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Demyelinating Optic Neuritis

Bayasgalan Purevdorj, MD, FICO, MMEdDepartment of Ophthalmology

Mongolian National University of Medical Sciences18th Dec 2018

Acknowledgement Cybersight/ ORBIS

Mongolian Ophthalmologists’ Society

Mongolian National University of Medical Sciences

Karl Golnik, MD

Oculoplastic Clinic

Судалгаа авч үзье!●Нүдний эмч - 1 ●Резидент эмч - 2 ●Мэдрэлийн эмч - 3●Оюутан - 4●Бусад- 5

Асуулт-1 ● Харааны мэдрэлийн миелингүйжих үрэвсэл

ихэвчлэн өндөр настай хүмүүс тохиолддог.

1. Үнэн2. Худал

Асуулт-2 ● Харааны мэдрэлийн миелингүйжих үрэвслийн үед

хараа сэргэх тавилан ерөнхийдөө муу байдаг.

1. Үнэн2. Худал

Асуулт-3● Харааны мэдрэлийн миелингүйжих үрэвслийн

дахих эрсдэл үйлчлүүлэгчид преднизолон схемээр уулгасан тохиолдолд буурдаг.

1. Үнэн 2. Худал

Асуулт-4● Харааны мэдрэлийн миелингүйжих үрэвслийн

дараа тархмал хатуурал өвчин үүсэх эрсдэл MRI шинжилгээнд өөрчлөлтгүй тохиолдолд буурдаг.

1. Үнэн 2. Худал

Subjects in the Optic Neuritis Treatment Trial, who

were enrolled between July 1, 1988, and June 30,

1991, were followed up prospectively for 15 years,

with the final examination in 2006.

Optic neuritis (ON)

● Inflammation of the optic nerve● Anterior optic neuritis- swollen optic disc “papillitis”

● Retrobulbar optic neuritis

● Highly associated with multiple sclerosis (MS)

● 15 -20 % MS presenting feature

Optic nerve● CN II● Part of CNS not peripheral nerve● Myelinated axons of the retinal ganglion cells (RGC) ● Interspersed with connective tissue septae● Approximately 800,000 to 1.5 million nerve fibers● End at Lateral geniculate nucleus (LGN)● 50 mm in length posterior scleraà optic chiasm

The 4 portions of the optic nerve. The lengths are given. (From Sadun AA: Anatomy and physiology. In Yanoff M, Duker JS [eds]: Ophthalmology, 2nd ed, St. Louis, Mosby, 2004.)

Elsevier items and derived items © 2005 by Elsevier Inc.

1. Intraocular

2.Intraobital

4 portions

3. Intracanalicular

4.Intracranial

Myelin of optic nerve

● Provided by Oligodendrocytes● Normally absent in the retina

and optic nerve head● First appearing posterior to the lamina cribrosa ● Provide the myelin sheath to RGC axons.

Intraocular portion

Role of myelin ● Physiologic properties

▪ ↑ resistance ; less leakage▪ ↓ capacitance of the axon ; less Na+ are needed

● ↓ amount of ionic are needed to change membrane potential

● Ionic homeostasis

Saltatory conduction

Pathophysiology

PathophysiologyInflammatory demyelination of the optic nerve

Genetic● Controversy● Histocompatibility antigens HLA-A3, HLA-A7, and

HLA-LD-a have been reported to be increased in optic neuritis and MS.

● In other studies, no significant differences were found in HLA distribution

Epidemiology● 2/3 woman● 18-50 years average 32 year● Annual incidence 2.2-6.4 per 100,000 in the united

stated● occurs more frequently in whites than blacks and

Asian● Incidence ON related with MS

Epidimiology

Clinical Features&Diagnosis●**Clinical diagnosis**● Classic triad of optic neuritis

1 Loss of vision2 Periocular pain3 Dyschromatopsia

● Visual disfunction● Asymptomatic+optic nerve dysfunction

Clinical symptoms

Loss of vision● Most common and important● > 90% diffuse loss of vision ● Within● Hour - 29% ● 1-2 days – 20%● 3-7 days – 23%● 1-2 wks – 7%

