Syndee J. Givre, MD,PhD - North Carolina State …€¢ demyelinating optic neuritis /MS • other inflammatory conditions (sarcoidosis,SLE) • infectious •toxic • nutritional

OPTIC NEUROPATHY

Syndee J. Givre, MD, PhD

Case 1

63 year old woman with gradually progressive, painless loss of vision OS for 2 years. She was told at a WFEI that she had a cataract.

20/50, left RAPD

Case 1ODOS

Case 1 Summary

63 year old with painless, progressive visual loss over 2 years with RAPD, normal appearing retina and optic nerve

visual loss accompanied by a relative afferent pupillary defect implies that either the retina or the optic nerve is not functioning

Case 1 Summary

63 year old with painless, progressive visual loss over 2 years with RAPD, normal appearing retina and optic nerve

when an RAPD exists but the retina and optic nerve are normal in appearance, it is more often the optic nerve that is not functioning, rather than the retina

Categories of Optic Neuropathies

• compressive• vascular (ischemic)• demyelinating optic neuritis / MS• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)• traumatic


• compressive– mass lesions / tumors

• symptoms are gradually progressive -over months to years, occasionally weeks

• affect any age group

• usually painless

cavernous hemangioma


• compressive– mass lesions / tumors

• symptoms are gradually progressive -over months to years, occasionally weeks

• affect any age group

• usually painless


• compressive• vascular (ischemic)

Categories of Optic Neuropathies• vascular (ischemic)

– anterior ischemic optic neuropathy

– posterior ischemic optic neuropathy

• sudden visual loss(stroke)

• older patients

• painless (ION from giant cell arteritis can be associated with headache)





• older patients






• older patients



• compressive• vascular (ischemic)• demyelinating optic neuritis / MS• other inflammatory conditions

(sarcoidosis, SLE)• infectious

Categories of Optic Neuropathies• demyelinating,

inflammatory and infectious

• typically painful

• progressive over days to weeks

• age– optic neuritis – young– inflammatory / infectious

– any age


• compressive• vascular (ischemic)• demyelinating optic neuritis / MS• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary


• toxic, nutritional,tobacco-alcohol,hereditary

• bilateral

• cecocentral or central visual field loss

• typically progressive over weeks

cecocentral vision loss


• compressive• vascular (ischemic)• demyelinating optic neuritis / MS• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)


• high intracranial pressure (papilledema)

• bilateral disc edema(but can by asymmetric oreven unilateral

• headaches and other neurologic symptoms


• compressive• vascular (ischemic)• demyelinating optic neuritis / MS• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)• trauma

Getting to the Diagnosis

• demographics / history

1. How old is the patient?

2. Was the visual loss sudden or gradual?

3. One eye or both?4. Painless or painful?

• exam data

1. What is the pattern of visual field loss?

2. Is there opticdisc edema or is it retrobulbar?

Age?

AGEyounger – optic neuritis (MS),

inflammatory, infectious, hereditary, toxic, nutritional, tobacco-alcohol, high intracranial pressure, compression (tumors)

older – ischemic (anterior, posterior, giant cell arteritis), toxic, nutritional, tobacco-alcohol, compression, inflammatory, infectious

TEMPO

Sudden vs. gradual?sudden – ischemic (anterior,

posterior, giant cell arteritis)

gradual – everything else

days – demyelination (MS), inflammatory, infectious

weeks – inflammatory, infectious, hereditary, toxic, nutritional, tobacco- alcohol, compression

months – compression

monocular vs. binocularmonocular or binocular?

