To report the clinical features, immunotherapy, and outcome of patients with cryptogenic new-onset refractory status epilepticus (C-NORSE).

NORSE was recently defined as a clinical presentation, not a specific diagnosis (2018 Epilepsy). The term “C-NORSE” is used when the cause is unknown despite extensive work-up including neuronal surface antibodies (NS-Abs). The use of immunotherapy is controversial.

This study included 30 patients (median age 25 years [5-73]; female 17 [56.7%]) with 2018 consensus definition of C-NORSE who were recruited in 15 hospitals in Japan. All patients had serum and CSF (2 cases only CSF available) negative for NS-Abs including NMDAR, LGI1, CASPR2, GABAaR, GABAbR, AMPAR, mGluR5, and neurexin. Their clinical features were compared with those of 34 NS-Ab-positive controls (NMDAR [n=29], female 29 [85.3%]) who developed status epilepticus.

Compared with NS-Ab-positive controls, patients with C-NORSE were more likely to have prodromal fever, mechanical ventilatory support, and symmetric brain MRI abnormalities, and less likely to have dyskinesias, prodromal psycho-behavioral alterations, CSF oligoclonal bands, and an underlying tumor, but CSF pleocytosis was not different between them. In the C-NORSE group, 29 (96.7%) patients received first-line immunotherapy including high-dose steroids (n=29), immunoglobulins (n=26), plasma exchange (n=9), or combined, and 8 (26.7%) patients additionally received second-line immunotherapy (7 cyclophosphamide, 1 rituximab). First-line immunotherapy started a median of 2 days (0-33) after seizure onset, but 25/30 [83.3%] patients received < 1 week treatment. Second-line immunotherapy started a median of 27 days (11-58), but 3/30 [10.0%] received < 3 weeks treatment. Outcome was poor (defined as mRS≥3) in 22 (73.3%) patients at the last followed-up (median 12.5 months, range 2.2-111); the outcome was good in 8 (26.7%) (mRS≤2).

Some clinical features may initially suggest the diagnosis of C-NORSE rather than autoimmune encephalitis. Most patients with C-NORSE were initially treated with immunotherapy, and approximately one-fourth had good outcome.