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NI FEATURE: FACING ADVERSITY…TOMORROW IS ANOTHER DAY! - LETTER TO EDITOR
Year : 2017  |  Volume : 65  |  Issue : 7  |  Page : 95-97

Phenytoin-induced fatal drug reactions in two patients with brain tumors: Need to re-think our routine anticonvulsant usage


1 Department of Anaesthesiology and Intensive Care, GB Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
2 Department of Neurosurgery, GB Pant Institute of Postgraduate Medical Education and Research, New Delhi, India

Date of Web Publication8-Mar-2017

Correspondence Address:
Pragati Ganjoo
GB Pant Institute of Postgraduate Medical Education and Research, JL Nehru Marg, New Delhi - - 110 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_587_16

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How to cite this article:
Faisal I, Ganjoo P, Garg D, Batra UB, Srivastava AK, Singh H. Phenytoin-induced fatal drug reactions in two patients with brain tumors: Need to re-think our routine anticonvulsant usage. Neurol India 2017;65, Suppl S1:95-7

How to cite this URL:
Faisal I, Ganjoo P, Garg D, Batra UB, Srivastava AK, Singh H. Phenytoin-induced fatal drug reactions in two patients with brain tumors: Need to re-think our routine anticonvulsant usage. Neurol India [serial online] 2017 [cited 2017 Sep 20];65, Suppl S1:95-7. Available from: http://www.neurologyindia.com/text.asp?2017/65/7/95/201673


Sir,

Antiepileptic drugs (AEDs) are routinely prescribed to patients with brain tumors for seizure treatment and prophylaxis, despite there being no evidence of their proven role in prophylaxis against seizures.[1] Phenytoin is the most commonly used drug for this purpose in our country because of its easy availability and low cost. The widespread use of phenytoin is further questionable in view of its seemingly higher adverse effects in patients with brain tumors, viz., worsening of immunosuppression in brain cancer, its role in decreasing the efficacy of concomitant chemotherapy and steroids, and the development of serious side effects such as liver dysfunction, myelosuppression, cognitive impairment, and life-threatening muco-cutaneous reactions of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).[2],[3] Among all AEDs, phenytoin is the most common drug implicated in the development of SJS–TEN (with its incidence being approximately 13.37%).[3] In this article, we report two patients who died from phenytoin-related SJS–TEN, and recommend the need to restrict its current rampant usage for seizure prophylaxis in patients harbouring a brain tumor.

Case 1

A 58-year-old male patient with a right cerebellar tumor was admitted with impaired sensorium and a 2-day history of fever and cough. He was on phenytoin prophylaxis for 8 days; acetazolamide and dexamethasone were added. Three days later, he abruptly developed clusters of non-pruritic, maculopapular rash, and small red blisters on the face, trunk, extremities, and genitalia; painful oral mucosal ulcers causing swallowing difficulty; and, minute conjunctival and corneal erosions. Bullous eruptions replaced the rashes, with peeling of the overlying skin, exposing the red, oozing, and painful dermis [Figure 1]; the denuded skin was roughly 10% of the body surface area (BSA), and the Nikolsky sign (skin peeling with gentle pressure) was positive. Skin biopsy showed mostly neutrophilic perivascular inflammatory dermal infiltrates with focal epidermal necrosis. The patient developed breathing difficulty, hypoxia, and hypotension, which rapidly progressed to adult respiratory distress syndrome (ARDS); he died approximately 40 hours after the appearance of the rash.
Figure 1: Denuded skin areas with erythematous background in Case 1, and widespread cutaneous blisters and maculopapular lesions in Case 2

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Case 2

A 42-year-old female patient with a left sphenoid wing meningioma was admitted with decreased light perception and an episode of seizure. She was started on phenytoin, acetazolamide, and dexamethasone, and underwent a craniotomy and tumor excision after 3 days. The next day, she developed extensive, blanchable erythematous macular lesions on the trunk, extremities, and face, as well as painful ulcers and erosions in her oral cavity, auditory canal, conjunctiva, and eyelids. Extensive skin denudation occurred over 55% of her BSA [Figure 1]. The skin biopsy revealed subepidermal separation and inflammatory infiltration. The patient soon developed a high fever, hypoxia, kidney and liver derangements, and refractory shock. She died 58 hours after the appearance of the rash.

Both the patients were managed with immediate phenytoin withdrawal, local treatment of the muco-cutaneous lesions, and an intensive care support.

