Vision Improves after giving Osimertinib in Paraneoplastic Optic Neuropathy tied to Lung Adenocarcinoma: Case study

Patients with Paraneoplastic optic neuropathy (PON) usually exhibit bilateral subacute vision loss and cerebellar ataxia, and other neurologic deficits are seen in some patients. It has been reported that anti-CV2/collapsin response mediator protein-5 (CRMP-5) antibody is detected in PON associated with small-cell lung cancer. In some patients with autoimmune optic neuropathies, visual function can be improved with corticosteroid treatment, and overall visual prognosis is better compared to those of CAR and MAR. Herein, Kubota et al described the clinical course of an older adult patient diagnosed with and treated for PON associated with lung adenocarcinoma.

Case Presentation

A 76-year-old woman presented with acute bilateral visual disturbances starting one week prior to the first visit. She had been diagnosed with advanced stage 4 lung adenocarcinoma two years prior and treated with the first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib, due to a somatic EGFR exon-19 deletion mutation.

Her decimal best-corrected visual acuity (BCVA) was 0.3 in the right eye (RE) and 0.7 in the left eye (LE). Slit-lamp examination showed mild cataracts and no inflammatory cells in the anterior chamber and media. Funduscopy revealed no abnormal findings in the optic disc, retina, or vitreous humor in both eyes (BE). One week after presentation, her BCVA was decreased to 0.15 in the LE with a relative afferent pupillary defect.

One week later, her BCVA was severely decreased to 0.2 in the RE and 0.01 in the LE. Goldman's perimetry showed a visual-field defect in the lower nasal RE and extensive visual-field loss in the LE. However, spectral-domain optical coherence tomography revealed no remarkable findings in all retinal layers nor swelling around the optic discs in BE.

Dark adapted single-flash electroretinograms using a strong flash (200 cd s m-2) showed normal amplitudes in BE.

Brain and orbital magnetic resonance imaging (MRI) revealed left optic neuritis but showed neither metastatic cancer nor the white matter lesions seen in multiple sclerosis. Cerebrospinal fluid examination revealed no remarkable findings. Full-field pattern-reversal visual evoked potentials (VEPs) showed decreased P100 amplitudes in BE, indicating bilateral optic neuropathy.

Three weeks after the first visit, her BCVA had further decreased to 0.02 in the RE and no light perception (NLP) in the LE, and ERG showed slightly decreased oscillatory potentials (OPs) in BE.

Treatment with oral prednisolone was started at 30mg per day and gradually tapered, but there was no improvement in visual function. Her BCVA decreased to light perception (LP) in the RE and NLP in the LE after the first treatment, and to NLP bilaterally one week later with dilated pupil and absence of the pupillary light reflex. Subsequently, three courses of methylprednisolone (1,000 mg per day) pulse treatment was administered for 3 days but her visual acuity did not improve; her BCVA remained NLP bilaterally at two months after the first visit.

Serum autoantibody tests were negative for antiaquaporin-4 and anti-myelin-oligodendrocyte glycoprotein (MOG) by enzyme-linked immunosorbent assay. Autoantibodies, such as anti-Tr/DNER, anti-GAD65, anti-ZIC4, anti-TITIN, anti-SX1, anti-recoverin, anti-Hu, anti-Yo, anti-Ri, anti-PNMA (Ma2/Ta), anti-CV2/CRMP-5, and amphiphysin antibodies, were negative by immunochromatography analysis. Clinically, PON was diagnosed by exclusion diagnosis.

As transbronchial lung biopsy of the primary lesion revealed the acquired EGFR T790M resistance mutation, her EGFR-TKI treatment was changed from gefitinib to osimertinib, a third-generation EGFR-TKI.

Subsequently, her primary and metastatic lung cancer lesions decreased in size. One week after the change in EGFR-TKI treatment, her BCVA had improved to hand motion in BE. Two months after the first visit, GP showed severe visual-field defects but recovered peripheral visual islands in BE. Orbital MRI showed improvement in the enhanced left optic nerve; however, the ERG response had not changed in BE.

Three months after the first visit, her BCVA further improved to counting fingers (CF) 20 cm in BE. However, pattern-reversal VEPs were nonrecordable in BE. The ERG showed markedly decreased OPs in BE. Funduscopy revealed optic disc pallor, and OCT showed thinning of all layers of the macula and the neuroretinal rim of the optic nerve head in BE, although there was improvement of visual acuity (from NLP to CF). Additional MRI scans performed during the course of the disease showed no evidence of optic neuropathy or optic nerve abnormalities.

At her final visit, approximately two years after the first visit, her BCVA remained 0.01 in the RE and CF 10 cm in the LE, and funduscopy showed optic disc pallor in BE. OCT revealed the thinned macula and optic nerve head. She died at the age of 79 years.

The differential diagnosis of a disease that causes rapid vision loss with no findings in the optic disc or retina at the first visit includes posterior ischemic optic neuropathy (PION), CAR, and PON.

In this case, an increase in the signal of the left eye on the MRI T2 image was considered to be consistent with the diagnosis of PON. PON is an autoimmune optic neuropathy, and CRMP5 has been most frequently reported as an autoantigen associated with PON. Anti-CRMP-5-positive PON develops as optic neuritis with anterior vitreous cells, optic disc swelling, and leakage of the optic disc on fluorescein angiography. In this case, serum autoantibody testing, including anti-CRMP-5, was negative and no retinal/vitreous inflammation nor optic disc swelling was observed during the clinical course. However, PON was diagnosed based on the history of lung adenocarcinoma and on clinical examination.

Because PON is an autoimmune disease, corticosteroid therapy is the first-line treatment, and plasma exchange/plasmapheresis or immunoglobulin therapies are considered second-line therapies.

There has been a report that plasmapheresis therapy in addition to immunosuppression therapies were effective to preserve visual acuity. In this patient, the first treatment with prednisolone did not influence visual acuity outcomes, and three courses of methylprednisolone pulse treatment were ineffective. However, after switching from gefitinib to osimertinib for systemic treatment with anticancer drugs, the primary lung cancer lesions and systemic metastasis were reduced, and visual acuity was notably improved.

In some cases, loss of visual acuity and visual-field defects can be improved transiently in response to corticosteroid monotherapy; however, it has been suggested that ultimate visual function cannot be preserved unless the tumor is reduced in size early after the onset of optic neuropathy. PON associated with lung adenocarcinoma may have a different mechanism from that of small-cell lung carcinoma, with which anti-CRMP-5 antibodies are associated identified. In this patient, the reduced tumor size by osimertinib treatment might lead to a reduction of unknown autoantibody production. Further studies on autoantibodies associated with PON are needed.

Generally, although loss of vision is improved by immunosuppressive treatment, such as corticosteroids, at an early stage in some cases of PON, improved visual function cannot be preserved without treatment of the underlying tumor. In this patient, changing treatment to osimertinib for primary lung adenocarcinoma resulted in visual acuity improvement. This indicates the importance of thoroughly treating the primary cancer for the treatment of PON.

Source: Kubota et al; Hindawi Case Reports in Ophthalmological Medicine Volume 2021

https://doi.org/10.1155/2021/2832021