Anti-Asialo GM1 Antibody-Positive Optic Neuritis and Optic Perineuritis in Chronic Inflammatory Demyelinating Polyneuropathy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Anti-Asialo GM1 Antibody–Positive Optic Neuritis and Optic Perineuritis in Chronic Inflammatory Demyelinating Polyneuropathy Celine Olivia, MChD, Melissa M. Chu, MBBS, Subahari Raviskanthan, MBBS, Peter W. Mortensen, MD, Andrew G. Lee, MD C hronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating neuropathy affecting the peripheral nervous system, characterized by progressive relapsing motor and/or sensory symptoms, demyelinating changes on electrophysiology, and albuminocytologic dissociation in the cerebrospinal fluid (CSF). Ganglioside (G) antibodies such as GM1, GD1a, GD1b, and GQ1b are found in a small proportion of patients with CIDP, but clinical– immunological correlation and pathogenicity remain poorly defined (1). CIDP does not commonly affect the central nervous system (CNS), and optic neuritis (ON) is a rare manifestation of CIDP (2). We report the case of a patient with anti-asialo GM1 antibody–associated CIDP who developed radiographic enhancement of the optic nerve and sheath consistent with ON and optic perineuritis (OPN). To the best of our knowledge, this is the first such reported case in the English language ophthalmic literature. A 63-year-old man presented with a 4-day history of progressively blurred vision in the left eye (OS) associated with retro-orbital pain and exacerbated by eye movements. His medical history was significant for CIDP diagnosed 5 years before, manifesting as progressive distal sensory loss, sensory ataxia, tremor, and areflexia. Nerve conduction studies (NCS) were consistent with a demyelinating sensorimotor polyneuropathy. Department of Neurology (CO, MMC), The Canberra Hospital, Canberra, ACT, Australia; Department of Ophthalmology (SR, PWM, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Ste 450 Houston, TX 77030; E-mail: aglee@ houstonmethodist.org Olivia et al: J Neuro-Ophthalmol 2022; 42: e539-e541 CSF studies revealed albuminocytologic dissociation. He was initially managed with IVIG for 5 years. The medical history also included hypertension, hyperlipidemia, and erectile dysfunction. His medications included aspirin, atorvastatin, and testosterone gel. On examination, the visual acuity (VA) was 20/20 in the right eye (OD) and hand motions in the left eye. His pupils were isocoric with a left relative afferent pupillary defect (RAPD). Slitlamp biomicroscopy was normal. Dilated fundus examination revealed Frisen grade 1–2 disc edema with choroidal folds in the left eye (Fig. 1). Extraocular motility and the cranial nerve examination were unremarkable. Automated perimetry (automated visual field 24-2) was normal in the right eye. The average retinal nerve fiber layer (RNFL) on optical coherence tomography (OCT) was 93 mm in the right eye and 230 mm in the left eye, consistent with the clinical optic disc edema in the left eye. The peripheral neurological examination was significant for a low amplitude, moderate frequency action tremor of the left upper limb. The tone was normal with mild weakness of hip flexion. There was diffuse areflexia and impaired pain to pinprick sensation and proprioception to the mid shins. The patient was admitted to hospital for further workup. Baseline laboratory studies for electrolytes, renal, and liver function were unremarkable. The erythrocyte sedimentation rate was 7 mm/hr (0–10 mm/hr). Serum protein electrophoresis, thyroid function tests, HbA1c, antinuclear antibody, Sjogren’s syndrome-related antigen A and B antibodies, angiotensin-converting enzyme, IgG4, syphilis serology, anti–aquaporin-4, myelin oligodendrocyte glycoprotein (MOG), and neurofascin 155 antibodies were negative. Repeat lumbar puncture was significant for elevated CSF protein 167 mg/dL (15–45 mg/dL). The CSF white blood cell count was 10 cells/mm3 (0–5), and the differential was 79% lymphocytes. The CSF red blood cell count was 47 per mL. MRI of the brain and orbits with contrast demonstrated asymmetric enhancement in the left optic nerve and optic nerve sheath, consistent with ON and OPN (Fig. 2). The patient was treated with e539 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus photographs at the time of initial presentation, showing grade 1 optic disc edema in the left eye. 1,000 mg of intravenous methylprednisolone (IVMP) for 3 days. Regular IVIG therapy was ceased, and he was commenced on 1,000 mg IVMP 2 weekly. Repeat NCS showed absence of sensory responses in both legs and the left arm, absence of common peroneal responses bilaterally, marked reduction in left ulnar conduction velocity along the forearm and elbow and a proximal conduction block in the left median nerve, fulfilling the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria for CIDP. Serum asialo-GM1 IgG was subsequently elevated at 1:100 (,1:100). At 4-month neuro-ophthalmic follow-up, his VA was 20/20 in the right eye and count fingers in the left eye