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. 2024 Jun;31(6):e16273.
doi: 10.1111/ene.16273. Epub 2024 Mar 11.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles

Georgios Mangioris  1 , Thorvardur R Halfdanarson  2 , Vanda A Lennon  1   3   4 , Bryce K Chang  3 , Divyanshu Dubey  1   3   5 , P James B Dyck  3 , Eoin P Flanagan  1   3   5 , Andrew McKeon  1   3   5 , John R Mills  1 , Sean J Pittock  1   3   5 , Anastasia Zekeridou  1   3   5
Affiliations

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles

Georgios Mangioris et al. Eur J Neurol. 2024 Jun.

Abstract

Background and purpose: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs).

Methods: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116).

Results: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome.

Discussion: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.

Keywords: carcinoid; cerebellar ataxia; encephalitis; myasthenia gravis; paraneoplastic syndromes.

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Conflict of interest statement

Georgios Mangioris, Bryce K. Chang, P. James B. Dyck have no relevant financial or non‐financial interests to disclose. Thorvardur R. Halfdanarson has received research support from Thermo Fisher Scientific, Advanced Accelerator Applications, Camurus, Crinetics, and ITM Isotopen Technologien Muenchen and has consulted or has been a part of an Advisory Board or Steering Committee for Ipsen, TerSera, Advanced Accelerator Applications, ITM Isotopen Technologien Muenchen, Crinetics, Viewpoint Molecular Targeting, and Camurus. Vanda A. Lennon receives royalties derived from Mayo Clinic licensing of tests for AQP4‐IgG testing performed outside Mayo Clinic as a diagnostic aid for neuromyelitis optica spectrum disorder. Divyanshu Dubey has consulted for UCB, Astellas, Argenx, Immunovant, and Arialys Pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He has patents pending for KLHL11–IgG, LUZP4–IgG and CAVIN4–IgG as markers of neurological autoimmunity. Eoin P. Flanagan serves on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB; has received speaker honoraria from Pharmacy Times; has received royalties from UpToDate; has been primary investigator in a randomized clinical trial on inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela‐Bio/Horizon Therapeutics; has received funding from the NIH (R01NS113828); has been a member of the medical advisory board of the MOG project; and has been an editorial board member for the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1–IgG as a biomarker of paraneoplastic autoimmunity. Andrew McKeon has received research funding from Alexion, Grifols and Viela Bio/MedImmune and has patents pending for IgGs as biomarkers of autoimmune neurologic disorders (septin‐5, kelch‐like protein 11, GFAP, PDE10A and MAP1B). John R. Mills holds patents on the use of mass spectrometry to measure monoclonal immunoglobulins and receives royalties related to these patents from the Binding Site. Sean J. Pittock reports grants, personal fees and nonfinancial support from Alexion Pharmaceuticals; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, nonfinancial support and other from Horizon Therapeutics (formerly from Viela Bio and MedImmune); personal fees for consulting services from Astellas; grants, personal fees, nonfinancial support and other from Roche/Genentech; and personal fees for consulting services from UCB; and has patent #9,891,219 (application #12–573,942), “Methods for treating neuromyelitis optica (NMO) by administration of eculizumab to an individual that is aquaporin‐4 (AQP4)‐IgG autoantibody positive”. Anastasia Zekeridou has patents submitted for PDE10A‐IgG, Tenascin‐R‐IgG and DACH1‐IgG as biomarkers of neurological autoimmunity, has consulted for Alexion Pharmaceuticals without personal compensation and has received research funding from Roche/Genentech not relevant to this work.

Figures

FIGURE 1
FIGURE 1
Clinical manifestations and neural autoantibody positivity rate of NEN‐associated neurological autoimmunity. Cumulative frequency of clinical manifestations in all patients (dark blue); frequency in ICI‐related cases (orange). *Two patients had intestinal pseudo‐obstruction (one was ICI‐related). †One patient had sensory ganglionopathy. Cranial neuropathy cases are shown separately. HMD, hyperkinetic movement disorder; ICI, immune checkpoint inhibitor; LEMS, Lambert–Eaton myasthenic syndrome; NEN, neuroendocrine neoplasm.
FIGURE 2
FIGURE 2
Ancillary testing results in NEN patients with neurological autoimmunity. (a) Spinal cord MRI in a patient with multifocal myeloradiculopathy with multilevel T2 hyperintensities (i) and gadolinium enhancement (ii), (iii). (b) Brain MRI with faint fluid‐attenuated inversion recovery hyperintensity in the right hippocampus in a patient with limbic encephalitis who was seropositive for GABABR and ANNA‐1 IgGs. (c) Thermoregulatory sweat test results in a patient with cerebellar ataxia and dysautonomia associated with NIF IgG, before (left) and after (right) corticosteroid therapy. Anhidrosis is indicated by lack of blue dye color change in skin, reflecting failure of sweat release. Anhidrosis was improved by therapy (decreased from 90.2% to 70.6%). (d) Thermoregulatory sweat test results in a patient with ICI‐associated dysautonomia before (left) and after (right) corticosteroid therapy and ICI discontinuation. Anhidrosis decreased from 74.1% to 10.4%. (e) Nerve biopsy of patient with vasculitic neuropathy presenting as mononeuritis multiplex with cranial nerve involvement. Sural nerve biopsy paraffin hematoxylin and eosin (i) and CD45 (ii) stained sections showed microvasculitis. Semithin epoxy sections showed active axonal degeneration and thickened perineurium (iii), (iv). ANNA‐1, anti‐neuronal nuclear antibody type 1; GABABR, γ‐aminobutyric acid‐B receptor; ICI, immune checkpoint inhibitor; IgG, immunoglobulin G; MRI, magnetic resonance imaging; NEN, neuroendocrine neoplasm; NIF, neuronal intermediate filament.
FIGURE 3
FIGURE 3
Neural autoantibody positivity rate in NEN patients with and without neurological autoimmunity. ‡The serum level in one patient (with neurological autoimmunity) was 1880 nmol/L (cerebrospinal fluid was also positive [1.09 nmol/L]). Serum levels in all other patients were <20 nmol/L (range 0.04–6.42 nmol/L); values <20 nmol/L were not included in the comparison as they are not predictive of neurological autoimmunity. §Statistically significant difference between the two groups. ‖All patients had low positive values 0.04 (two), 0.11 (two), 0.15 nmol/L (normal value ≤0.02 nmol/L). ANNA, anti‐neuronal nuclear autoantibody; CASPR2, contactin‐associated protein‐like 2; GABABR, γ‐aminobutyric acid‐B receptor; gAChR, ganglionic α3 nicotinic acetylcholine receptor; GAD65, glutamic acid decarboxylase 65; mAChR, muscle nicotinic acetylcholine receptor; NEN, neuroendocrine neoplasm; NIF, neuronal intermediate filament; TRIM46, tripartite motif containing 46; UNA, unclassified neural autoantibody; VGCC‐P/Q, voltage‐gated calcium channel, P/Q‐type.
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