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Optic Neuritis Review


CLINICAL CARE
Acute inflammatory demyelinating optic neuritis: current concepts in diagnosis and management
M. Tariq Bhatti, M.D.,a Nicholas J. Schmitt, M.D.,b and Randall L. Beatty, M.D., O.D.b
aDepartments of Ophthalmology, Neurology, and Neurological Surgery, University of Florida College of Medicine, Gainesville,
Florida and bAllegheny Ophthalmic and Orbital Associates, PC, Allegheny General Hospital, Pittsburgh, Pennsylvania
Background:Optic neuritis (ON), defined as an inflammatory demyelinating optic neuropathy, is a frequent cause of visual loss owing to optic nerve dysfunction in young or middle-aged patients. ON can be seen in isolation or in association with multiple sclerosis (MS). Highlighting the importance of this association is the fact that approximately 20% of patients with MS will present with ON.

Methods: Review was conducted of the literature and pertinent clinical trials.
Conclusion: Although the vision prognosis of patients with ON is excellent, with or without the use of corticosteroids, a minority of patients will suffer from significantly poor vision. ON may be the heralding manifestation of MS; the risk stratification for the future development of MS in patients presenting with ON can be determined by the number of white matter lesions on the baseline cerebral magnetic resonance imaging study. To date, 2 randomized, placebo-controlled studies have found that patients with a clinically isolated demyelinating syndrome, such as ON, at risk for MS, may benefit from the early institution of a disease-modifying drug.

Key Words: Optic neuritis, multiple sclerosis, magnetic resonance imaging, corticosteroids
Bhatti MT, Schmitt NJ, Beatty RL. Acute inflammatory demyelinating
optic neuritis: current concepts in diagnosis and
management. Optometry 2005;76:526-35.
Case Report
A 27-year-old white woman noted the sudden onset of decreased vision in the left eye associated with ocular pain exacerbated by eye motion. She had no previous history of a major illness and was not taking any daily medications. Before her vision loss she was in good health. On examination, visual acuity was 20/20 in the right eye and 20/400 in the left eye. With the Ishihara pseudoisochromatic plates, she was able to identify all the color plates in the right eye and none in the left eye. There was a left relative afferent pupillary defect. Slit-lamp examination findings were normal with normal intraocular pressures. Eye movements were full, and the neurologic examination findings were normal. Dilated fundus examination findings were normal in the right eye, and in the left eye the optic nerve was found to be swollen (see Figure 1A). Automated visual field perimetry of the right eye was normal, and in the left eye there was a centrocecal scotoma (see Figure 1B). Magnetic resonance imaging (MRI) of the brain and orbits with orbital fat suppression and gadolinium showed enhancement of the left optic nerve (see Figure 1C) and multiple cerebral white matter lesions (see Figure 1D). She received 3 days of intravenous methylprednisolone (1 g/d) followed by a 2-week oral prednisone taper. Four weeks later, her vision improved to 20/25 in the left eye with a subtle left relative afferent pupillary defect. The left optic nerve was mildly pale without swelling (not shown). The option of starting a disease-modifying drug was discussed with the patient.

Background
Visual loss owing to an optic neuropathy can be caused by a variety of infectious, inflammatory, metabolic, toxic, nutritional, vascular, neoplastic, compressive, traumatic, and hereditary etiologies (see Table 1).1 In particular, optic neuritis (ON), defined as an idiopathic inflammatory demyelinating disease of the optic nerve, is one of the most frequently encountered optic neuropathies in clinical practice. It is important to recognize the signs and symptoms of ON because of its associated therapeutic and diagnostic implications. Specifically, ON may be the presenting manifestation of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. In this review, the clinical presentation of acute ON in adults is described, the evidence-based treatment of ON outlined, and the role of MRI in predicting the future development of MS in patients with ON discussed.
Although childhood ON is not discussed in this review, it should be noted that its clinical presentation and association with MS are dissimilar from adult ON. Specifically, compared with adult ON, childhood ON more commonly presents
with bilateral visual loss with bilateral optic nerve edema, is more often preceded by a febrile illness, and is less frequently associated with MS.2,3 ON in the setting of Devic’s neuromyelitis optica also is not addressed in this review;
therefore, the reader is encouraged to refer to other published articles on the subject.4,5

