Benjamin Brooks directs the MDA/ALS Center at the University of Wisconsin. The center was established in 1987.

Wisconsin ALS Expert Pursuing Viruses, Tamoxifen & Gulf War Exposure

by Margaret Wahl

Q: How did you first become interested in research on amyotrophic lateral sclerosis (ALS)?

A: My interest in ALS came out of the polio era. I had a cousin who had polio, and I took care of him in the 1950s and 1960s, when I was a kid. He was in an iron lung, which was the old-time method of respiratory support. Polio was a formative experience for people born back then. [The polio virus affects the same muscle-controlling nerve cells, the motor neurons, that are affected in ALS.]

I got interested in viruses and went to work in John Enders' laboratory at Harvard University in 1967. Enders had figured out how to grow the polio virus and got the Nobel Prize for that in the 1950s. My particular interest has been in viruses that enter the nervous system — neurotrophic viruses.

Since then, it's been found that certain viruses, at least in mice, can activate other viruses that are lying dormant in the spinal cord. Whether there are linkages among various viruses and ALS or between viruses and other factors remains to be seen.

Q: Where is the research now with respect to a possible connection between viruses and ALS?

A: Well, for one thing, we know now that there's an increased prevalence of ALS in AIDS patients. AIDS is, of course, caused by the human immunodeficiency virus, or HIV, so that's an intriguing observation with respect to viruses and ALS.

Whether there's a link between other viruses and ALS isn't known, but there's some French work and some work going on at the University of California at Irvine that suggests there is.

Q: Does treating the viral disease treat the ALS?

A: Over the last 20 years or so, there have been isolated cases of ALS in AIDS patients, and sometimes the ALS has benefited when the AIDS was successfully treated.

But the question for which many people need an answer is this: Is there a downstream effect of the HIV virus once it gets into the nervous system that's common to both the virally associated ALS and the more common, or classic, ALS, in which no known virus can usually be found? If there is, then maybe treating ALS with antiviral drugs could have benefit.

Because of the theory that you might be able to treat some downstream viral effect that's common to all forms of ALS, they're now testing one of the AIDS drugs, indinavir (Crixivan) to see if it helps in non-AIDS-related ALS. There's a study under way in New York that's going to look at this question.

Q: I know you're conducting a clinical trial of tamoxifen (Nolvadex) at your center. What brought you to the idea of using tamoxifen, which is normally thought of as a breast cancer treatment, as an ALS drug?

Benjamin Brooks

A: We first got interested in tamoxifen when we had a patient with ALS who developed breast cancer about the same time. She went on tamoxifen and seemed to have a very slow course with her ALS. She seemed to actually increase in strength and then stayed at about the same level of function for over three years. So, we put that observation in the backs of our minds.

Then a paper came out suggesting that tamoxifen might help protect cells from glutamate toxicity. [Excessive stimulation by the central nervous system chemical glutamate has long been suspected of damaging nerve cells in ALS.]

That's when we thought we should look at this drug in animals. A preliminary study showed tamoxifen alone prolonged survival in mice with an ALS-like disorder. We're now giving the mice tamoxifen and AIDS drugs together. The patients are just getting tamoxifen. [The mice were given a virus called ts1, which causes an AIDS-like disorder that also resembles ALS.]

We think the animals got a little bit stronger with tamoxifen, and we'll be looking for the same signs with humans.

Q: Do you think the tamoxifen is treating the viral disease caused by the ts1?

A: As with the AIDS drug speculations, we're thinking the tamoxifen may be working on something common to the virally induced ALS and also the classic ALS — something "downstream" from where the virus enters the nervous system.

Q: What do you think tamoxifen is doing in the motor neurons — in the mice or in the patients?

A: My personal bias is that it's working at the level of the mitochondria [the energy-producing units of cells]. In the mice, we found the same effects in males and females, so that suggests that tamoxifen is having its beneficial effect in this ALS-like disorder at a location other than at the estrogen receptor, which is where it's thought to be working in breast cancer.

Another interesting observation is that tamoxifen inhibits an enzyme called neuronal nitric oxide synthase, which is thought to be involved in a death mechanism in nerve cells. This is new information, and we're going to be looking more at that.

