DIAGNOSIS

MS can be difficult to diagnose, as no single laboratory test clearly identifies the disease. It is primarily diagnosed by reviewing a person’s medical history and giving a neurological exam that tests for abnormal reflexes, muscle weakness or incoordination, alterations of sensation, damage to the optic nerve, and other signs of brain or spinal cord damage. Several tests can help confirm the diagnosis.

A diagnosis of MS usually begins with a thorough neurological examination and a discussion of your full medical history with your physician. However, even after this, it may still be difficult, if not impossible, to confirm the presence of MS without using advanced diagnostic procedures. The most commonly performed laboratory tests are: MRI scan, Lumbar puncture, Measuring "evoked potentials."

MRI Scan

MRI, short for Magnetic Resonance Imaging, uses a strong magnetic field to create images ("scans") of the brain (see figure 5, below) and spinal cord. The MRI scan shows any defects or lesions in the white matter. The name multiple sclerosis comes from these lesions—multiple areas of scarring, or sclerosis, in the brain and spinal cord. To positively diagnose MS, doctors must find evidence of lesions that occurred at different points in time in at least two places in the central nervous system. This type of examination has also shown that people with MS can have patches of inflamed myelin without symptoms. There is some link between the amount of disease activity shown on the MRI scan and the progress of the disease, but the link is not very clear and is difficult to interpret. Although most people with a definite diagnosis of MS have lesions revealed by MRI, the absence of lesions does not rule out the disease. This means, unfortunately, that it is not, at present, possible to use the results of MRI to predict how the disease will develop.

FIGURE 5. MRI scan of the brain with characteristic MS lesions. Around the butterfly shaped ventricular system (white), characteristic round to oval shaped MS lesions can be noticed (in white).

Lumbar Puncture

In the examination know as a lumbar puncture, a long, hollow needle is inserted into the spinal column to take a sample of the fluid surrounding the brain and spinal cord (the "cerebrospinal fluid"). This fluid in people with MS shows specific changes that match up with the presence of inflammation: slightly more inflammatory cells, greater number of inflammatory proteins. About 20% of all those who undergo this examination get headaches and dizzy spells, but these usually clear up after a few hours.

Evoked Potentials

By measuring what are known as evoked potentials or evoked responses, certain nerve fibers can be checked. This means that when MS is present it is possible to see whether certain nervous impulses are slowed down in the nerve fibers (because of demyelination). The more demyelination, the slower the transmission of impulses measured.

There are several different types of evoked potential test that can be performed to measure the response time of various nerve impulses throughout the body. Each one tests the transmission of nerve impulses from the brain to a specific part of the body that controls different body functions, such as hearing, sight, or motor function. A neurologist may wish to perform just one or all of these tests.

What You Can Learn from MRI

A medical technician places a ring around your head and slides you into a body-length tube on a motorized bed. As you lie there, as still as possible, you hear the hum of giant, hidden magnets as the machine takes detailed pictures of your brain. Welcome to magnetic resonance imaging (MRI), one of the most sophisticated picture-taking devices in modern medicine.

If you have multiple sclerosis (MS), the experience described above is probably familiar to you, since MRI is now a routine part of the diagnostic process. However, even if you've already undergone MRI more than once, you may not know exactly what it can tell you about your condition.

MRI Basics
Typically, unenhanced and enhanced MRI scans are performed as part of the diagnosis of MS. An unenhanced or "T2-weighted" MRI is done to obtain a picture of the number and location of brain lesions characteristic of MS. "Fully 95% of all people with MS show evidence of these brain lesions on MRI," says Stephen Reingold, PhD, Vice President of Research Programs at the National Multiple Sclerosis Society (NMSS).

After the unenhanced MRI, doctors may want some patients to undergo a second, "gadolinium-enhanced" MRI. "This MRI indicates active inflammation within the brain and enables doctors to evaluate a person's condition more precisely," says David Friedman, MD, codirector of the neuroradiology division at Thomas Jefferson University Hospital in Philadelphia, PA.

Most large hospitals have one or more MRI machines, says Dr. Friedman.

The cost of an average diagnostic session is $1,000 to $1,500 and is usually covered by medical insurance, adds Dr. Reingold.

After Diagnosis
While most experts agree that MRI is an extremely useful diagnostic tool, there is considerable disagreement over its usefulness in monitoring MS. That is because the number and location of MS brain lesions vary in each person as the disease goes through periods of activity and remission known as cycling. If MRI scans are performed during a relatively inactive period of disease progression, the resulting images may provide a misleading picture of a patient's medical status. "Cycling is the main reason why there is no agreed upon standard for using MRI to monitor MS," says Kottil Rammohan, MD, associate professor and vice chairman of the department of neurology at Ohio State University College of Medicine in Columbus, OH.

MRI in Clinical Trials
Despite the current limited use of MRI in monitoring MS, it is an essential tool for evaluating new MS therapies in clinical trials. That, say experts, is because when studying a large number of patients, the effects of cycling and the variability of MRI results even out over time. For example, the pivotal AVONEX® (Interferon beta-1a) study monitored MRI scans of more than 300 people.

"MRI is now an essential way to evaluate the effectiveness of an MS drug versus placebo," says Dr. Rammohan. "I don't think any clinical trial of an MS therapy would go forward without MRI."

MRI Reveals New Reasons To Treat Ms Early
Until recently, experts believed that the damaging loss of brain tissue that occurs in people with MS, known as brain atrophy, occurred only late in the disease process. However, a recent retrospective study analysis using MRI found that some brain atrophy actually occurs in relatively early stages of the disease.(1) The study suggests that early treatment of MS with AVONEX® should be considered before the effect on the brain becomes substantial. It is important to note that brain atrophy is a "silent" process that cannot be felt – and is best seen using MRI.

