Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies

Abstract

Background and objectives: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABA_BR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied.

Methods: Patients with GABA_BR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples.

Results: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs.

Discussion: Nonparaneoplastic GABA_BR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABA_BR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Figure 1. Flowchart

LEMS = Lambert-Eaton myasthenic syndrome.

Figure 2. Clinical Course Comparison of Paraneoplastic and Nonparaneoplastic GABA_BR-AE

IS = immunosuppressive, mRS = modified-Rankin scale. (A) Nonparaneoplastic forms of GABA_BR-AE occur in young adult women or middle-aged to elderly men, while paraneoplastic forms have a single incidence peak in the seventh decade of both sexes. After treatment, nonparaneoplastic cases evolve toward a better neurologic status (B) and have a better survival rate (C) within log-rank univariate analysis (p = 0.0048, data not shown) and Cox model multivariate analysis adjusted for confounding factors. Absence of tumor, lower age, and immunosuppressive drugs (second-line immunotherapy or chemotherapy) are associated with a better survival (D).

Figure 3. Bar Diagram Showing the Association of Paraneoplastic Cases With KCTD16-abs

Patients for which tumoral status could not be determined seem to have the same strong association with KCTD16-abs as paraneoplastic cases, suggesting an unfound malignancy.