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Conference overview

Fourth International Family Conference deemed best yet by those who attended 

By most accounts, the Fourth International NBIA Family Conference was one for the record books: our best ever. 

From the speakers to the time set aside for families to bond, most of the 81 people who attended the conference from May 4 to 6 in Cincinnati, Ohio, gave the conference the highest marks of any we’ve held. 

Held at the Embassy Suites, individuals and families from six countries were represented: the United States, Canada, England, Germany, Iceland and India. Sixty percent had never been to a previous NBIA conference. Yet, we were united as one big NBIA family sharing experiences, support and information with each other. 

For the first time, the conference was organized so families could come a day early and meet privately with members of our Scientific & Medical Advisory Board and ask questions about their medical situation. We also had most of our BioBank blood draws done that day to make it convenient for families to donate. 

Dr. Susan Hayflick, a chief NBIA researcher who has been at every conference, was joined by other SMAB doctors attending their second or third conference:  Penny Hogarth, Paul Kotzbauer, Leslie Shinobu and Amy Sun. In addition to meeting with families, they held a board meeting on Friday to discuss priorities for research in the coming year. Allison Gregory, a genetic counselor who works with Hayflick at Oregon Health & Science University, also was on hand. 

Our keynote speaker was Pat Furlong, founder and president of Parent Project Muscular Dystrophy. Her inspirational talk motivated our group as she described how she became an advocate after Duchenne Muscular Dystrophy affected her two sons and ultimately, lost their struggle. She talked about taking her cause to Washington, D.C., and collaborating with other groups. 

NBIA parent Ron Stretter led our “Getting to know you session” that broke the ice and helped families bond and learn more about each other early in the conference. Ron was a first-time attendee at our 2005 conference and suggested this session to help families connect. 

He was followed by a fantastic group of speakers who led our sessions and spoke on panels. Many of them were doctors from the Cincinnati area who volunteered to come out on Saturday and Sunday morning to discuss such topics as deep brain stimulation, stem cell research and pain management. Hayflick and Kotzbauer, along with Dr. Lars Timmermann who came from Germany to speak on DBS, gave participants an update on their research. 

You can read articles about most of these sessions in this issue of the newsletter. 

Having the conference in Cincinnati where four board members live and two others have family proved a big plus in recruiting volunteers who helped with many aspects of the conference. We had nurses who volunteered on Thursday and Friday to draw blood, pet therapists who brought dogs and music therapists who played their guitars and sang in the child care room. 

We had a picnic on Saturday afternoon that was all done by volunteers. Family and friends prepared and brought all the food and came and shared it with us. We played games and won prizes and had a lot of fun. We decided to spend more time socializing this year to give families more opportunities to get to know each other. On the evaluations, everyone said the time was well spent. We expect to continue the tradition at our next conference. 

We hope to see even more NBIA families in 2009 and make it better still.

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Deep Brain Stimulation draws intense interest at conference

Some NBIA parents, worried about seeing their children lose basic motor skills, are starting to wonder whether Deep Brain Stimulation (DBS) might be the answer. 

Although DBS is showing promise as a therapy, there are too few cases to draw any final conclusions about its effectiveness, Dr. Lars Timmermann, director of the Movement Disorders and DBS program at University Hospital in Cologne, Germany, said at the Fourth International NBIA Disorders Association Family Conference. 

Timmermann proposed a study of past and future DBS patients so that an international database showing the progress and outcomes of patients who have had the procedure is available. 

Hoffnungsbaum e.V., our sister organization in Germany, awarded a $15,000 grant to Timmermann to begin this study. The data would look at neurological outcome scales, but even more at patients’ quality of life after surgery and help doctors, parents and affected individuals decide whether DBS might be worthwhile. 

An international rating scale can be adopted to uniformly evaluate the progress of patients who have DBS, Timmermann said. The goal is to set up a standardized treatment plan for doctors to follow to get best results for NBIA individuals. 

“Pooling worldwide expertise is very essential,” said Dr. Penny Hogarth, a neurologist and researcher of NBIA and Parkinson’s disease at the Oregon Health & Science University. 

Although extremely rare in well-trained centers, DBS is not without risks, Timmermann said. The most severe is bleeding in the brain. Other surgery risks include infections, seizures and an allergic reaction to implanted materials. Side effects of the surgery may include increased dystonia and speech problems like whispering (dysarthria) and trouble forming words (dysphasia), which are usually reversible. However, Timmermann stated, the total number of severe complications are in the range of 1-2 % and therefore in most cases acceptable if you can estimate a good or very good operation outcome. 

