corresponding author. Department of Psychiatry, Tri-Service General Hospital, No. 325, Sec. 2, Cheng-Kung RD., Neihu District, 114, Taipei, Taiwan. Tel.: +886 2 87927431; fax: +886 2 87912161. E-mail address: [email protected] (I.-S. Shiah). 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.08.025
over 80% of TEN cases are specific medication related, as opposed to 50% with SJS (Warnock and Morris, 2003). Over 100 drugs have been implicated in the development of TEN and SJS, most commonly anticonvulsants, antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs) (Clennett and Hosking, 2003). The estimated mortality rate for SJS is approximately 10% while that for TEN is as high as 45%, with death mainly due to sepsis and homodynamic failure (Warnock and Morris, 2003). Lamotrigine is a relatively new anticonvulsant. It is effective in treating and preventing bipolar depression, and has been recently approved by the U.S. Food and Drug Administration (FDA) as a maintenance treatment for bipolar disorder (Yatham, 2004). The frequency of SJS and TEN in patients treated with lamotrigine is estimated to be 1 : 1000 for adults and 3 : 1000 for children (Messenheimer, 1998; Guberman et al., 1999). However, most reported cases of lamotrigineassociated TEN involved epileptic patients (Wadelius et al., 1996; Schlienger et al., 1998; Rzany et al., 1999; Clennett and Hosking, 2003; Hashim et al., 2004). Furthermore, the risk of TEN with combination lamotrigine and valproate is greater
148
C.-C. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 147 – 150
than with monotherapy. To our knowledge, the only case of lamotrigine-associated TEN in bipolar patient was published in a non-psychiatric journal (Sladden et al., 2004). We report here the emergence of lamotrigine-associated TEN in a 32-year-old bipolar woman who was concomitantly treated with lamotrigine, valproic acid and trazodone. 2. Case report Mrs. L, a 32-year-old Taiwanese woman, had her first depressive episode in 2000. This depressive episode persisted for longer than one year and was followed by a hypomanic episode lasting for three months. Her second depressive episode occurred in January 2003, and she was admitted to our psychiatric ward on January 24, 2003 under the impression of bipolar II disorder, most recent depressive episode, recurrent. After admission, she was treated with valproic acid (1000 mg/day) and trazodone (100 mg/day). Her depression responded to the combined treatment and she was discharged on February 20, 2003. However, her depression recurred in September 2004 because of noncompliance to her medications. She also developed persistent suicidal ideas. Thus she was admitted for the second time to our psychiatric ward on October 1, 2004. Apart from her diagnosis of bipolar II disorder, the patient’s medical history was unremarkable. She has no previous history of drug or food allergy. There was no history of previous upper respiratory tract infection or viral illness, in the patient, her family, or close contacts. Laboratory tests after her hospitalization including complete blood cell counts, tests of liver, renal and thyroid function, and urinalysis all showed no abnormal findings. After admission, the patient was restarted on valproic acid (1000 mg/day) and trazodone (200 mg/day). However, her depression did not improve after 2 weeks of the combined treatment. We thus added lamotrigine 12.5 mg/day to her medications on October 15. She tolerated the medication well for the first two weeks. No side effect of lamotrigine was reported but the patient remained depressed. We further increased her dose of lamotrigine up to 25 mg/day on October 29. The patient developed high spike fever (39.2 -C), dysphagia and sore throat after the dose of lamotrigine was increased. At that time, her physical examination showed swollen tonsils with diffuse exudative appearance and cervical lymphadenopathy. Laboratory tests including complete blood cell count with differential, liver panel, and electrolytes were all within normal limits except that Creactive protein (CRP) was 1.85 mg/dl (normal range: 0 –0.5 mg/dl). The workup to rule out infectious conditions including blood, sputum and urine cultures, IgG and IgM, serum antibody for herpes simplex, antigen for chlamydia, and antibody for mycoplasma were all negative. Antinuclear antibody was negative and chest radiograph was normal. Her blood level of valproic acid was 105.4 ng/ml (therapeutic range: 50– 100 ng/ml). On October 30, the patient showed diffuse, reddish, and pruritic rashes over her face, neck, chest and upper
