Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report

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Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report
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Hall, David Jeffrey
Fromm, Jason Steven
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Abstract:
Introduction: Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening hypersensitivity reaction with rash, fever, and internal organ involvement, often hepatitis, occurring most commonly two to eight weeks after initiation of a medication. The present case is an example of severe and potentially life-threatening hepatitis as a manifestation of drug reaction with eosinophilia and systemic symptoms syndrome. Case presentation: We report a case of anti-epileptic-induced drug reaction with eosinophilia and systemic symptoms syndrome in an 18-year-old African-American man who presented with a five-day history of rash, periorbital and upper extremity edema, hepatitis and fever. Laboratory findings revealed an atypical lymphocytosis, eosinophilia, and elevated serum transaminases. No drug allergies were reported at the time of presentation, but phenytoin and levetiracetam therapy had been initiated five weeks prior to hospital admission for new-onset seizures. Both medications were discontinued on hospital admission, and after three days of high-dose corticosteroid therapy the patient experienced resolution of both his symptoms and laboratory markers of inflammation. Conclusion: Given the significant mortality attributed to drug reaction with eosinophilia and systemic symptoms syndrome, medical personnel should be aware of the potential for this severe hypersensitivity reaction and should ensure close follow-up and offer anticipatory guidance when beginning any new medication, particularly anti-epileptic therapy. Early recognition of drug reaction with eosinophilia and systemic symptoms syndrome and initiation of appropriate therapy are imperative in limiting morbidity. Keywords: Allergy, Anti-epileptic, DRESS syndrome, Hepatitis, Hypersensitivity reaction, Levetiracetam Phenytoin, Rash
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Publication of this article was funded in part by the University of Florida Open-Access publishing Fund. In addition, requestors receiving funding through the UFOAP project are expected to submit a post-review, final draft of the article to UF's institutional repository, IR@UF, (www.uflib.ufl.edu/UFir) at the time of funding. The institutional Repository at the University of Florida community, with research, news, outreach, and educational materials.
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Hall and Fromm Journal of Medical Case Reports 2013, 7:2 http://www.jmedicalcasereports.com/content/7/1/2; Pages 1-5
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doi:10.1186/1752-1947-7-2 Cite this article as: Hall and Fromm: Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report. Journal of Medical Case Reports 2013 7:2.

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p Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report
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au id A1 snm Hallfnm David Jeffreyinsr iid I1 email halldj@ufl.edu
A2 ca yes FrommJason StevenI2 jason.fromm@medicine.ufl.edu
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ins College of Medicine, University of Florida College of Medicine, 1600 SW Archer Road, PO Box 100277, Gainesville, FL, 32610-0277, USA
Department of Medicine, University of Florida College of Medicine, 1600 SW Archer Road, PO Box 100277, Gainesville, FL, 32610-0277, USA
source Journal of Medical Case Reports
issn 1752-1947
pubdate 2013
volume 7
issue 1
fpage 2
url http://www.jmedicalcasereports.com/content/7/1/2
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history rec date day 17month 8year 2012acc 22112012pub 312013
cpyrt 2013collab Hall and Fromm; licensee BioMed Central Ltd.note This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
kwdg
kwd Allergy
Anti-epileptic
DRESS syndrome
Hepatitis
Hypersensitivity reaction
Levetiracetam
Phenytoin
Rash
abs
sec
st
Abstract
Introduction
Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening hypersensitivity reaction with rash, fever, and internal organ involvement, often hepatitis, occurring most commonly two to eight weeks after initiation of a medication. The present case is an example of severe and potentially life-threatening hepatitis as a manifestation of drug reaction with eosinophilia and systemic symptoms syndrome.
Case presentation
We report a case of anti-epileptic-induced drug reaction with eosinophilia and systemic symptoms syndrome in an 18-year-old African-American man who presented with a five-day history of rash, periorbital and upper extremity edema, hepatitis and fever. Laboratory findings revealed an atypical lymphocytosis, eosinophilia, and elevated serum transaminases. No drug allergies were reported at the time of presentation, but phenytoin and levetiracetam therapy had been initiated five weeks prior to hospital admission for new-onset seizures. Both medications were discontinued on hospital admission, and after three days of high-dose corticosteroid therapy the patient experienced resolution of both his symptoms and laboratory markers of inflammation.
Conclusion
Given the significant mortality attributed to drug reaction with eosinophilia and systemic symptoms syndrome, medical personnel should be aware of the potential for this severe hypersensitivity reaction and should ensure close follow-up and offer anticipatory guidance when beginning any new medication, particularly anti-epileptic therapy. Early recognition of drug reaction with eosinophilia and systemic symptoms syndrome and initiation of appropriate therapy are imperative in limiting morbidity.
bdy
Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is an under-recognized and potentially life-threatening hypersensitivity reaction associated with a variety of medications, many being anti-epileptics. Patients with DRESS syndrome typically present with rash, swelling, fever, and systemic manifestations such as a severe transaminitis abbrgrp
abbr bid B1 1
. In most cases, a patient’s face, trunk, and upper extremities are affected by a rash which is at first morbilliform then gradually transitions to maculopapular, and finally can progress to edema of the face, particularly in the periorbital region. Although rash and eosinophilia are commonly seen in hypersensitivity reactions, the defining characteristic of DRESS syndrome is organ dysfunction, most commonly of the liver, kidneys, heart, or lungs. These patients are typically found to have started one of a few select medications in the past two to eight weeks (Table tblr tid T1 1) with aromatic anti-epileptics being the most commonly implicated
B2 2
B3 3
B4 4
B5 5
B6 6
. Non-aromatic anti-epileptic medications such as a topiramate, ethosuximide, and levetiracetam were traditionally thought to be safer; however, a recent case report described DRESS syndrome in a patient taking only levetiracetam
B7 7
. Although the true incidence is unknown, DRESS syndrome has been estimated to occur in approximately one out of 1000 to 10,000 new users of anti-epileptic medications and is more commonly reported in African-American men
1
B8 8
B9 9
. Vitamin D deficiency has been implicated as a possible contributor to the pathogenesis of DRESS due to its protective effects against inflammatory and auto-immune conditions, and because vitamin D deficiency occurs more frequently in people with darker skin phenotypes
B10 10
.