Another sophisticated MRI test called spectroscopy is used to measure brain inflammation. Active brain inflammation is often a precursor to another form of disease activity in the brain known as axonal damage. Axons are nerve fibers essential to normal neurological function. Studies have already indicated that permanent axonal damage may occur relatively early in the disease process. This information provides still more support for early treatment of MS.

It is important to note that beta interferons have proven, strong results in MRI tests. Specifically, AVONEX® showed an 89% reduction in gadolinium-enhanced lesions over 2 years in patients with enhancement at baseline.(2) Since these lesions may cause axonal damage, it's vital to stop this inflammation as rapidly as possible. A non-interferon drug such as Copaxone® (glatiramer acetate), on the other hand, appears to work differently in that it has a delayed therapeutic effect.(3)

MRI is becoming an increasingly important tool for physicians and researchers who are concerned about MS. As is the case with many high-tech medical tools, its future potential is at least as vast as its present utility.

Editor's Note: The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression.

References: (1) Rudick RA, Fisher E, Lee J-C, et al. Use of brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology. 1999;53:1698-1704. (2) Data on file, Biogen, Inc. (3) Comi G, Filippi M. The effect of glatiramer acetate (Copaxone®) on disease activity as measured by cerebral MRI in patients with relapsing-remitting multiple sclerosis (RRMS): a multi-center, randomized, double-blind, placebo-controlled study extended by open-label treatment. Neurology. 1999;52(suppl 2):A289.

Diagnostic tests

Here is a quick guide to the most commonly used diagnostic tests, what is involved and how much they can tell you. The doctor or neurologist may want you to undertake all of these examinations before making a clinical diagnosis.

Medical History

The doctor will ask you for a detailed medical history which will include your past record of signs and symptoms as well as the current status of your health.

When the type of symptoms you have experienced, possibly over a long period of time, are examined their pattern may suggest MS. However, a full physical examination and medical tests will be needed to confirm the diagnosis.

Neurological Examination

A neurological examination looks at how well your nervous system is working. The neurologist is testing for abnormalities in the nerve pathways that take messages from the brain to the other parts of your body. They will look for changes in eye movements, limb co-ordination, weakness, balance, sensation, speech, and reflexes.

This examination may also uncover symptoms that suggest MS, but cannot be used to determine what is causing any problems that may exist. Other possible conditions that produce similar symptoms to MS must be eliminated.

Testing of Visual, Auditory and Somatosensory Evoked Potentials

In spite of their complicated sounding name, the point of these tests is straightforward. They are used to measure the speed at which messages from the brain pass along the nerves.

The speed of messages passing through the nervous system is measured by placing small electrodes on the head, which monitor brain waves in response to visual and auditory (hearing) or sensory stimuli. The most useful of the three tests is the visual evoked potential although nowadays, with increased use of MRI, the evoked potential test are required less often
These tests are not invasive or painful and therefore do not require a stay in hospital.

The time it takes for nerves to pass on messages from the brain is an indicator of the condition of the nervous system and is used to help determine whether demyelination has occurred.

Magnetic Resonance Imaging (MRI)

The MRI scanner is a more recent diagnostic test and takes very detailed pictures of ‘slices’ of the brain and spinal cord, showing any existing areas of sclerosis (lesions or plaques).

During an MRI scan the person being tested lies absolutely still on a table that moves inside a large tube which is part of the machine that contains the magnet. The person conducting the test sits in a separate room monitoring the equipment receiving the images; however they can also see the person being tested, usually through a large window.

There is no pain involved in MRI, but many people find it quite an unusual experience, and it can be both claustrophobic and noisy. Any discomfort can be alleviated by a mild sedative. Sometimes an injection is given in to a vein of a contrast agent containing gadolinium as this can show up new areas of inflammation and may help to make the diagnosis.

It is worth remembering that the person conducting the test us not usually able to give you any direct feedback and the images from the scan will be sent to your doctor for analysis.

Whilst this is the only test in which the lesions of Multiple Sclerosis can be seen, it cannot be regarded as conclusive. The scanner may not pick up all lesions, particularly in the early stages of the disease, and some other conditions can produce identical changes in the nervous system.

The MRI clearly shows the size, quantity and distribution of lesions and together with supporting evidence from medical history and neurological examination, is very significant indicator toward confirming the diagnosis of MS. It is abnormal in over 95% with a definite clinical diagnosis. The MRI is a very useful tool in clinical trials in assessing the value of new therapies, due to its ability to demonstrate changes in the disease’s activity.

Lumbar Puncture

There are several tests that can be carried out on cerebrospinal fluid (the fluid which flows around the brain and spinal cord), but usually with MS the patterns formed by proteins are examined.

The fluid is taken from the spinal cord by inserting a needle into the lower back. A local anaesthetic is given to numb the skin, and therefore whilst it is uncomfortable it is not usually painful.

This test requires the person to lay flat for a number of hours after the test, and headaches due to dehydration are a noted side effect; this can be alleviated by drinking fluids immediately after the procedure, to help the body rapidly replace the cerebrospinal fluid it has lost. Some people may require an overnight stay in hospital and a subsequent short period of recuperation.

The proteins in the spinal fluid of the majority people (90%) with established MS form a particular pattern when an electrical current is passed through them, and so this procedure can potentially confirm an MS diagnosis. However, the cerebrospinal fluid proteins of people with early or mild MS do not always show the same pattern, so again may not be conclusive. It is often used when MRI results have been inconclusive.