Bilateral Paraneoplastic Optic Neuropathy as the First Presentation of Preclinical Small Cell Lung Cancer: Case Report

Abstract

Introduction

Paraneoplastic optic neuropathy (PON) is a rare immune-mediated optic neuropathy, secondary to an underlying malignancy. This report describes a rare case of bilateral PON as the initial manifestation in a 77-year-old male, leading to the early detection and treatment of preclinical small cell lung cancer (SCLC).

Case Presentation

The patient initially presented with incidental bilateral disc swelling but was asymptomatic, with preserved visual function. Initial investigations, including orbito-cranial imaging, lumbar puncture, temporal artery ultrasound, and serological testing, were inconclusive. Six weeks later, the patient had persistent disc swelling with compromised bilateral visual function and was commenced on oral steroids. Further diagnostic workup identified paraneoplastic antibodies (anti-CV2/CRMP-5 and anti-Hu) and PET scan findings consistent with a nodular SCLC. Following biopsy confirmation, the patient underwent carboplatin and etoposide chemotherapy, followed by radiotherapy. Initial oral steroids, prior to cancer treatment, resulted in resolution of optic disc swelling and stabilization of visual function.

Conclusion

This case underscores the importance of a systematic approach to optic neuropathies where an initial diagnosis is not found, revisiting diagnostic pathways when initial findings remain ambiguous, and consideration of PON as a differential – even in the absence of known malignancy or typical cancer symptoms. Timely recognition allows for early intervention, improving patient outcomes. This report contributes to the limited literature on PON and highlights the role of multidisciplinary care in managing complex cases involving paraneoplastic syndromes.

Introduction

Paraneoplastic syndromes (PNS) are rare cancer-related complications arising from immune responses to malignancy. They are typically unrelated to tumour burden, invasiveness, or metastasis and may manifest before, during, or after the diagnosis of underlying malignancy [1].

Paraneoplastic visual syndromes encompass a range of conditions affecting the optic nerve and retina. Within the limited literature, paraneoplastic optic neuropathy (PON) was commonly reported in small cell lung cancer (SCLC) but has also been associated with breast cancer, thymoma, and gynaecological malignancies [2].

We describe a rare case of bilateral PON as the first finding in a patient, occurring prior to radiological evidence of malignancy, leading to an early diagnosis and successful treatment of small cell lung carcinoma. This case underscores the necessity of a systematic diagnostic approach to evaluating optic neuropathies, and the importance of revisiting and re-evaluating the diagnostic process in such cases.

Case Presentation

A 77-year-old Caucasian male patient was reviewed in the cataract clinic, where incidental bilateral optic disc swelling was identified. He was subsequently referred to the emergency eye clinic for further evaluation. He had no visual complaints and his only reported symptom was intermittent frontal headaches and a “funny sensation in the head” upon standing. He had a history of smoking, which contributed to his diagnosis of COPD, and rarely drinks alcohol. He lives with his son for support, and reported no significant animal contact or foreign travel.

Past medical history includes COPD, hypertension, hypercholesterolaemia, a single transient ischaemic episode and GORD. His only past ocular history is cataracts.

On examination, visual acuity was right eye (RE) 6/12 with glasses, 6/9 pinhole and left eye (LE) 6/12 with glasses, 6/9 pinhole. Colour vision was RE 14/15 fast, LE 15/15 fast. No RAPD was noted. Fields to confrontation were full – formal Humphreys visual fields were not performed on initial assessment. No extra-ocular movement deficit was noted. No intra-ocular inflammation was present. Figure 1 displays the patient’s bilateral swollen discs on optical coherence tomography, showing an elevated retinal nerve fibre layer and obscuration of vessels exiting the disc (Frisen Grade 3 both eyes).

Fig. 1.

OCT of both eyes, demonstrating bilateral optic disc swelling with increased RNFL thickness. OCT, optical coherence tomography.

Investigations on Admission

The patient was admitted to the medical team for further investigations. Blood pressure on admission was 144/78, with no evidence of postural drop. Table 1 summarises blood tests on admission.

Table 1.

Summary of initial blood tests

Blood test	Result
Full blood count	Normal
Urea and electrolytes	Normal
Liver function test	Normal
Lipid profile	Normal
B12 and folate	Normal
ESR	Elevated (41). Remained elevated 3 days later (31)
CRP	2
Syphilis serology	Negative
Tuberculosis screen	Negative
Serum ACE	Normal
Aquaporin-4 antibodies	Negative

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ACE, angiotensin-converting enzyme.

CT venogram confirmed no evidence of a mass lesion, haemorrhage, or venous thrombosis. MRI identified no abnormality. Subsequent lumbar puncture (decubitus position) demonstrated an opening pressure of 14 cm/H₂O, with normal cerebrospinal fluid constituents other than lymphocytosis. A repeat lumbar puncture several days later demonstrated an opening pressure of 9 cm/H₂O, with persistent lymphocytosis (98% T-cells). Cytology did not reveal any notable abnormality. No flow cytometry results were available.

