Ophthalmologic Manifestations of Paraneoplastic Syndromes
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Disease Entity
Paraneoplastic syndrome (PNS) is defined as signs and symptoms observed from cancer but not directly as a cause of the cancer tissue or its associated sites of metastasis.[1] Thus, the manifestations of PNS are a result of sites distant from the cancer origin.
Etiology
PNS result from immune mechanisms of the body directed against tumor related antigens but presumably cross react with normal antigens in other parts of the body. The host produces antibodies against the cancer antigen, resulting in an autoimmunization and then autoantibodies against normal host tissue.[2][3] The exact response varies on the malignancy and carries some autoantibody specificity. For example, in cancer-associated retinopathy (CAR), it has been reported that antibodies against recoverin, a retinal protein that binds calcium, may lead to vision deterioration observed in CAR.[4][5] There are many different types of conditions that can lead to PNS with ophthalmic symptoms including, but not limited to, CAR, optic neuropathy (ON), bilateral diffuse uveal melanocytic proliferation (BDUMP), Lambert-Eaton myasthenic syndrome (LEMS), melanoma-associated retinopathy (MAR) and paraneoplastic optic neuropathy (PON)[4][6].
Risk Factors
The risk factors for developing PNS are related to the underlying malignancy from which the syndrome originates. The most common cancers associated with PNS are small cell lung cancer, (SCLC) non-small cell lung cancer, melanoma, and cancers of the breast, uterine, and thyroid.[4] Rare causes of PNS are clear cell renal carcinoma, ampullary pancreatic tumor, lymphoma, myeloma, basal cell carcinoma, colon cancer, leukemia, mixed mullerian tumor, prostate cancer, and melanoma.[7][8][9]
Pathophysiology
In CAR patients, antibodies produced against recoverin and other retinal antigens may lead to degradation of retinal photoreceptor cells.[2] Autoantibodies against alpha-enolase, a protein implicated in skin, cervical, ovarian, and breast cancers, can result in death of retinal ganglion and bipolar cells, mediated by apoptosis.[2] Another PNS is paraneoplastic optic neuropathy (PON), in which patients have autoantibodies against collapsin-responsive mediator protein-5 (CRMP-5) or other optic nerve antigens. CRMP-5 realted PON typically produces optic disc edema and optic atrophy. [1][10] Other important PNS antibodies include anti-Hu, anti-Yo, anti-Ma2, anti-NMDA, anti-Ri, anti-GAD, and voltage-gated calcium channel antibody (VGCCA). Anti-Hu PNS involves the brainstem, cerebellum, and temporal lobes and are typically found in patients with SCLC, although a small percentage of people show no evidence of cancer anywhere in the body. [11] Reported ophthalmic manifestations of anti-Hu PNS include tonicpupils, and ophthalmoplegia. [12][13][14] Anti-Yo mainly affects the cerebellum and has been involved with opsoclonus-myoclonus syndrome (OMS).[15][16] Additionally, thymoma-related PNS can present as myasthenia gravis-like illness.[17] Acetylcholine receptor (AChR) and striational antibodies are associated with thymomas and myasthenia gravis (MG).[18] Other antigens reported in CAR are heat shock cognate protein 70 (HSC70)[6] anti-carbonic anhydrase II, anti-GAPDH, interphotoreceptor retinoid-binding protein, neurofilament proteins, tubby-like protein 1 (TULP1), arrestin, GCAP1 and 2, PNR photoreceptor cell-specific nuclear receptor, Rab6A GTPase (Rab6A)[9]. The most popular mechanism assumed for PON is apoptotic death of photoreceptors mediated by cascade dependent pathways, including intracellular calcium influx[6].
| Table 1: Paraneoplastic syndrome antibodies, ophthalmic findings, and associated cancers.
