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

Case report

In 2012, a 33-year-old woman was diagnosed with relapsing-remitting MS (RRMS) after fulfilling 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-like symptoms) and dimethyl fumarate (erythema and pruritus) to daclizumab. Two months after 2 applications of 150 mg daclizumab, she developed a self-limiting rash (figure 1A), followed by fever, headaches, meningismus, photophobia, nausea, paraesthesia, and itching of her upper body 1 month later. Blood test showed decreased lymphocyte counts of 1.7/μL (17.1%) and increased 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 intrathecal immunoglobulin synthesis (IgM 85%, IgA 43%, and IgG 38%). MRI showed periventricular contrast-enhancing lesions and a multisegmental cervical myelitis (C1–4). After 10 days, she further deteriorated by severe infratentorial edema with compression of the fourth ventricle and obstructive hydrocephalus (figure 1, B–F). At admission to our hospital, she obtained an external ventricle drainage showing normal opening pressure. Two days later, she had sudden increase in intracranial pressure requiring intubation and emergency decompressive surgery of the posterior fossa. Increased intracranial pressure (up to 40 mm Hg) due to global brain edema and subsequently complicated by a postoperative bleeding into the right frontal lobe after a brain biopsy (see below) was controlled by CSF drainage, deep analgosedation, dexamethasone, and osmotherapy. The atypical clinical picture with brain edema, rhombenecephalitis, and high CSF cell count was incompatible with MS relapse as initially suggested by the periventricular lesions and cervical myelitis. Because careful examinations revealed no other autoimmune or infectious diseases, we initially treated polypragmatically with aciclovir/ganciclovir, ceftriaxone/ampicillin, voriconazole/posaconazole, and IV immunoglobulins. Brain biopsies of the right frontal lobe, cerebellum, and cerebellar leptomeninges showed 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 (drug reaction with eosinophilia and systemic symptoms) since 6 of 7 Registry of Severe Cutaneous Adverse Reaction Criteria (RegiSCAR)¹ for DRESS were fulfilled (positive: hospitalization, reaction suspected to be drug-related, fever >38°C, skin rash, internal organ involvement, blood eosinophilia; negative: lymphadenopathy). Accordingly, the patient was treated with high-dose IV methylprednisolone (5 days with 1 g each) and 6 cycles of plasma exchange, followed by 1 mg/kg oral prednisolone with subsequent tapering. Thereafter, the patient improved dramatically and could be extubated 2 weeks after disease exacerbation. Postoperative disease course was complicated by wound infection, bacterial meningitis, persisting CSF effusion, and obstructive hydrocephalus that required a ventriculoperitoneal shunt. Four months later, neurologic syndromes with tetraparesis, choreoathetosis, cerebellar ataxia, and cognitive dysfunctions had regressed substantially (EDSS 3.5).

• Download figure
• Open in new tab
• Download powerpoint

Figure 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) Additionally diffuse 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 a pronounced inflammatory infiltrate. HE staining depicts meningitis with numerous T cells, plasma cells, and eosinophilic granulocytes (G). Histology of the right frontal lesion reveals a demyelinated lesion (H). Again, dominant inflammation, consisting of CD4- and CD8-positive T 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.