Cryptogenic NORSE

Objective: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments. Methods: A retrospective studywas conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSEwere identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE). Results: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6–111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with CNORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had aworse outcome. TheC-NORSE scorewas higher in patients with C-NORSE than those with NMDARE. Conclusions: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy. Neurol Neuroimmunol Neuroinflamm 2017;4:e396; doi: 10.1212/NXI.0000000000000396 GLOSSARY AE 5 autoimmune encephalitis; AED 5 antiepileptic drug; AERRPS 5 acute encephalitis with refractory repetitive partial seizures; AMPAR 5 a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; C-NORSE 5 cryptogenic new-onset refractory status epilepticus; DESC 5 devastating epileptic encephalopathy in school-age children; FIRES 5 febrile infectionrelated epilepsy syndrome; GABAaR 5 g-aminobutyric acid A receptor; GABAbR 5 g-aminobutyric acid B receptor; GCSE 5 generalized convulsive status epilepticus;HSV5 herpes simplex virus; IL5 interleukin; IVCPA5 IV cyclophosphamide; IVIg5 IV immunoglobulin; IVMP 5 IV high-dose methylprednisolone; LGI1 5 leucine-rich glioma-inactivated 1; mRS 5 modified Rankin Scale; NMDARE 5 anti-NMDA receptor encephalitis; NSA 5 neuronal cell-surface antigen; OCB 5 oligoclonal band; PLEX 5 plasma exchange; RSE 5 refractory status epilepticus; SE 5 status epilepticus; STESS 5 Status Epilepticus Severity Score. New-onset refractory status epilepticus (NORSE) is a rare but neurologic emergency condition characterized by refractory status epilepticus (RSE) without readily identifiable cause in otherwise healthy individuals. “NORSE” is currently viewed as a syndrome, not a distinct entity, and has received several names, including devastating epileptic encephalopathy in school-age From the Department of Neurology (T.I., N.K., J.K., N.T., A.Kaneko, D.I., E.K., K.N.), Department of Pediatrics (Y.N.), and Department of Pathology (A.H.), Kitasato University School of Medicine; Department of Clinical Laboratory (Y.O.), Kitasato University Hospital, Sagamihara, Japan; Department of Neurology (H.A., T.H.), Shizuoka City Shimizu Hospital, Shizuoka, Japan; Department of Emergency and Critical Care Medicine (J.K.), Nippon Medical School Tama Nagayama Hospital, Tama, Japan; Department of Neurology (K.Y., Y.S., Y.U.), School of Medicine, Fukushima Medical Hospital and Fukushima Global Medical Science Center (Y.U.), Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan; Department of Neurology (M.W., H.T.), Ehime Prefectural Central Hospital, Matsuyama, Japan; and Department of Neurology (A.Kosakai), Keiyu Hospital, Yokohama, Japan. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors. 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 downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Neurology.org/nn Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 children (DESC), febrile infection-related epilepsy syndrome (FIRES), acute encephalitis with refractory repetitive partial seizures (AERRPS), or NORSE. DESC, FIRES, and AERRPS are terms more frequently used in pediatric patients, whereas NORSE is more frequently used in adults. The concept of “acute encephalopathy with inflammationmediated status epilepticus (AEIMSE)” has also been proposed. Since the discovery of autoimmune encephalitis (AE) and autoantibodies against neuronal cell-surface antigens or synaptic proteins (NSA antibodies), a few cases of FIRES or NORSE associated with NSA antibodies have been documented. Furthermore, a recent large cohort demonstrated that a half of 130 patients with NORSE remained cryptogenic, but 37% were immune mediated; among those, the most common etiology was anti-NMDA receptor (NMDAR) encephalitis (NMDARE). Therapeutic approach with IV cyclophosphamide (IVCPA) has also been proposed in even cryptogenic cases. However, only 1 of 63 patients (2%) with cryptogenic NORSE (C-NORSE) received IVCPA in the cohort. In an emergency condition, antibody testing results may not be readily accessible, but it is important to differentiate C-NORSE from antibody-mediated