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.

HUMAN STUDIES

Recruitment (Table 1)

TN	Control	TN with surgery	TN without surgery	TN1	TN2	TN1/TN2
42	3	20	22	28	3	11

Forty-two TN patients (25 females) and three age and sex matched controls have been recruited and data from thirty-seven TN patients have been analyzed to date. One patient who had surgery no longer felt pain and was not scanned. Two patients did not complete the scan. Data from two recently scanned subjects have not been analyzed. We are planning to recruit additional TN and control subjects (N = 10-15/group) in the next few months.

Brain Activations during Trigeminal Pain Table 1

We recorded pain ratings during the fMRI scans to allow us to uncover brain regions that become activated during a TN pain episode. There are several interesting regions that are activated (Fig. 1) including the anterior insula, caudate, putamen, thalamus, and prefrontal cortex. This is important because identification of such brain regions serves as a fundamental and necessary step towards finding central-nervous system targets for effective therapeutic interventions in TN.

Fig 1. Regions of brain activation during TN pain episode.

Neuroinflammation and TN

The pontine crossing tract (PCT) is a region of the brain that links the brainstem and left/right cerebella and is an area of interest for processing trigeminal pain. We evaluated a free water (FW) analysis of this region as a marker for TN-related neuroinflammation. As shown in Fig. 2 (left), there is a significant positive correlation between free water in the PCT and disease duration in non-surgery TN1 patients. As a comparison, we analyzed scans from subjects with temporomandibular joint disease (TMD), another chronic orofacial pain condition. We found that the increase in FW in the PCT did not correlate with disease duration in the TMD cohort (Fig. 2 (right)). This finding is important because it indicates that there may be a specific mechanism or biomarker for TN, which is not present in other chronic orofacial pain disorders. These findings suggest that in non-surgery TN1, as the disease progresses, neuroinflammation becomes more severe; this pattern is specific to TN1 and not found in TMD. This is important because the FW analysis may be used as both a diagnostic biomarker of TN and to study mechanisms related to TN.

Fig 2. Pontine Crossing Tract (PCT) free-water (FW) as function of disease duration in non-surgery TN 1 (N=12) and in TMD.

Fig 3. Different thalamus and anterior cingulate (ACC) activity produces TN pain. During the scan (A), activity from ACC to the thalamus (B) unmasked pain activity from the thalamus to the ACC (C) ignited pain.

Novel regions related to TN pain: Central Ignition via Thalamic Disinhibition

For the six TN1 patients who exhibited clear on-off pain attack patterns in the scanner, we found that specific regions of the brain (thalamus and anterior cingulate cortex) affected the pain onset. In Fig. 3A (top), the up arrows indicate pain onset, and the colored intervals define the three time periods of analysis. Immediately prior to the onset of pain attacks (Pre-pain), top-down inhibitory influence from anterior cingulate cortex (ACC) to thalamic, ACCàThalamus, was reduced relative to a baseline condition (Resting) (Fig. 3B), causing thalamic disinhibition. Concurrently, the thalamic input into ACC, an important structure of the pain matrix, was increased (Fig. 3C) immediately preceding the onset of pain attacks, a phenomenon we referred to as central ignition. These results outline a clear mechanism of TN pain and suggest a possible therapeutic approach: by enhancing the ACC top-down influence we may restore the inhibitory control over the thalamus and thereby reduce the level of pain and the frequency of pain attacks. Our simulation study shows that transcranial direct current stimulation (tDCS) applied in a M1-SO configuration may be such a therapeutic approach. We tested the efficacy of the approach in patients to date. After 20-minutes of 2 mA tDCS stimulation, both patients reported ~40% reduction in pain level (from 50 to 30). We will continue the tDCS procedure as a pilot study to investigate the utility to modulate the brain regions identified in our previous studies.

ANIMAL STUDIES

Trigeminal Pain and Neuroimaging

Dr. Febo’s group has applied new analyses to the previously completed data set (~50 high-resolution fMRI scans of rats). The latest analysis compared rats with a trigeminal nerve injury (CCI) versus rats without the injury (sham). From this analysis, we found that there was connectivity in brain regions (Fig. 4), demonstrating that animals with trigeminal nerve injury show increased connections in pain sensitive structures within the brain. The different analyses used provide different ways of analyzing how these different structures interact and relate with other regions during different pain states. A number of regions were significantly different in CCI vs. Sham animals and this is important because this will allow us to compare the human and rat imaging results.