For information about participating in the tamoxifen trial, call (608) 262-7175 or (608) 263-9057, or e-mail alscrc@neurology.wisc.edu.

Q: Some people are suggesting that viruses or other organisms, such as bacteria, could be involved in the ALS that's been associated with the Gulf War. What do you think about that?

A: You know, the issue of whether the incidence of ALS goes up after a traumatic upheaval goes back all the way to [19th-century French neurologist] Jean Martin Charcot. There were anecdotes that the incidence increased in the late 1870s, after the Franco-Prussian War.

Then, after World War I, particularly in Belgium, and after World War II on the island of Guam in the Pacific, there was the same question of increased ALS incidence.

Now, since the Gulf War, you can do a lot of this epidemiology with computer systems. The information available from the Department of Veterans Affairs and the Department of Defense says the rate of ALS was significantly increased in military personnel who served in the Gulf War in the Air Force and Army but not in the Navy or Marines.

But what does it mean? One study is looking at genetic predispositions in those who got ALS. One hypothesis is that there might be some SOD1 variations that make people more susceptible to ALS under certain conditions. [SOD1 is a gene that, when mutated, can cause ALS in humans and animals.]

Another hypothesis suggests that the ALS increase is related to toxic exposures.

Here at the Veterans Affairs Hospital in Madison, I've seen people who have had what is called Gulf War syndrome who are now developing neurological signs. This may be the tip of an iceberg. We may see more cases as we go further away from the exposure time. It may be that the exposure causes damage to neurons such that when the aging process interacts with that exposure, you get ALS.

Researchers at the University of Washington, Seattle, have found that patients who develop ALS at age 40 or 50 have sometimes had extraordinary exposures earlier in life. Some people have had significantly higher exposure to pesticides, for example, between ages 15 and 25. So, in this Gulf War group, a separation of 20 to 30 years could occur before we see a peak of ALS incidence.

Q: What other kinds of toxic exposures? Could it be a combination, say, of a microorganism and other toxic substances?

A: It's a possibility. There's an Australian disease that affects the motor neurons in cattle. If the cattle get a certain virus infection and also drink water with a certain chemical in it, they get the motor neuron disease. But either thing alone won't cause it. So, it could be that two things have to happen at once.

In the veterans, one toxic exposure might be something like lighting the lamps in the camps with diesel fuel or maybe being around the oil wells that were burning all the time. Then, on the virus issue, it could be there was something that they picked up over there, some seemingly benign cold or other virus, such as an enterovirus. Of course, genetic predisposition could be acting in this mix as well.

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Art Imitates Life:
ALS Patient Visits Hollywood's Dr. Becker

by Tara Wood

It's hard to think of ALS as a laughing matter, but humor will indeed be mixed with some poignant moments on an upcoming episode of "Becker" that features a man struggling with the disease.

The March 18 episode of the CBS sitcom, which stars Ted Danson as the cantankerous yet caring Dr. John Becker, is inspired by the experiences of Claude Woody, a Californian who's battling ALS.

The story began its journey to the television screen when Woody, 77, received a diagnosis of ALS in April 2001. Woody's son, Russ, is a writer for "Becker."

The elder Woody had been experiencing difficulty with speaking, and doctors at first thought he'd had a stroke. The ALS diagnosis punctuated an especially tough time for the family as Claude's wife died unexpectedly the same week.

Russ Woody suggested that his father move from his home in Pahrump, Nev., to Studio City, Calif., where Russ lives with his wife, Cath Campbell, and their sons Joe, 4, and Henry, 6.

Claude, who can no longer speak and is planning to get a g-tube for easier feeding, agreed to move and now lives just a few blocks from his son.

Claude spends as much time as possible with his grandsons — sleepovers at his house, cooking pancakes and waffles on weekends, trips to a local farmer's market, and playtime in a backyard fort he built for the kids.

"My dad loves kids and these two little guys are his whole life. He just lights up when he sees them," Russ said.

Claude also finds time to visit Russ on the "Becker" set and, as a result, has become a favorite friend of the cast and crew.