table
Table 1
caption
b Drug groups commonly associated with drug reaction with eosinophilia and systemic symptoms syndrome
tgroup align left cols 2
colspec colname c1 colnum 1 colwidth 1*
c2
thead valign top
row rowsep
entry
Drug Groups:
Specific Examples:
tbody
Anticonvulsants
phenytoin, carbamazepine, phenobarbital, lamotrigine, valproate
Antidepressants
despiramine, amitriptyline, fluoxetine
Sulfonamides/sulfones
dapsone, sulfasalazine, trimethoprim-sulfamethoxazole
Anti-inflammatories
piroxicam, naproxen, diclofenac, sulindac, ibuprofen
Anti-infectives
abacavir, nevirapine, linezolid, doxycycline, nitrofurantoin
Angiotensin-converting enzyme inhibitors
captopril, enalapril
Beta-blockers
atenolol, celiprolol
DIHS was originally described in 1950 by Chaiken it et al. as a triad of fever, rash, and multi-organ failure
B11 11
. The acronym DRESS was then put forth by Bocquet et al. and often includes hepatitis, pericarditis, interstitial nephritis, or interstitial pneumonitis
1
B12 12
. Isolated elevation of liver transaminases is the most common laboratory manifestation of hepatitis in DRESS syndrome. In severe cases it can progress to fulminant liver failure, occurring in as many as 10% of cases and accounting for the principle cause of mortality in patients affected by DRESS syndrome
1
. Although the pathophysiology of DRESS syndrome remains unknown, eosinophilic infiltration is probably the mechanism for involvement of organs such as the liver and kidneys
2
.Prompt recognition and removal of the offending agent is the key to limiting further hepatic damage, although hepatitis may significantly worsen even after discontinuation of the drug and may take months to resolve completely. Although no randomized-controlled therapy trials have been done, corticosteroids are utilized in many reported cases
3
4
5
8
. No specific therapeutic regimen or dosing has been shown to be more beneficial than another, but it is important that therapy is continued for long enough in order to prevent the possibility of relapse. The following case report demonstrates the necessity of prompt recognition and initiation of appropriate therapy in preventing the potential sequelae of DRESS syndrome.
Case presentation
An 18-year-old African-American man presented with a five-day history of pruritic, maculopapular rash with associated periorbital swelling, fever, and transaminitis. Five days prior to presentation he noted pruritis and rash over his extremities, which over the next several days progressed to his chest, back, and face. He had a history of seizures that began 35 days prior to this admission treated with phenytoin extended-release ER 100mg daily and levetiracetam 500mg twice a day. After investigation, no specific focus or etiology of his seizures had been identified. He has had decreased verbal and reading skills since early childhood, but details about his delivery and early development are unclear because he was adopted. The patient had no other significant past medical history, drug allergies, or alcohol use. Review of systems was positive for non-productive cough, fever, and tea-colored urine, and negative for chest pain, abdominal pain, shortness of breath, nausea, vomiting, weight-loss, chills, or any recent altered mental status.On examination, the patient was febrile to 40.2°C (104.4°F) with a heart rate of 88 beats/minute, respiratory rate of 18, and blood pressure of 110/55mmHg. The patient was well nourished, well developed, alert and well oriented, and appeared uncomfortable but not in distress. A fine exanthematous rash was noted on the face, upper, and lower extremities in sun-exposed areas without involvement of the oral mucosa, palms, or soles. There was profound periorbital edema that prevented eye-opening. His abdomen was soft and non-distended with no tenderness, guarding, or hepatosplenomegaly. No focal deficits were appreciated on neurological examination. At this point the differential diagnosis included drug-induced hypersensitivity, erythema multiforme, toxic epidermal necrolysis, vasculitis, an exanthem due to viral infection such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV), and auto-immune conditions such as systemic lupus erythematosus.Laboratory results revealed a white blood cell count of 7.9 thousand/mmsup 3 (normal from 4.0 to 10.0 thousand/mm3), with 60% neutrophils, 8.0% lymphocytes, and 4.0% eosinophils (absolute 0.32 thousand/mm
3
). His free phenytoin level on admission was 0.4mcg/mL (therapeutic from 1.0 to 2.0mcg/mL). His basic metabolic panel was within normal limits. Hepatic function panel revealed an aspartate aminotransferase of 778U/L (normal from 0 to 37), and alanine aminotransferase (ALT) of 1274U/L (normal from 0 to 41). Acetaminophen and salicylate levels were below detectable limits. Evaluation for acute and chronic hepatitis with serologies was negative for hepatitis A, B, and C. An extensive workup was performed including electrocardiogram and echocardiogram which were negative for abnormalities. EBV, CMV, and HIV testing were all negative, as were the results of tests for antinuclear antibodies (ANA). The patient was admitted to our hospital with a presumptive diagnosis of drug-induced hypersensitivity. All medications were discontinued and the patient was monitored for signs of clinical recovery.On hospital day 1, the patient’s condition worsened with increased facial swelling and rash extending to his chest and abdomen. He began to show signs of liver synthetic dysfunction with an elevated prothombin time and international normalized ratio as well as an increasing transaminitis. A repeat complete blood count showed an atypical lymphocytosis and eosinophilia at 8.0%. Because of his deteriorating condition, the patient was started on dexamethasone 4mg orally four times daily. On hospital day 2, the patient showed a marked clinical recovery. Despite improvement in the patient’s rash, his levels of transaminases continued to climb, necessitating hepatology consultation to assist with evaluation for transplantation. On hospital day 3 his levels of transaminases began to improve, and by day 8 his transaminitis had substantially resolved (Figure figr fid F1 1) and he was discharged home on prednisone 50mg to be taken once a day until follow-up with a hepatologist.
fig Figure 1Serum measurements of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during the patient’s admissiontext
Serum measurements of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during the patient’s admission. Normal reference ranges are from 0 to 41U/L for ALT and from 0 to 37U/L for AST. Day 0 (*) represents the day of admission and discontinuation of phenytoin. Corticosteroid therapy was begun on Day 2 (**).
graphic file 1752-1947-7-2-1 Follow-up five months after discharge revealed that the patient was doing well with no recurrence of his rash or other symptoms, no seizures, and normalization of his serum transaminases. He experienced no flare after corticosteroid tapering or withdrawal and to date has not had any hepatic sequelae.