encephalitis at an early stage. Here, we report its distinctive clinical features and the C-NORSE score based on initial clinical assessments with conventional diagnostic tests and discuss the potential efficacy of IVCPA. METHODS Patient selection and antibody assays. A retrospective observational study was conducted in the Department of Neurology at Kitasato University. We first reviewed the clinical information of 136 patients with clinically suspected AE who underwent testing for NSA antibodies between January 1, 2007, and August 31, 2016 to make a diagnosis. These patients were admitted to Kitasato University Hospital or other academic or referral hospitals between January 1, 1999, and August 31, 2016; in 7 patients admitted to Kitasato University Hospital before January 1, 2007, archived serum/CSF samples obtained at symptom presentation were used for antibody assays. NSA antibodies were measured in all patients at the laboratory of Josep Dalmau (University of Barcelona) using both immunohistochemistry on rat brain tissue and cell-based assays; they included antibodies to the NMDAR, a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR), g-aminobutyric acid B receptor (GABAbR), g-aminobutyric acid A receptor (GABAaR), metabotropic glutamate receptor (mGluR) 1, contactin-associated protein-like 2, dipeptidyl peptidase-like protein 6, and leucine-rich glioma-inactivated 1 (LGI1). Both serum and CSF were examined in all patients except 3 patients (CSF was not available). NSA antibodies were detected in 39 patients; they included antibodies to NMDAR (n 5 33), AMPAR (n 5 3), LGI1 (n 5 2), GABAbR (n 5 1), GABAaR (n 5 1), and unknown antigens (n 5 2); however, 2 patients had multiple NSA antibodies (appendix e-1 at Neurology.org/nn). The other 2 developed autoimmune post–herpes simplex virus (HSV) encephalitis associated with NSA antibodies (NMDAR [n 5 1], unknown antigens [n 5 1]). The remaining seronegative 97 patients underwent further investigations for viral infection, collagen vascular disorders or other systemic autoimmune disorders, malignancy survey, or brain or skin biopsy when appropriate. After reasonable exclusion of alternative causes (appendix e-1), we identified 11 patients with C-NORSE. The final diagnoses of the seronegative 97 patients were described in appendix e-1. Criteria for C-NORSE. Patients were diagnosed with C-NORSE if those fulfilled the following 4 criteria: (1) age 17 years or older, (2) new-onset RSE in previously healthy individual, (3) refractoriness to conventional antiepileptic drug (AED) treatment, and (4) no etiology identified throughout the course of the disease. Status epilepticus (SE) was considered as refractory when it continued longer than 60 minutes, despite adequate administration of benzodiazepines and an adequate loading of standard IV AEDs. The etiology of NORSE was extensively investigated with CSF examination, malignancy survey, and serologic testing, including autoantibodies to NSA and classic paraneoplastic intracellular antigens (CV2/CRMP5, Ma2, Ri, Yo, Hu, GAD65, and amphiphysin), which were measured in serum with EUROLINE (Euroimmun AG). Treatment modalities. The treatment strategy was decided by individual patients’ physicians. Treatments were classified into (1) conventional AED treatment (AED, and continuously infused anesthetic agents [midazolam, propofol, thiopental, thiamylal, phenobarbital, or pentobarbital]), (2) the first-line immunotherapy (IV high-dose methylprednisolone [IVMP], 1,000 mg/day, for 3–5 days; IV immunoglobulin [IVIg], 0.4 g/ kg/day for 5 days; and plasma exchange [PLEX] alone or combined), (3) the second-line immunotherapy (IVCPA [500 mg/ m, monthly for 1–6 cycles] or rituximab [375 mg/m, once weekly, 4 doses]), (4) chronic immunosuppression (prednisone, tacrolimus, cyclosporine, azathioprine, or mycophenolate mofetil), and (5) tumor resection when appropriate. Outcome criteria and evaluation of clinical features. The primary outcome was neurologic disability evaluated by the modified Rankin Scale (mRS) at the last follow-up period. Good outcome was defined as an mRS score of 0–2, and poor outcome was defined as an mRS score of 3 or higher. The SE severity score (STESS) at the onset of SE was obtained in patients with CNORSE. The