Questions about the cause of trigeminal neuralgia inspire new genetics study by the Facial Pain Research Foundation
By Arline Phillips-Han, Science Reporter
Three pioneers in pain research are gearing up for an international study aimed at determining whether genetics plays a role in the excruciating facial pain of trigeminal neuralgia. The study begins at a time of increasing scientific evidence that the source of the pain is something more than the well-known injurious compression of the trigeminal nerve.
Trigeminal neuralgia, in its classic textbook form, affects only 10 in 100,000 adults, but its importance lies in its brutal bolts of facial pain that stop life in its tracks and, in rare instances, leads to suicide. The disease affects men, women and children worldwide.
Acting on educated presumptions that there are underlying genetic flaws, the researchers plan a direct chase to find markers of genetic abnormality, such as gene mutation, genetic variance or malfunction, or missing parts of genes that may heighten susceptibility to chronic facial pain.
The project, “In Search of a Cure…Finding the Genes That Predispose to Trigeminal Neuralgia,” will begin in February 2013. It is the fourth project initiated by The Facial Pain Research Foundation, a division of TNA-The Facial Pain Association, in a quest to cure TN and other neuropathic facial pain within ten years. Defects in one or several genes, if found, could provide targets for designing customized drugs or perhaps treatment through gene therapy, which is gaining momentum in the U.S. and is newly approved in Europe.
To patients suffering the lightning-like strikes of electrical pain in the face, the natural question is why me? To health-care professionals hounded by repeated failures in attempts to permanently end this pain, the question means everything. Finding a cure requires a breakthrough in more fully understanding the source of the problem.
The three researchers, widely known in the field of pain research, are joining forces to stop the pain that appears unstoppable in thousands of people worldwide, and they are doing so as volunteers. Project Coordinator Marshall Devor, Ph.D., who is The Alpert Professor of Pain Research at The Hebrew University of Jerusalem, says his reason for working pro bono goes back to his student years when he decided what he wanted to achieve in life would not be about making lots of money, but about solving human problems. He sees trigeminal neuralgia as “an immensely intriguing intellectual challenge, given its strange peculiarities— an electrical shock going off in your head, the pain often triggered by a light touch!” Yet he expresses optimism: “A cure for classic trigeminal neuralgia (TN1), which will prevent or modify the disease rather than just suppress the pain, is theoretically possible. Progress in understanding TN is also likely to have implications for other neuropathic pain conditions.”
Devor is joined in project leadership by principal investigators Ze’ev Seltzer, D.M.D., professor of genetics at the University of Toronto Center for the Study of Pain in Ontario, Canada, and Kim Burchiel, M.D., the John Raaf Professor and Chairman of the Department of Neurological Surgery at the Oregon Health and Science University in Portland. Physician/Scientist Joanna Zakrzewska, M.D., of London, the Foundation’s international neuroscience coordinator, recruited all three premier scientists to the project and will serve as senior consultant.
The Facial Pain Research Foundation is leading a campaign to raise $616,750 in donations to fund operational expenses involved in probing the genes of 500 patients with the extreme pain of TN1.
“We aim to obtain a genetic profile that will lend itself to finding an end to TN pain,” says Michael Pasternak, Ph.D., of Gainesville, Fl., founding trustee and former president of TNA. “We want to exploit knowledge of the pattern of genes in a way that will prevent the disease. The genetic patterns of these 500 patients will be painstakingly defined through analysis of DNA extracted from samples of their saliva.”
Why so few individuals are prone to the devastating pain of TN has stymied health-care professionals ever since the disorder was first described in the second century A.D. Although significant advances have been made in medications and surgery for the disease, some patients are unresponsive to treatment and pain recurs in a large percentage of other patients within months or several years after treatment. In either case, the resurgent pain typically worsens with time. Standard treatment starts with medication, but the selection of a drug is a trial and error process, since there is no way to determine in advance which drug will help an individual or may cause bothersome or intolerable side effects. In many cases, medications provide only transient benefits.
“Probing the genes of individuals with the pain of TN1 is the most direct route to finding the answers we seek,” says Devor. “If my hypothesis is correct—that only a few abnormal or malfunctioning genes are involved in patients with TN1—there is a high likelihood that the project will reveal these genes and ultimately the disease-causing mechanisms involved. No other plausible explanation has been presented for why it is that although many people have trigeminal root compression, this extreme facial pain attacks very few of them.”
