Clinical Update on Op’ ‘Acute idiopathic optic neuritis the most common cause of optic neuropathy in young patiens. I isan isolated inflamma- tory optic neuropathy secondary to demy- dlination andis one ofthe clinically isolated syndromes suggestive of multiple sclerosis (MS).' Opric neuritis is often the herald- ing manifestation of MS, and many patients with MS develop optic neuritis ar some point during the course of their disease. The Optic Neuritis Treatment Trial (ONTT) has provided the best prospec- tive daa regarding the clinical presentation, ‘outcome with respect to treatment, and de- velopment of MS in patents with optic neu- ris. Ths mul-centered study enrolled 448 patients who were teated cither with ora placebo, IV steroids followed by an oral pla- cexbo tapes, oF oral steroids alone. Patients ‘were followed for visual outcome as wel as, forthedevelopmentof dincaly definite MS. Demoarapiics Patinss with optic ncurts are eypically young, witha peak incidence in che third and fourth decade, and more women than rmen ate affected. In the ONTT, 77% of the patients were women, 85% were Cau- casian, and the mean age was 32. The an- nual incidence of optic nests in the USis approximately 5 cass per 100,000 and the prevalence is 115 cases per 100,000. ‘Symptoms Visual ess generally occurs over a pe- Fiod of hours to a fw days, and may progress cover? t0 10 days, Progressive deterioration of vision beyond 2 weeks is highly uncharacter- isicof optic neurits Reduced color visions common, and patients frequently report a darkening of vsion oF desaturation of color Pain, usually exacerbated by eye movement, js presenc in more than 90%6 of cass’ and ‘may precede or coincide with visual loss. Uhthof’s phenomenon (eansient worsen- ing of vision with elevation of body tempera- ‘ure such a5 afer exercise oF a hot shower) may be sen, though itis nonspecific and is alo noted with other optic neuropathics. Sicns Patients typically have reduced visual acuity ranging fom nearly normal to no light perception (NLP). In the ONT, 10% of the patents were 20/20, 25% were between 20/25 and 20/40, 29% were 20/50 to 201 ic Neu eons 190, and 369% were 20/200 to NLP2* Dys- chromatopsia can usually be identified by testing with Ishihara pscudoisochromatic color plates and noting asymmetry berween ces. The typical visual field defect is a cen tral scotoma burcan be of any type. The optic nerve appears normal in the acute phase in about wo thirds of cae (retrobulbar optic neuritis) and is swollen in about one third of cases (optic papilis)* In both cases, tem- poral pallor of the disc ofien develops after 4 10 6 weeks fiom onset of visual loss. Peri- papillary hemorthages and retinal exudates are uncommon findings? Discnosis “The diagnosis of optic neuritis prima- ‘ily adic one. ‘The ONTT showed thar routine blood tests, including ANA, ACE, FFTA-ABS, and chest xray are of no valve in ‘typical cases (young patients with subacute vision loss and pain on eye movement)* A. ‘more thorough asessment should be consid- cered when atypical eaures of optic neuiis are present, induding a very swollen optic rene, retinal exudates, absence of pain, and absence of any recovery within 30 days.” ‘An MRI of the brain with gadolinium should be obtained in all patients with optic neuritis. This study is sential to evaluate the rk of MS, and ie may be repeated overtime because che most recent criteria for che diag- nosis of MS incorporate the presence of MRI findings! In che ONTT, 59% of patents with a previously normal neurologic history had linicallyslene white mate lesions.” The most ‘ypical findings ae small T2-hyperineense Fe sions inthe periventricular white mater, sub- cortical white marer and pons.” Enhance- :ment of the lesions on T1-imaging indicates active plagues. Both short-term inversion re- covery (STIR) and fuid-atenuated inver- sion recovery (FLAIR) soquencesincrease the sensitivity of detecting these white matter ke Spinal cord imaging is usually not helpful in patients with clinically isolated optic neuritis." Dedicated orbital views (chin sections with far suppression and ga- dolinium administration) are only necesary in atypical optic neutits, as the documen: tation of optic nerve enhancement is not necessary in most typical cass." (CSF analysis was found by the ONTT to be unnecessary in the intial evaluation of patients with typical isolated optic neu- is and Mul Marjorie A. Murphy, MD ple Sclerosis ritis because ie neither changed the diag- nosis nor added information co that ob- tained from MRI in predicting future de- velopment of MS." A lumbar punecure should only