Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study

Abstract

Introduction: Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. Methods: We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. Results: In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. Discussion: The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.

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

“…We describe the neurological associations and neural autoantibody accompaniments of non-pulmonary NENs in a cohort of 34 patients, expanding the spectrum of neurological presentations and neural autoantibodies observed in patients with NENs [20,29]. The identified primary cancer sites were diverse and frequently included some that may be neglected during search for an underlying malignancy (e.g., Merkel cell carcinoma, small intestine NENs).…”

“…In contrast, neural autoantibodies that are not included in the current iteration of the paraneoplastic neurological syndrome diagnostic criteria, but that are highly predictive of cancer and their expression has been demonstrated in neuroendocrine tumors, such as ANNA-3/ DACH-1-IgG, NIF-IgG, and TRIM46-IgG, were more commonly encountered and will need to be considered as "high-risk" antibodies in the next iteration of the criteria [22,23,28]. These neural autoantibodies might be underrepresented in other cohorts due to neural autoantibody testing modalities [20,29].…”

“…The onset of neurological manifestations usually precedes cancer diagnosis and may lead to earlier cancer detection and treatment [1,2]. Although most studies focus on small-cell lung cancer (SCLC)-associated paraneoplastic neurological syndromes [3,4], diverse neurological manifestations have been described accompanying other neuroendocrine neoplasms (NENs), including "high-risk" paraneoplastic neurological phenotypes (e.g., Lambert-Eaton myasthenic syndrome, limbic encephalitis or rapidly progressive cerebellar syndrome) [5][6][7][8][9][10][11] and other classical presentations of neurological autoimmunity (e.g., brainstem encephalitis, myelopathy) [12][13][14][15][16][17][18][19][20]. A single patient may have multiple neural autoantibodies, the patient's serological profile reflects the antigenic makeup of the underlying tumor [21] and may herald tumor recurrence or predict better tumor survival [3,[21][22][23][24][25][26][27].…”

Gastrointestinal motility disorders in neurologic disease

“…Paraneoplastic neuropathy. Gastrointestinal symptoms may occur in association with small-cell carcinoma of the lung or pulmonary carcinoid or neuroendocrine (121) tumors. Symptoms include constipation, gastroparesis, intestinal pseudo-obstruction, and esophageal spasm or achalasia (122).…”