both eyes – hereditary optic neuropathy (Leber’s), toxic, nutritional, tobacco-alcohol, BIG tumors, compressive optic neuropathy from thyroid eye disease, high intracranial pressure (papilledema)

one eye – everything else

pain

Pain?yes – optic neuritis (MS) and

other inflammatory optic neuropathies, infectious

headaches with GCA, pseudotumor cerebri & other causes of papilledema, like brain tumors

no – everything else

exam datapattern of visual field loss

any optic neuropathy can produce any optic nerve visual field defect

bilateral cecocentral scotomas are the rule for hereditary optic neuropathy, most medication-induced optic neuropathies (e.g., ethambutol), nutritional, tobacco-alcohol and toxic optic neuropathies

exam data• bilateral cecocentral

scotomas are the rule for hereditary optic neuropathy, most medication-induced optic neuropathies (e.g., ethambutol), nutritional, toxic and tobacco-alcohol optic neuropathies

exam datadisc edema vs. normal disc

(optic disc pallor → optic neuropathy present a minimum of 4-6 weeks)

edema – AION, mass just behind the globe, inflammatory / demylelinating, infectious, high intracranial pressure

normal disc – PION, retrobulbar mass far behind the globe, retrobulbar inflammation / neuritis, infection or toxic, nutritional, tobacco-alcohol or hereditary

Case 1age- middle to older

include ischemic, unlikely optic neuritis

63, painless, progressive visual loss with RAPD, normal appearing retina and optic nerve

• compressive• vascular (ischemic)

• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)• trauma

🚫•demyelinating optic neuritis / MS

Case 1

age- middle to olderinclude ischemic,

unlikely optic neuritistempo- slow gradual

not ischemic• other inflammatory conditions (sarcoidosis, SLE)• infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)• trauma


• compressive🚫•vascular (ischemic)

🚫•demyelinating optic neuritis / MS

Case 1



not ischemicpainless

not likely infectious, inflammatory


• compressive🚫•vascular (ischemic)🚫•demyelinating optic neuritis / MS🚫•other inflammatory conditions (sarcoidosis, SLE)

🚫•infectious• toxic• nutritional / smoking-alcohol• hereditary• high intracranial pressure (papilledema)• trauma

Case 1





monocular


• compressive🚫•vascular (ischemic)🚫•demyelinating optic neuritis / MS🚫•other inflammatory conditions (sarcoidosis, SLE)🚫•infectious🚫•toxic🚫•nutritional / smoking-alcohol

🚫•hereditary• high intracranial pressure (papilledema)• trauma

Case 1





monocularno disc edema


• compressive🚫•vascular (ischemic)🚫•demyelinating optic neuritis / MS🚫•other inflammatory conditions (sarcoidosis, SLE)🚫•infectious🚫•toxic🚫•nutritional / smoking-alcohol🚫•hereditary🚫•high intracranial pressure (papilledema)

🚫•trauma

Case 1

Case 2• 34 year old man who noted painless

vision loss in both eyes for the past 3 - 4 weeks

• 20/200 & 20/200• no RAPD

Case 2

Case 2• 34 year old man who noted

painless vision loss in both eyes for the past 3 - 4 weeks

• 20/200 & 20/200• no RAPD

young gradual

painless

bilateral

central vision loss

no disc edema

• compressive🚫•vascular (ischemic)🚫•demyelinating optic neuritis / MS🚫•other inflammatory conditions

(sarcoidosis, SLE)🚫•infectious• toxic• nutritional / smoking-alcohol• hereditary🚫•high intracranial pressure (papilledema)

Case 2He stopped drinking

alcohol and drastically cut down on smoking.

20/25 20/25

SYNDEEJ GIVRE, MD, PHD(NEIL MILLER, MD& MARKKUPERSMITH, MD) M

NON-ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY(NAION)

ISCHEMIC OPTIC NEUROPATHY(ION)

• second most common optic nerve-related cause of permanent visual loss in adults after glaucoma

• 3 types• arteritic- due to giant cell / temporal arteritis• non-arteritic• perioperative

TYPICAL CASE

• a 62-year-old woman presents witha 2-day history of painless, blurredvision in the left eye

• noticed it when she awoke in the AM

• initially, the blurring was in the inferior field of vision, but spread to affect the entire field, although still worse inferiorly

• past medical history is significant for hypertension and hyperlipidemia

• Examination– VA: 20/25 OD, 20/200 OS– Pupils: no anisocoria; LRAPD– motility full OU

