NMO or NOT NMO, That Is the Question

A healthy 18-year-old woman presented with sub-acute painless vision loss in the left eye. On annual exam she was found to have a central scotoma in the left eye. Visual acuity was 20/15 in the right eye and 20/400 in the left eye, with an afferent pupillary defect. A visual evoked potential was normal on the right and showed increased latency of P100 on the left. A contrast enhanced MRI showed longitudinal enhancement of the left optic nerve.

NMO OR NOT NMO, THAT IS THE QUESTION Carolyne A. Riehle, DO, Emily Spoth, MS, Jill Wilson, MD, Bradley J. Katz, MD, PhD, Meagan D. Seay, DO, Sravanthi Vegunta, MD, Judith E. A. Warner, MD, Kathleen B. Digre, MD PRESENTED BY: CAROLYNE A. RIEHLE, DO MORAN EYE CENTER, UNIVERSITY OF UTAH ©UNIVERSITY OF UTAH HEALTH, 2018 DISCLOSURES • No relevant financial disclosures for any of the authors ©UNIVERSITY OF UTAH HEALTH, 2018 A HEALTHY 18-YEAR-OLD WOMAN WITH PAINLESS MONOCULAR VISION LOSS July 2013 Routine eye exam - asymptomatic VA: 20/15 OD, 20/400 OS; left rAPD MRI brain/orbits: Left optic nerve enhancement; normal brain MRI C/T spine: Increased T2 signal dorsal midline cord C3-4 to C6-7 One week later: IV methylprednisolone x 5 days After day 1, blurred vision OD, vision loss OS ©UNIVERSITY OF UTAH HEALTH, 2018 PRESENTED TO OUR INSTITUTION ONE MONTH LATER OD OS Visual Acuity 20/15 -1 NLP Pupils normal > 2.8 log rAPD Extraocular motility Full Full Color 13/13 0/13 OD OS Disc No pallor or edema Temporal pallor C/D Ratio 0.05 0.05 Macula Normal Normal ©UNIVERSITY OF UTAH HEALTH, 2018 1 MONTH AFTER INITIAL PRESENTATION ©UNIVERSITY OF UTAH HEALTH, 2018 MRI ORBITS WITH CONTRAST 2 WEEKS AFTER PRESENTATION Axial T1 Post Coronal T1 Post FS ©UNIVERSITY OF UTAH HEALTH, 2018 MRI CERVICAL SPINE 2 WEEKS AFTER PRESENTATION Axial T2 TSE Sagittal T2 Sagittal T1 post contrast ©UNIVERSITY OF UTAH HEALTH, 2018 ADDITIONAL NEGATIVE WORKUP • Lumbar Puncture – – – – – – WBC 0 Glucose 56 Protein 31 RBC 4 OCBs negative Cytology negative for malignant cells – Paraneoplastic Autoantibody, CSF negative • Serologies – – – – – – – – – – – AQP4 Ab negative ANCA negative ANA < 1:40 SSA 0 SSB 3 RF <10 Paraneoplastic panel negative Vitamin B1 113 Vitamin B12 230 RPR nonreactive Rapid Beta Strep Group A screen negative ©UNIVERSITY OF UTAH HEALTH, 2018 CLINICAL COURSE Two months after initial presentation: - 8 treatments of plasmapheresis - Azathioprine and prednisone 80 mg PO Three months: - Woke up with complete loss of vision OD - 5 days IVMP 1g/daily without improvement Four months: - Started Rituximab for 5 sessions ©UNIVERSITY OF UTAH HEALTH, 2018 REPEAT EXAM: 4 MONTHS AFTER PRESENTATION OD OS Acuity LP NLP Pupils 8 mm  5 mm 8 mm  5 mm, 1.2 log unit rAPD Extraocular motility Full Full OD OS Disc Pallor, worse temporally Diffuse pallor C/D Ratio 0.05 0.05 Macula Normal Normal Vessels Normal Normal Periphery Normal Normal ©UNIVERSITY OF UTAH HEALTH, 2018 Six months after initial presentation ©UNIVERSITY OF UTAH HEALTH, 2018 CLINICAL COURSE Next 6 – 24 months: Additional treatments with ACTH injections, plasmapheresis, rituximab, and IVIG without improvement Repeat AQP-4 IgG and MOG-IgG negative Repeat neuroimaging unchanged ©UNIVERSITY OF UTAH HEALTH, 2018 DIFFERENTIAL DIAGNOSIS – – – – – – – – – – Seronegative NMO MOG Sarcoidosis Granulomatosis with polyangiitis IgG4 SLE Metastasis/Neoplasm Paraneoplastic Mitochondrial disease Something else? ©UNIVERSITY OF UTAH HEALTH, 2018 Live Content Slide When playing as a slideshow, this slide will display live content Poll: What is the best next step? ©UNIVERSITY OF UTAH HEALTH, 2018 AN UNEXPECTED VISITOR COMES TO THE CLINIC… Shutterstock Illustration ©UNIVERSITY OF UTAH HEALTH, 2018 54-YEAR OLD FATHER PRESENTS… 5 YEARS AFTER DAUGHTER’S PRESENTATION • 1 week of gradual painless vision loss in the left eye – VA: OD 20/30, OS CF at 3 ft – Central scotoma OU on HVF • AQP-4 Ab: negative • MOG-Ab: negative • B12, MMA, B1, RPR, Vitamin E, Copper: normal ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S HISTORY • PMH: DM2, HTN, HLD, peripheral neuropathy • POH: Myopic astigmatism, strabismus, and amblyopia • FMHX: Father with poor vision – unknown etiology • Neurological Examination: – Vibratory sensation absent at the toes and decreased at the ankles bilaterally – Upgoing left plantar response ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S EXAM 6 MONTHS AFTER SYMPTOM ONSET OD OS Visual Acuity 20/200 at 1 foot HM Pupils 7 mm  4 mm 7 mm  4 mm, 0.6 log unit rAPD Visual Fields Central scotoma Central scotoma Extraocular Motility Full Full OD OS Disc Diffuse Pallor Diffuse pallor C/D Ratio 0.5 0.5 Macula Normal Normal Vessel Normal Normal ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S OCT RNFL Five Months After Symptoms Onset Eight Months After Symptom Onset ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S GOLDMANN PERIMETRY 8 MONTHS AFTER SYMPTOM ONSET ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S MRI CERVICAL SPINE 4 MONTHS AFTER INITIAL SYMPTOM Sagittal T2 Axial T2 ©UNIVERSITY OF UTAH HEALTH, 2018 FATHER’S MRI CERVICAL SPINE 4 MONTHS AFTER INITIAL SYMPTOMS Sagittal STIR Sagittal STIR ©UNIVERSITY OF UTAH HEALTH, 2018 GENETIC TESTING • Optic neuropathy and myelopathy in our patient and father strongly suggested a hereditary etiology. • Patient - comprehensive mitochondrial testing – normal • Father – Nuclear mitochondrial panel – normal • Whole exome sequencing – Allows investigation of genes of interest not included on panel testing. – Trio whole exome sequencing allowed testing on patient and parents simultaneously. ©UNIVERSITY OF UTAH HEALTH, 2018 FINAL DIAGNOSIS: PATERNALLY INHERITED MISSENSE VARIANT IN AFG3L2 GENE C.1276G>A; P.GLU426GLN ©UNIVERSITY OF UTAH HEALTH, 2018 AFG3L2 GENE C.1276G>A; P. GLU426GLN VARIANT • • • Autosomal Dominant Paternally Inherited in our patient Likely located in the ATPase domain, a mutational hotspot for Dominant Optic Atrophy Baderna 2020. Acta Neuropathol commun 8,93 Caporali 2020. Annals of Neurology. 88;18-32 ©UNIVERSITY OF UTAH HEALTH, 2018 AFG3L2 PATHOGENIC VARIANTS • Several studies have been reported of families with autosomal dominant optic atrophy with AFG3L2 variants. – Reported with MRI Brain T2-hyperintensity • Functional studies of several AFG3L2 pathogenic variants have shown altered OPA1 processing. Baderna 2020. Acta Neuropathol commun 8,93 Caporali 2020. Annals of Neurology. 88;18-32 ©UNIVERSITY OF UTAH HEALTH, 2018 ROLE OF AFG3L2 • Mitochondrial- AAA (M-AAA) complex is an ATP-dependent metalloprotease involved in protein quality control. – Comprised of subunits including AFG3L2 and SPG7 – Mutations in the subunits are associated with autosomal dominant spinocerebellar ataxia (SCA28) – Loss of AFG3L2 results in severe consequences as SPG7 is unable to form protease complexes without it. Caporali 2020. Ann Neurol. 88:18-32 ©UNIVERSITY OF UTAH HEALTH, 2018 LINK TO OPA1 PROCESSING • Autosomal dominant optic atrophy (ADOA) is characterized by bilateral degeneration of the optic nerves. – 75% of ADOA patients have a heterozygous mutations in OPA1 • OPA1 processing is regulated by AFG3L2 • Functional studies of several AFG3L2 pathogenic variants have shown altered OPA1 processing. Baderna 2020. Acta neuropathol Commun;8,93 Charif 2020. Neurology 6 (3) e428 ©UNIVERSITY OF UTAH HEALTH, 2018 VISUAL OUTCOME Visual Acuity Our Patient OD: 20/200 at 3 feet OS: NLP Patient’s Father OD: HM only OS: HM only ©UNIVERSITY OF UTAH HEALTH, 2018 TAKE AWAY POINTS • Presence of bilateral optic neuropathies, contrast enhancement of optic nerve, and cervical spinal lesions was highly suggestive of an autoimmune process (NMO). • Genetic causes of optic neuropathy can be associated with optic nerve enhancement on MRI. • Genetic etiologies should be considered when testing is unrevealing for a specific autoimmune etiology and patients are unresponsive to immunotherapy. ©UNIVERSITY OF UTAH HEALTH, 2018 THANK YOU Shutterstock Illustration ID: 125006384 ©UNIVERSITY OF UTAH HEALTH, 2018 RADIOLOGY PEARLS • OPA1 mutations reported to show – Multiple short segment spinal cord lesions – Unilateral or bilateral optic nerve enhancement or atrophy • Mimic MS, NMO, LHON-MS, other optic nerve inflammation or neoplasm Pathology Pearls • Choose your parents wisely