Clinical manifestations
ON can occur in any age, gender, or race, but it is seen most commonly in young to middleaged white women (see Figure 1). The visual loss associated with ON is most frequently unilateral on presentation with asymptomatic visual function impairment in the fellow eye in a minority of patients.6 Patients often will experience an acute onset of visual loss with progressive worsening of visual symptoms over several days. Phosphenes or transient flashes of light may occur before, during, or after a bout of ON in one third of patients. Although not specific for ON, approximately 90% of patients will complain of ocular discomfort, in particular, ocular pain exacerbated with eye movements.7 The degree of visual loss can range from minimal (_20/20) to severe (no light perception). Dyschromatopsia or the abnormal perception of color is invariably present in patients with ON and can be disproportionately adversely affected compared with the level of visual acuity loss. A reduction in contrast sensitivity occurs in the majority (98%) of patients.8 A variety of visual field abnormalities can be seen in patients with ON including altitudinal, quandrantic, centrocecal, hemianopic, arcuate, and central defects.8 In nearly 50% of patients there will be nonspecific, diffuse visual field loss.7 Visual-evoked potential tracings will show loss of the P100 response in acute ON. During the recovery phase of ON, the P100 response will recover, but there often will be a marked latency.
There often are few abnormal physical examination findings in patients with ON. In one third of cases, the optic nerve is swollen (anterior ON or papillitis) with the remaining two thirds of patients presenting with a normal-
appearing optic nerve (retrobulbar ON).7 The fundus characteristics of the optic nerve swelling are not specific to ON and can overlap with ischemic optic neuropathy, although hemorrhages are more commonly noted in ischemic optic neuropathy.9 Optic nerve pallor becomes evident either as the optic nerve swelling resolves or 4 to 6 weeks
after the onset of visual loss in retrobulbar ON. In nearly all patients with unilateral or asymmetric ON, the swinging flashlight test will find a relative afferent pupillary defect (RAPD). The lack of an RAPD should prompt consideration of an alternative diagnosis.Uveitis (granulomatous iritis or pars planitis) may be seen occasionally on careful slit-lamp
examination in patients with ON or MS.10 Perivenous sheathing is rarely evident on dilated retinal examination.1 Transient worsening of vision owing to a rise in body temperature (Uhthoff’s symptom) can be present
during an acute attack of ON but is more often a sequelae of ON.11 In one study, the presence of Uhthoff’s symptom was associated with a greater incidence of recurrent ON and the development of MS.12

Differential diagnosis and diagnostic considerations
“Typical” cases of ON may not warrant cerebrospinal fluid or serologic evaluation.8 In the Optic
Neuritis Treatment Trial (ONTT; see below), a typical patient was described as “a young adult
woman with visual loss progressing over several days, accompanied by eye pain usually worsened
by eye movement. . .”8 It should be noted that certain features, including bilateral simultaneous
vision loss, absence of ocular pain, nonwhite race, age greater than 46 years, retinal pathology (hemorrhage, exudates, or retinitis), intraocular inflammation, and lack of visual im- provement within 4 to 6 weeks of onset of symptoms
warrants appropriate diagnostic testing for alternative etiologies (see Table 1). It is important to interview the patient completely to elicit any historical fact that may point to some other optic neuropathy, for example, history of kitten exposure and constitutional symptoms of cat scratch disease.
Advancements in MRI technology have greatly influenced the management of patients with ON and MS. In fact, the documentation of dissemination of lesions in time and space, defining a patient with clinically definite MS, can be based on the radiologic findings on MRI.13 Although beyond the scope of this review, a variety of imaging sequences can be used in the evaluation of patients suspected of having MS. The characteristic finding is hyperintense lesions on the T2-weighted or FLAIR (fluid-attenuated inversion-recovery) sequences (see Figure 2A and B).
These lesions are most frequently seen in the periventricular white matter, corpus collosum, and infratentorial regions of the brain. Active MS lesions will show gadolinium enhancement on the spin-echo post-contrasted T1-weighted
images. The presence of gadolinium enhancement is indicative of disruption of the blood–brain barrier and active inflammation. An ominous sign is hypointense lesions on the T1-wieghted images, also known as black holes,
which indicate permanent axonal destruction (see Figure 2C).14 Patients with ON often have an abnormal brain
MRI. In the ONTT (see below), 41% of patients had a normal scan and nearly 27% of patients had _2 lesions.15 As many as 90% of patients

with ON will show enhancement of the orbital or intracranial portion(s) of the optic nerve on the fat suppressed postgadolinium T1-weighted images or increased signal on the short tau inversion recovery images.16,17

