Cryptogenic NORSE

Takahiro Iizuka, MD, Naomi Kanazawa, BS, Juntaro Kaneko, MD, Naomi Tominaga, MD, Yutaka Nonoda, MD, Atsuko Hara, MD, Yuya Onozawa, PhD, Hiroki Asari, MD, Takashi Hata, MD, Junya Kaneko, MD, Kenji Yoshida, MD, Yoshihiro Sugiura, MD, PhD, Yoshikazu Ugawa, MD, PhD, Masashi Watanabe, MD, Hitomi Tomita, MD, Arifumi Kosakai, MD, Atsushi Kaneko, MD, Daisuke Ishima, MD, Eiji Kitamura, MD and Kazutoshi Nishiyama, MD, PhD. Cryptogenic NORSE.  Its distinctive clinical features and response to immunotherapy.  Neurol Neuroimmunol Neuroinflamm November 2017 vol. 4 no. 6 e396.  Published online September 25, 2017

ABSTRACT

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 study was 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-NORSE were 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 C-NORSE 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 a worse outcome. The C-NORSE score was 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.

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From the article:

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 children (DESC),4 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 inflammation-mediated 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 FIRES15 or NORSE16 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…

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/m2, monthly for 1–6 cycles] or rituximab [375 mg/m2, once weekly, 4 doses]), (4) chronic immunosuppression (prednisone, tacrolimus, cyclosporine, azathioprine, or mycophenolate mofetil), and (5) tumor resection when appropriate…

The first-line immunotherapy was considered “not effective” in 8 of the 10 treated patients, but IVCPA was presumed to be “effective” in 4 of the 5 treated patients who failed to respond to the first-line immunotherapy. In IVCPA-responsive 4 patients (#3, 5, 9, and 11), IVCPA was started between days 20 and 59, but nonresponsive patient (#4) received IVCPA on day 173. In patient 3, the first-line immunotherapy started on day 6; nevertheless, symmetric brain lesions developed (figure 2). Because NMDARE was initially suspected, IVCPA was started on day 20, followed by PLEX, and IVCPA was repeated on day 52 with the first-line immunotherapy, resulting in marked improvement with resolution of brain MRI abnormalities. The patient became able to walk without assistance 11 months after the symptom onset; IVCPA was considered effective. By contrast, patient 4 was admitted to a city hospital and treated with conventional AED treatment and IVMP started on day 3. However, the patient became a state of unresponsive wakefulness with diffuse brain atrophy. Five months later, the patient was transferred to our hospital and treated with IVCPA (day 173) combined with the first-line immunotherapy because we had a few successful experiences of immunotherapy initiated 8–12 months after the symptom onset in patients with NMDARE with diffuse brain atrophy.26 Gadolinium enhancement disappeared after the immunotherapy, but IVCPA was considered not effective because this patient's mental status remained unchanged. In the other 3 treated patients, IVCPA was presumed to be effective…

The first-line immunotherapies are usually not effective in patients with NORSE,3 FIRES,5 or AERRPS.6 Lack of response is consistent with the absence of NSA antibodies; however, inflammation-mediated epileptogenesis has increasingly been proposed. One study showed upregulation of interleukin (IL)-6, C-X-C motif chemokine 10, and IL-8 in CSF of patients with AERRPS, suggesting a role for the innate and adaptive immune system,35 since IL-6 is a booster of adaptive immune mechanisms while IL-8 and CXC-10 enhance the innate immunity; IVCPA exerts its main activity rather on the T-cells than on the B-cells. Although we did not examine CSF cytokine or chemokine levels in our cases, IVCPA might have some beneficial effects on inflammation-mediated mechanisms.

In practice, physicians must judge whether their patients with NORSE are cryptogenic or immune mediated based on initial clinical assessments because antibody testing results are usually not readily accessible. Therefore, we listed 8 distinctive features in table 2 and created the C-NORSE score. When the patient has 5 or more of the first 6 clinical features without etiology readily identified, NSA antibodies would be less likely detected, and conventional AED treatments would not be expected to provide remarkable beneficial effects. In our cases, all had 5 or more C-NORSE scores. This scoring strategy may help physicians to identify cryptogenic cases, but this scoring system should be validated in the different cohort in the future.

It is known that 80% of patients with NMDARE achieve a good outcome at 24 months.36 Such a good outcome and lack of evident brain damage on MRI are strongly related to early and intensive immunotherapy, and the absence of a substantial infiltration of the brain with inflammatory cells and the lack of complement activation may protect the brain from massive structural damage.37 However, epilepsy-related irreversible brain damage occurs quickly in C-NORSE; therefore, it may require more aggressive and early initiation of immunotherapy such as IVCPA than antibody-mediated encephalitis…

Many issues remain unknown, including etiology, epileptogenesis, and response to immunotherapy in C-NORSE. Genetic analysis was not performed in our patients. One might argue that these patients may include those with seronegative autoimmune limbic encephalitis or genetic epileptic disorder underdiagnosed or with some new antibodies not detected yet. We cannot rule out such possibilities. It remains to be determined whether early administration of IVCPA and IVMP or IVIg with conventional AED treatment would improve long-term outcomes. These issues should be addressed in the future.

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