1. GRAND ROUNDS
Denise A. John
VEI
July 28th, 2006

2. Case HPI: 37 y/o ♂ presents with 6-day history of blurry vision OS.
(+) redness, tearing, pruritis; Ø floaters/photopsias/diplopia
ROS: Unremarkable, except upper face pressure
POHX: ø corrective wear/trauma/surgeries/laser
PMHX: Hyperlipidemia, obesity, sleep apnea s/p bilateral inf. turbinate reduction, sinusitis, eustachian tube dysfunction
FHX: DM; cancer; Paget’s dz
SHX: Occ. ETOH; ø tobacco/IVDA
ALL: Codeine
Meds: ø

3. Case 20/30 -1.00+0.25x160  20/20 VA sc 20/70 -0.50+0.25x056  NI
Motility: Full OU 21
IOPT
External/SLE: Unremarkable, except mild papillary reaction OU

7. Differential Diagnosis
Anterior ischemic optic neuropathy
Optic neuritis (idiopathic, demyelinating, infectious)
Infectious optic neuropathy (sinusitis, syphilis, lyme disease)
Inflammatory optic neuropathy (sarcoidosis, SLE & other vasculitides)
Infiltrative optic neuropathy (leukemia, lymphoma)
Posterior scleritis
Compressive optic neuropathy
Optic disc drusen

8. More Information…
History & ocular exam
Humphrey visual field
Imaging

9. More History & Exam… Scheduled for HVF; MRI + contrast/FLAIR sequence
Next day: VA sc OS 20/400
Pain with upgaze
Further probing…past episodes of diplopia & muscle weakness
Ocular exam:
14/14
Color vision
1/14
75% red de-saturation OS
Full
CVF
Constricted
Pupils: 1.8 log APD OS

10. More Information…
History & ocular exam
Humphrey visual field
Imaging

12. More Information…
History & ocular exam
Humphrey visual field
Imaging

13. Imaging MRI Head  discontinued/limited study
1.2cm hyperintense FLAIR signal in the corpus callosum
Non-specific finding: inflammatory, infectious, demyelinating plaque, or neoplastic lesion

14. More Information…
History & ocular exam
Humphrey visual field
Imaging

15. Optic Neuritis

16. Definitions Papillitis More common in children
Post - or para -infectious; post -immunizations
Retrobulbar neuritis
More common in adults
Multiple sclerosis (MS)
Neuroretinitis
Least common
Viral infections; cat-scratch fever, syphilis, lyme dz

17. Acute Demyelinating Optic Neuritis

18. Epidemiology Annual incidence: 5/100,000 Prevalence: 115/100,000
Age: yrs
♀ mean age: (9-55yrs)
♂ mean age: (16-60yrs)
More common in ♀
♀:♂  1.8:1
Caucasians of northern European descent
Rare in Asians & Africans

19. Demyelinating Diseases
Isolated optic neuritis
Multiple sclerosis (MS)
Devic dz (neuromyelitis optica)
Schilder dz

20. Multiple Sclerosis 70% of MS pts  evidence of optic neuritis (ON)
1st manifestation in 20%
1st episode of ON & nrl brain MRI  16% develop MS within 5 yrs
1st episode of ON & ø signs of MS  50% with demyelinating lesions on brain MRI
 risk of developing clinical definite MS (CDMS) within 5-10 yrs
CDMS: 2 attacks > 24hrs, separated > 1 month, separate parts of the CNS + abnormal neurologic exam

21. Pathophysiology
Autoreactive abs & T-Cells cross blood-brain barrier & damage myelin  demyelination
Genetic & environmental factors predispose to an autoimmune response
Genetic: HLA-Dw2; HLA-DR2
Environmental: Infection, stress, systemic antigens & metabolites

22. Pathophysiology Early: Myelin sheath loss Preservation of axons
 macrophages, lymphocytes & plasma cells
Late:
Loss of axons
Astrocytic proliferation  glial scar (plaque)

23. Anatomy of Optic Neuritis
Optic nerve head: 45%
Retrobulbar: 61%
Intracanalicular: 34%
Intracranially (prechiasmatic): 5%
Chiasmatic: 2%

24. Clinical Symptoms 70% unilateral Retrobulbar pain (53-88%)
Dull ache/sinus pain +/- globe tenderness
Esp. with EOM
Precedes visual symptoms
Subacute visual loss
Haze, cloud or dimness
Progresses over 2-7 days
< 20/60: 52%
20/70-20/100: 48%
< 20/200: 38%

