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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)
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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