Secondary Logo

Journal Logo

Severe Relapse of Vaccine-Induced Guillain–Barré Syndrome After Treatment With Nivolumab

Yuen, Carlen MD; Kamson, David MD; Soliven, Betty MD; Kramer, Christopher MD; Goldenberg, Fernando MD; Rezania, Kourosh MD

Journal of Clinical Neuromuscular Disease: June 2019 - Volume 20 - Issue 4 - p 194–199
doi: 10.1097/CND.0000000000000230
Case Review
Free

Cancer immunotherapy with checkpoint inhibitors may result in neuromuscular immune-related adverse reactions, including Guillain–Barré syndrome (GBS)-like disease. On the other hand, checkpoint inhibitor therapy may result in exacerbation of underlying autoimmune diseases such as myasthenia gravis and multiple sclerosis. We present a patient who developed a severe and fatal relapse of postvaccination GBS after he was treated with nivolumab, a monoclonal antibody directed to programmed death–1 (PD-1), during a GBS treatment-related fluctuation. We recommend that caution be exercised in starting treatment with PD-1 inhibitors in the acute stage or early in the recovery period of GBS.

Department of Neurology, University of Chicago Medical Center, Chicago, IL.

Reprints: Kourosh Rezania, MD, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637 (e-mail: krezania@neurology.bsd.uchicago.edu).

The authors report no conflicts of interest.

Back to Top | Article Outline

INTRODUCTION

Although the desired effect of treatment with checkpoint inhibitors (CPIs) is to selectively target tumor cells, autoimmune disease may occur as a result of uncontrolled immune response directed against autoantigens in a variety of organs including peripheral nerves, i.e., immune-related adverse reaction (irAE). Neurological irAEs occur in ∼3% of patients treated with PD1 inhibitors, some of which can be severe and even life threatening.1,2 Neuromuscular manifestations, including Guillain–Barré syndrome (GBS), vasculitic neuropathy, polyradiculitis, myasthenia gravis, and myositis, are the most common neurological manifestations.1,2 At least 20 de novo cases of GBS or GBS-like disease have so far been reported.1–3 Exacerbation of a preexisting autoimmune disease such as myasthenia gravis or multiple sclerosis has been reported in patients who have undergone CPI treatment for advanced cancer. Below we present a patient with postinfluenza vaccination GBS who had a severe, fatal GBS relapse after treatment with nivolumab.