Management
Much of our current understanding and management of ON is based on the results of the ONTT, a multicenter, prospective study funded by the National Eye Institute, designed to determine the efficacy of corticosteroid therapy in acute ON and to investigate the relationship of ON to MS.18 –20 Four hundred fifty-seven patients were enrolled from July 1988 to June 1991. Seventyseven percent of patients were women and 85% were white. The eligibility criteria for the study were:
1. Age 18-46 years
2. Acute unilateral ON with onset of visualsymptoms _8 days
3. The presence of an RAPD and visual field defect in the affected eye
4. No previous bouts of ON in the affected eye
5. No prior history of corticosteroid treatment for ON or MS
6. No systemic disease other than MS

There were 3 treatment arms to the study:
1. Oral prednisone (1 mg/kg/d) for 14 days
2. Intravenous methylprednisolone sodium succinate (250 mg q.i.d.) for 3 days followed by an oral prednisone taper (1 mg/ kg/d) for 14 days
3. Oral placebo for 14 days Initially, the 6-month results of the ONTT were reported followed by the 5-year outcomes, and most recently the 10-year data set was published.18,21–23 The results of the ONTT can be divided into the visual outcome measures and the association of ON to MS.

Visual outcome
At entry into the ONTT, 31% of patients had visual acuities of _20/20, 25% had visual acuities of 20/25 to 20/40, 49% had visual acuities of 20/50 to 20/800 and 16% had counting fingers vision or worse (3% of patients presented with
no light perception).7 In nearly all patients with ON, vision improvement was complete within 4 weeks of enrollment and in only a few patients did the vision slowly improve over a 6- to 12-month period.7,24 The only negative predictor of visual outcome was poor visual acuity on presentation (see Table 2). Seventy-six percent of patients with a visual acuity of counting fingers to no light perception at baseline on entry into the ONTT recovered to a vision of 20/40 or
better.21 The final visual outcome at 6 months and 10 years was not statistically different among the 3 treatment groups.21 At 6 months, 95% of all patients enjoyed a visual acuity of _20/40,7 and, after 10 years, 91% of patients had
a visual acuity of _20/40.21 Patients who were treated with intravenous methylprednisolone recovered visual function
(visual acuity, contrast sensitivity, and visual field) approximately 2 weeks sooner than those patients who received oral prednisone or oral placebo. There was no long-term benefit on visual function in the intravenous methylprednisolone-
or the oral prednisone–only groups compared with that in the placebo group. In addition, at the 6-month analysis period, the ONTT found a 2-fold increase in frequency of recurrent attacks of ON in the oral prednisone–
only group compared with that in the other 2 arms of the study, a difference that persisted at 10 years but did not reach statistical significance (see Figure 3).21 The ONTT concluded that oral prednisone alone is not effective in the treatment of acute ON and increases the risk of a second attack of ON, and intravenous methylprednisolone hastens the recovery
of vision but with no long-term visual outcome benefits. Furthermore, a report by the quality standards subcommittee of the American

Academy of Neurology concluded that oral prednisone at a dose of 1 mg/kg/d did not have a proven role in the treatment of ON.25 In addition, a meta-analysis of steroid treatment in randomized, controlled trials of 716 patients with ON found steroids only effective in accelerating vision recovery in the first 30 days of treatment with no effect after 6 months.26
In the ONTT, recurrent episodes of ON and vision impairment were more common in patients with MS (see Tables 3 and 4). Overall, after 10 years, 3% of patients were left with severe vision loss to a level of 20/200 or worse.21 Irreversible
vision impairment in patients with ON appears to be more common in African-Americans than whites.27 Unfortunately, there are no proven effective treatment options for patients with irreversible, chronic vision loss caused by ON. In an effort to treat such patients, a randomized trial using intravenous immunoglobulin did not show any benefit on visual outcome.28

