Facial Pain Research Foundation

Facing My Facial Pain

Tiffany Lynd

By Hanna Shae Smith

Hanna Shae Smith is a writer for the Facial Pain Research Foundation, award-winning journalist, student clinician, and daughter of a person with Trigeminal Neuralgia. Smith lives in Phoenix, Arizona, where she studies chronic pain neuropsychology and neuroscience, teaches emergency basic life support, and volunteers doing search and rescue/recovery.

Tiffany Lynd was only 18 years old when she first experienced the pain of Trigeminal Neuralgia. Eighteen, at the precipice of the rest of her life. Eighteen, anticipating all that could be subsequent. Lynd dreamed of working in sports – never that she would begin experiencing symptoms of facial neuralgia her senior year of high school.

The pain began on the lower, left side of her face and is described as “stabbing” and “sharp” – like an icepick or burning rod stabbed into her cheek. Lynd was examined by local physicians in her small Ohio town, however, was told at the time that it was unlikely she was experiencing Trigeminal Neuralgia.

“Everyone kept telling me, ‘you’re too young,’” Lynd says, a response which prompted visits to neighboring cities for consultation with specialists.

It was an oral surgeon first spoke the words that would change her life forever: Trigeminal Neuralgia.

“It changed my whole life,” she says. “I didn’t go to college because of it. It just changed the whole course of my life.”

The time span between first symptom onset and diagnosis was 1.5 years. Prior to her symptoms, Lynd was entirely unfamiliar with chronic pain disorders. She took to the day’s prominent social media platform Myspace, seeking connection with those who could empathize over a shared diagnosis, and was grateful to find a couple such individuals. However, in a time when the internet was not the well of information it has since developed into, Lynd relied on public libraries for literature on her illness – a search which yielded few results. So began her journey for knowledge and relief.

TREATMENT JOURNEY

Lynd’s diagnosing oral surgeon initially prescribed pain medication and she was subsequently given the nerve-pain-reducer/anticonvulsant Carbamazepine from an emergency room doctor. However, Lynd soon discovered that not only was she allergic to Carbamazepine, but also muscle relaxant Baclofen and nerve-pain-reducer/anticonvulsant Topamax. Although Lynd was prescribed anticonvulsant Gabapentin for several years, she ultimately made the personal choice to stop taking the pain medication after it stopped providing relief.

She now only takes her thyroid medication and blood pressure medication whenever she has a pain flare. Additionally, she has taken Fentora, a pain medication. The prescription regularly costs $8,000 per month for 112 pills, however, a grant allowed her to receive it free of charge. That cost is for the 200 milligram pills and increases per milligram amount. To replace Fentora, Lynd and her doctors are researching medical cannabis, which is legal in Ohio.

“I have not tried it before,” she says. “My family doctor is all for it. … I’ve tried CBD oil where you just drink it. But, it just kind of relaxes you.”

Lynd says while she has had a largely good experience with insurance companies paying for procedures, receiving assistance for medication can often be difficult.

“They don’t want to pay for them or don’t think you need them,” she says.

Lynd has been seen at seven hospitals and has undergone 17 surgeries, her first being a Gamma Knife Radiosurgery in 2000, which provided relief for approximately 11 months. She was then seen at the Mayo Clinic where she underwent a microvascular decompression in 2002. Several compressions of the nerve were located at that time, leading doctors to believe that the disease occurred from congenital malformation and subsequent compression. Lynd experienced pain relief following her 2002 MVD for five years.

Following the return of her pain, Lynd underwent multiple Percutaneous Rhizotomies and MVDs. During one operation, the surgeon severed the sensory portion of the trigeminal nerve in an effort to achieve numbness of the face. However, the pain persisted and resulted in a diagnosis of anesthesia dolorosa – translated: “numb pain” – in which a misinterpreted pain sensation continues in the affected area despite the nerve’s touch sensation being either eliminated or diminished. Lynd subsequently underwent another operation in 2012 with the intention of entirely severing the motor portion and re-severing the sensory portion of the nerve. The pain, however, returned worse than before after approximately six months. Additionally, Lynd is now deaf in her left ear and blind in her left eye. She is unable to chew food and is only able to consume soft foods and liquids. Lynd says she now regrets severing the nerve considering how it has negatively impacted her specific, individual case.

COMING TO TERMS

Undergoing multiple surgeries in hopes of relief, only to have the pain return is indescribably challenging, Lynd says. There were times she did not know if she could go on.

“There’s no explaining when the pain comes back, the fear and frustration. You feel so let down,” she says. “I had a neurosurgeon who told my parents that, ‘she’s either going to kill herself or she’s going to accidentally overdose.’ But, I think through God and my kids, I got through.”

Lynd’s sons: 15-year-old Eli and 17-year-old Isaiah. Her voice comes to life when she describes them as her motivation, purpose, and reason for living.

“I don’t know where I’d be without them,” she says.

Lynd acknowledges that her children have been affected negatively by Trigeminal Neuralgia, yet she says she is grateful for their continued love and support.

“They tell me it’s made them better people,” she says.

It’s difficult for Lynd to pinpoint exactly how TN has changed herself, however, considering that it’s been part of her life for 25 years – and especially because symptom onset began at highly pivotal developmental age.

