Background and Aims

Neurological immune-related adverse events (N-irAEs) with varying frequency and severity have been reported in patients with cancer treated with immune-checkpoint-inhibitors (ICIs). Severe N-irAEs can be similar to paraneoplastic neurological syndromes, but their association with antineuronal antibodies is not well known.

To describe the neurological AEs after ICIs treatment, the frequency of antineuronal and glial antibodies and its clinical implication.

Methods

Case series studied in the laboratory of Hospital Clínic-IDIBAPS between Jan ‘18 and Oct ‘19. Onconeural, neuronal surface and glial antibody detection by rat brain immunohistochemistry, and confirmatory cell/immunoblot assays. Review of clinical features, type of cancer, ICI treatment and outcome.

Results

18 patients were referred from 10 different hospitals for antibody studies. 12 (67%) were men; median age 61.5 years (range 41-82). 12 (67%) had lung cancer, 3 melanoma, 1 prostate, 1 breast and 1 Hodgkin lymphoma. 6 (33%) patients received nivolumab, 5 (28%) pembrolizumab, 4 (22%) nivolumab + ipilimumab, 2 durvalumab and 1 atezolizumab. The clinical presentation was encephalitis/encephalopathy in 12 (67%), visual disturbances 2, encephalomyelitis 1, cerebellar ataxia 1, meningitis 1 and intestinal pseudo-obstruction 1. Anti-neural antibodies were detected in 5 (28%) patients: 1 anti-GABA_BR, 1 anti-Hu, 1 anti-Ma2 and 2 anti-GFAP. In 2 patients the antibodies were present before ICI initiation. The majority of cases received treatment with corticosteroids, with improvement of neurological symptoms.

Conclusions

Nearly 30% of patients with N-AEs have anti-neural antibodies, and their presence associates with characteristic clinical syndromes and suggests a paraneoplastic origin.

Background and Aims

Onconeural antibodies are well-known markers of paraneoplastic neurological syndromes (PNS). Antibody screening plays an important role in prompt tumour diagnosis because in up to 75% of patients the neurological symptoms precede the tumour diagnosis. Antibody detection based on brain tissue followed by antigen specific techniques, such as immunoblot, have demonstrated high sensibility and specificity for PNS. For practical reasons many clinical diagnostic laboratories use only immunoblot for onconeural antibody testing.

To assess the PNS-specificity of immunoblot for onconeural antibody testing.

Methods

We reviewed all the patients tested for onconeural antibodies from October 1, 2016 until August 31, 2019 by an in-house immunohistochemistry on paraformaldehyde perfused rat cerebellum and by a commercial line blot assay (PNS12 Euroline Blot, Euroimmun). Reasons for additional testing by blot were confirmation of a suspicious positive result by immunohistochemistry or specific request to test the sample by line blot.

Results

96 patients’ sera showed positive bands for onconeural antibodies using immunoblot. Immunoblot bands matched with the brain immunohystochemical findings in 45 patients (46.9%) whereas the other 51 (53.1%) showed discordant results. Clinical information was available in 45 and 46 patients respectively. 40 (88.9%) of the 45 patients with concordant immunoblot and immunohistochemistry results had PNS, whereas only 4 (8.7%) of the 46 patients with discordant results had PNS. Discordant results were more common with Yo (70%) and Zic4 (74%) antibodies.

Conclusions

Onconeural antibody testing by immunoblot is highly sensitive but shows low specificity for the diagnosis of PNS. This low specificity is more prominent for Yo and ZIC4 antibodies.