At the conference, Chris and Michelle Frederick of West Liberty, Ky., said their daughter, Madison, one of the youngest patients to have had the procedure at age 6, is a living example of what DBS can do for a patient who is cascading downhill. 

Madison, who colored in a book while her parents spoke about her at the conference, has made remarkable progress regaining motor skills she had lost to NBIA, her parents said. 

“Her therapists were astounded” by her improvements, Michelle Frederick said. “We are very happy.” 

Madison’s doctors were at the conference and also were pleased with her results. The vast majority of DBS patients are adults with Parkinson’s disease. Consequently, they usually are awake during the procedure, something that wasn’t done for Madison because of her age, said Dr. George T. Mandybur, a neurosurgeon at the Mayfield Clinic and the Neuroscience Institute in Cincinnati. 

Doctors also normally do the procedure in two steps, with the second step involving an operation to install the battery pack that operates the electrodes that stimulate the brain. But in Madison’s case, everything was done during a single visit to the OR, while she was put under anesthesia, he said. 

After she woke up, she “looked awful,” her mother said. Her head was shaved and she looked so pale. When she asked her daughter what hurt, Madison simply said, her IV. 

She recovered well and “was a different child,” Michelle Frederick said. 

Another parent at the conference, Veronica Bonfiglio, of Fremont, Calif., who appeared on the panel with the doctors, said her 14-year-old son Brent had the surgery and “it hasn’t been a miracle.” 

But she also believes DBS halted a fast decline in his condition. When the stimulator accidentally gets turned off, he gets worse very quickly, she said. As soon as it is turned back on, he regains his skill level right away. 

Brent’s device was turned off three times in the past 16 months, Veronica said. Once he was playing with magnets, which is an obvious no-no, and Veronica caught the problem immediately. But the other two times remain question marks. 

Veronica speculates that the device could have switched off when Brent entered a store with an anti-theft alarm system. Now, she always checks him when they get home after such visits. Also, as a precaution, Brent gets checked once a week – it only takes 2 seconds and Brent can do it himself - to make sure the stimulator remains on. 

The device for checking that is called the Therapy Controller and is slightly larger than a computer mouse. It can be carried in a purse or backpack, Bonfiglio said. 

Some of the most popular DBS systems cannot alert the person or family member that the device is off. Kris McGourthy said her son Michael’s device does not have such an alert. If she thinks that there might be a problem, she makes sure to turn on the device, not knowing for sure if it already is on. 

Why would anyone get such a model? It allows for some adjustments to the stimulation parameters that Brent’s model doesn’t, and it has other features that some patients find more desirable. 

Overall, DBS has been helpful for her son, Bonfiglio said.  “We think it has stabilized him,” she said. “We think it has made a big improvement in his quality of life.” 

DBS involves the placement of electrodes in the brain, which are attached to wires leading to a battery-operated neurostimulator implanted in the chest. The neurostimulator sends pulses to targeted areas in the brain and takes “off line” the part of the brain that is sending too many signals and causing the muscles to move in painful ways as they do in dystonia, said Dr. Donald Gilbert, director of the Movement Disorders Clinic and Tourette’s Syndrome Clinic at Cincinnati Children’s Hospital Medical Center. 

DBS seems to help with many of the writhing, twisting, dystonic movements of NBIA, Hogarth said, but it doesn’t seem to do as much for balance. 

Bonfiglio saw her son’s dystonia and coordination improve the most since DBS. It did not seem to help as much with his speed in doing such things as tying his shoes, writing and walking as he is still slow when performing these activities. 

 “We don’t think this (the surgery) is affecting the degeneration, but this is restoring function,” Timmermann said. 

When the question was asked on whether turning off the battery pack for the stimulator at night when sleeping to conserve battery life (they need to be replaced every 2-3 years) was a good idea, doctors advised leaving the stimulator on overnight and when the patient is resting for optimal results. 

Improvement can be subjective, Dr. Fredy Revilla, a neurologist and head of the Movement Disorders Division at the University of Cincinnati, said. Some patients had to turn off stimulators to be convinced of how much the surgery had helped them. 

On the other hand, “sometimes, we don’t see much improvement, and patients say they see a lot,” Revilla said. 

Bonfiglio offered a list of questions she suggested parents ask before they consider a surgeon for DBS. They included asking about surgical problems the team might have encountered during DBS to asking surgeons whether they use any experimental devices when performing the procedure. 