“I have lost a lot of memories [as the result of multiple operations],” Lynd says. “I don’t remember a lot. A couple of the surgeries were really rough afterward. I was in the hospital because of brain swelling. People will send friend requests on Facebook that I supposedly went to school with. I don’t know who they are anymore. … You may have known Tiff back then, but the Tiff now is Tiff 2.0.”

Lynd also sees in herself some of the same tendencies that young, frightened teenage girl employed for protection.

“I still push people away. In my mind, I’m protecting them,” she says. “I know that’s hard to let people see you vulnerable. A lot of times, people don’t know the situation. I feel isolated. Sometimes you feel people will look right though you.”

TN entirely rerouted Lynd’s life, forcing her to rediscover herself and set a new course. She aspired to work in the sports industry prior to her symptoms onset and instead had to adapt to jobs in which she would not be forced to talk for long periods of time – beginning initially as a realtor and later transitioning to loan processing and then a loan officer. She has learned to adapt to her situation. Lynd’s typical day starts when she sends the kids off to school. The rest of the day is spent staying busy to keep her mind off the pain. She is highly involved with the boys’ education and enjoys cooking and baking in addition to doing yoga and meditation to find a measure of mental and emotional relaxation. She is an avid sports fan – especially football and the 49ers – and enjoys attending games and playing basketball with her kids. Lynd is also a writer, composing poetry and keeping journals documenting her thoughts and feelings.

“It’s a good way to get my frustration out,” she says. “I went through a lot of different emotions. I deal with a lot of anger. Anger at the whole situation.”

Often, she has difficulty sleeping due to the pain and typically does not sleep well or through the night. Lynd keeps record of her attacks and says that she is “electrocuted” about 200-250 times per day. The burning sensation, however, never is mediated. Nerve blocks do not assist with the burning pain.

One aspect of Lynd’s personality which she knows if gone, is a carefree nature. Simultaneously, despite everything which has changed, she says TN has taught her to be deeply appreciative for what and who she has in life.

“I take advantage of the good days because they don’t come along very often,” she says. “The main thing that’s changed is that I never take anything for granted anymore. I am just so lucky and blessed to wake up and live the life I do every day.”

FACING THE FUTURE

Lynd experiences Trigeminal Neuralgia on a daily basis and continues to make plans for future treatment. She is currently scheduled for a motor cortex stimulation, which will be her 18^th surgical procedure since diagnosis.

“(The surgeon) said he’s done it on others who have had the nerve cut and they have gotten some relief,” she says. “He said, ‘I bet you’d take 10-percent relief.’ I said absolutely.”

Lynd also continues the nerve blocks which she receives every 2-3 months. The relief typically last about 5-7 days and does not touch the burning pain sensation. She says she is grateful for what relief she gets, however.

There have been excellent doctors in Lynd’s life, mingled with some who have made the situation more difficult. She encourages medical professionals to listen to patients, be honest, and become more educated on chronic pain disorders.

“They need to be more educated and not jump to conclusions,” she says. “Some of them are so rude. Listen and be more understanding. … I’ve been to the ER and had a doctor look at me like I’m nuts. It’s just frustrating.”

To family members of those with chronic pain, Lynd encourages expressing compassion even if empathy is impossible. Since day one when her TN symptoms began, Lynd says that her parents have stood by her side unconditionally and fought for her wellbeing.

“Without them taking me all over looking for answers, I don’t know where I’d be,” she says, adding that her brother is also both her committed supporter and best friend.

Lynd says her family may not always understand what she is feeling, but they still provide unconditional support in her times of need.

“Even though they tell me they don’t know what I’m going through, they’ve always been there and I know not everybody’s family is like that,” she says. “Just stand by them no matter what.”

This type of understanding, Lynd says, is critical to maintaining relationships. Due to a frequent lack of this relational aspect, she has lost friends along the way.

“I don’t go out much with them and they don’t understand why,” Lynd says. “I just don’t want to be in a situation where I’m out and I get a bunch of pains.”

Social media, on the other hand, has been critical in both maintaining and creating relationships, Lynd says. She fondly lists name of her TN family, other patients whom she’s met across the internet. They even attend each other’s surgeries and their children spend time together.

“Without the internet, we all wouldn’t have met,” she says.

The internet has also been pivotal for Lynd because of increased access to research – as opposed to the libraries she used to browse with difficulty at the onset of her symptoms. This is how she first discovered the Facial Pain Research Foundation. Knowing that someone is out there advocating for her, Lynd says, brings great comfort.

“There are really no words to express how thankful you are. I’m so thankful for everything they’re doing,” she says. “I know that they are putting a lot of time and effort and if they only knew how much they’re helping us.”

Hope is what Lynd hinges her future on, like so many others in her position. For Lynd, it is the key ingredient of daily life and the greatest admonition she would offer to the frightened 18-year-old girl she once was and all the others who find themselves in her shoes.

“Don’t ever lose hope. I have to believe there’s a cure out there,” she says. “They’re never alone.”

Michael Pasternak, Ph.D., is a Founding Trustee of the Facial Pain Research Foundation. Dr. Pasternak spoke with Mervyn Rothstein, who was an editor and writer at The New York Times for 30 years. Mr. Rothstein now writes the "Stage Directions” column for Playbill.com. His first symptoms of trigeminal neuralgia occurred in 2005.

Mervyn Rothstein and Michael Pasternak

MR: Michael, much has happened since our last interview, more than three years ago. What’s the status of the search for a cure for Trigeminal Neuralgia and related neuropathic pain? How many scientists are seeking a cure, in how many cities and countries? What are the ways your medical researchers are seeking answers, and how are they doing so? Please talk about the nine ongoing research projects to find the cure.

