Losing Vision, Losing Sleep

A fifty-one-year-old man in good health presented with painless, right-sided visual deficits described as green-brown blotches, progressing to blurry vision and wavy lines in bilateral visual fields. Visual acuities were 20/50 OD, 20/25 OS. Ishihara plate scores were 5/8 OD and 8/8 OS. Automated perimetry demonstrated bilateral inferior arcuate visual field defects. Slit-lamp exam demonstrated anterior vitreous cells bilaterally. Funduscopy showed bilateral optic disc edema with telangiectasias. There was capillary leakage in both optic discs on fluorescein angiography. MRI of brain and orbits showed contrast enhancement of both optic nerve heads. The patient was initiated on IV methylprednisolone 1000 mg/day for 3 days, with partial visual improvement. He was discharged on high-dose oral steroids (60 mg daily) with taper, but self discontinued due to side effects after 2 weeks, resulting in symptom recurrence three weeks later. Visual deficits worsened to involve bilateral lower quadrants. The patient reported symptoms of disabling orthostatic dizziness. He had mild sleep apnea, but began experiencing nighttime insomnia, daytime somnolence and sleep-related twitching movements in his extremities. Slit-lamp exam continued to show vitreous cells. Funduscopy demonstrated largely resolved optic nerve edema, with interval left temporal pallor development, with telangiectatic vessels extending off the left optic nerve. OCT showed bilateral ganglion cell thinning. Neurological exam demonstrated new subtle torsional nystagmus in down and right gaze, diffuse hyperreflexia and ataxic and abnormal tandem gait. Serological testing was negative/normal for ANA, ACE, SSA/B, RF, ANCA, hepatitis B & C, HIV, Lyme, tuberculosis, syphilis, aquaporin-4 and MOG antibodies. CSF evaluation demonstrated normal opening pressure, 4 nucleated cells with lymphocytic predominance and elevated protein of 82 mg/dl, without oligoclonal bands. CSF cytology and infectious screens were negative. Whole-body PET-CT was unrevealing. Left testicular ultrasound demonstrated hyperechogenic foci suggestive of burned-out tumor or a prior inflammatory process. Orchiectomy did not demonstrate malignant tissue.

Losing Vision Losing Sleep Bart K. Chwalisz M.D. Aditi Varma-Doyle M.D. Jenny Linnoila M.D., Ph.D. MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY MGB / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY SERVICE Disclosures: None MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY HPI 51yo. healthy man with painless, right eye vision changes “Green-Brown Blotches” -> 4 weeks later: Bilateral blurry vision and wavy lines MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Ophthalmic Examination Exam​ Finding​ BCVA​ OD 20/50 OS 20/25 Ishihara​ OD 5/8 OS 8/8 Pupils Reactive OU, no rAPD Anterior segment​ 1+ AC cell OU Posterior segment​ 1+ vitreous cell OU MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Negative/Normal  ANA, SSA/B, RF, ANCA, Aqp4, MOG  HIV, syphilis, Lyme, hepatitis B&C, TB  CSF: nl opening pressure, WBC 4 (97% L), protein 87 mg/dL, glucose 63 mg/dL  Neg CSF oligoclonal bands, cytology, flow cytometry, IgH rearrangement, Myd88 mutation, VDRL MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY The Story Continues  IV methylprednisolone 1gm/d x 3 d → partial improvement → Prednisone taper from 60 mg/d, stopped after 2 weeks → Visual symptoms recur within 1-2 weeks Visual blurring lasting hours New symptoms:  Disabling orthostatic dizziness  Daytime somnolence  Sleep-related twitching in extremities MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Repeat Exam OD 20/40 OS 20/20 Ishihara OD 6/8 OS 8/8 1+ vitreous cell OU Presentation Now Neurologic Exam  Fully alert, oriented, appropriately interactive  Speech fluent without paraphasic errors, slight dysarthria  New subtle torsional nystagmus in down & right gaze  Cranial nerves otherwise intact  Diffuse hyperreflexia, positive L Babinski  Ataxic gait, unable to tandem MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Live Content Slide When playing as a slideshow, this slide will display live content Poll: What would you do next? Further Workup     Repeat MRI brain/orbit with resolution of prior findings Repeat CSF: protein 95, WBC 4 Negative whole body PET-CT Testicular ultrasound*: hyper-echogenicity (3x4x4 