A Rational Approach to Treating Inflammatory Optic Neuropathies: - - PowerPoint PPT Presentation

A Rational Approach to Treating Inflammatory Optic Neuropathies: Which Treatment and Why

Jeffrey L. Bennett, MD, PhD Gertrude Gilden Professor of Neurology Professor of Ophthalmology and Neuroscience University of Colorado School of Medicine

Hot Topics: What’s New in the Optic Nerve March 5, 2018

Di Disclos

• sures
• Research Grant: EMD-Serono
• Consultant
• Novartis
• Genzyme-Sanofi
• Genentech
• MedImmune
• Chugai
• Teva Pharmaceuticals

Obj Objec ectives es

• 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.

Ra Ration

• nal Approa
• ach to
• ON

N Treatment

• Etiology
• Prognosis
• Therapeutic Options/Data
• Risk of Recurrent Disease
• Preventative Therapy

ON ON: : Differ eren ential al Diag agno nosis

• Infection
• Ischemia
• Toxic
• Genetic

Infectious Optic Neuropathy

• Bilateral
• Optic Disc Heme
• Ocular Inflammation
• Uveitis
• Iritis
• Retinitis

Etiology Common Clinical Features Treatments

Syphilis (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

Etiology Common Clinical Features Treatments

NMOSD 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 Idiopathic Multiple Sclerosis Other (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; PLEX Corticosteroids Sarcoidosis Optic disc edema; ocular inflammation; multi-system disease Corticosteroids; TNF-a blocker

In Inflammatory Causes es of ON

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

ON ON: : MRI and and OC 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: 1077 Ratchford et al. Neurology (2009) vol. 73: 302

>15 micron loss

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)

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

• f normalization of

visual field, contrast sensitivity, and visual acuity

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, 74:736 Jarius 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

Staging Acute Therapy

Recovery from attack is often incomplete

Serial treatment generally moves non-responders to partial responders

189 12 73 10 N= N=

Kleiter et al. (2016). Ann Neurol, 79:206. Merle et al., (2012). Arch Ophthalmol, 130:858

PLEX: More complete responders

NMO Pathogenesis

Human Pathology

• Anti-complement Therapy
• Anti-C5 complement
• C1q esterase inhibition
• Anti-neutrophil elastase
• IVIg

Future Therapies?

MOG-IgG Disease Pathology

Type 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, 2:35 Peschl et al. (2017), J Neuroinflamm, 14:208 T cell B cell Ast Mac IgG Comp

Minimal Pathology in Experimental Systems

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