speaking firstly on the kind of pathophysiology and etiology of small fiber neuropathy, and then as the group progresses, we'll kind of go through our whole schema. I've served on medical advisory boards for Catalyst and ITF Therapeutics, received research report from Hereditary Neuropathy Foundation in Sarepta. After today, I hope we will be able to understand the anatomy of small fiber nerves, identify the phenotype of small fiber neuropathy in children, recognize the emerging causes of small fiber neuropathy, and briefly discuss the tools available to identify small fiber neuropathy. To start, I'd like to present one of my patients. She's a 17-year-old female with past medical history of back pain, who presented with pain in her neck, and intermittent numbness and tingling in her hands and her feet. Four months prior, she woke up from sleep and felt something pop, and then she felt a sharp pain in her back that radiated up to her head. One month later, she couldn't walk or pick up her arms, not due to pain, but not weakness. She described the quality of her pain as aching in the lateral upper arms, and a sharper pain going into her fingers. Sometimes she'd get cramping in her palm or aching between the joints, and sometimes touching her palm would lead to tingling. She didn't have any specific weakness, as I mentioned, though more recently, she had been having trouble with writing and pencil grip. The pain in her hands was intermittent, and sometimes a stabbing or sharper pain, focused mostly on the palm or thenar eminence. Her pain was worsened by sitting up, and therefore she spent most of our visit lying down. And she also had a burning pain in her feet that was of different quality than the pain in her back. She was very point tender on the C7 spinous process area. Sometimes she would get headaches, they were frontal, sharp, she felt nauseous with them. And maybe in review of systems, she doesn't sweat on her chest and her stomach. She had undergone multiple evaluations that I'll detail. She got steroid and lidocaine shots that maybe held for three to four days, and mom felt that naproxen helped, but that was the only thing that even touched her pain. She had an extensive workup before presenting to me. I won't go through this whole busy slide, but she was seen by three orthopedic surgeons, three neurosurgeons, one neurologist, one pain medicine specialist, two rheumatologists, and she was diagnosed with an undifferentiated MSK disorder, an overlying functional pain or amplified pain syndrome. Prior to seeing me, she had an EMG nerve conduction study that did show chronic C8 radiculopathies, but no active denervation. And she had MRIs of her cervical spine, her entire spine in fact, but she had three in total at varying institutions that showed mild hydromyelia from C4, C5 to T1, T2. And that was considered by three neurosurgeons to have no clinical significance. Due to the question of Hiriyama based on the C8 radiculopathies, she had an MRC spine with flexion and extension that didn't show any concern for Hiriyama. And she had a flex extend X-ray that showed no instability. She had various lab work that was all essentially unremarkable. After trying a few more symptomatic treatments with no relief, we obtained a sweat test, which showed 45.4% anhydrosis in a mixed pattern. And at that time, given our sweat test, we pursued serologic workup with inflammatory markers, antibody panels, CYS2, WashU, and the remainder of vitamin testing. And surprisingly, despite no complaints of significant GI symptoms or weight loss, her celiac test came back positive. And she had an endoscopy, which was confirmatory for celiac. I'll come back to her in a little bit, but to delve into small fiber neuropathy, I'd like to briefly review the peripheral nervous system, which of course is composed of motor sensory and autonomic fibers, all varying size and myelination status. A-alpha fibers are large myelinated fibers in charge of motor function, of course, but for the purposes of this talk, we'll focus on the smaller sensory fibers and autonomic fibers. The sensory nervous system is composed of three types of nerve fibers, large fiber sensory nerves, or A-beta fibers, which are large myelinated fibers, A-delta fibers, which are smaller, thinly myelinated fibers with a conduction velocity of about 10 to 15 meters per second, and the unmyelinated C fibers with a conduction velocity of about one to two meters per second. The autonomic nervous system is mostly comprised of unmyelinated C fibers and includes postganglionic sympathetic fibers, innervating internal organs, along with pseudomotor fibers, innervating sweat glands. Large fiber sensory nerve fibers are responsible for touch, vibration, and proprioception, and dysfunction of these fibers can lead to numbness, sensory ataxia, and areflexia. And obviously, these are the only sensory fibers we can test on our standard nerve conduction study. Small fiber sensory nerves include A-delta and unmyelinated C fibers, which are slightly more elusive to test. A-delta nerve fibers sense sharp pain and temperature, and symptoms of dysfunction include tingling, prickly pain, hyperalgesia, temperature sensitivity, or analgesia. C fibers sense dull pain and temperature and manifest as aching pain, burning, itching, and temperature sensitivity, or again, analgesia. A-delta are often known as that sharp first pain, and C fibers are known as that dull second pain. Autonomic fibers include vasomotor, pseudomotor, and visceromotor fibers, and they are responsible for symptoms including skin color, temperature change, hyper or hypohidrosis, bowel, bladder, and sexual dysfunction. And dysfunction of the small fibers is obviously termed small fiber neuropathy. It's thought to be widely underdiagnosed. Thus far, only two major studies have quantified the patients suffering from small fiber neuropathy. One from the Netherlands estimated the prevalence to be about 53 in 100,000, and a study out of Switzerland estimated 131.5 per 100,000 population in 2021. It's thought that with improved diagnostic methods and standardization of diagnostic criteria, likely over four million people worldwide suffer with the disease. There have been no wide-scale studies in the pediatric population, surprise, surprise, and in many reports, the diagnosis of small fiber neuropathy remains idiopathic in about 50% of cases. Because small fibers encompass both sensory and autonomic fibers, if autonomic symptoms predominate, it's often termed autonomic neuropathy, leading to some further confusion. And there are many syndromes or conditions that likely are caused by small fiber neuropathy, such as chronic fatigue, erythromyalgia, POTS, CRPS, and likely some functional neuropathic or pain disorders. This compounds the underdiagnosis. In our institution alone, a simple query of diagnoses revealed a total of 84 patients in the past five years with coded diagnoses of small fiber neuropathy, probably all seen by Dr. Koontz. However, 156 patients had diagnoses of fibromyalgia, 96 with chronic fatigue syndrome, 1,687 with POTS, 43 with erythromyalgia, 468 with complex regional pain syndrome, and 23,000 with chronic pain. Of these, how many are we missing potentially treatable small fiber neuropathy on? Levine and colleagues in 2018 suggested a spectrum of terminology to possibly help define phenotypes of small fiber neuropathy based on predominance of pain or autonomic symptoms, which would likely help to characterize small fiber neuropathy and allow us to better determine underlying etiology. However, this doesn't take into account small fiber neuropathies with predominant negative symptoms, such as lack of pain or numbness, though it is listed as a symptom under small fiber-mediated painful neuropathy. Length-dependent small fiber neuropathy is the most common type of small fiber neuropathy in adults, likely secondary to dysmetabolic syndromes being the most common cause in adults. In the Swiss study mentioned before, 79.8% of their population demonstrated a length-dependent pattern, but in children, non-length-dependent small fiber neuropathy can happen more often. Diagnosis and assessment are more challenging than in length-dependent small fiber neuropathy because of the atypical phenotype, sometimes reminiscent of a functional neurologic disorder, and it's likely that non-length-dependent small fiber neuropathy is under-recognized and can lead to a delay in diagnosis, and with the patchiness of non-length-dependent small fiber neuropathy, standard skin biopsy may miss that area. Non-length-dependent small fiber neuropathy has a higher association with immunologic conditions, more likely to have itchiness or aledinia, and be less responsive to traditional pain meds. Non-length-dependent small fiber neuropathy is more commonly intermittent and migratory, and usually worse at night, making diagnosis even more challenging. As genetic testing improves, we'll likely be able to see specific genes associated with non-length-dependent small fiber neuropathy. For example, while sensory disturbances in men with Fabry disease has been consistently described as length-dependent, a non-length-dependent pattern has been seen reported in heterozygous females. Clinical symptoms can be wide, and often patients and practitioners can