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Immune checkpoint inhibitor (ICI) indications have broadened considerably in the last few years.1 The aim of this study is to provide an update on clinical presentations, serological associations and outcomes of ICI-related neuropathy (irNeuropathy) in the context of expanding use of cancer immunotherapy for neuroendocrine tumours.
All patients with irNeuropathy who were evaluated at Mayo Clinic from 01 January 2015 to 10 October 2020 were identified by electronic medical record search. Patients with neuropathies secondary to cytotoxic chemotherapy, radiation, diabetes, structural or compressive aetiologies, prior to administration of ICIs were excluded. Clinical presentations, electrodiagnostic features, autoantibody profiles and clinical outcomes were reviewed.
Twenty patients (13 males) with irNeuropathy were identified. Median age was 64 (range 31–81) years. Two patients (10%) had a diagnosis of autoimmune disorders prior to ICI initiation; one with Graves’ disease and the other with rheumatoid arthritis. ICI regimens included programmed cell death-1 receptor (PD-1) or programmed death-ligand 1 inhibitors (n=15, 75%), cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor (n=2, 10%) and a combination of PD-1 and CTLA-4 (n=3, 15%). The median number of ICI cycles and median time from ICI initiation to onset of irNeuropathy symptoms were 2.5 cycles (range 1–20) and 9 weeks (range 1–56), respectively. ICIs were discontinued for all patients after diagnosis of irNeuropathy. Two non-neuroendocrine patients were restarted on different type of ICIs after irNeuropathy had resolved; one of these patients developed recurrent ICI-related phrenic neuropathy.
Neuroendocrine tumour associated irNeuropathies
All neuroendocrine tumour patients (small cell lung cancer, n=3; Merkel cell cancer, n=1) with irNeuropathies were seropositive for onconeural antibodies (type 1 antineuronal nuclear antibody (ANNA1, anti-Hu), n=2; ANNA1 and collapsin response mediator protein 5 (CRMP5, anti-CV2), n=1; CRMP5 and Purkinje cell antibody type-2, n=1). Presenting phenotypes among these patients were sensory neuronopathy (n=3), and asymmetric axonal polyradiculoneuropathy (n=1). Two patients had developed mild neuropathy symptoms (paresthesia, sensory ataxia) even before ICI administration. One of which (patient 4, (online supplemental table 1) was tested for onconeural antibodies, found to have ANNA1, and treated with intravenous immunoglobulin and methylprednisolone with improvement prior to ICI. Neuropathy symptoms relapsed after ICI initiation. Three patients (75%) had associated central nervous system complications after ICI. Patient 1 and 42 had signs and symptoms of cerebellar dysfunction (online supplemental table 1). Patient 2 developed bilateral central scotoma, grade 3 optic disc oedema, and was diagnosed with optic neuropathy at the same time as onset of irNeuropathy.
irNeuropathies associated with other tumours
Clinical presentations of these non-neuroendocrine tumour patients with irNeuropathy were reported in previous studies (online supplemental table 2).2 3 Non-neuroendocrine malignancies associated with irNeuropathies included melanoma (n=9), renal cell carcinoma (n=3), adenocarcinoma of lung/gastrointestinal/breast (n=3) and mesothelioma (n=1). Ten patients had neural specific antibody evaluation (serum (n=7) and both serum and cerebrospinal fluid (n=3)), and nine patients (90%) were negative. One patient who presented with subacute length-dependent neuropathy and fasciculations had leucine-rich glioma-inactivated1-IgG detected in serum. The most common neuropathy phenotype was polyradiculoneuropathy (n=7), followed by length-dependent sensorimotor peripheral neuropathy (n=3), unilateral/bilateral phrenic neuropathies (n=3), brachial plexopathy (n=2) and multiple mononeuropathies (n=1). Electrodiagnostic studies showed evidence of demyelination in three patients (18.8%), all with Guillain-Barre syndrome (GBS)-like presentation. Nerve biopsy revealed evidence of necrotising vasculitis in two patients (12.5%), one with multiple mononeuropathies and another with polyradiculoneuropathy.