● Progressive visual loss 7-10 days then stable● Mild visual loss – no PL

Periocular pain● > 90%● Eye movement● Preceding or coinciding with visual loss

● Central visual loss● 24-36 hrs most severe● Improve within 48-72 hrs● Cause : Theory

● Optic nerve sheaths --> Small branches of trigeminal N.● Inf lammation of optic N. in orbital apex ;extraocular m.sheath

fused nerve sheaths ● Retrobulbar optic neuritis > Papillitis

Dyschromatopsia /1/● Color vision defect ● 94%● Desaturation of colour● Out of proportion with VA

● Farnsworth-Munsell 100 Hue Test● More sensitivity 94%

Dyschromatopsia /2/

Phosphenes● lashes of light induced by eye movement or sound● Preceding or coinciding with visual loss● Same eye

Uhthoff’s phenomenon● 50% after ON● Significant related ● Abnormal MRI brainàrisk MS● Recurrent ON

● Aggrevated by ● Exercise● Heat● Sress

Pulfrich phenomenon● Motion of pendulum appears elliptical due to altered

depth perception from delayed conduction in the demyelinated nerve

Clinical signs

Visual acuity● Initial and Follow-up visual acuity (VA) in Patients with Acute Isolated

Optic Neuritis in the Optic Neuritis Treatment Trial (ONTT)

Acuity Initial 1 year 10 years 15 years

20/40 or better 35 % 93% 92% 92%

20/50-20/190 29 % 4% 5% 5%

20/200 – NLP 36 % 3% 3% 3%

NLP= no light perception

Visual field defect● Nerve fiber bundle

related VF defect● Recommend VF baseline

for follow up● In ONTT :

Central field > peripheral ● Focal defect (42%) :

Arcuate , Altitudinal , Nasal

Clinical signs● Pupillary reaction● Pupillary light reflex à

↓ abnormal eye● RAPD positive

papillitis

35%

retrobulbar neuritis

65%

Opthalmoscopic appearance

CMV may cause an “isolated” papillitis, check the periphery!

Neuroretinitis - disc swelling and macular star of exudate.

cat scratch disease, idiopathic, toxoplasmosis, syphillis

NOT MS!

Unusual ocular findings

●Marked anterior and/or posterior segment inflammation

●Marked periphlebitis (venous sheathing)●Markedly swollen optic nerve head●Marked optic disc haemorrhages●Macular star

Investigations● Neuroimaging● CT scan● MRI

● VEPs● CSF analysis

MRI scan● Sensitivity > CT scan● A magnetic resonance imaging study (MRI) of the brain

and orbits with gadolinium contrast provides ● confirmation of the diagnosis of acute demyelinating optic

neuritis ● important prognostic information àrisk of developing MS.

● Fat-suppression techniques and godolinium infusion-Best visualized lesions in the optic nerves of patients with symptomatic optic neuritis

MRI use in ● Atypical optic neuritis ● confirm diagnosis● find cause

● Typical optic neuritis● Prognostic indicator for future MS

MRI: Nerve Sheath Enhancement

●

MRI in MS● Neuroimaging study of choice for MS; MRI scan with● FLAIR –Fluid-attenuated inversion recovery sequencing● Godolinium infusion

● Superior to CT scan àposterior fossa and spinal cord

● 85% -95% àMultiple lesions with CDMS● Most common lesions :Periventricular ,ovoid and

multifocal lesions

MRI in MS● T1 scans with contrast.● Active new lesions àenhance with gadolinium-DPTA administration

MRI in MS● T2/FLAIR● Show the total amount of

lesion from MS from its onset.

● The pictures show both old and new inflammation.

VEP (visual evoked potential)

VEP● visual evoked potential● axonal demyelination● slowed conduction in the optic nerve● Latency is prolonged ; delay in the P100● Amplitude may be only mildly reduced● A normal VEP is sensitive in excluding a lesion of the

optic nerve, along its pathways in the anterior part of visual pathway

● Useful distinguish functional visual loss

Харааны дуудлагат потенциалын шинжилгээ

Optical coherence tomography● Optical coherence tomography (OCT)

● Measures the thickness in the retinal NFL

● Most of RNFL loss occurred between 3-6 months 85 % pts

● In one study, OCT was less sensitive than VER in detecting

subclinical optic neuritis .