25. Clinical Symptoms Obscuration of vision in bright light
Dyschromatopsia
ALWAYS present
 vividness of saturated colors
Photopsias/phosphenes
Induced with horizontal EOM/loud noise

26. Uthoff’s Phenomenon 50% of cases of ON
Active or recovered
Transient obscuration of vision with  body temp
Exercise
Hot bath/shower
Hot weather
Bad prognostic sign:
 presence of multifocal white matter lesions on brain MRI
 conversion to CDMS within 3.5 yrs
 recurrent ON

27. Clinical Signs Optic nerve dysfunction: Dyschromatopsia Visual acuity
Contrast sensitivity
Stereo–acuity
Visual field defects:
Central 30° > altitudinal/arcuate > focal central/cecocentral scotomas
Mild defects in fellow eye
Dyschromatopsia
Esp. for red
APD
Optic disc
64.7% nrl appearance
+/- temporal disc pallor in fellow eye
Other Findings:
Peripheral retinal venous sheathing
Uveitis

28. Optic Neuritis Treatment Trial
15 centers in the U.S. ( )
457 pts: acute unilateral ON & ø MS
18-46 yrs of age; 77% ♀; 85% caucasian
3 treatment groups:
(1) IV methylprednisolone 250mg Q6hrs x 3 days  11 days PO prednisone (1mg/kg)
(2) PO prednisone (1mg/kg) x 14 days
(3) Placebo
Baseline gadolinium-enhanced MRI of brain/orbits
1° visual outcome measures: visual acuity, color vision, contrast sensitivity & visual field; 2° outcome measure: development of CDMS

29. ONTT Effect of corticosteroids on speed & degree of visual recovery
PO steroids VS placebo: ø statistically significant difference in speed of visual recovery/degree of visual recovery at 6 months
IV steroids VS placebo: Faster visual recovery within first 2 wks; after 6 months ø difference in visual acuity between 3 treatment groups
Effect of corticosteroids on visual recovery
All pts showed improvement in vision within 1 month
Identification of factor(s) which may affect visual recovery
Degree of initial loss of vision best predictor of 6 month visual acuity outcome

30. ONTT
Identification of side-effects of short-term use of corticosteroids
All pts reported sleep disturbances, mood changes, stomach upset, skin flushing & weight gain
IV steroid group: 1 case each of psychotic depression & acute pancreatitis
Visual Field Profile of pts with ON
Variable patterns
Chiasmal/retrochiasmal defects  76% with abnormal baseline MRI
68.8% of fellow eyes with mild, but abnormal VF

31. ONTT
Gadolinium - enhanced, T2-weighted brain/orbit MRI  likelihood of developing CDMS
5-yr data, MS risk:
Ø lesions = 16%
1-2 lesions = 37%
> 3 lesions = 51%
Effects of corticosteroids on development of MS
IV steroids:  risk of CDMS in pts with an abnormal MRI (> 2 white matter lesions) during first 2 yrs
Effect of corticosteroids on recurrent ON
PO steroids  rate of recurrent ON
30% of pts: > 1 new episode of ON in either eye by 2nd yr; IV steroid group: 13%; placebo group: 16%
 recurrence in pts subsequently diagnosed with MS

32. CHAMPS/ETOMS
CHAMPS: Controlled High-risk Subjects Avonex Multiple Sclerosis Prevention Study; ETOMS: Early Treatment of Multiple Sclerosis
Pts with 1st episode of clinical demyelinating syndrome + lesions on brain MRI associated with  risk for CDMS
CHAMPS: placebo VS IFN ß-1a (Avonex) 30mcg IM weekly x 18 months
ETOMS: placebo VS IFN ß-1a (Rebif) 22mcg SC weekly x 24 months
CHAMPS & ETOMS:  conversion (44% & 24%, respectively) to CDMS within 18 to 24 months in IFN ß-treated groups.
 # of new/enlarging MRI lesions
 time to occurrence of second relapse