Control

Pain

Fig 4. Rat brain neural connectivity changes 2-weeks following chronic constriction injury (CCI) of the trigeminal nerve. Different analyses were completed in groups of animals that either had bilateral CCI (Pain) or sham (Control) surgeries. Significantly different regions include: dorsomedial striatum, paraventricular thalamus, posterior thalamus, ventral orbital cortex, ventral tegmental area, cerebellar nuclei. From the clustering coefficient analysis, we found these regions to be significantly different: cortical amygdala, ventromedial thalamus, anterior cingulate, ventral orbital cortex, somatosensory cortex.

For the six TN1 patients who exhibited clear on-off pain attack patterns in the scanner, we found that specific regions of the brain (thalamus and anterior cingulate cortex) affected the pain onset. In Fig. 3A (top), the up arrows indicate pain onset, and the colored intervals define the three time periods of analysis. Immediately prior to the onset of pain attacks (Pre-pain), top-down inhibitory influence from anterior cingulate cortex (ACC) to thalamic, ACCàThalamus, was reduced relative to a baseline condition (Resting) (Fig. 3B), causing thalamic disinhibition. Concurrently, the thalamic input into ACC, an important structure of the pain matrix, was increased (Fig. 3C) immediately preceding the onset of pain attacks, a phenomenon we referred to as central ignition. These results outline a clear mechanism of TN pain and suggest a possible therapeutic approach: by enhancing the ACC top-down influence we may restore the inhibitory control over the thalamus and thereby reduce the level of pain and the frequency of pain attacks. Our simulation study shows that transcranial direct current stimulation (tDCS) applied in a M1-SO configuration may be such a therapeutic approach. We tested the efficacy of the approach in patients to date. After 20-minutes of 2 mA tDCS stimulation, both patients reported ~40% reduction in pain level (from 50 to 30). We will continue the tDCS procedure as a pilot study to investigate the utility to modulate the brain regions identified in our previous studies.

FUTURE STUDIES

We plan to recruit and scan 15-20 more TN1 and control subjects. Dr. Febo’s group will continue to analyze the animal imaging data set. These results will be included in the preclinical animal imaging manuscript (in preparation)

Mervyn Rothstein Interviews

Dr. Wolfgang Liedtke

Wolfgang Liedtke, M.D., Ph. D., is a professor in the Departments of Neurology, Anesthesiology and Neurobiology at Duke University in Durham, North Carolina. He is an attending physician in the Neurology Clinics for Headache and Trigeminal Sensory Disorders and an attending physician in the Innovative Pain Therapy Clinics of the Department of Anesthesiology at Duke. Both as a physician and as a scientist, his focus is on understanding mechanisms critical for pain and inflammation in order to alleviate suffering of patients afflicted by therapy-refractory pain – pain that does not respond to treatment – with the emphasis on trigeminally-mediated pain (trigeminal nerve pain, also head-neck pain), but also other nerve and joint pain. As an attending physician, he has encountered more than 1,500 cases of refractory trigeminal pain disorders, as well as chronic migraines.

The Facial Pain Research Foundation has provided a grant to Dr. Liedtke and the Duke University Center for Translational Neuroscience as one of the Foundation’s projects to find cures for trigeminal neuralgia and related neuropathic pain. Dr. Liedtke and his group at Duke are exploring how material science and material science combined with cellular engineering can be used to make transmission of neural signals in the trigeminal system normal again.

Mervyn Rothstein, who was an editor and writer at The New York Times for 30 years, now writes the "Stage Directions" column for Playbill.com, and is a former member of the Tony Awards Nominating Committee. His first symptoms of trigeminal neuralgia occurred in 2005.

Dr. Liedtke spoke with Mervyn Rothstein.

MR: YOU ARE BOTH A NEUROLOGIST AND NEUROSCIENTIST. WHY DID YOU DECIDE TO FOCUS ON PAIN IN YOUR CAREER?

WF: As a junior trainee, I was exposed to pain because of the places where I trained, in Zurich, Switzerland, and in Germany. Programs there were run by expert and master physicians, and I was impressed by how they were able to help patients suffering from chronic pain. And I was also profoundly touched and moved in a very basic human level by the suffering that I saw, and that I could not fail to notice. Seeing how the physicians treated and diagnosed these patients impressed me, and I volunteered to help them from my junior perspective and work with them and do the first interview of the patient. I saw that I could do this pretty well. I have a good feel for it and can communicate well with patients who suffer from chronic pain.