Devor, a veteran of 40 years in pain research and winner of Israel’s prestigious 2012 EMET Prize for Art, Science and Culture, says a lot of the technology applied in the 13-year federally funded Human Genome Project will be applied in the study of TN. “Compared to the high cost of that massive genome project, ours will be cheap,” he says. “The knowledge we obtain is expected to help us better understand not only TN, but also non-trigeminal facial pains and nerve-related pains in other parts of the body.”
The first year of the project will be devoted to enrolling qualified patients who will contribute saliva samples for DNA analysis. The researchers will compare the newly collected genetic data to the same type of data obtained from people without TN in previous genetic studies and now readily available in the medical literature.
“If only a few gene abnormalities are found in the DNA samples from the 500 TN patients, the question about the role of genetics can be answered in this study,” Devor says. “But if we find many gene variances, in which each defective gene makes just a small contribution to the disease process, more samples would be needed for analysis. If no particular gene has a strong effect on the risk of developing TN1, the identity of many weak genes is unlikely to benefit patients except perhaps in the distant future.”
Prevention of the disease is as critical to the researchers as finding a cure. As Devor has explained to trustees of the Foundation, “If we identify genetic defects linked to TN1, we can test relatives of the patients, and if we find they have the same genetic pattern, we would then seek ways to keep them from developing the disease.”
Changing Paradigm
Eye-opening human brain imaging studies by co-principal investigator Kim Burchiel, M.D. provide compelling reasons to delve into genetics to find out what distinctive problem in TN1 patients may explain why they are selectively attacked by chronic facial pain.
In a tone of obvious frustration, Burchiel says a lot of what he was taught about trigeminal neuralgia as a resident in neurosurgery has been found not true in the light of his 32 years’ neurosurgical experience. “Things simply do not add up.” He says traditional concepts about the trigeminal nerve are cast into question by human brain images recently obtained through a combination of magnetic resonance imaging (MRI) and cerebral angiography. His own imaging studies using an MRI-MRA system developed at the Oregon Health and Science University, confirm that nerve compression is not the only thing going on that is linked to facial pain.
Through his studies of super-sharp 3-D human brain images in patients with and without TN, Burchiel found that close to 17 percent of mature adults have trigeminal nerve compression, but no facial pain. Since only 0.01 percent of people suffer from TN1 pain, it appears that most people (94 percent) with trigeminal nerve compression escape pain. In addition, an estimated 10 to 20 percent of individuals newly diagnosed with TN do not have nerve compression.
Burchiel now wonders why the disease does not affect more people.
He notes that OHSU’s imaging system, which he has used routinely for the past five years, yields high-resolution views of the entire region of the trigeminal nerve and surrounding blood vessels. The images help him determine who has trigeminal nerve compression and who is a candidate for microvascular decompression (MVD), the gold-standard corrective surgery for classic TN.
“Our studies indicate nerve compression is a very partial and unsatisfactory explanation of the facial pain disorder,” he says. “The disease probably results from many factors. If the classic type 1 form of TN is solely related to compression of the trigeminal nerve, why does it ever come back? That idea is another bit of heresy!”
In their project proposal, Devor, Seltzer and Burchiel hypothesize that a genetic co-factor is the most likely explanation of why only one in every 2,000 people with trigeminal nerve compression also has TN1.
“If we can link TN1 to known gene sequences, enzymes or structural membranes, we will have discovered what predisposes a person to chronic facial pain,” Burchiel says. He is preparing to carry out the first phase of the genetic study in 50 TN1 patients at the Portland campus, and will later enlist 9 to 10 other medical research centers as partners in the larger study. Preference will be given to enrolling young patients, based on the assumption that if a person developed TN1 at a young age, he or she is more likely to carry variant genes of major effect.”
Expectations for Success
Genetics Professor Ze’ev Seltzer, Ph.D., in his 36th year of research on the neurobiology of pain, predicts, “We believe we can come up with a cure in eight years, provided we have funds to complete all three phases of the study”. The stages include initial DNA analysis from the saliva samples of 50 TN patients, aimed at demonstrating feasibility of methods, to be followed by the enlisting of additional 450 qualified patients representing various ages and ethnic backgrounds, who will provide samples of their saliva for DNA analysis. The most critical aspect will involve the use of automated systems to perform genomic analysis of known elements within the DNA, followed by close examination of gene sequences in an effort to determine their function.