Tom Poston (right) plays an ALS patient of Dr. John Becker's (Ted Danson) on the March 18 episode of "Becker."

"Everybody calls him Woody and everybody hugs him when he comes to the show," Russ said, adding that his father is considered an "unofficial mascot" of the show.

Danson has been especially warm and welcoming, and enjoys tinkering with Claude's LightWRITER, an augmentative communication device that enables Claude to have conversations by typing in words that the computer "speaks" for him.

In fact, the LightWRITER actually led to the idea of a show about a person with ALS.

From a Joke to a Script

Russ Woody said that, while rewriting scripts for the episodes, the writers sometimes imitate the characters' voices while pitching jokes or ideas.

"Somebody was making fun and imitating my dad's machine, and then somebody else said we should do a story about it, and that's how it went," Russ said. He talked the idea over with Claude, who was all for it. "The rest of the writers really latched onto it, so I said I'd write it."

The story line goes like this: A woman brings her father, an elderly man named Joe Willakie, to Becker for help because ALS has rendered him unable to speak. Becker helps him get a LightWRITER, but when the machine gives Willakie a voice, everyone soon wishes he would shut up because of the insults he constantly expresses. Becker helps Willakie and his daughter deal with this and other challenges presented by ALS.

Tom Poston, who is all too familiar with ALS, plays the part of Joe Willakie. Poston, who has appeared on the Jerry Lewis MDA Telethon, lost his wife, Kay, to the disease in 1998.

Poston, Russ Woody said, did a terrific job and during the filming "spent some time with my dad and they goofed around a bit."

Danson Shares MDA Message

While no one contends that the half-hour "Becker" show will give viewers an in-depth education about ALS, the Woodys agree it will help bring about awareness of the disease.

In fact, both Woodys and Danson were interviewed by "Entertainment Tonight," which will air a feature segment, also slated for March 18, about the episode's inspiration. Articles about the show in People magazine and TV Guide may also be in the works, Russ said.

Claude Woody (with grandson Joe) was the inspiration for the "Becker" episode about ALS.

In addition, Danson taped a short public service announcement scheduled to air immediately following the show. It directs viewers to contact MDA for services and information about ALS.

Russ Woody hopes the show will alert other people to the benefits of devices such as the LightWRITER. The machine has helped open a new world for his dad.

"The machine has let me talk to my grandsons, and go shopping and talk to people without pen and paper," Claude Woody said.

The added attention the show is gathering, plus the fact that the episode is essentially based on his father, was "a bonus. I think he got a kick out of the attention," Russ said.

Claude said he "never dreamed of being involved" in his son's television show, but thinks "it is great that the spotlight is shined on ALS."

The Woody family stays hopeful and focused on the promise of research. They believe advances like stem cell therapy will soon win the war against ALS.

Meantime, Claude Woody shares this advice for other families challenged by ALS: "Do as much as you can to keep moving and doing things. Hang on."

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ALS Research Roundup

Unlocking the Mysteries of Guamanian ALS

In two recent studies, Gerard Schellenberg of the University of Washington and Veterans Affairs Medical Center in Seattle presents new data suggesting that a mixture of genetic susceptibility and environmental factors causes the Guamanian ALS cluster. (Also see "Wisconsin Expert.")

Shortly after World War II, scientists discovered that about 140 per 100,000 of the Chamorro people had ALS. This figure is, by some calculations, 50 times higher than the worldwide prevalence of the disease. Guamanian ALS is similar to ALS everywhere else, but is also associated with Parkinson-dementia complex (PDC), a disorder that combines the tremor of Parkinson's disease with the memory loss of Alzheimer's.

In the Jan. 8 issue of Neurology, Schellenberg and his group review surveys of Guamanian ALS from the 1950s to the present, and point out that in the 1980s, its prevalence dropped to about 8 per 100,000. In Schellenberg's own survey, from 1997 to 2000, the prevalence was similar. The shrinking but persistent ALS cluster in the Chamorro people suggests an interplay between genetic risk factors and changing environmental factors, he writes.