When I shifted more toward basic science in a laboratory setting, I happened to make a discovery that was important and relevant to pain, which was sort of serendipitous because I was aiming much deeper and looking for basic new mechanisms. It turned out that the TRPV4 ion channel, the signaling molecule, which I discovered two decades ago, is a relevant, significant player in pain, also craniofacial pain. We found it expressed in the trigeminal ganglion in small neurons, which meant this could be relevant to pain.

Then, moving to Duke University, for my first independent faculty position, with the lure of being both a physician and a scientist, I decided that pain would be a very appropriate theme for me because it would allow me to practice pain medicine and also move forward my pain-related discovery in the basic science research lab.

WHAT IS THE IMPORTANCE OF YOUR TRIGEMINAL NEURALGIA RESEARCH STUDY AND WHAT POTENTIAL IS THERE FOR HAVING AN IMPACT ON THE STUDY OF OTHER DISEASES AND POSSIBLE CURES?

I’m extremely grateful for the support of the Facial Pain Research Foundation because it enables me to take a project that is at the drawing board stage and has some initial data to it and give it a more solid base under its developing legs.

On the drawing board the imagination was to harness the power of stem cells that we engineer to become a certain type of cell that will help to function as an anti-pain generator and get that specifically engineered cell close to a key anatomical site of the trigeminal system, the cisternal trigeminal nerve root, which is the target of the well-known microvascular decompression operation and is also the target for the gamma knife radiation procedure [two medical methods of eliminating or alleviating trigeminal neuralgia pain]. Rather than operating or radiating we propose to bring cells close to the nerve root and engineering the cells so that they function anti-pain, so that they secrete and produce natural anti-pain modulators. By forcing them to reside close to the trigeminal nerve root, they will calm down and bring down the excitation level and inflammation level in the nerve root and in the entire trigeminal system.

And in positioning these cells right next to the cisternal trigeminal nerve root we will use a material that functions as a holding device. The cell-holding device we will also accomplish what the traditional, good old-fashioned microvascular decompression accomplishes, which is to protect this critical part of the trigeminal system against mechanical injury.

In a parallel approach, while we move forward with “encaged” cells, we will also try to take advantage of a new nanomaterial [material made up of building blocks that are at the nanoscale] that I have done work on previously through my collaborative network here at Duke University, where we have material scientists and chemists and we harness the novel advantageous properties of a model carbon nanomaterial to use as a shield/ wrapping material for the trigeminal system. It could be described as facilitating a neuro-protective environment.

These are the two approaches I’ve articulated and for which I’ve received support from the Facial Pain Research Foundation and which might have significant implications for other types of pain. These approaches could be applied to other nerves that were injured, resulting in nerve pain, for example a lumbar root of the sciatic nerve, the cervical nerve roots that supply the arm or other peripheral nerves (sciatic, ulnar, median). Both methods are translatable to these other types of neural injuries.

WHY HAVEN’T SCIENTISTS COMPLETED THIS RESEARCH YEARS AGO? WHEN SOMEONE ASKS YOU WHY DIDN’T YOU START THE RESEARCH MANY YEARS AGO HOW DO YOU RESPOND?

The conception of these ideas is based on the thoughts and fantasy and imagination one has but also on new theories or other findings that are sprouting up within the field, what you read and what you hear at conference meetings. Microvascular decompression works in a number of patients, not in all, and it has other issues involving it, so I was certainly not the only one thinking about trying to upgrade or make it more contemporary, more focused. What I’m proposing is based on relatively recent findings that I hope to take advantage of. So these ideas weren’t possible before these new findings were made public.

YOU SEE PATIENTS IN PAIN EVERY WEEK. DO YOU REALLY BELIEVE THAT CURES CAN BE FOUND FOR THIS DISORDER, WHICH IS OFTEN CALLED THE “SUICIDE DISEASE”?

I strongly and profoundly believe that transformative steps can be taken to deal with this form of pain. It depends on the definition of cure. There is the possibility of a so-called miracle cure, where something is done and the patient is totally cured – the pain is out of the life of the patient who was tormented by trigeminal neuralgia. But the miracle cure is harder to accomplish than a decent and what I call a transformative level of pain control, whereby pain is reduced to a level where patients can lead a normal life again, can participate in life and deal with the remaining amount of pain disturbance that the disease still poses. I believe that is something we can accomplish through implementing and translating research for more and more patients.

