Indian Journal of Paediatric Dermatology

: 2014  |  Volume : 15  |  Issue : 2  |  Page : 83--85

Injudicious use of anticonvulsants leading to life-threatening event

Pradeep Kumar Sharma1, Bhaskar Saikia2, Rachna Sharma2, Praveen Khilnani1,  
1 Department of Pediatrics, B L Kapur Super Speciality Hospital, New Delhi, India
2 Department of Pediatrics Intensive Care Unit, B L Kapur Super Speciality Hospital, New Delhi, India

Correspondence Address:
Pradeep Kumar Sharma
Flat No. 48, Pocket 7, Sector 21, Rohini, New Delhi - 110 086


Epilepsy is common childhood problem and advent of newer anticonvulsant drugs has led to injudicious uses. Anticonvulsant hypersensitivity syndrome (AHS) has been previously described developing secondary to aromatic anticonvulsants such as phenytoin and carbamazepine. AHS developing secondary to non-aromatic anticonvulsant agents such as lamotrigine (LTG) and valproic acid (VPA) is rare. We present a case of an 11-year-old girl with known epilepsy on VPA, LTG and carbamazepine therapy that developed fever with the clinical pattern of Steven-Johnson syndrome/toxic epidermal necrolysis requiring pediatric intensive care. Judicious use of anticonvulsant should be done in appropriate dose especially in pediatric population and when used in combination to prevent AHS like life-threatening event.

How to cite this article:
Sharma PK, Saikia B, Sharma R, Khilnani P. Injudicious use of anticonvulsants leading to life-threatening event.Indian J Paediatr Dermatol 2014;15:83-85

How to cite this URL:
Sharma PK, Saikia B, Sharma R, Khilnani P. Injudicious use of anticonvulsants leading to life-threatening event. Indian J Paediatr Dermatol [serial online] 2014 [cited 2021 Jun 24 ];15:83-85
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Anticonvulsant hypersensitivity syndrome (AHS) is a rare but life-threatening adverse effect of aromatic anticonvulsants such as phenytoin, phenobarbital and carbamazepine. [1],[2],[3],[4],[5],[6],[7] AHS has been reported with nonaromatic anticonvulsant such as valproic acid (VPA) and lamotrigine (LTG), through rare. [8],[9],[10] Incidence of AHS is 1/1000-1/10,000 exposures [1],[2] with a mortality rate of about 10%. We report a case of severe AHS secondary to injudicious combination of carbamazepine, LTG and VPA.


The present case report is about an 11-year-old female patient who was admitted with the complaints of fever, cough and rash for 5 days. Child was a known case of epilepsy. Child had a right complex partial seizure with secondary generalization 6 months back. She used to have 1-2 episodes daily, lasting for about 10 min. Child was started on Phenytoin, however seizures persisted. MRI brain revealed left temporal and occipital gliosis. Electroencephalography show epileptiform discharges from the left temporal region.

Child was subsequently started on VPA (17 mg/kg/day), LTG (6 mg/kg/day) by neurologist and phenytoin was gradually stopped. Seizures frequency decreased and Carbamazepine was also added after 10 days (11.8 mg/kg/day). Thereafter, child remained seizure free for next 4 months.

At present, child had fever and cough, treated with paracetamol, amoxycilin and clavulanic acid. Within 24 h she developed rash and was hospitalized. LTG, carbamazepine and amoxicillin were stopped. VPA was continued and rash continued to increase. Subsequently VPA was stopped and phenobarbitone was added. Child was referred to us in view of worsening of rash and hepatic involvement.

At admission, child was hemodynamically stable. Extensive vesicobullous lesions with nikolsky sign positivity were present. 30% of body surface area had cutaneous detachment. Mucosal surfaces, bilateral conjunctiva were also involved. Cornea was spared.

Laboratory investigations revealed Total leukocyte count of 14900, absolute eosinophil count of 5800, alanine transaminase 433, aspartate transaminase 158, total serum bilirubin 1.3 and prothrombin time/internation normalized ratio of 18.5/1.81. Cultures of blood and urine were sterile. Erythrocyte sedimentation rate, renal function test, urinalysis and chest radiograph were within normal limits. Serology for hepatitis A, B, C and E was nonreactive.

Child was managed conservatively. Phenobarbitone was stopped, levetiracetam was started and intravenous immunoglobulin (IVIG) was administered. Child improved with resolution of lesions. Child was finally discharged in stable condition with healing skin lesions.


