How An Artist Faces Her Facial Pain

Suneet Sethi is an artist, illustrator, performance artist, and art educator. She grew up in a Sikh family residing in New York.

She began drawing profusely as a quiet and curious child as a way to make sense of the world and the people around her. She later studied Communications at Boston University, and after receiving her BFA continued her studies as a graduate student at NYU. During this time she depicted multicultural and identity issues within her artwork. She created art installations and performed in various galleries and public spaces across New York. Her “Dress of a Thousand Secrets” performance was featured in the print magazine, “Bitch”.Suneet began her career as an art educator introducing questions of social, cultural, gender and political identities using multimedia including recycled materials, puppets(making), and video. She believes in the living, breathing, classroom-always evolving and changing and dependent on the lives and collaboration of its constituents- She often immerses in the learning process with her students by engaging them on contemporary art and issues meaningful to her students. While teaching at Country Day School at Marin County, she became inspired by a colleague to pursue animation. She taught herself various 2d/3d animation techniques before being accepted to the reputable Calarts Experimental MFA Program.While in graduate school, and following a routine dental extraction, Suneet began to suffer a dull ache in her gums that never seemed to abate but only worsened to a stabbing pain that extended to other parts of her face. The pain became so unbearable that she was forced to take a Medical Leave from her studies and put her life on hold.

In the beginning, many baffled health professionals including dentists found the pain to be mysterious, psychological, and idiopathic in nature. After a year of various testing, doctor office and ER visits, she was officially diagnosed with Trigeminal Neuralgia. Her next years were spent coping with and understanding the excruciating pain patterns of the condition. She was prescribed many of the anti-epileptic and neuropathic pain medicines but their many adverse and dangerous side effects only further reduced her quality of life, without reducing much of the pain. After two years of struggling with pain, simply daily activities such as eating, brushing her teeth, washing her hair, and talking became too challenging. After losing a significant amount of weight and dropping down to a dangerous 94 lbs., Suneet decided to undergo multiple Microvascular Decompression brain surgeries. The second one was successful enough to allow her the ability to not only survive with the pain, but to truly live again despite the pain. She began to examine what brought her most meaning in life and spent more time connecting with loved ones. She changed her lifestyle through diet, acupuncture, meditation, mindfulness, inner work, and began to accept the pain instead of fighting it.The pain gradually decreased and Suneet now aspires to spread awareness of the disease through her work. She still hopes for a cure everyday. Suneet is extremely grateful to the people she met during her journey including those who volunteer at the foundation to find a cure, neurosurgeons including Dr. Mark Linskey, and Dr. Jeffrey Brown, doctors, nurses, hospital staff, her family, friends, other survivors, who through their brilliance, profound empathy and unwavering love, save lives and spirits and carry them when they have fallen and can’t stand on their own. Without these brave people, she would not be alive today. During moments when severe breakthrough pain would last for days with no relief in sight and thoughts of giving up began to infiltrate her mind, the hope of her family and friends carried her. These people are her heroes. She survived and there are now hours and even some days without much pain. She thinks of herself as one of the lucky ones.

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)

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.

Characterizing A New Biological Therapy For Treating

Trigeminal Neuralgia

by Robert M. Caudle, Ph.D.

Department of Oral and Maxillofacial Surgery

University of Florida

Trigeminal Neuralgia is a devastating disease that is poorly controlled with current therapies. Tegretol is partially effective in some patients and vascular decompression surgery provides a bit of relief for others.

However, most patients do not find these therapies sufficiently effective because the root cause of Trigeminal Neuralgia is not known. It is difficult to address the underlying etiology with novel therapies.

We, however, have identified neurotransmitter systems on the trigeminal neurons that transmit the pain signals from the face to the brain. The receptors in the neurotransmitter systems offer unique targets for delivering biological agents that alter the function of the neurons. Although this form of therapy does not attack the cause of the disease, we can exploit these receptors to disrupt the transmission of pain to provide relief to the patients.

We have constructed a novel biological agent that can prevent the transmission of pain signals through trigeminal neurons that express the receptors associated with a specific neurotransmitter system.

Preliminary studies have demonstrated that the agent targets the appropriate neurons and that it retains its biological activity for at least 24 hours following uptake by the neurons. We expect that the agent will be functional for up to three months following administration.

In this project we will be scaling up production of the agent and conducting rodent studies to determine if the agent blocks pain from nerve injury as predicted. We will also evaluate the most appropriate route of administration, the dose, and the duration of action of the agent to optimize the therapy protocol. These studies are expected to provide the basis for initiating human clinical trials to develop this agent as a therapy for Trigeminal Neuralgia.

Note: The Facial Pain Research Foundation’s Board of Trustees is committed to funding Dr. Caudle’s research project described above. Start date of the project is June 1, 2019 and the first phase is to be completed within twelve months.

Amazon to Support The Facial Pain Research Foundation

It takes millions of dollars for scientists to find a cure. The world-wide support for The Facial Pain Research Foundation’s six research projects to find a cure for trigeminal neuralgia and related neuropathic pain has grown enormously over the last three years. Corporations, foundations, scientists, medical professionals, celebrities and individuals have donated their time, money and talents to help our international consortium of researchers. Much of the momentum is the result of friends with neuropathic pain asking their friends to help. As a result, Amazon has become a helper to our growing team of supporters. Please think about your friends and how they can also help us and let us know at This email address is being protected from spambots. You need JavaScript enabled to view it.

Amazon wants to help raise money for The Facial Pain Research Foundation through its Amazon Smile Program. It’s as easy as shopping on Amazon.com, in fact that’s exactly what you do. The Facial Pain Research Foundation is now supported by Amazon.com’s Smile program. The Smile program allows a portion of purchases made on Amazon Smile to go directly to The Facial Pain Research Foundation.

When you shop at smile.amazon.com, you’ll find the exact same low prices, vast selection and convenient shopping experience as Amazon.com, with the added bonus that Amazon will donate a portion of the purchase price to your favorite charitable organization.

If you already have an Amazon.com account

Simply type in Smile.Amazon.com on your browser and login

Click ‘Select and Start Shopping’.

In the top menu bar ‘click the down arrow’ to the right of ‘Your Account’, then click ‘Change Your Charity’ in the drop down list and choose The Facial Pain Research Foundation

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