Our research is making great progress. Our first-ever research studies are the biggest leap toward finding the causes and lasting cures for Trigeminal Neuralgia in the last 1,000 years. But it’s complicated. Very complicated. Because in the old days, nine years ago, when we got started – January 9, 2011, when we had our first meeting, we hadn’t even started the research, the trustees came together and we made the goal to find the cure – it was all based on the belief that compression on the trigeminal nerve was the only reason for all Trigeminal Neuralgia.

But as we began to develop projects, and do the research, we discovered that there are other reasons as well. We know that trigeminal pain can also be caused by the myelin that sheathes the nerves being unhealthy and damaged. We know that there can be mutated genes responsible, genes that are not functioning properly, that are not protecting the nervous system. We also know that the nerves themselves can be damaged, in one way or another, by surgery or for other reasons. So we had to undertake research in all those areas.

For that reason, we have 18 lead investigators working in the United States, Canada, Israel and the United Kingdom. Numerous locations. And in each location, we also have technical assistants, post-doctoral researchers, many, many people working on our nine different projects to find the cures.

For example, to deal with the damaged nerves, we reached out to Allan Basbaum at the University of California, San Francisco, who had done work on using neuro-stem cells to fix damaged nerves in other areas of the body. And we asked him to apply his work to the trigeminal nerve. That research is ongoing, and is making progress.

To cite another example, for our work on causal, damaged or mutated genes and DNA, we needed 1,000 DNA samples from people with Trigeminal Neuralgia from nine collection centers in the U.S., Canada and the U.K. And we needed to make sure that the people providing the samples really had TN and not some other related disease. And we succeeded.

No other rare-disease research has ever collected that number of samples in a process that assured excellent phenotyping – screening for the disease. And now we want to look at their DNA, we want to know where the mutant genes are, what the sufferers’ genes have in common. when you ask what’s the status, the answer has to be very complicated. But the status is that in each of our projects, we have made progress, and we continue to make progress. We now know, for example, where in the brain the pain is occurring. We know the pathway of the pain from the trigeminal nerve to the brain stem to the place in the brain where the pain is experienced. And now that we know this, we’re working on how to block the pain pathway – block the pain from getting to the pain centers.

So the answers, and the cures, are going to be different for different people. Some will need to have their myelin repaired. For example, in our research for the last eight years at the University of Florida, we know that in tested animals there are ways to repair the myelin that can put a stop to the pain. And now, as in most of our projects, we are beginning to talk about human studies.

MR: When the Foundation was started, you set a goal of finding a cure by the end of 2020. That’s now. How do things stand?

That’s a good question. We will soon formally announce that this year, we will be initiating our first two human treatment studies. In scientific timelines, that’s pretty amazing. Because you must remember that over the last 50 years, the treatments for Trigeminal Neuralgia have hardly changed. The same anti-seizure drugs, the same pain relievers, the same surgeries – very little has changed in that regard. And rates of cure using the old treatments have been really disappointing – in over 50 percent of microvascular decompression surgeries, the pain returns in 10 to 12 years, according to the National Institutes of Health. And the NIH says that the other, less invasive, surgeries have to be repeated in one to three years. They also recognized that in many pain patients the surgeries and the medications aren’t working.

This year we will have our first two human studies. And we feel terrific about that. (The people for the studies will be chosen by the scientific researchers, not by the Foundation.) And in each of our other projects, we can see on the horizon, and are preparing for it, that we will be able to move toward the trials. The Foundation has raised the necessary funds to pay for this research and the goals are becoming closer every day to being achievable.

Now some of these curative treatments may work for some and not for others, because there are those different causes. That is why we have to create different cures – to repair the myelin, to repair the nerves, to block the ability of the nervous system to send those pain signals to the brain. But we feel great about our progress during these nine years, and we’ll keep going until everyone has the opportunity to stop the pain.

MR: The Foundation is an all-volunteer organization. There are no paid employees. The volunteers handle communications, fund-raising, and all other functions. I volunteer my time because I know first-hand, as someone who has experienced and suffered from the excruciating pain of Trigeminal Neuralgia, how important it is to find a cure. How did you get the thousands of other volunteers to sign up?

I think we did an incredible job of speaking to the public. Remember when we got started, because of this disease, the suffering and the treatment, there were billions of dollars being lost annually in productivity and medical costs. And more important, and more humanly unaffordable, was how dearly the unfortunate people suffering from this disease paid in quality of life – their health and longevity and stability and dignity and independence, their careers and family roles, their relationships and social ties, their physical abilities, their shattered sense of hope, of meaning or purpose. Many of these people were totally disabled and many were reaching out and saying they’d rather be dead.

We had a very sad situation. Great strides had been made in curing other diseases or creating better treatments for them, but with Trigeminal Neuralgia nothing new had been achieved for more than 50 years. There were the same treatments for TN that had existed for a half century. So when we reached out with our communications to tell people that we wanted to create cures, and that we wouldn’t stop until we found the answers, we were readily and strongly embraced.

I think a part of it was that we expressed the commitment to be an all-volunteer organization – that nobody was going to make money off of this. That almost all of the money we collected – close to 98 percent – would go to the research projects.