Back to Top | Article Outline

CASE PRESENTATION

About 3 weeks after receiving a flu vaccination, a 66-year-old man developed bilateral finger and toe paresthesia followed by weakness of the lower and then upper limbs. He had a history of right thigh melanoma resection 3 years before. Examination 12 days after the onset of initial symptoms and a day after he lost the ability to walk revealed strength of 3/5 in upper-limb muscles, hip flexors, quadriceps, hamstrings, and 2/5 in the ankle dorsiflexors and plantar flexors, as assessed according to the Medical Research Council scale. Pinprick sensation was diminished up to the ankles and fingertips, vibration was lost at the toes, and deep tendon reflexes were absent at the knees and ankles. Cerebrospinal fluid (CSF) analysis showed white blood cell, 7 (56% monocytes, 44% lymphocytes); red blood cell, 21; protein, 37 mg/dL; and a negative cytology. A nerve conduction study 34 days after the flu vaccination demonstrated absent bilateral sural and right median sensory responses, prolonged distal and F wave latencies of the right median nerve, as well as very low amplitudes and very slow conduction velocities of all the motor responses (Table 1); needle electromyography (EMG) showed neurogenic recruitment in all the muscles tested in bilateral lower and right upper limbs and positive waves/fibrillation potentials in the cervical and lumbar paraspinal muscles. He was diagnosed with postvaccination GBS, and intravenous immunoglobulin (IVIg) 2 g/kg was then administered over a period of 5 days. Brain MRI showed a 4 × 5-mm enhancing lesion with associated T2 hyperintensity and restricted diffusion in the right superior medial precentral gyrus, consistent with a brain metastasis. Computed tomography scan of the abdomen and pelvis showed multiple hepatic hypodense nodules, biopsy of which demonstrated metastatic melanoma, BRAF-V600 wildtype. His weakness initially improved after IVIg treatment to the point that he was able to ambulate 100 feet with an assistive device. However, his weakness worsened about 3 weeks later when he lost his ability to ambulate. At that time, the treating physicians considered the possibility of acute onset chronic inflammatory demyelinating neuropathy or paraneoplastic neuropathy. He then received IVIg1 g/kg divided over a period of 2 days and was started on prednisone 60 mg/day and received nivolumab 240 mg, which was repeated after 13 days. His motor strength further declined dramatically about 12 days after the first dose of nivolumab, so that he was unable to sit in the wheelchair, resulting in his transfer to our center. Physical examination revealed motor strength of 3/5 in upper extremities, 1/5 hip flexion and hip extension, and 0/5 in remaining lower extremity muscle groups. His deep tendon reflexes were trace in the upper extremities and absent at the knees and ankles, and there was diminished pinprick sensation in stocking/glove distribution and absent vibratory sensation at the toes. CSF analysis showed white blood cell, 0; red blood cell, 0; and protein, 91 mg/dL. A follow-up EMG study 91 days after the flu vaccination showed severely prolonged distal latencies, reduced amplitudes, very slow conduction velocities, and markedly prolonged F wave latencies. Temporal dispersion of the compound muscle action potential was present with distal stimulation of all the motor nerves, and there was conduction blocks in the right ulnar motor response with stimulation below and above the elbow (Fig. 1 and Table 1). Needle EMG showed positive waves and fibrillation potentials and no motor unit activation in the right tibialis anterior and quadriceps, as well as severely reduced recruitment in right first dorsal interosseous, biceps, and deltoid.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

Antibodies to ANNA-1, Amphiphysin, ANNA-2, CRMP-5, PCA-1, PCA-2, PCA-Tr, GM1, and GD1b were negative. On day 2 of hospitalization, he developed respiratory distress, tachycardia, and hypotension. He was intubated and placed on mechanical ventilation, and then started on plasma exchange (PLEX). During the hospitalization, there were wide fluctuations in heart rate and blood pressure, which were partly attributed to dysautonomia secondary to acute inflammatory demyelinating polyneuropathy (AIDP) because they were persistent between the sessions of PLEX and present after other potential causes such as possible sepsis and dehydration were appropriately treated. He was started on midodrine on day 5 of hospitalization, but on day 9 became severely hypotensive and bradycardic, requiring pressure support, and subsequently expired as the family withdrew life-sustaining therapies. His GBS disability score4 during the course of his disease starting with administration of influenza vaccine is demonstrated in Figure 2.

FIGURE 2

FIGURE 2

Back to Top | Article Outline

DISCUSSION

Immune checkpoint receptors cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and PD-1 promote immune tolerance and prevent autoimmunity by a number of mechanisms that include inhibition of effector T (Teff) cells and increasing the number and activity of Foxp3+CD4+ regulatory T (Treg) cells.5 There is high expression of PD-1 on Treg cells and PD-1 signaling results in Treg proliferation and enhancement of their immunosuppressive activities.5 On the other hand, PD-1 signaling constitutes a major tumor resistance mechanism because different neoplasms express PD-1 ligands to evade the immune responses.5 Therefore, specific CPIs that are new immunotherapies for melanoma and other cancers heighten the immune response by increasing T-cell response against the tumoral tissues, through downregulation of Treg cells among other mechanisms.5,6 A recent study on mice with knock in human ctla-4, which were treated with ipilimumab, an anti-CTLA-4 monoclonal antibody, showed correlation between emergence of irAEs and systemic T-cell activation as indicated by low ratio of Treg/Teff cells.7 A previous study on experimental allergic neuritis, an animal model that mimics clinical, pathological, and electrophysiological features of GBS, suggests that upregulation of Treg cells likely has an important role in the recovery phase of the disease.8 On the other hand, peripheral blood Treg cells are lower in the in the acute stage and increase toward the level of normal controls in the recovery phase of the disease, and after IVIG treatment in patients with GBS.9,10 Furthermore, in a rat model for experimental allergic neuritis, administration of PD-1 ligand alleviated the disease course.11 In that study, PD-1 ligand treatment upregulated Treg and anti-inflammatory IL-4+CD4+ Th2 cells and decreased proinflammatory IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells.

