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Hormone Treatment for Multiple Sclerosis

September 10th, 2010

Medical researchers have noted for decades that women with multiple sclerosis seem to have much less frequent flare ups of the disease during pregnancy, especially during the third trimester. There has been an ongoing effort by scientists to identify the so-called pregnancy factor

which would explain this temporary but meaningful reprieve.

Women produce three kinds of estrogen, estrone (E1), estradiol (E2), and estriol (E3) with the latter increasing substantially during pregnancy. This prompted animal experimentation using a model for multiple sclerosis in mice. Mice treated with estriol actually demonstrated improvements in disability, clinical outcomes and favorable changes in their immune systems. This has prompted human research actually funded by the National Multiple Sclerosis Society to see if administering E3, 8mg per day (widely available from compounding pharmacies in the United States) will be effective in treating women with the disease.

The study will be carried out by Dr. Rhonda Voskuhl at UCLA. “I am excited by the prospect of finding an easily administered treatment for MS based on a naturally occurring phenomenon in pregnancy. At present the only approved treatments are anti-inflammatory drugs administered with injections,” said Voskuhl, a research scientist at UCLA’s Brain Research and Neuropsychiatric institutes. “Our findings also hold promise for finding new treatments for a host of other autoimmune disorders that improve during pregnancy, such as rheumatoid arthritis.”

http://www.scienceblog.com/community/older/2002/C/20025737.html

UV radiation, not vitamin D, might limit multiple sclerosis symptoms

August 15th, 2010

From ScienceNews.org:

Ultraviolet radiation from sunshine seems to thwart multiple sclerosis, but perhaps not the way most researchers had assumed, a new study in mice suggests.

If validated in further research, the finding could add a twist to a hypothesis that has gained credence in recent decades. The report appears online March 22 in the Proceedings of the National Academy of Sciences.

Scientists have hypothesized that MS is rare in the tropics because people synthesize ample vitamin D from exposure to the UV radiation in equatorial sunlight. What’s more, MS is more common in the high latitudes of northern parts of Europe and North America than in regions farther south. That pattern has led to the assumption that higher levels of vitamin D might prevent people from developing MS, what became known as the latitude hypothesis.

But a direct cause-and-effect relationship between vitamin D deficiency and MS has never been established. In past experiments, giving vitamin D supplements to mice with an MS-like disease required giving the animals harmful amounts of the nutrient, notes Hector DeLuca, a biochemist at the University of Wisconsin–Madison.

“It just didn’t add up,” he says. “We decided to go back and see if maybe UV light by itself was doing something.”

In MS, the fatty myelin sheaths that insulate nerves in the central nervous system are damaged by attacks by the immune system. In a series of experiments in mice, DeLuca and his team induced a condition comparable to human MS by injecting the animals with proteins that instigate similar myelin damage.

The researchers exposed some mice to UV radiation before and after giving the animals the damaging injection. Another group of mice got the injection but not the UV exposure.

The mice exposed to UV rays suppressed the effects of MS-like disease better than the control mice, the researchers found, even though the amount of radiation wasn’t enough to greatly increase the animals’ blood concentrations of vitamin D.

In another test, the researchers gave injected mice varying doses of vitamin D supplements, but no UV radiation. The supplements failed to control the disease onset, severity or progression.

“We concluded that UV light is doing something beyond [making] vitamin D,” DeLuca says.

There’s no question that the latitude hypothesis has merit, says George Ebers, a neurologist at the University of Oxford in England. “MS risk is geographically related.” But that risk is more complicated than exposure to UV radiation during an MS attack, as this mouse model used. For example, previous research has shown that children in northern latitudes who are born in May, after their mothers had spent a winter with little sunshine, are more likely to develop MS than are kids born in November, he says.

Ebers notes that mice in this study were exposed or not exposed to UV over a matter of weeks and were in the throes of an MS-like disease during the study. “That’s completely separate … from the question of whether your risk is boosted or diminished by where your mother lived,” he says.

Apart from the timing issue, MS risk might well be influenced by a biological mechanism apart from vitamin D blood levels, but many questions remain, Ebers says. Those include how UV radiation might inhibit MS and, more specifically, what is the effect of UV rays in suppressing the immune system. “It’s quite possible that UV exposure will have a number of other mechanisms and be involved in hormonal circuits,” he says.

