Currently, 12 cases (including our patient) of autoimmune encephalitis/encephalopathy after daclizumab therapy in MS are known worldwide and led to voluntary withdrawal of marketing authorization for daclizumab by the manufacturer Biogen (press release from European Medicines Agency, 07.03.2018).
Our findings suggest that early recognition of DRESS even with CNS manifestations and swift treatment with steroids and/or plasma exchange are essential to improve the longterm outcome

Harms, Lutz

Köhnlein, Martin

Meisel, Andreas

Metz, Imke

Radbruch, Helena

Scheibe, Franziska

Siebert, Eberhard

Wolf, Stefan

Institutional Repository of the Freie Universität Berlin

CLINICAL/SCIENTIFIC NOTES OPEN ACCESSDrug reaction with eosinophilia and systemicsymptoms after daclizumab therapy in MSFranziska Scheibe, MD, Imke Metz, MD, Helena Radbruch, MD, Eberhard Siebert, MD, Stefan Wolf, MD,Martin Ko¨hnlein, MD, Lutz Harms, MD, and Andreas Meisel, MDNeurol Neuroimmunol Neuroinﬂamm 2018;5:e479. doi:10.1212/NXI.0000000000000479CorrespondenceDr. Scheibefranziska.scheibe@charite.deCase reportIn 2012, a 33-year-old woman was diagnosed with relapsing-remitting MS (RRMS) afterfulﬁlling McDonald criteria and careful exclusion of other diﬀerential diagnoses. Five years later(EDSS 1), she changed her disease-modifying therapy after side eﬀects to betaferon (ﬂu-likesymptoms) and dimethyl fumarate (erythema and pruritus) to daclizumab. Twomonths after 2applications of 150 mg daclizumab, she developed a self-limiting rash (ﬁgure 1A), followed byfever, headaches, meningismus, photophobia, nausea, paraesthesia, and itching of her upperbody 1 month later. Blood test showed decreased lymphocyte counts of 1.7/μL (17.1%) andincreased eosinophil granulocytes of 1.5/μL (15.1%). CSF analysis revealed pleocytosis of 570/μL (1.8% eosinophilic granulocytes) and an initially negative, but 2 weeks later marked in-trathecal immunoglobulin synthesis (IgM 85%, IgA 43%, and IgG 38%). MRI showed peri-ventricular contrast-enhancing lesions and a multisegmental cervical myelitis (C1–4). After 10days, she further deteriorated by severe infratentorial edema with compression of the fourthventricle and obstructive hydrocephalus (ﬁgure 1, B–F). At admission to our hospital, sheobtained an external ventricle drainage showing normal opening pressure. Two days later, shehad sudden increase in intracranial pressure requiring intubation and emergency decom-pressive surgery of the posterior fossa. Increased intracranial pressure (up to 40 mmHg) due toglobal brain edema and subsequently complicated by a postoperative bleeding into the rightfrontal lobe after a brain biopsy (see below) was controlled by CSF drainage, deep analgose-dation, dexamethasone, and osmotherapy. The atypical clinical picture with brain edema,rhombenecephalitis, and high CSF cell count was incompatible with MS relapse as initiallysuggested by the periventricular lesions and cervical myelitis. Because careful examinationsrevealed no other autoimmune or infectious diseases, we initially treated polypragmatically withaciclovir/ganciclovir, ceftriaxone/ampicillin, voriconazole/posaconazole, and IV immunoglo-bulins. Brain biopsies of the right frontal lobe, cerebellum, and cerebellar leptomeningesshowed inﬂammatory demyelinating lesions with pronounced inﬂammation, numerous T cells,eosinophils, plasma cells, and an eosinophilic and lymphoplasmacellular meningitis (ﬁgure 1,G–J). We diagnosed the patient with CNS manifestation of daclizumab-induced DRESS (drugreaction with eosinophilia and systemic symptoms) since 6 of 7 Registry of Severe CutaneousAdverse Reaction Criteria (RegiSCAR)1 for DRESS were fulﬁlled (positive: hospitalization,reaction suspected to be drug-related, fever >38°C, skin rash, internal organ involvement, bloodeosinophilia; negative: lymphadenopathy). Accordingly, the patient was treated with