Abstract
Background
Immune checkpoint inhibitors (ICI) may trigger autoimmune neurological conditions, including movement disorders (MD).
Objectives
The aim of this study was to characterize MDs occurring as immune‐related adverse events (irAEs) of ICIs.
Methods
A systematic literature review of case reports/series of MDs as irAEs of ICIs was performed.
Results
Of 5682 eligible papers, 26 articles with 28 patients were included. MDs occur as a rare complication of cancer immunotherapy with heterogeneous clinical presentations and in most cases in association with other irAEs. Inflammatory basal ganglia T2/fluid attenuated inversion recovery abnormalities are rarely observed, but brain imaging is frequently unrevealing. Cerebrospinal fluid findings are frequently suggestive of inflammation. Half of cases are associated with a wide range of autoantibodies. Steroids and ICI withdrawal usually lead to improvement, even though some patients experienced relapses or a severe clinical course.
Conclusion
MDs are a rare complication of ICIs that should be promptly recognized to offer patients a correct diagnosis and treatment.
Keywords: paraneoplastic neurological syndrome, autoimmune movement disorders, immune checkpoint inhibitors, immune‐related adverse events
Autoimmune movement disorders (MD) include a heterogeneous spectrum of conditions characterized by immune dysregulation, usually related to specific neuronal antibodies. These conditions can be of idiopathic origin (ie, purely autoimmune), paraneoplastic (ie, occurring secondarily to associated tumors), or related to cancer immunotherapy. Immune‐related adverse events (irAE) have been reported to occur in patients undergoing immune checkpoint inhibitors (ICIs), the most commonly used cancer immunotherapy. The prompt and correct recognition of these conditions is of utmost importance to offer a correct treatment, based mostly on steroids and ICI discontinuation. 1 , 2 It seems plausible that the incidence of immune‐mediated MDs will increase over time, with the increasing use of ICIs for cancer immunotherapy.
The aim of this study was to characterize autoimmune MDs associated with ICIs through a systematic literature review to help clinicians in the prompt recognition and management of these conditions.
Patients and Methods
A systematic literature review was performed on PubMed and Scopus by 2 independent investigators to identify relevant articles reporting cases of MDs developing as irAEs to ICI treatment. The following search query was launched on May 15, 2023, and updated on August 23, 2023: (“immune‐related adverse event” OR “neurologic toxicity” OR “neurological toxicity” OR “neurotoxicity” OR “neurologic autoimmunity” OR “autoantibodies” OR “chorea” OR “dystonia” OR “tremor” OR “paroxysmal movement disorder” OR “parkinsonism” OR “opsoclonus” OR “myoclonus” OR “stiff*”) and (“immune checkpoint inhibitor” OR “nivolumab” OR “pembrolizumab” OR “atezolizumab” OR “ipilimumab” OR “durvalumab” OR “cemiplimab” OR “avelumab” OR “anti‐PD‐1” OR “PD‐1 inhibitor” OR “anti‐PD‐L1” OR “PD‐L1 inhibitor” OR “anti‐CTLA‐4” OR “CTLA‐4 inhibitor”). All relevant articles were cross‐referenced.
Inclusion criteria for papers with patient‐level data were (a) the development or worsening of any MD excluding isolated cerebellar ataxia or cerebellitis, which have been recently characterized elsewhere 3 ; (b) the exposure to cancer immunotherapy (per consensus 4 ); and (c) the reasonable exclusion of other causes. Reports with insufficient individual patient data, unclear etiology of MDs, or aggregate data were excluded from the analysis. Risk of bias was assessed using a specific scale for case reports. 5
Relevant data, including demographic and clinical features, oncological accompaniments, cancer immunotherapy and previous history of chemotherapy, paraclinical and neuroimaging features, antibody specificities, and treatments and outcomes, were extracted by 2 independent authors (A.D. and Mi.Tr.) in an electronic database. Controversies were resolved by consensus.