DeLuca and his colleagues speculate that UV radiation is playing a mysterious role in MS that is independent of vitamin D production. “We’re doing experiments trying to find out what it is,” he says.

MS patients push for new treatment testing

May 29th, 2010

From USAToday.com:

Under intense pressure from patients, some U.S. doctors are cautiously testing a provocative theory that abnormal blood drainage from the brain may play a role in multiple sclerosis — and that a surgical vein fix might help.
If it pans out, the approach suggested by a researcher in Italy could mark a vast change for MS, a disabling neurological disease long blamed on an immune system gone awry. But many patients frustrated by today’s limited therapies say they don’t have time to await the carefully controlled studies needed to prove if it really works and are searching out vein-opening treatment now — undeterred by one report of a dangerous complication.

STUDIES: Multiple sclerosis pills show promise, risk

“This made sense and I was hell-bent on doing it,” says Nicole Kane Gurland of Bethesda, Md., the first to receive the experimental treatment at Washington’s Georgetown University Hospital, which is set to closely track how a small number of patients fare before and after using a balloon to widen blocked veins.

In Buffalo, more than 1,000 people applied for 30 slots in a soon-to-start study of that same angioplasty procedure. When the University at Buffalo team started a larger study a few months ago just to compare if bad veins are more common in MS patients than in healthy people — not to treat them — more than 13,000 patients applied.

The demand worries Georgetown neurologist Dr. Carlo Tornatore, who teamed with vascular surgeon Dr. Richard Neville in hopes of getting some evidence to guide his own patients’ care.

“A lot of people are starting to go to fly-by-night places,” says Tornatore. Doing this research takes time, he said. “It’s a marathon, not a 100-yard sprint. We have to be very careful.”

Multiple sclerosis occurs when the protective insulation, called myelin, that coats nerve fibers gradually is destroyed and scar tissue builds up, short-circuiting messages from the brain and spinal cord to the rest of the body — impairing walking and causing fatigue and vision, speech, memory and other problems. It affects about 2.5 million people worldwide, including 350,000 Americans.

A condition with an unwieldy name has become the hottest topic of debate in MS: Chronic cerebrospinal venous insufficiency, or CCSVI. An Italian vascular specialist, Dr. Paolo Zamboni, was hunting ways to help his wife’s MS when he discovered that veins carrying oxygen-depleted blood down the neck or spinal cord were narrowed, blocked or twisted in a group of patients. Zamboni reported that made blood back up in a way that might be linked to MS’ damage, by causing tiny leaks of immune cells into the brain that start a cascade of inflammatory problems.

Then came the step that spread excitedly through MS patient Internet forums: In a pilot study, Zamboni’s team used balloon angioplasty — similar to a longtime method for unclogging heart arteries — to widen affected veins in 65 patients. He reported varying degrees of improvement, mostly in patients with the relapsing-remitting form of MS who experienced fewer flare-ups of symptoms over the next 18 months and some improvements in quality of life.

But nearly half had their veins relapse, and Zamboni urged a larger, more scientifically controlled study be done.

Next, Buffalo researchers scanned the veins of 500 people. About 55% of MS patients had signs of CCSVI, compared with 22% of healthy people, says lead researcher Dr. Robert Zivadinov, who will present his data next month at a major neurology meeting.

Meanwhile, a Stanford University surgeon tried implanting scaffolding-like stents — also developed for heart disease — into some MS patients’ narrowed veins. Dr. Michael Dake halted the work in December after 35 people were treated, saying in an e-mail to colleagues that he decided “after deep soul-searching” not to continue outside of a clinical trial. Stanford won’t discuss details, but the journal Annals of Neurology reported that one patient’s stent dislodged and flowed to the heart, requiring emergency open-heart surgery to remove it. (An earlier death was reported by family members to be from a stroke unrelated to the MS treatment.)

The MS Society soon will announce funding for additional studies.

Like many neurologists, Georgetown’s Tornatore watched the developments with a mixture of skepticism and curiosity. After all, decades ago some doctors first suggested circulation might play a role. The scars tend to cluster near veins, and blood-thinning treatment was tried before immune-targeting drugs were proven to help many MS patients.