Discussion
DRESS syndrome is an often under-diagnosed and under-recognized severe type IV (delayed type) hypersensitivity reaction that can occur with any medication but most commonly in response to aromatic anticonvulsants
1
2
6
9
10
12
B13 13
. Like most severe allergic reactions, DRESS syndrome involves rash, diffuse swelling, as well as eosinophilia
1
2
11
B14 14
. The hallmark of DRESS syndrome, however, is the presence of systemic manifestations such as inflammation of the liver, kidneys, heart, or other organs
1
12
13
. Although no formal diagnostic criteria have been widely accepted, a Japanese working group in 2007 established a set of diagnostic guidelines requiring the following: first, maculopapular rash developing greater than three weeks after starting a drug; second, prolonged clinical symptoms two weeks after discontinuation of the causative drug; third, fever greater than 38°C; fourth, liver abnormalities (including ALT greater than 100U/L); fifth, leukocyte abnormalities (either leukocytosis greater than 11×109/L, an atypical lymphocytosis, or eosinophilia greater than 1.5×109/L); sixth, lymphadenopathy; and seventh, human herpesvirus 6 (HHV-6) reactivation
2
. The patient described here met all of these described criteria for a diagnosis of DRESS. Although he had no palpable lymphadenopathy, an abdominal computed tomography scan confirmed profound retroperitoneal lymph node enlargement. Finally, a qualitative deoxyribonucleic acid (DNA) assay revealed the presence of HHV-6 type B in the patient’s blood, indicating the reactivation of HHV-6 associated with the patient’s DRESS syndrome
2
B15 15
B16 16
.Alternatively, Kardaun et al. of the Severe Cutaneous Adverse Reactions (RegiSCAR) study group published a scoring system in 2007 which has also been widely used to evaluate potential cases of DRESS syndrome
14
. The criteria for this system include: first, fever greater than 38.5°C; second, enlarged lymph nodes; third, eosinophilia; fourth, atypical lymphocytosis; fifth, skin involvement; sixth, organ involvement; seventh, resolution greater than 15 days; and eighth, evaluation of other causes (ANA, blood cultures, serology for hepatitis A virus, hepatitis B virus, hepatitis C virus, and chlamydia and/or mycoplasma). Using this scoring system, a final score of less than two indicates no case, a final score of between two and three indicates a possible case, a final score of between four and five indicates a probable case, and a final score of greater than five indicates a definite case. The patient in this case report had a score of six points (one each for lymphadenopathy, eosinophilia, atypical lymphocytosis, skin rash suggestive of DRESS, liver involvement, and evaluation of other potential causes), indicating a ‘definite case’ of DRESS per the RegiSCAR scoring guidelines.An important question to consider is which medication was actually the source of the patient’s reaction, as he had been started on phenytoin and levetiracetam within days of each other due to recurring seizures on phenytoin alone. Although DRESS was originally described in response to phenytoin and it has been one of the most common causative medications, Gómez-Zorrilla et al. published a case report earlier this year (2012) of a patient presenting with DRESS syndrome who took no medications other than levetiracetam
6
7
11
. If the patient were to again require anticonvulsant therapy, it would be prudent to avoid use of both phenytoin and levetiracetam, and to opt instead for an alternative non-aromatic anticonvulsant.Prompt recognition of the adverse drug reaction and discontinuation of offending medication are imperative steps in limiting the progression of DRESS syndrome. Pharmacological treatment of DRESS syndrome has to date not been studied with randomized controlled trials and instead has been established on the basis of case reports and retrospective analysis. Systemic corticosteroids have become a mainstay of therapy in severe cases and often produce marked improvement in clinical symptoms and laboratory measures in just a few days after the initiation of treatment
3
4
5
8
. If symptoms continue to progress despite the use of corticosteroids, other options include intravenous immunoglobulin (IVIG) and/or plasmapheresis
6
.The French Society of Dermatology published a report in 2010 outlining a consensus on therapeutic management of DRESS
B17 17
. They recommend the use of systemic corticosteroids at a dose equivalent to one mg/kg/day of prednisone in patients with any sign of severity including: transaminases greater than five times normal, renal involvement, pneumonia, hemophagocytosis, or cardiac involvement. They further recommend the use of IVIG at a dose of two g/kg over five days for a patient with life-threatening signs such as renal failure or respiratory failure. In addition, they propose the use of steroids in combination with ganciclovir in patients with signs of severity and confirmation of a major viral reactivation of HHV-6. However, because anti-HHV-6 immunoglobulin G titers are not currently widely available in all hospitals and laboratories, results often take several days or weeks to confirm viral reactivation. Because time is an important factor in the treatment of DRESS, it is not recommended to delay definitive therapy in order to confirm a major viral reactivation. Further study and randomized controlled trials of these and other potential pharmacologic therapies will be important in establishing a standard of care and to improve understanding of how best to treat patients affected by DRESS syndrome.
Conclusion
Given the significant mortality attributed to DRESS syndrome, clinicians should be aware of the potential for this severe hypersensitivity reaction particularly in starting any new anti-epileptic medication. In patients presenting with skin rash and systemic abnormalities after a recent change in medications, physicians should consider DRESS syndrome as a possible diagnosis and switch to more aggressive therapy if removal of the offending agent does not result in clinical improvement. Further study of potential pharmacological therapies is warranted given the significant morbidity associated with DRESS syndrome.
