Research Roundup

by Margaret Wahl and Amy Labbe

MDA-funded lithium trial is now open

Neurologist Robert Miller, director of the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco, has begun testing the drug lithium carbonate in an MDA-funded trial that expects to include 100 participants with ALS at 10 U.S. sites.

The MDA-funded trial is designed so that all participants will receive lithium.

Recruitment of participants is under way through the coordinating site in San Francisco (see below) and is expected to be under way soon at centers located in Arizona, California, Kansas, Missouri, Oregon, Pennsylvania, Texas and Utah.

Another study of lithium in ALS, coordinated by researchers at Massachusetts General Hospital in Boston, also is on the drawing board.

In February, an Italian study of lithium carbonate and riluzole in people with ALS showed the combination of the two drugs slowed progression of the disease. The results, published online Feb. 4 in Proceedings of the National Academy of Sciences, prompted Miller to plan and begin the new study, which aims to confirm or refute the effectiveness of lithium carbonate both in combination with riluzole and alone. (See Research Roundup, March 2008.)

Miller said the results of the Italian study are “important” and “the most positive ever reported for ALS” but that questions still exist for which the U.S. study should provide answers.

Participants in the new study will take twice-daily doses of lithium, designed to replicate the same blood serum levels tested in the Italian group, for one year.

The investigators will assess lithium’s safety and measure changes in general function (as detected by the ALS Functional Rating Scale – Revised), pulmonary function, quality of life and survival time. These measurements will be compared with those in people who participated in a recent ALS study but received only a placebo. This “historical control” design allows all participants in the current trial to receive the study drug.

Researchers hope positive results from an Italian study can be replicated in a U.S. trial of lithium.

Although investigators will “take all comers,” Miller says that because approximately 50 percent of people with ALS in the United States take riluzole, he expects to see roughly the same percentage of study participants taking the drug as well. The trial design will enable investigators to determine not only the effects of lithium, but any synergistic effect of the combination of riluzole and lithium.

“If riluzole is having a significant impact, it should be apparent,” he said.

Contact Dallas Forshew at (415) 600-3938 or forshed@cpmcri.org, and/or see www.mda.org/research/ctrials.aspx.

Phase 2 study of KNS-760704 is open

Knopp Neurosciences (www.knoppneurosciences.com), a Pittsburgh drug-discovery company, has announced the opening of a phase 2, 20-center trial of its experimental compound KNS-760704 in 80 people with ALS.

Knopp Neurosciences is following up on studies that showed (R+) pramipexole (KNS-760704), a mirror image of a Parkinson disease drug, might be effective in ALS.

The KNS-760704 molecule is a mirror image of (S-) pramipexole (Mirapex), a drug used to treat Parkinson disease. The mirrorimage compound, known as (R+) pramipexole, initially was developed for ALS at the University of Virginia in Charlottesville. It’s designed to have some of the characteristics of the original molecule, but not others.

(S-) pramipexole mimics the actions of dopamine, a carrier of signals in the brain, which is desirable for treating Parkinson disease but would be toxic in ALS at the doses that may be needed. However, it has antioxidant and anti-cell-death properties that are preserved in the mirror-image (R+) molecule and may benefit ALS patients. (See Research Roundup, November-December 2007.)

In February, the journal Amyotrophic Lateral Sclerosis reported that patients with earlystage ALS who took part in an exploratory, 30-person, nine-month study of (R+) pramipexole at the University of Virginia showed a slowing of their decline in function described as “encouraging but statistically nonsignificiant.”

The work at the University of Virginia has been “very valuable in pioneering a potentially promising approach to the treatment of patients with ALS,” said Tom Petzinger, executive vice president of Business Development, Strategy and Public Affairs at Knopp. “We’re encouraged by the early safety experience with (R+) pramipexole at UVA and by the data suggesting a hint of effectiveness.”

Now, he said, Knopp has developed a purified tablet formulation of (R+) pramipexole with its KNS-760704 compound and is on a path toward its commercial development for the treatment of ALS.

“The milestone we have achieved now is having completed a phase 1 study in 80 healthy subjects,” Petzinger said, in which KNS-760704 “demonstrated excellent levels of safety and tolerability.” The phase 2 study will test the drug in ALS patients.