SJS–TEN is a dreaded hypersensitivity reaction of phenytoin that causes epidermal necrolysis via infiltrating cytokine-releasing CD8 T-lymphocytes and macrophages; direct cell damage may occur via the release of toxic drug metabolites as a result of defective phenytoin metabolism. A genetic cause is implicated by the significant correlation observed between phenytoin-induced SJS–TEN and HLA-B*1502 allele in patients of Asian ancestry. Normal serum phenytoin levels suggest that the reaction is not dose-related, and its progression may not reverse with drug withdrawal.[4] The clinical manifestation occur within a few hours to up to 45 days (mean: 6 days) after phenytoin administration, with the peak levels being reached by the fourth day. The risk of mortality in SJS–TEN is high (SJS: 3.92%; TEN: 28.20%; transitional SJS–TEN: 5.26%) due to the occurrence of serious consequences such as septicemia, acute renal failure, shock, ARDS, metabolic encephalopathy, cardiovascular instability, and intracranial bleeding.[3],[2] Phenytoin-induced fatal SJS–TEN has been reported earlier, though infrequently [Table 1].[4],[5],[6],[7],[8],[9] Combining phenytoin with radiotherapy and steroids enhances the fatality risk, and is best avoided [Table 1].[4],[5],[6] The severity-of-illness score for toxic epidermal necrolysis (SCORTEN), a predictive score based on seven independent prognostic criteria, has a linear relationship with the mortality risk in SJS–TEN.[3] An increasing age as well as the presence of chronic conditions, infections, hematological malignancy, and renal failure were the predictors of mortality in a recently published study;[10] some previous authors have also observed a link between advanced age and mortality [Table 1].[5],[9] A prompt recognition of SJS–TEN is vital to averting a fatal outcome. A missed or delayed diagnosis is not uncommon, and hence there is a constant need to repeatedly educate neuro-clinicians regarding this grave complication. Development of any skin or mucosal lesion, preceded at times by a flu-like illness, should be viewed suspiciously in a patient on phenytoin, and immediate dermatology confirmation should be sought. Immunoglobulins and early dexamethasone therapy may help to reduce the mortality.[3]
Table 1: Phenytoin-induced fatal SJS-TEN cases in literature

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The sudden development of SJS–TEN causing rapid death of our otherwise stable patients with treatable brain tumors was alarming. Incidents such as these are grim reminders that AEDs should be administered judiciously in neurosurgical practice. A routine prophylactic treatment with anticonvulsants is not recommended in the presence of newly diagnosed brain tumors because of their lack of efficacy and the potentially serious side effects. Limiting AED therapy to patients with established seizures or to those at a considerable risk of developing seizures, and their discontinuation after the first postoperative week, is advocated.[1] Moreover, concerted efforts should be made toward replacing the traditional drug phenytoin with suitable alternatives that have a lower incidence of rash formation such as levetiracetam, gabapentin, valproic acid, topiramate, and zonisamide.[5] Levetiracetam is increasingly gaining popularity because of its lesser side effects, comparable clinical efficacy, and no constraints of serial drug level monitoring.[11],[12]

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest

 
 » References Top

1.
Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al. Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumours. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886-93.  Back to cited text no. 1
    
2.
Ahmad FU, Mahapatra AK. Phenytoin-induced toxic epidermal necrolysis in a neurosurgical patient. Neurol India 2007;55:181-2.  Back to cited text no. 2
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3.
Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013;79:389-98.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Khafaga YM, Jamshed A, Allam AAK, Mourad WA, Eisa AA, Ezzat A, et al. Stevens–Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol 1999;38:111-6.  Back to cited text no. 4
    
5.
Madaiah A, Gowda HN. Fatal phenytoin-induced Stevens–Johnson syndrome in an elderly person with metastatic lung carcinoma. Natl J Physiol Pharm Pharmacol 2016;6:175-7.  Back to cited text no. 5
    
6.
Kumari N, Shamkuwar CA, Dakhale GN, Sontakke SD, Khan S. Stevens–Johnson syndrome after cranial-thoracic radiotherapy and phenytoin treatment: A fatal case report. Int J Pharmacother 2014;4:128-30.  Back to cited text no. 6
    
7.
Budania RJ, Dakhale GN, Sontakke SD, Patnaik PS. Fatal Stevens-Johnson syndrome induced by phenytoin: A case report. Int J Basic Clin Pharmacol 2013;2:843-45.  Back to cited text no. 7
    
8.
Kelly DF, Hope DG. Fatal phenytoin-related toxic epidermal necrolysis: Case report. Neurosurgery 1989;25:976-8.  Back to cited text no. 8
    
9.
Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following re-exposure to phenytoin: A case report. Epilepsia 1983;24:440-3.  Back to cited text no. 9
    
10.
Hsu DY, Brieva J, Silverberg NB, Silverberg JI. Morbidity and mortality of stevens-johnson syndrome and toxic epidermal necrolysis in United States adults. J Invest Dermatol 2016;136:1387-97.  Back to cited text no. 10
    
11.
Cortes-Altamirano JL, Olmos-Hernández A, Bonilla-Jaime H, Bandala C, González-Maciel A, Alfaro-Rodríguez A. Levetiracetam as an antiepileptic, neuroprotective, and hyperalgesic drug. Neurol India 2016;64:1266-75.  Back to cited text no. 11
[PUBMED]  [Full text]  
12.
Newale S, Bachani DS. Demographic characteristics of epilepsy patients and antiepileptic drug utilization in adult patients: Results of a cross-sectional survey. Neurol India 2016;64:1180-6.  Back to cited text no. 12
[PUBMED]  [Full text]  


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