And I believe that this was very meaningful to the scientists as well. Many of their institutions dropped overhead costs for us, knowing that we were a nonprofit organization paying for this research. So we saved money in that way too. And I believe that it was the right time and the right place for a group of us who had been working hard to assist people with this terrible pain, and the public appreciated what we were doing, and they joined us.

In addition, I think that 90 percent of our volunteers are sufferers or family and friends of sufferers. They are people who have first-hand knowledge of the terrible toll of this disease, and they are contributing, they are developing fund-raising events and other activities. They are an important part of this Foundation. Without our volunteers we would not be able to fund the research to find the cures.

MR: Is it still true that 95 to 98 percent of the donations go directly to the research projects. And how is this possible?

It’s absolutely still true. We have no employees. I think if you add up the amounts of money that we save as a result, it’s far beyond the money that we spend on the research. Imagine hiring someone like you to do these articles for the Foundation, for the web newspaper. You’re not cheap, Merv. You’ve made a pretty good salary doing what you do. Just multiply that to all the little things that are done by all the volunteers – like a former college professor and a school principal who spend hours every week sending out thank you letters that are required by the I.R.S. for the donations. Imagine the volunteers who are meeting with the scientists on a regular basis, paying for their own travel costs to Canada or the U.K. or the East or West Coasts. When you start adding up the amounts of money that we are saving because of volunteers, it’s simply amazing what we’ve created.

MR: In the Foundation’s nine years of existence, how much money has it received in donations? How much more do you think you will need?

Cash coming in may have been $7 million, but the real number is closer to $45 million. Because we also have a program where we approach other foundations that give the money directly to our scientists – they prefer sending the money to the universities, for example. In many instances, people are giving in kind or matching money. Even the stamps we use for our envelopes are donated. It’s been very successful.

And another example is our Facebook page, which has been wonderful for getting donations. They can be $1 or $5 or $10 or $100 or $1,000, and they are anonymous. And much appreciated.

How much more will we need? That’s a great question. Much more, especially once you get to the human trials. For our first trial, much of it will be paid for by the National Institutes of Health, which is the first time something like this has occurred. But for the second trial, we’ll need probably another $3 million.

As an example, take Neurona, the company that was formed by Allan Basbaum out of U.C.S.F. for the neuro-stem research. Neurona raised close to $50 million to be able to take those neuro-stem cells and develop them, and they have 34 full-time scientists working on this project. Neurona has three directions they’re going – one is research on epilepsy, one is back pain and the third is Trigeminal Neuralgia and related neuropathic pain. They need those cells tested on animals by the very best testing service. We’re going to pay, at one of our centers, $370,000 to test those stem cells – which we believe are going to stop the pain and fix those nerves – on the animals.

When that is completed, Neurona is committed to putting at least millions into the Food and Drug Administration and clinical-trial approval process. We won’t have to pay for that. Neurona’s goal is to take the cures to the market. This one example of how our FPRF scientific consortium can work. In this case, the University of Florida, Neurona and us. This is the first time there are three distinct organizations pulling together to get a research job done. Neurona developed the cells, UF tested the cells and the Facial Pain Research Foundation covered the testing costs. And how that happened was simply a matter of bringing those scientists together at our International Consortium of Scientists, which we hold at least every other year. And the the scientists work together on their projects. How that happened was simply a matter of the FPRF functioning in a leadership role to say how can we get this done. And it just made sense to do it this way. And it’s not how things normally happen in scientific research.

MR: Both you and I have suffered from Trigeminal Neuralgia, and we both have been lucky. You, and other sufferers, have had a surgical procedure that has eliminated the excruciating pain. Others, like me, take medication that has been effective in keeping the pain at bay most of the time. But, as you’ve noted, the surgery and the medication don’t work for everyone, and often don’t last forever, and for the many others less fortunate, severe pain has been part of their daily existence. In truth, Trigeminal Neuralgia can be a fatal disease. It has historically been known as the suicide disease, and both you and I know of people who have so sadly decided they can no longer live with the horrible pain. What can you say to those who still suffer? Why isn’t the research moving faster? And what can be done to accelerate the pace? Will there be a cure?

The first thing I would say to them is that I’m sorry we didn’t start earlier. We relied too long on the medical community to create better answers and better treatments. And I can say to them to have hope. To believe that a cure can really be found. If you look at our scientists, you’ll see this is something meaningful. They are outstanding in their fields. Take a look at our work and you can see that progress is being made and that you need to have hope and that there are great people working on this problem. And we’re going to get the job done. We’re committed to doing it and we believe it can be done.

It’s going to take more money. It’s going to take a great deal of money. But no scientist has said no to us, and we have been able to raise funds all along, not dependent on federal money, because we can’t wait for federal money. That system works for some, but it’s very bureaucratic. And we can’t wait for the government to pay for this research. We need it tomorrow because people are suffering. We invite everyone to join us on this incredible journey to find the cures.

Facial Pain

Research Foundation

Awards Grant To

Dr. Allan Basbaum

The Facial Pain Research Foundation is pleased to have approved a research grant to Dr. Allan Basbaum at the University of California San Francisco. The funding is a continuation of his efforts to find cures for trigeminal neuralgia and related neuropathic pain. His research project is entitled “Novel sensory target genes for novel trigeminal neuralgia pharmacotherapies.” The Trustees of the Facial Pain Research Foundation believe that this research has the potential to make a significant difference in the lives of many in pain.

