Coordinated by Bobby Christensen, O.D., F.A.A.O.

therapeutic insights
Learn the Basics of MS
Multiple sclerosis is a devastating disease that often starts with ocular complaints.
Leonid Skorin, Jr., O.D., D.O., F.A.A.O., F.A.O.C.O.

Multiple sclerosis (MS) is a potentially devastating disease that affects young individuals during the most productive time of life -- most people developing MS are between 15 and 45 years of age. Females are affected twice as often as males. MS is rare in tropical and subtropical areas, but within temperate zones, disease rates increase with increasing latitude. Approximately 400,000 cases have been diagnosed in the United States.

What is MS?

We don't know the cause of MS but we believe it's an autoimmune disease triggered by a viral infection. Central nervous system (CNS) damage occurs when the myelin sheath surrounding and protecting nerve fibers becomes inflamed. The inflammatory response in the CNS consists predominately of activated T lymph- ocytes and macrophages resulting in the local secretion of cytokines and the synthesis of oligoclonal immunoglobulins. This causes the development of lesions or plaques on the myelin sheath that protects and insulates the spinal cord, brainstem, cerebellum and cerebrum. Irreparable damage occurs to nerve cell axons. Damaged axons and myelin sheathing interrupt the electrical signals throughout the brain and spinal cord. Symptoms include:

• Decreased visual acuity, decreased color vision, pain on eye movement, diplopia, visual field defects and scotomas
• Brainstem dysfunction such as dysarthria and vertigo
• Cerebellar dysfunction such as tremor and gait disturbances
• Muscle stiffness or tightness
• Weakness or paralysis of limbs
• Numbness, burning, pins and needles (paresthesias), feelings of constriction or pain
• Bowel/bladder dysfunction
• Fatigue
• Cognitive and emotional disturbances such as depression
• Sexual dysfunction
• Heat sensitivity.

Getting a bead on the enemy

The diagnosis of MS includes the occurrence of two or more episodes of unexplained neurological symptoms, localized in different parts of the CNS and separated in time. Supporting tests include the laboratory evaluation of cerebrospinal fluid for the presence of spinal fluid protein and elevated white blood cell count, increase of immunoglobulin G level and synthesis rate and oligoclonal banding. Visual-evoked potential studies may identify delayed response time along the visual pathways.

Magnetic resonance imaging (MRI) has recently been integrated into the overall diagnostic scheme because of its unique sensitivity to pathological change. Neuro-imaging using MRI technique is a sensitive indicator of demyelinating disease and can often identify "silent" lesions -- these are evidence of demyelinating disease even in the absence of clinical symptoms. Neuroimaging with MRI can also help denote the extent and severity of the disease and can be used to monitor changes and progression throughout its course.

Know the categories

Below are the four MS disease course categories:

1. Relapsing remitting. Abrupt onset, partial or total remission, inactive for months or years;

2. Primary progressive. Progression from onset, occasional plateaus and minor improvements;

3. Secondary progressive. Initial relapsing-remitting, converts to progressive;

4. Chronic progressive. Slow onset, progressive disability.

Most patients have an onset of MS with a relapsing-remitting course. Even in remission, there's underlying progressive disease activity as seen with "silent" MRI lesions. This results in a gradual deterioration of neurological function followed by shortened remission periods.

O.D.s on the line of defense

Because optic neuritis is often the first presenting finding in a patient who is at risk of developing MS, O.D.s must confirm the optic neuritis and either order an MRI or refer the patient to a neurologist or neuro-ophthalmologist who will evaluate him and initiate treatment if appropriate. A patient who has optic neuritis will complain of progressive vision loss in one eye, although bilateral vision loss can occur. Up to 90% of patients have accompanying periocular, retrobulbar or eye pain. It's usually aggravated by eye movement. Objective findings include an afferent pupillary defect, visual field changes (the classic central scotoma), impaired color vision and contrast sensitivity, abnormal visual evoked potential and, on occasion, a swollen optic disc and cells in the vitreous cavity.

The Medical Advisory Board of the National Multiple Sclerosis Society recommends beginning therapy as soon as possible after diagnosing MS. Doing so seems to result in a reduction in the frequency and severity of relapses in patients who have relapsing-remitting disease, slowing progression to disability. Hopefully with today's immunomodulatory drugs, actual disease modification will help reduce the inflammation of MS lesions and minimize future relapses.

Meet the drugs

Four immunomodulating agents are available for treating relapsing-remitting MS. They include interferon beta-1a (Avonex and Rebif), interferon beta-1b (Betaseron) and glateramer acetate (Copaxone). All four are available as injections (self administered by the patient). All four agents can cause flu-like symptoms; injection site reactions are also common. Immunomodulation therapy costs as much as $10,000 annually and must be sustained for years; if therapy is discontinued, pretreatment disease activity may resume.

Reason to believe

Yet studies do point to the drugs' efficacy. The Controlled High-Risk Avonex MS Study looked at 383 patients with first acute clinical demyelinating event and at least two clinically silent brain MRI lesions. Treatment consisted of intravenous steroids with follow-up therapy of Avonex or placebo.

After three years the steroid/ Avonex therapy reduced the risk of a second event of optic neuritis or another demyelinating event by 44%. There was a 91% reduction of T2 lesion volume on MRI scanning and a 57% reduction in new or enlarging T2 lesions; there were 67% fewer gadolinium-enhancing lesions. Placebo-treated patients had 82% new but silent MRI lesions within 18 months of initial onset.

The first study to compare the efficacy and safety of these agents to each other was recently released. In the Evidence for Interferon Dose-Response: European-North American Comparative Efficacy trial, the higher dose regimen of Rebif was superior to the lower dose Avonex in the prevention of relapses and MRI lesions. The proportion of patients who were relapse free was greater in the Rebif group (75%) than in the Avonex group (63%).

Also, approximately one-half of the relapses in the Avonex group required treatment with steroids, compared with just one-third of Rebif recipients. Finally, the Avonex recipients had 50% more active MRI brain lesions than the Rebif group.

The newest drug that the U.S. Food and Drug Administration has approved is mitoxantrone (Novantrone), an immunosuppressant agent also used as an anti-neoplastic medication. It's used in patients who have deterioration relapsing MS and who have secondary-progressive MS. Given intravenously, it's a dark purple fluid and may cause a bluish tint to the sclera and a blue cast to the urine; it may have cardiotoxic adverse effects.

For patients who have aggressive relapsing-remitting or secondary progressive MS whose disease is not controlled with interferon beta-1b, adding mitoxantrone reduced relapse rates by 64% and new MRI lesions by 88%.

Side effects watch

Because MS patients experience many disease-related symptoms that disrupt their quality of life, symptomatic pharmacological treatment is an important part of their care.

The accompanying chart features adverse reactions to commonly used medications as listed in the 2003 57th edition Physicians' Desk Reference. Note that many of the ophthalmic adverse reactions found with the use of these medications may be the result of the patient's MS and occur concurrently.

Dr. Skorin is adjunct professor of neuro-ophthalmology at Midwestern University in Chicago and a staff ophthalmologist at the Albert Lea Eye Clinic Mayo Health System. Contact him at (507) 373-8214 or at skorin.leonid@mayo.edu.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.