The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (37 page)
Authors: Rita Baron-Faust,Jill Buyon
The National Multiple Sclerosis Society (NMSS) issued revised criteria for diagnosing MS, which include the use of MRI and other tools to determine the amount of nerve damage and make a diagnosis more specific after an MS attack.
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An “MS attack” is defined as a “neurological disturbance typical of those seen in MS, either reported by the patient or observed by the physician,” lasting at least 24 hours. A single episode of muscle weakness wouldn’t qualify, but multiple episodes would.
There are three basic diagnostic categories: MS, “possible MS,” and “not MS.”
MS is diagnosed after finding evidence on MRI of damage in at least two separate areas of the central nervous system (the brain, spinal cord and optic nerves) occurring at least one month apart. All other possible diagnoses must be ruled out, stresses the NMSS.
Clinically isolated syndrome (CIS)
is defined as a single attack (or one or more symptoms characteristic of MS) with a very high risk of developing MS, when no other diseases or causes can be found.
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Several subtypes of MS have also been recognized, and you may hear these terms mentioned:
- Radiologically isolated syndrome (RIS)
is an incidental finding of typical MS lesions on MRI without evidence of clinical disease. This is sometimes called asymptomatic or preclinical MS.
12 - Malignant (fulminant) MS
is a rare form of MS with very fast progression, leading to significant disability or even death in a relatively short period of time.
12 - Single-attack progressive MS
is another a rare condition in which a single initial MS attack is followed by a progressive phase.
12 - Transitional MS
is considered to be a gradual transition phase between RRMS and SPMS.
12 - Benign MS
is a concept where an MS patient remains fully functional in all neurologic systems 15 years after an initial attack.
The new guidelines keep the older threshold of two separate attacks (or evidence of damage in two areas of the CNS) for a formal diagnosis of MS. But since MRI is so accurate, there’s no longer any need to wait for a second attack to start treatment.
The two attacks needed to make a formal MS diagnosis must be at least 30 days apart. A clinical evaluation and sometimes three tests—MRI, analysis of cerebrospinal fluid (CSF), and analysis of visual evoked potentials (VEPs)—are used to confirm a second attack. The clinical guidelines also allow for the diagnosis of people who’ve had only one attack, so they can be started on medication if needed. Evidence of a second attack must be seen on MRI.
There are also people who’ve had no obvious MS attacks, but have had steady progression of disability. For those people, the diagnostic criteria
require a positive CSF test, plus multiple lesions in the brain or spinal cord seen on MRI, or an abnormal VEP with fewer brain and spinal cord lesions.
Depending on the symptoms, the neurologist must also exclude other conditions that mimic MS. Blood tests may be needed to rule out other autoimmune diseases or Lyme disease; those tests usually turn out normal in MS patients.
Magnetic resonance imaging (MRI)
of the brain is the most frequently used test for multiple sclerosis, clearly showing the white plaques characteristic of MS. The addition of a contrast agent (
gadolinium
) can “light up” areas where inflammatory cells have crossed into the brain, causing demyelination.
Plaque that is seen in certain areas of the brain, such as the optic nerve, can be correlated with symptoms. The amount and location of plaques are taken into account in assessing the stage, severity, and progression of the disease. White matter makes up most of the brain and gets its name from the color of the myelin insulation. Gray matter makes up the cerebral cortex, the multifold outer layer of the brain where most information processing occurs. To be diagnosed with MS with an MRI, separate scans must find at least one
gadolinium-enhanced
lesion (or a new lesion suggesting inflammation), plus plaques in characteristic areas of the brain or in the spinal cord.
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MRI scans may be able to pick up the earliest signs of the disease in people who have only mild, intermittent symptoms, so they can be put on medication as soon as possible.
Evoked potentials (EPs)
are noninvasive tests that can reveal problems in myelin conduction. During a VEP test, you look at a checkerboard pattern or series of flashing lights while being monitored by a device that measures the conduction of visual images from the eyes to the brain. A delay or prolongation of conduction signals (or weaker conduction) is seen when there’s demyelination. EPs are especially useful in confirming a diagnosis of MS, because they can often detect lesions not seen on MRI.