The approach that Dr. Basbaum is taking differs considerably from genome wide screens that are seeking to identify genes that underlie the etiology of or predispose to TN. The approach will identify genes that can be targeted to regulate the ongoing pain and particularly the paroxysmal pains that are so debilitating to the TN patient. Rather than the traditional therapeutic approach that ameliorates its pain manifestation, identifying such genes is of great interest and could lead to a novel approaches to polypharmacological or even gene therapy approaches to the management of TN.

Dr. Basbaum is a Professor and Chair of the Department of Anatomy at the UCSF School of Medicine. He is considered by many as “the” outstanding researcher in the field of pain. Allan has provided significant leadership in the development of Stem Cell Replacement Therapy for TN and related neuropathic pain. Allan has been an important member of the Facial Pain Research Foundation’s International Consortium of Scientists. He has provided his expertise and support to a number of the FPRF research projects to find the cures.

As Dr. Doug Anderson says about Allan Basbaum working on FPRF projects: “Having a scientist of Dr. Basbaum’s caliber on your team is like having Justin Verlander, Babe Ruth, Derick Jeter and Mickey Mantle join your Little League Team!”

Race Against

Nerve Pain 5K

By Jamie Paplaczyk

I'll truly never understand why bad things happen to such good people. While organizing this event over the last year, I met some of the nicest and best people who are suffering from Trigeminal Neuralgia. My goal through creating this event was to raise money to donate to research but also to show people they aren't alone. Sadly, others too are suffering and my hope was for TN patients to network with one another because nobody understands the pain like a fellow TN warrior.

I am still overwhelmed with the support and success we received for our inaugural Race Against Nerve Pain 5k! I chose to organize this because I have a loved one who has suffered from TN for 11 years now and it's heartbreaking to see. Grandma Sue is one of the kindest and most genuine people you'd ever meet. She recently lost a friend to suicide who had been suffering from TN. While I felt helpless listening to her, I wanted to do something. I started searching for events in the area to bring TN people together and other than Laugh Your Face Off, I couldn't find other local events for us to participate in, so I contacted the Facial Pain Research Foundation and started brainstorming.

When the 5k idea was decided I started by contacting the village of Bartlett, found a venue, mapped a 5k course and pulled permits. I had so many people who reached out wanting to help so I formed a team of volunteers, scheduled monthly meetings, came up with a name for the race, designed a logo, built a website and made a flyer. With the help of many we found a vendor for our shirts and designed what we wanted them to look like, reached out to local restaurants/grocery stores for food & drink donations, found a chip timing company to time the race and started to promote it. We sent the flyer to different social media groups and pages, knocked on every business door possible in town, collected donations and raffle items and sent countless emails getting sponsorships.

We decided we wanted it to be an event, not just a 5k run, so we expanded a little further. We also offered a 1k walk and a kids 50 yard dash race. We got a tent to put up to give TN patients a place to socialize and get out of the wind. We had a booth for a chiropractor to stretch people out before and after the race and a table for NAMI, a mental health organization for people to contact them if they wanted to use their services. We had a kids area with toys and activities, archery set up with trained professionals teaching people and a train we brought in for kids to ride on. We hired a DJ to play music throughout the day and announce the runners as they finished and had a silent auction table and raffle prizes that were a huge success and raised a lot of money.

I initially thought we would map out a 5k course, pull permits and we'd all show up to run - boy was I wrong. A lot more went into it than I expected but every minute spent planning was so worth it when race day arrived. Seeing people lean on each other and pull strength from one another was truly something special to see. We raised over $37,000, had 234 people register who ran/walked and another 30-50 people who came out to show their support. Our team of volunteers was key and made race day run very smoothly. Tasks were broken down before race day and all volunteers were given an assignment before the race so they knew exactly what they were responsible for and what they were in charge of.

The Facial Pain Research Foundation is a big reason this event was as successful as it was. Every trustee and volunteer I spoke to and worked with was so appreciative of what we were doing. They went above and beyond to help navigate handling finances, creating an online program for race day and overall just checking in to see what they could help with. The foundation has been extremely thankful for every donation received, big or small and it makes you work even harder knowing how appreciative a group of people truly are.

I've learned over the past year that many people with TN don't talk about it. They feel like they are alone in this fight. My hope is that people saw there are others fighting along side them. If my team and I were able to put this together, anyone is able to. I'm happy to share all I've learned and to help anyone who would like to organize something similar. Thank you to all who helped make this such a huge success. We hope our efforts can one day help people live pain free lives but until that day, nobody is fighting this battle alone - Together let's find a cure!

Save the date for next year!

10/4/20

First Report

Fifth Science Meeting At

University Of Florida Orthopaedics & Sports Medicine Institute

Gainesville FL

Kim Burchiel, M.D., F.A.C.S

The Facial Pain Research Foundation convened its Fifth Scientific Meeting in Gainesville Florida March 7-8, 2019. The FPRF has assembled a group of world-class investigators as a consortium to find a cure for Trigeminal Neuralgia. Clinicians and scientists from the US, England, Canada, and Israel were on site, to lend their perspectives on the state of research on TN. The agenda was ambitious, but the science and discussions lived up to the promise that we are closing in on the new knowledge that will help us find the cure. Many new ideas were presented and as is true of high functioning groups, some of the best insights were developed during the dinners and social hours after the formal meeting.