(PCD = paraneoplastic cerebellar degeneration, CRMP = collapsin-response mediator protein, GAD = glutamic acid decarboxylase, SPS = stiff person syndrome, ARRON = autoimmune-related retinopathy and optic neuropathy, NMDA = N-methyl D-aspartate, HSVE = herpes simplex viral encephalitis, VGCCA = voltage-gated calcium channel antibody, PCA = Purkinje-cell antibody) | |||
|---|---|---|---|
|
Antibody |
Ophthalmic Findings |
Associated cancers |
Associated disorders |
|
Alpha-enolase |
Decreased acuity Central cone dysfunction Optic nerve pallor |
Skin Cervical Ovarian Breast |
CAR |
|
Anti-AChR/striational |
Diplopia Ptosis |
Thymoma |
MG |
|
Anti-CRMP5 |
Optic disc edema Optic atrophy |
SCLC Thymoma |
PON |
|
Anti-GAD |
Ptosis Ophthalmoplegia |
Breast SCLC |
SPS Cerebellar ataxia ARRON |
|
Anti-Hu |
Tonic pupil Ophthalmoplegia |
SCLC |
Encephalomyelitis LEMS |
|
Anti-Ma2 |
Vertical gaze paresis Ophthalmoplegia |
Testicular |
Encephalitis |
|
Anti-NMDA |
Mild visual dysfunction Decreased acuity |
Ovarian teratoma SCLC Testicular |
HSVE ON |
|
Anti-PCA-2 |
Optic disc edema Large vitreous cells |
SCLC |
ON |
|
Anti-recoverin |
Progressive vision loss OU |
SCLC |
CAR |
|
Anti-Ri |
Eye movement disorders Ptosis |
Breast SCLC |
OMS Ataxia |
|
Anti-Yo |
Ptosis Oscillopsia |
Ovarian Breast |
OMS PCD |
|
VGCCA |
Mild dry eye Ocular motor abnormalities |
SCLC Non-SCLC |
LEMS Cerebellar degeneration |
| Table 2. Paraneoplastic visual syndromes and their associated antibodies and ophthalmic manifestations. | ||
|---|---|---|
|
Condition |
Associated Antibody |
Ophthalmic Findings |
|
ARRON |
Anti-GAD Anti-CRMP5 |
Asymmetric vision loss Optic disc pallor |
|
BDUMP |
Unknown |
Rapid vision loss Patchy red fundus |
|
CAR |
Anti-recoverin Anti-alpha enolase Anti-transducin Anti-carbonic anhydrase |
Severe loss of vision Photosensitivity Ring scotoma Visual field defects |
|
MAR |
Anti-transducin b Anti-rhodopsin Anti-arrestin |
Night blindness Photopsia Loss of peripheral vision |
Diagnosis
Ophthalmic manifestations of PNS may present before or after the systemic cancer is detected. [19] Prompt recognition of the PNS can lead to earlier diagnosis and treatment of the underlying cancer. The diagnosis of the specific syndrome depends on the clinical presentation, the ophthalmologic findings and finally the identification of the offending antibodies. In CAR, the ocular symptoms are observed before a diagnosis of cancer about 50% of the time. [1] ] The onset of the retinopathy may also depend on the cancer diagnosis. Lymphoma and lung cancer may take weeks to months. Breast and prostate cancer may take years.[6] Although there is a strong correlation between certain cancers and specific autoantibodies, the presence of a certain antibody in patient serum does not guarantee a specific underlying malignancy. [5]
Symptoms
Painless progressive vision loss and positive visual phenomena are frequent complaints among patients with CAR, MAR, or PON. [5] [4][1] The vision loss is typically bilateral but may be asymmetric. Specifically, patients note decreased nighttime vision and worsened color detection.[19] The vision loss may be acute, subacute, and rarely chronic[6]. Photopsias may also be observed along with photosensitivity.[4][19] Scotomas and peripheral vision loss are less frequent symptoms.