be performed in selected arypi cal cases of optic neuritis, especially for bi- lateral cases, in childhood, or when an in- fectious or inflammatory disorder is sus- pected." Visual evoked potentials (VEPs) are only an extension of the ophthalmologic examination and should not be used «0 make a diagnosis of acute optic neuritis in the seeing of unexplained visual loss." As the diagnosis of acute optic neuritis is clinical, ophthalmologists do not recom: mend VEPs in the routine diagnosis or ‘management of acute optic neuropathies. ‘An MRI of the brain is eherefore the only requisite tet in eypical cases of optic neuritis. Criteria for atypical optic neuts include: 1) marked optic disc swelling, 2) Vitti, 3) evidence of orbital inflammation or infization 4) progressive visual loss after 2 weeks, 5) lack of partial recovery within 4 ‘weeks of onset of visual loss, and 6) peris- tent pain." An MRI of che orbits with fat suppression and administration of gado- linium will exclude compressive lesions, and laboratory worlup (RPR, FTA-ABS, Lyme titers, ACE, ESR, ANA, B12, ANCA, p- ANCA, and mitochondrial analysis) and Jumbar puncture may be obtained. Visuat. PROGNOSIS ‘The ONTT confiemed that sponta- neous visual recovery begins rapidly (within 3 weeks) in approximately 80% of patients with idiopathic acute optic neuritis and continues to improve for up to 1 yeat'*!” Ar one-year follow-up, at least 95% of pa tients had visual acuity beter than 20/40 in the affected eye. Although 50% of pa tients had a visual acuity of 20/20 in the affected eye, a majority of patients com: plained of permanent visual dysfunction such as impaired contrast sensitivity, de- creased color vision, difficulty with motion perception, and diminished intensity of light. At 10 years, visual acuity was > 20) 20 in 74% of patients and > 20/40 in 92%, with only 3% worse than 20/200." ‘Optic neuritis not uncommonly recurs ineither the same or Flow eye. In the ONT, 28% of patents developed recurence within 5 years and 35% at 10 years.” Recurrent VOLUME ®4 No.2 FEBRUARY 200858 episodes were more fequent in patents who eventually developed MS and in those who received treatment with orl prednisone alone. ‘The ONTT provided documentation ofthe effect of corticosteroid therapy on vi- sual outcome in optic neuritis. Intravenous methylprednisolone (IVMP) at a dose of 250 mg four times aday for 3 days, followed by 11 days of oral prednisone at 1 mg/kg resulted in increased rates of visual recovery dling the 15 days afer vision loss. Ax suc- cesivefllow-up examinations, howeves this effect diminished. By 6 months, there was minimal difference berween treated and pla- cebo groups, and by 1 year and chereaer, there was no significant long-term benefit forvisul function.” Hence, treatment with IVMP may speed recovery of vision in the first Rew weeks after onset but provides no longterm benef nal prednisone alone at doses admis iseered in che ONTT (1 mgfkg/d) pre duced no visual benefit, either for speed ing recovery or for long-term visual func: tion. Furthermore, ie was associated with a sigoificandly higher rate of recurrence in the affected or fellow eye (27% vs. 13% in the IVMP and placebo groups) at 6 months, an effect that was borne out through 10 years of follow-up.” The continuing rec- ommendation fiom che ONTT and the standard of practice in the US neuro-oph- thalmology community is not co treat ido pathic optic neuritis with oral prednisone." Risk oF peveLopinc MS In the ONTT, the overall rik for the development of clinically definite MS (CDMS) afieran inital isolated episode of ifiopathic optic neuritis was 30% at 5-year and 38% at 10-year follow-up.” Numerous studies have shown that brain MRI is che ‘most powerful predictor of future develop- ment MS in patients with acute idiopathic ‘opticneurits This is in accordance with the recent modification of MS diagnostic cie- fia, which now include MRI changes. Although the presence of white matter abnormalities (demyelinating sons isnoc suf ficient to make the diagnosis of CDMS, oes provide evidence of muhifocl brain involve- ment and in the dinical sting of optic new ris, aes the rik significantly. Inthe ONTT, the S-year Fide for CDMS was 169% with a normal brain MRI (no lesions), compared with 37% with one or two lesions and 51% ‘with three or more lesions.” At 10 year, the increased risk of CDMS with the presence of ‘white maersions wassusained, buthe only satisically significant difference was berwoen no sions (22% rsk) and one or more lesions (6566 isk) the gradually progressive sk wich increasing volume load oflesions seen at 5 years ‘was not continued at 10 years? The ONTT did noe show any demo- szaphic or clinical features of optic neuiis predictive of developing MS in parents with abnormal baseline MRI. However, in pa- tients with normal baseline MRI, the tsk of developing MS was three times lower for men than for women. The tsk was ako lower for those who had optic nerve head cedema. MS did not develop in any patient ‘witha normal MRI at 10-year follow-up who had 1) painless visual los, 2) absence of ight perception in the aed eye, 3) severe op- tic dis edema, 4) perippillary hemorthage, fr 5) macular exudates.” These findings emphasize the importance ofa dilated fun- duscopie examination by an ophthalmolo- gt in all patients wieh acute optic neuritis, a these findings should help identify a group cof patients with avery low rsk of MS.” the standard of practice. treat idiopathic opt neuritis with oral prednisone. Benerms oF THERAPY Corticosteroids At 2-year follow-up in the ONTT (in patients with ewo oF m ter lesions), the IVMP treatment group was found to show a significandly de- creased risk for the development of MS. However, the beneficial effect was not maintained for 3 years* The lack of a significant difference between the treat- rent groups in the subsequent develop- ment of MS was apparent regardless of the number of MRI abnormalities. This lack of benefit was borne our in subse- {quent 5- and 10-year follow-up studies? ce whie mat- Immunomodulation Therapy Three types of immunomodulation agents (IMAs) are available fr the treatment of relapsing-remitting multiple sclerosis (RRMS) : interferon bea -Ib (Betaeon),n- terferonbera-la Avanex, Reif), and thesyn- thetic copolymer glatiramer acetate (Copaxone). Several large-scale phase II] rmul-center clinical wialshave established that these agents are beneficial in reducing isbil- ity progresion, acute demyelinating inflam- mation (active white matter lsions on TI- ‘weighted MRD), total disease burden (cumu- lasive white marer lesions on ‘T2-weighted MRD, and brain atrophy (overall parenchy- ‘mal volume and “black holes” of focal ato phy) in patent with established retapsing dis- ce2se In 1998, the National MS Sociery in consensus statement recommended that IMA therapy be initiated immediarely upon cstablshing a diagnosis of RMS. More recent studies have addressed IMAS effectiveness in reducing the tsk of developing MS afer a single demyelinating episod. The Controled High-Risk Subjects ‘Avonex Multiple Sderosis Prevention Study (CHAMPS) * was designed 10 evaluate the cffect of Avonex in lowering the rate of devel oping MS after a single demyelinating event (optic neuritis, incomplete transverse myci- tis or brain-stern/cerebellar syndrome). Half ofthe paemtsenroled had isolated optic new ricisas this inital event. Allsubjectshad ewoor ‘more white matter lesions on brain MRI, and all recived IVMP followed by conicoseroid therapy within 14 days of onset, They were then randomized to weekly injections with citer incramuscular Avonex or placebo ‘Ac3 years ate che onset of treatment, the cumulative probability of CDMS was 35% in the Avonex group and 50% in the placebo group. In addition, Avonex was as- sociated with a significant eduction of new MBIT? lesions, gadolinium-enhanced le- sions, and T? lesion volume. New clinically silent MRI signal abnormalities appeared within 18 months in 829% of the placebo- treated patients?” Hence, this finding i cated that 2 large number of such high-risk patients had ongoing sent demyelination." The follow-up study, the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS), showed that these results were sustained at 5 years. abo suggested that there may be modest beneficial effec ofi ‘mediate treatment with Avonex compared with delayed initiation of treatment” Subsequent tials were conducted with the early use of ocher immunomodulatory drugs. The Early Treatment of MS (ETOMS)" study evaluated therapy with Rebif in patients with 2 fist neurologic epi- sode consistent with MS, asessing the effect on lowering the risk of subsequent CDMS. The study differed from the CHAMPS with regard toa numberof fearures including the inconsisene inital use of IVMP and a lower incidence of optic neurtisas the initial event (65% vs. 5096), However the results con- firmed the findings of the CHAMPS: the risk of subsequent CDMS was reducad at 2year follow-up fiom 45% with placebo 10 34% with treatment." In addition, the [MEDICINE & HEALTH/RHODE ISLAND‘number of new T2-MERI lesions and the in- crease in lesion burden were significantly lower with active treatment Similar findings were noted in the