I will summarize some of the exciting concepts discussed at the scientific sessions, by topic. I present not so much as a full representation of the work that is currently underway, but as an indication of the high-level science that is being devoted to finding a cure for TN. The conference commenced with discussions of FPRF funded research, and related investigations, of which I am most familiar.

Scott Diehl, Ze’ve Seltzer, and Kim Burchiel presented the latest on their project “Genes That Predispose to TN”.

Kim Burchiel from Oregon Health & Science University discussed new insights into the origins of TN, which relate to different populations of patients with TN. Data is emerging that younger patients, particularly females, develop TN without the requirement for neurovascular compression (NVC) of the nerve. Older patients do frequently have NVC, and their prognosis from MVD is directly related to the severity of that compression. The size of the skull compartment that houses the trigeminal nerve (posterior fossa) seems also to be directly related to the incidence of NVC. This new knowledge will help us direct our genetic search.

Scott Diehl from Rutgers University reviewed the latest analysis of the genetic work on TN. A number of genes are now coming into focus, all of which appear to be relevant to the development, or function, of nerves. Now that we have identified candidate genes, the next step is to “sequence” these genes to determine if the preliminary findings stand up, and to find the exact mutations in these candidate genes. The hope is that soon we will be able to determine the function of these genes to either discover or develop new drugs for TN, or even replace defective genes with “gene therapy”. Ze’ve Seltzer from the University of Toronto gave a broad overview of the role of genetics in the development of neuropathic pain, and how findings from his studies on phantom limb pain can provide insights into the genes that predispose to TN. Some preliminary data was presented which suggests that this strategy of comparison of large data sets from patients with neuropathic pain may well provide clues to the origins of TN.

Allen Basbaum from the University of California, San Francisco discussed his work to identify novel gene targets in pain processing, what he termed the "dark genes.”

Lucia Notterpek from the University of Florida presented her work on dysregulated lipid metabolism as a disease modifier in peripheral neuropathies.

Wolfgang Liedtke from Duke University discussed his work on the Trigeminal nerve root as a rational target for safe and effective treatment of trigeminal nerve pain.

Cory Nichols from Neurona, described the work of his company targeted on developing a human GABAergic interneuron cell therapy to treat refractory epilepsy and neuropathic pain disorders.

The second conference day was devoted to a range of new and innovative potential therapies for TN.

Todd Golde from the University of Florida talked about the possibility of gene therapy for Trigeminal Neuralgia.

Joanna Zakrzewska from the University of London, discussed what happens to our patients with TN over time.

John Neubert from the University of Florida provided an overview of his FPRF project on identifying the neurophysiologic signatures of trigeminal neuralgia pain.

Mingzhou Ding from the University of Florida related his findings on trigeminal neuralgia and multimodal neuroimaging.

Rob Caudle from the University of Florida presented his findings on a approach to ending neuropathic pain with a combination of substances for blocking pain transmission. A novel and unique approach using old compounds to inhibit neuropathic pain.

Allan Basbaum presented an update on the work of a company he is affiliated with which is working on a genetic “switch” that can potentially selectively turn off pain generation in the trigeminal system, using a benign oral drug.

Mike Iadarola from NIH expanded on the use of a compound to potentially control facial pain and plans to test for ending TN and related neuropathic pain.

Jerry Krbec concluded the day with a discussion on funding opportunities from other sources to support the work of the FPRF.

What I would like to leave you with is the sense of the awe I have for the FPRF, having taken on this mission of finding a cure for TN. Through hard volunteer work, diligent fund raising, and the assembling of scientific expertise, the FPRF has accomplished something which in my experience is very unique. The FPRF scientific consortium has become the “place to be” in the neuroscience of TN. Groundbreaking work is being accomplished, and I came away from this meeting with a sense of optimism that we are close to an understanding of how we may cure TN. In fact, the most encouraging aspect of this meeting was, to me, how many different avenues of new knowledge are opening up. I am proud to be part of this work, and am excited to see the next levels of understanding that await!

Kim Burchiel, M.D., F.A.C.S

Facing My Facial Pain

By Mandi Ginn-Franz

Nine years ago, I went to lunch with some colleagues at work, and when I returned to my office I had one of the worst toothaches I have ever felt. I immediately left work and went to the dentist, who after tests and x-rays, could not find anything wrong with the tooth. Throughout that week, though, the intense toothache continued to occur. After several dentist appointments and doctor visits that week, I was told I could possibly have Trigeminal Neuralgia. I was referred to a neurologist and that is where my TN story really begins. The neurologist put me on nuerontin right away and suggested an MRI of my brain. My MRI showed lesions on my brain and I was experiencing a lot of pain along with other symptoms, including tinnitus and very blurred vision. Due to this, I spent a day at the Medical College of Wisconsin with various doctors, including a neuro-ophthalmologist. It was during that visit that Lyme was suggested as a possible cause of my Trigeminal Neuralgia and other symptoms. I was referred to another specialist and tested for Lyme which came out positive right away. Since then, I have been treating both Lyme and Trigeminal Neuralgia.

Over the past 10 years, I have been referred to Mayo Clinic twice, but have never made the commitment to go. I have also consulted with several different surgeons about various options, but ultimately I am not a candidate for surgery due to the cause and type of TN I have. I take up to 22 pills daily, combination of medicine and supplements. I have tried most of the typical anti-seizure medications and currently find the most success with Topamax and Lexapro, along with pain relief (MMJ and Tramadol) as a combination. I also eat gluten, dairy, and sugar free which also has had an impact on managing my pain levels overall. I have found an amazing support network of other TN patients, and I do whatever I can to raise awareness and funding for a cure. In addition to my previous work on the Young Patients Committee, I work on the Laugh Your Face Off fundraiser in Chicago, and work hard to get many buildings in both Chicago and Milwaukee to light up teal every year for awareness day as the Chicago lead for the TN Awareness Day campaign.

