Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations

Abstract

Objective: To report the frequency and type of antibodies against neuronal surface antigens (NSA-ab) in limbic encephalitis (LE).

Methods: Analysis of clinical features, neuropathologic findings, and detection of NSA-ab using immunochemistry on rat tissue and neuronal cultures in a series of 45 patients with paraneoplastic (23) or idiopathic (22) LE.

Results: NSA-ab were identified in 29 patients (64%; 12 paraneoplastic, 17 idiopathic). Thirteen patients had voltage-gated potassium channels (VGKC)-ab, 11 novel NSA (nNSA)-ab, and 5 NMDA receptor (NMDAR)-ab. nNSA-ab did not identify a common antigen and were more frequent in paraneoplastic than idiopathic LE (39% vs 9%; p = 0.03). When compared with VGKC-ab or NMDAR-ab, the nNSA associated more frequently with intraneuronal antibodies (11% vs 73%; p = 0.001). Of 12 patients (9 nNSA-ab, 2 VGKC-ab, 1 NMDAR-ab) with paraneoplastic LE and NSA-ab, concomitant intraneuronal antibodies occurred in 9 (75%). None of these 12 patients improved with immunotherapy. The autopsy of three of them showed neuronal loss, microgliosis, and cytotoxic T cell infiltrates in the hippocampus and amygdala. These findings were compatible with a T-cell mediated neuronal damage. In contrast, 13 of 17 (76%) patients with idiopathic LE and NSA-ab (8 VGKC-ab, 4 NMDAR-ab, 1 nNSA-ab) and 1 of 5 (20%) without antibodies had clinical improvement (p = 0.04).

Conclusions: In paraneoplastic limbic encephalitis (LE), novel antibodies against neuronal surface antigens (nNSA-ab) occur frequently, coexist with antibodies against intracellular antigens, and these cases are refractory to immunotherapy. In idiopathic LE, the likelihood of improvement is significantly higher in patients with NSA-ab than in those without antibodies.

Figure 1 Distribution of limbic encephalitis according to etiology and serum antibody reactivity NMDAR = NMDA receptor; NSA = neuronal surface antigens; VGKC = voltage-gated potassium channel.

Figure 2 Two sera with novel NSA antibodies as defined by the labeling of non-permeabilized rat hippocampal neurons (A, C) presenting different immunoreactivity on sections of rat brain (B, D) The first serum (A, B), which also had Hu antibodies as seen in the rat brain section, do not immunolabel the neuropil in contrast to the robust reactivity with the neuropil of the hippocampus of the second serum (C, D). Bar = 10 μm (A), 180 μm (B), 20 μm (C), 200 μm (D).

Figure 3 Photomicrographs of the hippocampus of the patient with isolated NMDAR-ab (A, B) and the patient with amhiphysin and nNSA-ab (C, D) There is mild neuronal loss in the pyramidal layer of the first patient (A), in contrast with the severe loss observed in the hippocampus of the patient with amhiphysin and nNSA-ab (C). Both hippocampi presented perivascular and parenchimatous infiltrates of CD3 + cells (T-cells) (B, D). However, Tia-1 + cells (cytotoxic T-cells) in close apposition with neurons were only observed in the hippocampus of the patient with amhiphysin and nNSA-ab (D, insert). Bar = 100 μm (A and C), 15 μm (B, D, and insert).