● A number of studies have found that a greater severity of optic

nerve injury seen on OCT suggests neuromyelitis optica (NMO)

rather than optic neuritis associated with multiple sclerosis .

Clinical Features /1/Features of typical demyelinating ON in adults

● Acute to subacute onset – progressive over a few days to 2 weeks

● Young adult patient, typically < 45 years of age, but may be of any age

● Periocular pain (90%), especially with eye movement

– preceding or coinciding with visual loss

● Unilateral loss of visual acuity – variable severity

● Reduced contrast and colour vision – out of proportion to loss of VA

Clinical Features /2/● Uhthoff’s phenomenon● Ipsilateral RAPD● Normal (65%) or swollen (35%) optic nerve head● Mild periphlebitis (venous sheathing)● VF defect – almost any type● Spontaneous visual improvement in >90% starting within

2–3 weeks regardless of treatment● No deterioration in vision when corticosteroids are

withdrawn

Clinical Features /3/● optic disc pallor is seen within 4–6 weeks from onset

of visual loss● Overall, 50% of clinically isolated cases of ON go on to

develop a second MS-defining episode by 15 years.● The risk of developing MS is ● 25% when baseline MRI is normal and ● 75% when MRI has one or more brain lesions typical for

MS● Ancillary investigations suggestive of MS

MRI in MS● T2/FLAIR● Show the total amount of

lesion from MS from its onset.

● The pictures show both old and new inflammation.

Cumulative Probability of CDMSby Number of Brain MRI Lesions

0.

15.

30.

45.

60.

0. 1. 2. 3. 4. 5.

% C

DM

S

Year

16% No lesions

37% 1-2 lesions

51% > 3 lesions

Residual Visual defects after Resolution of ON

● VA 15 – 30 %● Contrast sensitivity 63-100 %● Color vision 33- 100 %● Visual field 62 – 100 %● Steropsis 89%● Light bright sense 89-100%● Pupillary reaction to light 55 -92 %● Optic disc appearance 60 – 80% ● VEP 63 -100 %

Differential diagnosisDifferential diagnosis of Optic Neuritis

● Corticosteroid-responsive optic neuropathiesSarcoidosis, systemic lupus erythematosus, Behçet Syndrome,

autoimmune ON, NMO, chronic relapsing inflammatory optic neuropathy●Other inflammatory conditions

Post-infection, post-vaccination, neuroretinitis, acute disseminated encephalomyelitis

● Compressive optic neuropathiesPrimary tumours, gliomas, meningioma, pituitary tumours – particularly craniopharyngioma in children, metastases, sinus mucocoeles, arterial

aneurysms● Ischaemic optic neuropathies

Anterior and posterior ischaemic optic neuropathy,giant cell arteritis, diabetic papillopathy

Differential diagnosis● Infective conditions

Tuberculosis, syphilis, Lyme disease, viral ON,toxocariasis or helminthitis (usually visible retinal/optic head lesion)

● Toxic and nutritional optic neuropathyVitamin B12 deficiency, tobacco-ethanol amblyopia,methanol intoxication, ethambutol toxicity

● Inherited conditionsLeber hereditary optic neuropathy

● Ocular causesPosterior scleritis, maculopathy, retinopathy, big blind spot syndrome

● Periorbital infectionCellulitis, severe suppurative sinusitis

● Factitious visual lossIntentional or ‘hysterical’

Overlap of Optic Neuritis & Anterior Ischemic Optic Neuropathy (AION)

Optic neuritis AIONDermographicsMean age ,yrs(range)Gender, % femaleRace, % CaucasianAnnual incidence,per 100000

33 (5-70)70%85%2-6

66 (11-90)45%95%1-6

SymptomsPainProgression for daysImprovement

92%70%>90%

10%30-45%>40%

SignAcuityField defect(most common)

Disc edema

20/15 – NLPCentral scotoma,generalized depression

35%

20/15 – NLPNerve fiber bundle(inferior altitudinal)

100%

Neuromyelitis optica ● Diagnosis criteria (99% sensitivity,94% specificity)

● Optic neuritis (unilateral or bilateral)

● Acute myelitis● Plus at least 2 of the following:

● a contiguous spinal cord lesion on MRI involving 3 vertebral segments or more

● a brain MRI nondiagnostic for MS● a positive NMO-IgG serologic

test

● The Arrow indicates spinal cord inflammation in NMO.

