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

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

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

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

More Information… History & ocular exam Humphrey visual field Imaging

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

More Information… History & ocular exam Humphrey visual field Imaging

More Information… History & ocular exam Humphrey visual field Imaging

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

More Information… History & ocular exam Humphrey visual field Imaging

Optic Neuritis

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

Acute Demyelinating Optic Neuritis

Epidemiology Annual incidence: 5/100,000 Prevalence: 115/100,000 Age: 20-50 yrs ♀ mean age: 30.2 (9-55yrs) ♂ mean age: 31.1 (16-60yrs) More common in ♀ ♀:♂  1.8:1 Caucasians of northern European descent Rare in Asians & Africans

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

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

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

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

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

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%

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

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

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

Optic Neuritis Treatment Trial 15 centers in the U.S. (1988-92) 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

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

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

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

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

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

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; 106:2047-53

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

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

HVF

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

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