Suspicion for temporal arteritis was low (Giant Cell Arteritis Probability Score = 4), however, in view of the persistently raised ESR (41 then 31), a temporal artery ultrasound was performed which was negative. The patient was subsequently discharged from hospital and followed up with ophthalmology.

6-Week Review

Six weeks after initial ophthalmic review, the patient was seen again. He no longer reported headaches, however, had now developed bilateral blurred vision.

On examination, visual acuity was RE 6/18 with glasses, 6/9 pinhole and LE 6/18 with glasses, 6/9 pinhole. No RAPD was noted. Humphreys 24-2 visual fields demonstrated early bitemporal inferior field defects, emphasised on the pattern deviation display (shown in Fig. 2).

Fig. 2.

Humphreys visual field tests confirming loss of visual fields. SITA, Swedish Interactive Thresholding Algorithm; GHT, glaucoma Hemifield test; VFI, visual field index; MD24-2, mean deviation 24-2; PSD24-2, pattern standard deviation.

Examination confirmed persistent bilateral Frisen Grade 3 disc swelling, with slight improvement of retinal nerve fibre layer thickness in the RE, but worse in the left eye. Given the persistent disc swelling, visual field defects, and reported blurred vision, the patient was commenced oral prednisolone 40 mg for 2 weeks, then taper by 10 mg every 2 weeks.

Further Investigations

Electrodiagnostic testing demonstrated acceptable multi-focal ERG responses with well-maintained cone and rod function in both eyes. RE pattern ERG was low end normal, and LE was less well-defined with poor N95. Flash VEP is repeatable, though RE response was slightly earlier than LE. Pattern VEP whilst present tended to be at the lower limit of normal for amplitude, particularly in the LE. Pattern reversal VEP responses were reduced, although these may be due to the cataracts or swollen discs. Retinal responses otherwise were acceptable.

CT thorax, abdomen, and pelvis demonstrated no significant findings, with no splenomegaly or pathological lymphadenopathy. Oesophago-gastro-duodenoscopy and colonoscopy identified no abnormality.

Following these negative investigations, a paraneoplastic antibody screen tested positive for anti-collapsing response mediated protein (anti-CV2/CRMP-5), and also anti-Hu. This led to a PET-CT scan which demonstrated increased metabolic activity of a nodule in the right hilar region (as shown in Fig. 3).

Fig. 3.

Positron-emission tomography highlighting right hilar nodular activity.

Although initial CT thorax demonstrated no suspicious lesions, when compared to the more recent PET-CT, growth of a right upper lobe endobronchial nodule was noted, from 9 × 5 mm to 19 × 16 mm. The appearance was consistent with a primary lung malignancy, and endobronchial ultrasound-guided biopsy confirmed a SCLC.

Treatment

The right upper lobe small cell endobronchial carcinoma was graded as T1cN1M0. The patient underwent carboplatin and etoposide chemotherapy, followed by sequential radical radiotherapy 40 Gy/15#. Eighteen months post-diagnosis, the patient demonstrated no evidence of recurrence of malignancy.

Three months after the original steroid initiation, he was reviewed by the ophthalmology team upon which he had completed his steroid course. His optic disc swelling has fully resolved, with preservation of visual function. His final visual acuity was 6/7.5 both eyes, Ishihara colour vision testing RE 14/15 fast, LE 15/15 fast. Patient reported no subjective worsening of symptoms. No RAPD noted. Unfortunately, patient failed to attend further appointments so did not have repeat visual field testing.

The CARE checklist that has been completed by the authors has been provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543516).

Discussion

PNS are a rare group of disorders, affecting 1 in 300 patients with malignancy, with a population-level incidence of 1–8 per 100,000 [3]. These syndromes are triggered by an immune response to tumour-associated antigens, resulting in antibodies that cross react with normal tissue. This immune-mediated process results in inflammation and damage in systems distance from the tumour site, including rheumatological, dermatological, and neurological systems [4].

In 2021, Graus et al. [5] introduced an updated diagnostic criteria for PNS that integrates clinical phenotype, antibody type, cancer association, and follow-up data (PNS-Care Score). A diagnosis of “definite” is supported by high-risk antibodies (>70% cancer association), or intermediate-risk antibodies (30%–70% cancer association) alongside a compatible neurological syndrome. For patients who do not meet these criteria or express lower-risk antibodies, a comprehensive cancer screen is recommended. The criteria acknowledge that PNS can be diagnosed without detectable malignancy. The PNS-Care score has demonstrated 93% sensitivity, and 100% specificity, emphasising its diagnostic accuracy [6].