AHS is characterized by fever, eosinophilia, internal organ involvement and skin rash including generalized maculopapular and/or exfoliative eruption, or toxic epidermal necrolysis (TEN)/Steven-Johnson syndrome (SJS). [1]

Bessmertny et al. [2] in their study have reported AHS manifestations as: Fever (100%), rash (100%), lymphocytosis (71%), elevation of liver enzymes (64%), lymphadenopathy (57%), atypical lymphocytes (50%), eosinophilia (43%), coagulopathy (43%), hyperbilirubinemia (36%), leukocytosis (36%), leucopenia (36%) and nephritis (7%).

AHS generally develops 2-8 weeks after initiation of anticonvulsant drugs, but can occur even after 12 weeks or longer. Fever is low-grade and can be accompanied by cervical adenopathy. Rash occurs in 90% of patients and ranges from mere exanthem to severe manifestations like SJS/TEN. Other cutaneous effects include periorbital, facial edema and conjunctivitis. Internal organ involvement usually develops between 1 and 2 weeks after cutaneous eruption and may be symptomatic or asymptomatic [Table 1]. [1] Hepatic involvement is most common with manifestations ranging from a mild to fulminant hepatitis. Other commonly involved organ is the kidney leading to interstitial nephritis. Heart, lung, muscle and pancreas may also be involved. [1],[3] Transient hypothyroidism may appear 3 months after onset of the reaction. [1],[3]{Table 1}

Laboratory features may reveal Leukocytosis, eosinophilia, atypical lymphocytosis, agranulocytosis, aplastic anemia, hemolytic anemia, thrombocytopenia and hypo-gammaglobulinemia.

Exact etiopathogenesis of AHS is unknown. Some theories point to toxic mechanisms of allergic hypersensitivity as well as immune-mediated mechanisms of graft versus host-type. There is strong evidence that relative excess of toxic metabolites of aromatic anticonvulsants, namely arene oxides, play a major role. [1],[3] These metabolites are further detoxified by epoxide hydroxylase. A structural and/or functional defect in this enzyme may inhibit the excretion of arene oxide metabolites, which cause direct toxic effects on cells, in addition to inducing type IV hypersensitivity reactions. [1],[3]

Management is supportive with maintenance of hydration, electrolyte balance and nutrition. An alternative anticonvulsant may be prescribed such as levetiracetam, gabapentin or vigabatrin. The role of corticosteroids has been debated, most clinicians initiate treatment with corticosteroids if the symptoms are severe. [1],[3],[4] Benefits of other immunomodulatory measures (plasmapheresis and IVIG) have not been evaluated by large controlled trials, it may be logical to use these measures in patients with life-threatening or organ-threatening disease. [1],[5] A recent report suggested that IVIG seems to be safe therapy in children with SJS/TEN. [5]

The incidence of rash associated with LTG was three in 1,000 adults (0.3%) and one in 100 children (1%). The spectrum of serious rashes includes hypersensitivity syndrome, SJS and TEN. [8] Factors appear to increase the risk for LTG rashes are: Excessive initial dose or rate of titration, combination of LTG with VPA/divalproex sodium. [8] Although LTG is not an aromatic anticonvulsant and is primarily metabolized by conjugation, its ability to cause AHS and its cross-sensitivity with other aromatic anticonvulsants has been demonstrated in vitro. [3],[9]

In our case, child was on carbamazepine (11.8 mg/kg/day), LTG [8] (6 mg/kg/day) and VPA [10] (17 mg/kg/day) and each of these individual agents can lead to AHS, SJS/TEN. Child had right complex partial seizure and drug of choice is either oxcarbazepine (20-40 mg/kg/day) or carbamazepine (10-20 mg/kg/day). VPA (10-40 mg/kg/day), LTG (5-15 mg/kg/day, 1-5 mg/kg/day with VPA) and levetiracetam (20-40 mg/kg/day) are useful as add on drugs. Only one drug should be used initially and the dose increased until complete control is achieved or until side-effects prohibit further increases. Then and only then, may another drug be added and the initial one subsequently tapered. Control with 1 drug (monotherapy) should be the goal, although some patients eventually need to take multiple drugs. A combination of LTG and VPA is known to enhance risk of rash and severity, especially if initial dose of LTG is high, as in our case (6 mg/kg/day instead of 0.2-0.5 mg/kg/day). [8] Addition of carbamazepine is also inappropriate as it enhances metabolism of both VPA and LTG. In our case, a needless combination of drugs along with inappropriate doses may have precipitated severe degree AHS.

First-degree relatives of an afflicted individual have a fourfold higher risk of drug sensitivity than the population at large. Therefore, family counseling plays important role in management of these patients.


Judicious use of anticonvulsant should be done in appropriate dose especially in pediatric population and when used in combination to prevent AHS like life-threatening event.


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