eMedicine Specialties > Ophthalmology > Neurologic Disorders

Multiple Sclerosis

Andrew G Lee, MD, Professor, Departments of Ophthalmology, Neurology and Neurosurgery, University of Iowa Hospitals and Clinics
Fiona Costello, MD, FRCP, Assistant Professor, Departments of Ophthalmology and Medicine (Neurology), Neuro-ophthalmologist, Clinical Neurologist and Clinical Investigator, University of Ottawa; Cecil L Berlie, MD, Consulting Staff, Department of Ophthalmology, Luther Midelfort Eye Clinic

Updated: Jan 26, 2007

Introduction

Background

Multiple sclerosis (MS) is a common neurologic disorder with protean manifestations. The disease is characterized by myriad multifocal neurologic signs and symptoms, which tend to relapse and remit in the initial stages of the illness and then culminate in progressive neurologic disability over time.

Clinical subtypes of MS include the following: clinically isolated syndromes, primary progressive MS (PPMS), relapsing remitting MS (RRMS), and secondary progressive MS (SPMS).

It is not uncommon for patients with MS to present initially to the ophthalmologist with symptoms, including acute monocular visual loss (ie, optic neuritis [ON]), diplopia (eg, internuclear ophthalmoplegia, sixth nerve palsy), or oscillopsia (ie, nystagmus). No single test can be done to help establish or exclude a diagnosis of MS. Instead, MS is a clinical diagnosis supported by laboratory studies and neuroimaging findings. Early recognition of the disease is important because several immunomodulatory therapies are currently available that might slow the rate of conversion to clinically definite MS (CDMS) after a clinically isolated syndrome (eg, ON) and potentially reduce the progression of the disorder.

Ophthalmologic manifestations of MS that are discussed in this article include ON, nystagmus, and internuclear ophthalmoplegia (INO).

Pathophysiology

The pathophysiology of MS is not known but is probably multifactorial. Several mechanisms have been proposed, including immune mediated; postinfectious (eg, viral), environmental, and geographical exposures; and hereditary factors. The underlying pathologic insult is demyelinating and inflammatory, but, ultimately, axonal loss may result in permanent neurologic deficit. Demyelinating lesions that may produce clinical symptoms occur in the periventricular white matter, the brainstem, the cerebellum, the spinal cord, and optic nerves.

Frequency

United States

Prevalence rates of 17-90 cases per 100,000 have been reported. One population-based study conducted in Rochester, Minnesota, reported an annual incidence of all cases of ON to be 6.4 per 100,000.

International

An increase in prevalence exists with increasing latitude from the equator. This condition is less frequent in the Mediterranean region and is rare in Africa and Asia.

Studies in Europe and Scandinavia demonstrate an incidence of 0.94-2.5 cases per 100,000. The following prevalence rates have been reported (per 100,000): Canada (100); Italy (30-60); Sardinia (60-100); Spain (4-50); Japan, Taiwan, Korea, Malaysia, and China (1-4); Kuwait, Libya, and Saudi Arabia (6-8); and Australia (18-75, south-to-north decreasing prevalence).

Mortality/Morbidity

Mortality in MS can be attributed to numerous factors late in the disease course. The disease itself is extremely variable in severity. Patients with severe MS may succumb to respiratory failure or infection. In the Danish Multiple Sclerosis Registry (n=9881), the median survival time from onset was approximately 10 years shorter for patients with MS than for the age-matched general population, and MS was associated with an almost 3-fold increase in the risk for death. According to death certificates, more than half (56.4%) of the patients had died from complications of MS.

Race

MS is more frequent in whites of northern European origin, and, in this population, up to 1 in 1000 develop MS. MS is less common in individuals of African, Asian, or Mediterranean extraction.

Sex

A female preponderance of 1.6:1 exists in MS, but, in the primary progressive form, males predominate. In the Optic Neuritis Treatment Trial (ONTT), 77% of patients with ON were female. Miller reported that, on average, women were 3 times more likely to develop ON than men. The reason for this difference between men and women is not known.

