Paraneoplastic Optic Neuropathy and Pineal Germinoma With Collapsin Response-Mediating Protein Antibodies

Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant cross-referenced citations, editorials, and reviews. Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with adequate controls and methods to record ocular fixation are needed.

Clinical Correspondence Paraneoplastic Optic Neuropathy and Pineal Germinoma With Collapsin Response-Mediating Protein Antibodies Shripaad Y. Shukla, MD, John H. Pula, MD, Samira Khan, MD, John M. Lee, MD, PhD 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. Departments of Ophthalmology and Visual Sciences (SYS), The University of Chicago, Chicago, Illinois; Department of Ophthalmology (SYS), Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, Oklahoma; Department of Neurology (JHP), NorthShore University Health System, Glenview, Ilinois; Departments of Ophthalmology and Visual Sciences (SK), NorthShore University Health System, Glenview, Illinois; and Department of Pathology (JML), NorthShore University Health System, Evanston, Illinois. The authors report no conflicts of interest. Address correspondence to John H. Pula, MD, Department of Neurology, NorthShore University Health System, 2100 Pfingsten Road, Glenview, IL 60026; E-mail: [e-mail] 198 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, melanomaassociated 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 Shukla et al: J Neuro-Ophthalmol 2018; 38: 198-199 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Funduscopy revealed bilateral optic disc edema with vitritis and retinal periphlebitis B. Fluorescein angiography of the right (5 minutes) and left (6 minutes) eye show optic nerve and perivenular leakage. FIG. 2. Pineal germinoma. A. Aggregated germinoma cells are present (arrow) with a lymphocytic infiltrate (arrowheads). Immunostaining is positive for eKit (c01170), (B), OCT ¾ (C), and placental alkaline phosphatase (PLAP) (D) (A, B, C, and D, ·400). context they can facilitate making the correct diagnosis and instituting appropriate treatment. REFERENCES 1. Margolin E, Flint A, Trobe JD. High-Titer Collapsin ResponseMediating 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. Shukla et al: J Neuro-Ophthalmol 2018; 38: 198-199 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. 199 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.