Cytokine Dermatitis and Febrile Seizure From Imiquimod

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Cytokine Dermatitis and Febrile Seizure From

Imiquimod

abstract

Cytokine dermatitis is a well-known and common clinical adverse effect of imiquimod 5% cream (Aldara, 3M). Data from initial Phase III clinical trials reveal a minority of study drug patients experience systemic ad-verse effects, including fever, arthralgia, headache, myalgia, and lymphadenopathy. These adverse effects are caused, presumably, from increased absorption of study drug over the area of dermatitis, leading to systemic cytokine release. Furthermore, the incidence of systemic reactions was rarely statistically increased above control patients. We describe herein a case of severe cytokine dermatitis in a 2-year-old female patient treated with daily imiquimod for molluscum contagio-sum who subsequently developed febrile seizure. We believe this to be theﬁrst reported case of seizure associated with imiquimod 5% cream (Aldara, 3M) in a pediatric setting.Pediatrics2012;129:e519–e522

AUTHORS:J. Suzanne Mosher, MD,a_{and Peter Lio, MD}b a_{Harvard Vanguard Medical Associates, Watertown,}

Massachusetts; andb_{Northwestern University, Feinberg School of}

Medicine, Dermatology & Aesthetics of Wicker Park, Chicago, Illinois

KEY WORDS

adverse effect, carcinoma, fever, imiquimod, immunomodulator, keratosis, seizure, Toll-like receptor 7, topical

This case report was written by Drs Mosher and Lio. When the patient was seen, Dr Mosher was the resident physician and Dr Lio was the attending physician who were called to consult on the patient, make the diagnosis of interferon dermatitis, and treat the patient accordingly. Both Drs Mosher and Lio have contributed substantial intellectual information to the authorship of this case report. Before submitting as a case report, this case was presented for the annual New England Dermatology Society case conference at Harvard Medical School, Beth Israel Deaconess Medical Center, February 4, 2006. Both Drs. Mosher and Lio were primarily responsible for interviewing the patient, collecting the laboratory data and reviewing the medical records, drafting the article, performing the literature review, and ensuring the intellectual content of the case presentation.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-0936

doi:10.1542/peds.2011-0936

Accepted for publication Oct 5, 2011

Address correspondence to Dr J. Suzanne Mosher, Harvard Vanguard Medical Associates, 485 Arsenal St, Watertown, MA 02472. E-mail: suzanne_mosher@vmed.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

FINANCIAL DISCLOSURE:The authors have indicated they have noﬁnancial relationships relevant to this article to disclose.

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Topical imiquimod has been associated with fever in Phase III clinical trials targeting actinic keratoses and basal cell carcinomas1–3_{and in a report of}

children treated for molluscum con-tagiosum.4 _{Our literature search did}

not uncover any association between topical immunomodulators and seiz-ures. Systemically administered inter-feron, however, has been associated with seizures in 1% to 4% of patients,5–8

and cytokines have further been linked directly with febrile seizure in animal models.9–11_{Our review of the literature}

revealed few other data relating topical imiquimod to systemic adverse effects. We searched all literature included in the PubMed database through Sep-tember 24, 2011. The search terms used were “imiquimod,” “seizure,” “carcinoma,”and“cytokine dermatitis.” We report here a case of imiquimod-induced dermatitis and subsequent fe-brile seizure. Given that the mechanism for febrile seizures is poorly under-stood, it is uncertain whether the imi-quimod directly caused the seizures or whether the patient might have had seizures in any febrile setting.

PATIENT PRESENTATION

A previously healthy 2-year-old girl was admitted to the hospital in October 2005, with fever and the diagnosis of groin cellulitis. The patient had no documented history of neurologic or developmental delay. Approximately 4 weeks before admission, she had been diagnosed with molluscum contagiosum of the lower abdomen and groin. Treat-ment was initiated with imiquimod cream (Aldara) once daily. Within 2 weeks, she developed dysuria and signiﬁcant er-ythema of the treated area. In a local emergency department, she was di-agnosed with candidiasis, started on nystatin and her treatment of the molluscum contagiosum with imiquimod was continued. Nine days before admis-sion, she began experiencing intermittent

fevers. Her primary care physician prescribed cephalexin for presumed groin cellulitis, and imiquimod was continued.

On the day of admission, the patient had a generalized 3-minute tonic-clonic seizure with vomiting and postictal somnolence in the setting of fever (102°F). She had no previous neuro-logic abnormality, and no history of febrile seizures or other seizure dis-order. In a local emergency department, she was started on ceftriaxone for pre-sumed cellulitis of the groin and was transferred to our hospital for admis-sion. After admission to the emergency department, results of a neurologic ex-amination were unremarkable.

The dermatology service was consulted on hospital day 2. Physical examination revealed an uncomfortable, febrile fe-male with multiple umbilicated 3- to 8-mm papules and large surrounding erythematous erosions on the abdom-inal and external genital area (Fig 1).

At admission to the outside hospital, the patient’s white blood cell count was 6.8, hematocrit level was 35, and platelet count was 257. At no time did the white blood cell count become

elevated. Electrolyte levels were within normal limits. Two sets of blood cul-tures remained negative at the outside hospital. Results of a chest radiograph were normal. Herpes simplex virus and varicella zoster virus cultures of the eroded papules were negative.

The imiquimod was stopped, and within 1 hospital day the intermittent fevers subsided and the erythema was sub-stantially improved in the groin area. The patient felt signiﬁcantly improved, and no further seizures were noted. Follow-up 1 week later revealed near-complete resolution of the groin dermatitis.

