First Published June 13, 2014
Dr. Mark Linskey is a Professor of Neurological Surgery currently practicing at the University of CA, Irvine, in Orange County, CA (http://www.faculty.uci.edu//profile.cfm?faculty_id=5322). He trained in microvascular decompression (MVD) for 7 years with Peter Jannetta and in Gamma Knife stereotactic radiosurgery (GKSR), glycerol rhizotomy and radiofrequency lesioning for 7 years with L Dade Lunsford at the first US gamma Knife unit at the University of Pittsburgh. He has continuously served on the Medical Advisory Board of TNA - The Facial pain association since 2003; currently serving as their Western Regional Director. In practice and out of training for more than 20 years, he published the first prospective cohort comparative clinical trial of MVD versus GKSR for typical trigeminal neuralgia and is an internationally-recognized expert, and experienced surgical subspecialist, in trigeminal neuralgia. He is currently the American College of Physicians (ACP) Trigeminal Neuralgia module editor for their physician point of care decision support tool "Smart Medicine" (formerly PIER - Physician Information & Education Resource). He is also the Co-Editor of the Trigeminal Neuralgia module for the rigorous evidence-based medicine periodic systematic review tool and physician decision-support resource, "Clinical Evidence", published by the BMJ (British Medical Journal) for the British Medical Association.
Facial Pain The Research Imperative
By Mark E. Linskey, M.D.
From a twisted and perverse perspective, among facial pain patients, patients with classical trigeminal neuralgia (TN), are comparatively fortunate. We at least have surgical treatment options with reasonable chances for successful pain relief when current medical therapy fails. Yet even for TN patients, not all patients fare well. While in expert and experienced surgical hands, microvascular decompression (MVD) can lead to durable complete pain relief in about 80% of patients, this still leaves one in five TN patients still suffering. Patients seeking care in the general medical community are not so fortunate. MVD results can vary significantly surgeon-to-surgeon. Empiric experience over the last 20 years in my practice, would suggest that the success rate among less experienced and expert surgeons might run as low as 50%.
For those patients with multiple sclerosis-related TN, or who fail MVD, their plight can be improved with palliative destructive procedures directed towards the trigeminal nerve [stereotactic radiosurgery (SR, radiofrequency lesioning (RFL), glycerol rhizotomy (GR), and balloon compression (BC)]. However, these procedures serve best as temporizing measures, with up to 50% of patients with classical TN recurring within five years of the procedure. Each palliative destructive procedure runs the risk of facial numbness with its associated risk of new de-afferentation pain from nerve damage, and these risks accumulate and compound as destructive procedures are repeated. Thus overall, across the U.S., even for patients with classical TN, surgical intervention may realistically not provide adequate or long-lasting relief in an estimated 30-50% of cases.
But what about those patients with other forms of facial pain? In 2008, after 18 years of existence, The Trigeminal Neuralgia Association (TNA) changed its name to TNA – The Facial Pain Association (TNA-FPA) in recognition of the fact that patients with facial pain other than classical TN also needed education, support and help too. These conditions include TN2, neuropathic facial pain, facial pain of obscure etiology, and anesthesia dolorosa, among many others. For these patients, MVD rarely leaves a patient pain-free. Furthermore, while palliative destructive procedures can, and do help, they not only are less successful than for classical TN patients, they may actually worsen the situation through increased de-afferentation, despite the best of surgical intentions. While surgical stimulator surgery can help these patients in very select cases, the overall percentage of patients enjoying significant and durable relief is disappointingly small. If we now broaden our inquiry to include all facial pain patients that seek help from TNA-FPA, it seems likely that only about half will achieve adequate or long-lasting relief from their suffering through surgery. Clearly surgery alone is not the answer for too many of our patients, friends, and family who suffer from facial pain.
The word imperative refers to something that is both necessary and of vital or crucial importance. It may also refer to the expression of a command. For facial pain syndromes new discovery and therapeutic breakthroughs through basic science research is an absolute imperative in the first sense and an imperative from our patients and their loved ones in the second sense.