33. Recommendations Typical acute monosymptomatic demyelinating ON
Gadolinium - enhanced MRI of brain/orbits to determine risk for CDMS
> 2 white matter lesions (> 3mm in diameter, >1 lesion periventricular/ovoid:)  risk for CDMS
IV methylprednisolone 1gm/day x 3 days  oral prednisone (1mg/kg/day) x 11 days  4-day taper (20mg, then 10mg, then 0mg, then 10mg)
Avonex 30mcg IM weekly or Rebif 22mcg SC weekly
< 2 white matter lesions or pt with prior ON/known MS: use of IV methylprednisolone considered on an individual basis
Oral prednisone ALONE should be avoided

34. THE IMPACT OF THE ONTT ON PRACTICES OF OPHTHALMOLOGISTS & NEUROLOGISTS
Reported Δ
(%)
Less Use
More Use
Prednisone
Alone
Ophthal (n=112) 90
100
Neuro (n=114) 95
IV solumedrol + PO prednisone
Ophthal (n=97) 67 8 92
Neuro (n=109) 82 4 96
ø treatment
Ophthal (n=118) 32 40 60
Neuro (n=107) 24 54 46
Trobe et al. The impact of the ONTT on the practices of ophthalmologists & neurologists. Ophthal. 1999; 106:

35. Prognosis Maximal visual recovery usually reached by 6 months
ONTT: + treatment
1-yr VA:
> 20/40: 90%
5-yr VA:
> 20/25: 87%; 20/25-20/40: 7%; 20/50-20/190: 3%; < 20/200: 3%
Abnormalities may be seen/perceived in other visual parameters despite return to normal acuity
ONTT
63% of pts reported vision not recovered by 6 months
80% -> 1-4 abnormal visual parameters
20% -> all 4 visual parameters normal
A mild APD may remain

36. Back to our patient… Assessment: Acute optic neuritis Plan:
1gm IV solumedrol x 3 days  60mg PO prednisione daily x 11 days  PO taper
F/U 1 month  Neuro-ophthalmology: VA OS 20/3020/20; color vision 10/14; VF
Referred to Neurology (2 months later)
VA OS 20/20
(+) paresthesias right torso; binocular diplopia; bilateral INO
LFT’s, ANA, ANCA, ESR, RF, Anti-DNA, Anti-SSA/SSB  negative
MRI (cervical & thoracic spine): Herniated disc; several T2 hyperintense signals throughout cervical spine consistent with MS
Diagnosis: Relapsing/remitting MS
Started on Rebif 44mcg SC 3x/wk

37. HVF

38. Take Home Points…
Classic triad: (1) loss of vision (2) eye pain (3) dyschromatopsia
Atypical ON ( visual loss progressing > 1 wk, vitritis, > 45 yrs of age, ø pain): work-up for another etiology
Typical cases & ø history of ON/MS: IV + PO steroids +/- IFN ß-1a
Anti-ulcer medication
Steroid-dependent optic neuropathies (neoplastic, paraneoplastic & inflammatory) worsen when off steroids; ø typical of ON

39. Bibliography BCSC. Neuro-ophthalmology. AAO. 2004-05
BCSC. Pathology. AAO
Yanoff. Ophthalmology, 2nd Ed. Mosby
Kanski. Clinical Ophthalmology, 5th Ed. Butterworth Heinemann
E-medicine: Optic Neuritis
Beck RW, Cleary PA, Anderson MA, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992; 326:581–8.
Beck RW, Cleary PA, Backlund JC, et al. The course of visual recovery after optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1994; 101:1771–8.
Arnold AC. Visual field defects in the Optic Neuritis Treatment Trial: central vs. peripheral, focal vs. global. Am J Ophthalmol. 1999;128:632–4
Beck RW, Kupersmith MJ, Cleary PA, et al. Fellow eye abnormalities in acute unilateral optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1993;100:691–8.
Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med. 1993;329:1764–9.
Cleary PA, Beck RW, Bourque LB, et al. Visual symptoms after optic neuritis: results from the Optic Neuritis Treatment Trial. J Neuroophthalmol. 1997; 17:18–28.
Trobe JD, Sieving PC, Guire KE, et al. The impact of the Optic Neuritis Treatment Trial on the practices of ophthalmologists and neurologists. Ophthalmology. 1999;106:2047–53.
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon β-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898–904.
CHAMPS Study Group. Interferon β-1a for optic neuritis patients at high risk for multiple sclerosis. Am J Ophthalmol. 2001;132:463–71
Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet. 2001;357: 1576–82.