Ophthalmologic Manifestations of Paraneoplastic Syndromes

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 by Aroucha Vickers, DO on January 15, 2020.


Ophthalmologic Manifestations of Paraneoplastic Syndromes


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) and melanoma-associated retinopathy (MAR).[4]

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]

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][6] 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. [7] Reported ophthalmic manifestations of anti-Hu PNS include tonicpupils, and ophthalmoplegia. [8][9][10] Anti-Yo mainly affects the cerebellum and has been involved with opsoclonus-myoclonus syndrome (OMS).[11][12] Additionally, thymoma-related PNS can present as myasthenia gravis-like illness.[13] Acetylcholine receptor (AChR) and striational antibodies are associated with thymomas and myasthenia gravis (MG).[14]

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

Nystagmus

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

Retinal detachment

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. [15] 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] 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]

Physical examination

The results of a fundoscopic, again, depend on the type of malignancy that is causing the paraneoplastic syndrome[6]. 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)

Signs and 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.[15] Photopsias may also be observed along with photosensitivity.[4][15] Scotomas and peripheral vision loss are less frequent symptoms.

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]

Possible diagnostic procedures

  • ERG
  • Immunohistochemical assays for retinal autoantibodies
  • Western blot
  • CT/MRI/PET (tumor detection)
  • Visual fields
  • Fundus fluorescein angiogram and fundus photography
  • Cerebrospinal fluid (CSF) analysis

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. 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. [16][17]

Management and General treatment

Clinicians generally focus on treating the underlying malignancy, the tumor, in order to treat the PNS. [18] Immunosuppression is often employed using corticosteroids in attempts to attenuate the immune response in PNS. [19] Intravenous immunoglobulin (IVIG) has shown mixed effects in improving visual symptoms in CAR, MAR, ON, and OMS. [2][20] [21] 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. [15][21]

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. [13]

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. [18] Overall, visual prognosis remains poor and unpredictable even through a wide variety of treatments.

References

  1. 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. 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.
  3. Albert ML, Darnell RB. Paraneoplastic neurological degenerations: Keys to tumor immunity. Nature 2004;4(1)36-44.
  4. 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. 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. 6.0 6.1 Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmic manifestations of paraneoplastic syndromes. J Neuro-Ophthal 2008;28:58-68.
  7. Graus F, Keime-Guibert F, René R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148.
  8. 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.
  9. Gordon WC, Leach MTJ. Lung carcinoma with anti-Hu paraneoplastic syndrome. N Engl J Med 2006; 355(4).
  10. Chan JW. Subacute complete ophthalmoplegia: an anti-Hu paraneoplastic manifestation of myxoid liposarcoma. Clinical and Experimental Ophthalmology 2007;35:491-498.
  11. 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.
  12. Fanous I, Dillon P. Paraneoplastic neurological complications of breast cancer. Experimental Hematology & Oncology 2016;5(29).
  13. 13.0 13.1 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.
  14. 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.
  15. 15.0 15.1 15.2 15.3 Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2011;86(4):364.
  16. 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.
  17. 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.
  18. 18.0 18.1 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-54.
  19. Damek DM. Paraneoplastic retinopathy/optic neuropathy. Curr Treat Options Neurol. 2005;7(1):57-67.
  20. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Survey of Ophthalmology 2003;48(1):12-38.
  21. 21.0 21.1 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.