Physical examination
The results of a fundoscopic, again, depend on the type of malignancy that is causing the paraneoplastic syndrome[10]. Patients may have:
- Visual field defects
- Optic disc pallor
- Retinal arterial attenuations
- Vision loss
- Decreased visual acuity
- Photopsia
- Retinal detachment, retinal pigmentation and cataracts (BDUMP)
Other findings may include cones and rods degenerations with photoaversion, prolonged glare after light exposure, decreased color perception, central scotoma, ring scotoma, prolonged dark adaptation, nyctalopia, low-grade inflammation in anterior chamber, cellular debris in anterior vitreous, bony spicules or atrophy of retinal pigment epithelium, vascular sheathing, macular edema, periphlebitis, chorioretinitis atrophy, vitritis.[6][9]
Clinical diagnosis
The clinical exam suggestive of CAR, MAR, or PON should prompt further evaluation for retinal and optic nerve autoantibodies (e.g., immunohistochemical assays and/or Western blot) and electroretinography (ERG). Once the antibodies are confirmed, referral to an oncologist is recommended to search for the underlying malignancy.[5] Evidence such as retinal degeneration, atrophic changes in retinal pigment epithelium, and optic pallor with concurrent clinical manifestations may also indicate PON.[6]
Possible diagnostic procedures
- ERG
- Immunohistochemical assays for retinal autoantibodies
- Western blot
- Enzyme-linked immunosorbent assay (ELISA)
- CT/MRI/PET (tumor detection)
- Cerebrospinal fluid (CSF) analysis
- Visual fields
- Fundus fluorescein angiogram and fundus photography
- Fundus autoflorescence (FAF)
- Spectral-Domains Optical Coherence Tomography (SD-OCT)
Differential diagnosis
If paraneoplastic syndromes develop prior to diagnosis of cancer, there is a possibility that the ophthalmic symptoms are not the result of any underlying malignancy. The specificity of antibodies for certain neoplasms is not necessarily high. The diagnosis may even be preceded by the presence of anti-retinal antibodies.[6] In fact, some studies have shown that people with antibodies for a certain antigen may have a non-cancer-related explanation for their visual symptoms. [20][21] The differential diagnosis can include: retinitis pigmentosa, non-paraneoplastic autoimmune retinopathy, acute zonal outer occult retinopathy (AZOOR) along with other white dot syndromes, cone dystrophy, toxic retinopathy, toxic optic neuropathy, Leber hereditary optic neuropathy (LHON), nutritional optic neuropathy, chronic central serous chorioretinopathy (CSCR), and vitamin A deficiency.[9]
Management and General treatment
Clinicians generally focus on treating the underlying malignancy, the tumor, in order to treat the PNS. [22] Immunosuppression is often employed using corticosteroids in attempts to attenuate the immune response in PNS. [23] Treatment using corticosteroids are associated with mild to moderate improvements in visual functions.[6] Intravenous immunoglobulin (IVIG) has shown mixed effects in improving visual symptoms in CAR, MAR, ON, and OMS. [2][24] [25] Other treatments may include alemtuzumab, rituximab, plasmapheresis, azathioprine, cyclosporine, mycophenolate mofetil, lutein, vitamin C, vitamin E, and beta carotene.[6][9] Successful treatments resulting in improvement of symptoms are either anecdotal or found in mice; no controlled human studies have shown improvement of visual symptoms by any means of treatment. [19][25]
Surgery
Ocular surgery is not indicated for PNS. Surgeries may be conducted for tumor excision, which may treat the underlying malignancy. Recently, there has been evidence that in thymoma-associated paraneoplastic syndrome, thymectomy actually improves patients’ symptoms. [17]
Prognosis
There is evidence suggesting that having a tumor with accompanying PNS may lead to a better prognosis than having a tumor and no accompanying PNS perhaps related to earlier detection of tumor. [22] Overall, visual prognosis remains poor and unpredictable even through a wide variety of treatments.
References
- ↑ 1.0 1.1 1.2 1.3 Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management. Survey of Ophthalmology 2013;58:430-458.
