Journal Pre-proof

Papillitis associated with IgLON5 autoimmunity: A novel clinical

phenotype

Xiaoyang Li, John J. Chen, Minjun Hur, Gillian R. Paton, Andrew

McKeon, Anastasia Zekeridou

PII: S0165-5728(24)00030-4
DOI: https://doi.org/10.1016/j.jneuroim.2024.578312
Reference: JNI 578312

To appear in: Journal of Neuroimmunology

Received date: 27 October 2023

Revised date: 22 January 2024
Accepted date: 4 February 2024

Please cite this article as: X. Li, J.J. Chen, M. Hur, et al., Papillitis associated with
IgLON5 autoimmunity: A novel clinical phenotype, Journal of Neuroimmunology (2023),
https://doi.org/10.1016/j.jneuroim.2024.578312

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© 2024 Published by Elsevier B.V.

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Papillitis Associated With IgLON5 Autoimmunity: A Novel Clinical Phenotype.

Xiaoyang Li MDa, John J. Chen MD, PhD a,b,c, Minjun Hur MD a,b, Gillian R. Paton MDd, Andrew
McKeon MDa,c,e, Anastasia Zekeridou MD, PhDa,c,e

a
Department of Neurology, Mayo Clinic, Rochester
b
Department of Ophthalmology, Mayo Clinic, Rochester
c
Center of MS and Autoimmune Neurology, Mayo Clinic, Rochester
d
Casey Eye Institute Division of Neuro-ophthalmology, Oregon Health & Science University
e
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester

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Correspondence:

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Anastasia Zekeridou MD, PhD
Department of Neurology
Department of Laboratory Medicine and Pathology -p
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Mayo Clinic, Rochester
200 First Street SW, Rochester, MN, 55905, USA
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Email: zekeridou.anastasia@mayo.edu
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Conflict of Interest: John J. Chen serves as a consultant for UCB and Horizon; Andrew McKeon reports
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research funding from the National Institutes of Health (NIH: RO1NS126227, U01NS120901), patents
issued for GFAP and MAP1B-IgGs and patents pending for PDE10A, Septins-5 and -7, and KLCHL11-
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IgGs, and has consulted for Janssen and Roche pharmaceuticals, without personal compensation;
Anastasia Zekeridou reports patents pending for PDE10A-IgG, Tenascin-R-IgG and DACH1-IgG as
biomarkers of neurological autoimmunity; research funding from Roche not relevant to the current
project; consulting for Alexion Pharmaceuticals with no personal compensation;
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Abstract:

Objectives: To describe papillitis as a clinical phenotype of IgLON5 autoimmunity.

Methods: We retrospectively reviewed patients with IgLON5 autoimmunity who had optic neuropathy,
optic neuritis, or optic disc edema. Sera from patients with recurrent papillitis were tested for IgLON5
antibodies.

Results: We found two elderly males presenting with papillitis in the presence of IgLON5 antibodies.
CSF pleocytosis was present and partial vision improvement occurred in one patient despite
immunotherapy. Sera from 18 patients with recurrent papillitis were negative for IgLON5 antibodies.

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Conclusion: Papillitis could be a manifestation of IgLON5 disease, with or without accompanying
cognitive, sleep, and movement disorders.

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Keywords: IgLON5, papillitis, papilledema, optic nerve, optic disc edema
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1. Introduction
IgLON5 autoimmunity commonly affects the elderly population and may present insidiously posing
diagnostic challenges (Gaig et al., 2018; Gelpi et al., 2016; Honorat et al.,2017; Sabater et al., 2014). The
clinical presentation is heterogeneous with phenotypes including cognitive impairment, sleep disturbance,
gait/movement disorders, bulbar dysfunction, and motor neuron disease-like syndrome (Gaig et al., 2017;
Gruter et al., 2023; Honorat et al., 2017; Sista et al., 2022). Early recognition and immunotherapy within
the first year of disease presentation are associated with better outcomes (Gruter et al., 2023). Oculomotor
involvement such as supranuclear gaze palsy has been reported, however, optic nerve involvement is not
an established clinical presentation in this disease. We report two cases of papillitis associated with
IgLON5 autoimmunity, suggesting a possible new clinical phenotype in this rare disorder.

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2. Methods

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This study was approved by the Mayo Clinic IRB; patients gave consent for the use of their medical
records for research. We retrospectively identified patients with IgLON5 autoimmunity (defined as the
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presence of IgLON5-IgG in serum and/or CSF, tested with both a tissue-based and cell-based indirect
immunofluorescence assay, as previously described) (Honorat et al., 2017) and optic neuropathy. We also
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tested 18 patients' sera with recurrent papillitis for IgLON5-IgG.

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3. Results
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Two patients were identified meeting the inclusion criteria of IgLON5-IgG positivity and optic
neuropathy. All sera tested from the 18 patients with recurrent papillitis were negative for IgLON5-IgG.
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Patient 1

A man in his late 60s, with a prior history of pericarditis, basal-cell carcinoma, and Grover’s disease,
presented with rapid sequential painless vision loss in both eyes (right>left) and no other neurological
symptoms. At nadir, the visual acuity was no light perception (right) and 20/25 (left). Fundoscopic
examination revealed bilateral optic disc edema (right > left). On optical coherence tomography (OCT),
the peripapillary retinal nerve fiber layer (RNFL) thickness was elevated at 217 microns (right) and 195
microns (left). Brain and orbit MRI were normal. CSF analysis showed normal opening pressure (OP, 15
cm H2O), 8 nucleated cells/μL (91% lymphocytes), normal protein, glucose, and no oligoclonal bands.
Cytology, meningitis/encephalitis panel, bacterial and fungal cultures were negative. Serum aquaporin-4
(AQP-4) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. IgLON5-IgG was
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positive in both serum (1:15360) and CSF (1:16). HLA genotyping was not performed. He was treated
with intravenous (IV) methylprednisolone 1000 mg daily for 5 days followed by 7 sessions of therapeutic
plasma exchange and intravenous immunoglobulin (IVIG) 1g/kg divided over 3 days, continued at
0.4g/kg every 3 weeks as maintenance. Upon follow-up 2 months later, his vision improved from no light
perception to counting fingers (right) and 20/20 (left) with an improved color vision on the left (Ishihara
plate from 2/14 to 13/14). On fundoscopic exam, there was disc pallor in the right eye and chronic grade
3 disc edema on the left. (Fig. 1A). OCT showed RNFL layer thickness of 85 microns (right) and 184
microns (left). There were no abnormalities of the macula to suggest neuroretinitis. (Fig. 1D) The
fluorescein angiogram was normal other than leakage from the left optic disc. A thyroid nodule was
incidentally noted and subsequently proven to be metastatic medullary thyroid carcinoma.

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Patient 2

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A man in his late 50s developed episodes of transient binocular diplopia and pressure-like sensation in his

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head. He was evaluated by an ophthalmologist and had grade 2 disc edema in both eyes, bilateral superior
arcuate visual field loss (Fig. 1F), and right abduction deficit. Initial CSF analysis had normal OP (20 cm
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H2O), 17 nucleated cells (95% lymphocytes), elevated protein at 86 mg/dL, and normal glucose. MRI
/MR venogram was unremarkable but he was treated with acetazolamide for presumed papilledema
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despite the normal OP. He was evaluated in our institution 6 months later: optic disc edema had resolved,
and superior arcuate defects were stable in both eyes. On OCT, average RNFL thickness decreased from
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132 microns to 76 microns (right) and from 135 microns to 70 microns (left). (Fig. 1E) There were no
abnormalities of the macula on OCT. In the context of normal OP, the presence of pleocytosis, and
significant superior arcuate defects in the setting of only grade 2 (mild) optic disc edema that would not
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normally cause vision loss, papillitis was favored over papilledema from intracranial hypertension;
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acetazolamide was discontinued. The patient also complained of gait imbalance with a reassuring exam
and insomnia. A repeat lumbar puncture 1 year after symptom onset revealed a normal OP of 24cm H2O,
persistent pleocytosis (7 nucleated cells, 88% lymphocytes), and elevated protein of 93 mg/dL. IgLON5-
IgG was positive (1:32). HLA genotyping was not performed. There was no recurrence of the papilledema
off acetazolamide. A sleep study was notable for rapid eye movement (REM) sleep without atonia.
Neuropsychometric test showed mild cognitive deficits in executive functions, visual memory, and
learning. He was treated with IV methylprednisolone 1g for 3 days, followed by 1g weekly for 11 weeks
with a repeat CSF analysis after showing resolved pleocytosis but elevated OP at 39 cm H2O, with no
recurrence of optic disc edema and stable visual field defects. Due to symptom resolution, no further
immunotherapy was pursued and the patient was stable one year later.
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4. Discussion

We describe two cases of papillitis associated with IgLON5 autoimmunity, both presenting subacutely
and with lymphocytic pleocytosis in the CSF. In the first case, papillitis was the sole clinical
manifestation, while the second patient had some minor cognitive and gait symptoms with a reassuring
exam. While non-arteritic anterior ischemic optic neuropathy (NAION) is the most common cause of
optic neuropathy in elderly patients, the spinal fluid evaluation showed pleocytosis in both patients that
would not be compatible with NAION; the bilateral simultaneous involvement would also argue against
this diagnosis. In addition, the first patient presented with no light perception vision in one eye that
improved to counting fingers with immunotherapy, which would be atypical for NAION. The second