Age

Symptoms of MS typically present in persons aged 18-50 years, and the age of onset of ON is typically younger for women than for men. According to a study conducted by Wray, the mean age of onset for women is 30.2 years, with a range of 9-55 years. Men typically have a later average age of onset of ON (31.1 y) than women, with the range being 16-60 years. MS can develop in children and in older adults.

Clinical

History

The classic clinical picture of MS is one of multiple neurologic symptoms "disseminated in space and time." More specifically, patients manifest episodic neurologic dysfunction due to inflammation in different regions of the central nervous system over time. Common neuro-ophthalmologic symptoms include unilateral visual loss due to ON and oscillopsia due to nystagmus and diplopia (eg, INO, ocular motor palsy). Other common neurologic symptoms include sensory disturbances, motor weakness, and trigeminal neuralgia. For this reason, patients with ophthalmic symptoms consistent with a possible MS attack should be questioned about historical features that may be suggestive of MS (eg, prior neurologic deficit, prior diplopia or loss of vision, prior neuroimaging studies).

• Afferent visual pathway manifestations - ON
  • Frequency in MS: Approximately 20% of patients with MS present with ON as a first demyelinating event, while 40% of patients may present with ON during the course of their disease. Pathological studies have demonstrated that subclinical optic nerve involvement is very common among patients with MS, and the percentage of patients with anterior visual axis involvement from the disease is likely much higher. Therefore, diagnosing ON is potentially an important step in providing appropriate therapy for the patient; however, not everyone who develops ON develops MS.
  • Clinical onset: ON typically causes acute-to-subacute unilateral loss of visual acuity (which may progress over days to weeks), color and contrast sensitivity, and visual field changes.
  • Pain: Most patients with ON develop retrobulbar pain that is worse with extraocular movement. In the ONTT, mild to severe pain was present in 92.2% of patients. Pain was constant in 7.3% of patients, was constant and worse upon extraocular motility in 51.3% of patients, and was noted only with eye movement in 35.8% of patients.
  • Visual acuity: The loss of visual acuity in patients with ON may range from minimal to profound. At entry into the ONTT, 35% of patients had visual acuities of 20/40 or better, 30% of patients had visual acuities of between 20/50 and 20/200, and 35% of patients had visual acuities of 20/200 or worse. Only 3% of patients were no light perception (NLP). Therefore, NLP should be considered a red flag for a diagnosis of ON, and other potential etiologies for vision loss (eg, inflammatory, infiltrative, neoplastic) might need to be considered.
  • Color vision: In the ONTT, nearly 100% of patients whose visual acuities were 20/50 or worse had a defect in their color sensitivity, and, in those patients with visual acuities of 20/20 or better, 51-70% had altered color vision.
  • Phosphenes: Patients with ON may describe phosphenes or transient flashes of light or black squares lasting from hours to months. Either movement or sound may induce them. They may occur before or during an ON event or even several months following recovery.
  • Visual field function: Visual field changes are common in patients with ON and are typically nerve fiber layer defects. The classic visual field defect of ON is the central scotoma, but any nerve fiber type defect may occur. In the ONTT, the most common visual field defects were, in decreasing order of frequency: altitudinal (28.8%), 3 quadrant (14.0%), 1 quadrant (11.8%), centrocecal (8.7%), hemianopic (8.3%), peripheral rim (7.0%), arcuate (7.4%), central (7.0%), enlarged blind spot (2.6%), and nasal step (1.3%).
  • Other visual symptoms: Other reported visual changes in patients with ON include decreased visual acuity in bright light (about 50% of patients see better in dim light than in bright light), flickering scotomata, and the Uhthoff phenomenon. The Uhthoff phenomenon is an exacerbation of the patient's symptoms when exercising or when exposed to temperature change. The most notable symptoms affected by the Uhthoff phenomenon are transient visual obscurations, dyschromatopsia, and contrast sensitivity changes. The symptoms tend to resolve with restoration of euthermic conditions. Most symptoms of the Uhthoff phenomenon resolve from within 60 minutes to 24 hours.
  • Clinical course: The ONTT found that 74% of patients with ON recovered visual acuities of 20/60 or better by 8 weeks, and most patients had visual acuities of better than 20/40 by 6 months. Although visual acuity typically recovers after ON, patients may continue to complain of residual deficits in color, contrast sensitivity, brightness, and stereovision.
• Efferent visual pathway manifestations - Diplopia, oscillopsia, and nystagmus
  • Diplopia may be due to an INO or an ocular motor cranial neuropathy (typically a sixth nerve palsy).
  • Brainstem involvement producing gaze palsies, nystagmus, or a skew deviation may occur.
  • The occurrence of bilateral INO is considered to be highly suggestive of MS, especially in young patients.