He ticks off the possibilities: This could be a blind alley, like so many to befall MS over the years. Or it could work a little. Or it might be revolutionary.

“I have no idea. I’m not predisposed to any of them,” Tornatore says.

But he and Neville decided angioplasty was the least risky option for a limited test. In 30 patients who’ve undergone a $400 ultrasound exam so far, about half have evidence of the vein abnormality.

Gurland was the first treated earlier this month, her jugular veins blocked so tightly that Neville had a hard time even pushing the tiny angioplasty wire inside. But right after the treatment, Gurland’s feet that for years had been cold and purplish became warmer and normally colored.

What about MS’ hallmark fatigue and weakness, and her scarred nerve cells? While Gurland thinks her balance in the morning, often her worst time, is improving a bit, it’s too soon to know; those tests are yet to come.

But last week, her close friend Heather Tuck, 61, came in for a vein check, too — calling it the first MS test she ever hoped to pass.

Nine Lives: Cats’ Central Nervous System Can Repair Itself And Restore Function

December 3rd, 2009

From ScienceDaily.com:

Scientists studying a mysterious neurological affliction in cats have discovered a surprising ability of the central nervous system to repair itself and restore function.
In a study published March 30, 2009 in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison reports that the restoration in cats of myelin — a fatty insulator of nerve fibers that degrades in a host of human central nervous system disorders, the most common of which is multiple sclerosis — can lead to functional recovery.
“The fundamental point of the study is that it proves unequivocally that extensive remyelination can lead to recovery from a severe neurological disorder,” says Ian Duncan, the UW-Madison neuroscientist who led the research. “It indicates the profound ability of the central nervous system to repair itself.”
The finding is important because it underscores the validity of strategies to reestablish myelin as a therapy for treating a range of severe neurological diseases associated with the loss or damage of myelin, but where the nerves themselves remain intact.
Myelin is a fatty substance that forms a sheath for nerve fibers, known as axons, and facilitates the conduction of nerve signals. Its loss through disease causes impairment of sensation, movement, cognition and other functions, depending on which nerves are affected.
The new study arose from a mysterious affliction of pregnant cats. A company testing the effects on growth and development in cats using diets that had been irradiated reported that some cats developed severe neurological dysfunction, including movement disorders, vision loss and paralysis. Taken off the diet, the cats recovered slowly, but eventually all lost functions were restored.
“After being on the diet for three to four months, the pregnant cats started to develop progressive neurological disease,” says Duncan, a professor of medical sciences at the UW-Madison School of Veterinary Medicine and an authority on demyelinating diseases. “Cats put back on a normal diet recovered. It’s a very puzzling demyelinating disease.”
The afflicted cats were shown to have severe and widely distributed demyelination of the central nervous system, according to Duncan. And while the neurological symptoms exhibited by the cats are similar to those experienced by humans with demyelination disorders, the malady does not seem to be like any of the known myelin-related diseases of humans.
In cats removed from the diet, recovery was slow, but all of the previously demyelinated axons became remyelinated. The restored myelin sheaths, however, were not as thick as healthy myelin, Duncan notes.
“It’s not normal, but from a physiological standpoint, the thin myelin membrane restores function,” he says. “It’s doing what it is supposed to do.”
Knowing that the central nervous system retains the ability to forge new myelin sheaths anywhere the nerves themselves are preserved provides strong support for the idea that if myelin can be restored in diseases such as multiple sclerosis, it may be possible for patients to regain lost or impaired functions: “The key thing is that it absolutely confirms the notion that remyelinating strategies are clinically important,” Duncan says.
The exact cause of the neurological affliction in the cats on the experimental diet is unknown, says Duncan, who was not involved in the original study of diet.
“We think it is extremely unlikely that [irradiated food] could become a human health problem,” Duncan explains. “We think it is species specific. It’s important to note these cats were fed a diet of irradiated food for a period of time.”
In addition to Duncan, authors of the new PNAS study include Alexandra Brower of the Wisconsin Veterinary Diagnostic Laboratory; Yoichi Kondo and Ronald Schultz of the UW-Madison School of Veterinary Medicine; and Joseph Curlee, Jr. of Harlan Laboratories in Madison.

Radical MS Theory Stirs Interest

December 2nd, 2009

From MedPageToday.com:

Can multiple sclerosis be treated with a simple surgical procedure?