My advice to any TN patient would be to find ways to get your power back. I cannot control TN, but I can keep fighting to help others, to bring awareness, and hope for a cure or better treatment. My support network is very important to me, and I rely on other TN patients to help me cope and understand on those really bad days. Find your tribe and then find the small ways that you can fight back against TN. Be a Warrior! I may have TN but I refuse to let it have me.

Facial Pain Research

Foundation

2018 Research Progress

Compiled and Submitted

April, 2019

By Douglas K. Anderson, Ph.D.

Eminent Scholar Professor and Chair Emeritus Department of Neuroscience

University of Florida College of Medicine

And Director of Research and Trustee

Facial Pain Research Foundation

Trigeminal Neuralgia (TN), is a prime example of neuropathic pain which is pain caused by inmalfunctioning of the nervous system and is considered to be one of the most painful disease conditions known to humans. In addition to the debilitating effects on the lives of those afflicted with neuropathic pain, the cost disorders like TN adds to the U.S. health care system exceeds $100 billion/year. Yet despite the very obvious escalating and pain fueled humanitarian and economic crises, funding targeted at discovering the basic molecular mechanisms underlying neuropathic pain conditions from traditional federal agencies, continues to be inadequate.

The meagerness of funding from these traditional sources has led the growing realization that discovering the root cause of and treatment for TN and other neuropathic pain conditions is going to have to be accomplished with funding from the private sector. To this end, The Facial Pain Research Foundation (FPRF) was created in January, 2011 to provide the critical elements that are necessary and sufficient to study these facial pain conditions. Consequently, the sole mission of the FPRF is “…to establish a well-funded translational (i.e., fundamental discovery to clinical application) research continuum that is dedicated to identifying the mechanisms underlying neuropathic facial pain and to develop novel new therapeutic strategies that will permanently stop the pain of TN and related neuropathic pain syndromes”.

Since its inception a little over eight years ago, the FPRF has raised millions of dollars to support eight separate and distinct research projects. The FPRF uses three fundamental criteria in choosing which proposals are to be considered for funding: (1) the projects are novel and unique; (2) the investigator(s) responsible for each project are among the leading researchers in their respective fields; and (3) there is significant diversification in the research strategies among the projects. It is important to note that these FPRF funds have also served in a multiplier capacity in that some of our investigators have used FPRF support as seed funding to jury to or generate the necessary preliminary data which contributed to these investigators acquiring large grants from the NIH and other foundations and, in some cases, the acquisition of venture capital. Total dollars from other sources that came to our consortium of investigators emanating, all or in part, from FPRF seed funds, is estimated to be somewhere over $40,000,000. The purpose of this yearly update is to briefly summarize these six projects and to highlight the progress that each achieved in 2018. I have also provided summaries of two new FPRF research projects beginning this Summer 2019.

"Investigating Protein-Lipid Interactions in Peripheral Nerve Myelin"

Lucia Notterpek, Ph.D. (Principal Investigator) Professor and Chair Department of Neuroscience
University of Florida College of Medicine

Progress report (Year 4): May 2018-April 2019

Project 1: Cholesterol homeostasis in peripheral nerve myelin Study staff: Ye Zhou, MS, graduate student

We made excellent progress on this project during the past year, with Ye Zhou the graduate student leading the work in the lab. Because of the great progress, Ye has successfully defended her PhD in March 2019, and will be graduating in May 2019. At the bottom of the progress report, I list publications related to this work that are now in press, or under review.

As described previously in my progress reports, the absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents, and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and peripheral nerves from PMP22 knockout (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with the levels of proteins involved in cholesterol transport, apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1), highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the cholesterol transporter at the cell membrane and diminished secretion of apoE-cholesterol. In nerves from normal mice, we identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein, ABCA1.

Significance of the described results (lay terms):
Understanding the subcellular events that underlie abnormal myelin formation is critical for advancing therapy development for neuropathies. PMP22 is an essential peripheral myelin protein, as its genetic abnormalities account for approximately 80% of hereditary neuropathies. Here we demonstrated that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells plasma membrane are altered, and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay between PMP22, cholesterol, apoE and the major cholesterol-efflux transporter protein ABCA1. These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in peripheral nerves and provide new knowledge for efforts toward therapy development.

Project 2: Cholesterol homeostasis in peripheral nerve myelin, with a focus on statins Year 12: May 2018-April 2019

Mohammed Al Salihi, MD, PhD, postdoctoral fellow was the key investigator on this project, but he resigned in March 2019, and returned to training in medicine. I will be hiring a new person shortly.