Physical

• Patients with ON typically have loss of both visual acuity and visual field in the ipsilateral eye. Contralateral and often asymptomatic visual field loss may also be detected. A relative afferent pupillary defect is present in unilateral cases and bilateral but asymmetric cases, but the relative afferent pupillary defect may be absent in bilateral and symmetric cases. The visual field defect is often a central scotoma but may be of any optic nerve related field loss.
• Anterior ON (ie, papillitis): Although most patients with demyelinating ON have retrobulbar neuritis, the disc may show mild hyperemia. Severe disc edema, marked hemorrhages, or exudate should prompt reconsideration of a diagnosis of demyelinating ON.
• Posterior ON (ie, retrobulbar ON): Most cases of ON are retrobulbar. In these cases, "the patient sees nothing, and the doctor sees nothing" (ie, the fundus is normal).
• Optic disc pallor, sector or diffuse, often follows either anterior ON or posterior ON.
• Other fundus findings, including anterior uveitis, vitreitis, vascular sheathing, and disc and papillary hemorrhages, as well as compromise of the central arterial and venous circulations, are uncommon. The amount of inflammation, the changes in visual field, and the loss of visual acuity do not correlate directly with the appearance of the disc.
• Patients with MS may present with diplopia due to an INO. In an INO, an adduction deficit of the ipsilateral eye is present, with horizontal gaze nystagmus in the contralateral abducting eye. The lesion involves the medial longitudinal fasciculus (MLF). As stated previously, a bilateral INO is strongly suggestive of a diagnosis of MS. Diplopia in MS may also be due to an ocular motor cranial neuropathy, and a sixth nerve palsy is the most common manifestation. Third and fourth cranial neuropathies are uncommon in MS. Combinations of deficits, including horizontal or vertical gaze palsies, wall-eyed bilateral INO (WEBINO) or wall-eyed monocular INO (WEMINO), paralytic pontine exotropia, or the one-and-a-half syndrome, may also occur in MS.
• Oscillopsia secondary to various types of nystagmus may occur in MS. A new onset acquired pendular nystagmus is relatively common, but upbeat, downbeat, convergence-retraction, and other forms of nystagmus may occur in MS depending on the location of the demyelinating lesion.

Causes

The most important association of ON is with MS. Although ON is generally an idiopathic or demyelinating process, other conditions can produce an optic neuropathy, including the following:

• Inflammatory (eg, sarcoidosis, systemic lupus erythematosus, polyarteritis nodosa, Wegener granulomatosis)
• Infectious (eg, spirochetes, Lyme disease, syphilis, hepatitis B, varicella zoster, human immunodeficiency, Epstein-Barr, cytomegalovirus, mycobacteria, fungi)
• Infiltrative processes (eg, leukemia, lymphoma)
• Toxins (eg, antimetabolites, phenothiazines, isoniazid, ethambutol)
• Nutritional deficiencies (eg, vitamin B-12 level, folate)
• Compressive lesions (eg, tumor, aneurysm, thyroid orbitopathy)
• Ischemic optic neuropathy (eg, anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, antiphospholipid antibody syndrome)

Differential Diagnoses

Other Problems to Be Considered

Ischemic optic neuropathy: The major differential in a case of unilateral and acute optic neuropathy with optic disc edema is either ON or ischemic optic neuropathy. Typically, a younger patient has ON, and an older patient has anterior ischemic optic neuropathy (AION). Although the visual loss is sudden in both ON and AION, pain is less likely to occur in AION unlike in ON, and only mild-to-moderate visual improvement occurs after AION. The disc swelling in AION is typically more severe than in ON, and associated hemorrhages and exudates are features that argue against demyelinating ON.

