A 17-year-old man was referred for bilateral optic disc edema found on a routine examination. He had no visual or systemic complaints. His mother had a brain tumor of unknown type. Vision was 20/20 bilaterally with normal color vision, pupillary reactions, ocular motility, and anterior segment examination. The patient had bilateral optic disc edema, vitritis with peripheral inferior snowballs, and retinal periphlebitis (Fig. 1A). Retinal fluorescein angiography demonstrated bilateral optic disc and retinal vascular leakage (Fig. 1B). Automated visual field testing demonstrated enlarged blind spots. Laboratory evaluation was unremarkable, including investigations for sarcoid, tuberculosis, and syphilis. Brain MRI demonstrated an irregular 21.9 × 19.3 × 23.4-mm pineal region mass with mild compression of the sylvian aqueduct without signs of increased intracranial pressure. Magnetic resonance venography was unremarkable.
The pineal mass was debulked, and pathology was consistent with a germinoma (OCT3/4+, PLAP+, c-kit+, hCG negative, and pankeratin negative) (Fig. 2). Antiretinal antibodies were ordered (Ocular Immunology Laboratory, Oregon Health and Science University, Casey Eye Institute, Portland, OR). Western blot and immunohistochemistry were positive for several, including the 62-kDa, 30 kDa (carbonic anhydrase II), 40-kDa, 46-kDa (enolase), 80-kDa, and 112-kDa proteins. We concluded that the patient had an autoimmune paraneoplastic optic neuropathy due to collapsin response-mediating protein (CRMP-5) antibodies from the pineal germinoma. He initially was treated with chemotherapy (ACNS 1123 protocol) but this was discontinued due to cytopenia. He then underwent radiation therapy. Brain MRI showed no signs of tumor progression or dissemination and the patient remained stable, without visual complaints during 7 months of follow-up.
Pathological autoantibodies may be due to a paraneoplastic or autoimmune process. Clinical syndromes resulting from paraneoplastic and autoimmune antibodies can be similar. In addition, patients with the same autoantibody can have variability in their manifestations.
In the eye, the most common pathological autoantibodies are antiretinal antibodies. Syndromes from these antibodies include cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation.
Paraneoplastic optic neuropathy is clinically distinct from paraneoplastic retinopathy. It commonly presents as subacute vision loss with bilateral disc edema, visual field defects, vitreous cells, and vascular leakage. Many, but not all, patients have other neurologic symptoms. There are other reports of paraneoplastic optic neuropathy associated with CRMP-5 and Purkinje cell antibody (PCA-2) in patients with small cell lung cancer (1,2).
Intracranial germ cell tumors comprise approximately 1% of all primary brain tumors, with germinomas consisting of approximately 65% of these. Germinomas typically affect adolescent males arising in the suprasellar or pineal region, potentially causing ophthalmic symptoms of dorsal midbrain syndrome and/or papilledema. There are 2 previous reports of germinoma-related paraneoplastic syndrome involving the eye. Chang et al (3) described a 14-year-old boy with visual acuity of 20/40 in each eye, bilateral vitreous cells, and optic disc edema with retinal vascular sheathing and exudates in a “candle wax dripping” pattern. He also had signs of dorsal midbrain syndrome, tremor, and gait imbalance. Evaluation revealed a 3-cm pineal germinoma. After radiotherapy, complete resolution of retinal findings occurred. Autoantibodies were not reported. Forooghian et al (4) reported a 14-year-old boy with a pineal gland tumor who was 20/20 in both eyes but had bilateral disc edema with retinal periphlebitis and findings of dorsal midbrain syndrome. He was treated with radiation and chemotherapy, and at 6-month follow-up, ocular findings had resolved. An antibody to a 35-kDa retinal protein was the only reported positive seromarker.
The pineal gland may possess photoreceptor-like tissue, explaining why antibodies react to the retina and optic nerve. Although paraneoplastic antibodies are neither sensitive nor specific biomarkers, in the proper clinical context they can facilitate making the correct diagnosis and instituting appropriate treatment.
1. Margolin E, Flint A, Trobe JD. High-Titer Collapsin Response-Mediating Protein-Associated (CRMP-5) paraneoplastic optic neuropathy and vitritis as the only clinical manifestations in a patient with small cell lung cancer. J Neuroophthalmol. 2008;28:17–22.
2. Micieli JA, Margolin EA. Paraneoplastic optic neuropathy associated with purkinje cell antibody-2 in a patient with small cell lung cancer. J Neuroophthalmol. 2017;37:53–55.
3. Chang CW, Hay D, Chang TS, Nguyen R, Lyons CJ. Retinal periphlebitis in a patient with pineal germinoma. Arch Ophthalmol. 1999;117:1434–1436.
4. Forooghian F, Chew HF, Muni RH, Adamus G, Drake JM, Buncic JR. Paraneoplastic optic disc oedema and retinal periphlebitis associated with pineal germinoma. Br J Ophthalmol. 2007;91:985–986.