“The genetic analysis is complex, since the genes whose function is known constitute only two to three percent of the genome; about 95 percent of the human genome has no known function,” Seltzer says. Yet a lot of what was once considered ‘junk DNA’ is not junk at all, but does have some function. Our effort to identify gene defects that affect a person’s vulnerability to TN pain can be compared to looking for a needle in a very large haystack.”
Seltzer likens the study to “a great adventure story” for which he envisions a practical outcome. He expects what is learned about the genetics of TN1 will lead to development of diagnostic kits that can be used to guide treatment choices when a person in pain first enters a clinic or hospital emergency room. To reach such a goal, he says a holistic approach is needed to focus not only on the pain and the genes linked to it, but also the full scope of a patient’s life to understand pain tolerance, stresses and factors affecting ability to cope with pain, environmental factors that may contribute to depression, anxiety, other health or family problems. To this end, Seltzer plans to implement questionnaires that will provide extensive information on a patient’s pain and lifestyle.
“The resulting patient profiles may help us better design treatments that address the pain problem a patient has or may develop,” he says.
“This is the most important study to be undertaken regarding trigeminal neuralgia and other painful conditions affecting the nervous system,” says Seltzer. His productive scientific work provides an ideal background for exploring the genetics linked to TN and other neuropathic facial pain disorders. He has developed several animal models of painful nerve- related diseases and authored many journal articles and book chapters reporting his findings on the genetics of neuropathic pain.
Seltzer has good reason to expect useful results. In two of his published studies, he and his colleagues reported they used a gene they had discovered in mice and rats in subsequent models of neuropathic pain to test whether they are relevant to human medicine. They discovered that the gene found in the rodents does have clinical relevance. He also was the principal investigator in a newly ended five-year project funded by The National Institutes of Health, in which researchers mapped the genome of the mouse to define the role of genes in the spread of neuropathic pain following injury to the trigeminal nerve system. His team currently studies the genetic abnormalities that predispose carriers to develop chronic pain following limb amputation and mastectomy.
Forecasts for Enduring Pain Relief
In light of relentless, treatment-resistant facial pain that many trigeminal neuralgia patients struggle with every day, the announcement of a first-of-its-kind probe of genes related to classic TN prompts excitement among people who know the limits of contemporary medicine related to pain.
Roger Levy, a founding trustee of The Facial Pain Research Foundation and immediate past chairman (12 years’ service) of the TNA-FPA Board of Directors, says, “There is no doubt in my mind that this is potentially the most exciting opportunity for helping patients since neurosurgeon Peter Jannetta performed the first MVD in 1966. If you want to win, you need to pick the best team you can, and this is what we’ve done.”
For University of Florida neuroscientist Douglas Anderson, Ph.D., Foundation trustee and director of its research programs, the study is the next scientific frontier in which to seek cause and solution for TN. As guest speaker at the 2004 TNA conference in Orlando, he pointed out how odd it is that the anatomy of compressed nerves has been found in a significant number of people, but only a few have TN. In visionary fashion, he encouraged the Association to embark on genetic research.
“Before you can begin to correct the problem, you have to define the cause,” Anderson says. “If, in probing the genetic makeup of TN patients, some abnormality pops up that is different from the genes in people who have vascular compression of the trigeminal nerve but no pain, we may be able to stop or mute the pain. The situation is like being in a room with a number of locked doors. Without a key (i.e. knowing the right gene), there is little or no chance that the correct exit door can be found. However, if one has a key, this key can be tried in doors until the right door is identified. Finding the genes involved will reveal a lot that can aid the development of treatment.”`
“We are moving forward with a sense of urgency, almost as if flying on a magic carpet, to realize our dream of finding a cure,” says Writer-Publisher Myron (Mike) Hirsch of Naples, FL, also a Foundation founding trustee and former president of the TNA- FPA. “We see a rapid pace of change in genetics research in many parts of the world as men and women of science, who have devoted years of their lives to this field of study, are learning how genes affect our health and how they can replace genes to maintain our health. We are absolutely blessed to have recruited three of the world’s best-known pain scientists to help us reach our goals to help those who suffe