McGourthy, who was not on the panel but provided a before and after DBS video for those interested to view, offered suggestions later and said it is important to have a good relationship with the doctor who does the adjustments to the device. “This is who you see the most,” she said. “It’s also important that they are willing to listen to the other doctors that are doing adjustments for NBIA patients.” 

Bonfiglio said it is very important for the parents and patients to understand that nobody knows for sure what will be the best settings for each person, so anyone who has the procedure should be prepared for a lot of “troubleshooting.” 

Brent has had a lot of ups and downs, and, fortunately, Bonfiglio said, Timmermann seems to have identified some guidelines for patients with the PKAN form of the disease so it will be easier for future cases. 

After speaking with Timmermann at the conference, Bonfiglio said: “We already made one of the changes he suggested, and we noticed a small but clear improvement. We are very excited to continue his protocol and see where it will lead us.” 

Veronica Bonfiglio suggested these questions to ask doctors regarding DBS surgery: 

Before the Surgery:

How to prepare him for surgery?

What tests are performed before surgery?

What are the potential risks and benefits?

What is the probability of improvement in motor control functions? (walking, balance, gait)

How does the operation affect the cognitive abilities?

Anything special we should know before the surgery?

Is he a good candidate for this procedure?  What is the criteria for patient selection and the targeting techniques to increase the likelihood of a successful surgery? 

If we do the surgery there, and months later there's an unforeseen adjustment need, do they have any type of agreement with a local physician?

About the Surgery:

What can we expect on the day of surgery?

How long does it last?

Is any part of it painful?

How do you perform the procedure?

How long is the hospital stay?

How long is the recuperation period?

Do you use devices which are at the experimental stage?

How do you reach the best compromise for accuracy vs. speed in the surgery?

Are there any side effects and if so, what are they and can they be controlled?

Surgical team:

What is the surgeon’s training and how long has he/she been performing DBS?

Who is on the surgical team? How long has the team worked together?

Are there back-ups for each doctor on the team?

What are the diagnostic evaluations? (MRI, Full physical exam, EKG, chest x-ray, cardiologist work-up, PET scan, neuropsychological and cognitive evaluations)

Does the team do stereotactic procedures?  How many have they done?

What type of surgery does the team specialize in? (STN, VIM or GPI)

What are the statistics of the team?  Have they encountered problems with hardware failure, incorrect placement of the electrodes, bleeding, infections, stroke or seizures?

For the specific complications that your team encountered:

1. Is the cause well understood?
2. Were they recoverable/reversible?
3. Is a procedure in place to avoid a similar occurrence?

What is the follow-up protocol? 

How are follow-ups scheduled?

Are there provisions for immediately needed appointments?

After the surgery:

What happens after surgery?

What is the procedure and scheduling for programming the stimulus?

What medication will he need after surgery and for how long?

How long after surgery do symptoms improve?

How long does the battery last?  How easy is it to replace (hospitalization, surgery, scars)?

What are the risks of infection following surgery related to the everyday environment?

(crowd, places, pets, amusement parks, x-rays, travel, metal detectors, etc)

What activities can be risky after surgery? Are there any forbidden activities after the treatment?

What precautions to take? How should we be prepared at all times?

Adjustments/medications:

Where do patients need to go for adjustments?

Who does the adjustments?

How do you select the frequency for the stimulator?

How often can adjustments be expected?

Who supervises the medications (if any)? 

Who coordinates the meds with stimulator adjustments?

Who prescribes additional or different meds when needed? 

If patients have special problems and questions regarding DBS in NBIA individuals, Dr. Timmermann offers that he can be contacted via his email lars.timmermann@uk-koeln.de or phone +49-(0)221-478-7494/7231.

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Pain considered the ‘fifth’ vital sign and hard to treat in NBIA patients 

Will your pain-stricken child become addicted to narcotics? Does everyone on Baclofen eventually build up a tolerance to it? And how effective is Botox for muscle pain? 

Two doctors speaking at the May NBIA conference in Cincinnati addressed those issues head-on in their discussion of how to treat pain in NBIA patients. 

“Some parents see pain as an opportunity to develop coping skills or an opportunity to build character,” said Dr. Mark Meyer, a staff anesthesiologist and an attending physician in the Division of Pain Management at Cincinnati Children’s Hospital Medical Center. “But untreated post-operative pain is not the way to do it.” 

