JAMANeurology | OriginalInvestigation … · 2021. 1. 20. · N eurologicalcomplicationsareanincreasinglyrecog-nizedconsequenceoftheuseofanti–programmed death1(PD-1)antibodiesinthetreatmentofsolid-organtumors

Neurological Complications AssociatedWith Anti–Programmed Death 1 (PD-1) AntibodiesJustin C. Kao, MBChB; Bing Liao, MD, PhD; Svetomir N. Markovic, MD, PhD; Christopher J. Klein, MD;Elie Naddaf, MD; Nathan P. Staff, MD, PhD; Teerin Liewluck, MD; Julie E. Hammack, MD; Paola Sandroni, MD, PhD;Heidi Finnes, PharmD, RPh; Michelle L. Mauermann, MD

IMPORTANCE Neurological complications are an increasingly recognized consequence of theuse of anti–programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors,with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatmentapproach are not established.

OBJECTIVE To investigate the frequency, clinical spectrum, and optimum treatment approachto neurological complications associated with anti–PD-1 therapy.

DESIGN, SETTING, AND PARTICIPANTS This single-center, retrospective cohort study wasconducted from either September or December 2014 (the approval dates of the study drugsby the US Food and Drug Administration) to May 19, 2016. All patients receiving anti–PD-1monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patientswith development of neurological symptoms within 12 months of anti–PD-1 therapy wereincluded. Patients with neurological complications directly attributable to metastatic diseaseor other concurrent cancer-related treatments were excluded.

MAIN OUTCOMES AND MEASURES Clinical and pathological characteristics, time todevelopment of neurological symptoms, and modified Rankin Scale (mRS) score.

RESULTS Among 347 patients treated with anti–PD1 monoclonal antibodies (pembrolizumabor nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Sevenpatients were receiving pembrolizumab, and 3 patients were receiving nivolumab. Thepatients included 8 men and 2 women. Their median age was 71 years (age range, 31-78years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles ofanti–PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclearophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal anddemyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), andasymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity variedfrom 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mildto moderate disability. Five patients experienced other systemic immune-mediatedcomplications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1).Treatment with anti–PD-1 antibodies was discontinued in 7 patients. Treatment includedcorticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1).Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severenecrotizing myopathy died.

CONCLUSIONS AND RELEVANCE Neurological adverse events associated with anti–PD-1therapy have a diverse phenotype, with more frequent neuromuscular complications.Although rare, they will likely be encountered with increasing frequency as anti–PD-1 therapyexpands to other cancers. The time of onset is unpredictable, and evolution may be rapid andlife-threatening. Prompt recognition and discontinuation of anti–PD-1 therapy isrecommended. In some cases, immune rescue treatment may be required.

JAMA Neurol. 2017;74(10):1216-1222. doi:10.1001/jamaneurol.2017.1912Published online September 5, 2017. Corrected on October 9, 2017.

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Author Affiliations: Department ofNeurology, Mayo Clinic, Rochester,Minnesota (Kao, Liao, Klein, Naddaf,Staff, Liewluck, Hammack, Sandroni,Mauermann); Department ofOncology, Mayo Clinic, Rochester,Minnesota (Markovic); PharmacyServices, Mayo Clinic, Rochester,Minnesota (Finnes).

Corresponding Author: Michelle L.Mauermann, MD, Department ofNeurology, Mayo Clinic, 200 First StSW, Rochester, MN 55905([email protected]).

Research

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N eurological complications are an increasingly recog-nized consequence of the use of anti–programmeddeath 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%.1 The ma-jor role of the human cell surface receptor PD-1 is to limit T-cellactivity in peripheral tissues, which is important in self-tolerance and prevention of autoimmunity. When bound byits ligands PDL1 and PDL2, PD-1 inhibits T-cell activation andlimits immune effector responses.2 Tumors can express PD-L1as one mechanism of inhibiting antitumor T-cell–mediated re-sponses in the tumor microenvironment. Therapeutic block-ade of this pathway with the use of anti–PD-1 monoclonal an-tibodies, such as pembrolizumab and nivolumab, can therebyincrease the immune response against tumor cells.2 Initiallyapproved for the treatment of unresectable metastatic mela-noma and non–small cell lung cancer, they are now increas-ingly used to treat a variety of solid-organ and hematologicalcancers.