Petzinger said Knopp will move on to a much larger study later this year if there are no safety or tolerability problems.

See www.knoppneurosciences.com, or contact Tom Petzinger at (412) 488-1776 or tom@knoppneurosciences.com.

High-dose coenzyme Q10 showed no benefit

Petra Kaufmann, principal investigator, said the results of the high-dose coenzyme Q10 were disappointing but that they free patients from believing they have to buy the supplement and free resources to test other drugs.

High-dose coenzyme Q10 (coQ10) is not promising enough to warrant further study as a treatment for ALS, reported principal investigator Petra Kaufmann from Columbia University Medical Center in New York at the 60th annual meeting of the American Academy of Neurology in April. (For more news from this meeting, see “Researchers Gather at AAN meeting” under What’s New at www.mda.org.)

Kaufmann, with colleagues at 19 U.S. centers and funding from the National Institutes of Health, tested coQ10 at dosages up to 2,700 milligrams per day against an inactive substance (placebo) in 185 people with ALS.

“The difference between the 2,700-milligram coQ10 group and the placebo group was not large enough to suggest that one would find a meaningful difference in a future phase 3 [large-scale] trial,” Kaufmann said. She added, however, that the study didn’t address the question of whether coQ10 might be helpful in combination with other drugs.

Kaufmann said the result was disappointing because they didn’t find a drug that helps people with ALS. However, she noted, it frees ALS patients from believing they have to buy coQ10, and it frees resources to test other drugs rather than conducting an expensive, phase 3 trial of coQ10.

Leaks in blood-spinal cord barrier come before nervous-system damage in mice with SOD1 ALS

A research team that included MDA grantees M. Kerry O’Banion at the University of Rochester (N.Y.) Medical Center and Severine Boillee at the University of California-San Diego has found that leaks in the blood vessels of the spinal cord precede damage to the nervous system in ALS in mice with the SOD1-related form of the disease.

Berislav Zlokovic at the University of Rochester and colleagues, who published their findings in the April issue of Nature Neuroscience, found that mice with mutated SOD1 genes had disruptions in the barrier between the spinal cord and bloodstream that normally protects the central nervous system from toxins and injury.

In these mice, the blood-spinal cord barrier was disrupted because of reduced levels of three of the so-called “tight junction” proteins that normally keep it together, the investigators noted.

The disruptions resulted in inflammation, as well as reductions in blood flow and, in some areas, small hemorrhages with release of toxins.

The researchers said their study demonstrates that an increase in the permeability of the spinal-cord blood vessels probably makes an important contribution to degeneration of the muscle-controlling nerve cells (motor neurons), which is the hallmark of ALS.

They also noted that damage to these blood vessels is among the earliest events in a “toxic cascade” set in motion by SOD1 gene mutations. (Research published last year showed damage to these blood vessels in mice with SOD1-related ALS, but the investigators couldn’t determine whether the damage came before or after damage to nerve cells.) “Genetic or pharmacologic interventions targeted specifically to the endothelium [lining of blood vessels] will help to determine both the causality between the blood-spinal cord barrier leakage and motor neuron degeneration and how such damage may [affect] disease onset and/or progression,” the researchers note. (The University of Rochester Medical Center says the team is currently testing a compound that may help seal leaky blood vessels.)

A caveat is that these experiments were conducted in mice with SOD1-related ALS. Their meaning for ALS resulting from other causes (the most common kind) isn’t known.

Fighting for Benefits & Coverage

by Alyssa Quintero

Getting benefits and coverage from insurance companies and federal programs shouldn’t have to be a battle, but sometimes it is. To win, it pays to know every detail of your policy and benefits plan like the back of your hand.

Understanding the plan’s policies, benefits and eligibility criteria before you file a claim can save you a denial and some headaches in the long run.

And if you’re denied, knowing your policy will enable you to make a stronger appeal by referring to specific sections, or reciting actual language in the benefits plan.

