a rational approach to treating inflammatory optic ... meeting'/2018/rep slides... · etiology...
TRANSCRIPT
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A Rational Approach to Treating Inflammatory Optic Neuropathies:
Which Treatment and Why
Jeffrey L. Bennett, MD, PhDGertrude Gilden Professor of Neurology
Professor of Ophthalmology and NeuroscienceUniversity of Colorado School of Medicine
Hot Topics: What’s New in the Optic NerveMarch 5, 2018
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Disclosures•Research Grant: EMD-Serono•Consultant•Novartis•Genzyme-Sanofi•Genentech•MedImmune•Chugai•Teva Pharmaceuticals
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Objectives•Enumerate immune and infectious causes of
inflammatory optic neuropathy.
• List clinical and diagnostic data impacting treatment of inflammatory optic neuropathy.
•Describe data supporting various treatments of acute inflammatory optic neuropathy.
• List inflammatory optic neuropathies with high risk of poor visual recovery or recurrent disease.
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Rational Approach to ON Treatment
•Etiology•Prognosis•Therapeutic Options/Data•Risk of Recurrent Disease•Preventative Therapy
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ON: Differential Diagnosis
•Infection•Ischemia•Toxic•Genetic
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Infectious Optic Neuropathy•Bilateral•Optic Disc Heme•Ocular Inflammation•Uveitis• Iritis•Retinitis
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Etiology Common Clinical Features TreatmentsSyphilis (Treponema) Uveitis, chorioretinitis, vasculitis,
papillitis (varied)Penicillin
Cat-scratch (Bartonella) Neuroretinitis (macular star) Corticosteroids; antibiotics: azithromycin, ciprofloxacin, tetracycline, sulfamethoxazole-trimethoprim
Lyme Disease (Borrelia) Optic disc edema; reports of intermediate uveitis or papilledema
Ceftriaxone; doxycycline
Tuberculosis (Mycobacteria)
Papillitis, uveitis, neuroretinitis Isoniazid, rifampicin, pyrazinamide, ethambutol
Viral(WNV, HIV, VZV)
Variable: mild optic disc edema, chorioretinitis, vitritis (WNV); normal, mild microangiopathy(HIV); hemorrhagic optic disc edema, cotton wool spots (VZV)
HAART (HIV); acyclovir (VZV)
Treatment of Infectious Causes of ON
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Etiology Common Clinical Features TreatmentsNMOSD Recurrent, MRI-optic nerve
enhancement/extensive lesions; chiasm, NMO-IgG
IVSM; PLEX
MOG Recurrent; MRI-optic nerve enhancement/extensive lesions; MOG-IgG
Corticosteroids – may require prolonged treatment
GFAP Optic disc papillitis; MRI-perivascular enhancement; GFAP-IgG
Corticosteroids
Paraneoplastic Bilateral; disc edema; vitreal cell; vascular leakage; paraneoplastic antibodies
IVIg; PLEX; corticosteroids; identify and remove inciting neoplasm
IdiopathicMultiple SclerosisOther (CRION, AON)
Occasional mild disc edema; MRI-optic nerve enhancement/T2 signal
Recurrent, isolated; MRI-optic nerve enhancement/T2 signal; IgG on skin biopsy
IVSM; PLEXCorticosteroids
Sarcoidosis Optic disc edema; ocular inflammation; multi-system disease
Corticosteroids; TNF-ablocker
Inflammatory Causes of ON
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Inflammatory Optic Neuritis: Clinical Suspicion•NMOSD• Severe vision loss/field loss (<20/200; MD <11dB)• MRI: Posterior optic nerve or chiasm involvement
•MOG-IgG• Recurrent optic neuritis; simultaneous TM and ON• Steroid sensitive• MRI: Significant ON nerve/sheath enhancement
• RION/CRION/AON• Recurrent optic neuritis• Steroid sensitive
• Paraneoplastic• Subacute onset, older age; painless• Vitreal cell, retinal vascular leakage
• Sarcoidosis• Acute or subacute onset; ocular inflammation• MRI: Perineuritis, chiasmitis, enlargement/enhancement optic nerve
• GFAP-IgG• Meningoencephalitis; papillitis
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ON: MRI and OCT
NMOSD
Sarcoid
MOG-ON
Jurynczyk et al. Brain 2017: 140; 3128 Pache et al. J Neuroinflammation 2016;13(1):282.Naismith et al. Neurology (2009) vol. 72: 1077Ratchford et al. Neurology (2009) vol. 73: 302
>15 micron loss
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Laboratory Clues –Serology and CSF•Serology•ANA: NMOSD and MOG-IgG (~42%)•Anti-neural antibodies: GFAP-IgG• NMDA-R-IgG, anti-GAD65, ion channel antibodies
•Thyroid Abs – 16.7%•AchR Abs – 11%; Anti-GAD Abs – 15%
• CSF•MOG-IgG: Pleocytosis ≥100 cells/ml•Oligoclonal bands: MS-related, GFAP-IgG•Eosinophils: NMOSD
Pittock, Arch Neurol (2008); McKeon, Muscle & Nerve (2009);Jarius, J Neuroinflamm (2016); Flanagan, Ann Neurol (2017)
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Optic Neuritis Treatment Trial (ONTT)
No difference in visual acuity between steroid and placebo groups at 6 months*.
(NEJM 326:581, 1992)
*Increase in the rate of normalization of visual field, contrast sensitivity, and visual acuity
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Visual Prognosis• Average recovery after vision loss
• NMOSD: logMAR 0.4 (~42% worse than 1.0)• MOG-IgG: 20/20• Sarcoidosis: 20/40• CRION/RION/AON & GFAP-IgG: “Good”
• High risk of relapse• NMOSD: 63% by 1 year untreated
• ARR w/treatment: 0.38 (0.04-2.25; N = 83)• MOG-IgG
Collongues, et al. (2010). Neurology, 74:736Jarius et al. (2012). J Neuroinflamm, 9:14.Weinshenker et al. (2006). Neurology, 59:566–569.Jurynczyk et al. Brain 2017: 140; 3128 Kidd et al., Brain 2003; 126:276
MOG-IgG
MOG-IgG
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Staging Acute TherapyRecovery from attack is often incomplete
Serial treatment generally moves non-responders to partial
responders
189 12 73 10N= N=
Kleiter et al. (2016). Ann Neurol, 79:206.Merle et al., (2012). Arch Ophthalmol, 130:858
PLEX: More complete responders
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NMO Pathogenesis
Human Pathology
• Anti-complement Therapy• Anti-C5 complement• C1q esterase inhibition
• Anti-neutrophil elastase• IVIg
Future Therapies?
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MOG-IgG Disease PathologyType II MS Pathology: Lymphocytic infiltrate, IgG, complement
Spadara et al., (2015) Ann Clin Transl Neurol, 2:295;Jarius et al., (2016) Mult Scler, 22:1541 Saadoun et al. (2014), Acta Neuropathol Comm, 2:35Peschl et al. (2017), J Neuroinflamm, 14:208
T cell B cell
Ast
Mac IgG
Comp
Minimal Pathology in Experimental Systems
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Rational Approach to Optic Neuritis Treatment•Identify the cause• Infectious or non-infectious•Clinical, imaging, laboratory clues
•Prognosis•Generally good•Recurrent ON and NMOSD are likely exceptions
•Treatment• Intravenous methylprednisolone•Early plasma exchange for NMOSD and recurrent ON
•Lingering Questions•Combination Therapy•Direct treatment of immune effectors (CDC, ADCC)•Early use of immunosuppression/immunomodulators