And in the November issue of Archives of Neurology, Schellenberg's group provides evidence that a variant of the tau gene might be a genetic risk factor for ALS-PDC among the Chamorros. The tau protein is a structural component within neurons, and has been shown to form abnormal clumps in the brains of people who have Alzheimer's, ALS-PDC and other neurodegenerative disorders.

Study of ALS Rat Supports Glutamate Toxicity Idea

MDA devotes more than $5.5 million a year to ALS research and services — more than any other U.S. national voluntary, private-sector health agency.

The achievement, the second of its kind in as many months (see "Stem Cell Therapy Research Taking Several Paths," December 2001), is expected to speed ALS research by improving on the widely used mouse model of the disease. Like the mice, the rats are bred to carry mutations in the SOD1 gene — which cause familial ALS in people — but they're larger and therefore more amenable to surgical procedures.

Rothstein and his group found that the rats went through the characteristic disease process observed in humans and mice with ALS — a rapid degeneration of motor neurons, followed by paralysis. But they also found evidence for a more controversial process — loss of the glutamate transporter EEAT2.

Normally, EEAT2 mops up the brain chemical glutamate, which can be toxic to neurons. Many people with ALS have reduced levels of EEAT2, which has led to the theory that glutamate toxicity plays an important role in the disease. In the rats, Rothstein found an obvious decline in EAAT2 before disease onset. That result strengthens the argument "that the loss of EAAT2 may contribute to motor neuron degeneration" in ALS, Rothstein writes in the Feb. 5 issue of Proceedings of the National Academy of Sciences.

Three New Trials Still Open

The trial of celecoxib (Celebrex), an arthritis drug, is being coordinated at Massachusetts General Hospital in Boston. For information contact

Fran Murphy at (617) 726-9122 or fmurphy@partners.org.

Participants are being screened for a trial of tamoxifen (Nolvadex), a drug used to treat breast cancer, at the University of Wisconsin in Madison. Contact Kathryn Roelke or Jennifer Parnell at (608) 262-7175, (608) 263-9057, (608) 265-2451, or alscrc@neurology.wisc.edu. For details, visit www.neurology.wisc.edu/Clinicaltrials/trialist.htm#ALS.

A trial of minocycline (Minocin), an antibiotic in the tetracycline family, is open for enrollment at the University of New Mexico in Albuquerque. For more information, contact Martha Meister at (505) 272-3194.

New CoQ10 Trial Starts in New York

A new double-blind study will assess the effectiveness of coQ10 on saving motor units, using a neuroimaging technique.

For information about participation, contact Maura Del Bene at (212) 305-1319 or alscenter@columbia.edu.

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Rilutek Assistance

The National Organization for Rare Disorders (NORD) provides assistance for those unable to afford this expensive drug, which is made by Aventis Pharmaceuticals.

Maria Hardin, vice president of patient services for NORD, noted that the organization's Rilutek Patient Assistance Program is a "source of last resort" for patients whose federal, state and private health insurance or other resources don't cover the cost of Rilutek. NORD is a nonprofit organization dedicated to the identification, treatment and cure of rare, or "orphan," diseases.

Eligibility for assistance is determined by medical and financial criteria. For more information or to obtain an application for assistance, call (800) 459-7599.

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ALS Is a 'Gift in Disguise' for Noted Physical Therapist

by Chris Medvescek

Caffiero, 68, is MDA's 2001 New York State Personal Achievement Award recipient. This award recognizes the accomplishments and community service of people with disabilities caused by any of the neuromuscular diseases in MDA's program.

Caffiero received his ALS diagnosis in 1996. "Al" — as he's affectionately known by his former patients in upstate New York — can no longer speak clearly or walk unassisted. But his mind continues to run at high speed: organizing programs and fund-raisers for MDA, participating in a creatine research study at Syracuse University, designing his own research projects and speaking out for more research into the use of stem cells.

Physical Therapy Innovator

Caffiero, of Williamson, N.Y., began practicing and teaching physical therapy in upstate New York after his graduation from Ithaca College in 1960. Originally specializing in treatment for amputees, he says he was the first in the area to implement a team approach to treatment that included physicians, other therapists and family members. His firm, Western New York Physical Therapy Group, became known as "the leaders in the community when it came to new ideas," he says proudly.