DISCUSSION

Imiquimod is a potent immunomodu-lator that is approved by the US Food and Drug Administration for the treat-ment of genital warts, actinic keratoses, and superﬁcial basal cell carcinomas. In addition, it has met with therapeutic success in off-label treatments of mol-luscum contagiosum and nonmelanoma skin cancer.12,13_{Imiquimod appears to}

induce its effects by binding to cell surface receptors, speciﬁcally Toll-like receptor 7, and inducing secretion of proinﬂammatory cytokines, predominantly

FIGURE 1

Image of 2-year-old girl with erythematous, eroded papules coalescing into plaques on the abdomen and external genitalia.

e520 MOSHER and LIO

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interferon-a, tumor necrosis factor

a, and interleukin-12.14 _These

cyto-kines in turn enhance a Th1 (cytotoxic) cell-mediated immune response that is implemented inﬁghting viral infec-tions. This mechanism likely explains the success of imiquimod in treating molluscum contagiosum.

Case reports of the dermatologic ad-verse effects of topical imiquimod have included angioedema,15 _pemphigus,16,17

aphthous ulcers,18,19_{epidermoid cysts,}20

vitiligo-like hypopigmentation, and ex-acerbation of psoriasis.21,22 _{From the}

initial Phase III clinical trials, cytokine dermatitis has been a well-known ad-verse effect of immunomodulators such as imiquimod.1,2_{Systemic absorption}

of imiquimod has been linked to aﬂare of spondyloarthropathy, chronic neuro-pathic pain, and a report of severeﬂu symptoms with night sweats, a 7-kg weight loss, elevated erythrocyte sedi-mentation rate, and hypotension.23_–26

In the Phase III clinical trials1,2_{of Aldara}

for the treatment of genital warts, ac-tinic keratoses, and basal cell carci-nomas, application site reactions were the most commonly reported adverse event. The incidence of application site reactions was statistically signiﬁcantly higher in the treatment arms com-pared with the controls, and the se-verity of the reaction correlated to the frequency of study drug application. In the trials for the treatment of actinic keratoses, 1,27 _{there was a trend}

to-ward increased fever in patients re-ceiving Aldara (1.4%–2.9%) versus control patients (0%–0.4%), which was noted to reach statistical signiﬁcance

in the study by Korman et al.28_{For the}

trials of basal cell carcinomas, fever was present in 1.6% of those treated with Aldara compared with 0% of con-trols.2,29,30 _These _differences _were

small, and no mention was made of any statistical signiﬁcance. We could not

ﬁnd fever incidence data reported in patients treated for genital warts.31

Outside of the clinical trials, Campanelli et al4_{reported only fevers associated}

with the use of Aldara in children. With regard to other systemic adverse effects in the Phase III trials we reviewed, an increased incidence of headache oc-curred in treated patients versus control patients in the 5-applications-per-week arm in the basal cell carcinoma study.2

No other systemic adverse effects were reported to be statistically signiﬁcantly increased in the treatment arms, and no seizures were reported in any of the studies we reviewed.

To the best of our knowledge, there are no case reports in the literature link-ing the use of topical imiquimod with seizures. However, postmarketing ex-perience revealed 2 cases of febrile seizures associated with imiquimod from the Adverse Event Reporting Sys-tem database,32,33 _{obtained from the}

US Food and Drug Administration’s Cen-ter for Drug Evaluation and Research, Ofﬁce of Surveillance and Epidemi-ology. Theﬁrst case was a 3-year-old boy hospitalized for febrile seizure

∼40 days after starting Aldara 3 times

weekly to treat molluscum

con-tagiosum. The patient was also using Tazorac 0.1% cream and Cancuthus topical simultaneously. All medications

were discontinued in the hospital. Aldara was restarted 2 weeks later for 21 days. At the end of the 21 days, no additional seizures had been repor-ted.31 _{The second case revealed a}

6-year-old boy hospitalized 4 days after starting imiquimod for molluscum contagiosum after the child experi-enced 2 episodes in which he was found staring into space. Results of blood tests, urinalysis, and computed tomography scan were all negative. Aldara was discontinued again and was later restarted, and the boy ex-perienced another episode of staring into space∼3 days later. He was taken to the emergency department and di-agnosed with petit mal seizure. Aldara was again discontinued. Three days later the drug was started yet again, and the patient experienced a grand mal seizure 10 days later. Results of an EEG were inconclusive and an MRIﬁ nd-ings were negative.32

There is compelling neurologic litera-ture suggesting a direct link between cytokines and seizures,5–8_particularly

in the context of febrile seizures.9–11_We

speculate that the initial cytokine der-matitis in our patient allowed for in-creased absorption of imiquimod cream in the groin area and that the fevers were related to systemic cytokine release.

Given the complex mechanism of febrile seizures, it remains possible that our patient may have had seizures in any fever context. Nonetheless, this report highlights the potential for signiﬁcant systemic adverse effects from this topical medication.

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DOI: 10.1542/peds.2011-0936 originally published online January 4, 2012;

2012;129;e519

Pediatrics

J. Suzanne Mosher and Peter Lio

Cytokine Dermatitis and Febrile Seizure From Imiquimod

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DOI: 10.1542/peds.2011-0936 originally published online January 4, 2012;

2012;129;e519

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J. Suzanne Mosher and Peter Lio

Cytokine Dermatitis and Febrile Seizure From Imiquimod

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