We know that vascular compression is a necessary cause for the majority of classical TN patients. Yet up to 40% of normal living patients and up to 50% of patients studied at autopsy have these vascular contacts without having TN. Clearly vascular compression, while necessary, is not sufficient. The logical additional factor, that many have speculated about, likely involves additional predispositions related to genetics and/or the biology of myelin nerve insulation, axonal damage, or both. In my opinion, studies of deferential gene expression comparing classical TN patients to normal population controls carry the highest chance of uncovering potentially new fruitful areas for investigation and future therapeutic exploitation for patients with classical TN.
While the hoped for discoveries from studying differential gene expression in cases of classical TN might be more generalizable to help patients with other facial pain syndromes, this is by no means certain. Thus, simultaneous additional lines of research inquiry are also desperately needed. These include the urgent need for a better understanding of the neurochemistry and the psycho-biology of chronic neuropathic pain and the fast-track development of new agents for clinical testing. It includes studies into the biology of nerve repair and regeneration, through both pharmacological means as well as potential cellular therapies including stem cells. It also includes the need to study safe means of modulating pain perception at the brain level through brain stimulation technology.
While it is simple and conceptually satisfying to talk about the search for one “cure”, this may be an elusive goal given the heterogeneity and wide variety of facial pain syndromes suffered by patients seeking help through the TNA-FPA. More than one “cure” may be needed depending on the individual circumstances of each patient. Yet the quest for a “cure”, whether one or many, all still depend on basic science research advances which are expensive and which take years to develop, test and realize.
As a surgeon, I long for the day when we have therapies that can increase our MVD results to near 100% success, as well as offer hope and more predictable treatment success chances to our non-classical TN facial pain patients. While I am biased by my surgical background, I doubt that these advances will involve a new pill distributing an agent non-specifically throughout our body. I strongly suspect that they will involve therapies that will be most effective locally and selectively at the site of pathology or damage, either through direct open surgical application, or needle or electrode delivery into the trigeminal nerve root, ganglia, or brain. Thus surgery will likely be an important component of any success realized through our research efforts.
If we wish the state of care for patients with facial pain to improve from the levels currently available, we are indeed faced with a research imperative. The need is great and the costs are considerable. The best way that most can help is through generous donation and ongoing, sustained, support for efforts such as those fostered by our own Facial Pain Research Foundation http://www.facingfacialpain.org/ . We need everyone’s help and support to drive this mission forward and ultimately succeed.
$500,000 Matching Gift
For
“The William H. and Leila A. Cilker Genetics Research Program
To Find a Cure for Trigeminal Neuralgia”
EVERY DOLLAR YOU GIVE
WILL Be Matched
HERE’S YOUR CHANCE TO DOUBLE YOUR GIFT....DONATE NOW
https://today.duke.edu/2017/11/why-head-and-face-pain-causes-more-suffering
Why Head and Face Pain
Causes More Suffering
Sensory neurons in the head and face tap directly into the brain’s
emotional pathways
November 13, 2017
Hate headaches? The distress you feel is not all in your -- well, head. People consistently rate pain of the head, face, eyeballs, ears and teeth as more disruptive, and more emotionally draining, than pain elsewhere in the body.
Duke University scientists have discovered how the brain's wiring makes us suffer more from head and face pain. The answer may lie not just in what is reported to us by the five senses, but in how that sensation makes us feel emotionally.
The team found that sensory neurons that serve the head and face are wired directly into one of the brain’s principal emotional signaling hubs. Sensory neurons elsewhere in the body are also connected to this hub, but only indirectly.
The results may pave the way toward more effective treatments for pain mediated by the craniofacial nerve, such as chronic headaches and neuropathic face pain.
“Usually doctors focus on treating the sensation of pain, but this shows the we really need to treat the emotional aspects of pain as well,” said Fan Wang, a professor of neurobiology and cell biology at Duke, and senior author of the study. The results appear online Nov. 13 in Nature Neuroscience.