Consent
Written informed consent was obtained from the patient and his legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
DH analyzed and interpreted the data regarding the patient’s condition and wrote the first draft of the manuscript. JF examined and administered treatment to the patient and was a major contributor in writing and editing the manuscript. Both authors read and approved the final manuscript.
bm
refgrp Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS)BocquetHBagotMRoujeauJCSemin Cutan Med Surg199615250lpage 25710.1016/S1085-5629(96)80038-1link fulltext 9069593The diagnosis of DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivationsShioharaTIijimaMIkezawaZHashimotoKResponse Br J Dermatol20071561045109210.1111/j.1365-2133.2007.07775.xVancomycin-induced DRESS syndrome in a female patientVautheyLUckayIAbrassartSBernardLAssalMFerryTDjordjevicMRoussosCVaudauxPPharmacology20088213814110.1159/00014272918607115Linezolid-associated acute interstitial nephritis and drug rash with eosinophilia and systemic symptoms (DRESS) syndromeSavardSDesmeulesSRiopelJAgharaziiMAm J Kidney Dis200954e17e2010.1053/j.ajkd.2009.07.01319733945DRESS syndrome caused by nitrofurantoinVelemaMSVoermanHJNeth J Med20096714714919581659Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-induced Hypersensitivity Syndrome (DIHS): a review of current conceptsCriadoPRCriadoRFJde AvanciniMSantiCGAn Bras Dermatol201287343544910.1590/S0365-0596201200030001322714760Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndromeGómez-ZorrillaSFerrazAVPedrósCLemusMPeñaCAnn Pharmacother2012467–8e2022764327Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage studyTennisPStemRSNeurology19974954254610.1212/WNL.49.2.5429270593Drug-induced hypersensitivity syndrome in pediatric patientsCarrollMCYueng-YueKAEsterlyNBDroletBAPediatrics2001108248549210.1542/peds.108.2.48511483822Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patientsBen m’radMLeclerc-MercierSBlanchePFranckNRozenbergFFullaYGuesmiMRollotFDehouxMGuillevinLMoachonLMedicine (Baltimore)20098813114010.1097/MD.0b013e3181a4d1a1Dilantin sensitivity; report of a case of hepatitis with jaundice, pyrexia and exfoliative dermatitisChaikenBHGoldbergBISegalJPN Engl J Med19502422389789810.1056/NEJM19500608242230415416921The DRESS syndrome: a literature overviewCacoubPMusettePDescampsVMeyerOSpeirsCFinziLRoujeauJCAm J Med2011124758859710.1016/j.amjmed.2011.01.01721592453Drug rash with eosinophilia and systemic symptomsFrielingGJessupCMihmMDiagnostic Pathology: Non-neoplastic Dermatopathologypublisher Salt Lake City, UT: Amirsys Publishing, Inceditor Hall BJ, Hall JC, Cockerell CJedition 120121011Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?KardaunSHSidoroffAValeyrie-AllanoreLHalevySDavidoviciBBMockenhauptMRoujeauJCBr J Dermatol2007156360961110.1111/j.1365-2133.2006.07704.x17300272Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndromeSuzukiYInagiRAonoTYamanishiKShioharaTArch Dermatol19981341108111210.1001/archderm.134.9.11089762023Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemiaKanoYInaokaMShioharaTArch Dermatol200414018318810.1001/archderm.140.2.18314967790Management of drug reaction with eosinophilia and systemic symptoms (DRESS)DescampsVBen-SaïdBSassolasBTruchetetFAvenel-AudranMGirardinPGuinnepainMTMathelier-FusadePAssierHMilpiedBModianoPLebrun-VignesBBarbaudAcnm groupe Toxidermies de la Société française de dermatologieAnn Dermatol Venereol201013770370810.1016/j.annder.2010.04.02421074653


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Abstract
Introduction
Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening hypersensitivity reaction with rash, fever, and internal organ involvement, often hepatitis, occurring most commonly two to eight weeks after initiation of a medication. The present case is an example of severe and potentially life-threatening hepatitis as a manifestation of drug reaction with eosinophilia and systemic symptoms syndrome.
Case presentation
We report a case of anti-epileptic-induced drug reaction with eosinophilia and systemic symptoms syndrome in an 18-year-old African-American man who presented with a five-day history of rash, periorbital and upper extremity edema, hepatitis and fever. Laboratory findings revealed an atypical lymphocytosis, eosinophilia, and elevated serum transaminases. No drug allergies were reported at the time of presentation, but phenytoin and levetiracetam therapy had been initiated five weeks prior to hospital admission for new-onset seizures. Both medications were discontinued on hospital admission, and after three days of high-dose corticosteroid therapy the patient experienced resolution of both his symptoms and laboratory markers of inflammation.
Conclusion
Given the significant mortality attributed to drug reaction with eosinophilia and systemic symptoms syndrome, medical personnel should be aware of the potential for this severe hypersensitivity reaction and should ensure close follow-up and offer anticipatory guidance when beginning any new medication, particularly anti-epileptic therapy. Early recognition of drug reaction with eosinophilia and systemic symptoms syndrome and initiation of appropriate therapy are imperative in limiting morbidity.