Some basic tips:

• Read the insurance and benefits plan carefully.
• Understand the eligibility requirements in order to continue receiving full benefits.
• Understand any specific requirements for filing an appeal, especially the number of days you have to file an appeal.
• Consider submitting forms and letters via certified mail to ensure they arrive in the correct place and on time, and to have a record of your correspondence.
• Keep a log of all contact, and be sure to jot down dates of phone calls and names of people with whom you’ve spoken, and keep a file of sent e-mails and subsequent replies.
• Follow up. Don’t wait a month before calling again or sending an e-mail or letter. Be persistent!

It’s all in the language

The language used in physicians’ letters of medical necessity and appeal letters can mean the difference between approval and denial.

Certain words or language may trigger either coverage or denial, so focus on the medical issues behind a request. Some doctors don’t mind if you draft a letter of medical necessity, and get his/her approval and signature.

It’s important to do your homework, says Martin Burkhardt of Baldwinsville, N.Y. Burkhardt, 66, is in the process of waiting for Medicare to approve his doctor’s request for a power wheelchair. His doctor submitted a lengthy, detailed letter explaining the medical necessity of a power wheelchair, and his staff included relevant reports about his condition, as well as a copy of the doctor’s notes and a prescription.

Set out to prove medical necessity from the get-go; don’t wait until your claim is denied. However, if you receive a denial letter, your doctor and his staff may be able to help you sort through the reasons why a claim was denied, and help rewrite the letter to ensure a better chance of being approved the second time.

While you’ll encounter doctors who’ve written letters of medical necessity several times over, don’t take it for granted that they know best.

The doctor must make a stronger case than the person at the insurance company who’s reviewing your file. The point is to make it hard for the insurance company to say no a second time.

Adele Abramowitz, whose son Jason has Duchenne muscular dystrophy, says that every piece of equipment he uses initially was denied, but the denials eventually were reversed and approved.

“I appealed and got Jason’s doctors to write letters. If they felt that they couldn’t write the appropriate letter, I wrote the letter, and had them read and sign,” Adele Abramowitz says.

“It’s sometimes not what you ask for but how you ask for it. If you ask for a shower chair, you will not get it because it’s not medically necessary to take a shower. But, if you ask for a commode rehab chair, you’ll get it. It’s all in the language.”

Unfortunately, you can’t make one call and expect someone else to do the work for you.

“Don’t take no for an answer the first three times, and if you get denied, request documentation to show why you don’t qualify for a program or service,” Abramowitz recommends. “Get written proof, and ask to see where it says in the program’s regulations that you don’t qualify.”

I’ll see your denial and raise an appeal

It can be useful to explain the progression of the disease in the letter, because it’s not certain the person reading the file is knowledgeable about ALS.

Mark Airel, 43, of Liverpool, N.Y., was denied four times for a power wheelchair before he finally was approved for a Permobil C300 with tilt and recline.

“The insurance didn’t think he needed it at the time,” says Mark’s wife, Patti. “Once the doctor wrote out all of the terms explaining Mark’s progression, especially that his legs were weakening, and said that he’d need it soon, that took care of it. The doctor explained that with the progression of ALS, Mark may walk one day, and he may not be able to walk the next day.”

Patti says that insurance companies “really don’t understand the progression of ALS.” For instance, the insurance company said it needed more scientific proof that a power wheelchair would benefit someone with ALS. So, in his e-mails to the company, Mark included the definition of ALS in every message.

In more specific terms, the doctor wrote another letter of medical necessity, explaining that Mark needed a power wheelchair instead of a manual chair because he can’t use his arms, and he needs trunk support.

“Make sure the doctor says exactly what he means, and make sure he spells it out in language that a child can understand,” urges Patti Airel.

Danny Dandignac of Leander, Texas, received a diagnosis of ALS in 2000, and he advises people with ALS to always challenge denials from private insurance or government programs like Medicare and Medicaid.

“They make their profit by denying you services,” says Dandignac, 49. “They rely on the fact that more than half the patients that are denied never call them on it. You might have to appeal several times, but there are avenues available. Knowing what you’re entitled to is your best friend.”

Dandignac suggests anticipating that the insurance company will deny the most expensive items or attempt to replace them with cheaper items. That way, the letter of medical necessity covers all the bases with very specific information and details.