Infiltrative optic nerve processes: Leukemic infiltration and lymphomatous lesions may create symptoms and a disc appearance similar to that of ON. If a history of such a disorder exists, ruling out either a progression or a relapse of the lymphoproliferative condition is essential. An infiltrate that is visible on the disc head itself is often a clue regarding the underlying etiology. Inflammatory disorders (eg, sarcoid, lupus, other autoimmune disorders) can produce an inflammatory optic neuropathy. The presence of associated anterior or posterior uveitis, a steroid dependent or markedly steroid responsive course, and a history of systemic inflammatory disease are helpful in differentiating these conditions from ON. Magnetic resonance imaging (MRI) is helpful in these cases.

Graves disease: Although thyroid ophthalmopathy (Graves ophthalmopathy) may produce a compressive optic neuropathy, a gradual rather than an acute decrease in visual acuity typically occurs. Usually, the patient has a history of autoimmune thyroid disease and signs of thyroid orbitopathy (eg, upper lid retraction, lid lag, ophthalmoplegia, proptosis). Orbital imaging differentiates compressive optic neuropathy from Graves disease and from ON.

Intraorbital/intracranial compressive lesions: These lesions typically produce painless, progressive, compressive optic neuropathy (eg, optic nerve sheath and intracranial meningiomas, sellar lesions). Neuroimaging studies are important for all cases of atypical ON (eg, chronic ON, pituitary apoplexy, inflammatory or infiltrative ON).

Leber hereditary optic neuropathy: This is a painless, progressive, and typically bilateral optic neuropathy that produces a central or cecocentral scotoma. The disorder is mitochondrially inherited and primarily affects young men.

Toxins and medications: Certain toxins and medications (eg, tobacco, ethanol, methanol, ethambutol, isoniazid, chloroquine, vitamin deficiencies, some anti-neoplastic agents) can produce an optic neuropathy. Typically, these patients have a bilateral and simultaneous central or cecocentral loss.

Neuromyelitis optica

Workup

Laboratory Studies

• In the ONTT, laboratory studies were not deemed helpful in establishing a diagnosis of typical demyelinating ON (ie, acute, unilateral optic neuropathy in a young patient with pain on extraocular movement and improvement over time).
• Laboratory studies can be helpful in patients with features that are atypical for demyelinating ON. These laboratory studies should be performed as a directed evaluation based upon the history and physical examination findings.
  • Complete blood count (CBC)
  • Serum vitamin B-12 level and folate (eg, bilateral central scotoma)
  • Chest radiographs (eg, sarcoidosis, tuberculosis)
  • Lyme titers (eg, endemic area, tick exposure, rash)
  • Tuberculosis (TB) skin test (eg, TB exposure, endemic area)
  • Fluorescent treponemal antibody (FTA) test (eg, syphilis)
  • Venereal Disease Research Laboratory (VDRL) test or rapid plasma reagin (RPR) test (eg, syphilis)
  • Antinuclear antibody (ANA) (eg, systemic lupus erythematosus)
  • Human immunodeficiency virus (HIV) (eg, high-risk patients)
  • Angiotensin-converting enzyme (ACE) level (eg, sarcoidosis)
  • Erythrocyte sedimentation rate (ESR) (eg, inflammatory disorders)
• Although some interest has been shown in HLA typing in ON (eg, HLA-DR2, HLA-B7, HLA-Dr4, HLA-Dw2), the clinical utility of these tests remains unproven.