- ↑ 2.0 2.1 2.2 2.3 Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmunity Reviews 2009;8(5):410-414.
- ↑ Albert ML, Darnell RB. Paraneoplastic neurological degenerations: Keys to tumor immunity. Nature 2004;4(1)36-44.
- ↑ 4.0 4.1 4.2 4.3 4.4 Alabduljalil T, Behbehani, R. Paraneoplastic syndromes in neuro-ophthalmology. Current Opinions in Ophthalmology 2007;18:463-469.
- ↑ 5.0 5.1 5.2 5.3 Adamus, G Ren, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmology 2004;4:5.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Naramala, S., Ahmad, J., Adapa, S., Gavini, F., & Konala, V. M. (2019). Case series of cancer-associated retinopathy (CAR). Cureus. https://doi.org/10.7759/cureus.4872
- ↑ Wagley, S., Tran, T. M., Mallory, P. W., Lee, M. S., Armbrust, K. R., Trautman, B., & Montezuma, S. R. (2020). Cancer-associated retinopathy due to clear cell renal carcinoma. Ocular Oncology and Pathology, 1–5. https://doi.org/10.1159/000511189
- ↑ Ghadiri, N., Yang, Y., & Burton, B. J. L. (2019). Cancer-associated retinopathy in ampullary pancreatic cancer. BMJ Case Reports, 12(11). https://doi.org/10.1136/bcr-2019-231444
- ↑ 9.0 9.1 9.2 9.3 9.4 Singh, D.&Tripathy, K. (2022). Cancer Associated Retinopathy. National Library of Medicine .Retrieved August 2, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK578183/
- ↑ 10.0 10.1 Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmic manifestations of paraneoplastic syndromes. J Neuro-Ophthal 2008;28:58-68.
- ↑ Graus F, Keime-Guibert F, René R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148.
- ↑ Bruno MK, Winterkorn JMS, Edgar MA et al. Unilateral Adie pupil as sole ophthalmic sign of anti-Hu paraneoplastic syndrome. J Neuro-Ophthal 2000;20(4):248-249.
- ↑ Gordon WC, Leach MTJ. Lung carcinoma with anti-Hu paraneoplastic syndrome. N Engl J Med 2006; 355(4).
- ↑ Chan JW. Subacute complete ophthalmoplegia: an anti-Hu paraneoplastic manifestation of myxoid liposarcoma. Clinical and Experimental Ophthalmology 2007;35:491-498.
- ↑ Rojas I, Graus F, Keime-Guibert F, Reñé et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000;15(5):713-715.
- ↑ Fanous I, Dillon P. Paraneoplastic neurological complications of breast cancer. Experimental Hematology & Oncology 2016;5(29).
- ↑ 17.0 17.1 Suh JW, Haam SJ, Song SW et al. Paraneoplastic encephalitis associated with thymoma: a case report. Korean J Thorac Cardiovasc Surg. 2013;46(3):234-236.
- ↑ Hammoud K, Kandimala G, Warnack W, Vernino S. Multifocal paraneoplastic cortical encephalitis associated with myasthenia gravis and thymoma. Arch Neurol. 2009;66(11):1407-9.
- ↑ 19.0 19.1 19.2 19.3 Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2011;86(4):364.
- ↑ Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol. 1998;126(2):230-237.
- ↑ Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N. Autoimmune retinopathy patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol. 2000;118(11):1525–1533.
- ↑ 22.0 22.1 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-54.
- ↑ Damek DM. Paraneoplastic retinopathy/optic neuropathy. Curr Treat Options Neurol. 2005;7(1):57-67.
- ↑ Chan JW. Paraneoplastic retinopathies and optic neuropathies. Survey of Ophthalmology 2003;48(1):12-38.
- ↑ 25.0 25.1 Subhadra C, Dudek AZ, Rath PP, Lee MS. Improvement in visual fields in a patient with melanoma-associated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol. 2008;28(1):23-26.