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CASEREPORTOpenAccessDrugreactionwitheosinophiliaandsystemic symptomssyndromeinapatienttaking phenytoinandlevetiracetam:acasereportDavidJeffreyHall1andJasonStevenFromm2*AbstractIntroduction: Drugreactionwitheosinophiliaandsystemicsymptomssyndromeisapotentiallylife-threatening hypersensitivityreactionwithrash,fever,andinternalorganinvolvement,oftenhepatitis,occurringmostcommonly twotoeightweeksafterinitiationofamedication.Thepresentcaseisanexampleofsevereandpotentially life-threateninghepatitisasamanifestationofdrugreactionwitheosinophiliaandsystemicsymptomssyndrome. Casepresentation: Wereportacaseofanti-epileptic-induceddrugreactionwitheosinophiliaandsystemic symptomssyndromeinan18-year-oldAfrican-Americanmanwhopresentedwithafive-dayhistoryofrash, periorbitalandupperextremityedema,hepatitisandfever.Laboratoryfindingsrevealedanatypicallymphocytosis, eosinophilia,andelevatedserumtransaminases.Nodrugallergieswerereportedatthetimeofpresentation,but phenytoinandlevetiracetamtherapyhadbeeninitiatedfiveweekspriortohospitaladmissionfornew-onset seizures.Bothmedicationswerediscontinuedonhospitaladmission,andafterthreedaysofhigh-dose corticosteroidtherapythepatientexperiencedresolutionofbothhissymptomsandlaboratorymarkersof inflammation. Conclusion: Giventhesignificantmortalityattributedtodrugreactionwitheosinophiliaandsystemicsymptoms syndrome,medicalpersonnelshouldbeawareofthepotentialforthisseverehypersensitivityreactionandshould ensureclosefollow-upandofferanticipatoryguidancewhenbeginninganynewmedication,particularly anti-epileptictherapy.Earlyrecognitionofdrugreactionwitheosinophiliaandsystemicsymptomssyndromeand initiationofappropriatetherapyareimperativeinlimitingmorbidity. Keywords: Allergy,Anti-epileptic,DRESSsyndrome,Hepatitis,Hypersensitivityreaction,Levetiracetam Phenytoin,RashIntroductionDrugreactionwitheosinophiliaandsystemicsymptoms (DRESS)syndrome,alsoknownasdrug-inducedhypersensitivitysyndrome(DIHS),isanunder-recognized andpotentiallylife-threateninghypersensitivityreaction associatedwithavarietyofmedications,manybeing anti-epileptics.PatientswithDRESSsyndrometypically presentwithrash,swelling,fever,andsystemicmanifestationssuchasaseveretransaminitis[1].Inmostcases, apatient ’ sface,trunk,andupperextremitiesareaffected byarashwhichisatfirstmorbilliformthengradually transitionstomaculopapular,andfinallycanprogressto edemaoftheface,particularlyintheperiorbitalregion. Althoughrashandeosinophiliaarecommonlyseenin hypersensitivityreactions,thedefiningcharacteristicof DRESSsyndromeisorgandysfunction,mostcommonly oftheliver,kidneys,heart,orlungs.Thesepatientsare typicallyfoundtohavestartedoneofafewselectmedicationsinthepasttwotoeightweeks(Table1)witharomaticanti-epilepticsbeingthemostcommonly implicated[2-6].Non-aromaticanti-epilepticmedicationssuchasatopiramate,ethosuximide,andlevetiracetamweretraditionallythoughttobesafer;however,a recentcasereportdescribedDRESSsyndromeinapatienttakingonlylevetiracetam[7].Althoughthetrueincidenceisunknown,DRESSsyndromehasbeen *Correspondence: jason.fromm@medicine.ufl.edu2DepartmentofMedicine,UniversityofFloridaCollegeofMedicine,1600SW ArcherRoad,POBox100277,Gainesville,FL32610-0277,USA Fulllistofauthorinformationisavailableattheendofthearticle JOURNAL OF MEDICALCASE REPORTS 2013HallandFromm;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse, distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.HallandFromm JournalofMedicalCaseReports 2013, 7 :2 http://www.jmedicalcasereports.com/content/7/1/2

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estimatedtooccurinapproximatelyoneoutof1000to 10,000newusersofanti-epilepticmedicationsandis morecommonlyreportedinAfrican-Americanmen [1,8,9].VitaminDdeficiencyhasbeenimplicatedasa possiblecontributortothepathogenesisofDRESSdue toitsprotectiveeffectsagainstinflammatoryandautoimmuneconditions,andbecausevitaminDdeficiency occursmorefrequentlyinpeoplewithdarkerskin phenotypes[10]. DIHSwasoriginallydescribedin1950byChaiken etal .asatriadoffever,rash,andmulti-organfailure [11].TheacronymDRESSwasthenputforthby Bocquet etal. andoftenincludeshepatitis,pericarditis, interstitialnephritis,orinterstitialpneumonitis[1,12]. Isolatedelevationoflivertransaminasesisthemost commonlaboratorymanifestationofhepatitisinDRESS syndrome.Inseverecasesitcanprogresstofulminant liverfailure,occurringinasmanyas10%ofcasesand accountingfortheprinciplecauseofmortalityin patientsaffectedbyDRESSsyndrome[1].Althoughthe pathophysiologyofDRESSsyndromeremainsunknown, eosinophilicinfiltrationisprobablythemechanismfor involvementoforganssuchastheliverandkidneys[2]. Promptrecognitionandremovaloftheoffending agentisthekeytolimitingfurtherhepaticdamage, althoughhepatitismaysignificantlyworsenevenafter discontinuationofthedrugandmaytakemonthsto resolvecompletely.Althoughnorandomized-controlled therapytrialshavebeendone,corticosteroidsareutilized inmanyreportedcases[3-5,8].Nospecifictherapeutic regimenordosinghasbeenshowntobemorebeneficial thananother,butitisimportantthattherapyiscontinuedforlongenoughinordertopreventthepossibility