Immune checkpoint inhibitors are generally thought tohave a unique adverse effect profile in the form of immune-mediated adverse events, with disruption of immune check-point inhibition leading to imbalances in immune tolerance.However, the exact mechanism underpinning these adverseevents largely remains unknown. Limited insight in favor ofan immune mechanism comes from experience with cyto-toxic T-lymphocyte antigen 4 (CTLA-4) inhibitors.3,4

From the series of KEYNOTE clinical trials with PD-1 in-hibitors, a number of adverse events with an immune-mediated mechanism were identified as being of special in-terest, including thyroid dysfunction, pneumonitis, colitis,hepatitis, nephritis, hypophysitis, uveitis, type 1 diabetes, andmyositis.5,6 With the exception of thyroid dysfunction, coli-tis, and hepatitis, most of these complications were rare, oc-curring in less than 1% of treated patients. Severe (grade 3-4)adverse events occur in approximately 7% to 12% of patientstreated with PD-1 inhibitors,7 with the likelihood of adverseevents rising to as high as 55% in those treated with the com-bination of a PD-1 inhibitor and a CTLA-4 inhibitor(ipilimumab).8

More recently, there has been an increase in the numberof case reports of neurological complications associated withanti–PD-1 therapy. Neuromuscular complications appear to bethe most common and include myasthenia gravis,1,9-11 necro-tizing myopathy,12,13 vasculitic neuropathy,14 and polyradi-culoneuropathy.15,16 Other neurological complications thathave been described include focal seizures associated withinflammatory cerebral lesions on magnetic resonance imaging(MRI),17 limbic encephalitis,18 and retinopathy.19 However, thefull spectrum of neurological complications relating to anti–PD-1 therapy and the clinical phenotype are not well charac-terized. The severity of these complications and the optimumapproach for evaluation and treatment are also not wellknown to date. We aimed to define the frequency, pheno-types, and severity of neurological complications associatedwith anti–PD-1 therapy at a single center. Furthermore, wegathered information regarding prognosis and treatment anddefined an approach to evaluation and treatment of thesepatients.

Methods

Standard Protocol Approvals, Registrations,and Patient ConsentsMayo Clinic Investigational Review Board approved the study.We included patients who had given written informed consentallowing their medical records to be used for research purposes.

Patient SelectionWe searched the Mayo Cancer Pharmacy Database in Roches-ter, Minnesota, for patients receiving anti–PD-1 monoclonal an-tibodies (pembrolizumab or nivolumab) for the treatment ofmalignant melanoma or other solid-organ tumors from Sep-tember and December 2014 (the approval dates of the studydrugs by the US Food and Drug Administration) to May 19, 2016.We identified those patients who developed neurological dis-orders after treatment with these medications.

For inclusion, the neurological condition must have oc-curred within 12 months of anti–PD-1 antibody use. Any newneurological symptoms occurring during treatment were in-cluded. We excluded those patients with neurological symp-toms that were found to be directly attributable to their meta-static disease or other concurrent cancer-related treatments.Clinical, laboratory, electrodiagnostic, radiological, and patho-logical information was extracted by retrospective medical rec-ord review. Clinical follow-up and management were re-viewed in all cases.

Scoring of the SeverityThe modified Rankin Scale (mRS) score was used to measurethe degree of dependence in daily activities referable to theneurological complication.20 The scale ranges from 0 (no symp-toms) to 6 (death).

Electrodiagnostic TestingNerve conduction studies and electromyography (EMG) wereperformed. These assessments used methods standard for theEMG laboratory at Mayo Clinic.