Meyer, who also cares for patients in a pediatric hospice program at Cincinnati Children’s, believes surgical interventions can be a part of palliativecare. Calling pain the “fifth vital sign,” he believes in treating pain as comprehensively as possible. The trouble is, pain is hard to access and treat in certain patients, especially when the person has a disease as confounding as NBIA or when the patient is a 2-year-old, he said. 

While strong pain medications can have side effects and complications, Meyer said, these problems can be minimized when actively managed by physicians. 

Baclofen, which is given to help reduce the pain of twisting and other abnormal movements, can also be helpful, he said. Despite what some people say, it’s not true that every patient on Baclofen eventually becomes resistant to it, said Dr. Penny Hogarth, a neurologist and an assistant professor at the Oregon Health & Science University. It can be a long-haul treatment for patients, and she suggested that gathering data on its use in the NBIA community would be a way to help gauge its effectiveness. 

As for Botox, which comes from the botulinum toxin and also is used to relax muscles, resistance to it is a real phenomenon, Hogarth said.  As a result, that treatment could lose its effectiveness over time because the body makes antibodies to combat the toxin. 

Overall, Hogarth and Meyer said, treating pain remains a challenge for NBIA doctors and patients.

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NBIA research sparks links to other labs, better known diseases 

The discovery of a second NBIA-related gene in 2006 has opened up new collaborations and new research frontiers, scientists reported at the Fourth International Family Conference in Cincinnati, Ohio. 

Fundraising by families continues to play a key role in ongoing research and provided crucial seed money that led to the latest gene discovery, said Dr. Susan Hayflick of the Oregon Health & Science University. 

“It reminds us of why we come to work everyday,” Hayflick told about 80 conference participants who gathered from around the world in early May. “We are trying to beat this thing.” 

A clinical test is now available at the OHSU DNA Diagnostic Lab to help families determine their chances of passing NBIA to their children if they have the second gene, known as PLA2G6. 

Hayflick’s lab worked with researchers from the University of Birmingham School of Medicine in the United Kingdom and from the University of California San Francisco to identify the gene, and those scientists continue to collaborate on research now underway. 

Mouse studies are helping to reveal the NBIA disease process and will also be used to test new therapies. In one area of research, UCSF scientists removed B5 from the diet of healthy mice and the animals developed dystonia, a common symptom of NBIA, Hayflick said. 

Dr. Paul Kotzbauer, a neurologist and researcher at Washington University in St. Louis, and Lars Timmermann at University Hospital in Cologne, Germany, also are among those collaborating on NBIA research. 

Kotzbauer has been studying mice with mutations in the PLA2G6 gene to examine changes in brain function that may be similar to those that occur in NBIA patients. He also noted that the same Lewy bodies – fibrous protein deposits in nerve cells – that are seen in the brains of Parkinson’s patients also can be found in NBIA patients. 

The connections between NBIA and Parkinson’s as well as Alzheimer’s disease have become more apparent since the discovery of the PLA2G6 gene. 

 “I can argue in grant applications to the NIH,” Kotzbauer said, referring to the National Institutes of Health, that NBIA “is important to study…because what we learn can be important for Parkinson’s disease and Alzheimer’s disease.” 

Pointing out such links can be increasingly important because money from the NIH, the federal agency that funds much of the nation’s medical research, is declining, Hayflick said. 

Timmermann is studying Deep Brain Stimulation and wants to learn more about how effective it is for NBIA patients. The data, while promising, is sparse. 

Timmermann is seeking participants for a study so that he can follow patients having the procedure and see how they fare a year or longer after the procedure, he said. Such data could help parents and NBIA individuals make more informed decisions about whether to seek the procedure. (See article on DBS, page XX.) 

All of the research costs money, and the NBIA Disorders Association has provided eight $30,000 grants since 2003 and expects to award one or more this year, thanks to member-sponsored events.

Without the seed money from family fund fundraisers and other NBIA member-sponsored events, Hayflick said her lab might not have been considered for additional federal grants needed to move her work forward.  NIH grants are more competitive than they ever have been in her career, she said, and she is convinced: there are more NBIA-related genes waiting to be discovered.

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Stem cells might offer treatment to NBIA patients--someday, doctors say 

Stems cells have been debated for years by politicians, ethicists and the religious community, but will the day ever come when these special cells with seemingly magical properties are used to cure people with severe illnesses like NBIA? 