Considering the fact that immunotherapy may result in exacerbation of autoimmunity, patients with baseline autoimmune disease were generally excluded from trials with CPIs. In a small, retrospective multicenter study on patients with advanced melanoma and preexisting autoimmune disease who received ipilimumab, 8 (27%) had exacerbation of their autoimmune disease (increasing joint pain in patients with arthritis and new plaques in patients with psoriasis), which were successfully managed with corticosteroids.12 In the same study, grade 3–5 (severe, life-threatening, or fatal) de novo irAEs, occurred in 10 (33%) of the patients, including fatal outcome in 2 patients. In another recent review,13 approximately 50% of 123 patients with history of underlying autoimmune disease who underwent treatment with CPIs developed exacerbation of underlying autoimmune disease, including deterioration in 2 of 6 patients with multiple sclerosis and 3 of 4 who had preexisting myasthenia gravis.13 In the aforementioned study, 1 patient with a history of GBS did not experience recurrence after CPI therapy. Among the patients with underlying autoimmune neurological disease who received CPI, relapse of myasthenia gravis has been reported in several cases previously14–16; the symptoms could generally be controlled with steroids, sometimes with IVIG.

The subacute course of the neuropathy in our patient and the timing of vaccination were consistent with a postinfluenza virus vaccination GBS. GBS occurs after seasonal flu vaccination in the North America with an estimated risk of 1 case per every 1 million vaccinations, with mean odds ratio of 1.7 (95% CI, 1.0–2.8; P = 0.04).17 Our patient had the demyelinating variant of GBS (AIDP) considering the results of the second EMG/nerve conduction study, despite the fact that first study did not meet the criteria for AIDP. Follow-up study is often needed to differentiate AIDP from axonal variants of GBS.18 Furthermore, although the normal CSF protein level in our patient is atypical for AIDP patients in general, normal CSF protein in the second week of the disease was encountered in about 25% of patients with postflu vaccination GBS in a previous study.19 Recurrence or relapse occurs in about 6%–10% of patients with GBS.20 The initial relapse of GBS in our patient, which occurred shortly after partial response to IVIG treatment, is consistent with a treatment-related fluctuation (TRF).20 TRFs are more frequent in patients treated with IVIG or PLEX early in the disease course and usually respond to additional treatment with IVIG or PLEX.20,21 TRFs occurred in 18.7% of patients in a cohort of 48 cases of postflu vaccination GBS, and only 1 patient (2.1%) had a fatal outcome.19 Most of the previously reported GBS or GBS-like patients associated with CPI therapy improved with steroid and IVIG treatment,1,13 although fatal outcome has been reported in at least 3 previous cases.22–24 Dysautonomia, which contributed to fatal outcome in our patient, was the initial manifestation of GBS secondary to CPI treatment in another report.25 Although it is likely that CPI treatment with nivolumab given during a recovery stage of AIDP resulted in disease exacerbation, the possibility of primary disease progression in our patient cannot be completely excluded.

Our patient is the first report of severe GBS relapse after treatment with nivolumab, which was administered during a TRF. We conclude that administration of CPI treatment during the acute stage of GBS may result in a severe, potentially fatal exacerbation and recommend exercising caution in starting administration of such treatments in patients who are in the acute stage or early in the recovery phase of GBS. Further studies for targeted therapies to treat life-threatening irAEs are warranted.

