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Indian J Pharmacol. 2012 Nov-Dec; 44(6): 798–800.
PMCID: PMC3523513
Lamotrigine induced DRESS syndrome
Kikkeri Narayanasetty Naveen, Mysore Satyanarayana Ravindra,1 Varadraj V. Pai, Vijetha Rai, Sharatchandra B. Athanikar, and Meravanige Girish2
Department of Dermatology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India
1Department of Paediatrics, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India
2Department of Pharmacology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India
Correspondence to: Dr. Kikkeri Narayanasetty Naveen, E-mail: naveenkn80/at/yahoo.com
Received June 14, 2012; Revised July 19, 2012; Accepted August 31, 2012.
Abstract
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and life-threatening delayed drug hypersensitivity reaction characterized by skin eruption, fever, lymphadenopathies, and visceral involvement. Here, we are presenting a 12 year old boy, who developed rare but life threatening DRESS syndrome due to Lamotrigine. Early detection and treatment led to his rapid recovery. This case is presented to highlight the importance of early detection of rare fatal syndrome.
KEY WORDS: DRESS, early detection, lamotrigine
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and life-threatening delayed drug hypersensitivity reaction characterized by skin eruption, fever, lymphadenopathies, and visceral involvement.[1]
Lamotrigine [6-(2,3-dichlorophenyl)-1,2,4-triazine- 3,5-diamine] is an antiepileptic drug, effective for a broad range of seizures in adults and children, which is structurally and pharmacologically unrelated to other antiepileptic medications.[2] Several reports of lamotrigine-induced DRESS syndrome have been reported in the literature.[35]
Here we report a case of DRESS syndrome induced by lamotrigine, which was detected early and completely responded to the treatment/thereby reducing the morbidity in the patient.
A 12 year old boy, with a known case of seizure disorder presented to the casualty with generalized maculopapular rash, fever and facial puffiness. The patient had been operated for gastric perforation when he was 3 days old following which the seizure episodes started. He was treated with phenobarbitone till the age of five. The drug was gradually withdrawn on the advice of a physician. Six months ago he suffered an episode of convulsion. He was started on sodium valproate and levetiracetam. One month back levetiracetam was stopped and lamotrigine was initiated. The patient was taking 1 tablet of 25mg daily for the first 15 days; later the dose was doubled. On the 18th day, patient presented with generalized maculopapular rash, itching and fever and on 20th day he developed colicky abdominal pain and vomiting followed by facial puffiness.
On examination, he was alert and oriented, with a temperature of 100°F and pulse was 114/ minutes. There was significant angioedema of his face with edematous lips and swollen ears, and an extensive maculo-papular rash on his entire trunk [Figure 1], buttocks, extremities and face. The whole body had a red tinge. Examination showed yellow sclera, conjunctival congestion and crusting over his lips. He experienced no joint pain or neurological symptoms, and no abdominal or respiratory complaints. There was no history of any allergies. The birth history and immunization were uneventful. He had 3 siblings: one of them also had history of epileptic disorders for which she was on treatment.
Figure 1
Figure 1
Maculo-papular rashes on the trunk
Investigations revealed leukocytosis (15,960cells/cmm) with eosinophilia (19%) AEC=2600/cmm. Hemoglobin was 10.8gm%, platelet count 2.53lakhs/cmm; ESR and PCV were normal. Liver enzymes were raised with SGOT=905U/l, SGPT=495U/l, ALP=855U/l and GGT= 155U/l. Total bilirubin was 1.5mg% (direct 0.51mg% and indirect 0.99mg%). Blood urea and creatinine were normal. Routine examination of the urine was normal. Provisional diagnosis of DRESS was made based on the above findings.
Parental cortisteroids and systemic antihistamines were initiated. Lamotrigine was stopped. Within 5 days the rash subsided. Patient's general condition improved. On discharge patient was given oral steroids and antihistaminic's.
