GFAPα IgG-associated encephalitis upon daclizumab treatment of MS

Case report

We describe a 32-year-old Caucasian man with the first onset of RRMS in 2013 presenting with sensory spinal syndrome below thoracic vertebra (Th) 7. MRI scans showed disseminated cerebral and spinal lesions including 2 asymptomatic contrast-enhancing left parietal lesions. Analysis of CSF showed pleocytosis with 14 white blood cells (WBCs)/μL (100% mononuclear cells) and the presence of oligoclonal bands. Differential diagnoses were tested for and thus ruled out. The diagnosis of RRMS was therefore made according to McDonald Criteria 2010. Treatment with interferon β-1a (Avonex; Biogen, Cambridge, MA) was initiated. Because of clinical and paraclinical disease activity, therapy was escalated to dimethyl fumarate (Tecfidera; Biogen, Cambridge, MA) in September 2016 (figure 1A). Because of gastrointestinal side effects under dimethyl fumarate, daclizumab therapy was started in December 2016. The recommended blood examinations were uneventful.

Figure 1 MRI findings over time

(A) Upper row: FLAIR axial images show progressive white matter lesions without contrast enhancement and distinct cerebral atrophy. Middle row: T1Gd-weighted images show no gadolinium enhancement. Lower row: T2-weighted sagittal images. A prominent radial pattern within T2-weighted axial pictures resembles a previously published patient with glial fibrillary acidic protein meningoencephalitis with a radial pattern of periventricular gadolinium enhancement. (B) T2-weighted sagittal images before daclizumab therapy and during encephalitic illness. T2-weighted axial image shows new focal gliosis at Th 3/4. FLAIR = fluid attenuated inversion recovery; Gd = gadolinium; Th = thoracic vertebra.

In August 2017, the patient demonstrated aggressive behavior and occasionally expressed suicidal thoughts. Because of fluctuating dysarthria, progressive memory loss, fatigue, and depression, the patient was admitted to our hospital in December 2017. On initial examination, the patient was afebrile and demonstrated perceptive impairment, confusion, incoherent thoughts, and delusions. Neurologic examination revealed ataxia and nystagmus. His blood tests and differential blood count were normal. Lymphocyte subset analysis revealed values within the range of untreated patients with RRMS.² The MRI scan showed a new juxtacortical right frontal lesion and a new focal gliosis at Th 3/4 (figure 1B), both without contrast enhancement. Electroencephalography showed moderately severe encephalopathy with generalized theta activity. A lumbar puncture revealed 74 WBC/μL (100% mononuclear cells), a CSF protein level of 61.5 mg/dL, and a CSF lactate level of 2.7 mmol/L. Oligoclonal bands and intrathecal immunoglobulin A (IgA) synthesis were present (figure 2A). Diagnostic tests (detailed in Supplement, links.lww.com/NXI/A60) did not disclose any infectious agent. Immunostaining of rat hippocampal tissue exhibited GFAP immunoglobulin G (IgG) antibodies in CSF (figure 2B, diagnostic laboratory of Euroimmun AG; Lübeck, Germany). GFAP antibodies could not be detected in serum (figure 2C). Antigen specificity was further confirmed by GFAPα-transfected HEK293 cell-based assay. Patient GFAP-IgGs reacted with GFAPα isoform (figure 2D), whereas no reaction was observed on control-transfected cells (figure 2E).

Figure 2 Overview of the patient's history and immunofluorescence pattern of patient CSF IgG

(A) Disability assessed by the EDSS is displayed as a blue line. Clinical relapses and MRI activity (red arrows) are indicated. Duration of immunomodulatory treatments is depicted with lines of different colors on the top of the diagram. (B) Distribution of patient CSF IgG (green) in the rat hippocampus parenchyma is consistent with astrocytes (arrows). (C) Absence of specific patient serum IgG binding (diluted 1:100, green) in the brain parenchyma. (D) Antigen specificity of CSF IgG was further confirmed by glial fibrillary acidic protein α-transfected HEK293 cell-based assay CBA. (E) Absence of CSF IgG binding on control-transfected cells. Scale bars: 20 μm (B–E). DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; IgG = immunoglobulin G; WBC = white blood cell.

Magnetic resonance (MR) angiography did not show vascular abnormalities, but it demonstrated a slight brain edema as volume increase in comparison to pre-MRI from 2016 (figure 1B). An additional 18F-Fluorodeoxyglucose (FDG)-PET scan revealed no evidence of tumors. Chest CT findings were normal.

With a diagnosis of autoimmune GFAPα astrocytopathy, we started treatment with 1,000 mg methylprednisolone/d, followed by 5 courses of plasma exchange every other day. The patient gradually improved while methylprednisolone was continued with 100 mg/d orally and tapered over time. Neuropsychologic examination thereafter demonstrated ongoing impairment in all cognitive domains including attention span, attention selectivity, information processing, short-term memory, verbal and figural long-term memory, and executive functions. However, there were no incoherent thoughts or noticeable behavioral disturbances, no signs of depression, and no ataxia.

Despite the clinical improvement, the follow-up MRI in March 2018 showed, apart from a reduction in swelling, progressive non–contrast-enhancing white matter lesions with a prominent radial pattern, which resembles a previously published patient with GFAP meningoencephalitis.³ Follow-up CSF analysis revealed 39 WBC/μL, persistent intrathecal synthesis of IgA, but normal CSF protein and lactate levels.

In the context of MRI results and persistent CSF pleocytosis under continuous steroid therapy, treatment with rituximab (MabThera; Roche, Basel, BS) was added. This led to a stabilization of the clinical status. Although neuropsychologic testing in general still showed significant deficits, the performance in some cognitive domains had improved. Currently, the patient is capable of participating in daily life activities again. Anonymized data will be shared on request from any qualified investigator.