Data are reported as median (range) or number (percentage), as appropriate. The association between different irAEs in patients with multifocal involvement and between specific MDs and autoantibodies is reported using circos plots (R, circlize package 6 ). The paraneoplastic neurologic syndrome (PNS)‐Care score was calculated in each case with sufficient available information, as previously described. 7 Finally, we estimated the incidence of irAE MDs in larger reports (ie, >15 patients with neurological irAEs) that fulfilled inclusion criteria (Supporting Information).
Results
Of 5682 eligible papers, 26 articles 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 reporting 28 patients were included. A detailed PRISMA flowchart, the assessment of the risk of bias for each study, and the estimation of frequency in larger cohorts of patients with neurological irAEs are provided in Supporting Information.
Of the included patients, 20 (74%) were male, and the median age at onset was 66 years (range: 18–77). Oncological accompaniments were non‐small‐cell lung cancer in 7 cases (25%); melanoma in 6 (21%); small‐cell lung cancer in 3 (10%); renal cancer, prostatic cancer, and genitourinary cancer in 2 (7%) each; and gastric cancer, mesothelioma, uterine cancer, and coexisting melanoma and breast cancer in 1 (4%) case each.
The most frequently administered ICI was anti‐programmed cell death protein‐1 (anti‐PD‐1, n = 14, 50%), followed by anti‐cytotoxic T‐lymphocyte antigen‐4 (anti‐CTLA‐4, n = 5, 18%), a combination of anti‐PD1 and anti‐CTLA‐4 (n = 4, 14%), and anti‐programmed cell death‐ligand‐1 (anti‐PD‐L1, n = 5, 18%).
MDs always had either an acute or a subacute onset and rarely occurred in isolation (n = 7, 25%). In cases of multifocal involvement (n = 21), 15 (71%) patients had concomitant immune‐related (ir)‐encephalitis, 1 (6%) ir‐meningitis, 1 (6%) ir‐neuropathy, and 4 (27%) with a combination of different irAEs. The relationship between MDs and other neurological irAEs is summarized in Figure 1A.
FIG 1.
Circos plots demonstrating (A) the distribution of core clinical features in patients presenting with either isolated movement disorders or movement disorders associated with immune‐related (ir) encephalitis, ir‐neuropathy, or ir‐meningits (according to Guidon et al. 4 ); (B) the association between specific oncological accompaniments and core clinical features; and (C) the relationship between core clinical features and antibody specificities. Only data obtained from patients without missing information were used for these plots. In case of combined results (ie, ir‐encephalitis plus irneuropathy or double‐positive antibody results), data were computed twice, each for individual result. These findings suggest that movement disorders are frequently observed in association with other neurological syndromes and rarely represent an isolated complication of cancer immunotherapy. Furthermore, oncological accompaniments, clinical features, and antibody specificities show highly heterogeneous relationships that frequently overcome the boundaries of typical paraneoplastic movement disorders.
Types of MDs were tremor (n = 4), myoclonus (n = 3), opsoclonus (n = 3), stiff person (n = 3), parkinsonism (n = 3), chorea (n = 3), opsoclonus plus myoclonus (n = 2), myoclonus plus tremor (n = 2), hemiballismus (n = 1), akathisia (n = 1), chorea/dyskinesia (n = 1), myoclonus plus dystonia plus tremor (n = 1), and uncharacterized MD (n = 1). The association between oncological accompaniments and core clinical features is shown in Figure 1B.
Autoantibodies were detected in 13 of 23 (56%) patients, and their relationship with specific core clinical features is shown in Figure 1C. Antibody specificities included anti‐Hu (n = 2, 9%), PDE10A (n = 2, 9%), Ri (n = 2, 9%), CV/CRMP5 (n = 1, 4%), CASPR2 (n = 1, 4%), GAD65 (n = 1, 4%), GlyR (n = 1, 4%), Hu and SOX1 (n = 1, 4%), Ma2 (n = 1, 4%), and uncharacterized novel antigen (n = 1, 4%).