Pain signals from the head versus those from the body are carried to the brain through two different groups of sensory neurons, and it is possible that neurons from the head are simply more sensitive to pain than neurons from the body.
But differences in sensitivity would not explain the greater fear and emotional suffering that patients experience in response to head-face pain than body pain, Wang said.
Personal accounts of greater fear and suffering are backed up by functional Magnetic Resonance Imaging (fMRI), which shows greater activity in the amygdala -- a region of the brain involved in emotional experiences -- in response to head pain than in response to body pain.
“There has been this observation in human studies that pain in the head and face seems to activate the emotional system more extensively,” Wang said. “But the underlying mechanisms remained unclear.”
To examine the neural circuitry underlying the two types of pain, Wang and her team tracked brain activity in mice after irritating either a paw or the face. They found that irritating the face led to higher activity in the brain’s parabrachial nucleus (PBL), a region that is directly wired into the brain’s instinctive and emotional centers.
Then they used methods based on a novel technology recently pioneered by Wang’s group, called CANE, to pinpoint the sources of neurons that caused this elevated PBL activity.
“It was a eureka moment because the body neurons only have this indirect pathway to the PBL, whereas the head and face neurons, in addition to this indirect pathway, also have a direct input,” Wang said. “This could explain why you have stronger activation in the amygdala and the brain’s emotional centers from head and face pain.”
Further experiments showed that activating this pathway prompted face pain, while silencing the pathway reduced it.
“We have the first biological explanation for why this type of pain can be so much more emotionally taxing than others,” said Wolfgang Liedtke, a professor of neurology at Duke University Medical Center and a co-author on Wang’s paper, who is also treating patients with head- and face-pain. “This will open the door toward not only a more profound understanding of chronic head and face pain, but also toward translating this insight into treatments that will benefit people.”
Chronic head-face pain such cluster headaches and trigeminal neuralgia can become so severe that patients seek surgical solutions, including severing the known neural pathways that carry pain signals from the head and face to the hindbrain. But a substantial number of patients continue to suffer, even after these invasive measures.
“Some of the most debilitating forms of pain occur in the head regions, such as migraine,” said Qiufu Ma, a professor of neurobiology at Harvard Medical School, who was not involved in the study. “The discovery of this direct pain pathway might provide an explanation why facial pain is more severe and more unpleasant.”
Liedtke said targeting the neural pathway identified here can be a new approach toward developing innovative treatments for this devastating head and face pain.
This research was supported by grants from the National Institutes of Health (DP1MH103908, F31 DE025197-03, K12DE022793). Dr Liedtke is also supported by the Facial Pain Research Foundation (Gainesville FL).
CITATION: "A Craniofacial-Specific Monosynaptic Circuit Enables Heightened Affective Pain," Erica Rodriguez, Katsuyasu Sakurai, Jennie Xu, Yong Chen, Koji Toda, Shengli Zhao, Bao-Xia Han, David Ryu, Henry Yin, Wolfgang Liedtke and Fan Wang. Nature Neuroscience, Nov. 13, 2017. DOI: 10.1038/s41593-017-0012-1
Editorial Note
Mervyn Rothstein
|
Mervyn Rothstein who was an editor and writer at The New York Times for 29 years. Mr. Rothstein now writes the monthly "Regional  Theatre" column for Playbill Magazine and is a former member of the Tony Awards Nominating Committee. His first symptoms of trigeminal neuralgia occurred in 2005. |
John K. Neubert, D.D.S., Ph.D., is the principal investigator for the scientific research project entitled Mapping Towards a Cure: Identification of Neurophysiologic Signatures of Trigeminal Neuralgia Pain, at the Evelyn F. and William L. McKnight Brain Institute of the University of Florida. Dr. Neubert is a tenured associate professor in the Department of Orthodontics at the University of Florida College of Dentistry. He also has an adjunct appointment in the Department of Neuroscience at the University of Florida College of Medicine and is on the faculty of the McKnight Brain Institute. Dr. Neubert spoke by telephone from Florida with Mervyn Rothstein, who was an editor and writer at The New York Times for 29 years. Mr. Rothstein now writes the monthly “Regional Theatre” column for Playbill Magazine and is a voting member of the Drama Desk, an association of theater journalists. His first symptoms of trigeminal neuralgia occurred in 2005.