WHAT ARE THE BIGGEST OBSTACLES YOU FACE IN TRANSLATING YOUR PRECLINICAL FINDINGS TO THE CLINIC? WHAT ARE SOME OF THE WAYS YOU HOPE TO OVERCOME THEM?

We live in exciting times. We have so many tools at our fingertips. If only we had the money. That is one obstacle – availability of funding to realize our ideas – not just bold ideas that lead to brave new experimental approaches on the laboratory bench but also something is translatable, and is equally daring or has a decent chance of leading to dramatic advances.

Also there are administrative and so-called red tape obstacles that would not cost a lot of money to overcome - rewriting or redoing the complex rules that govern the scientific research game and especially the rules governing translation into new treatments that will be available to patients. Scientists and doctors can make their voices heard, but this is an involved national and international decision-making process where our views are of limited impact. I am enthusiastic that the Facial Pain Research Foundation is becoming partial to the ways of how to revisit and reform the process.

THE FACIAL PAIN RESEARCH FOUNDATION IS MOVING FORWARD WITH A SENSE OF URGENCY TO FIND CURES FOR TRIGEMINAL NEURALGIA AND RELATED FACIAL PAIN. WHY HAVE YOU LINKED YOUR EFFORTS TO SUCH A NEW ORGANIZATION IN THE FIELD OF PAIN RESEARCH? AND HOW IMPORTANT IS THE FACIAL PAIN RESEARCH FOUNDATION TO YOU AND YOUR WORK?

I feel privileged and I’m very happy about this association. They are like-minded people. I intend to go after this disease. I attempt to accomplish this goal of transformative change of treatment effectiveness through novel engineered treatments. That is my mantra. And there is nothing hollow about it. Every single letter of that is true to the core of who I am as a professional.

So with that, I notice that the Facial Pain Research Foundation is managed and is driven by people with whom I have zero disagreement in that respect. I am so happy and so proud to be a part of it.

First Published 12 January 2011

EMILY'S STORY

By Laurel Garland

In 2003, When Emily was about 2 ½ years old, I remember her starting to cry at the table one day when she was eating. I thought she had bitten her tongue or her cheek. It didn’t seem like anything serious, so I just comforted her and thought nothing of it. It happened a few more times at the dinner table over the next few days, so I thought she had done it again. I checked her mouth and didn’t see anything. She was talking, but didn’t have enough words to tell me what had happened.

After several weeks, a similar incident occurred, and I reacted in the same way. Over the course of the next year or so, this happened from time to time, and I really thought she had just bitten her tongue or something. Several weeks or even months would go by in between and I would completely forget about it. After a while I started to think it must be a toothache, so when she was 3 I made an appointment with a dentist and took her in. He did a visual exam and said that it wasn’t a toothache because he would be able to see it if it was bad enough to be causing pain. I didn’t know what to think. Very soon after the appointment, the pain disappeared again and I guess I just decided it was over.

Within a few months, she started crying and putting her hand to her cheek in the bathtub. She has always loved her bath, and even loves to have water dumped over her head. She can’t get enough of the water. Looking back, I think when she started having trouble in the bathtub it was from water splashing on her face. I didn’t know it at the time and again wrote it off to a cheek bite or something. All she could tell us is that her cheek hurt. She wasn’t able to describe the pain or articulate what was happening. Again, these occurrences were extremely irregular and unpredictable, with several weeks or months in between, so I tended to forget about it when the pain went away.

I think when we really started to realize something was going on, she was close to 4 years old. The pain was becoming worse, more frequent and it was lasting longer. She started to have pain when we brushed her teeth and when we would dress and undress her. She also would have trouble sometimes if I kissed or touched her cheek. The hard part was that these “triggers” didn’t always cause pain, so it seemed like there was no pattern. I was completely confused and didn’t know what it could be. I thought again that she must have a cavity, so I took her back to the same dentist’s office. She was examined again with the same result. I was really starting to be concerned and frustrated.

At that point we decided we should take her to her pediatrician. As always, during the exam Emily was completely fine, even when the doctor would poke and prod her cheek and mouth. So, the doctor had to go strictly by my explanation. Emily still couldn’t really describe it (the pain) herself. The pediatrician examined her and recommended that we should go to an ENT because she thought Emily might have stones in her salivary glands.