extremities. In light of these cutaneous adverse reactions, we discontinued lamotrigine and valproic acid immediately. However, the skin eruptions become generalized and confluent erythema covering more than 60% of the total body surface area (TBSA) on October 31. These dermatological lesions looked like large areas of burn-damaged skin. Extensive erosions over oral, conjunctival and genital mucosa were noticed. The patient was transferred to medical ward on November 1 and she was treated with oral antihistamines (cetirizine 10 mg/day and cyproheptadine 12 mg/day), intravenous fluid supplement and supportive medical care. At that time, her psychotropic medications were all stopped, and her laboratory tests including blood, urine, and sputum cultures were all within normal limits except CRP was 13.68 mg/dl. Over the following 24 h, the patient developed confluent bullae and her skin began to slough from her back, trunk and extremities that accounted for 15% TBSA epidermal loss. She was then transferred to our burn center on November 2, five days after the onset of her adverse cutaneous reactions. Skin biopsies and pathological examinations showed separation of the dermis and epidermis with full-thickness necrosis of the epidermis, broad areas of subepidermal blisters and a few inflammatory cells in the dermis. These presentations, together with a positive Nikolsky’s sign (shearing off of the epidermis with lateral pressure), were compatible with the diagnosis of TEN. Given the diagnosis of TEN, the patient was treated with oral antihistamines, aggressive hydration, parenteral analgesia, empiric antibiotics and porcine xenograft applications to all open skin lesions. On November 4, the patient’s medical condition including level of consciousness and oxygenation status deteriorated markedly despite intensive resuscitation. She continued to have spiking fever (38.7 -C). Her blood pressure was 113/58 mmHg, heart rate 92 beats/min, and respiration rate 26/min. All cultures were negative. Her maximum skin shedding involved 40% of the TBSA and hemorrhagic crusting of mucous membranes was noticed. Besides, her laboratory evaluations showed abnormalities including anemia, thrombocytopenia, impaired liver function, electrolyte imbalance, hypoalbuminea, and increased inflammatory parameters. Her chest radiograph revealed diffuse ground – glass opacity over both lung fields. Since the patient’s allergic reactions became more severe and involved multiple organ systems, she was given intravenous methylprednisolone 120 mg/day, ventilatory and circulatory support, broad spectrum antibiotics, special wound care, and pain control. With these treatments, her critical condition improved and was finally stabilized. One week after her use of parenteral corticosteroid, the patient’s skin showed regrowth of epidermis and islands of granulating tissue. After 14 days of hospitalization at the burn center, our patient was sent back to medical ward because of significant improvement in her medical condition. Her parenteral corticosteroid was tapered gradually and changed to oral prednisolone 30 mg/day. A follow-up chest radiograph revealed no more active lung disease and all her laboratory abnormalities returned to normal limits. She was discharged
C.-C. Chang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 147 – 150
with a stable condition on November 16. Besides pigmentary changes over her lower extremities, she is doing well to date with lithium (600 mg/day) and clonazepam (2 mg/day) at our outpatient clinic. There was no any evidence of relapse of bipolar disorder or adverse drug reactions. 3. Discussion Previous reports on epileptic (Schlienger et al., 1998; Rzany et al., 1999) and bipolar patients (Calabrese et al., 2002) have suggested that the risk of lamotrigine-associated cutaneous reactions can be increased by co-administration with valproic acid, exceeding recommended initial dose, and exceeding the recommended dose escalation schedule. The international prescribing guideline (Guberman et al., 1999) recommended that adult patients taking concomitant valproate and lamotrigine should be initiated at dosage of 12.5 mg once daily for the first two weeks, followed by 25 mg once daily for the next two weeks, and increased thereafter by 25 mg every other week until a maintenance dosage of 100 –200 mg daily. Such a prudent titration schedule is especially important for patients with bipolar depression because most of them are difficult to treat and often need the combined treatment of valproate and lamotrigine. Our patient is an adult and has no history of allergies to other anticonvulsants. Her starting dose of lamotrigine and its rate of escalation were all based on the recommended dosing guideline. It appears that the only risk factor for our patient’s TEN is the concomitant use of valproate. Of note, the patient’s blood level of valproic acid (105.4 ug/dL) was higher than therapeutic range while she had been receiving lamotrigine add-on therapy. This is very likely to predispose the patient to the development