Key PointsQuestion What are the frequency and characteristics ofneurological complications from anti–programmed death 1 (PD-1)antibody use?

Findings Among 347 patients treated with anti–programmeddeath 1 (PD-1) antibody use (pembrolizumab or nivolumab), thiscohort study supports a low frequency (2.9%) of neurologicalcomplications associated with anti–PD-1 therapy. The range andseverity of complications are diverse, including necrotizingmyopathy, various neuropathies, cerebellar ataxia, internuclearophthalmoplegia, retinopathy, and headache; the median modifiedRankin Scale score of 2.5 indicates mild to moderate disability.

Meaning Subacute presentation of neurological symptoms in apatient receiving anti–PD-1 therapy should prompt considerationof an association and discontinuation of anti–PD-1 antibody useand possible treatment with corticosteroids or other immunetreatment depending on the severity.

Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies Original Investigation Research

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Statistical AnalysisDescriptive summaries are presented as frequencies and per-centages for categorical variables. They are presented as themedian and range for continuous variables.

ResultsIn total, 347 patients had received treatment with an anti–PD-1antibody at the time of our study, with 204 patients receivingpembrolizumaband142patientsreceivingnivolumab.Therewasalso one additional patient who initially received nivolumab andthen was switched over to pembrolizumab.

We identified 10 patients of the 347 with neurological com-plications related to the treatment, giving a frequency of 2.9%.One case has been previously reported13 (patient 1 in Table 1).

We excluded an additional 4 patients, including 1 patient withfoot drop from peroneal neuropathy related to weight loss, 1patient with peripheral neuropathy from the use of brentux-imab, and 2 patients with subacute decline in mobility (1 withhydrocephalus on neuroimaging and 1 multifactorial).

The patients included 8 men and 2 women. Their medianage was 71 years (age range, 31-78 years). Melanoma was themost common cancer (n = 5), followed by lung adenocarci-noma (n = 2), peritoneal mesothelioma (n = 1), esophageal ad-enocarcinoma (n = 1), and leiomyosarcoma (n = 1). All pa-tients had stage IV metastatic disease. None of the patients hada history of autoimmune or neurological disease.

Seven patients had complications during pembrolizumabtherapy, and 3 patients had complications during nivolumabtherapy. Neuromuscular disorders were the most commonneurological complications and included myopathy (n = 2) and

Table 1. Clinical Features and Outcomes After Treatment

PatientNo./Sexa

CancerDiagnosis Treatment

Cycles toOnset ofNeurologicalComplication

NeurologicalDiagnosis

ModifiedRankinScaleScore

TreatmentStopped

AdditionalTreatments

NeurologicalOutcome

ModifiedRankin ScaleScore AfterTreatment

1/Male Stage IVmelanoma

Pembrolizumab 2 Severenecrotizingmyopathy

5 Yes Prednisone (80 mgdaily) for 12 d,3 sessions ofplasmapheresis

Death 6


Pembrolizumab 1 Myopathy 1 Yes Methylpred-nisolone (1-gsingle dose),prednisone(100 mg daily) for3 d and thenprednisone (60 mgdaily), taperingweekly over 1 mo

Improved 0


Pembrolizumab 10 Axonalthoracolumbarpolyradiculopathy

4 Yes Prednisone (30 mgdaily), weeklytaper over 1 mo,IVIG (1 g/kg) for2 doses

Improved 2


Pembrolizumab 6 Severedemyelinatinglength-dependentperipheralneuropathywith axonal loss