At the ENT appointment, the doctor did an exam and said that she didn’t have stones in her glands. He didn’t know what else it could be, so we left without an answer. He said to come back if it got worse. I was unhappy with that recommendation because we had been dealing with this for at least a year by now. I knew it wasn’t going to just go away.

So I made another appointment with her pediatrician. This time she said that she thought Emily might be faking it to get attention. We didn’t know what to think, because we had been to 2 doctors and a dentist who all said there was nothing wrong. So, my husband and I decided that we were going to stop giving her attention when she complained about her cheek to see if that would take care of it. For several days we ignored her when she cried and even told her that there was nothing wrong with her and that her cheek didn’t hurt. It seems insane now when I look back at that, and I feel extremely guilty for not comforting her or doing anything to help her during that time. We were completely at a loss, and didn’t know what to do.

In the summer of 2004, Emily started waking up crying in the middle of the night with cheek pain. Of course we knew then, without a doubt, she was not faking it. I became extremely concerned at this point, and I decided to take her to a different dentist. This time I found a pediatric dentist and made an appointment. He did an exam, and for the first time, Emily showed pain symptoms during the exam. She cried and was inconsolable throughout the exam. I told them I wanted X-rays, and they tried, but Emily couldn’t stand to have the little film cards in her mouth. So we left with the same result. He said her teeth were fine.

I remembered that the ENT who examined her told us to come back if her pain got worse, so I made another appointment. I had pretty low expectations about this visit, because he had already told us he couldn’t find anything, but I had to do something. He did another exam and again told us there was nothing wrong that he could see.

In August of 2004, I opened up the phone book and went to the Yellow Pages to find another pediatric dentist. I just figured that until Emily’s teeth were X-rayed, I wouldn’t be satisfied. And we had nothing to lose and no other ideas. I went to the Yellow Pages and found a pediatric dentist who was near where I live. I made an appointment and we got in right away.

Before Dr. Hishaw had even examined Emily, I explained her history with cheek pain and told her about all the doctors I’d taken her to, including previous dentists. As soon as I finished our story, Dr. Hishaw said “that sounds like trigeminal neuralgia.” I had to have her repeat herself. I had never heard of it, so she gave me a brief explanation and then said that I should take Emily to a neurologist, who could evaluate her and make a diagnosis. Then she did a full exam, including X-rays, and said Emily’s teeth were fine.

I contacted Emily’s pediatrician, who referred me to a pediatric neurologist, and I made an appointment. He ordered an MRI to rule out other possible causes, but he thought it might be TN too. Emily had her MRI, which was normal, so he prescribed neurontin, an anti-seizure medication that was supposed to suppress the nerve impulses that were causing pain. He told us that pain-killers like codeine were useless against this type of pain. By then we had already figured that out, because the Tylenol with codeine that Dr. Hishaw had prescribed wasn’t helping.

We were so excited to finally have a diagnosis and thought that our problems were behind us. We didn’t realize it then, but everything was about to get 100 times worse. While Emily was on the medication, her pain got progressively worse over several weeks. The neurologist increased the dose about every 7-10 days, but it wasn’t helping.

It got so bad, that finally in October of 2004, she stopped eating, drinking and sleeping. She was in so much pain that she was screaming about every 10 minutes or so, and she had lost her voice. She was also drooling because she couldn’t stand to swallow. She sat on the couch like a zombie, afraid to move because literally any movement triggered the pain. There was no way we could brush her teeth. We could barely get her medicine down. I called the neurologist’s office, and his nurse told me to take her to urgent care. I was very skeptical, because I knew by now that TN was a rare condition and I doubted that an urgent care doctor would be able to treat it effectively.

We went to urgent care, and waited for hours to get in to see the doctor. Emily was screaming in the waiting room, but because she looked fine, I guess they didn’t think she was a priority case. When I finally got Emily into an exam room, the pain had disappeared. The doctor looked at me like I was crazy when I told her what was happening. By then, Emily was acting like herself! The doctor prescribed more Tylenol with codeine even though I told her that it hadn’t worked in the past and that her neurologist had said that it wouldn’t be effective. She also prescribed oxycontin, which is a stronger narcotic. I gave Emily the oxycontin, which didn’t work at all, except to make her even more tired and disoriented.