Drug hypersensitivity syndrome (DHS), recently being also referred to as DRESS (drug reaction with eosinophilia and systemic symptoms) or DIDMOHS (drug-induced delayed multi-organ hypersensitivity syndrome), is a distinct type of adverse drug reaction. It was first associated with the aromatic antiepileptic drugs (AEDs). DHS is characterized by a constellation of symptoms involving various organs and organ systems. The skin, liver and hematologic system are most commonly involved, with cutaneous changes being the most apparent.[6] The presence of the 2 criteria, as given by Bocquet et al., has high sensitivity (>95%) but weak specificity (<80%).[7] [Table 1]. In the present case, there was eosinophilia, lymphadenopathy and liver enzymes were raised, which satisfied the criteria, and established a diagnosis of DRESS. Prompt resolution of the symptoms after the withdrawal of the lamotrigine, further supported the diagnosis. Lamotrigine was the probable cause of DRESS syndrome in the present case, as assessed by the Naranjo causality criteria.[8]
Table 1
Table 1
Diagnostic criteria for drug hypersensitivity syndrome[7]
The liver is the most commonly involved organ in DRESS. The degree of hepatitis is related to the interval between the onset of the syndrome and the discontinuation of the anticonvulsant. This emphasizes the importance of early recognition of the syndrome.[9]
The mechanism of the hypersensitivity syndrome is unknown. Several theories have been proposed. The reaction is either secondary to circulating antibodies or involves toxic metabolites. Associated infection by human herpes virus 6 may also play a role in its development. Hypersensitivity reactions to aromatic antiepileptic drugs appear to have an immune etiology, much like the lamotrigine-induced reaction: bio activation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. Another theory involves toxic metabolites. The aromatic antiepileptic agents are metabolized by cytochrome P-450 to an arene oxide metabolite.[10] These are usually detoxified by the enzyme epoxide hydrolase, which may be lacking or mutated in persons that develop the syndrome. Lamotrigine exhibits first-order linear elimination. It is chiefly metabolized by hepatic glucuronidation; the resulting metabolite has no pharmacologic activity and is excreted in urine. The average elimination half-life in adults is 20 to 35 hours.[3]
Our patient was comfortable when he was receiving single dose of lamotrigine, but he developed DRESS, 3 days after the dose was doubled. This may be explained by the fact that, there may be a threshold concentration of lamotrigine above which the body's ability to metabolize the drug may be overwhelmed, leading to a hypersensitivity reaction.[5] In pediatric age group who are on sodium valproate sudden increase in dosage of lamotrigine increases the risk of lamotrigine induced rash.
The incidence of DHS (approximately 1 in 1,000 to 1 in 10,000 exposures)[11] is probably underestimated. Though no standard treatment has been proposed, intravenous corticosteroids may be effective. In severe cases, pulse therapy with high dose of intravenous methyl prednisolone, plasmapharesis and human intravenous immunoglobin may be tried.[6]
Lamotrigine treatment has been associated with multiorgan failure, DRESS syndrome, acute hepatic failure, and disseminated intravascular coagulation.[12,13] We suggest that these potentially fatal side effects should be considered in any patient when clinical deterioration follows treatment with this drug. Early recognition and withdrawal of the suspected agent may avoid irreversible damage to the liver and will be life saving.
This case reiterates the necessity of early recognition of this syndrome, especially when lamotrigine is given concurrently with sodium valproate. It helps in the rapid resolution of DRESS, thereby mitigating the morbidity and mortality in the patient.
Footnotes
Source of Support: Nil.
Conflict of Interest: No.
1. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS) Semin Cutan Med Surg. 1996;15:250–7. [PubMed]
2. Jawad S, Yuen WC, Peck AW, Hamilton MJ, Oxley JR, Richens A. Lamotrigine: Single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res. 1987;1:194–201. [PubMed]
3. Shawcross D, Auzinger G. Lamotrigine and the risk of fulminant hepatic failure. Lancet. 2008;371:649–50. [PubMed]
4. Roquin G, Peres M, Lerolle N, Dib N, Mercat A, Croue A, et al. First report of lamotrigine-induced drug rash with eosinophilia and systemic symptoms syndrome with pancreatitis. Ann Pharmacother. 2010;44:1998–2000. [PubMed]
5. Amante MF, Filippini AV, Cejas N, Lendoire J, Imventarza O, Parisi C. Dress syndrome and fulminant hepatic failure induced by lamotrigine. Ann Hepatol. 2009;8:75–7. [PubMed]
6. Kumari R, Timshina DK, Thappa DM. Drug hypersensitivity syndrome. Indian J Dermatol Venereol Leprol. 2011;77:7–15. [PubMed]
7. Valliant L. Drug hypersensitivity syndrome: Drug rash with eosinophilia and systemic symptoms. J Dermatolog Treat. 1999;10:267–72.
8. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285–90. [PubMed]
9. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. [PubMed]
10. Veyrac G, Marcade G, Chiffoleau A, Bourin M, Jolliet P. Characteristics of hypersensitivity syndrome to lamotrigine: Review of one case reported in the Regional Center of Pharmacovigilance of Nantes. Therapie. 2002;57:289–96. [PubMed]
11. Knowles SR, Shapiro L, Shear NH. Anticonvulsant hypersensitivity syndrome: Incidence prevention and management. Drug Saf. 1999;21:489–501. [PubMed]
12. Schaub JE, Williamson PJ, Barnes EW, Trewby PN. Multisystem adverse reaction to lamotrigine. Lancet. 1994;344:481. [PubMed]
13. Makin AJ, Fitt S, Williams R, Duncan JS. Fulminant hepatic failure induced by lamotrigine. BMJ. 1995;311:292. [PMC free article] [PubMed]
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