Optic neuritis and MS
Before the ONTT, it was well known that patients with ON could have cerebral white matter lesions on MRI identical to that seen in patients with MS. Also, it was recognized that ON might precede the development of MS based on a small number of prospective studies with a limited number of patients. In a prospective study published the same year the ONTT started enrollment, MS developed in 35 of 60 patients (58%) during a mean followup time of 14.9 years.29 In
the same study, the investigators reviewed the literature on 9 prospective studies from 1978 through 1986 regarding the relationship of ON to MS and noted a wide range of results (8.3% to 56% conversion rate).29 At the time of enrollment and subsequent followup examinations all patients in the ONTT were examined by a neurologist for the presence of MS.19,30 An MRI was performed at the initial visit to identify the presence or absence of cerebral white matter lesions. Forty percent of patients had a normal MRI at presentation.8 The only prognostic factor found to be associated with the future development of MS was the number of cerebral white matter lesions present on the baseline MRI. The MRI was graded on a scale of 0 to 4, as determined by size (_3 or _3 mm), location (periventricular or nonperiventricular), and shape (ovoid or nonovoid) of the cerebral white matter lesions:
● Grade 0: no lesions
● Grade 1: _1 lesion, nonperiventricular or nonovoid in shape, less than 3 mm in size
● Grade 2: 1 lesion, periventricular or ovoid in shape, _3 mm in size
● Grade 3: 2 lesions, periventricular or ovoid in shape, _3 mm in size
● Grade 4: _3 lesions, periventricular or ovoid in shape, _3 mm in size
At 5 years, the risk for MS in patients with a normal baseline MRI was 16% compared with 51% for those patients with _3 lesions (Grade 4).31 The overall 10-year risk for MS was 38% (145/388). The number of cerebral white matter lesions did not statistically alter the chance of MS development. However, what was predictive was whether the MRI was normal or showed cerebral white matter lesions. The 10-year risk for MS in the presence of a normal MRI at
presentation was 22% compared with 56% in the presence of an abnormal MRI (_1 lesion; see Table 5).30 A subanalysis of the data found that MS developed in no patients if the brain MRI was normal and one of the following findings
was present: no light perception vision, severe optic nerve edema, peripapillary hemorrhages, retinal exudates, or lack of ocular pain. These findings are atypical of ON. For those patients in whom MS developed after they were enrolled in
the ONTT for at least 10 years, 65% had an Expanded Disability Status Scale value less than 3.0, suggesting that MS patients presenting with ON will have a relatively benign course of dis- ease.32 Interestingly, the ONTT did not find any correlation between the number of baseline MRI lesions and degree of disability.32