have difficulty with piecing the variety of complaints into a unified picture. Adults describe symptoms of increased pain with words like burning, stabbing, tingling. Alternatively, patients can have decreased pain sensation and present with ulcers or injuries to their feet without knowing it. Autonomic complaints can include those related to cardiovascular function, like palpitations or dizziness. Changes in sweating or secretions can be harder to differentiate, but may present as overheating or irritated, dry, itchy eyes from lack of secretion. GI and GU symptoms can be vast, like constipation or diarrhea, dyspepsia, urinary retention or overactivity, and skin changes like discoloration or temperature changes in the hands and the feet. Again, symptoms are usually worse at night. Bed sheet sensitivity of the feet is so often reported in adults that it's used as an outcome on clinical trials. And symptoms can be exacerbated by extremes in ambient temperature and often worse in cold weather. But in children, description of painful symptoms is challenging. Not until five years of age are children even expected to be able to use adjectives and adverbs and sentences. And according to Piaget, children from two to seven are still in the pre-operational stage of cognitive development, making description and abstract thinking difficult. Generally, they begin to be able to discuss the intensity and location of the pain, but less so the quality. In concrete operational stages of development between ages seven and 11, children can start to understand concrete quantitative measures of pain, like the pain scale, and it can be used and can begin to use abstraction and description of the quality of the pain, but still lack specific vocabulary. And not until age 12 do children enter the formal operational stage of cognition, where children can hypothesize and comprehend more abstract ideas and concepts. Therefore, children don't use words or descriptions that fit neatly into formal medical language. In our experience, we have heard patients describe burning pain as blasting rockets or bees buzzing, lack of pain as parents noticing that they have no reaction to stepping on Legos, cardiac symptoms can be interpreted as fatigue or laziness, hypohidrosis as overheating or flushing, GI symptoms as tummy butterflies or crying, and skin changes as hands being on fire. It's an important concept in potentially developing clinical trials for small fiber neuropathy in children, as many traditional scales would not be appropriate. While many studies cite up to 50% of small fiber neuropathy as idiopathic, as technology and particularly genetic and immunologic testing involves, that number continues to decrease. In adults, metabolic dysmetabolism is the most common case cause of small fiber neuropathy. That includes diabetes, but also prediabetes and impaired glucose tolerance. In a study out of Mayo, about 15% of their patients were classified as having small fiber neuropathy due to diabetes. Though notably, by the end of the seven year study period, 50% were diagnosed with diabetes. The frequency of glucose dysmetabolism causing small fiber peripheral neuropathy has not clearly been identified in children. However, it has been documented. Immune mediated conditions include lupus, sarcoidosis, and scleroderma, and are more commonly seen in non-length dependent small fiber neuropathy at a rate of 14.3% compared to 3.4% of length dependent small fiber neuropathies. Sjogren's syndrome is the leading systemic immune condition associated with small fiber neuropathy and remains underdiagnosed. Paraneoplastic or antibody related syndromes can cause painful symptoms, particularly anti-HU and anti-CRMP5. Levine and colleagues in 2020 published on 48% of previously identified idiopathic small fiber neuropathy may have had antibodies to TSHDS or FGFR3, though there is some controversy with these. Antiplexin D1 antibodies were found in neuropathic pain and comorbid with collagen vascular disease. HIV and hepatitis C historically has been associated with small fiber neuropathy, and now more commonly COVID-19, perhaps with a strong autonomic component. Vitamin deficiencies or toxicities are associated with small fiber neuropathy, but often have a large fiber component as well. It's been suggested that these, however, might not be high yield in all patients. Toxic drugs are associated with small fiber neuropathy, including alcohol, chemotherapy, and certain antibiotics. And genetic causes have been becoming more prevalent and should be particularly considered with early onset or positive family history, but we'll delve into those a little bit deeper. The causal nature of small fiber neuropathy in children is different than adults, of course, owing largely to the time course associated with some of the acquired causes of small fiber neuropathy. Diabetes is only prevalent in about 0.35% of children as compared to 14.7% of adults, though with the rising rate of prediabetes in children, this may become more prevalent. Lupus has a prevalence of 150 cases per 100,000 adults, but only 0.5 cases per 100 in children. Sjogren's, the second most common autoimmune disorder in adults, and present in about 1% of the adult population. Of all cases of Sjogren's, only 1.3% are in pediatrics. Rheumatoid arthritis is the most common autoimmune disorder in adults at 1%, again, but it's exceedingly uncommon in children. Celiac disease is present in 1% of adults in between one to 3% of children, so it is a relevant etiology. IBD is present in about 1.3% of adults, and of all IBD cases, children account for about 20%, so again, a relevant etiology. HIV and hepatitis C are thankfully exceedingly uncommon in children, though COVID-19, of course, is not. Vitamin deficiencies are important to consider, particularly in children with restricted diets, such as those with autism or sensory processing disorder, and I've certainly picked that up. Genetic conditions need to be considered more strongly in children, and we'll talk about it a little bit more. SCN gene mutations are continuously being updated and associated with small fiber neuropathy. SCN9A is the most widely recognized encoding for the voltage-gated sodium channel 1.7 alpha subunit, which is expressed in most nociceptive dorsal root ganglion, and peripherally in free nerve endings in the epidermis. It's also found centrally in the dorsal horn of the spinal cord and in sympathetic neurons. Gain-of-function mutations lead to pain that mainly starts in the distal extremities and is aggravated by warmth, and many have autonomic symptoms. Those certain variants, such as R185H, present with slightly different phenotypes, such as less autonomic symptoms. The I739V variant, however, has been described as associated with congenital insensitivity to pain. In a study of 28 patients with skin biopsy-confirmed idiopathic small fiber neuropathy, 28.6% were found to carry mutations in the SCN9A gene with resultant dorsal root ganglion hyperexcitability. SCN10A encodes for the 1.8 alpha subunit. Variants have been associated with severe allodynia and hyperalgesia, as well as burning and intense paroxysmal itch. Faber and colleagues also found in their cohort 8% of patients had SCN10A mutations leading to small fiber neuropathy. And 3.5% had SCN11A mutations encoding for the 1.9 alpha subunit, most presented with tingling and paresthesias in their distal extremities. Non-SCN genes have been identified in small fiber neuropathies by Eganoff and colleagues, including TRPA1, TRPM4, and FBLN5. Most were middle-aged and had generalized moderate to severe burning. The hereditary sensory and autonomic neuropathies family includes five subtypes associated with hyper and hyposensitivity to pain. HCN1 is an autosomal dominant disorder and presents during adolescence with painless injuries. Length-dependent motor abnormalities can develop and sensory neural hearing loss can be seen. It's associated with the SPTLC1 and 2 genes. HCN2 is present at birth or early childhood and associated with loss of pain, temperature, and touch sensation, and can have autonomic involvement such as tonic pupils or excess sweating. HCN3, also known as Riley-Day syndrome or familial dysautonomia, presents as GI dysmotility, decreased pain and temperature sensation, and cardiac instability at birth. Half of affected individuals will experience an autonomic crisis involving BP instability or cardiac dysarrhythmias in their lifetime. Absence of fungiform papillae and tearless crying, as seen in this picture, are clinical clues. HCN4 is known as congenital insensitivity to pain with anhydrosis or CIPA. As per the name, patients have anhydrosis and no response to pain. Mutilation of extremities and cornea are common and cognitive delays can be seen. HCN5 is also present with congenital insensitivity to pain, secondary to the NGF beta gene mutation. Joint deformities and painless fractures are noted as seen in this picture. Small fiber neuropathy can be associated with other genetic conditions. This is by far not an exhaustive list, but the more commonly described conditions, including Febre, a glycolipid storage disease, is a common disease presenting in early childhood with peripheral pain, angiokeratomas, and cornea verticillata. The first neurologic symptoms of