Optic neuritis

Optic neuritis- newer advances and studies
treatment in adults and children

1. Optic Neuritis Dr. Sachin Adukia

2. Definition, Incidence , epidemiology Optic neuritis is an inflammatory, demyelinating condition that causes acute, usually monocular , visual loss. presenting feature in 15 to 20 % of patients of MS Occurs in 50 percent at some time during the illness occur in women ( two thirds), typically between age 20 and 40 years age highest in higher latitudes, lowest close to equator In the United States, 6.4/ 1,00,000 whites > blacks, More in Southeast Asia relative to incidence of MS

3. Pathology and pathophysiology pathologic basis is inflammatory demyelination of the optic nerve. pathology is similar to MS plaques in the brain perivascular cuffing, edema in the myelinated nerve sheaths, myelin breakdown Myelin loss exceeds axonal loss. demyelination immune mediated , but specific mechanism and target antigen- unknown. Systemic T cell activation occurs at symptom onset and precedes changes in CSF T cell activation leads to the release of cytokines B cell activation against myelin basic protein is not seen in peripheral blood but in CSF genetic susceptibility Overrepresentation of certain HLA types in ON

4. Unilateral vs bilateral in 10 %, both eyes, either simultaneously or in rapid succession Bilateral ON is more common in children - 12 to 15 years also in Asian and black South Africans Because bilateral symptoms are relatively uncommon, search for alternative diagnosis

5. Clinical features the Optic Neuritis Treatment Trial (ONTT), enrolled 457 patients, 18 to 46 years, with acute unilateral ON 2 most common symtoms Vision loss develops over hours to days, peaking within 1-2 weeks. Continued deterioration suggests alternative diagnosis > 90 % inONTT had significant decrease in central visual acuity. Eye pain in 92%- often worsened with eye movement onset of pain generally coincided with visual acuity loss and improved along with it.

6. Visual field loss RAPD always occurs in ON if other eye is uninvolved demonstrated by swinging light test, finding that direct response to light is more sluggish in the affected eye. visual field defect Typically, central scotoma in the ONTT, diffuse vision loss and altitudinal, arcuate , hemianopic , and cecocentral defects. defect that extends to periphery - compressive lesion, while altitudinal defect, particularly inferior altitudinal- AION Visual field defects usually resolve; in the ONTT, 56 percent - normalized at one year 73 percent - normalized at 10 years

7. Fundoscopy Papillitis with hyperemia and swelling of the disk, blurring of disk margins, and distended veins is seen 1/3 of ON 2/3 of this pool have retrobulbar neuritis with a normal fundus more common in children <14 black South Africans and Southeast Asians Peripapillary hemorrhages rare in optic neuritis but commonly accompanies papillitis due to AION

8. Other clinical features Photopsias (flickering or flashes of light) precipitated with eye movement 30 % of patients in the ONTT Loss of color of vision out of proportion to the loss of visual acuity is specific to optic nerve pathology. Abnormal color vision by Ishihara plates 88 % in the ONTT by the more sensitive Farnsworth Munsell 100 hue test - 94 % Funduscopic or slit lamp examination Perivenous sheathing or periphlebitis retinae – 12 % in ON implies a high risk for MS Uveitis , cells in the anterior chamber pars planitis Uncommon in ON more typical of infections and otherautoimmune diseases

9. CHRONIC CLINICAL FEATURES Persistent visual loss . Most recover functional vision within one year. However, on testing, deficits in color vision, contrast sensitivity, stereo acuity, and light brightness are detectable in most patients till 2 years RAPD in 25% till 2 years Color desaturation refers to a qualitative intereye difference in color perception that can be tested by comparing vision of a red object with each eye. Eg . monocular "red desaturation"

10. Uhthoff's phenomenon- temporary exacerbations Optic atrophy follows ON, despite return of visual acuity Normal, 20/20 visual acuity requires less than ½ of normal foveal axons temporal pallor The pattern-shift VER remains delayed, even with visual recovery.