high-doseIV methylprednisolone (5 days with 1 g each) and 6 cycles of plasma exchange, followed by 1mg/kg oral prednisolone with subsequent tapering. Thereafter, the patient improved dra-matically and could be extubated 2 weeks after disease exacerbation. Postoperative diseasecourse was complicated by wound infection, bacterial meningitis, persisting CSF eﬀusion, andFrom the Department of Neurology (F.S., M.K., L.H., A.M.), Charite´—Universita¨tsmedizin Berlin; Institute of Neuropathology (I.M.), Universita¨tsmedizin Go¨ttingen, Go¨ttingen, Ger-many; Institute of Neuropathology (H.R.), Charite´—Universita¨tsmedizin Berlin, Institute of Neuroradiology (E.S.), Charite´—Universita¨tsmedizin Berlin; Department of Neurosurgery(S.W.), Charite´—Universita¨tsmedizin Berlin; NeuroCure Clinical Research Center (A.M.), Charite´—Universita¨tsmedizin Berlin; and Center for Stroke Research Berlin (F.S., A.M.),Charite´—Universita¨tsmedizin Berlin, Germany.Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article atNeurology.org/NN.The Article Processing Charge was funded by Charite´—Universita¨tsmedizin Berlin.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1obstructive hydrocephalus that required a ventriculoper-itoneal shunt. Four months later, neurologic syndromes withtetraparesis, choreoathetosis, cerebellar ataxia, and cognitivedysfunctions had regressed substantially (EDSS 3.5).DiscussionDaclizumab is approved for RRMS therapy since it revealedeﬃcacy by reducing relapse rates andMRI lesion load.2 It bindsto the interleukin-2 receptor and leads to reduction of activatedT cells and regulatory T cells and expansion of natural killercells.3,4 Common daclizumab side eﬀects comprise infections(59%), cutaneous (33%), gastrointestinal (25%), and hepaticdisorders (16%).5 Until recently, no persuasive evidence ofDRESS existed in daclizumab-treated patients,5 especially notwith CNS manifestation. Several drugs including immuno-modulators can trigger DRESS presenting with skin eruption,hematologic abnormalities, lymphadenopathy, and internalorgan involvement.6 DRESS usually develops with a latency of2 to 12 weeks after drug exposure showing often a prolongedcourse and can be lethal in;10% of cases. The pathogenesis ofDRESS remains unclear, but reactivation of herpesviridae andpharmacogenomic association with certain human leukocyteantigen haplotypes may cause the increased susceptibility toDRESS and its associated drug-speciﬁc immune dysfunction.6CNS DRESS is extremely rare and typically presents witha vasculitis-like pattern.7Core symptoms of our patient comprised fever, skin rash,blood eosinophilia, and eosinophilic meningoencephalo-myelitis. We diagnosed our patient with daclizumab-inducedDRESS with CNS manifestation since a recent publicationpresented 2 further cases of daclizumab-induced DRESS inMS.8 In line with our case, these patients showed similarclinical symptoms, fulﬁlled RegiSCAR criteria of DRESS, andwere characterized by the same unique histopathologic ﬁnd-ings with demyelinating lesions consisting of lympho-plasmacellular and eosinophilic inﬁltrates and a vasculitic-likepattern. Other diﬀerential diagnosis like parasitosis or neu-romyelitis optica (NMO) was excluded. NMO can showeosinophilic inﬁltrates in demyelinating lesions, but furtherNMO characteristics like aquaporin-4 loss, dystrophic astro-cytes, or loss of oligodendrocytes were missing, andaquaporin-4 antibody testing was negative in our patient.Although DRESS criteria were formally fulﬁlled, it remainsopen whether DRESS alone best explains pathophysiology orwhether other/further mechanisms are involved indaclizumab-induced immune dysfunction. In contrast toFigure Clinical presentation of daclizumab side effects with skin rash and meningoencephalomyelitis(A) Skin rash of the neckline. (B and C) MRI shows multiple actively contrast-enhancing MS-like lesions