The Interview
MR: Why did you decide to focus on pain in your career?
That’s a good question. When you go through your dental-student career, you learn that pain is very much a part of the public perception of dentistry. That’s what people associate dentists with. As a dental student, I was fortunate enough to be able to do research with someone with studied facial pain and who saw facial pain patients. And I became interested in trying to find better ways of eliminating pain.
MR: Your research involves locating and imaging the signature centers in the brain for trigeminal pain, and the pathways to those centers. Once you do that, what happens next? What are the research steps that need to be taken to find the cure – to stop the pain – and how difficult is this process of moving from finding the cause to eliminating it?
The first step is the imaging part. We’re hoping that we can find a common signature center, where the pain starts, in the different patients that we’re scanning. We’re also doing a similar study in our animal models. We’re hoping also that there’s an overlap in what we see in trigeminal injury models in rats, and in what we see in humans. Once we can identify the signature center, that will be the target for possible future therapeutic treatments.
It’s a difficult process. The first problem is the relatively small number of patients who have trigeminal neuralgia. It’s a relatively rare disorder. So to get a sufficient number of subjects is the first challenge. And the next challenge is to see if there’s that overlap in brain activity in a signature center. The last difficulty comes in translating these results into therapies, and in getting those therapies approved. What’s helping us is that we are working in parallel on the basic side – our animal work – trying therapeutics, so once we are ready to move to the human side we will hopefully have things ready to go as far as therapeutics are concerned.
MR: What is the importance of this trigeminal neuralgia study and what potential is there for having an impact on the study of other diseases and possible cures?
We’re hopeful we can come up with new therapies, because it’s a disease that’s largely resistant to many treatments, and people even after surgery can still have horrible pain. As far as impacting other disorders, the mechanisms that occur in the face are very similar to mechanisms that occur elsewhere in the body, so we have a very clean model for studying pain.
MR: How have you and your research colleagues attacked this problem from a new perspective?
The neural imaging aspect is one of the more novel parts. People have done imaging for a number of years, and they’ve gotten very good at it. We’re using it in the sense of a biological marker, and we’re hoping that this neural image may also serve as a diagnostic tool. It could help people diagnose trigeminal neuralgia versus some other disorder that’s causing the pain. Our project Co-Investigator, Mingzhou Ding, is reknowned for his imaging expertise. I also work with a lot of very innovative investigators here at the University of Florida in terms of the therapeutic side of things. My collaborators on the project, Robert Caudle and Marcello Febo, have some novel therapeutics as far as targeting specific pain fibers. And we’re working with another investigator here, Todd Golde, who is an expert on viral delivery of pain therapeutics.
That’s the direction we’re going to take in terms of innovation, in what we think will be the best approach for treating trigeminal neuralgia. It’s basically a very safe virus that you can program to modify certain genes. You can have genes and proteins increase or decrease, depending on what you program into this vector.
The nice thing about these vectors is that it’s just an injection. People who have trigeminal neuralgia start out with some medication like Tegretol and if that doesn’t work they go to some kind of surgery and they may go to another surgery. So the idea of using one of these viral vectors would be to do the injection prior to having surgery, to see how it works, Because you could always do the surgery afterward. It makes sense to have this kind of therapy. I think people would prefer it if we could just inject something to end the pain.
MR: Why haven’t researchers completed this research years ago?
Two main reasons come up. It’s like a lot of things – technology and money. Advances in technology relating to computer power have really accelerated in the last five or ten years. Our imaging studies, as far as analyzing the data and narrowing the resolution of what we’re trying to locate, use very powerful magnets and computers.
It also really comes down to funding. Trigeminal neuralgia is a relatively rare disease, and there’s not a lot of emphasis on trying to get money to study this disorder. Pain is one of those disorders that’s not a disease. There’s a tremendous need to find new products, new pain therapies, but the situation doesn’t fit nicely in any of the National Institutes of Health categories as far as funding needs go.