That question — raised by the research of an Italian physician — is causing a stir among those who study the condition, which has long been regarded as an autoimmune disease.

Instead, according to Paolo Zamboni, MD, of the University of Ferrara, in Ferrara, Italy, MS may result from poor vascular circulation in the brain.

The theory is this: Abnormal flow through the azygous and jugular venous systems results in a build-up of iron in the brain. The excess iron damages blood vessels and allows the metal, as well as other substances, to cross the blood-brain barrier.

The hypothesis has immediate clinical implications. First, if narrowed or obstructed veins are the cause of the condition, people might easily be screened for MS long before symptoms appear.

And second, a simple surgical procedure — a percutaneous transluminal angioplasty — could open the veins and perhaps halt or reverse the course of the disease.

The case is not proved, and experts caution that more study is needed to overthrow the reigning paradigm. In particular, they warn patients against seeking vascular surgery before the issue is settled — one way or another — by a full-scale, randomized blinded controlled trial.

“Most experts regard it as a long shot” that needs to be studied, said John Richert, MD, executive vice president for research and clinical programs at the National Multiple Sclerosis Society.

But Zamboni told a Canadian newspaper recently, “I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis.”

Researchers in Buffalo, led by Robert Zivadinov, MD, PhD, of the Buffalo Neuroimaging Analysis Center, are currently trying to determine whether people with MS are more likely to have what has been dubbed “chronic cerebrospinal venous insufficiency.”

They are enrolling 1,100 patients diagnosed with possible or definite MS, 300 age-and-sex-matched normal controls, and 300 patients with other autoimmune and neurodegenerative diseases.

“If we can prove our hypothesis, that cerebrospinal venous insufficiency is the underlying cause of MS,” Zivadinov said in a statement, “it is going to change the face of how we understand MS.”

The investigators are following up a small pilot study, as well as one conducted by Zamboni and colleagues and reported late last year in the Journal of Neurology, Neurosurgery & Psychiatry.

In that study, Zamboni and colleagues looked at venous outflow in 65 patients with clinically defined multiple sclerosis and 235 controls, using transcranial and extracranial Color-Doppler high-resolution examination.

The MS patients were 43 times more likely to have abnormalities than the controls, they reported (OR 43.0, 95% CI 29 to 65, P<0.0001).

Zivadinov and colleagues found a similar result in their small pilot study of 16 patients with relapsing-remitting MS and eight healthy controls: all the patients, but none of the controls, had chronic insufficient blood flow from the brain.

Also, in a report in press at the Journal of Vascular Surgery, Zamboni and colleagues offer results of a study in which they surgically treated 65 MS patients with abnormal cerebral venous outflow.

The effect of the surgery on MS symptoms was compared with rates of symptoms during the two years before the procedure.

According to published reports — the final paper is not yet available — during the 18 months following surgery, half of the patients with the remitting-relapsing form of the disease had no attacks. The corresponding rate before surgery was 27%.

As well, the proportion of patients with active gadolinium-enhanced lesions seen on MRI scanning fell from 50% to 12%.

While the results seem promising, they fall well short of proof, according to the MS society’s Richert. “This is something that requires a well-controlled, blinded prospective study,” he said.

One danger is that patients may jump the gun, Richert said. “There are a number of patients who may be expecting that they can just go to a vascular surgeon and get this done,” he said.

“Our feeling is that this is an experimental procedure and that it should be undertaken by people with MS only as part of a formal clinical trial,” Richert added.

Richert added that the results of Zamboni’s surgical trial — while good science — aren’t enough yet to overturn the existing paradigm.

Among other things, Richert said, it’s possible that the apparent benefit was a long-lasting placebo effect.

In clinical trials with a placebo, he noted “reproducibly and consistently, the group on placebo does better on the trial than they did prior to entering the trial.”

Zamboni and colleagues measured MS symptoms in patients before and after the procedure, rather than comparing surgical and control groups.

The changes that they saw, Richert said, are similar to those “that we tend to see in placebo groups in major drug trials.”

He added that the MS society is “anticipating” proposals for a randomized trial of the surgery by its February grant deadline. The Canadian MS society said earlier this week that it will support such research if a proposal is made.