Febre disease may be chronic pain, burning, with superimposed acute attacks of neuropathic pain, and are present in about 40 to 80% of patients. Autonomic symptoms are also common. With Pompe disease, the small fiber neuropathy is more common in the late-onset form. Rarely it's been associated with the infantile-onset form. In a screening of about 44 patients with Pompe, over half screened positive for the small fiber neuropathy. Acute intermittent porphyria can present with attacks of autonomic neuropathy, but often also involves a large fiber component. Cold-induced sweating syndrome is a disease that develops in the first decade of life, where children profusely sweat with temperatures below 20 degrees Celsius, but sweat very little in warm temperatures. They also develop scoliosis, interestingly, later in life. LR-Stanlose is obviously connective tissue disorder, categorized into 13 different variants based on clinical presentation. In a study of 20 patients with hypermobility EDS out of Italy, all but one reported neuropathic pain. At least 80% of fragile X tremor ataxia syndrome patients have peripheral neuropathy, though it's most likely under-recognized. Numbness, neuropathic pain, and autonomic dysfunction are common and usually occurs before the motor symptoms. And there are many other genetic conditions that have been reported to be associated with small fiber neuropathy, though more definitive causality needs to be elucidated. Dr. Kuntz is gonna be presenting much further on this, but there are multiple modalities outside of EMG nerve conduction study to test for small fiber neuropathy. Skin biopsy and cornea confocal microscopy offer quantification of small fibers. TST, Q-START, sympathetic skin response, electrochemical skin conductance, neuropad, and stimulated skin wrinkling all help to assess the functionality of small fiber. And to wrap up, small fiber is incredibly important entity that is commonly under-recognized, especially in the pediatric population due to the difficulty with description of symptoms, lack of knowledge of small fiber neuropathy in the pediatric physician community, lack of good quantification measures tolerated by children, and often frustration in treatment and comorbid psychiatric conditions that can develop with chronic pain. But back to our patient. When we can recognize and treat these patients, sometimes they do get better. These are my citations. Any questions? I think we're gonna take questions at the end, so I might let Dr. Kuntz speak. Thank you. And again, the same type of learning objectives, really wanting to understand the presenting symptoms and identify some ways of evaluating it. My financial disclosures, none of them relate to anything with small fiber, most of them with SMA and DMD. I think it's really important to recognize that small fibers, sensory and autonomic are really diffuse, and that makes it very difficult. I have people coming to me with a litany of prior evaluations that you heard from Bridget about her patient, where this is the 10th attempt to get some understanding of some very diffuse but some very bothersome problem. Their question usually is, after reading the blogs, is this autonomic? Is this dysautonomia? And really thinking about the span of the autonomic nervous system, I find that always a very, very difficult question to answer. We talked a little bit about the differential diagnosis, and I would again just emphasize that there are many things that are very, very important. One thing that she touched on very briefly was the toxicity from some of the important medications that are being used to prolong life in children, all of the chemotherapy agents. The post-transplant anti-rejection agents have a lot of small fiber toxicity. And I'm always impressed with the fact that we're testing neuropsychological panels on children who go through chemotherapy two and three times just to make sure that we're not affecting their cognition. But 48% of kids who are long survivors of chemotherapy tend to, say, report as young adults or adults that they have morbidity due to small fiber involvement, either autonomically or with pain. And yet we're not testing that at all to really try to pick up early signs of problem. Our neuromuscular toolkit, we're good at these sorts of things. If it's a standard neuropathy, we know how to do nerve conductions on children, motor and sensory. We're adding in ultrasound. We know how to do MRI. We don't do as many muscle biopsies as we used to, but there are all these things that can be helpful. But for small fibers, it doesn't help. And you heard very eloquently and with much better graphics from Bridget about the different types of small fibers. But the important thing is this. Thinly myelinated or unmyelinated fibers have very high stimulations of threshold. We actually did some trials when I was at Mayo as a trainee where they were trying to isolate C fibers and stimulate them. And there was only one farm person, a really tough, wonderful friend of mine, a woman, who could tolerate the amount of stimulus that it would take to stimulate an unmyelinated C fiber. Everybody else went running for the hills. And again, if you're stimulating something that has the small myelinated or unmyelinated fibers and the others, their stimulation threshold is lower. And so that potential that you get from the large fibers is going to obscure any ability to record these. So trying to record them through direct stimulation is not a good strategy. Ways of trying to look for small fiber function. And let's go quickly through each of these. And I have to say before as a disclosure before we start, most of these are unquantified yet in children or under development. I think this is going to be my life's project, working on many of these things. So for clinical things, again, you heard very eloquently about how hard it is to hear the report of some of these things. But a lot of times trying to differentiate fatigue from some of these small fiber problems from weakness. I mean, we are neuromuscular people and we get a lot of people refer to us and you do your quantitative muscles testing that they're not weak. So you have to try to figure out what it is that they're trying to tell you. Physical signs. I actually dislike scales for pain from zero to 10 because I have too many patients coming in saying that their pain is 15 out of 10 while they sit there and swipe on their phone and have perfectly manicured nails and a thousand other things going on and are almost too busy to talk to you and give you a history, but their pain is 15 out of 10. On the other hand, I've had patients come in looking like this girl on the right where in the middle of February in Chicago, she obviously had not let anybody touch, wash or shave her legs in about three or four months and she was a very upscale, very well ordered young woman in general until the onset of her pain. And so she came in with almost no clothes, just some loose baggy short shorts and flip flops in the middle of winter because she couldn't stand anything to touch her legs. Now I think that's a very poignant description of hyperpathy. Wheel and flare sometimes. It turns out that the control for a lot of skin allergy testing is something that can let you see a wheel and flare, so sometimes that's something that you can use to differentiate a small fiber function in children and Bridget talked a little bit about the difficulties sometimes differentiating normal tongues from tongues without papillae, but again that can be another sign. One thing that's very useful I think by history as well as by testing is the pruning or the wrinkling you get in your skin in response to immersion. So if you concentrate on the left, that's supposed to be an ultrasound to show you some of, but I think the important thing is on the right. On the top there is a digit with no skin wrinkling and on the bottom there's a lot of wrinkling and you can actually grade it. Now everybody with 30 minutes of water immersion tends to develop skin wrinkling. Well that's kind of messy in a neurology clinic, but it turns out that if you put Emlacream on a digit and cover it with Tegaderm for 30 minutes, you'll get the exact same response. So if you ever want to check for skin wrinkling as just a way to screen or a way to convince you to go on with more elaborate testing or a referral or not, that's something very helpful. Quantitative sensory testing is very difficult, I mean just the history as you heard from Bridget can be very difficult, so trying to get a sensation quantitated in young children can be very difficult. It turns out there are probably two different methods around the universe that have been really worked on to try to quantitate sensation. One is from a German network on neuropathic pain and they have about $20,000 worth of equipment that you can bring to bear and a script. It's a very distinct script that I dislike very much because it talks about burning and searing and pain and other words that would just make most children stand up and leave the room, and yet you're supposed to read this verbatim and then get responses from the children about these different stimuli you apply to their body. Another approach has been used by Dr. Dick, P.J. Dick at Mayo Clinic, who did a very brilliant thing a