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Pearls, Pitfalls and Advances in

Neuro-OphthalmologyNancy J. Newman, MD

Emory UniversityAtlanta, GA

Consultant for Gensight Biologics, SantheraData Safety Monitoring Board for Quark AION StudyMedical-legal consultant (IIH and peri-op vision loss)

Causes• Inflammatory•Vascular•Compressive/Infiltrative•Toxic/Nutritional•Hereditary•Traumatic•Elevated intracranial pressure•Elevated intraocular pressure

Optic Neuropathy

Optic NeuropathyAnterior Ischemic Optic Neuropathy• Ischemia to the optic nerve head• M:F 1:1• Age: older than 50• Diabetes, hypertension• Painless• Swollen disc• Permanent visual loss• Associated with giant cell arteritis

c/d:0.8 c/d:0.5 c/d:0.1

� Small cup-to-disc ratio

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AION vs ON

Age Older (>50) YoungerGender M = F F > M

Visual loss Acute Rapidly progressivePain Infrequent Frequent with EOMColor Vision May be normal Commonly abnormalVisual Field Altitudinal defect Central defectsOptic Disc Acute: edema Normal or edema

Small c/dLate: seg pallor Temporal pallor

MRI Nl optic nerve Abnl optic nerveVisual prognosis Poor Good

Systemic disease HTN, DM, r/o GCA Subsequent MS 0

5

10

15

20

25

30

35

40

Nu

mb

er

<25 25-29 30-34 35-39 40-44 45-49

Age at onset (years )

Distribution of age and sex in 169 young patients with AION

Male ( n = 97 )

Female ( n = 72 )

23% of NAION patients are less than 50 years-old

AION vs. ON

• Prognosis for

visual recovery• Recognition of

giant cell arteritis

• Prognosis for multiple sclerosis

• Treatment of demyelination

JAMA Ophthalmol 2015; 133: 797-804

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J Sex Med. 2015 Jan;12(1):139-51.

Risk of AION increased by 3.86 when taken within the week preceding the AION vs. when taken 7 weeks priorRisk of 2.36 when taken the day before vs. within the 29 days before

• Intravitreal injection of QPI-1007 (small interfering ribonucleic acid that blocks Caspase 2 apoptosis)

• NAION 50-80 years old • Within 14 days of visual loss• USA• India, Israel, Italy, Germany,

Australia, and China.

Giant Cell Arteritis

• Rule-out giant cell arteritis (ESR, CRP, platelets) in all > 50 yo patients with ischemic optic neuropathy

• Arteritic ION:– AION or PION– Systemic symptoms of GCA absent in 25%– Often with transient visual loss or diplopia– Bilateral if no treatment– Steroids emergently, then temporal artery biopsy– Poor visual prognosis

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JAMA Neurol 2015; 11: 1281

Perioperative Visual LossIschemic Optic Neuropathy

• Anterior optic nerve– Acute: swelling of disc– > 6 wks: pallor of disc

• Posterior optic nerve– Acute: normal fundus– > 6 wks: pallor of disc

• Mechanism: ischemia

3%

14%

10%

73%

OtherHead and neck

Cardiopulmonarybypass Spine

ASA Registry- n=131

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Perioperative Visual LossASA Registry – Spine (n=93)

60%

9%

11%

20%

PION

AION

CRAOUnspecified ION

Anesthesiology 2012; 116: 15-24

Causes• Inflammatory•Vascular•Compressive•Toxic/Nutritional•Hereditary•Traumatic•Elevated intracranial pressure•Elevated intraocular pressure

Optic Neuropathy Toxic Optic Neuropathies• Ethambutol

– Dose-related– Early dyschromatopsia

• Linezolide– Dose-related– Mild disc edema– Peripheral neuropathy

• Amiodarone– Disc edema (mimics AION)

• Cobalt-chromium metallosis– Hip implants

• Methanol and ethylene glycol

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Causes• Inflammatory•Vascular•Compressive•Toxic/Nutritional•Hereditary•Traumatic•Elevated intracranial pressure•Elevated intraocular pressure

Optic Neuropathy

Optic NeuropathyHereditary

•Maternal/Mitochondrial (Leber’s)•Autosomal dominant (Kjer’s)

Optic NeuropathyHereditary

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Hereditary Optic Neuropathies

Treatment

• Genetic counseling

• Symptomatic

• Disease-modifying

• Mitochondrial diseases• Hereditary optic neuropathies

• Idebenone (900mg/d)

• Gene therapy (ongoing clinical trials)

Leber Hereditary Optic Neuropathy

Treatment – Idebenone?

-Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain 2011;134:1-5/e188

Leber Hereditary Optic NeuropathyGene Therapy

Am J Hum Genet. 2008 Sep;83(3):373-87.

Proc Natl Acad Sci U S A. 2012 May 15;109(20):E1238-47

AllotopicRescue

Safety and Tolerability Study• Intravitreal injection of rAAV2/2-ND4 in one eye

of 9 patients (3 groups escalating doses) with LHON (11778) and chronic visual loss

• Excellent systemic safety and tolerance• No vector shedding

• Good local tolerance with mild AE’s• Mild ↑IOP (23-34) and ocular inflammation:

• Treatment responsive and reversible• No unexpected adverse events

NANOS, ARVO and AAO meetings, 2015

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Rescue & Reverse Studies• Two, simultaneous, parallel Phase III clinical trials

of intravitreal gene therapy for the treatment of LHON, occurring at 7 study sites worldwide (Atlanta, Los Angeles, Philadelphia, Paris, London, Munich, Bologna)

• Goal is to randomize 36 patients for each study over 1 year with 2-year followup

• Social media growth makes it easier for LHON patients and families to connect– Global LHON Facebook (2,500+ members)– Clinical database (3,400+ entries)

• Website and social media facilitate study trial recruitment with just a “click”

From a Patient’s Perspective

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Probability of Improvement vs Time Since Injury

Time Since Injury (months)

0 1 2 3 4 5 6

Pro

bab

ility

of I

mpr

ovem

ent

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Probability95% CI

(2015)

10

39

2004

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JAMA Neurol 2015; 72: 1170

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What’s New Next Year??

– Nonmydriatic fundus photography– Idiopathic intracranial hypertension clinical trial– OCT and MS Trials– Treatment of NMO– Treatment of GCA– Ocular myasthenia gravis– LHON (Gene therapy clinical trials)– Diagnosis of concussion

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http://novel.utah.edu/