ofrelapse.Thefollowingcasereportdemonstratesthe necessityofpromptrecognitionandinitiationofappropriatetherapyinpreventingthepotentialsequelaeof DRESSsyndrome.CasepresentationAn18-year-oldAfrican-Americanmanpresentedwitha five-dayhistoryofpruritic,maculopapularrashwith associatedperiorbitalswelling,fever,andtransaminitis. Fivedayspriortopresentationhenotedpruritisand rashoverhisextremities,whichoverthenextseveral daysprogressedtohischest,back,andface.Hehada historyofseizuresthatbegan35dayspriortothis admissiontreatedwithphenytoinextended-releaseER 100mgdailyandlevetiracetam500mgtwiceaday.After investigation,nospecificfocusoretiologyofhisseizures hadbeenidentified.Hehashaddecreasedverbaland readingskillssinceearlychildhood,butdetailsabouthis deliveryandearlydevelopmentareunclearbecausehe wasadopted.Thepatienthadnoothersignificantpast medicalhistory,drugallergies,oralcoholuse.Reviewof systemswaspositivefornon-productivecough,fever, andtea-coloredurine,andnegativeforchestpain,abdominalpain,shortnessofbreath,nausea,vomiting, weight-loss,chills,oranyrecentalteredmentalstatus. Onexamination,thepatientwasfebrileto40.2C (104.4F)withaheartrateof88beats/minute,respiratoryrateof18,andbloodpressureof110/55mmHg.The patientwaswellnourished,welldeveloped,alertand welloriented,andappeareduncomfortablebutnotin distress.Afineexanthematousrashwasnotedonthe face,upper,andlowerextremitiesinsun-exposedareas withoutinvolvementoftheoralmucosa,palms,orsoles. Therewasprofoundperiorbitaledemathatprevented eye-opening.Hisabdomenwassoftandnon-distended withnotenderness,guarding,orhepatosplenomegaly. Nofocaldeficitswereappreciatedonneurologicalexamination.Atthispointthedifferentialdiagnosisincluded drug-inducedhypersensitivity,erythemamultiforme, toxicepidermalnecrolysis,vasculitis,anexanthemdue toviralinfectionsuchasEpstein – Barrvirus(EBV),cytomegalovirus(CMV),andhumanimmunodeficiencyvirus (HIV),andauto-immuneconditionssuchassystemic lupuserythematosus. Laboratoryresultsrevealedawhitebloodcellcountof 7.9thousand/mm3(normalfrom4.0to10.0thousand/ mm3),with60%neutrophils,8.0%lymphocytes,and4.0% eosinophils(absolute0.32thousand/mm[3]).Hisfree phenytoinlevelonadmissionwas0.4mcg/mL(therapeutic from1.0to2.0mcg/mL).Hisbasicmetabolicpanelwas withinnormallimits.Hepaticfunctionpanelrevealedan aspartateaminotransferaseof778U/L(normalfrom 0to37),andalanineaminotransferase(ALT)of1274U/L (normalfrom0to41).Acetaminophenandsalicylate levelswerebelowdetectablelimits.Evaluationforacute andchronichepatitiswithserologieswasnegativefor hepatitisA,B,andC.Anextensiveworkupwasperformed includingelectrocardiogramandechocardiogramwhich werenegativeforabnormalities.EBV,CMV,andHIV Table1Druggroupscommonlyassociatedwithdrug reactionwitheosinophiliaandsystemicsymptoms syndromeDrugGroups:SpecificExamples: Anticonvulsantsphenytoin,carbamazepine, phenobarbital,lamotrigine,valproate Antidepressantsdespiramine,amitriptyline,fluoxetine Sulfonamides/sulfonesdapsone,sulfasalazine,trimethoprimsulfamethoxazole Anti-inflammatoriespiroxicam,naproxen,diclofenac, sulindac,ibuprofen Anti-infectivesabacavir,nevirapine,linezolid, doxycycline,nitrofurantoin Angiotensin-converting enzymeinhibitors captopril,enalapril Beta-blockersatenolol,celiprolol HallandFromm JournalofMedicalCaseReports 2013, 7 :2Page2of5 http://www.jmedicalcasereports.com/content/7/1/2

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testingwereallnegative,asweretheresultsoftestsfor antinuclearantibodies(ANA).Thepatientwasadmitted toourhospitalwithapresumptivediagnosisofdruginducedhypersensitivity.Allmedicationswerediscontinuedandthepatientwasmonitoredforsignsofclinical recovery. Onhospitalday1,thepatient ’ sconditionworsened withincreasedfacialswellingandrashextendingtohis chestandabdomen.Hebegantoshowsignsofliver syntheticdysfunctionwithanelevatedprothombintime andinternationalnormalizedratioaswellasanincreasingtransaminitis.Arepeatcompletebloodcount showedanatypicallymphocytosisandeosinophiliaat 8.0%.Becauseofhisdeterioratingcondition,thepatient wasstartedondexamethasone4mgorallyfourtimes daily.Onhospitalday2,thepatientshowedamarked clinicalrecovery.Despiteimprovementinthepatient ’ s rash,hislevelsoftransaminasescontinuedtoclimb, necessitatinghepatologyc onsultationtoassistwith evaluationfortransplantation.Onhospitalday3his levelsoftransaminasesbegantoimprove,andbyday 8histransaminitishadsubstantiallyresolved(Figure1) andhewasdischargedhomeonprednisone50mg tobetakenonceadayuntilfollow-upwitha hepatologist. Follow-upfivemonthsafterdischargerevealedthat thepatientwasdoingwellwithnorecurrenceofhisrash orothersymptoms,noseizures,andnormalizationof hisserumtransaminases.Heexperiencednoflareafter corticosteroidtaperingorwithdrawalandtodatehas nothadanyhepaticsequelae.DiscussionDRESSsyndromeisanoftenunder-diagnosedandunderrecognizedseveretypeIV(delayedtype)hypersensitivity reactionthatcanoccurwithanymedicationbutmost commonlyinresponsetoaromaticanticonvulsants [1,2,6,9,10,12,13].Likemostsevereallergicreactions, DRESSsyndromeinvolvesrash,diffuseswelling,aswellas eosinophilia[1,2,11,14].ThehallmarkofDRESSsyndrome,however,isthepresenceofsystemicmanifestationssuchasinflammationoftheliver,kidneys,heart,or otherorgans[1,12,13].Althoughnoformaldiagnostic criteriahavebeenwidelyaccepted,aJapaneseworking groupin2007establishedasetofdiagnosticguidelines requiringthefollowing:first,maculopapularrashdevelopinggreaterthanthreeweeksafterstartingadrug;second, prolongedclinicalsymptomstwoweeksafterdiscontinuationofthecausativedrug;third,fevergreaterthan38C; fourth,liverabnormalities(includingALTgreaterthan 100U/L);fifth,leukocyteabnormalities(eitherleukocytosis greaterthan11109/L,anatypicallymphocytosis,or eosinophiliagreaterthan1.5109/L);sixth,lymphadenopathy;andseventh,humanherpesvirus6(HHV-6)reactivation[2].Thepatientdescribedheremetallofthese describedcriteriaforadiagnosisofDRESS.Althoughhe hadnopalpablelymphadenopathy,anabdominalcomputedtomographyscanconfirmedprofoundretroperitoneallymphnodeenlargement.Finally,aqualitative deoxyribonucleicacid(DNA)assayrevealedthepresence ofHHV-6typeBinthepatient ’ sblood,indicatingthe reactivationofHHV-6associatedwiththepatient ’ sDRESS syndrome[2,15,16]. Alternatively,Kardaun etal. oftheSevereCutaneous AdverseReactions(RegiSCAR)studygrouppublisheda scoringsystemin2007whichhasalsobeenwidelyused toevaluatepotentialcasesofDRESSsyndrome[14].The criteriaforthissysteminclude:first,fevergreaterthan 38.5C;second,enlargedlymphnodes;third,eosinophilia;fourth,atypicallymphocytosis;fifth,skininvolvement;sixth,organinvolvement;seventh,resolution greaterthan15days;andeighth,evaluationofother causes(ANA,bloodcultures,serologyforhepatitisA virus,hepatitisBvirus,hepatitisCvirus,andchlamydia and/ormycoplasma).Usingthisscoringsystem,afinal scoreoflessthantwoindicatesnocase,afinalscoreof betweentwoandthreeindicatesapossiblecase,afinal scoreofbetweenfourandfiveindicatesaprobablecase, andafinalscoreofgreaterthanfiveindicatesadefinite case.Thepatientinthiscasereporthadascoreofsix points(oneeachforlymphadenopathy,eosinophilia, atypicallymphocytosis,skinrashsuggestiveofDRESS, liverinvolvement,andevaluationofotherpotential causes),indicatinga ‘ definitecase ’ ofDRESSperthe RegiSCARscoringguidelines. Animportantquestiontoconsideriswhichmedication wasactuallythesourceofthepatient ’ sreaction,ashehad beenstartedonphenytoinandlevetiracetamwithindays ofeachotherduetorecurringseizuresonphenytoin Figure1 Serummeasurementsofalanineaminotransferase (ALT)andaspartateaminotransferase(AST)duringthepatient ’ s admission. Normalreferencerangesarefrom0to41U/LforALT andfrom0to37U/LforAST.Day0(*)representsthedayof admissionanddiscontinuationofphenytoin.Corticosteroidtherapy wasbegunonDay2(**). HallandFromm JournalofMedicalCaseReports 2013, 7 :2Page3of5 http://www.jmedicalcasereports.com/content/7/1/2

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alone.AlthoughDRESSwasoriginallydescribedin responsetophenytoinandithasbeenoneofthemost commoncausativemedications,Gmez-Zorrilla etal. publishedacasereportearlierthisyear(2012)ofapatient presentingwithDRESSsyndromewhotooknomedicationsotherthanlevetiracetam[6,7,11].Ifthepatientwere toagainrequireanticonvulsanttherapy,itwouldbe prudenttoavoiduseofbothphenytoinandlevetiracetam, andtooptinsteadforanalternativenon-aromatic anticonvulsant. Promptrecognitionoftheadversedrugreactionand discontinuationofoffendingmedicationareimperative stepsinlimitingtheprogressionofDRESSsyndrome. PharmacologicaltreatmentofDRESSsyndromehasto datenotbeenstudiedwithrandomizedcontrolledtrials andinsteadhasbeenestablishedonthebasisofcase reportsandretrospectiveanalysis.Systemiccorticosteroidshavebecomeamainstayoftherapyinseverecases andoftenproducemarkedimprovementinclinical symptomsandlaboratorymeasuresinjustafewdays aftertheinitiationoftreatment[3-5,8].Ifsymptoms continuetoprogressdespitetheuseofcorticosteroids, otheroptionsincludeintravenousimmunoglobulin (IVIG)and/orplasmapheresis[6]. TheFrenchSocietyofDermatologypublishedareport in2010outliningaconsensusontherapeuticmanagementofDRESS[17].Theyrecommendtheuseof systemiccorticosteroidsatadoseequivalenttoonemg/ kg/dayofprednisoneinpatientswithanysignofseverity including:transaminasesgreaterthanfivetimesnormal, renalinvolvement,pneumonia,hemophagocytosis,or cardiacinvolvement.Theyfurtherrecommendtheuse ofIVIGatadoseoftwog/kgoverfivedaysforapatient withlife-threateningsignssuchasrenalfailureorrespiratoryfailure.Inaddition,theyproposetheuseof steroidsincombinationwithganciclovirinpatientswith signsofseverityandconfirmationofamajorviralreactivationofHHV-6.However,becauseanti-HHV-6immunoglobulinGtitersarenotcurrentlywidelyavailable inallhospitalsandlaboratories,resultsoftentakeseveraldaysorweekstoconfirmviralreactivation.Because timeisanimportantfactorinthetreatmentofDRESS, itisnotrecommendedtodelaydefinitivetherapyin ordertoconfirmamajorviralreactivation.Further studyandrandomizedcontrolledtrialsoftheseand otherpotentialpharmacologictherapieswillbeimportantinestablishingastandardofcareandtoimprove understandingofhowbesttotreatpatientsaffectedby DRESSsyndrome.ConclusionGiventhesignificantmortalityattributedtoDRESS syndrome,cliniciansshouldbeawareofthepotentialfor thisseverehypersensitivityreactionparticularlyin startinganynewanti-epilepticmedication.Inpatients presentingwithskinrashandsystemicabnormalities afterarecentchangeinmedications,physiciansshould considerDRESSsyndromeasapossiblediagnosisand switchtomoreaggressivetherapyifremovalofthe offendingagentdoesnotresultinclinicalimprovement. Furtherstudyofpotentialpharmacologicaltherapiesis warrantedgiventhesignificantmorbidityassociatedwith DRESSsyndrome.ConsentWritteninformedconsentwasobtainedfromthepatient andhislegalguardianforpublicationofthiscasereport andanyaccompanyingimages.AcopyofthewrittenconsentisavailableforreviewbytheEditor-in-Chiefofthis journal.Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions DHanalyzedandinterpretedthedataregardingthepatient ’ sconditionand wrotethefirstdraftofthemanuscript.JFexaminedandadministered treatmenttothepatientandwasamajorcontributorinwritingandediting themanuscript.Bothauthorsreadandapprovedthefinalmanuscript. Authordetails1CollegeofMedicine,UniversityofFloridaCollegeofMedicine,1600SW ArcherRoad,POBox100277,Gainesville,FL32610-0277,USA.2Department ofMedicine,UniversityofFloridaCollegeofMedicine,1600SWArcherRoad, POBox100277,Gainesville,FL32610-0277,USA. Received:17August2012Accepted:22November2012 Published:3January2013 References1.BocquetH,BagotM,RoujeauJC: Drug-inducedpseudolymphomaand drughypersensitivitysyndrome(DrugRashwithEosinophiliaand SystemicSymptoms:DRESS). SeminCutanMedSurg 1996, 15: 250 – 257. 2.ShioharaT,IijimaM,IkezawaZ,HashimotoK: ThediagnosisofDRESS syndromehasbeensufficientlyestablishedonthebasisoftypical clinicalfeaturesandviralreactivations. ResponseBrJDermatol 2007, 156: 1045 – 1092. 3.VautheyL,UckayI,AbrassartS,BernardL,AssalM,FerryT,DjordjevicM, RoussosC,VaudauxP: Vancomycin-inducedDRESSsyndromeinafemale patient. Pharmacology 2008, 82: 138 – 141. 4.SavardS,DesmeulesS,RiopelJ,AgharaziiM: Linezolid-associatedacute interstitialnephritisanddrugrashwitheosinophiliaandsystemic symptoms(DRESS)syndrome. AmJKidneyDis 2009, 54: e17 – e20. 5.VelemaMS,VoermanHJ: DRESSsyndromecausedbynitrofurantoin. NethJMed 2009, 67: 147 – 149. 6.CriadoPR,CriadoRF,JdeAvanciniM,SantiCG: Drugreactionwith EosinophiliaandSystemicSymptoms(DRESS)/Drug-induced HypersensitivitySyndrome(DIHS):areviewofcurrentconcepts. AnBras Dermatol 2012, 87 (3):435 – 449. 7.Gmez-ZorrillaS,FerrazAV,PedrsC,LemusM,PeaC: Levetiracetam-induceddrugreactionwitheosinophiliaandsystemic symptomssyndrome. AnnPharmacother 2012, 46 (7 – 8):e20. 8.TennisP,StemRS: Riskofseriouscutaneousdisordersafterinitiationof useofphenytoin,carbamazepine,orsodiumvalproate:arecordlinkage study. Neurology 1997, 49: 542 – 546. 9.CarrollMC,Yueng-YueKA,EsterlyNB,DroletBA: Drug-induced hypersensitivitysyndromeinpediatricpatients. Pediatrics 2001, 108 (2):485 – 492. 10.Benm ’ radM,Leclerc-MercierS,BlancheP,FranckN,RozenbergF,FullaY, GuesmiM,RollotF,DehouxM,GuillevinL,MoachonL: Drug-inducedHallandFromm JournalofMedicalCaseReports 2013, 7 :2Page4of5 http://www.jmedicalcasereports.com/content/7/1/2

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hypersensitivitysyndrome:clinicalandbiologicdiseasepatternsin24 patients. Medicine(Baltimore) 2009, 88: 131 – 140. 11.ChaikenBH,GoldbergBI,SegalJP: Dilantinsensitivity;reportofacaseof hepatitiswithjaundice,pyrexiaandexfoliativedermatitis. NEnglJMed 1950, 242 (23):897 – 898. 12.CacoubP,MusetteP,DescampsV,MeyerO,SpeirsC,FinziL,RoujeauJC: TheDRESSsyndrome:aliteratureoverview. AmJMed 2011, 124 (7):588 – 597. 13.FrielingG,JessupC,MihmM: Drugrashwitheosinophiliaandsystemic symptoms .In DiagnosticPathology:Non-neoplasticDermatopathology 1stedition.EditedbyHallBJ,HallJC,CockerellCJ.SaltLakeCity,UT: AmirsysPublishing,Inc;2012:10 – 11. 14.KardaunSH,SidoroffA,Valeyrie-AllanoreL,HalevyS,DavidoviciBB, MockenhauptM,RoujeauJC: Variabilityintheclinicalpatternof cutaneousside-effectsofdrugswithsystemicsymptoms:doesaDRESS syndromereallyexist? BrJDermatol 2007, 156 (3):609 – 611. 15.SuzukiY,InagiR,AonoT,YamanishiK,ShioharaT: Humanherpesvirus6 infectionasariskfactorforthedevelopmentofseveredrug-induced hypersensitivitysyndrome. ArchDermatol 1998, 134: 1108 – 1112. 16.KanoY,InaokaM,ShioharaT: Associationbetweenanticonvulsant hypersensitivitysyndromeandhumanherpesvirus6reactivationand hypogammaglobulinemia. ArchDermatol 2004, 140: 183 – 188. 17.DescampsV,Ben-SadB,SassolasB,TruchetetF,Avenel-AudranM, GirardinP,GuinnepainMT,Mathelier-FusadeP,AssierH,MilpiedB, ModianoP,Lebrun-VignesB,BarbaudA,groupeToxidermiesdelaSocit franaisededermatologie: Managementofdrugreactionwith eosinophiliaandsystemicsymptoms(DRESS). AnnDermatolVenereol 2010, 137: 703 – 708.doi:10.1186/1752-1947-7-2 Citethisarticleas: HallandFromm: Drugreactionwitheosinophiliaand systemicsymptomssyndromeinapatienttakingphenytoinand levetiracetam:acasereport. JournalofMedicalCaseReports 2013 7 :2. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit HallandFromm JournalofMedicalCaseReports 2013, 7 :2Page5of5 http://www.jmedicalcasereports.com/content/7/1/2