Imaging Studies

• Typical cases of ON do not warrant extensive investigations. Advances in MRI techniques have improved the ability to visualize damage to the anterior visual axis. Yet the main role for cranial MRI is to identify the future risk of MS, as the presence of asymptomatic white matter lesions on the MRI is a predictor for this diagnosis.
• The most important prognostic imaging study for the development of MS in patients with ON is a cranial MRI. MRI is superior to CT scanning for MS. Although secondary causes of ON, including neoplastic changes, granulomatous lesions, neuropathies, and other inflammatory conditions, may be seen on a cranial MRI, the major rationale for performing a cranial MRI is to evaluate demyelinating lesions.
• In 2001, the International Panel on the Diagnosis of MS put forth the so-called McDonald criteria (named after Dr. Ian McDonald who chaired the panel). These criteria were intended to aid in the diagnostic evaluation of MS by incorporating MRI findings into the evaluation and diagnosis of the disease. According to Polman and colleagues, the McDonald criteria have been extensively assessed and used since 2001, and the 2005 revisions helped to simplify and speed diagnosis, while maintaining adequate sensitivity and specificity.
• The lesions on an MRI are typically bright on T2-weighted imaging and can be highlighted by suppressing the normal cerebrospinal fluid signal using fluid-attenuated inversion recovery (FLAIR).
• MS plaques are usually periventricular, ovoid in shape, large, and multiple. Involvement of the corpus callosum is particularly suggestive of demyelinating disease. Active MS plaques may show enhancement after gadolinium administration.
• The optic nerve in ON often shows enhancement after contrast in T1-weighted MRI. Orbital fat suppression techniques might be useful for visualizing optic nerve enhancement involving the intraorbital portion of the optic nerve.
• Although a high number of white matter lesions present on a cranial MRI are more suggestive of MS, even one white matter lesion may be significant. On the other hand, a normal MRI at onset lessens (<20%) the chance for future development of MS but does not exclude the possibility of MS.

Other Tests

• Visual evoked potentials (VEPs) are not typically necessary for patients with clear clinical evidence of ON. VEPs may be a valuable means of assessing any subclinical fellow eye involvement.

Procedures

• In the ONTT, a lumbar puncture was optional and only showed evidence of demyelinating disease in patients with ON. The cerebrospinal fluid may be useful for diagnostic purposes in atypical cases of ON or in patients in whom a diagnosis of MS requires support from additional paraclinical evidence (eg, elevated immunoglobulin G [IgG] synthesis, oligoclonal bands).

Histologic Findings

The most common form of ON is a unilateral, idiopathic, inflammatory, demyelinative process involving neutrophils, lymphocytes, plasma cells, and macrophages, occurring either anterior or posterior to the lamina cribrosa. Although demyelination is a process that causes a mostly mononuclear infiltration of the perivascular spaces, initial examinations of the axons may show no structural changes until the disease has progressed.

Once the disease has progressed, inflammatory and cellular responses cause the breakdown of myelin into fat globules, thereby altering the structure of the nerve. Ingestion of fat droplets by macrophages causes the stimulation of astrocytes and the formation of glial tissue visualized as plaques on an MRI. This process is responsible for damaging neurons and increasing latency and transmission times along the axons. This process is also responsible for the formation of plaques visualized on T2-weighted imaging.

Thus, the pathologic findings in MS include inflammation, demyelination, and axonal loss. The degree of axonal loss may explain the lack of a complete recovery of function in patients with MS, especially after repeated attacks.

Treatment

Medical Care

The ONTT provides class I evidence (ie, randomized clinical trial) for recommended treatment of patients with ON. The ONTT results suggest that IV steroids, oral steroids, and placebo all result in recovery of visual function over time. IV steroids hasten the rate of recovery but do not change the final visual outcome. In the ONTT, IV steroids seemed to decrease the incidence of the development of MS over a 2-year period, but this effect was not sustained after year 3.

Although all 3 treatment arms of the study had equal visual outcomes, oral prednisone in conventional doses increased the likelihood for a recurrent episode of ON and is not recommended. Higher doses of oral methylprednisolone have not produced similar increased recurrence rates of ON, but the number of patients in these studies was small.