After a median follow‐up of 5 months (range: 1–27), 12 of 24 (46%) patients improved, 7 of 24 (27%) were deceased, 3 of 24 obtained neurological remission (11%), 2 of 24 (8%) were stable, and 2 of 24 (8%) worsened. Relapses were reported in 6 patients (20%) mostly in association with rapid steroid tapering or cancer immunotherapy rechallenge.
Data regarding clinical, neuroimaging, and laboratory findings; treatment regimen; and PNS‐CARE score evaluation are provided in Table 1.
TABLE 1.
Summary of relevant clinical data of included cases (n = 28)
| Sex (male) | 20/27 (74%) |
| Age at onset (n = 27) | 66 (18–77) |
| Associated neoplasms | Non‐small‐cell lung cancer, n = 7 (25%) |
| Melanoma, n = 6 (21%) | |
| Small‐cell lung cancer, n = 3 (10%) | |
| Renal cancer, n = 2 (7%) | |
| Prostatic cancer, n = 2 (7%) | |
| Hodgkin's lymphoma, n = 2 (7%) | |
| Genitourinary cancer, n = 2 (7%) | |
| Gastric cancer, n = 1 (4%) | |
| Mesothelioma, n = 1 (4%) | |
| Uterine cancer, n = 1 (4%) | |
| Melanoma + breast cancer, n = 1 (4%) | |
| History of previous chemotherapy | n = 10 (36%) |
| Associated ICI | Anti‐PD‐1, n = 14 (50%) |
| Anti‐CLTA‐4, n = 5 (18%) | |
| Anti‐PD1 and anti‐CTLA‐4, n = 4 (14%) | |
| Anti‐PD‐L1, n = 5 (18%) | |
| Other nonneurological irAEs | Thyroiditis (n = 5) |
| Hyphophysitis (n = 2) | |
| Colitis (n = 2) | |
| Dermatological manifestations (n = 2) | |
| Interstitial pneumonia (n = 1) | |
| Increased liver enzymes (n = 1) | |
| Time from ICI to irAE (weeks), n = 20 | 2 (1–52) |
| Number of ICI doses, n = 19 | 5 (1–17) |
| Time from last ICI infusion to irAE (days), n = 20 | 12 (5–365) |
| Onset (n = 20) | Acute, n = 8 (40%) |
| Subacute, n = 12 (60%) | |
| Isolated movement disorder | n = 7 (25%) |
| Concomitant neurological syndrome, n = 21 | Encephalitis, n = 5 |
| Cerebellitis, n = 3 | |
| OMS, n = 4 | |
| PERM, n = 2 | |
| Meningoencephalitis, n = 1 | |
| Limbic encephalitis, n = 1 | |
| Peripheral neuropathy, n = 1 | |
| Combination, n = 4 (encephalitis plus peripheral neuropathy; meningitis plus peripheral neuropathy; OMS plus encephalitis; cerebellitis plus myelitis) | |
| Type of movement disorders a | Tremor, n = 4 |
| Myoclonus, n = 3 | |
| Opsoclonus, n = 3 | |
| Stiff person, n = 3 | |
| Parkinsonism, n = 3 | |
| Chorea, n = 3 | |
| Opsoclonus plus myoclonus, n = 2 | |
| Myoclonus plus tremor, n = 2 | |
| Hemiballismus, n = 1 | |
| Akathisia, n = 1 | |
| Chorea/dyskinesia, n = 1 | |
| Myoclonus plus dystonia plus tremor, n = 1 | |
| Uncharacterized, n = 1 | |
| Abnormal MRI scans b | 11/26 (42%) |
| Increased CSF cell count | 13/23 (66%) |
| CSF cell count (n = 14) | 18 (1–705) |
| Increased CSF protein concentration | 12/18 (67%) |
| CSF protein concentration (mg/dL) (n = 10) | 67 (35–1040) |
| CSF restricted oligoclonal bands | 6/13 (46%) |
| Antibody specificities (n = 23) | Negative, n = 10 (44%) |
| Hu, n = 2 (9%) | |
| PDE10A, n = 2 (9%) | |
| Ri, n = 2 (9%) | |
| CV2/CRMP5, n = 1 (4%) | |
| CASPR2, n = 1 (4%) | |
| GAD65, n = 1 (4%) | |
| GlyR, n = 1 (4%) | |
| Hu + SOX1, n = 1 (4%) | |
| Ma2, n = 1 (4%) | |
| UNA, n = 1 (4%) | |
| Number of treatments per patient | 1 (0–3) |
| Patients receiving >1 treatment c | 13 (46%) |
| Administered treatments | Steroids, n = 24 |
| Intravenous immunoglobulins, n = 7 | |
| Plasma exchange, n = 5 | |
| Other treatments, n = 6 d | |
| ICI discontinuation | 23/24 (96%) |