If you threaten a lawsuit against a private or government insurance program, proceed with caution. Lawsuits are pricey and lengthy, and it may not be worth it in the long run. And if you’re bluffing, be prepared for the insurance company to call your bluff.

One strategy is to copy your attorney or legal advocate on appeal letters and all other written correspondence with the insurance company — a subtle approach that may grab the company’s attention.

Finding help

If nothing else works, contact your state department of insurance, which offers resources for consumers. You can file a request for assistance in resolving an insurance problem, as well as file a complaint against an insurance company.

Your state’s Protection & Advocacy System (P&A) also has the authority to provide legal representation and other advocacy services for people with disabilities.

And, if you’ve been denied a claim for assistive technology and other related durable medical equipment, many P&As help people obtain AT devices and services through the Protection & Advocacy for Assistive Technology (PAAT) programs.

When hiring a private attorney, find one who specializes in disability-related issues. An elder-law attorney can help you wade through confusing insurance policies and federal benefits programs. The National Academy of Elder Law Attorneys offers a searchable state directory of member attorneys, including those who are certified elder-law attorneys (CELA). To learn more about other legal aid programs, see “It’s All in the Plan,” October 2007.

Local Agencies on Aging and Aging & Disability Resource Centers also can provide benefits counseling. While they can’t provide legal assistance, staffers will examine your case, find out what’s missing from your appeal and provide advocacy services.

Could This Happen To You?

by Sally Coffin

Did you know your insurance company can change and even revoke the care you’re getting? What you think is covered can be changed without warning. That’s just what happened to my 48-year-old son, Gene, last December.

Gene’s Story

Gene Coffin

In 2001, Gene was diagnosed with bulbar-onset ALS. He came to live with me in 2006. Gene is ventilator dependent and only can move his eyes. He uses a feeding tube and catheter, and depends on registered nurses (RNs) for all his physical needs, 24 hours a day, seven days a week.

We’ve managed to keep Gene alive and at home because of this RN care. Without it, he would have to move hours away to an out-of-state nursing facility that accepts people on ventilators. Gene is doing well for someone with such a serious illness. His mind is completely alert and his heart is strong. My son always has been identified in his medical records as being “full code.” In other words, Gene opts to be resuscitated should his heart stop.

On Friday, December 7, at 4:30 p.m., I got a call from Blue Cross Blue Shield (BCBS) saying that Gene’s nursing care had been revoked. We still aren’t sure why they came to this decision. We do know that Gene’s 24/7 care is covered under BCBS’s hospice benefit. And we know that in November 2007, BCBS reviewed Gene’s case, and Gene said he still wanted to be full code. I guess bells started ringing at the insurance company at this time.

Gene’s care was turned over to Elder Independence of Maine (EIM), the state agency that administers home care through Medicaid. EIM provided Gene with only 28 hours a week of RN care. The remaining 140 hours each week would be covered by licensed practical nurses (LPNs) and personal support specialists (PSSs), who have lower levels of training than RNs. For example, they’re not trained in patient assessment, an essential aspect of caring for a person with ALS.

This meant training many new caregivers. My son only can respond to “yes” or “no” questions by moving his eyes. Removing the qualified caregivers who knew how to interpret his needs and make appropriate interventions was enormously stressful. Gene’s medical condition went into a downhill slide. It was a nightmarish time for all of us.

The appeals process

We immediately began the appeals process. This included identifying all the tasks the RNs did to keep Gene stable and out of the hospital. We also contacted the Maine Bureau of Insurance and the offices of our senators and governor. Each of these offices contacted BCBS to learn more about their actions.

While the appeals process went ahead, BCBS temporarily reinstated Gene’s RN coverage. This helped ease some of the awful tension.

By revoking RN care, BCBS put Gene at risk of needing institutionalization, which obviously would cost them much more in the long run. This was one of the main points we made in the appeals process.

After months of effort and with the input of Gene’s doctor, BCBS announced in February they were reversing their decision and approved RN coverage for the next 12 months.

As you can imagine, this was an enormous relief. Even now, when I think about what we went through because of some mysterious machinations on the part of the insurance company, I get very angry. Gene and I don’t want this to happen to anyone else struggling with one of the cruelest diseases on earth.