number of decades ago. He developed some methods of looking at cooling, heat, and vibration and touch, but then he decided that he wanted to get rid of people's personalities and so he had a forced choice. He got a little radio shack thing, put an LED for one and an LED for number two. He said, now during one of these time periods you will feel a stimulus. This isn't a candid camera. You will feel a stimulus, but if it's below threshold and you don't feel it, you have to guess. He calls it forced choice. Basically what that does is really very much tighten the response. His computer-assisted sensory examination is really wonderful. On the other hand, the method of limits that the German group uses has some normative data down to six years of age, again with the limitations that I mentioned, which are that I think it's not at all child-friendly, whereas the method at Mayo with the forced choice has normal values only down to age 18. You can see here in one of my patients when I was still at Mayo, a 10-year-old can do it. Here's a girl who presented just with complaints of absolutely disabling, burning pain in her feet. On the left side you can see all the standard tests, the nerve conduction studies and the EMG is all completely normal. On the other hand, when you did this computer-assisted sensory testing, you could see that there was some hyperpathy and some abnormalities in the heat and pain method. So it can be used, but it's not quantified below age 10. That's one of my goals, is to combine these methods to have a child-friendly script, some of these methods from the German group and then with a forced choice, put it all together and then get some normal values for children. I think one of the most important things and something that I'm hoping can be put into this monitoring of children on toxic medication for chemotherapy and anti-rejection post-transplant is this wind-up ratio, which I think is a way of looking at hyperpathy. Basically there is a pinprick stimulator that's uncomfortable and it has different weights and you just put it on the skin like I'm trying to demonstrate on my own hand the other day. For hyperpathy, what happens is that instead of just one stimulus and people grading it, you take 10 stimuli in a very small area, so not the exact same area, but adjacent points within a one centimeter radius with a metronome to have you do it over in a scheduled way once every second. What happens is that most people find it's no different the 10th for the first, but people who are having abnormal or irritable nerves find that it really builds up this wind-up ratio. So I think that this may be very helpful over time. Again, full disclosure, I've not worked on it yet. Again, this is just some data to remind us to be very aware that nerve conduction studies pick up abnormalities in the sensory system much less than quantitative sensory testing or other things that will pick up the small fiber abnormalities. So all of this would be kind of a clinical approach, ways of trying to intuit from the clinical exam and interaction with the patient, is there small fiber involvement? What physiologic things can we add to that? Well, there are a lot of cardio-vagal things. I can remember being in adolescent medicine rotation as a pediatric intern, and the very smart senior internal medicine resident would go nuts with how much variation there was in heart rate. They kept trying to do cardiology consults on all these kids, and basically it was just normal sinus arrhythmia, which in children, again, is much more prominent. There turned out to be ways you can quantitate this by having six deep breaths per minute, usually with a metronome or some kind of visual stimuli to get people breathing that way, and then just monitoring how the heart rate varies. Absence of heart rate variability is not a good sign in the ICU, in older people with diabetes and all kinds of chronic diseases, but it's not really limited to the geriatric group. You can see here that we've always known that with the fetal heart traces, just monitoring a labor of a yet unborn baby, that losing the heart rate variability is very difficult. You can try to look at just the heart rate variability on a single trace, or there are a little bit more elaborate ways of doing this. I have a colleague who studies congenital central hypoventilation syndrome and has noted that if you take a Holter monitor and then just do a Poincaré plot, which is just sort of the beat-to-beat difference, one versus two, two versus three, three versus four, and so forth, that if you have a healthy control, you get something that looks like an ice cream cone, a nice flare in the variability of the heart rate, whereas with these CCHS patients, it's a cigar. They have very little variability in their heart rate, and that's abnormal. Valsalva maneuvering, or in other words, a closed glottis bearing down, can give you a lot of information in terms of the reflex change in heart rate, as well as the blood pressure. I mean, this can measure the baroreflex. Baroreflexes don't go abnormal very often in children, but I had a teenager who had been through 10 workups all over the Midwest, and his problem was that he would, as an elite tennis player, in the middle of a match, he would just go weak. He would just start staring and look around and couldn't quite cope, and his doubles partner would walk him off and fan him down and whatever, and basically, it took a long time, but we figured out that he actually had a baroreflex failure, that he didn't have that normal autonomic response, and he'd get overheated, and things would go really awry. So you get both a heart rate response, as well as the adrenergic response of the blood pressure in response to this. Now, the way it's usually done is people have a leaky bugle that you blow on and then try to maintain some pressure, and that way, you know, you have the affirmation that there is glottic closure, and it can be done. Here's one that is a tracing from a seven-year-old girl, and younger ones can do it if they're in the mood. Here, again, is just a graphic showing the baroreflex and how this can be monitored. Head up tilt can be very, very helpful looking at autonomic change. Here you can see both blood pressure. There are three things for blood pressure, means, systolic and diastolic, as well as then the heart rate, and the mechanical bed that can put people into a 70-degree head up tilt provokes a much more robust orthostatic reaction than just the supine-to-stand test, but you can do that as a screening in the office, and all of these help you with cardiovagal and androgenetic things. One thing that we have noticed in our process of doing autonomic tilts to try to evaluate dizziness and fatigue and other things in children is that there are a subset of children who have what, for all the world, looks like pot symptoms, who particularly complain of brain fog. They really get upset. And yet, if you put on a NIRS, the Near Infrared Spectroscopy Patch, like people are using in the NICU and in the PICU these days to monitor relative cerebral blood flow, some of these kids have a drop, as you can see on the bottom right, a drop in their regional cerebral blood flow. So I particularly think that this may be the third well-documented example of loss of cerebral autoregulation. We know from the 1990s that it happens in ill preterm neonates when they get really sick. Their cerebral blood flow starts going up and down with peripheral blood pressure when they're particularly septic and in trouble, and that's when they get their intraventricular hemorrhage. We know it happens post-concussion, and that's what's led to the rules for return to play, where you don't let kids return to play until they're really way past it, because they don't have cerebral autoregulation. If they get a second hit, they're very vulnerable to flash edema and dying. And this might be the third example. We've been trying to get normal values to show that this doesn't happen in kids who aren't being screened for POTS, but COVID and other things have interfered. So eventually we'll get this written up. Pupillometry can be very helpful. You know, as we all know, most of the time, clinically, you just see, you just put the light there, and all you know is that then the pupil's down. You don't have the opportunity to see it. But every once in a while in clinic, you'll actually see the pupil coming down. And that is something that we all need to pay attention to, because that's very, very abnormal. And you can quantify this. The ICU people have had pupillometers forever to be able to quantitate the pupil size. And so what happens here, oh, I'll just go through, we don't want to, is here. One of the very interesting things, it turns out there's a autoimmune attack that can happen on the alpha-3 subunit of the acetylcholine receptor, which is the one that is different in autonomic ganglia from neuromuscular ganglia. So the acetylcholine receptor, but the alpha-3 subunit. And if that is the target of attack in a Guillain-Barre-like or CIDP-like fashion, you get autoimmune autonomic ganglionopathy. And one of the ways of documenting this with problems all over the autonomic system is to actually use a long light stimulus. A colleague of mine tried to do repetitive stimulation, you