clinical features of 11 patients with C-NORSE were compared with those of 32 patients with NMDARE as a disease control. One patient with autoimmune post-HSV encephalitis with NMDAR antibodies was excluded because depression was the sole symptom. The other 6 seropositive patients were also excluded because of the small sample size of each antibody group. None of these 6 patients developed EEG-confirmed RSE. Response to immunotherapy. In patients with C-NORSE, individual patients’ physicians (authors) were requested to report whether their patients responded to immunotherapy or not, with 2 Neurology: Neuroimmunology & Neuroinflammation either “yes” or “no” based on reduction in seizure frequency, decrement of IV anesthetic drugs, mental status improvement, or resolution of MRI abnormalities. Response of seizure to immunotherapy was not evaluated in the disease control because only 6 of the 32 patients with NMDARE developed EEGconfirmed SE. Standard protocol approvals, registrations, and patient consents. This study was approved by Institutional Review Boards of Kitasato University (B16-148). Written or oral informed consent was obtained from the patients or their family members. Information on symptoms, CSF, MRI, EEG, treatments, outcomes, and response to immunotherapy, were obtained from the authors or referring physicians. Statistical analysis. The Fisher exact test was performed for comparison of categorical variables, and the Mann-Whitney test was used for continuous variables. The statistical significance was set at p, 0.05. We used JMP, version 11.2.0 (SAS Institute Inc.) for statistical analyses. RESULTS Clinical and paraclinical features of patients with C-NORSE. Eleven patients with C-NORSE were identified; 7 patients (64%) were women; median age at symptom onset was 27 years (range, 17–59 years). Clinical information is shown in tables 1, e-1 and e-2. The STESS was median 3 (range, 2–3). Three patients had a family history of febrile convulsion or seizure, and 1 had a history of febrile convulsion (table e-1). All patients had prodromal symptoms; among those, high fever of unknown origin was most frequently seen in 10 patients (91%), and headache in 6 (55%). Following prodromal symptoms, generalized convulsive SE (GCSE) developed within median 5 days (range, 4–14 days), but none of the 11 patients had psychobehavioral or memory symptoms before the onset of epileptic seizures. CSF examination revealed mild inflammatory changes (median white blood cells 6/mL [range, 1– 224/mL]), but 5 patients (45%) had no pleocytosis. The protein level was mildly elevated. Oligoclonal bands (OCBs) were not detected in 10 examined patients, and the IgG index was elevated in only 1 of 7 patients. No tumor was found in any individual. Brain MRIs were normal or nonspecific at the onset of SE, but follow-up MRIs showed symmetric increased diffusion-weighted images or T2/fluidattenuated inversion recovery signals in the hippocampus, amygdala, insula, claustrum, thalamus, perisylvian operculum, and basal ganglia in 8 patients (73%) (figures 1 and 2, e-1). These MRI changes developed along with persistent seizure activity (figure e-2). Diffuse or frontotemporal atrophy developed in 9 patients (82%) and cerebellar atrophy in 3 (patients 1, 7, and 9). GCSE that often began with facial twitching was highly refractory to the first-line and second-line AEDs and required continuous infusion of anesthetic drugs with mechanical ventilatory support. All patients were initially treated with IV acyclovir for possible HSV encephalitis, but HSV-DNA was not Table 1 Comparison of clinical features between C-NORSE and NMDARE C-NORSE (n 5 11) NMDARE (n 5 32) p Value Sex (female) 7 (64%) 24 (75%) 0.467 Median age at symptom onset, y 27 (17–59) 27 (12–47) 0.549 Prodromal symptoms 11 (100%) 27 (84%) 0.306 Headache 6 (55%) 18 (56%) 1.000 Fever 10 (91%) 12 (38%) 0.004 Initial psychiatric or memory alterations 0 (0%) 30 (94%) ,0.0001 Seizures 11 (100%) 28 (88%) 0.558 GCSE or NCSE 11 (100%) 6 (19%) ,0.0001 Mechanical ventilatory support 11 (100%) 22 (69%) 0.043 Involuntary movements 3 (27%) 30 (94%) ,0.0001 Symmetric brain MRI abnormalities 8 (73%) 5 (16%) 0.001 EEG abnormalities 11 (100%) 28/30 (93%) 1.000 Serum thyroid (Tg or TPO) antibodies 1/9 (11%) 1/16 (6%) 1.000