3 Yes Prednisone(120 mg daily),followed by slowtaper over 2.5 mo

Improved 2


Pembrolizumab 20 Facial diplegicvariant ofGuillain-Barrésyndrome

2 Yes IVIG (0.4 g/kgdaily) for 5 d

Improved 1

6/Male Stage IVperitonealmesothelioma

Nivolumab 5 Asymmetricvasculiticneuropathy

3 Yes Methylpred-nisolone (1 gintravenouslydaily) for 5 d,prednisone (60 mgdaily), taperingover 3 wk

Improved 3

7/Male Stage IV lungadenocarcinoma

Pembrolizumab 11 Cerebellarataxia anddysarthria

4 Yes None Improved 2

8/Male Stage IVesophagealadenocarcinoma

Pembrolizumab 3 Autoimmuneretinopathy

2 No IVIG (0.4 g/kg) 3consecutive daysevery 3 wk

Improved 2

9/Female Stage IVleiomyosarcoma

Nivolumab 3 Bilateralinternuclearophthalmoplegia

2 No Corticosteroid(dose unknown) for1 wk

Improved 0

10/Female Stage IV lungadenocarcinoma

Nivolumab 14 Headache 2 No Dexamethasone(4 mg twice daily)for 1 wk

Improved 0

Abbreviation: IVIG, intravenous immunoglobulin.a Ages range from 31-78 years.

Research Original Investigation Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

1218 JAMA Neurology October 2017 Volume 74, Number 10 (Reprinted) jamaneurology.com




neuropathy (n = 4). There were also single cases of cerebellarataxia, autoimmune retinopathy, bilateral internuclear ophthal-moplegia, and headache. Neurological complications occurredafteramedianof5.5(range,1-20)cyclesofanti–PD-1therapy.Eachcyclewasdefinedasthe3-weekintervalbetweentreatments.Thetime of onset to maximum symptom severity varied consider-ably, ranging from 1 day to more than 3 months.

The cases of myopathy are summarized in Table 2. Patient 1hadanaggressivenecrotizingmyopathywithseveralunusualfea-tures,includingsevereextraocular,bulbar,andrespiratorymuscleweakness. Muscle biopsy of the right triceps showed confluentareas of muscle fiber necrosis (Figure, A). Patient 2 had a mildproximal myopathy clinically and on electrodiagnostic testing.Muscle biopsy of the right biceps showed only scattered necrotic

Table 2. Clinical, Laboratory, Imaging, and Pathological Features of Patients With Myopathy

PatientNo.

ClinicalFindings

Onset toMaximumSeverity CK Electromyography

MagneticResonanceImaging

HistopathologicalFindings Antibodies

ConnectiveTissue Markers ESR/CRP

1 Extraocular,bulbar, andproximal limbgirdle weakness

3 wk 3.8 TimesULN

Proximal myopathywith fibrillationpotentials,repetitive nervestimulation normal

IncreasedT2-weightedsignal and deepparaspinalmusculatureenhancement

Necrotizingmyopathy(Figure, A)

HMGCR, SRP, PNP,and AChR antibodynegative, striatedmuscle antibody1:61440,anti–PM/Sclantibody positive(36 U)

ANA 0.2, SSA,SSB, Sm, RNP,Scl-70, Jo-1negative

ESR 20 mm/h,CRP 3.9 mg/L

2 Mild proximalshoulderweakness

9 d 21 TimesULN

Proximal myopathywithout fibrillationpotentials,length-dependentperipheralneuropathy

NA Myopathy: 3necrotic fibers,many ring andlobulated fiberson oxidativeenzyme staining(Figure, B)

HMGCR negative,PNP and AChRantibody negative

ANA 0.5 NA

Abbreviations: AChR, acetylcholine receptor; ANA, antinuclear antigen;CK, creatine kinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate;HMGCR, 3-hydroxy-3-methylglutaryl–coenzyme A reductase; Jo-1, histidyl tRNAsynthetase; NA, not applicable; PM/Scl, anti-exosome; PNP, paraneoplastic;RNP, ribonucleoprotein; Scl 70, anti–topoisomerase I; Sm, Smith; SRP, signal

recognition particle; SSA, Sjögren syndrome–related antigen A; SSB, Sjögrensyndrome–related antigen B; ULN, upper limit of normal.

SI conversion factor: To convert C-reactive protein level to nanomoles per liter,multiply by 9.524.