mm) suggestive of infection/trauma vs burned-out tumor *Remember that testicles may not show on body PET-CT! MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY An additional study was obtained… CSF Autoimmune Encephalopathy Ab panel + IgLON 5 antibody (1:8 titer, confirmed by cell-based assay) MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Final Diagnosis: IgLON 5* autoimmune encephalitis with optic neuritis/papillitis *immunoglobulin-like cell adhesion molecule 5 MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Clinical Course   Second IV steroid burst → taper Cyclophosphamide 750mg/m2 BSA monthly x 6 months 3 months s/p CYC Mycophenolate Improvement in neurologic & ophthalmic symptoms, stable exam 6 months s/p CYC MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Orchiectomy (performed given positive “paraneoplastic Ab”)  No evidence of tumor grossly or microscopically (extensive sampling)  No evidence of vasculitis, necrosis, or granulomatous inflammation  Azoospermia and seminiferous tubule atrophy, likely secondary to chemotherapy* *Patient had been treated with cyclophosphamide MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY OCT: Optic atrophy MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY IgLON 5 autoimmune encephalitis  IgLON5: neuronal cell surface antigen  Ordered as part of autoimmune/ “paraneoplastic” Ab panel  But no definite paraneoplastic association (so far)  Clinical syndrome resembles autoimmune encephalitis but may be chronic:  Prominent sleep symptoms: parasomnias, sleep-disordered breathing  Low PNS-Care Score → is full tumor workup needed?  Bulbar symptoms: dysphagia, sialorrhea, stridor/acute resp. insufficiency, nystagmus, gaze palsy, square wave jerks, saccadic intrusions  Gait & movement disorders: hyperkinesis, chorea, ataxia  PSP-like neurodegenerative syndrome, With tau accumulation & unresponsive to immunotherapy MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY IgLON 5 autoimmune encephalitis with optic neuropathy  First report of optic neuritis as the presenting symptom*  Initially, optic disc edema, vitreous cell, disc leakage  Progressed to brainstem (nystagmus) and sleep symptoms, ataxia, hyperreflexia  Treatment is still being defined  Left untreated may become neurodegenerative  Late cases may not respond (initial reports)  But this report and other recent ones suggest early treatment may be helpful  Steroids, IVIg, PLEX, azathioprine rituximab, cyclophosphamide *But John Chen and Mayo colleagues recently reporting the same MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY Teaching Points  Anti-IgLON5 disease is a complex disorder with characteristic manifestations that can present  subacutely  slowly (“PSP-like”)  Optic neuritis/papillitis may be presenting sign of IgLON5 disease  No clear paraneoplastic associations  Early treatment with immunosuppressive therapy appears crucial for avoiding irreversible neurologic injury MGB / MGH / MASS EYE AND EAR | HARVARD NEURO-OPHTHALMOLOGY PATHOLOGY PEARLS Dr. Sandra Camelo-Piragua, Neuropathology University of Michigan AUTOIMMUNE ENCEPHALITIS Greenfields Neuropathology 9th Edition Ellison and Love Neuropathology 3rd Edition ANTI-IgLON5-RELATED DISEASE • Ig cell adhesion molecule strongly expressed in the surface of neurons • Associated with HLA-DRB1*1001 and HLA-DQB1*0501 haplotype, which is very rare in the normal population • Significant overlap with other neuromuscular and neurodegenerative diseases: myasthenia gravis, Huntington disease, progressive supranuclear palsy, multiple system atrophy ANTI-IgLON5-RELATED DISEASE Hypothalamus Locus ceruleus Tegmentum AANP DSS 2023-10 ANTI-IgLON5-RELATED DISEASE p-Tau Gelpi E, et al Acta Neuropathol 2016 ANTI-IgLON5-RELATED DISEASE 9 patients. Mean age: 71 (53-82). MDD: 6 years (0.5-13) MDD: 1.5 years Anti-IgLON5 IgG4 without Tau pathology MDD: 9 years IgLON5-related Tauopathy: Autoimmunity Berger-Sieczkowski E, et a. Acta Neuropathol 2023 Neurodegeneration MDD: Median Disease Duration ANTI-IgLON5-RELATED DISEASE Modified from Gelpi E, et al Acata Nueropathol 2014. * Erro ME et al, Neurol Neuroimm Neuroinflam 2019 From AANP DSS 2023-10 RADIOLOGY PEARLS Dr. Hemant A. Parmar, Neuroradiology University of Michigan Front Immunol 2024;14:1-6 Autoimmune Encephalitis (GAD65) Limbic Encephalitis (Testicular cancer) Gliomatosis Herpes Encephalitis