How to make sure Gene’s story doesn’t become your story

One of the best things you can do is have a detailed understanding of what’s covered in your health insurance policy. Don’t wait for the insurance company to tell you what’s covered.

Be aware of the requirements for eligibility. Because we still haven’t gotten a clear answer from BCBS about their actions, we only can guess at the reasons. We assume it was because Gene was listed as a hospice patient but still had full-code status. It’s possible they were clutching at any excuse to stop his coverage. But there’s nothing in Gene’s policy that states that full-code status precludes eligibility for hospice coverage.

As stressful and traumatic as this experience was, it’s ended, for now, with Gene’s services intact. This wouldn’t be the case had it not been for the efforts of our legislators, governor’s office, and Maine Bureau of Insurance. Without them, we could have been caught in the appeals process for a long time. We’re forever grateful for their support.

Sally Coffin is the mother of Gene Coffin, 48, of West Bath, Maine, a former construction business owner and commercial fisherman, with a wide range of interests and a passion for NASCAR. Gene and his mother want to create a ventilator-friendly care facility in Maine “where ALS patients can live with dignity and kindness in a loving, caring atmosphere and where friends and family can still be part of their lives and help them maintain as normal a life as possible.”

Tips for Tackling Depression
Recognition and treatment are key

by Amy Labbe

A bout of depression can bring added difficulty to a life already complicated by ALS. To keep depression from bringing you down, check out these 10 tips — culled from a variety of expert sources — for understanding, spotting and stopping it.

1. A common misconception about depression in people with terminal illness is that in such situations depression is “understandable” or “normal” and nothing to worry about. In fact, studies have shown that most people with late-stage ALS aren’t depressed. Identifying and treating depression, rather than accepting it as “normal,” can have a tremendous positive effect on quality of life.


2. Depression may be a result of suffering; it also may cause it. Untreated depression can reduce the effectiveness of the immune system and lower the pain threshold, leading to even more difficulties.


3. Depression is treatable, and those who receive early diagnosis and treatment tend to have better outcomes than those who wait.


4. Sometimes it’s difficult to distinguish between the symptoms of depression and other emotions, such as grief. Determining what’s actually going on is important for finding the right treatment. A doctor or counselor can help.


5. It also can be hard to distinguish the cause of physical symptoms such as fatigue or sleep difficulties, which may be caused by depression or by ALS itself.


6. Feeling unable to make a contribution to the world can be depressing. It’s important to find new ways to maintain connections and engage with others, such as through consulting, tutoring, music, painting, journaling, and seeking social outlets such as visiting with friends and attending church, club meetings and sports events.


7. Fear can trigger or exacerbate depression and must be identified and addressed. Common fears include: abandonment by family members who the patient feels may be overburdened by the disease; fear of the unknowns involved with the disease; and fear of death and ideas of an afterlife.


8. Some find relief from depression through simple life adjustments — communicating with family and friends, seeking out the positives, enjoying nature, finding ways to stay socially active, and relaxation or meditation exercises.


9. Effective treatment of depression may involve psychological and spiritual support, such as professional or pastoral counseling. Also included may be drugs such as selective serotonin reuptake inhibitors (SSRIs) including citalopram (Celexa), escitalopram oxalate (Lexapro), fluoxetine (Prozac), paroxetine (Paxil) or sertraline (Zoloft), or tricyclic antidepressants such as amitriptyline (Elavil).


10. Each individual’s unique circumstances should be taken into account when selecting medications to control depression — including the desirability of certain side effects. Not all side effects are bad. For example, the SSRIs are known to have an analgesic effect, which may help reduce pain. One of the side effects of the tricyclic antidepressant amitriptyline (Elavil) is reduced saliva production, which can help those having difficulty controlling their oral secretions.

He Takes His Mountains One at a Time

by Bill Norman

Most people, upon learning they have ALS, begin to take life slower. Felix Slamovics climbed mountains and skyscrapers.

Slamovics uses a hybrid climbing apparatus incorporating bicycle parts and mountain rescue equipment. A climbing buddy, on his own rig, checks Slamovics’ condition.