Even today, he continues to work on a research project for a treatment technique he developed to decrease the painful and debilitating effects of reflex sympathetic dystrophy.

One of Caffiero's innovations led to his participation in an MDA research project years before he received his ALS diagnosis — and he wonders now if it also might have led to his ALS.

Al Caffiero appears on MDA "Love Network" station WGRZ of Buffalo, N.Y., with Jodi Johnston at the ATC Golf Classic for MDA.

In the mid-1970s, Caffiero began treating injured hockey players with a machine called the Russian Stimulator, which builds up muscle by delivering electrical stimulation that causes the muscle to contract. His treatment ultimately was adopted by the Buffalo Bills and Buffalo Sabres football and hockey teams, and came to the attention of MDA researcher Michael Hudecki of the State University of New York at Buffalo. Caffiero helped Hudecki set up a study of the effect of electrical stimulation on the muscles of chickens with muscular dystrophy, which was published in 1985 in Experimental Neurology.

Ever curious, Caffiero wondered if the Russian Stimulator also could be used to break down stomach fat, and to test this out he subjected his own stomach to very high doses of electrical stimulation over a two-week period — strong enough to draw up his body almost into a sit-up. Sure enough — blood work showed high lipids in his blood, a sign of fat breakdown.

But there was a downside. While electrically stimulating muscle has tremendous value in rehab, the levels he was using on himself were way too high, he says.

[Editor's Note: Caffiero used a much higher dose of electricity than is delivered by the commercial units now being sold on TV.]

Noting that a few studies have linked electrical injury (especially when it results in unconsciousness) with the development of ALS, Caffiero says ironically, "My luck. But what did someone once say, 'If it weren't for bad luck, I wouldn't have any luck at all?'"

PT and ALS

Caffiero strongly believes that stem cells hold the greatest hope for ALS treatment. His daughter, Elizabeth Ann Smietana, has been writing to legislators and researchers on his behalf, encouraging more work in this area and offering her father as a research subject.

In the meantime, he's enrolled in a clinical trial at Syracuse University of the organic acid creatine, and says his strength has dropped off only slightly since he entered the double-blind study. He also takes Rilutek, Celebrex, co-enzyme Q10 and vitamin E, and participates in swimming and aerobic exercise.

Physical therapy is still a part of his life, both as a patient and as an advocate. "Is PT helpful for ALS?" he asks rhetorically. "I could write a book. [It's good] for muscle building and stretching, and for the family interaction, through home care. A home therapist is the savior for the family."

Home therapists evaluate the home situation for a person with a chronic condition, move furniture, get equipment, teach primary caregivers how to help without hurting themselves, make arrangements for occupational or speech therapy and more, he says.

Giving Back

Home care, especially family training, is so important that Caffiero set up a program through his physical therapy clinic that gives half-price treatment to anyone referred by the local MDA office.

A formerly active tennis player and golfer, he also got together with business partners and friends to organize a charity golf tournament to benefit MDA. "I didn't realize the MDA did so much," he said. "This is my way of helping MDA."

But of all the ALS treatments available or imagined, Caffiero is convinced that communication is among the most important, and so offers himself — body and mind — to the ALS community.

"One of the things I always told my staff and all my students was that as a therapist you can make all the difference in a serious disease. You can give them hope that will make them go on.

"I guess you can see why the loss of my ability to speak is more painful than anything one can experience. But I will fight to the last straw to make sure anyone who contacts me will feel better when I get done with them."

This interview was conducted via e-mail. Alfred Caffiero can be contacted at AlfredCaf@aol.com.