Acute Therapeutic options for Optic neuritis

Recommended regimen● 1 g IV Methylprednisolone sodium succinate/day x 3

days● 1 mg/kg qd for 11 days, followed by a four-day taper● An oral taper, however, is not normally necessary as this short

treatment is unlikely to suppress the hypothalamic-pituitary axis.● Review within 1 month is recommended to ensure that vision does

not deteriorate after cessation of treatment.● Appropriate consent should be taken prior to commencing

corticosteroids.

Acute Therapeutic options for Optic neuritis

● High-dose intravenous corticosteroids were effective in improving short-term visual recovery

● no statistically significant benefit in long-term outcome ● Corticosteroids do cause side-effects

● minor such as insomnia, weight gain and mood alterations● major including psychotic depression, pancreatitis and

osteonecrosis

Acute Therapeutic options for Optic neuritis

● Corticosteroids are considered for patients who require faster recovery such as ● monocular patients● patients with severe bilateral visual loss● those with occupations requiring normal visual acuity

Risk of recurrence of Optic neuritis● In the ONTT, Recurrence 28% à 5 yrs

35%à 10 yrs● More common in patients with MS ● Oral prednisolone alone is not recommended● no benefit ● associated with an increased recurrence rate double

than of the other groups

Probability of Recurrent Optic Neuritis in Either Eye by Treatment Group

0.

12.5

25.

37.5

50.

0. 1. 2. 3. 4. 5.

% w

ith fi

rst r

ecur

renc

e

Year

41% Oral Prednisone

25% Placebo

25% Intravenous

P=0.004 Prednisone vs PlaceboP=0.003 Prednisone vs Intravenous

Neuromyelitis optica (NMO)● Prognosis-Both visual and neurologic prognosis in

NMO are poorer than in MS● Episodes of visual loss are recurrent● Severe visual impairment (<20/200) common in at

least 1 eye ● Treatment not been well studied● Immunosuppressive agents remain the mainstay of

therapy for acute episodes● IV Methylprednisolone 1 g/day x 5 d then oral pred

Immunomodulatory therapy● Immunodulatory agents; disease-modifying agents

Immunodulatory agents● Interferon beta 1b (Betaseron)● Interferon beta 1a subcutaneous(Rebif)● Interferon beta 1a intramuscular(Avonex)● Glatiramer acetate (Copaxone)● Tysabri (natalizumab)

Randomised,double masked,placebo-controlled trials

● The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS)

● The Early Treatment of Multiple Sclerosis trial (ETOMS)

● The Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment trial (BENEFIT)

● Reduce MS exacerbations ~ 1/3● Time interval between first and secondary relapses● Fewer lesions on brain MRI● Current research suggests early diagnosis and therapy are

advantage

Optic neuritis in children● 50 – 75% Bilateral vision loss● Swelling of optic nerves● IV Methylprednisolone 1-4 mg/kg/day 3-5 days then ● Oral prednisolone 1 mg/kg/day tape off 4 wks● Low risk of MS● > 80% good visual prognosis

Асуулт-1 ● Харааны мэдрэлийн миелингүйжих үрэвсэл

ихэвчлэн өндөр настай хүмүүс тохиолддог.

1. Үнэн2. Худал

Асуулт-2 ● Харааны мэдрэлийн миелингүйжих үрэвслийн үед

хараа сэргэх тавилан ерөнхийдөө муу байдаг.

1. Үнэн2. Худал

Асуулт-3● Харааны мэдрэлийн миелингүйжих үрэвслийн

дахих эрсдэл үйлчлүүлэгчид преднизолон схемээр уулгасан тохиолдолд буурдаг.