A panel at the recent NBIA conference in Cincinnati discussed the ways stem cells are already being used—and might be used someday—to help conquer diseases, including NBIA. Congress has approved expanding stem cell research, but President Bush has pledged to veto the any such bills. Some states, including California, are taking matters into their own hands. They’re passing legislation allowing researchers to create new cell lines and study them. 

Embryonic stem cells show the greatest promise for taking on the characteristics of other cells in the body and, thus, being able to heal diseased tissue and organs. But they also are controversial because the cells come from embryos that could have sustained life. Adult stem cells are found in the body, and while using them is not controversial, they are not believed to be as flexible or as useful as embryonic stem cells. 

Already, stems cells from bone marrow are being used to treat cancer, said Dr. David Williams, director of the division of experimental hematology and attending physician in hematology/oncology at Cincinnati Children’s Hospital Medical Center. Stem cells from cord blood are used to treat 40 diseases, he said. 

Cord blood banks, such as ViaCord in Cambridge, Mass., will store a newborn’s umbilical cord blood in the event the stem cells are ever needed for potential therapeutic use, said Mindy Lind, an account business manager. ViaCord, in business since 1993, does medical research and its scientists are looking into using stem cells to treat certain types of cancer and blood disorders.

The unique stem cells in cord blood have the ability to develop into white blood cells, red blood cells and blood platelets, which could offer hope to cancer patients, Lind said.

Whether stem cells will prove to be a useful therapy for a range of illnesses, including NBIA, remains to be seen, Williams said. “We’re a long way from many of those” therapies, he said, adding that the only way to reap the potential of stem cells is through advocacy for more research funding.

People affected by serious illnesses, disease organizations and others interested in stem cell research have a variety of ways to get their voices heard, said Jennifer Hobin, science policy analyst in the public affairs office at the Federation of American Societies for Experimental Biology.

As Congress, the White House and state legislatures wrestle with stem cells, Hobin offered the following suggestions to conference participants who want to be stem cell advocates:

• Write letters to the editor or op-ed pieces and submit them to your local newspaper.

• Call or write your elected representatives in Congress and the state legislature and state your position on stem cells.

• Be specific and mention any pending legislation.

• Keep your message simple.

• Make your message relevant to the current debate.

• Avoid jargon.

• If you have a personal stake (a family member affected by serious illness, for example) share it, if you feel comfortable doing so.

• Be nice!

• Additional resources are available from Hobin’s organization at www.faseb.org.

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A two-day marathon of blood giving during the Fourth  International Family Conference in Cincinnati provided the first opportunity to collect samples for the NBIA Disorders Association’s BioBank in the United States.

The collections follow a similar activity by our sister group in Germany, which obtained 22 samples from nine NBIA families at its third Family Conference in November. The combined efforts bring the samples in our BioBank to 101, representing 33 NBIA families. These families come from all over the world, including Canada, England, France, Germany, Iceland, India and the United States.

Although many families have donated blood in previous years, the new samples were necessary because the prior ones went to the registry at Oregon Health & Science University. They have been depleted by research. Faced with the choice of sending a miniscule amount of blood to the BioBank, the NBIA Disorders Association chose to collect new samples. It wants all NBIA affected individuals and immediate family members to donate to the BioBank, created by the Genetic Alliance, an umbrella organization for groups representing rare diseases.

The NBIA Disorders Association is a founding member of the Genetic Alliance BioBank, which provides storage facilities and support to organizations like ours. The NBIA Disorders Association’s BioBank collects, stores, processes and distributes biological samples to aid in research. The BioBank has the potential of collecting and storing many types of samples, such as blood, tissue, cells and DNA, from NBIA-affected individuals and their immediate relatives.

These biological samples, along with medical information from individuals with NBIA and their relatives, are essential for studying NBIA. The samples and information can be used to help researchers find other gene mutations responsible for NBIA and conduct research that will explore the causes of and potential treatments for NBIA.

Researchers interested in studying the samples submit proposals  to the NBIA Disorders Association’s Scientific and Medical Advisory Board. That board reviews the proposals and determines which ones merit approval.

At the association’s Cincinnati conference, collecting the samples was a remarkable endeavor on the part of many people. Thanks to the families who meticulously completed the many consent documents and clinical history forms. Their cooperation is greatly appreciated

On a personal note, it was a pleasure to finally meet all of the families with whom I corresponded before the conference. Fellow board member Susan Laupola coordinated the efforts of the phlebotomists; she and her staff were extraordinary and deserve much credit for their expertise.

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