Comparison of irNeuropathies associated with neuroendorcrine versus others
Comparisons of irNeuropathies among patients with neuroendocrine and other tumours are summarised in figure 1 and table 1. Median INCAT disability score at nadir among irNeuropathies associated with neuroendocrine tumours was significantly higher (7.5 (range 2–10) vs 2 (range 0–7), p=0.027) and frequency of wheelchair-dependence was also more common among the neuroendocrine tumour group (75% vs 12.5%, p=0.010). Despite aggressive immunotherapy, none of the patients with neuroendocrine tumour had improvement of neuropathic symptoms. While among the non-neuroendocrine tumour patients with irNeuropathy, majority had improvement in mRS (75%) and INCAT disability (56%) score after immunosuppressive treatment. Two of four neuroendocrine tumour patients with irNeuropathy died due to progressive neurological deterioration, both within 1 month after irNeuropathy onset. The other two still experienced irNeuropathy symptoms at follow-up time of 28 and 6 months. In the non-neuroendocrine tumour group, eight deaths were reported during median follow-up time of 11 months, seven of which from metastatic disease and one patient from ICI-associated hepatitis resulting in liver failure.
Sensory neuronopathy and/or gastroparesis presentations of irNeuropathy, which were seen exclusively in neuroendocrine tumour patients in our cohort, mimicked classic paraneoplastic neurological syndromes (PNS).1 2 Their aggressive course and refractoriness to immunosuppressive therapy also resembled the long-term outcomes of their PNS counterparts.1 4 Additionally, all neuroendocrine tumour cases who developed irNeuropathy were seropositive for at least one or more onconeural antibody. In contrast, only one non-neuroendocrine tumour patient with irNeuropathy had neuronal cell surface autoantibody detected and did not have the typical presentation of PNS. Presenting phenotypes of irNeuropathy in non-neuroendocrine tumour patients in our study was similar to those described previously.2 3 5 The presenting phenotypes were heterogenous, including GBS-like presentations, length-dependent neuropathies, brachial plexopathies and phrenic neuropathies. In addition, the immunotherapy response and long-term outcomes among these cases were also relatively favourable.5
Onconeural antibody seropositive irNeuropathies may be triggered due to ICI-stimulated cross reactive immune response against autoantigens expressed in both the tumour and neural cells, resembling PNS pathogenesis. On the other hand, many of the seronegative irNeuropathies may be secondary to ICI-induced augmentation of latent predisposition to neurological autoimmunity.1 2 As the use and indications of ICI expands, we will likely come across onconeural antibody seropositive irNeuropathies even among the non-neuroendocrine tumours.1
Evaluation of neural-specific antibodies among irNeuropathies is important, especially among tumours classically associated with PNS. Furthermore, considering evaluation of these antibodies in patients with neuropathic symptoms without clear aetiology prior to starting ICI therapy is imperative. This will help identify pre-existing paraneoplastic autoimmunity which will likely significantly worsen post-ICI.
Our study supports that the presentations and outcomes of irNeuropathies are changing, as ICI indications are broadened to include tumours classically associated with PNS. Recognition of clinical features suggestive of pre-existing paraneoplastic neuropathy and onconeural autoantibody evaluations is critical prior to ICI initiation to avoid irreversible neurological decline among these patients.
Patient consent for publication
Mayo Clinic Institutional Review Board ID 08-006647.
Contributors PC and DD conceptualised the study. PC carried major role in acquisition of data, analysed the data and drafted the manuscript for intellectual content. AZ and SS contributed to acquisition of data. All coauthors (AZ, SS, MR, PJD, CJK, SJP, MM and DD) revised the manuscript for intellectual content. All authors gave final approval for the submitted article and take responsibility for the accuracy and integrity of this work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SJP has patent pending for MAP1B as a marker of neurological autoimmunity.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.