Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes

Abstract

Seronegative autoimmune encephalitis (AE) is AE without any identifiable pathogenic antibody. Although it is a major subtype of AE, many unmet clinical needs exist in terms of clinical characteristics, treatments, and prognosis. In this institutional cohort study, patients diagnosed with seronegative AE with available 2-year outcomes were analysed for the disease course, 2-year outcome prediction system, effect of immunotherapy, necessity of further immunotherapy at 6 or 12 months, and pattern of brain atrophy. Seronegative AE was subcategorized into antibody-negative probable AE (ANPRA), autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Poor 2-year outcome was defined by modified Rankin scale [mRS] scores 3‒6, and the 2-year serial data of Clinical Assessment Scales in Autoimmune Encephalitis (CASE) score was used for longitudinal data analyses. A total of 147 patients were included. The frequency of achieving a good 2-year outcome (mRS 0‒2) was 56.5%. The ANPRA subtype exhibited the poorest outcomes, although the baseline severity was similar among the subtypes. The RAPID score, consisting of five early utilizable clinical factors, refractory status epilepticus, age of onset ≥ 60 years, probable AE (ANPRA subtype), infratentorial involvement, and delay of immunotherapy ≥ 1 month, was associated with poorer 2-year outcomes. Any immunotherapy was associated with clinical improvement in the patients with low risk for poor 2-year outcomes (RAPID scores 0–1), and the combination immunotherapy of steroid, immunoglobulin, rituximab, and tocilizumab was associated with better outcomes in the patients with high risk for poor 2-year outcomes (RAPID scores 2-5). In patients with persistent disease at 6 months, continuing immunotherapy was associated with more improvement, while the effect of continuing immunotherapy for more than 12 months was unclear. In the longitudinal analysis of MRI, the development of cerebellar atrophy indicated poor outcomes, while the absence of diffuse cerebral atrophy or medial temporal atrophy indicated the possibility of a good outcome. This study provides information about the clinical characteristics and courses, the effect of immunotherapy and its duration, and prognostic factors in seronegative AE.

Seronegative autoimmune encephalitis: exploring the unknown

“…Twenty-three patients with seronegative definite autoimmune LE were described by Lee et al , 3 and 2-year outcomes were better in this subgroup (78%) than among patients with ANPRA. In an earlier study of 12 patients with seronegative definite autoimmune LE, treatment outcomes were worse, with only half of patients showing improvement after immunotherapy.…”

“…However, descriptions of the clinical features and underlying pathogenic mechanisms of seronegative AE are limited. In this issue of Brain , Lee and colleagues 3 provide the first extensive description in a large cohort of the clinical features, treatment response and prognosis of seronegative AE.…”

“…An alternative potential explanation is the contribution of T cell-mediated neuronal cytotoxicity, as seen in syndromes with classical onconeuronal autoantibodies, which are strongly associated with cancer. Intriguingly, an underlying malignancy was identified in only three of 147 patients in the study by Lee et al ., 3 but T cell-mediated cytotoxicity is still likely in a subset of patients with ANPRA.…”

“…Lee et al . 3 present an easily assessable 2-year outcome scoring system (RAPID score), including five factors: refractory status epilepticus (RSE), age of onset ≥60, ANPRA subtype, infratentorial involvement and delay of immunotherapy ≥1 month. The RAPID score correlated particularly well with 2-year outcome in the ANPRA and LE subtypes.…”

“…The beneficial effect of second-line immunotherapy has been demonstrated previously in anti-NMDAR encephalitis, with second-line treatment found to be effective if first-line immunotherapy had failed. 6 However, it remains questionable whether similar conclusions about second-line immunotherapy in seronegative AE can be drawn based on the LMM, as Lee and colleagues 3 also acknowledge in their discussion. The same patients were categorized in the same order in different treatment groups (first-line and second-line immunotherapy) and were compared with each other in the model, while time is also an important factor for follow-up prediction.…”