11. DD’s:- Causes of optic neuropathy Ischemic optic neuropathy Arteritic ischemic optic neuropathy Nonarteritic ischemic optic neuropathy Optic neuritis Infections NeMeningitis (any cause) Syphilis, Lyme diseaseuroretinitis : viruses, toxoplasmosis, bartonella , others Inflammatory Parainfectious Systemic autoimmune disease: SLE, SjS , , others Paraneoplastic Sarcoidosis Genetic Leber's hereditary optic neuropathy Kjer type autosomal dominant optic atrophy

12. Neoplasms (compressive, infiltrative) Optic glioma Meningioma Metastasis Lymphoma Compression Abscess Carotid-ophthalmic artery aneurysm Thyroid ophthalmopathy Orbital pseudotumor Pseudotumor cerebri Toxic/metabolic DrugsToxins Nutritional deficiency (vitamin B1, B12, folate ) Tobacco-Alcohol amblyopia Radiation Trauma Recurrent ON in non-NMO or MS sarcoidosis , Lupus chronic relapsing inflammatory optic neuropathy (CRION), paraneoplastic optic neuropathy (serum CRMP5/ CV2 antibody)).

13. Evaluation History - Neurological examination - Fundus examination MRI Orbit with Gandolinium contrast longitudinal extent of nerve involvement correlates with visual impairment at presentation and with visual prognosis Gadolinium enhancement persists for a mean of 30 days since onset brain MRI – white matter abnormalities characteristic of MS Typical lesions are ovoid, periventricular , >3 mm. prevalence of white matter abnormalities varies 23 to 75 percent Individuals with white matter abnormalities are at a higher risk of developing MS Yield of MRI spinal cord imaging is low in unselected patients.

14. Brain MRI of a 30-year-old woman presenting with optic neuritis . Fat saturated T2-weighted coronal (A) image shows hyperintensity in the right optic nerve (arrow). Post-gadolinium fat-saturated T1-weighted coronal (B) image shows abnormal enhancement in the right optic nerve (arrow). Four years later, sagittal FLAIR (C) shows two plaques radiating outward from the corpus callosum

15. CSF Analysis not an essential diagnostic test Considered in atypical cases bilateral presentation, <15 years in age symptoms suggesting infection 60 to 80 percent of ON- nonspecific abnormalities in CSF lymphocytes (10 to 100) elevated protein Other CSF OCB implies a higher risk of developing MS. However, since OCB are also associated with white matter lesions on brain MRI, they are not an independent prognostic importance

16. Other tests- to be done when considering an alternative diagnosis ESR, ANA, Sr. ACE level, serologic and CSF tests for Lyme disease and syphilis Fluorescein angiography not routinely performed in evaluation of ON and is often normal. Up to 25 percent demonstrate either dye leakage or perivenous sheathing may identify patients at somewhat higher risk for developing MS. Visual evoked response delay in the P100 of VER is the electrophysiologic manifestation - as a result of axonal demyelination helpful if there is a suspicion that the visual loss is functional. Multifocal VER - more sensitive and specific but generally not available

17. Optical coherence tomography measures the thickness in the retinal nerve fiber layer detects thinning in 85 percent% of ON lower values correlate with impaired visual outcome, prognostic Value- limited as abnormal values do not show up until early swelling disappears. greater severity of optic nerve injury – suggests NMO > ON associated with MS

18. Aquaporin 4 specific serum autoantibody patients with either severe or recurrent optic neuritis, may be seropositive for Aquaporin 4 specific serum autoantibody seropositivity for the aquaporin4specific serum autoantibody was predictive of subsequent NMO in recurrent ON Serum NMO antibody test is suggested with recurrent ON, particularly if MRI brain is negative for any abnormal T2/FLAIR lesions outside of the affected optic nerve(s). The role for testing to myelinoligodendrocyte glycoprotein (MOG) antibodies is investigational

19. Prognosis Recovery of vision — Without treatment, vision begins to improve after a few weeks Can continue over many months; 90 percent have 20/40 or better vision at one year Lower visual acuity at presentation = less complete recovery Longer lesions in the optic nerve on MRI, particularly those extending into the optic canal= poorer visual outcome Most children have a good visual outcome despite a more severe visual deficit on presentation approximately 20 % - persistent functional visual impairment MS= poor outcome Aquaporin 4 specific serum autoab . positive= poor outcome