with a persistent RAPD in the left eye. His OCT RNFL was 98 mm in the right eye and 45 mm in the left eye, consistent with optic atrophy in the left eye. Neurological assessment after 6 IVMP doses revealed objective improvement in lower-limb sensation and subjective improvement in strength, with a self-reported 80% improvement in limb function, without significant fluctuations toward the end of the dosing interval. Repeat MRI showed resolution of the optic nerve sheath enhancement in the left eye, with T2 hyperintensity consistent with optic atrophy. The patient is now continued on 1,000 mg IVMP monthly. Gangliosides are found in abundance on neuronal membranes and have a role in protecting against complement-mediated damage (3). Antiganglioside antibodies are named for the number of sialic acid residues and inner sugar moieties (3). Asialo-GM1 (Ganglio-N-tetraosylceramide) contains 4 sugar moieties but no sialic acid (3). Antiganglioside antibodies have been detected in immune-mediated neuropathies such as Guillain–Barré syndrome and Miller Fisher syndrome, where they are believed to mediate complement activation and cell-mediated damage (3). The pathogenic mechanism of antiganglioside antibodies in ON or OPN is yet to be elucidated. Antiganglioside antibodies and specifically anti-asialo GM1 have been demonstrated to disrupt and cross the blood–brain barrier, and therefore, it is possible that OPN in this setting shares pathophysiological similarities to peripheral immune-mediated demyelination (4). To date, there are no reported cases of CIDPassociated OPN in the literature. However, 6 cases of CIDP-associated ON in adult patients have been reported (involving 11 eyes in total) (2). These patients were aged between 18 and 57 at diagnosis, with 4 men and 2 women. Funduscopy demonstrated disc swelling in one case, demonstrated disc atrophy in 3 cases, and FIG. 2. MRI of the brain and orbits with contrast, demonstrating subtle asymmetric enhancement in the left optic nerve sheath consistent with optic perineuritis in the coronal (A) and axial (B) sequences, marked with arrows. e540 Olivia et al: J Neuro-Ophthalmol 2022; 42: e539-e541 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence was normal in 2 cases. Three patients had optic nerve enhancement on MRI. Visual-evoked potentials were prolonged in 3 patients. All cases were treated with steroids, with improvement in vision at follow-up in all except one case, where vision deteriorated to light perception only (2). Of note, none of the patients had antibody testing, although this is not required by the current diagnostic criteria for CIDP. To the best of our knowledge, this is the first reported case of anti-asialo GM1 antibody–positive clinical and radiographic ON and OPN in a patient with CIDP. This case report adds to our understanding of clinical– immunological correlates in CIDP associated with ganglioside antibodies. Both ON and OPN may present in a similar clinical manner (e.g., loss of vision, RAPD, and normal or swollen optic disc), but involvement of the optic nerve sheath is the distinctive radiographic feature of OPN. In contrast to multiple sclerosis–related ON which typically demonstrates short-segment optic nerve enhancement, antibody-mediated forms of ON (e.g., anti-MOG ON) may show enhancement of the optic nerve sheath suggestive of OPN. Thus, orbital and cranial MRI should be performed in patients with an acute optic neuropathy to differentiate optic nerve sheath enhancement (OPN) from optic nerve parenchymal enhancement (ON) or both. Clinicians should be aware Olivia et al: J Neuro-Ophthalmol 2022; 42: e539-e541 of the possible CNS manifestations of CIDP including ON and OPN. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee; b. Acquisition of data: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee; c. Analysis and interpretation of data: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee. Category 2: a. Drafting the manuscript: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee; b. Revising it for intellectual content: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee. Category 3: a. Final approval of the completed manuscript: C. Olivia, M. Chu, S. Raviskanthan, P. Mortensen, and A. Lee. REFERENCES 1. Querol L, Siles AM, Alba-Rovira R, Jáuregui A, Devaux J, Faivre-Sarrailh C, Araque J, Rojas-Garcia R, Diaz-Manera J, Cortés-Vicente E, Nogales-Gadea G, Navas-Madroñal M, Gallardo E, Illa I. Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy. Sci Rep. 2017;7:14411. 2. Lin KY, Wang IH, Jou JR, Chu HJ, Wei W, Lee SH, Lin SY. Bilateral optic neuritis related to chronic inflammatory demyelinating polyneuropathy. Taiwan J Ophthalmol. 2015;5:40–43. 3. Cutillo G, Saariaho AH, Meri S. Physiology of gangliosides and the role of antiganglioside antibodies in human diseases. Cell Mol Immunol. 2020;17:313–322. 4. Ariga T. Pathogenic role of ganglioside metabolism in neurodegenerative diseases. J Neurosci Res. 2014;92:1227–1242. e541 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.