I started searching online to find out anything I could about TN. I found the TN Association Website and a local support group. I called the support group leader, who answered right away and talked to me for about 40 minutes about TN. He gave me loads of information about what TN is, what causes it, different treatments, etc. He also told me about a local neurosurgeon who worked with the support group and who specialized in treating TN. He got us in to see Dr. Sanan the next day. Dr. Sanan did an exam and told me that he thought Emily should try Tegretol, another anti-seizure medicine. He called Emily’s pediatric neurologist and they worked together to find the right dose for her. Tegretol is a very strong medicine that can have severe side-effects, including liver damage. Emily would have to have regular blood tests to monitor her liver function while on the medication. I got the prescription filled at about 5:30 that day. I gave Emily a dose in the car after leaving the pharmacy, and within about 30 minutes she was completely fine.

We didn’t do any celebrating yet because we thought it was entirely possible that it was just a coincidence. Emily’s pain had been coming and going randomly for close to 2 years, so we were reluctant to believe that it was over just like that. In a follow-up visit with Dr. Sanan, he explained that Tegretol did have an immediate effect, and the fact that it had worked so dramatically for Emily confirmed she did have TN.

The Tegretol worked for Emily for more than a year, but we kept having to increase the dose because her body was building a tolerance to it. We knew that medication was not a permanent solution, and continued to investigate other options. We learned about Microvascular Decompression (MVD), which is a surgery performed on the trigeminal nerve next to the brain. We were cautioned about this surgery by the pediatric neurologist who was managing Emily’s care at the time, and we decided we would put the surgery off for as long as we could.

In the fall of 2006, Emily was on the highest acceptable dose of Tegretol and her symptoms had returned. She was in her second year of kindergarten, and was having a very hard time. She was in pain much of the time, and wasn’t learning. She wasn’t reading at all after a full year of kindergarten and she had even begun to have difficulty spelling and writing her name. This is something she had been able to do before she started school. We were becoming more and more concerned about the side effects from the medication and were starting to feel desperate again. We wondered if the medication was doing more harm than good.

That fall I also attended the bi-annual TNA conference in Portland, Oregon. I was looking forward to talking to doctors from all over the world who specialize in the treatment of TN and I wanted to learn more about surgical options. Emily’s story had come to the attention of the Trigeminal Neuralgia Association because of a news article done by our local paper, and a Discovery Channel show that profiled her earlier that year. At the conference, several doctors came to me to talk about her situation, including Dr. Mark Linskey from UCI Medical Center in Irvine, CA. He was very encouraging about the surgery option and urged me to consider it. He told me he had performed MVD on children before, and all were now pain free.

I called his office and made an appointment as soon as I got home, and within a month had an appointment for surgery. Dr. Linskey performed an MVD in October, 2006. It was extremely scary, but I also remember feeling a great deal of hope. For the first time in years, I felt the possibility that Emily could be “cured.” Her surgery was about 5 hours long. Dr. Linskey said her condition was one of the most severe he had seen. He showed us pictures of the clusters of veins that were wrapped around and even running through her trigeminal nerve. He was confident that the surgery was a success. She was in the hospital for three days and then had to stay in near the hospital for 2 weeks before she could return home. The surgery was 100% successful with no side effects or complications. She hasn’t felt a single twinge of pain in her cheek since she woke up in the recovery room.

As she began to recover from surgery and the medication began to leave her system, we started noticing her personality and behavior change. She wasn’t as “clumsy” as she had been. Looking back, I remember her legs being full of bruises from tripping, falling and bumping into things. I didn’t understand what the medication had been doing to her. She began to do better in school, and within about 6 months was reading above grade level. She had more energy and she became more confident in her day to day activity. Within a few months she didn’t shy away from water or her toothbrush. She began eating crunchy foods again. It didn’t bother her to drink from a straw or suck on candy or chew gum. She didn’t mind changing clothes or being kissed on the cheek anymore.

Now, 4 years later, Emily is 10 years old (she will be 11 in January 2011) and is still pain free. All she has to show for her ordeal is a three-inch scar behind her right ear and the memories of the pain. She talks about it every once in a while. She also talks about Dr. Linskey and how he “fixed her cheek.”

Sometimes it feels like it was yesterday that we were going through the nightmare of TN. It’s hard to explain the fear and panic that we experienced. For almost four years, it took over our lives. Emily suffered so much. It was hard to watch and not feel completely helpless. It took more than a year after her surgery before I could go a full day without thinking about it and worrying that it would come back.

We’re extremely lucky that Emily’s story turned out so well in the end and I wish there was a cure for everyone who suffers with this condition.

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 "RegionalÂ Â 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

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