Statins are lipid-lowering agents that are used in the treatment of dyslipidemia by the inhibition of the HMG-CoA reductase enzyme, which is the rate-limiting step in cellular cholesterol biosynthesis. The influence of statins on the nervous system is controversial, particularly concerning peripheral nerves. Currently it is debated whether statins alleviate or aggravate neuropathic pain, and/or whether they cause the neuropathic pain. Based on our investigations of lipid metabolism in peripheral nerves, and these mentioned clinical observations, we hypothesize that in certain individuals, statins alter the stability of myelin making it susceptible to localized compression-induced demyelination with a subsequent painful neuropathy. Dr. Al Salihi has been testing the effects of statins on Schwann cells and on myelination of neurites in vitro, and has found that statins lead to myelin fragmentation. With Mohammed leaving the lab, we are now repeating these results and expanding the studies to more in depth analyses of myelin and Schwann cells viability. Related to the statin project, Ye is exploring the influence of exogenous cholesterol supplementation on myelinating cultures from heterozygous PMP22 knock out mice, which model compression-induced neuropathy. Quantification of internodal myelin segments and internode numbers indicate beneficial influence of cholesterol supplementation. Together, these studies will help us unravel how intracellularly made cholesterol and exogenously supplied cholesterol impact Schwann cell biology, specifically myelin formation and stability.
In a related project, we examined the influence of a neutral lipid-enriched diet on myelination in neuropathic mice. For our studies we used Trembler J (TrJ) mice that carry a spontaneous mutation in peripheral myelin protein 22 (PMP22) and model early-onset, severe neuropathy. While it is known that lipid metabolism is critical for myelination and myelin maintenance, the impact of a cholesterol-enriched diet on early-onset neuropathies has not been examined. Furthermore, the mechanisms by which dietary lipid supplementation and/or substitution (no increase in overall calorie intake) benefit nerve myelin are unclear. To address these questions, we examined the lipid profile of peripheral nerves from 6-month old TrJ mice and tested the impact of a 6-week long neutral lipid-enriched high-fat diet (HFD) on neuropathy progression in young, newly-weaned mice. Oil Red O staining showed pronounced neutral lipid accumulation in nerves from affected, neuropathic mice, along with elevated levels of key cholesterol and triglyceride transport proteins including apoE, LRP1 and ABCA1, compared with wild type (Wt). In young mice, the short-term HFD intervention increased serum cholesterol levels, without impacting triglycerides, or body and liver weights. Nerves from neuropathic TrJ mice showed improvements in the maintenance of myelinated fibers after the 6-week long dietary intervention. Concomitantly, aberrant Schwann cell proliferation was attenuated, as detected by reduction in mitotic markers and in c-Jun expression. Nerves from HFD fed TrJ mice also contained fewer macrophages, with a normalized count of inflammatory CD11b+ cells. In addition, we detected an increase in neutral lipids in the nerve endoneurium and a trend toward normalization of apoE, LRP1, and ABCA1 expression, after the HFD feeding. Together, these results demonstrate a beneficial influence of a neutral lipid-enriched diet on neuropathy progression in young TrJ mice, and support further work in investigating the potential benefits of dietary lipids on demyelinating neuropathies. In our next set of studies, we plan to further optimize the lipid-enriched diet and examine sensory deficits in the various neuropathic models, with and without dietary intervention.

Related to these studies we have the following manuscripts at various stages of publication:
1. Zhou Y, Lee S, Bazick, H, Miles J, Tavori H, Landreth GE, Fazio S, , Notterpek L. PMP22 regulates cholesterol trafficking and ABCA1-mediated cholesterol efflux. J Neuroscience, 2019 (in press).
2. Zhou Y, Lee S, Bazick, H, Miles J, Fethiere A, AISalihi M, Tavori H, Fazio S, , Notterpek L. “A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice. Experimental Neurology (under review)
3. Zhou Y, et al., Steatosis and cholesterol mislocalization in the liver of PMP22-deficient mice (In preparation for Journal of Lipid Research)
4. Zhou Y, et al., PMP22 senses cellular cholesterol homeostasis and regulates cholesterol subcellular trafficking via CRAC domain(In preparation for Cellular Neuroscience)
5. AlSalihi, Bazick et al., HMG-CoA reductase inhibitors and their effect on Rat Schwann cells and myelination (In preparation but still collecting data)

"Mapping Towards a Cure: Identification of Neurophysiologic Signatures of Trigeminal Neuralgia Pain"

Summary:

A University of Florida (UF) team consisting of John K, Neubert, D.D.S.,Ph.D. (Project Leader), Mingzhou Ding, Ph.D., Robert Caudle, Ph.D., Marcelo Febo, Ph.D., and Todd Golde, M.D., Ph.D. are investigating the neurophysiological signature of trigeminal neuralgia (TN) pain and developing promising new therapies. This group represents expertise in facial pain, structural and functional neuroimaging, neurophysiology, molecular biology, pharmacology, and viral vectors. Initially, this project was developed to include both preclinical animal models of trigeminal nerve pain and human studies using imaging studies from TN subjects to investigate the cause of TN. The preclinical animal studies have yielded the novel therapeutic agent, CGRP-Botox (see Dr. Caudle’s separate report). Dr. Febo has provided additional animal imaging analyses and has identified unique connections within the brain following trigeminal nerve injury. These findings confirm unique pathways relevant to trigeminal nerve pain and can provide a foundation for studying humans using the same imaging analyses. The human studies have found critical brain regions important in transmitting pain in TN patients and we identified an exciting relationship relating to neuroinflammation, chronicity, and surgery (see below in Human Studies). These findings provide the foundation for the journal article that is in preparation and will be submitted in the next few months. We have made significant progress towards completing the goals of this project and will expand on these exciting results (see Future Directions) to provide a pathway for finding a cure for TN.