Clinically isolated syndromes
There currently are 5 FDA-approved medications on the market for the treatment of the relapsing forms of MS:
● Interferon-_1a: Rebif®; Serono InternationalSA, Geneva, Switzerland.
● Interferon-_1a: Avonex®; Biogen Idec, Cambridge, MA.
● Interferon _1b: Betaseron®; Berlex Laboratories, Montville, NJ.
● Glatiramer acetate: Copaxone®; Teva-Marion Partners, Kansas City, MO.
● Mitoxantrone: Novantrone®; Serono International SA, Geneva, Switzerland. Beyond the scope of this review, in general, these disease-modifying therapies have been shown in randomized, double-blinded and placebo-controlled studies to decrease the number of existing and new brain T2-weighted MRI lesions, reduce the number of relapses, and slow the progression of disability in patients with relapsing-remitting MS.33–35
The ONTT found that intravenous methylprednisolone reduced the risk of MS development for the first 2 years only (methylprednisolone group, 7.5%; oral prednisone group, 14.7%; and placebo group 16.7%), but at 5 and 10 years, the risk of MS development was similar among the 3 treatment groups.19,23,30 CHAMPS (The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study) and ETOMS (Early Treatment of Multiple Sclerosis) were designed to evaluate the benefit of reducing the risk of MS development by initiating disease-modifying therapy at the onset of a single demyelinating episode or clinically isolated syndrome (CIS), such as ON.
CHAMPS was a multicenter, North American study that enrolled 383 patients with ON, transverse myelitis, or brainstem/cerebellar syndrome. Similar to the ONTT, three fourths of patients were women and nearly 90% were white. To be enrolled in the study, all patients had to have an abnormal MRI, defined as _2 cerebral white matter lesions, one of which had to periventricular and at least 3 mm in diameter.36 Fifty percent of the patients in the study presented with ON.Patients were selected randomly within 27 days of the onset of symptoms into 2 treatment groups: (1) intravenous methylprednisolone (with an oral prednisone taper) followed by weekly intramuscular injections of
Avonex (30 _g/wk) or (2) same initial treatment followed by weekly injections of a placebo. Both the treating and examining neurologists were blinded to treatment. The primary endpoint of the study was the development of MS with the secondary endpoints based on the MRI findings. At 3 years, the cumulative probability of MS development
was 35% in the Avonex group and 50% in the placebo group (rate ratio, 0.56; p _ 0.002). There was no statistical difference on the effect of treatment based on the presenting manifestation (i.e., ON, transverse myelitis, or cerebellar/brainstem syndrome).37 In addition, patients in the Avonex group had a reduced volume of cerebral white matter lesions, fewer new or enlarging T2-weighted lesions, and fewer gadolinium-enhancing lesions. In terms of adverse events, flulike symptoms and depression were more common in the Avonex group. ETOMS was a multicenter study performed in Europe that enrolled 309 patients with ON, transverse myelitis, or cerebellar/ brainstem syndrome.38 The primary purpose of ETOMS was similar to that of CHAMPS, which was to investigate the effect of early interferon treatment in patients with CIS on the conversion to MS. However, ETOMS differed from CHAMPS in several respects. First, eligible patients had to have an abnormal MRI with either _4 cerebral
white matter lesions or 3 lesions with 1 lesion being infratentorial or enhancing. Second, patients were enrolled within 3 months of the onset of their symptom(s). Third, patients were allowed to have more than 1 symptom at time of
entry into the study (polysymptomatic). Fourth, intravenous corticosteroids were not routinely given to all patients, only to those with an initial attack categorized as moderate or severe. Fifth, patients were assigned randomly to treatment with either Rebif, 22 _g subcutaneous injection weekly (recommended package insert dosage of
Rebif is 44 _g thrice weekly), or placebo subcutaneous injection weekly. At 2 years, 34% of patients in the Rebif group went from CIS to MS and 45% of patients in the placebo group converted to MS (odds ratio, 0.61; p _ 0.047). Furthermore, those patients in the Rebif group who converted to MS did so over a longer period of time (569 days in the Rebif group versus 252 days in the placebo group). The MRI results showed fewer new or enlarging T2 lesions and enhancing lesions in the Rebif group. Adverse events were seen more commonly in the treatment arm and included inflammation, fever, myalgia, and chills.
Conclusions
The results of ONTT, CHAMPS, and ETOMS have greatly influenced our current understanding and management of ON. Physicians (including optometrists and ophthalmologists) should be able to recognize the signs and symptoms of ON. Aside from an MRI, further diagnostic testing is necessary if the diagnosis of ON is in doubt. In general, the visual prognosis of patients with ON is very favorable with or without treatment. Intravenous methylprednisolone can be offered to hasten the recovery of vision and may be particularly beneficial in patients with bilateral visual loss from ON, monocular patients with visual loss caused by ON in their only remaining eye, and patients who require the rapid return of binocular vision. An MRI should be obtained to assess the risk of the future development of MS. If the MRI is abnormal, initiation of disease-modifying therapy should be considered to lower the conversion rate to MS.
Acknowledgment
This work was supported in part by an unrestricted departmental grant from
Research to Prevent Blindness, Inc. (New York, NY).


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Corresponding author:
M. Tariq Bhatti, M.D.
Department of Ophthalmology
University of Florida College of Medicine
Box 100284 JHMHSC
Gainesville, Florida 32610-0284
tbhatti@eye.ufl.edu
tariq.bhatti@duke.edu


Written by: M. Tariq Bhatti, M.D.
http://www.duke.edu

 
 

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