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Respiratory Issues in ALS

by Anne Markovich, RN, BSN
Nurse Coordinator, Neuromuscular Disorders Program MDA Clinic, Northwestern University, Chicago

Pneumonia/Flu

While those with ALS are not truly more susceptible to pneumonia or flu than the general public, they do have a more difficult time dealing with the conditions if they should develop. Pneumonia and flu are caused by a bacterial or viral infection. Pneumonia may also be caused by aspiration of food/fluid into the lungs. It is important to be aware of the signs of pneumonia and respiratory forms of flu and to seek care before a crisis. The signs of pneumonia and respiratory flu are:

To Prevent Pneumonia or Flu

Secretions

Secretions in the back of the throat (not to be confused with excess saliva which can occur in ALS) are often a problem in ALS, especially if they become very thick and cannot be coughed out. These secretions are generally a result of postnasal drip or drainage of sinus fluids in the throat.

To Manage Thick Secretions

Reprinted with permission from Chicago Cares, the MDA/ALS Division Newsletter from Chicago

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Do You Call Yourself a 'Caregiver'?
Maybe You Should, Says NFCA Report

People who call themselves "caregivers" in conversations with others say this self-identification has helped them become more proactive in getting resources and services for their loved ones, and more confident in dealing with the health care system. They also report feeling somewhat less isolated and slightly more likely to take better care of themselves.

NFCA, a nonprofit organization that supports American caregivers, commissioned the September 2001 "Survey of Self-Identified Family Caregivers." Results are based on 236 responses from a select group of family caregivers who belong to the Caregivers Advisory Panel, a market research and consulting organization.

Researchers generally acknowledge that the majority of family caregivers don't identify themselves as such to others, making it difficult to provide them with outreach services, organize them on political issues, or "inform, support and educate them," according to the NFCA.

The survey found that the biggest factor that led the respondents to identify themselves as "caregivers" was providing personal care to their charges (for example, helping with bathing and dressing, as opposed to helping with shopping and housecleaning).

The report concludes, "When family caregivers self-identify and become more self-aware, they can be a force for societal change in the effort to make our health care system and government policies more supportive of those with chronic, long-term illnesses or disabilities."

To learn more about the survey and the NFCA, visit www.nfcacares.org on the Internet or call (800) 896-3650. To become part of the Caregivers Advisory Panel, call (877) 595-6227 or visit www.caregiversadvisorypanel.com.

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Congress Considers Homebound Reform, Gulf War Benefits

Also pending is a bill that would grant permanent federal health care disability benefits to Gulf War veterans who developed ALS.

Homebound Restriction

"Because of budget priorities right now, we are concerned that Medicare reform will take a back seat to homeland security and defense," commented Angelique Skoulas, a legislative aide to Congressman Edward Markey (D-Mass.). Markey co-sponsored H.R. 1490, the Homebound Clarification Act, in April.

The homebound bill seeks to loosen the restrictions placed on people receiving Medicare home health services. Current recipients, including many with ALS, must remain in their homes at all times except for absences of "infrequent and short duration," or risk being denied home health care benefits.

A vote on the act, originally scheduled for fall, was postponed due to the events of Sept. 11.

HELP FIGHT ALS You can earmark your contributions to MDA specifically for the ALS Division. For information on how to remember MDA's ALS Division in your retirement or estate plans, call MDA's Planned Giving Department at (800) 572-1717.

Rare Diseases

The Rare Diseases Act of 2001 (S. 1379) also has been tied up since it was passed in October by the Senate Health, Education, Labor and Pensions (HELP) Committee.

The Rare Diseases Act would make permanent the Office of Rare Diseases at the National Institutes of Health. It also would fund both rare-disease research centers of excellence and the FDA's Orphan Products Grant Program for drug development. ALS is among the 6,000 rare diseases covered by the act.

Gulf War Legislation

Rep. Lane Evans (D-Ill.) has introduced a bill that ensures Department of Veterans Affairs (VA) benefits for Gulf War veterans who have developed ALS.

H.R. 3461 would make permanent the temporary decision by the VA to view ALS as a service-connected disability for Gulf War veterans.

Passage of H.R. 3461 would guarantee that Gulf War vets who how have ALS, and any who develop the disease in the future, are eligible for VA health care disability benefits.

Supporters of any of these bills should contact their senators and representatives about co-sponsoring and voting for the proposed new laws.

You can get the names and contact information of your congressional representatives at www.house.gov or www.senate.gov.

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