of TEN because valproate can interact with lamotrigine and result in a decrease in the clearance of lamotrigine (Guberman et al., 1999). We thus suggest that if bipolar patients need concomitant valproic acid treatment in addition to their lamotrigine, blood level of valproic acid should be monitored closely and that the recommended dosing guideline should also be followed strictly. Management of patients with severe SJS or TEN should be performed in an intensive care or burn unit. General supportive measures should include immediate withdrawal of offending agents, careful fluid monitoring, nutritional support, antibacterial treatment, heat regulation, and pain control (Warnock and Morris, 2003). There is little evidence to support any specific therapeutic agent that is effective in treating patients with TEN. In this regard, the role of corticosteroids is still controversial. However, most clinicians would choose to try it if patient’s adverse reactions are severe (Knowles et al., 1999). Uncontrolled studies suggested that human intravenous immunoglobulin (Clennett and Hosking, 2003; Mayorga et al., 2003), cyclosporin (Hashim et al., 2004) and plasmaphresis (Sladden et al., 2004) may be efficacious in the treatment of TEN. These treatments need to be validated further for their effectiveness. In the beginning of her illness course, our patient did not respond to antihistamine treatment; however, she obtained a favorable outcome after
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her having received systemic corticosteroid therapy. Thus our case might suggest that early use of systemic corticosteroid is beneficial in treating TEN patients, if there is not any clinical contraindication. Because it is impossible to predict which rash will be benign or severe, any patient who develops a rash associated with lamotrigine should discontinue it immediately. It is also imperative to know that early manifestations of TEN (e.g., fever, malaise, pharyngitis, lymphadenopathy) may be present even though a rash is not evident. Before initiation of treatment with lamotrigine, the patient should be instructed that a rash or other early constitutional symptoms may herald a serious adverse reaction such as SJS or TEN, and that the patient should report any such occurrences to their psychiatrist immediately within 24 h on an emergency basis (Faught et al., 1999; Guberman et al., 1999). If the clinical presentations are compatible with SJS or TEN, immediate hospitalization and consultations with a dermatologist and other specialists are recommended. Finally, although there are a couple of reports of successful rechallenge with slowly titrated lamotrigine after a mild rash (Besag et al., 2000; Manfredi et al., 2004), those patients who have had SJS or TEN should not be rechallenged with lamotrigine. 4. Conclusion In conclusion, we present the emergence of TEN in a patient with bipolar II depression who was concomitantly treated with lamotrigine and valproate. With systemic corticosteroid and intensive resuscitation, the patient made a full recovery without any sequela. Our case suggests that early use of systemic corticosteroid might be beneficial in treating TEN patients, if there is not any clinical contraindication. References Bastuji-Garin, S., Rzany, B., Stern, R.S., Shear, N.H., Naldi, L., Roujeau, J.C., 1993. Clinical classification of cases of toxic epidermal necrolysis, StevensJohnson syndrome, and erythema multiforme. Arch. Dermatol. 129, 92 – 96. Besag, F.M., Ng, G.Y., Pool, F., 2000. Successful re-introduction of lamotrigine after initial rash. Seizure 9, 282 – 286. Calabrese, J.R., Sullivan, J.R., Bowden, C.L., Suppes, T., Goldberg, J.F., Sachs, G.S., Shelton, M.D., Goodwin, F.K., Frye, M.A., Kusumakar, V., 2002. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J. Clin. Psychiatry 63, 1012 – 1019. Clennett, S., Hosking, G., 2003. Management of toxic epidermal necrolysis in a 15-year-old girl. J. Wound Care 12, 151 – 154. Faught, E., Morris, G., Jacobson, M., French, J., Harden, C., Montouris, G., Rosenfeld, W., 1999. Adding lamotrigine to valproate: incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group. Epilepsia 40, 1135 – 1140. Guberman, A.H., Besag, F.M., Brodie, M.J., Dooley, J.M., Duchowny, M.S., Pellock, J.M., Richens, A., Stern, R.S., Trevathan, E., 1999. Lamotrigineassociated rash: risk/benefit considerations in adults and children. Epilepsia 40, 985 – 991. Hashim, N., Bandara, D., Tan, E., Ilchyshyn, A., 2004. Early cyclosporine treatment of incipient toxic epidermal necrolysis induced by concomitant use of lamotrigine and sodium valproate. Acta Derm.-Venereol. 84, 90 – 91. Knowles, S.R., Shapiro, L.E., Shear, N.H., 1999. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 21, 489 – 501.
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