– VF full to confrontation and automated threshold testing OD; inferior depression to confrontation and automated threshold testing OS

▸ she has no symptoms of GCA

▸ ESR, CRP and PLT arenormal

▸ a diagnosis of non-arteritic anterior ischemic optic neuropathy (NAION) is made

NON-ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY(NAION)

• Usually in patients over age 55• Men and women equally affected• Occurs in 3-10 per 100,000 in the US• Underlying systemic vasculopathy usually present but

may not be known at time of visual loss– hypertension*– dyslipidemia*– diabetes mellitus*– smoking?– sleep apnea?

NAION

• Usually unilateral• Eye pain rare; severe pain is very rare, and pain on

eye movement extremely rare• anterior form (AION) represents about 90% of all

cases of non-arteritic ION (rest are retrobulbar-PION)

NAION

• Visual acuity loss variable: 20/20 to HM or worse

• Color vision usually mirrors acuity

• Visual field usually shows altitudinal or arcuatedefect

• RAPD always present if unilateral andno abnormality in opposite eye

• Disc usually hyperemic• Peripapillary flame-shaped hemorrhages

often present

***contralateral optic disc small or normal-sized with little or no cup

NAION

NAION

▸ if the contralateral, normal disc has a

normal sized cup rethink the diagnosis- NAION should probably not be on the list

NAION

NAION

▸ the typical progression

NAION

Risk Factors for Most Cases

• A normal or congenitally small disc with little or no cup

PLUS

• Vascular compromise

NAION PATHOGENESIS

NAION PATHOGENESIS

• Ischemia at level of prelaminar/laminar portion of optic nerve supplied by circle of Zinn-Haller via short posterior ciliary arteries

• No evidence of SPCAocclusion/clot– DL Knox, JR Duke. TAAOO 75:1065, 1971– LA Levin,A Louhab.Arch Ophthalmol 114:488, l996

– NR Miller. Unpublished

• Blood flow velocities of PCAs and CRA are reducedin eyes with acute NAION compared with controls

NAION PROGNOSIS

• About 40% improve spontaneously (IONDT)• Visual acuity more likely to improve than visual

field• Disc swelling persists for 6-11 weeks (Hayreh et

al., 2007), then becomes pale but not cupped

small risk for recurrent NAION in same eye (3-5%)

NAION PROGNOSIS FELLOWEYE

• Variable risk (15-25%) for involvement of fellow eye– Factors include age, vascular disease, visual acuity

– Fair-to-moderate vs no correlation between “visual prognosis” in the twoeyes

– Magnitude of PRNFL loss similar, and greater similarity in field loss than in acuity

– No prophylactic therapy (reduce/eliminate risk factors,?ASA)

NAION SYSTEMIC PROGNOSIS

• Patients at risk for subsequent cerebrovascular and cardiovascular events (eg, TIA, Stroke, MI)*

• Increased mortality from vascular disease*

• PATIENTS WHO DEVELOP NAION NEEDA COMPLETE PHYSICALEXAMINATION!

NAION TREATMENT

• Dilantin: Not beneficial, BUT randomized study begun3 months after onset

• ASA: No class I or II data• ONSF: Not helpful and may be harmful

• Steroids (Hayreh: Yes; Rebolleda and others: No): Most often used in the USA andEurope

• Anti-VEGF agents (eg, ranibizumab, bevicizumab)• Erythropoietin or erythropoitin agonists

NAION MANAGEMENT/SUMMARY

• Distinguish from arteriticAION– If in doubt, ESR and CRP, consider beginning steroids until results back and/or

TAbiopsy

• Discuss potential effects of drugs (eg, amiodarone, ED drugs)

• Discuss visual and systemic prognoses and refer to internist/PCP forcomplete physical exam and modification of identified vascular riskfactors