Newer studies have supported the benefit of using immunomodulatory agents (eg, interferon beta-1) in the reduction of CDMS.

The role for disease modifying agents in the treatment of ON is not to expedite the recovery of optic nerve function, which tends to be good, but rather to impact the risk of future MS. Three studies have addressed the role of interferon therapy for acute monosymptomatic ON and the future development of CDMS.

The first of these studies was the Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS), in which patients with a single clinically isolated neurologic event (ie, ON, brainstem or cerebellar syndrome, incomplete transverse myelitis) were enrolled into a randomized, placebo-controlled trial if they had 2 or more clinically silent lesions on a cranial MRI. After initial treatment with high-dose IV methylprednisolone, one half of the patients received weekly interferon beta-1a (30 mcg once per week), and one half of the patients received placebo. The primary endpoint was the development of CDMS, and the secondary endpoint was the brain MRI. This study demonstrated a significantly lower rate (44%) of development of CDMS among the treatment group, and a relative reduction of new lesions in the cranial MRIs among patients treated with interferon versus the placebo group.

A second study, the Early Treatment of MS (ETOMS) trial enrolled a similar group of patients, with 4 asymptomatic white matter lesions (or 3 lesions if one enhanced with gadolinium) present on the cranial MRI at presentation. One half of the patients received subcutaneous interferon beta-1a (22 mcg once per week), and one half of the patients received placebo. After 2 years, the odds ratio for the development of CDMS was 0.61 (95% confidence interval [CI] 0.37-0.99; p=0.045) in the treatment group versus the control group. More specifically, 45% of the placebo group developed CDMS after 2 years as compared to 34% of the treatment group. During the treatment study period, the MRI activity and burden of disease measured by MRI were significantly reduced in the treatment group.

In the third and most recent study, the Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial looked at the role of disease modifying therapy in patients with clinically isolated syndromes (either monofocal or multifocal) and at least 2 clinically silent brain MRI lesions. Subjects were randomized to receive 250 mcg of interferon beta-1b subcutaneously on alternate days or placebo until CDMS was diagnosed or the study period of 24 months was reached. Overall, interferon beta-1b delayed the time to diagnosis of MS by clinical and McDonald criteria.

Consultations

Patients with ON, particularly those with an abnormal MRI, should be offered the opportunity to consult with a neurologist regarding the possibility of MS.

Activity

Patients with ON should be cautioned to avoid work and other activities that may require greater visual skills than they possess. Machinery, heavy equipment, sharp instruments, and other visually demanding activities might have to be avoided until they recover sufficient vision, stereovision, color vision, and contrast acuities.

Patients should know that vigorous physical activity, hot baths, and other activities that raise their core body temperature might result in temporary decreases in vision because of the Uhthoff phenomenon.

Medication

Although corticosteroids are known to have multiple short- and long-term adverse effects, in general, a day course of IV methylprednisolone followed by an oral taper over 10-14 days does not produce significant or permanent adverse effects in otherwise healthy young patients.

Corticosteroids

Have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Methylprednisolone (Solu-Medrol, Adlone, Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

250 mg IV q6h for 3 d

Pediatric

Administer as in adults

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Adverse effects include hypertension, depression, mania, pseudotumor cerebri, meningitis, psychosis, seizures, pancreatitis, ulcer exacerbation, GI bleeding, peritonitis, toxic megacolon, hyperglycemia, adrenal suppression, Cushing syndrome, growth retardation, hyperlipidemia, cataracts, glaucoma, toxoplasmosis reactivation, TB reactivation, osteoporosis, hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections

Prednisone (Deltasone, Orasone, Meticorten)

Should only be used in conjunction with IV methylprednisolone.

Dosing

Adult

1 mg/kg/d PO for 11 d

Pediatric

Administer as in adults

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Caution in mania and depression, GI distress and bleeding, Cushing syndrome, or poor wound healing; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Interferons

Are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.