Climbing wasn’t new to the 45-year-old Israeli citizen and resident of Tel Aviv. He was one of that country’s foremost rock climbers for more than 25 years. The difference was climbing with ALS.

When Slamovics received his ALS diagnosis in 2002, he reacted to it with the same aggressive embrace he bestowed on vertical rock walls.

“I climbed in many European countries. Straight walls, preferably with an overhang, were my favorite,” he said in a telephone interview.

And he preferred to climb unbelayed, that is, without a safety rope to catch him if he fell. “You have to know what you can and can’t do,” he wryly observed. “People who don’t know that don’t grow old.”

Visit www.felixproject.org to see photos of Slamovics climbing. The site opens with the question, “What is stronger? Fear? Or hope?” Climbing, according to Slamovics, is “a meditative state in which man unites both with himself and the mountain above him [and] the fear disappears.”

Slamovics knew he wanted to continue climbing as long as he could, but as ALS sapped his strength and dexterity he had to improvise.

Enter the ‘Harley Felixson’

In 2005, Slamovics made a partial ascent of El Capitan, a forbidding bastion of stone in Yosemite Park in California. In 2007, he climbed the 614-foot Azrieli Tower building in Tel Aviv.

In both cases, he used a homemade contraption dubbed the “Harley Felixson” that incorporates bicycle parts and mountain rescue equipment. With a ventilator strapped to his face, suspended in a harness, feet dangling, “pedaling” with his hands, he propelled himself up a rope, scant millimeters at a time. A clamping device prevented backsliding, while two bicycle wheels affixed to a horizontal axle behind him kept him from banging into the climbing surface. His climbing buddies accompanied him on their own ropes, to keep an eye on his condition.

“That building [Azrieli Tower] is all mirrored windows, and it was a hot day. I felt like I was in a toaster,” he recalled. “My lung capacity at that time was only 11 percent, and my ventilator was blowing really, really warm air into my nose.”

That laborious haul took him nearly six hours to complete. Even the iron-willed Slamovics said he would not have made it except for one thing: Television crews followed his ascent, enabling him to call public attention to ALS and the importance of finding a cure.

Travel via voice control

With a ventilator strapped to his face, Slamovics patiently inches up the face of a high-rise building.

Slamovics, who often lectures about what it has meant for him to live with ALS, travels in a power wheelchair and an adapted van, most of whose controls (for headlights, windshield wipers and gear changes) are voice activated.

“The voice control for the gears is the only one that makes me confirm that I really want to shift gears. Sometimes I get impatient and slam the thing into gear myself,” he said.

That dogged determination is what motivated him to set up a caving trip this summer, in one of Israel’s deepest caves, about 250 feet underground. He’ll be going “piggyback” in a cave rescue rig carried by friends who are experienced cavers. TV cameras again will follow their progress, as part of the Israeli ALS Research Association’s public awareness efforts (Slamovics is an executive member of the association).

“I asked some other people with ALS to join me, but they’re afraid, I think. I can’t understand why.” In the telephone interview for this article, from halfway around the world, it certainly sounded as if Felix’ face was wreathed in a mischievous grin.

Still the same inside

Slamovics teaches climbing techniques to kids — him in his chair, them on an artificial climbing wall. “When they first see me, knowing how many years I was a top climber, I can read their minds,” he said. “They think, ‘he must be sad and depressed.’ But then they hear me talk and they realize I’m the same guy I was before. What’s inside of me is the exact opposite of me outside.”

The tough guy now has decided he wants to wean himself off his ventilator, through a combination of exercises and yoga. Last year his lung capacity was at 11 percent; now it’s 20 percent, he said (he’s gone without wearing the vent for up to one-and-a-half hours), and he’s aiming for 100 percent. Two at-home caregivers, one daytime, one evening, help him shift positions as needed, whether during exercise or sleep.

He lays out his theory and his resolve. “As long as your brain is working, you’re not sick. I have a disability, not a disease, and this disability is going to have to work very hard to take me. I’m not going to cooperate.”

His e-mail signature quote says it all: “I can’t die; it would ruin my image.”