Paraneoplastic syndromes (PNS) are a group of disorders caused by a host immune response against tumor-associated antigens that cross-react with normal tissues, rather than direct effects of the cancer or its metastases. In ophthalmology, various sites such as the retina, optic nerve, and ocular motor system can be affected.
The main types of ophthalmic PNS are as follows:
The main malignancy associated with CAR is small cell lung cancer, followed by gastrointestinal and gynecological cancers. There is no gender difference. MAR is caused only by malignant melanoma, and cases have been reported in Japan. Other PNS are associated with non-small cell lung cancer, breast cancer, uterine cancer, thyroid cancer, lymphoma, etc.
The onset time varies depending on the type of cancer. In lymphoma and lung cancer, retinopathy develops within weeks to months, whereas in breast and prostate cancer, it may take several years.
In CAR, eye symptoms appear before the cancer diagnosis in about 50% of cases. Unexplained progressive vision loss may lead to further examination and discovery of a malignant tumor.
The main subjective symptoms common to CAR, MAR, and PON are as follows.
Characteristic fundus findings and test results vary depending on the type of disease.
CAR
Optic disc pallor: Pallor reflecting atrophy.
Retinal artery narrowing: Narrowing of blood vessels is observed.
Retinal pigment epithelium mottling: Irregular changes in the RPE.
Bone spicule pigmentation: Findings similar to retinitis pigmentosa.
Mild vitreous cell infiltration: Presence of mild inflammatory cells.
MAR
Predominance of night blindness: Rod dysfunction is prominent.
Photopsia: Patients often report persistent flashes of light.
Fundus nearly normal in early stages: Even with progression, fundus changes may be relatively subtle.
Negative electroretinogram: The a-wave is nearly normal, while the b-wave is markedly reduced (reflecting bipolar cell dysfunction).
PON
Optic disc edema: Characteristic of CRMP-5 antibody-associated disease.
Optic atrophy: Occurs as a sequela of edema.
Retinitis and vitreous inflammatory cells: CRMP-5-associated cases present with retinitis and vitreous inflammatory cells2).
BDUMP
Rapid vision loss: Characterized by a rapid course.
Patchy red fundus: Diffuse fundus changes.
Exudative retinal detachment: Presents with bilateral detachment.
The pathogenesis of PNS involves an autoimmune mechanism in which nervous system antigens ectopically expressed in tumor tissue are recognized by the immune system. Autoantibodies against tumor-associated antigens are produced and attack normal nerve and retinal tissues that express the same antigens.
The main causative malignancies and associated disease types are as follows:
The types of autoantibodies and associated disease types are as follows:
The basis of diagnosis is a combination of clinical symptoms, ophthalmologic findings, and identification of causative autoantibodies. Since ocular symptoms precede cancer diagnosis in about 50% of CAR cases, prompt recognition of this condition can also lead to early cancer detection.
The following findings raise suspicion for this condition.
Differentiation between CAR and MAR based on electroretinogram patterns is important.
| Disease | a-wave | b-wave | Pattern |
|---|---|---|---|
| CAR | Decreased | Decreased | Overall flattening |
| MAR | Nearly normal | Markedly decreased | Negative electroretinogram |
Goldmann perimetry reveals ring scotomas, central scotomas, and central visual field constriction.
Antibody detection by immunohistochemical staining assay, Western blot, and ELISA is necessary for definitive diagnosis. The presence of anti-recoverin antibodies is strong evidence for CAR. For a definitive diagnosis of MAR, demonstration of serum anti-retinal bipolar cell antibodies is required.
Antibodies may not be detected on initial testing. At least three or more repeated measurements are necessary.
Since ocular symptoms often precede the primary tumor, when this condition is suspected, a thorough systemic examination of the respiratory, gastrointestinal, urological, and gynecological systems is essential.
The main differential diagnoses include the following.
The most important differentiating point is the electroretinogram pattern. CAR shows overall flattening with reduction of both a-wave and b-wave, whereas MAR is characterized by a negative electroretinogram with nearly normal a-wave and markedly reduced b-wave, reflecting bipolar cell dysfunction.
Treatment of the underlying malignant tumor is the highest priority. No definitive treatment for CAR and MAR has been established, and there are no controlled human studies showing improvement in visual symptoms.
There is no indication for ophthalmic surgery for PNS. Resection of the underlying malignancy is the treatment for the underlying disease. For PNS associated with thymoma, there is evidence that thymectomy improves symptoms.
No established treatment exists. Treatment of the underlying malignancy is the highest priority. Immunosuppressive therapy, IVIG, and plasma exchange have been attempted, but only case reports of success exist, with no controlled studies. Patients should be informed that the visual prognosis is generally poor.
Malignant tumors ectopically express proteins specific to the nervous system (such as recoverin). The immune system recognizes these as tumor antigens and produces specific antibodies. These antibodies cross-react with the same antigens on retinal photoreceptor cells, causing photoreceptor degeneration and apoptosis.
The main autoantibodies and targets reported in CAR are as follows.
| Autoantibody | Main target cells | Main associated cancer |
|---|---|---|
| Anti-recoverin | Rod and cone photoreceptors | Small cell lung cancer |
| α-Enolase | Retinal ganglion cells and bipolar cells | Small cell lung cancer |
| Anti-hsc70 | Photoreceptor cells | Various cancers |
Alpha-enolase antibodies induce death of retinal ganglion cells and bipolar cells via apoptosis.
CRMP-5 (CV2)-IgG antibodies present with a wide range of peripheral and central nervous system phenotypes, typically paraneoplastic, with small cell lung cancer being the most common 1). In CRMP-5-related optic neuritis, bilateral optic disc edema is characteristic, accompanied by retinitis and vitreous inflammatory cells 2). The most common mechanism as optic neuritis is considered to be photoreceptor apoptosis via a cascade-dependent pathway involving intracellular calcium influx.
There are also case reports of optic neuritis involving anti-recoverin antibodies 3).
Anti-recoverin, α-enolase, and hsc70 are involved in CAR, and CRMP-5 is a representative causative antibody for PON. Additionally, anti-Hu, anti-Yo, anti-AChR, and VGCCA antibodies correspond to each disease type. Symptom patterns and associated cancers differ depending on the type of autoantibody (see “Diagnosis and Testing Methods” section for details).
Kaushik et al. (2024) reported a case of anti-recoverin antibody-positive optic neuritis that responded to a combination of chemotherapy, steroids, and plasma exchange 3). Although not an established standard treatment, it is noted as an example suggesting the potential effectiveness of a multifaceted therapeutic approach.
In a rat model of CAR, calcium channel blockers have been suggested to be effective. This finding indicates the involvement of intracellular calcium influx in photoreceptor apoptosis and may serve as a basis for future treatment development.
It has been suggested that tumors with PNS may have a better prognosis than those without PNS. The autoimmune response may simultaneously function as antitumor immunity, and an association with early cancer detection has been suggested. On the other hand, visual prognosis is generally poor, and the unpredictable course despite various treatments remains a challenge.