Interferon beta-1a (Avonex, Rebif)

For treatment of relapsing remitting MS. Believed to act via ability to counteract cell surface expression of proinflammatory or proadhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. Only differs from interferon beta-1b in that it has amino acid sequence identical to that of natural compound and is glycosylated. Presence of glycosylation may lead to structural stability and presumably to higher biological potency. Interferons act through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, lead to activation of interferon-responsive genes. Interferon beta may decrease expression of B7-1 (a proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory) in circulation of patients with MS.

Dosing

Adult

Avonex: 30 mcg IM qwk
Rebif: 44 mcg SC 3 times/wk (at least 48 h between each dose)

Pediatric

Not established

Interactions

Hematologic abnormalities, including anemia, thrombocytopenia, and development of agranulocytopenia, may occur when administered concomitantly with ACE inhibitors; may increase anticoagulant effects of warfarin; may increase toxicity of zidovudine

Contraindications

Documented hypersensitivity; liver dysfunction; severe leucopenia; thrombocytopenia; lactation

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in preexisting seizure disorder; cases of exacerbation of thyroid dysfunction have been described; caution when using interferon beta-1a in patients with uncontrolled thyroid dysfunction; besides a flulike illness, patients may experience injection-site skin reactions; interferons are abortifacient; data on teratogenicity are limited; extreme caution in patients with severe depression

Antibiotics

Used for suspected bacterial infections.

Tobramycin 0.3% ophthalmic (AK Tob, Tobrex)

Interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits, which results in a defective bacterial cell membrane. Available as a solution, ointment, and lotion.

Dosing

Adult

1-2 gtt instilled in the eye q4h while awake for 5 d

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

Effects decrease when used concurrently with gentamicin

Contraindications

Documented hypersensitivity; mycobacterial, viral, and fungal infections of the eye; steroid combinations after uncomplicated removal of a foreign body from cornea

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not use in deep-seated ocular infections or in those that may become systemic; prolonged use of antibiotics may result in bacterial or fungal overgrowth of nonsusceptible organisms

Follow-up

In/Out Patient Meds:

• Methylprednisolone (Solu-Medrol), prednisone taper, and interferon beta therapy can be administered either at home or in a hospital setting. The location of care should be determined by the severity of the patient's condition, as well as by the patient's ability to comply with prescribed health care, present financial status, and other coexisting medical and psychological issues.

Prognosis:

• The risk of the development of MS after ON is variable in the literature depending on length of follow-up with higher estimates of MS in studies with longer follow-up intervals. An abnormal baseline MRI is the strongest predictor of future development of MS. Five years after the original ONTT, 16% of patients with no plaques on the baseline MRI developed MS. Forty percent of patients with 1 or 2 high-signal densities developed MS, and, of those with more than 2 lesions, 51% developed CDMS over the same period of time. After 10 years of follow-up, after the ONTT, patients who had 1 or more lesions on the baseline MRI had a 56% risk of CDMS, and those patients with no lesions had a 22% risk of future development of MS.
• Among patients who had no lesions on their baseline MRI, male gender and optic disc swelling were associated with a lower risk of MS, as were the following features: no light perception vision; lack of pain; and fundus findings of severe optic disc edema, peripapillary hemorrhage, or retinal exudates. The strongest predictor for future development of MS was the presence of white matter lesions on an MRI, and this risk was increased with the presence of spinal lesions. Disability from MS has been reported to be less likely in patients who present with ON as their first demyelinating event, few or no MRI lesions, a long period to first relapse, and no disability after the first 5 years of diagnosis.
• Nevertheless, neither the presence nor the absence of signal abnormalities on the MRI is 100% predictive of whether a patient will develop MS.
• The size and the location of ON enhancement may be of prognostic significance in ON. Miller et al reported that lesions greater than 1 cm in length or located within the optic canal were associated with a decreased rate and quality of visual recovery. Dunker and Wiegand also reported incomplete recovery in lesions greater than 17.5 mm in length and/or located intracanalicularly.
  • Other predictive factors include a prior history of ON, an early recurrence of ON, early age of onset, a positive family history of MS, an HLA-DR2 tissue haplotype, and northern European ancestry.
  • Male patients who have NLP vision, experience no pain, or have an atypical optic disc appearance (eg, hemorrhages, marked swelling) are less likely to develop MS.
• Abnormalities in the cerebrospinal fluid (eg, IgG, oligoclonal bands) may be predictive of the development of MS.
• Various aspects of vision were found to recover differently following resolution of acute ON. One article discussed a study of individuals who experienced ON in either one eye or both (simultaneous) eyes and then recovered vision acuities of 20/30 or better at 6 months. In this study, 85% of 27 patients noted some improved change in the quality of their vision. Objectively, relative afferent pupillary defects (89%) were determined to be the most commonly retained defects, followed by persistent decreased brightness (89%) and altered stereo acuity (80%). Following these changes were disc pallor (77%), depressed contrast sensitivity (72%), dyschromatopsia (57%), and perimetry defects (26%).
• Visual acuity recovers well in most individuals. Following the ONTT, the 5-year visual outcomes of most of its study patients were assessed. At the time of follow-up, most patients had near normal visual acuity, even if they had a recurrent episode of ON. They found that 87% had visual acuities of 20/25 or better, 7% had visual acuities between 20/25 and 20/40, and 6% had visual acuities worse than 20/50; of the 6%, one half had visual acuities of 20/200 or worse. Findings from the ONTT showed that the visual acuity results obtained did not statistically differ by the type of treatment the patient received, but the rate of recovery did.