know, like the two to three hertz you do on the peripheral nerves, tried to do that on the pupil, and it turns out it doesn't work so well. But if you use a long light stimulus, what you'd find is that it fatigues. So on the top, A, on the top on the left, you see that the long line is when the two-second light stimulus ends. The pupil stays down until the light goes out, and then the pupil comes back. That's normal. But look at some of these others. Before the light stimulus ends, one or both sides of the pupil escape. That's abnormal. That's pupillary fatigue, and that's very significant. That's the easiest thing to find because the other issues are GI dysmotility and orthostatic intolerance and whatever, and they're much harder to document. Now we do nerve conduction studies and we're very good at it, right? You use a supermaximal stimuli, you're sure you're getting the optimum response and whatever. There are other ways of looking at nerves. I used the example to some fellows, well, it would be like taking all of the pediatric residents in a children's hospital and saying, well, who's tallest and who's talks fastest, you know, and characterizing the entire group in that way. But there are some things you can get by looking at the characteristics of the whole group. So nerve excitability studies are ways of using supermaximal stimuli and paired stimuli to either depolarize or hyperpolarize the nerve and get a sense more of what the threshold is like, what the refractory period is like, and so on and so forth. This is something that if you just do it, you know, de novo, can take days to accomplish on a patient. However, some very clever physiologists at University of College London have developed an algorithm on software that allows you in 15 minutes to get some of these characteristics. Now, again, it takes very special amplifiers and other things, and I'm teaching myself to use this, particularly sensory nerve excitability, to see if we can use this for monitoring early injury from chemotherapy, but these are the kind of graphs you get, you know, things that look at the excitability of the nerves, the threshold, the real base, cron-axi, does any of this come back to you from college? And people have used this in things like erythromelalgia to document the differences in response of the nerve. Now, erythromelalgia is not a specific diagnosis. I think it's probably best used as a term that includes that entire triad. So if you have redness, warmth, and pain, it's erythromelalgia. Now, sometimes this will be primary, as in some of the genetic disorders that Bridget was discussing, and other times it will be secondary to another kind of problem, but it can be really very dramatic, as you can see in this young baby. They've done studies in adults, and they've shown that no matter what the problem is with small fibers, that many times the test, you know, the cardio-vagal of the heart rate and the responses and the sweating and pupillary and blah, blah, blah, of all the different kind of ways you can try to go at the autonomic nervous system, the one that tends to be abnormal most first, earliest, and most reliably is pseudomotor, or sweat, and that's why we're going to go through this. The original method at Mayo was called QSART, Quantitative Pseudomotor Axon Reflex Test, and it's been simplified and made commercial as QSWET. It's basically the same thing, slightly different normal values, but there are these little plastic cages that are put on the skin in four different places. You can see the forearm in three places in the lower extremity, and a very small current is put through this, and in one of the concentric rings, acetylcholine liquid is put to stimulate sweating, and then as you can see up in the upper left corner, that would stimulate and send that message up to the, you know, brain and spinal cord, but it also reflexly comes to adjacent sweat glands, and so you get a little bit of sweat there. So the robust response we see on the top of the list is normal, and you get one of those for each of these places, and the obvious problem is that if you have something that's very diffuse, then you'll be able to see the responses here, but if you have something that's patchy or non-length dependent, as you've heard Dr. McGowan talk about, you may miss it. So it takes 15 minutes. It's easy to do. It's not too bothersome for the kids, but it's focal, and you may miss something. At Mayo Clinic, for many years, for about three decades now, they've been doing a thermoregulatory sweat test, which basically was a gurney with flaps around it, and I actually talked them in when I was practicing there to doing some of our kids, all the way down to 18 months of age. The little ones would have to lie on the gurney with the parent on their side sitting there singing a song or something to get them to be quiet enough. You paint a little powder. You get the humid, hot environment, and everybody sweats if your core temperature goes up one degree centigrade or at least to 38 degrees, and at least to 38 degrees, and of all the hundred children that I put through that for diagnostic purposes, the only people who couldn't tolerate that were gnarly teenagers. There were two out of the hundred. All the little kids did just fine, but when I moved to Mayo, I had them build something a little bit more child-friendly, and you see here, it's just a little chamber, a little room. It's got big windows. It's got a little space next to it so somebody could stand next to the bed, so it's just a little bit less intimidating, but this is our thermoregulatory sweat chamber at Mayo, I mean at Lurie in Chicago, and here are some examples. I had a child who was in Florida playing with, a six-year-old playing with starfish on the beach, and he was told he shouldn't, and he woke up one morning with diffuse rockets bursting through his hands and pain all over his body, and he had every test known to man three times in Florida and again in Chicago, and nobody could find anything wrong. He eventually ended up in a psychiatric ward with people thinking he had just completely lost it, and his parents finally took him out and brought him up to Mayo, and we did the only test he already had done five times, and that was a TST, and you can see that on the left, and he wasn't sweating very much over his body. I promise you I am now an expert on starfish. I cannot relate this to starfish in any way. I think it was just an autoimmune sort of thing, and it gradually got better, but this test is very, very helpful as long as the children aren't on antihistamines. This is just a poster showing all the findings in those 100 kids we put through, and you can look at peripheral skin temperature with thermography, but thermography cameras are very expensive, maybe $10,000 or $20,000, and it can be quite difficult. Right now, we're beginning to use this tiny little handheld device up on the top right to measure temperature with literally just a handheld device. You'd think your core would be a lot warmer, and then as you get out distally to your digits of your fingers and toes, it would be uniformly cooler and cooler. I'm running to all these kids with weird autonomic things where distally is warmer than their elbow, for example, and so on and so forth. I think it's something that we have to understand a lot better, but I think that some of these kids have really abnormal peripheral vasculature, and frankly, living in Chicago, are at risk for frostbite. Sympathetic skin response is just this electrochemical kind of reaction, but it's very, very interesting. EMGs can do it very easily. You just put an electrode on the palm, the dorsum, both hands, sole and dorsum of both feet, and hook it up with a very long thing because you're looking for seconds of response rather than milliseconds, a long sweep. Almost any kind of unusual, unexpected stimulus will produce a response, so it could be a single electrical shock. That's on the left. It could be a loud noise. That's the acoustic stimulus. It could be a loud clap. People have used this to find hearing thresholds in kids with cochlear implants, for example. Inspiratory gasp is something that will suddenly cause these reactions to occur. I was at a meeting with some colleagues in Europe, and one of my colleagues leaned over to the technology company representative who was volunteering to be our subject for some of these demonstrations and whispered in her ear, you're fired. She got a huge response, so it was just that unexpected, you're fired, did her in. The problem with this is that it's less quantifiable, and it fatigues. I just reviewed, I think I can say this out loud, an article from colleagues in China, and they're doing large numbers, hundreds of children at various ages with this. They found that everybody above age three reliably had this response, but there were rare children under the age of three who didn't. This is something very simple that you can kind of do. Here's just a way of quantifying it differently, so rather than just having that electrical response in the skin, here's a different kind of Doppler ultrasound, and this is in response to an inspiratory gasp. This was from an article where a neurologist from the UK went to an endemic area for leprosy and found that this was the cheapest way