Figure. Pathological Features of Necrotizing Myopathy and Vasculitic Neuropathy AssociatedWith Anti-Programmed Death 1 (PD-1) Therapy

Patient 1 triceps muscle biopsy specimenA

Patient 6 sural nerve biopsy specimenC

Patient 2 biceps muscle biopsy specimenB

Patient 6 teased nerve fiber preparationD

A, Hematoxylin-eosin staindemonstrates multifocal confluentareas of muscle fiber necrosisreplaced by macrophages(arrowheads) (original magnification×10). B, Nicotinamide adeninedinucleotide dehydrogenase–reactedsection revealed numerous ring fibers(asterisks) (original magnification×20). C, Transverse paraffin sectionwith Gomori trichrome staindemonstrates a large collection ofmononuclear cells (yellowarrowhead) invading and destroyingan epineurial arteriole with fibrinoidnecrosis (black arrowhead).Mononuclear cells reacted for CD-45(leukocyte common antigen)preparation with predominantly CD-3(T cell) positivity with scatteredCD-20 (B cell) positivity (originalmagnification ×400). D, Teased fiberpreparation shows all fibersundergoing axonal degeneration(original magnification ×160).






fibers,alongwithsomeringandlobulatedfibers(Figure,B).Therewas absence of inflammatory cells in both patients on muscle bi-opsy. Patient 1 had anti-exosome (PM/Scl) antibody (35 U, withnormalbeing

treatment was 30 days (range, 1-70 days). Seven patients re-ceived corticosteroids as part of their treatment, which weretypically administered as prednisone (1 mg/kg daily), taper-ing by 10 mg each week. The mean duration of treatment withcorticosteroids was 27 days (range, 7-75 days). Also, 3 pa-tients received courses of intravenous immunoglobulin(2 g/kg), 2 as monotherapy and the other in conjunction withprednisone, and 1 patient with myopathy received plasma ex-change in addition to prednisone.

Ninepatientsimproved,1spontaneouslyand8withimmunerescue treatment, with a median mRS score of 2 (range, 0-6). De-spite high-dose prednisone and plasma exchange, patient 1 diedafter withdrawal of ventilatory support 1 month after onset ofsymptoms.Ofthe9patientswhosurvived,3hadsubsequentpro-gression of their cancer and eventually died of their underlyingdisease,2patientsremainedincompleteremission,andtheother4 patients were stable. Four of 10 patients received subsequentanti–PD-1 therapy. Patient 2 developed worsening liver functiontest results after 1 cycle, and the drug was discontinued again.Patients 8, 9, and 10 were able to tolerate further treatment, but2 required maintenance intravenous immunoglobulin (patient8) or dexamethasone (patient 10) for immunomodulation.

DiscussionInourseries,weidentified10casesofneurologicaladverseeventsamong a total of 347 patients treated with anti–PD-1 monoclo-nal antibodies (pembrolizumab or nivolumab) (frequency, 2.9%).Therefore, a neurological complication from anti–PD-1 therapystill appears to be rare. This frequency is similar to the rate in arecent retrospective review by Zimmer et al1: from a total of 496patients treated with anti–PD-1 therapy, they identified 6 patientswith polyradiculitis or polyneuropathy, 2 patients with isolatedcranial neuropathy, 1 patient with myasthenia gravis, 5 patientswith myositis or muscle-related weakness, 3 patients with sei-zures (one of whom also had parkinsonism and bradykinesia),and 4 patients with uveitis or iritis. As in our series, neuromus-cularcomplicationswerethemostcommonneurologicaladverseevents from anti–PD-1 therapy. Referral bias may also be a fac-torbecauseourcenterseescomplexoncologypatients,oftenwithmultiple comorbidities, who may be at greater risk of treatment-related toxic effects. In addition, due to the retrospective natureof this cohort study, there is limited control over data collection,and existing data may be incomplete, inaccurate, or inconsis-tently measured among participants.