Back to Top | Article Outline

REFERENCES

1. Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74:1216–1222.
2. Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–225.
3. Gu Y, Menzies AM, Long GV, et al. Immune mediated neuropathy following checkpoint immunotherapy. J Clin Neurosci. 2017;45:14–17.
4. Hughes RA, Newsom-Davis JM, Perkin GD, et al. Controlled trial prednisolone in acute polyneuropathy. Lancet. 1978;2:750–753.
5. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.
6. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98–106.
7. Du X, Liu M, Su J, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res. 2018;28:433–447.
8. Luo B, Han F, Xu K, et al. Resolvin D1 programs inflammation resolution by increasing TGF-beta expression induced by dying cell clearance in experimental autoimmune neuritis. J Neurosci. 2016;36:9590–9603.
9. Pritchard J, Makowska A, Gregson NA, et al. Reduced circulating CD4+CD25+ cell populations in Guillain-Barre syndrome. J Neuroimmunol. 2007;183:232–238.
10. Chi LJ, Wang HB, Zhang Y, et al. Abnormality of circulating CD4(+)CD25(+) regulatory T cell in patients with Guillain-Barre syndrome. J Neuroimmunol. 2007;192:206–214.
11. Ding Y, Han R, Jiang W, et al. Programmed death ligand 1 plays a neuroprotective role in experimental autoimmune neuritis by controlling peripheral nervous system inflammation of rats. J Immunol. 2016;197:3831–3840.
12. Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2:234–240.
13. Abdel-Wahab N, Shah M, Lopez-Olivo MA, et al. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease a systematic review. Ann Intern Med. 2018;168:121–130.
14. Lau KH, Kumar A, Yang IH, et al. Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve. 2016;54:157–161.
15. Zhu J, Li Y. Myasthenia gravis exacerbation associated with pembrolizumab. Muscle Nerve. 2016;54:506–507.
16. Mitsune A, Yanagisawa S, Fukuhara T, et al. Relapsed myasthenia gravis after nivolumab treatment. Intern Med. 2018;57:1893–1897.
17. Vellozzi C, Iqbal S, Broder K. Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence. Clin Infect Dis. 2014;58:1149–1155.
18. Kuwabara S, Yuki N. Axonal Guillain-Barre syndrome: concepts and controversies. Lancet Neurol. 2013;12:1180–1188.
19. Park YS, Lee KJ, Kim SW, et al. Clinical features of post-vaccination Guillain-Barre syndrome (GBS) in Korea. J Korean Med Sci. 2017;32:1154–1159.
20. Ruts L, Drenthen J, Jacobs BC, et al. Distinguishing acute-onset CIDP from fluctuating Guillain-Barre syndrome: a prospective study. Neurology. 2010;74:1680–1686.
21. Visser LH, van der Meche FG, Meulstee J, et al. Risk factors for treatment related clinical fluctuations in Guillain-Barre syndrome. Dutch Guillain-Barre study group. J Neurol Neurosurg Psychiatry. 1998;64:242–244.
22. Bot I, Blank CU, Boogerd W, et al. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13:278–280.
23. Gaudy-Marqueste C, Monestier S, Franques J, et al. A severe case of ipilimumab-induced Guillain-Barre syndrome revealed by an occlusive enteric neuropathy: a differential diagnosis for ipilimumab-induced colitis. J Immunother. 2013;36:77–78.
24. Jacob A, Unnikrishnan DC, Mathew A, et al. A case of fatal Guillain-Barre syndrome from anti-PD1 monoclonal antibody use. J Cancer Res Clin Oncol. 2016;142:1869–1870.
25. Kelly Wu W, Broman KK, Brownie ER, et al. Ipilimumab-induced Guillain-Barre syndrome presenting as dysautonomia: an unusual presentation of a rare complication of immunotherapy. J Immunother. 2017;40:196–199.
Keywords:

Guillain–Barre syndrome; checkpoint inhibitor; dysautonomia; nivolumab; PD-1

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved