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Abstract

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

Case Presentation

A 16-year-old adolescent boy presented in September 2021 with relapsing-remitting neurologic symptoms (Figure 1). He had a normal birth history and normal development until seizures began in 2019 at age 14 years, after which he required individualized services at school. He was treated with valproic acid and topiramate for presumed myoclonic epilepsy. Brain MRI was normal in 2020 at 15 years. There were no concurrent medical conditions, and family history was negative for developmental delay, seizures, or autoimmune disorders. He denied alcohol or illicit drug use, but was a frequent marijuana smoker.
Figure 1 Timeline of the Patient's History
COVID-19 = coronavirus disease 2019; IVIG = IV immunoglobulin; OCB = oligoclonal band; PLEX = plasmapheresis; URI = upper respiratory infection.
The patient was diagnosed with an asymptomatic COVID-19 infection in August 2021. One month later, he developed right-sided numbness, followed by right-sided weakness and agitation. There was no other preceding illness or travel. In the emergency department, he had a right hemiparesis but could ambulate without assistance. Brain MRI revealed 3 large enhancing white matter lesions on T2 FLAIR imaging that involved the left frontoparietal lobe, left parietal lobe, and right periatrial region (Figures 2A and 2B). MR spectroscopy revealed lactate doublets and a decreased NAA:Cr ratio in the areas of hyperintensity (Figure 2C). Spinal cord MRI showed no lesions. Serum studies were negative for myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies (Mayo Clinic Laboratory). ANA was positive (1:160). Serology for Epstein-Barr virus was positive for IgM (78.2 U/mL) and IgG (401.0 U/mL) antibodies, consistent with recent infection. CSF showed 1 white blood cell (WBC) and normal protein and glucose. CSF meningitis-encephalitis panel and cultures were negative. There were ≥5 CSF-restricted oligoclonal bands (OCBs). He received IV steroids (IV SoluMEDROL 100 mg every 6 hours) for 1 day but did not tolerate the IV steroid because of agitation. He was discharged on an oral steroid taper (prednisone 60 mg for 10 days, followed by 5-day taper). His symptoms fully resolved over 4 weeks.
Figure 2 Initial MRI
(A) T2 FLAIR imaging revealing hyperintensities within the white matter of the left frontoparietal lobe (3.2 cm), left parietal lobe (3.6 cm), and right periatrial region (4.1 cm). (B) Post-contrast imaging revealing partial enhancement of all lesions. (C) MR spectroscopy revealed lactate doublets and a decreased NAA:Cr ratio in the area of hyperintensity.
In mid-November 2021, after a mild upper respiratory infection and root canal procedure, he developed left-sided sensory loss and weakness, necessitating a wheelchair. Repeat MRI showed a 3–5mm increase in size of the left frontoparietal lesion and decrease in size of other lesions. There was a new T2-hyperintense lesion in the right centrum semiovale. Some lesions showed restricted diffusion; he did not tolerate contrast imaging. He was treated with IVIG (1 g/kg/d given for 2 days) and IV corticosteroids (SoluMEDROL 100 mg every 6 hours for 3 days). He was discharged on a steroid taper (prednisone 60 mg for 10 days, followed by a 5-day taper). Within a month after discharge, he could walk with bilateral assistance.
He established care with a MS specialist. Surveillance brain MRI in January 2022 showed increased size of the juxtacortical and deep white matter lesions with peripheral enhancement and a new nonenhancing left cerebellar lesion. Other lesions had decreased in size and degree of enhancement. Some lesions demonstrated areas of encephalomalacia. He received rituximab (1 g × 2 doses) in March 2022 for a presumed immune-mediated process. No CD19(+) B cells were detectable in the blood 3 months later.
In May 2022, he developed status epilepticus requiring intubation in the setting of mild parainfluenza virus infection. MRI showed new nonenhancing brain lesions including the right thalamus and left brachium pontis. Restricted diffusion was present in areas that had enhanced on prior MRI scans. The patient received IV steroids (1 g daily for 3 days).
Within 2 weeks of discharge, he was readmitted with anarthria and weakness of the right lower face and all extremities. Repeat MRI revealed new and enlarging lesions, some with enhancement, involving the bilateral frontal, parietal, and occipital lobes; pons; and middle cerebellar peduncle (Figure 3A). Repeat CSF examination revealed 0 WBC, 11 OCBs, and an elevated IgG index of 1.12 (range 0.28–0.66). Serum and CSF lactate were negative. He was treated with plasmapheresis (7 exchanges), followed by IVIG (1 g/kg/d given for 3 days) with little improvement. For diagnostic clarity, the patient underwent stereotactic brain biopsy of the left parietal lesion (Figure 3B), which revealed mildly hypercellular white matter, lipid-containing macrophages, histiocytic infiltrates, scant perivascular T-cell inflammation, some degree of endovascular cell swelling, and reactive gliosis (Figure 3, C–J). Luxol fast blue staining showed intact myelin (Figure 3E); neurofilament histochemistry showed preserved axons with rare axonal spheroids (Figure 3F). The surrogate type I interferon marker myxovirus protein A (MXA) was positive in the endothelium of the microvessels. Microvascular deposits of C3d, C4d, and C5b-9 were not observed (Figure 3J). Subsequent testing for systemic type I interferon response (serum interferon-alpha from Quest Diagnostics, gene expression assay from DxTerity laboratories) was normal.
Figure 3 Repeat MRI and Biopsy Results
(A) T2 FLAIR imaging revealed new and enlarging lesions, some with enhancement (not shown), involving the bilateral frontal, parietal, occipital lobes, pons, and middle cerebellar peduncle. (B) Post-biopsy site (yellow circle) in the area of hyperintense lesion as seen on MRI. (C–J) Biopsy results. (C and D) Hypercellular white matter with perivascular and parenchymal histiocytic inflammation (H&E stains). (E) A Luxol H&E stain demonstrates intact myelination of the white matter. (F) Neurofilament IHC highlights several axonal swellings, consistent with axonal injury (arrowheads). (G) CD163 IHC highlights histiocytes in a perivascular and parenchymal distribution. (H) CD3 IHC reveals few scattered T cells in a predominantly perivascular distribution. (I) GFAP IHC highlights diffuse gliosis and the cell bodies of reactive astrocytes (arrows). Scale bar = 100 μm (C–I). (J) Myxovirus protein A (MXA) expression is highlighted in the endothelium of microvessels (IHC; 1,000×).
The patient was referred for molecular genetic evaluation, which included chromosomal microarray, next-generation sequencing gene panel for leukodystrophies and leukoencephalopathies, and duo exome sequencing, all of which were unremarkable. Mitochondrial genome testing from a buccal sample revealed a pathogenic homoplasmic variant in the MT-ND6 gene [m.14484 T>C p.(M64V)], associated with Leber hereditary optic neuropathy (LHON).
While the patient denied visual symptoms, he was referred for neuro-ophthalmologic evaluation in view of his genetic finding. His visual acuities were 20/40-1 in the right eye and 20/25-2 in the left eye (without improvement with pinhole). He correctly identified 4/12 Ishihara color plates in the right eye and 8/12 in the left eye. He had concomitant loss of several lines on the Pelli-Robson low contrast chart with the right eye. There was red desaturation of the right eye, but no afferent pupillary defect. Ophthalmoscopy revealed mild optic atrophy of the right nerve greatest temporally. Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) was significant for papillomacular bundle thinning in the right eye; however, average thickness was 101 μm in the right eye and 109 μm in the left eye (>5 μm difference between eyes) (eFigure 1A, links.lww.com/NXI/A975). Humphrey visual field testing suggested an inferonasal defect in the right eye. On follow-up examination 10 months later, he had persistent papillomacular bundle thinning and OCT revealed 100 μm in the right eye and 112 μm in the left eye (>5 μm difference between eyes) (eFigure 1B).

Differential Diagnosis

Pediatric-Onset Multiple Sclerosis (POMS)

POMS is the most common relapsing demyelinating syndrome in children1 and typically follows a relapsing-remitting course. POMS is more inflammatory than adult-onset MS with greater T2 lesion volume and more frequent relapses, although generally with better recovery from attacks.2 Our patient's features suggestive of POMS were an aggressive relapsing-remitting course; positive oligoclonal bands and an elevated IgG index in CSF (nonspecific but sensitive for MS); and MRI lesions located in periventricular, juxtacortical, and infratentorial regions, with changes in enhancement and location over time. However, relapses after commencing rituximab are atypical for MS, especially in the setting of adequate B-cell suppression. Finally, brain biopsy did not reveal demyelination, making the diagnosis of MS unlikely.

Other Neuroinflammatory Disorders and MS Mimics

MOGAD and NMOSD occur in children; therefore, MOG and AQP4 antibody testing should be sent on any pediatric presentation atypical for MS, particularly when optic nerves are involved. It is possible to have rituximab breakthrough in these disorders. MOGAD is especially common in children and may have preceding illness as a trigger. In our patient, these 2 antibodies were absent and brain pathology was not consistent with either disease. Less common causes of relapsing white matter disorders include CNS manifestations of systemic autoimmune and granulomatous diseases (SLE, sarcoidosis, Behcet, Sjogren) and hemophagocytic lymphohistiocytosis (diagnosed with specific clinical features and laboratory abnormalities). Our patient's rheumatologic workup rendered these possibilities unlikely.

Leukodystrophies and Genetic Leukoencephalopathies

Genetic considerations include both leukodystrophies and genetic leukoencephalopathies, such as inborn errors of metabolism (e.g., biotinidase deficiency)3 or genetic small vessel disorders (e.g., CADASIL).4 These diseases were largely ruled out with broad molecular genetic studies.

Mitochondrial Disorders

Primary mitochondrial disease occurs when pathogenic variants in either the nuclear or mitochondrial genome lead to errors in mitochondrial structure or function.5 Positive family history of neurologic disease, vision or hearing loss, seizures, or multiorgan involvement (i.e., heart, liver, pancreas, and kidneys) raise suspicion for a mitochondrial disorder. A relapsing-remitting course is possible in primary mitochondrial disease, such as MELAS,6 POLG-related disorders,1 or MT-ND5–related disorders.7

Final Diagnostic Considerations

In view of genetic test results, our patient was diagnosed with MT-ND6–related mitochondrial metabolism disorder. He was started on a combination of nutritional supplements, including coenzyme Q10, and valproic acid was transitioned to lamotrigine. He was advised to avoid both heavy alcohol use and tobacco/nicotine exposure because these may worsen symptoms.

Discussion

LHON is one of the most common inherited mitochondrial disorders. LHON classically affects young male patients between 10 and 30 years but can occur outside of this age range and in female patients. The typical presentation is painless unilateral vision loss due to an optic neuropathy that progresses to bilateral involvement over weeks to months. Less common presentations include cardiac arrhythmias, movement disorders, seizures, and MS-like illness.8
Three variants account for over 90% of LHON carriers and are m.11778-G>A, m.14484-T>C, and m.3460-G>A, in order of frequency. LHON is maternally inherited and has incomplete penetrance. Male patients are 5 times more likely to be affected than female patients.9 Environment can play a role, with cigarette smoke and excessive alcohol consumption being negative risk factors (likely through the production of reactive oxygen species).9 The m.14484-T>C genotype has the least penetrance and greatest likelihood of at least partial visual recovery.10,11 Close to 50% of male patients with m.14484-T>C lose vision around a median age of 20 years but may have some subsequent recovery.12
The occurrence of multiple sclerosis–like illness has been described in patients with LHON and is termed LHON-MS, or Harding disease, after Harding's publication of 8 cases in 1992.13 As of 2019, there were 57 cases of LHON-MS reported worldwide.14
LHON-MS shares many commonalities with MS, both clinically and radiographically, although there are important differences. The vision loss that occurs in classic demyelinating optic neuritis (painful, typically unilateral, good recovery) is different from that of LHON (painless, sequential over weeks to months, poor recovery).15 However, these features are not pathognomonic, and overlap does occur. LHON vision loss is characteristic of optic neuropathies in the toxic-metabolic category of disease, with acuities in the 20/200 counting fingers range, color vision loss, and central scotomas. Acutely, the optic discs may appear normal or show pseudo-swelling with excess telangiectatic vessels at the optic nerve head. The triad of LHON vision loss—circumpapillary telangiectatic microangiopathy, swelling of the peripapillary RNFL, and absent staining of fluorescein angiography on the eye fundus15—is characteristic but not always seen. Chronically, the optic nerves appear pale. Although a unilateral initial acute presentation is common, LHON is unique among other optic neuropathies in that an afferent pupillary defect may not be present despite marked acuity loss. This has been attributed to sparing of the melanopsin-expressing retinal ganglion cells by the mitochondrial process.16 From a paraclinical standpoint, patients with LHON-MS can have CSF-restricted OCBs17 and neuroimaging indistinguishable from MS. In a study of 30 patients with MS and 11 patients with LHON-MS, neuroradiologists blinded to the underlying diagnosis were unable to differentiate MS vs LHON-MS. MRI features of LHON-MS include T2-hyperintense lesions, T1-hypointense lesions, and brain atrophy.18
The etiology of LHON-MS is debated. Some argue that MS is occurring in those with LHON solely by chance because homoplasmic LHON mtDNA variants are not uncommon, seen in approximately 1 in 1,000 in Northern European populations.19 Others believe MS-like brain lesions in LHON-MS represent neuroinflammatory or ischemic manifestation of mitochondrial disease.20
Our patient with MS-like illness, biopsied brain lesion, and a LHON-causing homoplasmic pathogenic variant in MT-ND6 affords an interesting opportunity to reflect on the entity of LHON-MS. The patient's neuro-ophthalmologic finding of mild optic neuropathy may reflect early involvement of the optic nerves in LHON because male patients with the m.14484-T>C variant most commonly lose vision at a later age, around 20 years.12 The severity of his brain disease relative to optic neuropathy would be atypical for LHON, but in a large cohort of LHON-MS, 26% of individuals (12/46) initially presented with MS-like symptoms and developed visual loss around 7 years later.20 Brain findings in our patient showed intact myelin and preserved axons, which is not consistent with MS. These results are in contrast to a brain autopsy reported in a woman with the m.14484-T>C variant, bilateral optic neuropathy, widespread MS-like lesions, and seizures who had evidence of demyelinating plaques, axonal damage, cystic necrosis with CD8-positive T cells, and vacuolation of the white matter (e1). It is possible that previously reported cases represent a coincident MS in patients with LHON. In our patient, the absence of demyelination made MS unlikely and the brain lesions could represent LHON brain involvement. The type I interferon staining is of interest and could reflect triggering of a type I interferon response. The interferon response could be a by-product of increased mitochondrial reactive oxygen species and the release of mitochondrial DNA into the cytosol of the cell, leading to a mitochondrial-based proapoptotic microenvironment (e2).
It is important to revisit the differential diagnosis when a rare disease has an atypical clinical course. For our patient, further genetic testing revealed a m.14484-T>C variant. The most plausible explanation for our patient's presentation (optic neuropathy, relapsing-remitting brain disease, and seizures) is mitochondrial disease associated with this variant. As novel genetic therapies are on the horizon for certain subtypes of LHON (e3), it is critical to better understand the relation between MS-like illnesses and LHON to determine whether these emerging treatments may be re-engineered or repurposed to address disabling manifestations of the disease outside of the optic nerve.

Glossary

AQP4
aquaporin-4
LHON
Leber hereditary optic neuropathy
MOG
myelin oligodendrocyte glycoprotein
OCB
oligoclonal bands
OCT
optical coherence tomography
POMS
pediatric-onset multiple sclerosis
RNFL
retinal nerve fiber layer
WBC
white blood cell

Acknowledgment

The authors thank the patient and his family for reviewing the manuscript and consenting to its publication. The authors are also grateful to the National Multiple Sclerosis Society including Ms. Hope Nearhood and to Ms. Jill Gregory for the development of Figure 1, which details the complex chronological semiology of this patient's story.

Appendix Authors

NameLocationContribution
Kimberly A. O'Neill, MDDepartment of Neurology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Andrew Dugue, MDDepartment of Neurology; Department of Ophthalmology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data
Nicolas J. Abreu, MDDepartment of Neurology; Division of Neurogenetics, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Laura J. Balcer, MD, MSCEDepartment of Neurology; Department of Ophthalmology; Department of Population Health, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content
Marc Branche, MDDepartment of Radiology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content
Steven Galetta, MDDepartment of Neurology; Department of Ophthalmology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content
Jennifer Graves, MD, PhDDepartment of Neurosciences, University of California, San DiegoDrafting/revision of the manuscript for content, including medical writing for content
Ilya Kister, MDDepartment of Neurology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Cynthia Magro, MDDepartment of Pathology, Weill Cornell MedicineDrafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Claire Miller, MD, PhDDepartment of Neurology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content
Scott D. Newsome, DODepartment of Neurology, Johns Hopkins UniversityDrafting/revision of the manuscript for content, including medical writing for content
John Pappas, MDDepartment of Pediatrics, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Janet Rucker, MDDepartment of Neurology; Department of Ophthalmology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content
Connolly Steigerwald, MSDivision of Neurogenetics, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Christopher M. William, MD, PhDDepartment of Neurology; Department of Pathology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Scott S. Zamvil, MD, PhDDepartment of Neurology, University of California, San FranciscoDrafting/revision of the manuscript for content, including medical writing for content
Scott N. Grossman, MDDepartment of Neurology; Department of Ophthalmology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Lauren B. Krupp, MDDepartment of Neurology, NYU Grossman School of MedicineDrafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Supplementary Material

File (supplementary_data1.pdf)
File (supplementary_figure1.pdf)

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Moura ALA, Nagy BV, La Morgia C, et al. The pupil light reflex in Leber's hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells. Invest Ophthalmol Vis Sci. 2013;54(7):4471-4477.
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Bargiela D, Chinnery PF. Mitochondria in neuroinflammation–multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS. Neurosci Lett. 2019;710:132932.
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eReferences are listed at links.lww.com/NXI/A976.

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Published In

Neurology® Neuroimmunology & Neuroinflammation
Volume 11Number 2March 2024
PubMed: 38181317

Publication History

Received: September 25, 2023
Accepted: November 28, 2023
Published online: January 5, 2024
Published in print: March 2024

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Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.

Study Funding

The authors report no targeted funding.

Authors

Affiliations & Disclosures

Kimberly A. O'Neill, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
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Andrew Dugue, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
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From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
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Commercial - Sangamo: Clinical trial
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Commercial - Takeda: Observational study, education
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Governmental - NCATS, NIH (UL1 TR001445): Institutional KL2 program
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Laura J. Balcer, MD, MSCE https://orcid.org/0000-0002-5136-4539
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
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Editor-in-Chief Stipend - Journal of Neuro-Ophthalmology - North American Neuro-Ophthalmology Society
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Royalty to Spouse - Children's Hospital of Philadelphia: NMDA Receptor Antibody Assay
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Marc Branche, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
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1.
NONE
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Editorial Board - Neurology
2.
Editorial Board - Journal of Neuro-ophthalmology
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Jennifer Graves, MD, PhD https://orcid.org/0000-0003-1539-1940
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Steering Committee - Novartis
2.
Advisory Board - Horizon
3.
Advistory Board - TG Therapeutics
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Served as a consultant - Horizon
2.
Served as a consultant - F. HOFFMANN-LA ROCHE
3.
Served as a consultant - EMD Serono
Research Support:
1.
Commercial - Genentech: investigator-initiated grant
2.
Commercial - Sanofi Genzyme: investigator-initiated grant
3.
Commercial - Biogen: investigator-initiated grant
4.
Commercial - EMD Serono: investigator-initiated grant
Stock, Stock Options & Royalties:
1.
Royalty payment - Walters-Kluwer: Book royalties for 'Top 100 Diagnosis in Neurology'
Legal Proceedings:
1.
NONE
Cynthia Magro, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Claire Miller, MD, PhD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Scientific advisory board - Biogen
2.
Scientific advisory board - Genentech
3.
Scientific advisory board - Bristol Myers Squibb
4.
Scientific advisory board - EMD Serono
5.
Scientific advisory board - Greenwich Biosciences
6.
Scientific advisory board - Novartis
7.
Scientific advisory board - Horizon Therapeutics
8.
Scientific advisory board - TG Therapeutics
Research Support:
1.
Commercial - Roche: Lead PI for clinical trial
2.
Commercial - Roche: Clinical trial (paid directly to institution)
3.
Commercial - Genentech: Clinical trial (paid directly to institution)
4.
Commercial - Biogen: Clinical trial (paid directly to institution)
5.
Commercial - Lundbeck: Clinical trial (paid directly to institution)
6.
Society - National MS Society : Clinical trial (paid directly to institution)
7.
Governmental - Department of Defense: Clinical trial (paid directly to institution)
8.
Foundation - Patient Centered Outcome Research Institute: Clinical trial (paid directly to institution)
9.
Foundation - Stiff Person Syndrome Research Foundation: Research support
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
John Pappas, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Janet Rucker, MD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Connolly Steigerwald, MS
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Served as a consultant - Vigil Neuroscience
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Christopher M. William, MD, PhD
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Scott S. Zamvil, MD, PhD https://orcid.org/0000-0003-2720-9915
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
Consulting - Genzyme
2.
Consulting - Alexion
3.
Consulting - Roche
4.
Consulting - Novartis
5.
Consulting - Horizon (Amgen)
Research Support:
1.
NIH - NIAID (1 R01AI131624-01A1): Repertoire selection of AQP4-specific T cells that cause CNS autoimmune disease
2.
NIH - NIAID (1 RO1 AI170863-01A1): Characterization of T cells in MOG antibody-associated disease
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Department of Neurology (K.A.O., A.D., N.J.A., L.J.B., S.G., I.K., C.M., J.R., C.M.W., S.N.G., L.B.K.); Department of Ophthalmology (A.D.); Division of Neurogenetics (NJA, CS); Department of Ophthalmology (L.J.B., S.G., S.N.G.); Department of Population Health (L.J.B.); Department of Radiology (M.B.), NYU Grossman School of Medicine, New York, NY; Department of Neurosciences (J.G.), University of California, San Diego; Department of Pathology (C.M.), Weill Cornell Medicine, New York, NY; Department of Neurology (S.D.N.), Johns Hopkins University, Baltimore, MD; Departments of Pediatrics (J.P.) and Pathology (C.M.W.), NYU Grossman School of Medicine, New York, NY; and Department of Neurology (S.S.Z.), University of California, San Francisco.
Disclosure
Financial Disclosure:
1.
DSMB membership - Biogen
2.
Consultant - Hoffman La ROche
3.
Steering Committee - Novartis
4.
Consultant - Bristol Myer Squibb
5.
Travel - Bristol Myer Squibb
6.
Travel - Celgene
7.
Consultant - Novartis
8.
Travel - Novartis
Research Support:
1.
Commercial - Biogen (n/a): database of patients in MSPATH, quantitative measures
2.
Commerical - Novartis (n/a): cross-ssectional analysis of metabolic factors in adult and pediatric MS
3.
Society/Foundation - National Multiple Sclerosis Society ((grants RG150705285 and HC-1509-06233).): Pediatric MS clinical and cognitive features
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
Expert Witness for MCIC-Vermont in 2022

Notes

Correspondence Dr. O'Neill [email protected]
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by NMSS.
Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.

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