Optic Perineuritis Associated with Nivolumab Treatment for Non-Small Cell Lung Cancer

Nivolumab is a human monoclonal antibody against programmed cell death 1 with antitumor effects on lung cancer [1]. The increasing use of nivolumab and other immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in immune-related adverse events (irAEs). Skin, gastrointestinal, and endocrine irAEs are often reported. However, optic neuritis frequency is low, and its clinical features are unknown [2-4]. We report a case of optic perineuritis (OPN) during nivolumab therapy for squamous cell lung cancer, which was challenging to treat due to steroid resistance.

A 54-year-old man was diagnosed with squamous cell lung cancer. He underwent right upper lobectomy and concomitant chest wall resection in July 2017. Following the surgery, he received thoracic radiotherapy (RT) for the residual lesion in the intervertebral foramen of the fourth thoracic vertebra (total 60 Gy per 30 fractions). Two months after thoracic RT, multiple pulmonary metastases were observed in the bilateral lung field. He was initially treated with combination chemotherapy comprising carboplatin and nab-paclitaxel although his disease progressed after 2 chemotherapy cycles. As second-line chemotherapy, nivolumab (at a dose of 3 mg/kg, biweekly) was administered in April 2018. During nivolumab treatment, muscle metastasis in the neck occurred with pain. Additional RT achieved tumor shrinkage. Computed tomography scans also showed a reduction in the size of lung metastases. Therefore, we continued nivolumab treatment.

After the seventh dose of nivolumab, visual loss in the right eye was noted in July 2018. An ophthalmologist performed visual acuity test and Goldmann perimetry. His right visual acuity declined to 20/2000, and an inferior nasal visual field defect was observed (Fig. 1). Gadolinium-enhanced cranial magnetic resonance imaging showed enhancement around the optic nerve sheath (Fig. 2). There were no abnormal findings in the brain, optic disc, or retina. Based on the radiological findings and his symptoms, the patient was diagnosed with OPN.

Laboratory findings revealed slightly elevated C-reactive protein level at 0.48 mg/dL, without leukocytosis (Table 1). Serologic examination revealed a negative rheumatoid factor and antinuclear antibody test results. In addition, double-stranded deoxyribonucleic acid-specific antibody, anti-cyclic citrullinated peptide antibody, anti-neutrophil cytoplasmic antibody, and immunoglobulin G4 levels were not elevated. Further, anti-aquaporin-4 antibody, which is recognized in patients with optic neuromyelitis, was also negative. Examination of the cerebrospinal fluid was not conducted because of the patient’s refusal.

OPN was likely caused by nivolumab. Thus, we discontinued further nivolumab administration. Instead, we initiated steroid pulse therapy (intravenous methylprednisolone 1,000 mg/day for 3 days), followed by oral prednisolone (30 mg). Despite these therapies, his visual acuity did not improve, and there was no remarkable change in his visual field defect. A second steroid pulse therapy was administered although the effect was temporary. We considered administering immunosuppressants against OPN although his lung cancer progressed rapidly. He did not want to receive further anticancer treatment and requested palliative care. We subsequently reduced the steroid dose to oral prednisolone (15 mg) because of the poor efficacy of OPN. He was transferred to a palliative care unit at another hospital.

OPN is an inflammatory disease that causes inflammation of the optic nerve sheath, resulting in eye pain and visual loss in most patients [5, 6]. Gadolinium-enhanced cranial MRI, as well as visual acuity and field examinations, is useful to diagnose OPN. Typically, the optic nerve sheath is enhanced. It exhibits the tram-tracks sign on axial view and doughnut sign on a coronal view [5, 7]. The present case involved visual loss, and the tram-track and doughnut signs were observed on enhanced MRI. Thus, the patient was diagnosed with OPN.

OPN is divided into 2 categories, idiopathic and secondary, depending on the cause of the disease. The causes of secondary OPN include sarcoidosis [8], immunoglobulin G4-related disease [6], Behcet’s disease [9], vasculitis [10], infection [11], and neoplasms [12, 13]. There was no evidence of infectious disease or autoimmune disease in the laboratory findings in the present case, as shown in Table 1. Malignancies aside from the preexisting lung cancer were not detected on computed tomography scans and cranial MRI.

It is unclear whether the present case was idiopathic. The outcome of steroid treatment is dependent on the time between the appearance of symptoms and initiation of treatment [5, 11]. The idiopathic group reportedly had a better convalescence than the second group [14]. In the present case, steroid administration had little effect on the patient’s symptoms despite prompt treatment initiation. Considering his medical history, particularly nivolumab treatment, we considered OPN as an irAE rather than idiopathic.

Neurologic irAEs are less common than skin, gastrointestinal, or endocrine irAEs. The frequently observed orbital adverse events of ICIs include uveitis and eye dryness. However, optic neuritis has been associated with ICIs [15-17]. To the best of our knowledge, no reports on OPN as an irAE have been published. Although OPN is a rare irAE, it can cause irreversible visual loss despite appropriate treatment, as in our case. Thus, this irAE should be considered when prescribing ICIs because OPN negatively affects the patients’ quality of life.

Written informed consent for publication of this case report and any accompanying images was obtained from the patient’s wife.

The authors state that they have no conflicts of interest.

We declare that the authors received no funds for this case report.

All the authors contributed to this manuscript and approved the final version.