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Year : 2012  |  Volume : 57  |  Issue : 6  |  Page : 504
Lamotrigine hypersensitivity syndrome and spiking fever

1 Department of Dermatology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands
2 Department of Pathology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands

Date of Web Publication1-Nov-2012

Correspondence Address:
Christiaan V Bakker
Selwerderstraat 22, 9717 GK, Groningen
The Netherlands
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.103087

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We report a case of a 26 year old woman with rash, lymphadenopathy, liver enzyme abnormalities and spiking fever. She was diagnosed with drug-induced hypersensitivity syndrome (DHS) to lamotrigine. Spiking fever in relation to drug-induced hypersensitivity syndrome has not earlier been described in adults. Spiking fever is an important symptom of the wide spectrum of disease presentation. The syndrome is commonly referred to as either Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) or DHS. In accord with previous authors we see both syndromes as two ends of a spectrum, with a wide range of symptoms and presentations. Therefore we plea for unity in nomenclature.

Keywords: DRESS, hypersensitivity syndrome, lamotrigine, spiking fever

How to cite this article:
Bakker CV, Hegt VN, Van Praag MC. Lamotrigine hypersensitivity syndrome and spiking fever. Indian J Dermatol 2012;57:504

How to cite this URL:
Bakker CV, Hegt VN, Van Praag MC. Lamotrigine hypersensitivity syndrome and spiking fever. Indian J Dermatol [serial online] 2012 [cited 2022 Dec 9];57:504. Available from:

What was known? Drug hypersensitivity syndrome or DRESS is a severe idiosyncratic reaction including rash, fever and systemic symptoms.

   Introduction Top

Pregnancy in epileptic women puts physicians in a difficult position on choice for anticonvulsant therapy. Valproic acid increases risk of teratogenity compared to normal population. Carbamazepine reports vary from little to more significant risk on teratogenity. [1] A new generation anticonvulsant, lamotrigine, is reported to have lower risk on teratogenity than valproic acid and lower or equal prevalence in comparison to carbamazepine. [1],[2] Therefore, lamotrigine is an increasingly used alternative treatment for pregnant epileptic women with as a result, more often noted side effects. We report a case of a young woman with lamotrigine hypersensitivity syndrome with spiking fever and are the first to describe this entity in combination with spiking fever.

   Case History Top

A 24-year-old woman of Turkish origin was admitted to our hospital with rash, fever and severe itching. In childhood, she was diagnosed with juvenile myoclonic epilepsy. Six weeks before presentation at our hospital, she started using lamotrigine (50 mg twice daily) instead of valproic acid, because of her wish for pregnancy. Four weeks later, lamotrigine was stopped because of first symptom of rash and itching. She was treated with desloratadine 5 mg daily and mometasone ointment. Later that week, itching kept her from sleeping; furthermore nausea, vomiting and gastric pain were present every day. She was then treated with hydroxyzine 25 mg and levocetirizine 5 mg daily. A day later, she developed fever over 38.6°C.

During admission at our hospital, the above symptoms existed. Medical examination showed a symmetrical maculopapular exanthema, combined with facial edema, palpable lymph nodes (1 cm diameter) in front of the musculus sternocleidomastoideus [Figure 1]. Furthermore, she had fever (39.4°C) and a heart rate of 140 per min. Laboratory findings were: CRP 30, hemoglobin 8.4, ASAT 228 U/L, ALAT 236 U/L, LD 1876 U/L, alkaline phosphatase 215 U/L, leukocytes 14.8 × 10 9 /L. In differential diagnosis we considered drug hypersensitivity syndrome to lamotrigine (DHS) / drug reaction with eosinophilia and systemic symptoms (DRESS) to lamotrigine, epstein-barr (EBV) or cytomegalovirus (CMV) infection or a lymph proliferative disorder. Awaiting serology and radiological examination, we started with triamcinolone 0.1% cream. Ultrasound showed an enlarged spleen (18 cm), with normal aspect; liver showed no abnormalities. Chest X-ray was normal. Fever was present in a two to three day spiking pattern despite of continuous acetaminophen administration [Figure 2]. We excluded malaria as causing agent, since our patient had not been in malaria endemic areas the past 5 years; even more the spiking fever pattern did not match with temperature curve of malaria. Biopsy of skin was characteristic for an exanthematous drug reaction [Figure 3]. Several pink apoptotic keratinocytes (Civatte bodies) and mild exocystosis of lymphocytes were present in the epidermis. There was some vacuolar change involving the basal layer. The papillar dermis revealed a perivascular infiltrate of lymphocytes. No eosinophils were present. The serology of EBV, CMV and human herpes virus 6 (HHV6) were negative. We diagnosed patient symptoms as DHS and started prednisone 80 mg i.v. daily. Skin symptoms improved as well as laboratory findings. However, spiking fever still remained for 6 days. Fourteen days after admission, patient was released from hospital in good health. A patch test on lamotrigine (10% in petrolatum) was done 7 weeks thereafter and was positive.
Figure 1: Upon admission to the hospital, patient presented with symmetrical maculopapular exanthema and facial oedema. Furthermore lymph nodes were palpable in front of the sternocleidomastoidic muscle

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Figure 2: Fever development in our patient from day of admission to the hospital. The temperature, in degree Celcius, fluctuated eleven days from febrile to non - febrile in a 2 - 3 day pattern. Despite of continuous acetaminophen treatment, pattern developed and remained for six days after cutaneous symptoms disappeared