with distinct perifocal edema. (D and E) Additionallydiffuse cerebellar edema is present accompanied by infratentorial leptomeningeal enhancement indicative of meningeal and cerebellar inflammation.Resulting mass effect and occlusive hydrocephalus required suboccipital decompression (E). Also note simultaneous cervical cord inflammatory lesion. (F)Complete resolution of perifocal edema after disease remission. Note the right frontal hemorrhagic biopsy defect. (G–J) Biopsies of cerebellar meninges (G)and a right frontal lesion (H–J) show apronounced inflammatory infiltrate. HE staining depictsmeningitis with numerous T cells, plasma cells, and eosinophilicgranulocytes (G). Histology of the right frontal lesion reveals a demyelinated lesion (H). Again, dominant inflammation, consisting of CD4- and CD8-positiveT cells (I, anti-CD8), CD138-positive plasma cells (J, anti-CD138), and eosinophilic granulocytes, is evident. Inflammatory cells densely infiltrate vessel walls,resembling vasculitis. In addition, pronounced parenchymal inflammation is evident. HE = hematoxylin/eosin, LFB/PAS = luxol fast blue/periodic acid-Schiff.Scale bars: G = 100 μm, H = 1 mm, and I (valid for I and J) = 200 μm.2 Neurology: Neuroimmunology & Neuroinflammation | Volume 5, Number 5 | September 2018 Neurology.org/NNregular DRESS that barely aﬀects the CNS, daclizumab-induced DRESS seems to occur predominantly within theCNS. The cause of this idiosyncratic drug reaction remainsspeculative, but a certain genetic, viral, and autoimmunesusceptibility in the context of MS has to be considered. Atleast, a viral association (human herpes virus-6, cytomegalo-virus, and Epstein-Barr virus) of DRESS was excluded in ourcase.Currently, 12 cases (including our patient) of autoimmuneencephalitis/encephalopathy after daclizumab therapy in MSare known worldwide and led to voluntary withdrawal ofmarketing authorization for daclizumab by the manufacturerBiogen (press release from European Medicines Agency,07.03.2018).9Our ﬁndings suggest that early recognition of DRESS evenwith CNS manifestations and swift treatment with steroidsand/or plasma exchange are essential to improve the long-term outcome.Author contributionsF. Scheibe: patient care, data acquisition, analysis and in-terpretation of data, and writing of the manuscript. I. Metzand H. Radbruch: histopathologic analysis and writing of themanuscript. E. Siebert: neuroradiologic interpretation of dataand writing of the manuscript. S. Wolf and M. Ko¨hnlein:patient care and writing of the manuscript. L. Harms: criticalrevision of the manuscript for intellectual content. A. Meisel:patient care, writing of the manuscript, and critical revision ofthe manuscript for intellectual content.AcknowledgmentThe authors thank the patient for participation in the study.Study fundingThe authors acknowledge support from the Open AccessPublication Fund of Charite´—Universita¨tsmedizin Berlin.DisclosureF. Scheibe reports no disclosures. I. Metz served on the advi-sory board of Roche; received speaker honoraria and travelgrants from Biogen Idec, Bayer Healthcare, Teva, MerckSerono, Novartis, andGenzyme; and received research supportfrom Biogen Idec and German Ministry of Education andResearch. H. Radbruch received travel funding and/or speakerhonoraria from Novartis and Sanoﬁ and received researchsupport from Novartis, Sanoﬁ, and Deutsche For-schungsgemeinschaft. E. Siebert, S. Wolf, and M. Koehnleinreport no disclosures. L. Harms serves on the advisory board ofNovartis, Sanoﬁ/Genzyme, Roche, and Biogen and receivedspeaker honoraria and/or travel funding from Biogen, MerckSerono, Genzyme, Teva, Bayer Healthcare, Novartis, andGrifols. A. Meisel received speaker honoraria from Alexion andGrifols; served on the editorial board of PLoS One, Journal ofCerebral Blood Floow & Metabolism, and BMC Neurology;consulted for Alexion and Deutsche Myasthenie Gesellschaft;served on the speakers’ bureau of Frau Schneider GmbH; andreceived research support from Octapharma and DeutscheForschungsgemeinschaft NeuroCure Cluster of Excellence andCollaborative Research Centers and Bundesministerium fu¨rBildung und ForschungCenter for Stroke Research Berlin. Fulldisclosure form information provided by the authors is availablewith the full text of this article at Neurology.org/NN.Received March 19, 2018. Accepted in ﬁnal form May 29, 2018.References1. Kardaun SH, Sidoroﬀ A, Valeyrie-Allanore L, et al. Variability in the clinical pattern ofcutaneous side-eﬀects of drugs with systemic symptoms: does a DRESS syndromereally exist? Br J Dermatol 2007;156:609–611.2. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a inrelapsing multiple sclerosis. N Engl J Med 2015;373:1418–1428.3. Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56(bright) nat-ural killer cells mediate immunomodulatory eﬀects of IL-2Ralpha-targeted therapy(daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006;103:5941–5946.4. Elkins J, Sheridan J, Amaravadi L, et al. CD56(bright) natural killer cells and responseto daclizumab HYP in relapsing-remitting MS. Neurol Neuroimmunol Neuroinﬂamm2015;2:e65. doi: 10.1212/NXI.0000000000000065.5. Giovannoni G, Kappos L, Gold R, et al. Safety and tolerability proﬁle of daclizumab inpatients with relapsing-remitting multiple sclerosis: an integrated analysis of clinicalstudies. Mult Scler Relat Disord 2016;9:36–46.6. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review.Am J Med 2011;124:588–597.7. Gaha M, Landry D, Be´lair M, Paquet B, Chapdelaine H, Bard C. DRESS syndrome:cerebral vasculitic-like presentation. Neuroradiology 2015;57:1015–1021.8. Rauer S, Stork L, Urbach H, et al. Drug reaction with eosinophilia and systemicsymptoms after daclizumab therapy. Neurology 2018. Epub ahead of print.9. Press release by the European Medicines Agency (EMA): multiple sclerosis medicineZinbryta suspended in the EU. In: EMA Homepage [online]. Available at: ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Zinbryta/human_referral_prac_000074.jsp&mid=WC0b01ac05805c516f. Accessed March 7, 2018.Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 5, Number 5 | September 2018 3DOI 10.1212/NXI.00000000000004792018;5; Neurol Neuroimmunol Neuroinflamm Franziska Scheibe, Imke Metz, Helena Radbruch, et al. MSDrug reaction with eosinophilia and systemic symptoms after daclizumab therapy inThis information is current as of July 10, 2018ServicesUpdated Information & http://nn.neurology.org/content/5/5/e479.full.htmlincluding high resolution figures, can be found at:References http://nn.neurology.org/content/5/5/e479.full.html##ref-list-1This article cites 7 articles, 1 of which you can access for free at: Subspecialty Collections http://nn.neurology.org//cgi/collection/vasculitisVasculitis http://nn.neurology.org//cgi/collection/multiple_sclerosisMultiple sclerosis http://nn.neurology.org//cgi/collection/critical_careCritical care http://nn.neurology.org//cgi/collection/autoimmune_diseasesAutoimmune diseasesfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://nn.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://nn.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:Academy of Neurology.. All rights reserved. Online ISSN: 2332-7812.Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the AmericanPublished since April 2014, it is an open-access, online-only, continuous publication journal. Copyright is an official journal of the American Academy of Neurology.Neurol Neuroimmunol Neuroinflamm 

Drug reaction with eosinophilia and systemic symptoms after daclizumab therapy in MS

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Drug reaction with eosinophilia and systemic symptoms after daclizumab therapy in MS

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