to find out who had abnormal nerves, with an inspiratory gasp and watching the response of the blood vessels. Here's just a bunch of findings from someone who had an autonomic ganglionopathy. You found that all of these things were abnormal, the gastric emptying, the pupil studies with prolonged light stimulus, their tilt test and their sweat test. So we've talked about this whole range of physiologic things, some of which are very easy to do, some of which require tens of thousands of dollars of equipment to do, and most of which have limited normative data. So it's really a challenge, it's a future direction where we all need to go and collaborate to come up with better norms. There are some anatomic things. I think the corneal confocal nerve fiber density is very good. They've done this a lot in children with diabetes and shown that the branching and the density of the small fibers in the cornea is very different with advanced diabetes. And I'm not just talking about end stage diabetes, but even early uncontrolled diabetes. There are big changes here. And then in addition to this, but you've got to have a collaborative ophthalmology group to do that because, again, it's expensive equipment. And then you can do intraepidermal nerve fiber density, and these very small biopsies aren't hard to do. The problem is I think that many people are doing a lot of them when we don't really know what they mean yet. As you can see, the difference here between normal and abnormal densities or absence of the small fibers, but when you look at the norms, they really go down to age 20. And there's such a broad range of what's normal. A lot of children that I've either had bring me their biopsies for review or the few that I've done myself, they've been in the normal range, but the question is, is it way lower than it used to be? Or as I suspect, I suspect that really the under 20s should be much higher than the 30s to 50s year old patients. And so even being in the normal range for adults may be low for their own age. And we have yet to work this out. So I guess I would just encourage us to figure out some way to be relatively cautious with this because it's probably a bit more invasive. I mean, it's only a small scar, but still it's a little bit of a deal until we get more data to know what's normal. So takeaway messages, you know, some neuropathic processes affect both large and small fibers. And so all of our traditional, well-vetted, well-normed nerve conduction studies and other things like that will help us with that. And then adding on just a few clinical features make us realize it's probably large and small fiber and you're not without a diagnosis. However, some neuropathic processes either begin with the small fibers or are limited to small fibers and you can have completely normal results. And that is what leads to, for example, that little boy being hospitalized in a psychiatric ward because his standard nerve conduction studies were robust and yet he kept complaining of pain and people thought it was bizarre. So those testing approaches include clinical ones that we've reviewed, physiologic ones, anatomic ones. Again, there's a lot of exciting work to be done over the next decade or so as we try to figure out which are the most reliable, which are the most well-tolerated, and which help us most with diagnosing small fiber disease when it exists in isolation. So we wanted to, before we have any more questions about just all that you've heard so far, we've included a physiatrist in our group. And I'd like to have Monica come up now to begin to kind of close the loop on this and talk a little bit about small fiber dysfunction is not just for diagnosing, but also addressing clinically. So, Monica. Thank you. Good morning. So my background comes from physical medicine and rehabilitation, but I also completed neuromuscular medicine fellowship. And during eight years when I worked as a neuromuscular provider in New Mexico, for five years out of those eight, I was actually the only pediatric neuromuscular provider in the whole state. And I also have to admit that now, probably more than 21 years ago, right when I finished residency, I actually did a pain management fellowship, and I spent several months in a great multidisciplinary pediatric pain management program at the Children's Hospital in Wisconsin, in Milwaukee area. And they really had awesome program for the kids, which is kind of important when we do management of the small fiber neuropathies in kids. So I have nothing to disclose. My colleagues already mentioned, you know, what is small fiber polyneuropathy, that it involves thinly myelinated A-delta fibers and unmyelinated C-sensory fibers, as well as autonomic and trophic fibers. And our first presenter already mentioned that there are really not many population-based data studies on small fiber neuropathy, and we are talking about the entire population. So there is very, like, up to several years ago, there was really only the study from Netherlands. I believe you mentioned the Swiss study. I also found that they did a study in Olmsted, Minnesota, which probably came from Mayo Clinic, that, you know, they found prevalence of about 13.3 patients per 100,000. And in the Olmsted study, the mean onset of age, mean onset age was 54 years, but they included the range of between 14 years to 83 years. And I would like to, you know, mention and underline that really the small fiber neuropathy in children with regards to scientific literature, the data is very scarce, is very incomplete. Most often when you do literature review, with regards to at least management, you often find case series of, you know, five cases, eight cases, or, you know, case reports, single case reports. And for example, basically, there were other studies done. For example, Dr. Oaklander and colleagues in Pediatrics 2013 found that more than half among a large series of patients, large series, which means 41 patients, with childhood onset, unexplained chronic widespread pain, met rigorous multi-test diagnostic criteria for small fiber peripheral neuropathy. In adults with fibromyalgia, another study from 2019 showed that basically approximately 45% had abnormally low epidermal neurite density. Also, a study published in 2021 among patients with juvenile fibromyalgia found that 53%, which was in the study 8 out of 15, had the decreased neurite density of less than a fifth percentile versus only 4%, which is 1 out of 23 of healthy controls. However, basically, the study published also on the implications of nerve fiber density on the diagnosis and treatment of juvenile fibromyalgia, and that study was recently, relatively recently published, found that really with regards to juvenile fibromyalgia patients, you have like two phenotypes of the patients, one that have abnormal skin fiber density and one they don't. So you have to be very careful, and you have to really identify which phenotype your patient has because this can give some implications for the treatment. So treatment of a small fiber neuropathy in children is very, very important because, as we know, the small fiber neuropathy symptoms can interfere with activity of daily living, can hinder normal development. Small fibers normally grow throughout the life, so therefore there is definitely, this is very important for any interventions that can improve basically the small fiber function, may permit regrowth, slow progression, and prevent permanent damage. And therefore, particularly in children and young adults, prompt diagnosis, not years of diagnosis, like leading to diagnosis, and treatment is really needed to restore a life trajectory. My colleagues already described the symptoms of small fiber neuropathies, including various sensory symptoms like pain, paresthesias, allodynia, thermal sensory loss, pinprick loss, sheet or sack intolerance, almost restless leg syndrome, and various autonomic symptoms, including particularly dry eyes, dry mouth, hyperhidrosis or hypohidrosis, bowel disturbances, orthostatic, dizziness, cardiac palpitations, and so on. When you look actually for scientific literature on the treatment, very often you have to kind of, like when you do search actually, what are the treatments, what's recommended treatment for patients, pediatric patients with small fiber neuropathies, you really don't find much. Particularly, again, few case series. So you have to kind of venture, venture to some, there are some publications, how to treat erythromelalgia in pediatric populations, some publications on treatment of PADS, or even as Bridget mentioned, complex regional pain syndrome, and so on. So erythromelalgia was actually described, I was surprised when I was preparing that, it was described already in 1878 by Silas Ware Mitchell, and this is basically swollen, painful, burning, red feet or limbs that respond with relief to cooling, and the symptoms obviously are worse by, aggravated by warmth and exercise, and it represents the spontaneous activity of damaged sensory C fibers. And in numerous studies that, some of those studies I listed on the slide, published in 2016, 2019, it was identified that erythromelalgia was like a manifestation, a symptom of under-recognized small fiber neuropathy in children. And we already, previous presenters already mentioned