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Figure 3: Biopsy of skin showed several pink apoptotic keratinocytes (Civatte bodies) and mild exocystosis of lymphocytes in the epidermis as can be seen in cutaneous drug reaction. No eosinophils were present

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   Discussion Top

Drug hypersensitivity syndrome or DRESS is characterized by a severe idiosyncratic reaction including rash and fever, with associated hepatitis, renal dysfunction, lymphadenopathy and hematologic abnormalities such as atypical lymphocytes or eosinophilia. Much is written on whether DHS and DRESS are truly different entities or lie within the same spectrum. [3],[4] In both, a drug induced skin reaction takes place, with fever, systemic symptoms and hematologic abnormalities. The presence or absence of eosinophilia in itself does not play a significant role in the diagnostic or clinical path and does not alter treatment. Kano observed that DHS like symptoms can be seen as a more severe type of DRESS like symptoms. [4] In conclusion, there seems to be just one syndrome with a wide spectrum of presentation. Discussion on naming the syndrome DHS or DRESS has the risk of becoming somewhat an issue of semantics. Therefore, we would plea for unity in nomenclature. In our opinion, DHS seems a more appropriate term as it does not differentiate between existence and absence of eosinophilia. We will use DHS as clinical term in the rest of the article. Many drugs, mainly anticonvulsants, have been reported to induce DHS, [3],[4],[5] among them lamotrigine. Drug hypersensitivity syndrome is a rare condition; the overall risk of hypersensitivity to, for example, phenytoin is between 1/1,000 to 1/10,000. [6] The cause of hypersensitivity syndrome is still under debate. Some patients have a genetic deficiency of epoxide hydrolase, a hepatic enzyme that detoxifies the azene oxide metabolites of antiepileptic drugs. [7] Virus as HHV 6 and 7, EBV and CMV, may increase the risk of an individual developing DHS. [8] The exanthematous drug reaction in DHS is considered to be a delayed type IV hypersensitivity reaction, just like an allergic contact dermatitis. Not surprisingly, patch testing to lamotrigine, like in our patient, is found positive in 80% of DHS cases. [9]

The hypersensitivity syndrome usually occurs 2 to 6 weeks and sometimes 12 weeks after first usage of the drug. [3],[4] The skin reaction can be morbilliform, erythroderma, with follicular papules, pustules, bullae or purpura. Moreover, facial edema usually occurs. Eighty seven percent have fever with rash and 75% have lymphadenopathy. Most often the liver is affected, yet renal failure, splenic, pulmonary or cardial disease also have been reported. [3],[4] The mechanism of lamotrigine toxicity in these organs remains unclear so far. In case of lamotrigine, only 19% presented with eosinophilia in an analysis of 26 patients. [5]

Fever is commonly present in DHS. However, we could not find earlier reports on spiking fever in relation to DHS to lamotrigine in adults. One case report involved a 6-year-old child with DHS to lamotrigine and a high spiking, but persistent, fever. [10] This is different from our patient, who had a truly periodic fever, with feverless days in between [Figure 2]. Our case adds to the wide spectrum of presentation of DHS. Spiking fever is an important clinical marker for malaria and abscess formation. It can therefore lead to diagnostic and clinical confusion. Malaria and abscess formation must be excluded in any patient with DHS and spiking fever. When these causes are excluded, oral corticosteroid therapy should be started promptly. Management of fever and explanation to the patient of the cause of fever is important.

   References Top

1.Berwaerts K, Sienaert P, De Fruyt J. Teratogenic effects of lamotrigine in women with bipolar disorder. Tijdschr Psychiatr 2009;51:741-50.  Back to cited text no. 1
2.Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin 2009;27:993-1002.  Back to cited text no. 2
3.Sullivan JR, Shear NH. The drug hypersensitivity syndrome: What is the pathogenesis? Arch Dermatol 2001;137:357-64.  Back to cited text no. 3
4.Kano Y, Shiohara T. The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug. Immunol Allergy Clin North Am 2009;29:481-501.  Back to cited text no. 4
5.Schlienger RG, Knowles SR, Shear NH. Lamotrigine-associated anticonvulsant hypersensitivity syndrome. Neurology 1998;51:1172-5.  Back to cited text no. 5
6.Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85.  Back to cited text no. 6
7.Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin Drug Saf 2010;9:15-21.  Back to cited text no. 7
8.Gentile I, Talamo M, Borgia G. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review. BMC Infect Dis 2010;10:49.  Back to cited text no. 8
9.Taillia H, Alla P, Fournier B, Bounolleau P, Ouologem M, Ricard D, et al. Anticonvulsant hypersensitivity syndrome and lamotrigine-associated anticonvulsant hypersensitivity syndrome. Rev Neurol (Paris) 2009;165:821-7.  Back to cited text no. 9
10.Brown TS, Appel JE, Kasteler JS, Callen JP. Hypersensitivity reaction in a child due to lamotrigine. Pediatr Dermatol 1999;16:46-9.  Back to cited text no. 10

What is new? Hypersensitivity syndrome can occur with spiking fever, resembling infectious diseases. Spiking fever can lead to diagnostic confusion. In time recognition of hypersensitivity syndrome is important as there can be serious morbidity


  [Figure 1], [Figure 2], [Figure 3]

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