Patient Education:

• Patients should be reassured that most people with ON improve regardless of treatment.
• Patients, especially those in higher risk populations, should be informed of the relationship between specific monosymptomatic ophthalmologic events (eg, INO, ON) and MS.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Multiple Sclerosis.

Miscellaneous

Medicolegal Pitfalls

• The major pitfalls for misdiagnosis of ON are making a diagnosis of ON in a patient with atypical features (eg, older age, progression rather than recovery, marked hemorrhages or exudates) and failing to perform neuroimaging studies, especially in atypical cases (eg, painful acute retrobulbar visual loss with bitemporal hemianopsia in pituitary apoplexy).

Special Concerns

• The association of MS with ON is a delicate subject that requires a great deal of patient education, reassurance, instruction, and counseling. A formal consultation with a neurologist may be indicated, especially if the referring physician is unable or unwilling to discuss the complex issues surrounding the evaluation, treatment, and prognosis of MS.

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Keywords

MS, neurologic disorder, optic neuritis, ON, optic nerve, nystagmus, internuclear ophthalmoplegia, INO

Contributor Information and Disclosures

Author

Andrew G Lee, MD, Professor, Departments of Ophthalmology, Neurology and Neurosurgery, University of Iowa Hospitals and Clinics
Andrew G Lee, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Academy of Ophthalmology, American Geriatrics Society, North American Neuro-Ophthalmology Society, Pan-American Association of Ophthalmology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Fiona Costello, MD, FRCP, Assistant Professor, Departments of Ophthalmology and Medicine (Neurology), Neuro-ophthalmologist, Clinical Neurologist and Clinical Investigator, University of Ottawa
Fiona Costello, MD, FRCP is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, American Medical Association, Canadian Medical Protective Association, College of Physicians and Surgeons of Ontario, North American Neuro-Ophthalmology Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Cecil L Berlie, MD, Consulting Staff, Department of Ophthalmology, Luther Midelfort Eye Clinic
Cecil L Berlie, MD is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Andrew W Lawton, MD, Medical Director of Neuro-Ophthalmology Service, Section of Ophthalmology, Baptist Eye Center, Baptist Health Medical Center
Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Brian R Younge, MD, Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society
Disclosure: Nothing to disclose.

CME Editor

Ralph Garzia, OD, Assistant Dean for Clinical Programs, Associate Professor, School of Optometry, University of Missouri at St Louis
Ralph Garzia, OD is a member of the following medical societies: American Academy of Optometry and American Optometric Association
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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