• Ask about snoring, recommend sleep study when appropriate

• Discuss possible treatment with steroids, other

NAIONCLINICAL TRIAL

QUARKPHARMACEUTICALS ANDNORDIC (NEURO-OPHTHALMOLOGY RESEARCHDISEASE INVESTIGATOR CONSORTIUM) COLLABORATION

• neuro‐ophthalmologists in clinical practices and in academic institutions will work together with Quark Pharmaceuticals and NORDIC to enroll ~530 participants

• This is an investigational drug trial to evaluate a neuroprotection therapy for acute NAION

• This is an opportunity for eye care specialists and neuro‐ophthalmology to advance NAION care

NAION CLINICAL TRIAL

QPI-1007 is a small interfering ribonucleic acid (siRNA) designed to temporarily block cells from producing Caspase 2, which controls cell apoptosis

• High levels of caspase 2 are found when cells are damaged due to lack of oxygen.

• Hypothesis: In NAION, retinal ganglion cells are damaged due to a lack of oxygen/blood elevating caspase 2. Local temporary inhibition of caspase 2 could give the cells more time to repair/recover which may prevent further loss of vision and possibly improve vision.


QPI-1007 is a small interfering ribonucleic acid (siRNA) designed to temporarily block cells from producing Caspase 2, which controls cell apoptosis

• High levels of caspase 2 are found when cells are damaged due to lack of oxygen.

• Hypothesis: In NAION, retinal ganglion cells are damaged due to a lack of oxygen/blood elevating caspase 2. Local temporary inhibition of caspase 2 could give the cells more time to repair/recover which may prevent further loss of vision and possibly improve vision.

damage/trauma/ischemia

caspase 2


▸ QPI-1007 can be detected in all layers of rat retina when injected into thevitreous

▸ had protective effect in rat opticnerve crush model

▸ Phase 1 safety studies have shown it to be well tolerated when injected into human vitreous (in chronic NAION)

TEXT


Phase 2/3, Randomized, Double‐Masked, Sham‐Controlled Trial of QPI‐1007 in Acute NAION

single injection‣ dose 1.5 mg day 1, sham months 2 & 4‣ dose 3.0 mg day 1, sham months 2 & 4 multiple injection regimen‣ dose 1.5 mg day 1, month 2, month 4‣ dose 3.0 mg day 1, month 2, month 4 sham injection‣ sham day 1, months 2 & 4

***Day 1 must be within 14 days of the onset of the vision loss***

**Patient must be seen, deemed eligible, sign consent and be randomized into the study within 13 days of the vision loss**


• PRIMARY ENDPOINTS

– Efficacy: proportion of subjects who lose 15 letters or more in BCVA score from Baseline to Month 12

– Safety: safety and tolerability of QPI‐1007 in recent‐onset NAION

• SECONDARY ENDPOINTS

– Mean change from Day 1 to Month 12 in BCVA score in study eye.

– Mean change of VF; mean deviation from Day 1 to Month 12 in study eye

NAION CLINICAL TRIALMAJOR INCLUSION CRITERIA

◆ Diagnosis of first episode of NAION in study eye with symptom onset within 14 days prior to Study Day 1.

◆ Subjects 50‐80 years of age◆ BCVA in the study eye is better than or equal to 15 letter score, using ETDRS at presentation exam

◆ NAION diagnosis requires: disc edema, field loss, RAPD

MAJOR EXCLUSION CRITERIA

• Present use or history of any treatment for the current episode of NAION, including systemic steroids, brimonidine, etc

• Prior episode of NAION in the study eye only

• Bilateral acute NAION with bilateral disc swelling at presentation

• Clinical evidence of temporal arteritis based on: symptoms or signs, OR C‐reactive protein (CRP), OR abnormal Westergren sedimentation rate

OFFICE 919-325-4260CELL [email protected]

ANY PATIENT WITH SUSPECTED AION, CONTACT ME IMMEDIATELY

Documents

Syndee J. Givre, MD,PhD - North Carolina State …€¢ demyelinating optic neuritis /MS • other inflammatory conditions (sarcoidosis,SLE) • infectious •toxic • nutritional