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patient presented with bilateral superior arcuate visual field deficits which would be out of proportion to
the mild optic disc edema if this were papilledema from raised intracranial pressure. Further complicating

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the course was the elevated OP detected on the subsequent lumbar puncture (normal when the patient was
initially symptomatic), however, the optic disc edema was no longer present arguing against the
correlation between the two.
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IgLON5-IgG detection is based on the characteristic staining on murine tissue indirect
immunofluorescence and the positivity on a cell-based assay making this antibody highly specific when
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properly tested, as in our patients; multiple control patients with recurrent papillitis phenotype (in this
study), as well as IgLON5 autoimmunity mimics (evaluated previously), were all negative (Honorat et al.,
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2017). Although alternative causes for papillitis such as unidentified antibodies and non-humoral
inflammation are possible, IgLON5 autoimmunity remains most likely given the presence of some mild
symptoms (gait, sleep disturbances) consistent with IgLON5 autoimmunity and the similarities between
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the two cases. Interestingly, the first patient was found to have medullary thyroid carcinoma as a part of
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the systemic evaluation. Paraneoplastic optic neuropathies have been well-reported, particularly in
neuroendocrine tumor patients (Thirkill et al., 1989; Cross et al., 2003; Slamovitis et al., 2013). However,
paraneoplastic IgLON5 autoimmunity is uncommon and IgLON5 expression was not investigated in the
tumor to prove a potential paraneoplastic phenomenon (Gaig et al., 2017; Graus et al., 2021; Gruter et al.,
2023; Honorat et al., 2017).

The optic nerve involvement seen in these two cases was papillitis, as the optic nerve head seemed to be
preferentially affected without signal abnormalities or enhancement in other segments of the optic nerve
on the orbit MRI. IgLON5 mRNA transcripts were found in the ganglion cell layer of the retina in a
developing mouse, which may explain the involvement of the optic nerve head (Fearnley et al., 2021).
Therefore, we suspect that papillitis could be a unique presentation of IgLON5 autoimmunity, as seen for
example in patients with glial fibrillary acidic protein or collapsin response mediator protein-5
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autoimmunity (Cohen et al., 2020; Chen et al., 2018). Recently another patient was briefly described with
IgLON5 autoimmunity and bilateral optic disc edema followed by sleep disorders and orthostatic
intolerance, which further supports that papillitis could potentially be a unique presentation in this disease
(Varma-Doyle et al., 2023). Future studies are needed to characterize IgLON5 expression and
mechanisms of autoimmunity in patients with this rare opthalmic presentation. In addition, another case
of cranial nerve (trigeminal) involvement was described recently in IgLON5 autoimmunity (Gluse et al.,
2023) raising the question of the spectrum of IgLON5 autoimmunity.

5. Conclusions

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Our study suggests that the optic nerve can rarely be involved in IgLON5 autoimmunity. Checking for
IgLON5 antibodies could be considered in patients with papillitis of unclear etiology, especially in elderly

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patients with or without accompanying cognitive, sleep, and movement disorders. Early immunotherapy

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in patients with IgLON5 autoimmunity is associated with better outcomes hence early recognition of this
disease is critical (Gruter et al., 2023). Larger scale studies are needed to further confirm and characterize
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this rare phenotype.
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Fig 1. (A-D, Patient 1): A. Funduscopic examination showed optic disc pallor in the right eye and grade
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3 optic disc edema in the left eye 2 months after the onset of vision loss; B. PET-CT showed intensely
FDG avid superior mediastinal/right paratracheal mass (arrow); C. MRI orbits T1 post-contrast axial
image showed no optic nerve enhancement. D. OCT macular cuts demonstrated intact retinal structures in
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both eyes with no signs of neuroretinitis. (E-F, Patient 2): E. OCT demonstrated bilateral optic disc
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edema with average RNFL of 132 μm in the right eye and 135 μm in the left eye. F. Visual field testing
demonstrated bilateral superior arcuate visual field defects in both eyes stable at the last follow-up (>2
years).

Funding: None.

Conflict of Interest: John J. Chen serves as a consultant for UCB and Horizon; Andrew McKeon reports
research funding from the National Institutes of Health (NIH: RO1NS126227, U01NS120901), patents
issued for GFAP and MAP1B-IgGs and patents pending for PDE10A, Septins-5 and -7, and KLCHL11-
IgGs, and has consulted for Janssen and Roche pharmaceuticals, without personal compensation;
Anastasia Zekeridou reports patents pending for PDE10A-IgG, Tenascin-R-IgG and DACH1-IgG as
 Journal Pre-proof

biomarkers of neurological autoimmunity; research funding from Roche not relevant to the current
project; consulting for Alexion Pharmaceuticals with no personal compensation;

Acknowledgments: We thank the patients and their families for their participation in this study.

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