Our series expands the clinical phenotype of these disordersand provides important serological, electrodiagnostic, radiologi-cal, and pathological findings that, to our knowledge, have notbeen previously discussed in detail. Involvement of the periph-eral nervous system appears to be more common in our study,which may be an incidental finding and needs to be replicatedat other centers. The range of neuromuscular complications isdiverse, without one specific phenotype. The spectrum of neu-ropathies suggests that there can be both axonal and demyelin-ating types. While there has been a previous report of a micro-vasculitis of nerve,14 our series demonstrates the first case ofnecrotizing vasculitis to date. The myopathy due to anti–PD-1

therapy seems to have a unique pathological profile with evi-dence of necrotizing myopathy, and the clinical phenotype canrange from a mild proximal myopathy to a severe myopathy withprominent respiratory, bulbar, and extraocular involvement. Wedid not observe any disorder involving the neuromuscularjunction in our series; however, the prominent bulbar involve-ment of the myopathy could be mistaken for a disorder of theneuromuscular junction. In addition, we found single cases ofcerebellar ataxia and bilateral internuclear ophthalmoplegia thathave not been described to date in association with anti–PD-1therapy. There were also single cases of autoimmune retinopa-thyandheadache.Autoimmuneretinopathyhasbeenpreviouslyreported,19 while headache is a commonly reported adverseevent, with an estimated frequency between 12% and 24%.21 Ourseries demonstrates the importance of careful clinical evaluationand testing, as well as pathological confirmation, to understandthese conditions and guide treatment.

The time from starting anti–PD-1 therapy to developmentof neurological complications was variable; therefore, the cli-nician needs to maintain a high suspicion for these disorders.This observation is consistent with the variability in pub-lished individual case reports. Furthermore, the timeline ofthese adverse events can also vary considerably, with somecases starting more insidiously and evolving over months butwith other cases progressing rapidly over days to weeks.

The muscle and nerve biopsies provide additional informa-tion regarding the potential pathogenesis of adverse neurologi-cal events with anti–PD-1 antibodies. The patient with necro-tizing vasculitis (patient 6) had large epineurial perivascularinflammatory collections composed of primarily T lymphocytes.TheinflammatoryreactionislikelyduetotheblockadeofthePD-1pathway, enhancing the activity of effector T cells in tissues.2 Pa-tient 1 had no inflammation on muscle biopsy, which may be duetothebroadermechanismofactionofanti–PD-1antibodies,whichincludesnotonlyenhancingtheactivityofeffectorTcellsbutalsoenhancing natural killer cell activity, as well as promoting anti-body production indirectly or through direct effects on PD1-positive B cells.2 This theory is further supported by the positiveanti-PM/Scl antibody that can be found in patients with derma-tomyositis, polymyositis, systemic sclerosis, and systemic auto-immune disease overlap syndromes.22

LimitationsBased on the small number of cases in our series, it is notpossible to determine the optimum treatment regimen for thesecomplications. Guidelines for the best treatment of these neu-rologicaladverseeventsremainsparse.Previouslypublishedrec-ommendations include discontinuation of the medication inmoderate to severe (grade 2-4) adverse reactions, plus a courseof high-dose prednisone (0.5-2 mg/kg daily) tapered over at least1 month, with additional immunosuppressive therapy reservedfor those who worsen despite corticosteroid therapy.7 In our se-ries, all but 3 patients had prompt discontinuation of treatmentwithanti–PD-1antibodies.Mostpatientsinourseriesalsoreceivedhigh-dose prednisone (1 mg/kg), followed by a taper of 10 mg perweek, with generally favorable outcomes. However, it was notclearif immunesuppressanttreatmentwasrequiredinallofthesepatients, including 2 of the 3 patients continuing on therapy with