20. Recurrence In the ONTT, 35 percent recurrence of optic neuritis at 10 years 14 percent in the original eye, 12 percent in the other eye, 9 percent in both eyes recurrent optic neuritis = greater risk of developing MS Recurrent ON + seropositivity for the aquaporin 4 specific serum autoantibody predicts subsequent NMO

21. Higher Risk of Subsequent multiple sclerosis In the ONTT, five year incidence of clinically definite MS – 30% 40 %at 12 years and 50 % at 15 years F>M Caucasians > Asians African –Americans more likely to develop NMO MRI abnormalities: presence of characteristic demyelinating lesions - a strong predictor of, independent of no. of lesions Retinal perivenous sheathing = higher risk of MS OCB in CSF= higher risk of MS HLADR2 alleles = higher risk of MS

22. Lower Risk of Subsequent multiple sclerosis simultaneous bilateral involvement at initial presentation Age- risk is lower if the initial attack of ON occurs in childhood Patients at an older age (>35 to 40) are less likely to develop MS ON relatively uncommon in over 40 years

23. Treatment = Steroids Patients in Optic Neuritis Treatment Trial (ONTT) were randomly assigned to oral prednisone ( 1 mg/kg/d) for 14 days with 4 day t aper IV methylprednisolone (250 mg four times/d) for 3 days f/b oral prednisone (1 mg/kg per day) for 11 days with a four day taper oral placebo for 14 days IV methylprednisolone accelerated the recovery of visual function also reduced the risk of conversion to MS Whereas, risk of recurrent ON in both eyes was higher in oral steroid arm

24. IV treatment is used in abnormal high signal abnormalities on brain MRI, since this may delay the onset of MS. severe or bilateral vision loss- may speed up recovery IVIG and PLEX- do not have established efficacy in ON

25. Trial Name Drug Outcome at 3 years The Controlled High Risk Avonex MS Prevention Study (CHAMPS) 383 pts Interferon beta-1a ( Avonex ), 30 μg IM each week versus placebo significantly reduced 3 year cumulative risk of developing MS smaller number of gadolinium enhancing lesions on brain MRI The total volume of T2 lesions on MRI was also smaller in Early Treatment of Multiple Sclerosis Study (ETOMS) 308 pts interferon beta1a ( Rebif ), 22 μg s/c each week versus placebo reduced longterm risk of developing MS The time to occurrence of the next demyelinating event was longer Fewer treated patients had new T2 weighted lesions the BENEFIT trial, 483 pts 250 μ g interferon 1b ( Betaseron ) s/c or placebo every other day --------Outcomes similar to ETOMS----------- PreCISe study 481 patients glatiramer acetate 20 mg s/c or placebo each day --------Outcomes similar to ETOMS-----------

26. Common side effects Depression injection site reactions, Flu like Symptoms Deranged LFTs potential benefits longer attack free interval Reduced number of demyelinating attacks delay to MS associated disability

27. Treatment in children Clinical trials have been limited to adults IV Methylprednisolone to be considered for acute treatment for severe debilitating bilateral vision In general, immunomodulatory treatments with interferons are not used in younger children, Older children (>15 years) are probably appropriately treated under the same guidelines as adults

28. Investigational treatments Alfampridine ( 4- aminopyridine ; fampridine ), a potassium channel blocker, may improve axonal function in demyelinating disease . Erythropoietin – in a phase II clinical trial active treatment was safe associated with reduced retinal nerve fiber layer thinning on OCT shortened latencies on VEP at 16 weeks.

29. References The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group . Arch Ophthalmol 1991; 109:1673 Beck RW, Gal RL, Bhatti MT, et al. Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial. Am J Ophthalmol 2004; 137:77 Beck RW, Trobe JD, Moke PS, et al. High and low risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 2003; 121:944 . Nilsson P, Larsson EM, Maly Sundgren P , et al. Predicting the outcome of optic neuritis: evaluation of risk factors after 30 years of followup . J Neurol 2005; 252:396 Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome ( PreCISe study): a randomised , doubleblind , placebo controlled trial . Lancet 2009; 374:1503.

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