1. Үнэн 2. Худал

Асуулт-4● Харааны мэдрэлийн миелингүйжих үрэвслийн

дараа тархмал хатуурал өвчин үүсэх эрсдэл MRI шинжилгээнд өөрчлөлтгүй тохиолдолд буурдаг.

1. Үнэн 2. Худал

Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006.

The Optic Neuritis Treatment Trial (ONTT)● Objective: to evaluate the role of corticosteroids in the

treatment of unilateral optic neuritis

● Inclusion criteria: unilateral optic neuritis

Brain MRI in the Diagnosis of Multiple Sclerosis*Dissemination in Space $ Dissemination in Time- One or more gadolinium enhancing lesions#or nine hyperintense white matter lesions on T2 weighted MRI (if no enhancing lesion present)- One or more infratentorial lesion- One or more juxtacortical lesions- Three or more periventricular lesions- A spinal cord lesion can substitute for one infratentorial brain lesion

Gadolinium enhancing lesion > 3 months after initial clinical event

New T2 lesion at any time > 30 days after the baseline brain MRI

*Revised Mcdonald Criteria172$ Need to fulfill at least 3 of these criteria# lesions should be 3 or more millimeters

The ONTT: Methods● Randomization to one of 3 groups

1. IV steroids: 250 mg methylprednisolone qid x 3 days, oral prednisone (1mg/kg) x 11 days

2. Oral steroids: prednisone 1mg/kg/day x 14 days

3. Oral placebo: 14 days

Update Diagnosis Criteria for MS. The Diagnosis of Multiple Sclerosis Depends upon Dissemination in Time(Attacks Seperated by at Least One month) and Space. Evidence of dissemination can be Determined by Clinical Examination,MRI,and/or Lumbar Puncture

#Attacks* #Attack with Objective Clinical Evidence

Proof Required for Dissemination inTime

Proof Required for Dissemination in Space

≥ 2 ≥ 2 None None

≥ 2 1 None MRI or 2+ MRI lesions and abnl CSF or second attack

1 ≥ 2 MRI or second attack None

1 1 MRI or second attack MRI or 2+ MRI lesions and abnl CSF or second attack

Insidious neurological progression suggestive of MS :

abnl CSF + Dissemination in time demonstrated by MRI +

a) ≥9 T2 MRI lesions or≥2 spinal cord lesions or 4–8 brain MRI lesions + 1 spinal cord lesion

ora) Abnormal VEP‡ + [≥4 brain MRI lesions or <4 MRI lesions + 1 spinal cord lesion]

Clinical FeaturesFeatures of atypical ON in adults ● Age >50 or <12 years● Bilateral simultaneous or rapidly sequential ON and

chiasmitis● Severe visual loss – no light perception● Progressive visual loss for >2 weeks from onset● Painless visual loss● Pain following onset of visual loss or persistent pain for

>2 weeks from onset

Clinical Features● Severe pain that restricts eye movements or wakes

patient from sleep● Unusual ocular findings:

● Marked anterior and/or posterior segment inflammation● Marked periphlebitis (venous sheathing)● Markedly swollen optic nerve head● Marked optic disc haemorrhages● Macular star

● Lack of any visual recovery within 5 weeks or continued deterioration in visual function

Clinical Features● Symptoms or signs of a systemic disorder other than MS● African or Asian race● Family history● Corticosteroid-dependent optic neuropathy/deterioration

in vision when corticosteroids are withdrawn● Previous history of neoplasia● Ancillary investigations suggestive of a diagnosis

other than MS (NMO, sarcoidosis, Behçet syndrome

Feature NMO MS

Clinical involvement beyond the spinal cord and optic nerves

Rarely Usually

Attacks are bilateral Usually Rarely

Oligoclonal bands in spinal fluid

Rarely Frequently

White matter lesions on brain MRI

Rarely and usually resolvingUsually

Transverse myelitis as presentation

In 20% of cases Rarely

Swelling and signal change on MRI

Often Less often than NMO

Tissue destruction and cavitation

More than MS Less than NMO

Protein content in cerebrospinal fluid

Higher than MS Lower than NMO