Paraneoplastic visual syndromes not only affect the optic nerve but can also affect retinal function, manifesting as cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse uveal melanocytic proliferation. Cancer-associated retinopathy results from anti-recoverin antibodies targeting recoverin, a calcium-binding protein in receptors. Presentations vary, but may include a triad of photosensitivity, ring scotomas, and attenuated retinal arterioles, with a guarded prognosis. It is commonly linked to SCLC but may also occur in breast, endocrine and gynaecological malignancies. MAR, associated with metastatic malignant melanoma, involves damage to bipolar cells, leading to nyctalopia and visual field loss, with a characteristic negative ERG. Symptoms may arise years after initial cancer diagnosis. Bilateral diffuse uveal melanocytic proliferation is marked by uveal melanocytic proliferation, causing severe bilateral visual loss, and is often associated with pancreatic and lung cancer [7–9].

The incidence of PON is poorly defined due to its rarity. Previously, a clinical diagnosis, key onconeural antibody associations have since been identified, categorised as follows: (1) antibodies strongly associated with specific malignancies (anti-Hu, anti-Ri, anti-amphiphysin, anti-CV2), (2) partially characterised antibodies (ANNA-3, anti-mGluR1, anti-Tr), and (3) antibodies linked to both cancerous and non-cancerous conditions (AchR, anti-VGCC) [10, 11]. These antibodies cross react with neuronal and glial tissue, causing optic nerve dysfunction, resulting in subacute vision loss and optic disc swelling. PON typically manifests after cancer diagnosis with visual complaints, often involving subacute uni- or bilateral visual deterioration, vitritis, or neurological sequelae (including but not limited to internuclear ophthalmoplegia, mononeuropathy, parkinsonism, and myoclonus) [12].

In cases of bilateral disc swelling, it is reasonable to initially consider more common aetiologies, including raised intracranial pressure, ischaemic optic neuropathy, uveitis, inflammatory optic neuropathy, and infections. However, in the context of a known malignancy, paraneoplastic syndrome, carcinomatous meningitis, orbital and intracranial metastases, optic nerve infiltration, or chemotherapy toxicity must be considered [12].

Supportive investigations include MRI/MRV to evaluate orbital and intracranial spaces, exclude venous sinus thrombosis or optic nerve infiltration. Lumbar puncture for opening pressure, cytology, flow cytometry and a paraneoplastic panel can help assess for metastatic CNS spread [12]. For inflammatory causes, MRI should include brain and spine to investigate for neuromyelitis optica. Close ophthalmic monitoring is essential, focussing on visual function (high contrast visual acuity, colour vision, pupil reaction assessment, and formal visual fields) and observing for cranial nerve palsies or extra-ocular movement abnormalities. This facilitates monitoring disease progression and treatment response.

Treatment of PON primarily targets the underlying malignancy and reduces auto-antibody activity [12]. Timely management of malignancies such as SCLC, through surgery, chemotherapy, radiotherapy, or immunotherapy is crucial and may stabilise or improve the optic neuropathy [13]. High-dose corticosteroids, intravenous immunoglobulin, and plasmapheresis have shown efficacy in lowering auto-antibodies and cytokines that drive optic nerve inflammation [12]. Additionally, intra-vitreal triamcinolone has been used in CRMP-5 related optic neuropathy to reduce local inflammation [14].

Due to the rarity of PON, no standardised treatment protocol exists, but a combination of oncological and immunomodulatory therapies remains the cornerstone of management. In this case, whilst the patient responded well to steroids, with improved visual acuity and resolution of disc swelling, further follow-up would have been beneficial. Assessment of contrast sensitivity and visual fields would have provided a more comprehensive assessment, helping gauge response to steroid and cancer treatment from an ophthalmic perspective.

Conclusion

PON is an important differential diagnosis for optic neuropathy and can serve as an early indicator of underlying malignancy. This case underscores the need for a systematic approach to optic neuropathies, and revisiting previous investigations in patients without a definitive diagnosis. Whilst well-characterised antibodies, such as anti-CV2, were detected, further screening for partially characterised antibodies, such as ANNA-3 and anti-TR, may provide additional diagnostic support. PNSs should still be considered even in the absence of detectable malignancy, and ongoing cancer screening over several years may be warranted. It is evident from the literature that there is no standardised approach in the treatment of PON. This is a potential area for future research which can improve the management and subsequent outcomes of patients with PON. A multidisciplinary approach involving neurology, ophthalmology, radiology, and oncology is essential for comprehensive patient care and a timely diagnosis, as demonstrated in this case.

Statement of Ethics

The processes involved in this research adhered to the tenets of the Declaration of Helsinki. Ethics approval was not required, in accordance with the local research ethics guidance. Written informed consent has been obtained from the patient for publication of the details of their medical case, and all accompanying investigations and imaging. The CARE checklist has been completed by the authors for this report.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Sara Sharif: responsible for compilation and analysis of data, and drafting of article and tables. Dhruv Gor: responsible for drafting of article. Haider Shah: responsible for patient consent, compilation and analysis of data, and supporting article drafting. Nima Ghadiri: supervising consultant involved in patient care, conception of work, and approval of final manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All case report information is included within the article. Further enquiries can be directed to the corresponding author.