anti–PD-1 antibodies who were given ongoing immune rescuetreatment. The one clear exception was the patient with severenecrotizing myopathy, who did not respond to corticosteroidsor the addition of plasma exchange. The severe bulbar weaknesslikely contributed to the poor outcome in that particular case. Ifa complication related to anti–PD-1 use is suspected, then promptdiscontinuation of the anti–PD-1 antibody treatment is recom-mended, while evaluation is pursued. As part of the workup ofneuromuscular complications, we recommend electrodiagnos-tic studies and consideration of muscle or nerve biopsy to bet-ter understand the pathophysiological mechanisms underlyingthese adverse events. If the clinical examination demonstratessevere clinical deficits at onset or worsens despite medicationdiscontinuation, additional immune suppressant treatmentshould be considered. Corticosteroid treatment is the most com-mon first-line agent, and a regimen of prednisone (1 mg/kg) witha taper over 1 month is recommended. The addition of intrave-nous immunoglobulin or plasma exchange can be considered ifthere is continued clinical worsening.

Conclusions

Patientsreceivingtreatmentwithanti–PD-1antibodieshavemeta-static cancer and are at risk of developing neurological compli-cations related to their underlying disease. A thorough differen-tial diagnosis and search for other potential causes must be per-formed in each case. As our series demonstrates, it is importantto appreciate that new neurological symptoms in these patientscould also herald onset of immune-mediated complications re-lated to the treatment itself. The clinician must remain vigilantat all stages of treatment and even for a period after treatment hasbeen completed. The neurological deficits can evolve rapidly andmay be severe or life-threatening in some cases. However, withprompt recognition and intervention, the outcomes are gener-ally favorable. Although neurological complications relating toanti–PD-1 antibody therapy appear to be rare, we will likely en-counter more cases in the future as the use of these medicationsin the treatment of metastatic cancer continues to expand.

ARTICLE INFORMATIONAccepted for Publication: May 20, 2017.

Published Online: September 5, 2017.doi:10.1001/jamaneurol.2017.1912

Correction: This article was corrected onOctober 9, 2017, to fix an error in the abstract.

Author Contributions: Dr Mauermann had fullaccess to all of the data in the study and takesresponsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: Liao, Klein, Naddaf, Staff,Mauermann.Acquisition, analysis, or interpretation of data: Kao,Liao, Markovic, Naddaf, Staff, Liewluck, Hammack,Sandroni, Finnes, Mauermann.Drafting of the manuscript: Kao, Staff, Finnes,Mauermann.Critical revision of the manuscript for importantintellectual content: All authors.Statistical analysis: Kao, Mauermann.Administrative, technical, or material support: Liao,Naddaf, Finnes.Study supervision: Markovic, Hammack, Sandroni,Mauermann.

Conflict of Interest Disclosures: Dr Liewluckreported receiving an honorarium from theAmerican Association of Neuromuscular &Electrodiagnostic Medicine (AANEM) for a lecture.Dr Mauermann reported received honoraria fromthe AANEM and the American Academy ofNeurology for lectures, reported receivinghonoraria from the Continuum: Lifelong Learning inNeurology journal for manuscripts published,reported receiving consultant fees from IonisPharmaceuticals for the transthyretin amyloidclinical trials, reported receiving research supportfrom Ionis Pharmaceuticals and Alnylam for thetransthyretin amyloid clinical trials, and reportedreceiving royalties from the book AutonomicFailure: A Textbook of Clinical Disorders of theAutonomic Nervous System, published by OxfordUniversity Press. No other disclosures were reported.

Additional Contributions: Janean Engelstad,HT (Peripheral Nerve Laboratory, Mayo Clinic,Rochester, Minnesota) prepared the figure. Nocompensation was received.

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Research Original Investigation Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

1222 JAMA Neurology October 2017 Volume 74, Number 10 (Reprinted) jamaneurology.com


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JAMANeurology | OriginalInvestigation … · 2021. 1. 20. · N eurologicalcomplicationsareanincreasinglyrecog-nizedconsequenceoftheuseofanti–programmed death1(PD-1)antibodiesinthetreatmentofsolid-organtumors