that in pediatric population, instead of this more of the length-dependent pattern, we often see patchy, diffuse pattern. So when we talk about pediatric small fiber neuropathies, particularly we have to focus on the immune-mediated inflammatory, toxic, including chemotherapy, the whole group of hereditary causes, but unfortunately, even when we do a very good evaluation for associated conditions, approximately, depend on the studies, but approximately 50% remain idiopathic. And, this is really very sad that due to lack of robust research data on small fiber neuropathies in children, there are really no specific treatment regimens available. When you consider the best research, treatment recommendations, are really based on the studies regarding general pediatric neuropathic pain treatment, and this probably would be the best guidelines to use with regards to the treatment. So in 2020, there was a very good study published by Michel Vecchio from, and colleagues from Italy, that was a systematic review of pharmacological and rehabilitative treatment options of small fiber neuropathy. However, among 42 publications that they reviewed, and that they met their inclusion criteria, only one publication on pediatric patients was included, and this publication came from 2016 year. This was literally discussion of two case reports of pediatric patients with small fiber neuropathy, so very scant data. And, in this systematic review, pharmacological approaches were discussed based on majority of the studies in adults. Also, they mentioned about potentials for stellate ganglion blockade, also based on adult studies. When I actually pulled those available case reports for pediatric patients with small fiber neuropathies, you know, the following treatments were used for the patients. So intravenous immunoglobulin, steroids like prednisone, metal prednisone, duloxetine, and other antidepressants, including tricyclic antidepressants, selective serotonin, areoptic inhibitors, anticonvulsants like pregabalin, gabapentin, mexilatin, anti-interleukin-1 agents, tramadol, topical lidocaine, and very occasionally opioids. Also, when you look into the published studies of treatment used for pediatric patients with erythromyalgia, you essentially have the similar, you know, use of medications. And as you can see, the kind of orange line is actually, actually I would say the blue line is, you know, how many basically patients underwent trial of those medications, and the orange line is what are the reported benefits. So very clearly, you know, we have basically groups of patients that they were tried the particular medication for treatment, but you can see that the efficacy or reported improvement went only in, you know, much smaller groups of those patients. So at least, you know, when I was doing basically, when we think about treating of pediatric patients with small fiber neuropathies with appropriate secondary etiologies, you can say, okay, at least we can try immunoglobulins, okay? Well, in June of 2023, our own ANEM published basically the consensus statement that for pediatric patients, obviously IVIG were recommended for Guillain-Barre syndrome. So if you consider, some actually consider that certain presentation of pediatric small fiber neuropathies can be almost considered presentation like the autonomic small fiber Guillain-Barre syndrome, yes, you know, then you will have the indication for the steroids for basically IVIG. But there were also publications, like I think Bridget mentioned, in pediatric population with particular antibodies like TSHDS or the fibroblast growth factor receptor three autoantibodies. And this consensus statement by ANEM from 2023 did not recommend to use IVIG because we often get actually that question, did not recommend to use IVIG for the patients, both adults or pediatric with those antibodies. So they basically mentioned, this is a fragment from that consensus statement and that almost one before last paragraph, they did mention that there was a number of retrospective case series evaluating the use of IVIG in immune-mediated small fiber neuropathies due to chagrin or sarcoidosis or celiac disease and conditions associated with autoimmune markers. And those small case series reported beneficial effect on pain. So something to consider, I think more research is needed, especially for pediatric population. And I mentioned, I just wanted to bring to you those like limited case series. So for example, in this case series published by Dr. Alan Pestron group from 2017, when they found, when they presented eight patients, again, very small case series, who had basically antibodies against the TSHDS or the mainly actually they found the TSHDS in this case series. So they did mention that two out of eight patients were treated with immune-modulating therapy. And this immune-modulating therapy in this case series was hydroxychloroquine for juvenile idiopathic arthritis. So again, this search for secondary potentially underlying conditions and using appropriate medications can be helpful. Then there was another study published in 2019, when basically they were like using mix combination, for example, of maxillitin plus immunotherapy, including metoprednisolone and IVIG for basically two patients and they found benefits. And these were the patients, pediatric patients with acute monophasic erythromelalgia. And again, another study from more recent from 2018, when a pediatric patient developed well-documented small fiber neuropathy following antitumor necrosis factor alpha therapy for ulcerative colitis. And this patient responded with some relief to basically treatment with IVIG. However, in 2022, there was a big study mainly on adult patients. And they basically used IVIG for small fiber neuropathy associated with TSHDS and FGFR3 autoantibodies. And the conclusion was that they did not detect any benefit of treatment with IVIG in patients with small fiber neuropathies and these two types of autoantibodies. So with regards to rehabilitation program, which is also very important as we know from broad literature regarding treatment of pediatric neuropathic pain, we know that rehabilitation can be the first step of therapy or it can be added to pharmacological treatment as a complementary treatment, or it can be used in the absence of pharmacological results. And the aim of rehabilitation program is to relieve the neuropathic symptoms, reduce pain, improve quality of life and improve the ability to participate in activities, which is very important for pediatric population. We can try some specific exercises with proprioceptive and superficial sensibility stimulation and this can enhance recovery. And there are some studies showing that the exercise may positively influence the pathological factors by promoting microvascular dilation, reducing oxidative stress and increasing neurotrophic factors. However, in this previously mentioned comprehensive review of predominantly adult studies, except for one of patients with small fiber neuropathies, as you can see what they consider rehabilitation program, that's what listed. So really, not much with regards to rehabilitation was studied. For example, this is basically number, and again, the first patient, the first study was on those two pediatric cases. They only mentioned in that study because I actually went to the study that rehabilitation program was added, that's all. A second study started some vibration, basically treatment. And then a third study studied a 10-week exercise program with both aerobic and strengthening and resistance exercises. And this program basically found to be beneficial. And that's kind of what I remember when we had multidisciplinary pediatric chronic pain management programs. But I would like to caution you that when you consider sending pediatric patients for concomitant or supplementary rehabilitation program, including exercises, I would not recommend sending these kids to the most commonly available orthopedic therapist, physical therapist, because they really, even for neuromuscular patients, what we are finding that they're kind of, they are used to, their approach is different. What I would probably recommend, try to find pediatric chronic pain management program, potentially in the regional pediatric hospital, when you have physical therapists that are accustomed to tailor this rehabilitation program, even with the aerobic exercises, gentle, multi-moderate strengthening, stretching, to basically patients with chronic pain. There was a study published in 2023 on management of, again, pediatric erythromelalgia. And this is a very nice graph when they say what factors can aggravate pediatric erythromelalgia, what factors actually decrease symptoms. And as you can basically notice that any exercise strenuous activity can actually aggravate the symptoms. So you would like a gentle exercise, gentle, basically activity. So they found from the study that the most effective non-pharmacological strategies for relief reported by their cohort were ice pack, cooling, immersion in cold water, use of air conditioning fans, and resting, sitting. I also would like to remind you that for pediatric patients, or in general for patients with basically chronic pain symptoms, it is very important to add the cognitive behavioral therapy