MR: What are the biggest obstacles you face in translating your preclinical findings to the clinic?
Probably it’s just going to be dealing with the Food and Drug Administration’s regulatory process as far as getting a new therapeutic treatment approved. That process can take many years. So if we’re thinking about injecting a viral vector or using some kind of other therapeutic, a lot of other studies have to be completed first. Toxicology has to be worked out – we have to make sure it’s a safe approach. And then evaluate the therapeutic efficacy later. One of the problems we run into as researchers and trying to translate things is that many substances or therapeutics work very well in mice or rats, but we’ve seen previously that when you take the same substances and try them on humans, a lot of times they fail. That’s always an issue. Something that works on a rat doesn’t always work on a person.
MR: Every day many people in pain are contacting the Facial Pain Research Foundation asking if it is truly possible to find a cure for trigeminal neuralgia. How would you respond to their question?
I would say it is possible. We’re putting a lot of resources and a lot of brainpower into the problem and we’re hopeful that we can find something. This is a collective “we” I’m talking about – including the other investigators who are involved with the Facial Pain Research Foundation, the groups in Israel, Toronto, Portland, San Francisco, London, New Jersey, North Carolina and Florida. There are a lot of smart people working on this project to find a cure.
Volunteers Suffering from Trigeminal Neuralgia Needed for this Brain Imaging Study
Enrolling eligible volunteers to participate in a research study about brain imaging:
To be eligible you must be:
-18-75 years old
-Suffer from Trigeminal Neuralgia…diagnosed with Trigeminal Neuralgia
-Prefer Classical TN (Type 1) and Atypical TN (Type 2)
-Average Pain in the moderate to severe range
-No additional major health problems
-Be able to go to Gainesville Florida and spend approximately 4 hours
-Fluent in English (written and spoken)
Exclusion:
-Unable to complete a magnetic resonance imaging (MRI) scan due to implanted
or un-movable metal material in your body or severe claustrophobia.
For further information about volunteering for this study call or email:
Dr. John Neubert (352) 273-5687 or This email address is being protected from spambots. You need JavaScript enabled to view it.
This Study is directed by Dr. John Neubert, UF College of Dentistry, McKnight Brain Institute
Meet Tina Johnson
Tina Johnson is a Trigeminal Neuralgia patient who has been volunteering with the Facial
Pain Research Foundation for a couple of years now. Tina discovered the Foundation as she
was doing research about TN and reached out to see what she could do to help. Tina organized
two fundraisers in Central Florida to raise funds and awareness about TN. Tina has also started
a Central Florida area support group that she has been hosting at ORMC in Orlando.
Hello everyone!
Tina here. I wanted to take some time to thank everyone for the warm welcome and well wishesI have received as I take over helping with Communications. The Facial Pain Research Foundation is very important to me as I am a Trigeminal Neuralgia patient.
I was diagnosed in 2015 and had MVD on the left side in the same year. I’m still in pain. I discovered the FPRF as I was doing some research on TN post surgery. I quickly got involved and hosted a couple of fundraisers in the Central Florida area. I have also started a Central Florida area support group for TN which I have been hosting at ORMC in Orlando. The next meeting is in June if you are local! And at all of 5’, I know I have some big shoes to fill.
Frank was one of the first who I interacted with at the Foundation and I am so thankful to him for all he has done for me, but mostly for all he did for this ever important cause. Please feel free to reach out to me should you wish to brainstorm on volunteering, fundraising events, to make sure you are receiving our newsletter, or just to talk TN.
I am honored and consider this a huge privilege to be able to continue being an active part of and representing the FPRF in new and exciting ways.
All my best!
Tina
Communications Coordinator
This email address is being protected from spambots. You need JavaScript enabled to view it.
This email address is being protected from spambots. You need JavaScript enabled to view it.This email address is being protected from spambots. You need JavaScript enabled to view it.