Lumbar puncture (spinal tap)
tests a sample of cerebrospinal fluid for antibodies and proteins that result from the breakdown of myelin. Under local anesthesia, a hollow needle is inserted into the spine to withdraw a small
sample of the fluid bathing the spinal cord and brain. The fluid is then examined for the presence of abnormal levels of immunoglobulins (which are occasionally autoantibodies), fragments of myelin basic protein produced by inflammation, and immune cells. This helps to distinguish MS from other nervous system diseases. A spinal tap is usually done when an MRI is inconclusive.
The severity of MS is scored using a numerical scale.
The Extended Disability Status Score (EDSS)
measures vision, sensation, coordination, strength, and walking ability. For example, a score of 0 indicates a normal neurological exam. A score of 1.0 to 1.5 indicates an abnormal neurological exam, but no disability. A score of 2.0 to 2.5 shows mild disability, while a score of 3.0 to 3.5 shows mild to moderate disability. By the time patients have a score of 6.0, they need a cane to help them walk.
Some clinical signs can also provide helpful clues to potential neurological damage. For example, women who present with optic neuritis show paleness in the back of the eye after symptoms resolve; the paleness indicates a lesion on the optic nerve that caused demyelination, says Dr. Reder. Some women may show an impaired response to a pinprick, heat, or light touch in areas that correlate to areas of nerve damage. Clumsiness and an impaired ability to sense vibrations can be signs of demyelination that can sometimes be correlated with an MRI (however, often MRIs do not correlate with symptoms).
Ana’s story continues:
I recall that years ago when I was trying to get pregnant and was losing each pregnancy after a few weeks, I was told I had some kind of “autoimmune” problem. I didn’t pay much attention to it at the time. I was seeing a fertility specialist and she took some blood tests. I was told I had IgG antibodies, and that my body was rejecting the pregnancy. I was put on heparin, this blood thinner, and they wanted to put me on prednisone and put me in some kind of clinical trial. But I wouldn’t take it. Eventually I decided to adopt. But I think now there must have been some kind of autoimmune thing going on even then.
Over the years, there have been hints that female hormones may play a role in MS. For one thing, there are fewer MS relapses during pregnancy, when estrogen levels are increased. This may be partly due to pregnancy-associated elevations of a weaker form of estrogen called
estriol
, normally produced in small amounts in fatty tissues. Lower levels of estrogen that are usually present in the body may not be enough to protect against MS. Animal studies also show that
testosterone
may be protective, and this may be one reason men get MS less frequently (and later in life when testosterone levels decline).
“There are all sorts of immunosuppressant substances produced during pregnancy. When you look at women with relapsing-remitting MS who become pregnant, the relapse rate during the nine months of pregnancy goes dramatically down, especially in the third trimester, compared to prepregnancy levels,” says UCLA’s Dr. Giesser. “There’s an increase in the relapse rate immediately postpartum, in the three to six months after delivery, and then the relapse rate returns to prepregnancy levels.” She cites one study that included MRIs of pregnant women with MS. “Two women who were in a study protocol happened to get pregnant, and they elected to stay in the study. They were given MRIs during pregnancy, and lesion activity went down during pregnancy and rebounded after they delivered.”
Studies that have followed women with MS for long periods of time after pregnancy have found that they do not have increased long-term disability compared to women who have not been pregnant. “And there are a couple of
studies to suggest that pregnancy may even have kind of a protective effect, that women who became pregnant may have a little longer time before increased disability, or the onset of things may be delayed,” she adds. Again, it’s not clear if that’s due to hormones.
“A lot of the sex differences in MS may be due to the protective effects of testosterone, and pregnancy-associated levels of estriol. But that’s probably not the whole story. Sex chromosomes may also have a role in making the disease better or worse,” says Rhonda Voskuhl, MD, a professor of neurology and the Jack H. Skirball Chair for Multiple Sclerosis at the University of California, Los Angeles.