Betaseron in Newly Emerging Multiple Sclerosis for Initial ‘Treatment (BENEFIT) study.” in which 28% of patients in the Betascron-treated group developed clinically definite MS,com- pared with 45% in the placebo group. MANAGEMENT OF OPTIC NEURITIS Initial therapeutic options Acute treatment options for idiopahic optic neuritis include intravenous methyl- prednisolone or observation alone. IVMP hastens visual recovery but has no effect on the final visual outcome. The decision to use IVMP should be individualized, considering such factors as the patient’ visual function, results of brsin MRI and side effec.” With regard to visual function, this regimen is only considered for those patient requiting faster recovery such as monocular patiens, chose ‘with severe bilateral visual los, o chose with ‘vocational requirements fora high lve of vi- sual acaity oF depth perception."* Although the ONTT prococl involved daily IVMP in divided doses, pus therapyis now commonly administered 3s a single daly outpatient dose of methylprednisolone, 1 gram daily for 3 days. The subsequent oral prednisone taper (mg/h daily for 11 days witha 4-day taper thereafe) is sill used by many bur nor all ophthalmologists. Oral prednisone alone should not be use in the treatment of idior pathic acute optic neuritis. peutic options MS has traditionally been considered a disease in which early inflammatory events injured myelin bur spared axons, with the ‘cumulative effec of multiple episodes pro- ducing axonal damage and permanent neu- rologic disbilty only late in the course of the disease." However, recent pathological and MRI studies sugges chat axonal dam- age occurs erly in MS.""” Once this axonal damage occurs, permanent neurological deficits may result. The issue of axonal dam- age is at che center of an ongoing debate cover whether to intervene ealy with disease IMAs in patients with clinically isolated gyn- ddsomes."” especially those predicted a high sik for the subsequent development of MS. Results of the CHAMPS ®” and ETOMS, © srudies suggest that patients with optic neuris and abnormal baseline MRI (“high tis. patients?) should be considered for ine terferon beta-1a therapy. Moreover, the CHAMPIONS seudy* suggested thar such treatment should be initiated early after the fise demyelinating event. In addition, the results of the BENEFIT study suggest that incerferon bea-b should be considered t0 delay progression to definite MS in patients with a frst clinically isolated syndrome, in- ding acute idiopathic optic neuritis Al patients presenting with idiopathic demyelinating optic neuritis and a high-risk brain MRI should be informed of the thera- peutic option of IMA for reducing the risk of MS." ‘The data on the benefits of IMAs apply only to patents with a east ewo typical (MRI white mare lesions in those with lower risk based on MRI, the benefis of IMAs are unproved. Addivional considerations include the high cost of therapy, commitment tolong- ‘erm weekly injections with associated side f- feats, and the possibilty that therapy in any individual may be unnecessary" At 10-yeat follow-up in he ONTT, 4496 of patients were disease fee without therapy, and there i evi- dence thatthe clinical course of MS that de- ‘eops after optic neuritis may be less severe than other cases of MS.” There is no consen- sus on this issue: expert recommendations range from treatment in all cases, to treatment only in cases with a east wo MRE lesions, 0 ‘ueatment only for those who, on repeat MRI 6 to 6 months), show newly active lions, suggesting ongoing demyelinating activ- ity’®” The decison to initiate IMA therapy ae initially isolated optic neuritis should be individualized and requires a carl discus sion of al aspects of therapy. REFERENCES rohan EM, Frohman TC, et al Lane New 200524 11-21, 2, Beck RW, Clay PA cal NEJM 1992326 581-8 3. Opec Newsits Sdy Grp. 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Tray Loyan WashemheTHTM, Nal 99: 4 463.76, 38. Fkan EM, Rade Mane Noon A Na 216057 930-2 39, Baar LJ NEJM2006-384:1273:80. 40. Opi nes Stady Group. Ars Nal 20046 1869. Marjorie A Murphy, MD, is a Clini eal Associate Professor in the Deparment of Ophthalmology, Rhode Iiland Hospital The Warren Alpert Medical School at Brown University and Director of Newro- Ophrhalmalogy at Rhode Island Hospital Disclosure of Financial interests The author has no financial int ests to disclose. Conresronpence Marjorie A. Murphy, MD Department of Ophthalmalogy Rhode Island Hospital APC 7 593 Baldy St. Providence, RI 02903 Phone: (401) 444-4669 E-mail: margiemurphy@cox.net 59 VowME 91 No.2 FEBRUARY 2008