| ICI rechallenge e | 4/10 (40%) |
| Outcomes (n = 26) f | Improved, n = 12 (46%) |
| Death, n = 7 (27%) | |
| Remission, n = 3 (11%) | |
| Stable, n = 2 (8%) | |
| Worsened, n = 2 (8%) | |
| Follow‐up duration (mo), n = 22 | 5 (1–27) |
| PNS‐Care score (n = 23) | 4 (1–10) |
| PNS diagnostic criteria (n = 23) | Non‐PNS, n = 9 (39%) |
| Possible PNS, n = 7 (31%) | |
| Probable PNS, n = 1 (4%) | |
| Definite PNS, n = 6 (26%) |
Data are reported as median (range) and number (percentage) as appropriate. If not otherwise specified in case of missing data, the total number of patients is 28.
Abbreviations: ICI, immune checkpoint inhibitor; PD‐1, programmed cell death protein‐1; CTLA‐4, cytotoxic T‐lymphocyte antigen‐4; PD‐L1, programmed cell death‐ligand‐1; OMS, opsoclonus‐myoclonus‐ataxia syndrome, PERM, progressive encephalomyelitis with rigidity and myoclonus; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; PDEA10A, phosphodiesterase 10A; CASPR2, contactin‐associated protein‐like 2; GAD65, glutamic acid decarboxylase 65‐kilodalton isoform; GylR, glycine receptor; UNA, uncharacterized novel antigen; PNS, paraneoplastic neurological syndrome; FLAIR, fluid attenuated inversion recovery.
Two patients had a previous movement disorder (opsoclonus, n = 1; myoclonus, n = 1) that worsened after the introduction of ICI.
A wide range of MRI abnormalities, including dural enhancement or cortical/limbic involvement, were reported, mostly in patients with multifocal irAEs. In 5 cases inflammatory T2/FLAIR hyperintensity of the basal ganglia was noted, and in 1 case a dopaminergic deficit was evident on I‐123 ioflupane single‐photon emission computed tomography.
Three patients received no treatment, 11 received 1 treatment only, 9 received 2 different treatments, and 4 received 3 different treatments.
Other treatments included infliximab (n = 1), cyclophosphamide (n = 2), rituximab (n = 2), and tacrolimus (n = 1).
Two patients experienced relapses, whereas 2 did not relapse after treatment rechallenge.
Six patients experienced relapses, 2 related to treatment rechallenge.
Discussion
Our study reviews autoimmune MDs complicating ICI administration and provides a description of clinical, paraclinical, and oncological accompaniments. Overall, our study describes peculiar features useful for the correct recognition of these disorders, helpful to avoid diagnostic and treatment delays.
Our findings show that MDs are rare neurological irAEs (ie, 3%–5% in larger cohorts of patients with neurological irAEs) and rarely occur in isolation. Consistent with previous reports, 34 these side effects occur in the context of concomitant immune‐related encephalitis, meningitis, or neuropathy.
The spectrum of MDs associated with cancer immunotherapy appears to be wide, but most patients present with a single core feature. Disease course is acute/subacute in all cases, thus representing a major diagnostic clue for suspecting a correlation to ICI administration, in particular for those MDs such as parkinsonism or tremor, that usually present a more chronic disease course. Moreover, inflammatory cerebrospinal fluid (CSF) findings and negative magnetic resonance imaging (MRI) or the evidence, in single cases with Ma2 or PDE10A antibodies, of inflammatory T2/fluid attenuated inversion recovery (FLAIR) hyperintensity of the basal ganglia are further supportive features.
Autoantibodies are detected in half of cases and mostly included those targeting well‐characterized intracellular antigens, even though novel reactivities (eg, PDE10A) or antibodies targeting neuronal surface antigens (eg, CASPR2, glycine receptor) were reported. These findings highlight the importance of searching for autoantibodies when evaluating patients with MDs in the setting of a suspected irAE. In addition to commercially available assays, tissue‐based assays and live cell‐based assays are extremely useful to detect novel reactivities that may otherwise be missed; thus, referring samples to expert reference laboratories is of utmost importance. 35 , 36
Finally, the application of the 2021 diagnostic criteria for PNS demonstrates that only 5 of 21 patients fulfill the criteria for definite PNS, whereas most of them are classified either as probable or as non‐PNS. The absence of autoantibodies or the presence of atypical oncological accompaniments justifies the different levels of diagnostic certainty encountered. In line with current evidence, we found that only a minority of cases have a paraneoplastic‐like syndrome phenotype, which probably differs in terms of pathogenesis, oncological accompaniments, and outcomes from cases with a non‐PNS‐like syndrome. 37 Other factors, such as cytokines, 38 could play a pathogenetic role in the absence of autoantibodies or in patients not fulfilling PNS criteria.
The main limitations of our study include (a) the small sample size, (b) the potential reporting bias, and (c) the inability of the authors to directly verify the reported clinical data or to address missing information, which are intrinsic to the study design. Potential perspectives on this topic include the design of multicentric observational studies along with expert video‐rating evaluations, which can help to phenotype MDs, as those previously reported in association with N‐methyl‐d‐aspartate receptor antibody‐mediated encephalitis. 39
To conclude, our study provides a systematic characterization of MDs occurring as a complication of cancer immunotherapy based on current literature. Features suggestive of an autoimmune etiology are, in association with concomitant autoantibodies, an acute/subacute onset, the presence of MDs in association with other syndromes known to occur as irAEs, and the presence of inflammatory CSF findings with negative brain imaging (or in some cases T2/FLAIR basal ganglia inflammatory abnormalities).
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique.
A.D.: 1A, 1B, 1C, 2A, 2B, 3A
Mi.Tr.: 1C, 2B, 3B
S.C.: 1C, 2B, 3B
E.M.: 1C, 2B, 2C, 2B, 3B
S.F.: 1C, 2C, 3B
S.T.: 1C, 2C, 3B
Mi.Ti.: 1C, 2C, 3B
S.M.: 1A, 1B, 1C, 2C, 3B.
Disclosures
Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that patient consent was not required for this work. Informed consent was not obtained. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Supporting information
Figure S1. PRISMA flowchart of the study. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. For more information, visit http://www.prisma-statement.org/. Sechi (2020) and Zekeridou (2019) reported duplicate patients.
Table S1. Evaluation of the risk of bias of the included studies according to Murad et al. (2018). 5 N, no; N/A, not applicable; NR, not reported; Y, yes.
Table S2. Application of PNS‐Care score to cases with available clinical information. PNS, paraneoplastic neurologic syndrome.
Acknowledgment
None.
Milena Trentinaglia and Sara Carta have contributed equally to this work.
Contributor Information
Alessandro Dinoto, Email: alessandro.dinoto@univr.it.
Sara Mariotto, Email: sara.mariotto@univr.it.
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Associated Data
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Supplementary Materials
Figure S1. PRISMA flowchart of the study. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. For more information, visit http://www.prisma-statement.org/. Sechi (2020) and Zekeridou (2019) reported duplicate patients.
Table S1. Evaluation of the risk of bias of the included studies according to Murad et al. (2018). 5 N, no; N/A, not applicable; NR, not reported; Y, yes.
Table S2. Application of PNS‐Care score to cases with available clinical information. PNS, paraneoplastic neurologic syndrome.