Relapsing-remitting MS is largely inflammatory, and estrogen may act as an anti-inflammatory agent, observes Dr. Voskuhl, who is also director of the UCLA Multiple Sclerosis Program. When female mice, engineered to develop an MS-like disease,
experimental autoimmune encephalomyelitis (EAE)
, are given estrogen, they produce higher levels of an anti-inflammatory cytokine. And the effects of estrogen during pregnancy also dampen inflammation in the immune system, she notes.
Dr. Voskuhl initially studied the effects of estriol in mice with EAE and found that they had fewer exacerbations, less disability, and improved health compared to mice not treated with the hormone.
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Based on these results, she conducted a small pilot study of estriol among 12 women, six of whom had relapsing-remitting MS and the other six with secondary progressive disease. “We saw a beneficial effect on the immune system, and on MRI we saw a reduction in gadolinium enhancing lesions, a marker of inflammation in the brain. Secondary progressive patients with a less inflammatory stage of MS did not show these changes,” she says. That early research has led to two clinical trials of estriol in MS. One, a phase II trial of an estriol preparation (
Trimesta
) given with
glatiramer acetate (Copaxone)
in relapsing-remitting MS showed a reduction in relapses among the estriol group versus those given placebo.
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The second clinical trial, involving estriol taken in combination with standard MS anti-inflammatory drugs is ongoing. It is investigating whether estriol treatment can improve cognitive testing compared to placebo in either relapsing or progressive types of MS who have some evidence of cognitive disability at baseline.
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Oral contraceptives don’t seem to affect the risk or the course of MS, although research has been very sparse.
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Some studies have suggested that
women who get their periods at an earlier age may have an increased risk of MS, but this has never been proven conclusively. The same can be said of the effect of having children or not having children.
Another sex difference may be due to inflammatory cytokines. During pregnancy, levels of
interferon gamma
(a damaging inflammatory cytokine associated with MS) are lower. One small study at the Cleveland Clinic Foundation revealed that when T cells from women with MS were stimulated with a myelin protein, they produced higher levels of interferon gamma compared to men. At the same time, women with MS produced none of a regulatory cytokine that may dampen the disease process. It’s not clear what role, if any, sex hormones may play in this response.
However, the inflammatory immune response does switch to a regulatory response during pregnancy (so the body doesn’t reject the fetus), and MS typically improves during pregnancy, when estrogen and estriol levels are high. Researchers at the Cleveland Clinic Foundation say a possible new direction in MS therapy would be stimulating that regulatory response.
One of the ways estrogen suppresses EAE in mice is by changing the action of T cells and the activity of brain cells called
microglia
, which can produce toxic molecules that attack myelin-producing cells.
However, Dr. Giesser believes that estrogen—either in birth control pills or in hormone replacement therapy—can be safely used by women with MS, as long as they’re being followed by a gynecologist.
Ana’s story continues:
I had a hard time getting used to the Avonex. They had to put me on half doses, and then took me off it. I was then put on Copaxone for a while, and felt great. But then they noticed that I had an allergic reaction at the injection site, and I had to go back on Avonex. And that was rough. So I started with tiny doses and gradually increased the dose until I could get acclimated to the drug. You learn to live with a lot. I had to learn to give myself injections. That was difficult. What is wonderful is that these drugs are shipped right to your home, and there are nurses you can call with questions. And that makes it easier. For example, the nurses told me to drink a lot of water the day I get the injection and the day after, to keep me hydrated. You use every piece of information they give you, and it all makes you feel that much better.
I was also fortunate to have a gynecologist who works with my neurologist, and when I started to have hot flashes she said I should absolutely be on estrogen. Since heat can make MS feel worse, I thought it was a good thing to do. Menopausal symptoms are just one more thing I don’t want to worry about.