which is a time limited usually anywhere from eight to 11 weeks and a goal-oriented psychological treatment. It focuses on teaching individuals the ways to identify and challenge dysfunctional thoughts or behaviors and to replace them with the ones that are more adaptive. So basically that adaptation is also very important aspect. And there is extensive scientific literature supporting use of cognitive behavioral therapy for reducing chronic pain and also in pediatric and adolescent populations. It is used in treatment of migraines, sickle cell disease, cancer, abdominal pain disorders, fibromyalgia, and so on. And in the last several years, they actually came with options of the web-based or internet-based cognitive behavioral therapy or even application-based. So everybody has app for everything. So this could potentially be further investigated. And this combination of cognitive behavioral therapy and exercise-based interventions are very often used in those multidisciplinary pediatric pain treatment programs. They did not have any studies on cognitive behavioral therapy in pediatric small fiber neuropathy patients or hereditary sensory autonomic neuropathy patients. But again, multiple studies on cognitive behavioral therapy used in juvenile fibromyalgia. And we know that percentage of juvenile fibromyalgia patients have small fiber dysfunction was showing effectiveness on improving daily functioning and coping with pain, those adaptations in adolescents. So I will finish with my conclusion and based on basically available studies that more research is needed, okay? And we need to build evidence what is the best therapy and also to delineate the most definitive treatment protocol for pediatric patients with small fiber neuropathy. Thank you very much. Thank you. My colleagues, when I was practicing at Mayo, used compounded things that their own pharmacy would make. And there are a number of ways of doing it. I usually try to stick to three components or no more. That way, you know, if you're having good luck or you have a reaction, it's easier. There are some places around the country you can get like seven different things in a brew and that makes it more difficult. I usually use ketamine, amitriptyline, and lidocaine. But this can be, you know, there are a lot of different components. And frankly, I'd have to look back up the percentage. I've usually gone back to the compounding pharmacy at Mayo Clinic Rochester because their pharmacists have been very helpful at doing this. It's very expensive. And insurance frequently won't cover it, which is part of the problem. So most of the time, I will start off with just lidocaine patches first. And only if that doesn't work will I go to the others. I kind of had similar basically experience. Usually, I would not recommend more than three. Yes. The Mayo pharmacists are fabulous. I'm a product of my training. And they have two different recipes that they use for their compounded amitriptyline, ketamine, and lidocaine cream. And one has like a 15% ketamine or something and 5% lido. And so they actually talked me through it the first time I ordered it. Any other questions? Hi. Thank you so much for your talk today. I am from, I guess, the largest little children's hospital in Alabama. And we don't have a whole lot of resources. So if I was going to try to petition for getting something for evaluation for small fiber neuropathy, what do you feel would be the most helpful testing modality? I mean, I can send kids older than nine across the street to the grown-up hospital, but they're like a year wait. It's impossible. What would you suggest I try to push for? What an appropriate question. And it's hard. One of the things that I try to do is use, one advantage you may have down in Alabama that we don't have in Chicago is that you can use real-world evidence for some of this. So if sweating is one of the most important things, you can kind of ask about it. And you've got to be very, very specific if you're going to try to figure out if this person has a sweat deficit. Because you say, do you sweat? I've actually had children brought to me for excess sweating. And it turns out that they drip 24 hours a day on their shirt collar, and that bothers the parents. But the reason that they're sweating on their shirt collar all summer is that that's the only place in their body they sweat. So, you know, I usually say, what about your T-shirt? Does it stick to you? What about your waistband? What about your socks? And try to get a real sense. And that if in, when they're out playing basketball, when they're out playing soccer, when they're out in the hot weather, if everybody else is sweating. You know, there are a lot of these... to make it buffered lidocaine so that it So that, and you can, you know, get some sense. And if it's really abnormal, then it would be very, very helpful. So that's probably something that's least equipment requiring at this point in time. And I just really think that with the rest of it, we just have to work really hard. Because the other thing you could try is talk to your ophthalmologist. You may find a really collaborative, wonderful ophthalmologist. They have the equipment there for the confocal nerve fiber density, or the confocal pictures. They just take a picture. And you could, you know, probably score it yourself. Any particular lab that you would recommend, because we all know who do the, you know, skin biopsies. Any particular lab that you had good experiences? Well, you know, I can't speak about all the labs, because I haven't used all the labs, but I'm a medical doctor. out there and and frankly that there were some I'll let you all know when I do it, this wind-up ratio, I really, you know, it really is basically summating the response into an irritated nerve, because that's what you, that's what we all find clinically, right, when people have elevated sensory thresholds, what you usually find is that, you know, there's nothing, nothing, nothing, nothing, nothing, then all of a sudden, ah, you know, the hyperpathy when you finally get it. So that's what I'm going to try to quantitate. I had a question about the sympathetic response. Is this something that's available on most like nor like normal EMG software so that you can record over several seconds rather than, you know, just a few milliseconds. And I think at one point in time, way back, TECA used to, the old TECA machines used to have a thing. And I think maybe some of the native ones do, but it. Yeah. But I think, I'll try to get the, some references for you, because you can just easily do it. It's very, very easy to do, like I say. And what you want to do, again, is have everything mellow. No upset, no fighting, no, you know, no whatever. Really just, you know, distract, you know, da-da-da-da-da. Because the first time you do it, that's it. It's kind of like with Lambert Eaton. If you sit there and you, you know, stimulate and get all ready to try to do then, you know, the fast repetitive stimulation, you've lost the thing because you've already gone past the facilitation. So the first shock or the first clap or the first scare, the first inspiratory gasp will get you your thing. So for anybody who's interested, there is an international group of crazies who are interested in, it's called Improving the Use of Electromyography in Children. And this has been meeting once every two years since 1987. And a man at Hospital for Sick Kids in London started it because he felt so isolated. And now it's been in France some. And the next one will be in Milan, Italy in October 2025. I'm on the organizing committee. And I did a workshop there, but I haven't done any here on kids. Maybe that's a suggestion. Thank you for your talks. I'm wondering about IVIG treatment and you know I've definitely had cases with clear IVIG responsiveness and I think the pediatric patients we're seeing are different from the adult FGFR3 and TSHDS positive patients, but one thing I always struggle with is how to quantify treatment response. You know there have been cases that are more clear where you know I had a patient with very acute onset bowel and bladder incontinence just resolved within four days of IVIG, very clear response, but then a lot of the others are you know we're treating pain, erythromelalgia, fatigue, brain fog, and just wondering how you quantify some of those more nebulous symptoms. Unfortunately I think sometimes it's repeating autonomic studies like the head up tilt with our cerebral mirrors. I don't really have anything else to add other than what I just said. I mean my only hesitation in trying and suggesting this session this morning is that I see the need for not only developing these non-invasive child friendly or child acceptable techniques but to validate them and have normal values and things like that so that we can have them available, but it's really a need. discussion and hopefully have some answers for you. But right now it's not easy. It's repeating those things that are very indirect. I mean, you know, what does a sweat test have to do with brain fog or dizziness? But, you know, if that's the test you have and that was the one that was abnormal, then you can try to repeat it. So first of all, I feel like it's my duty to thank and welcome you guys to Savannah because I'm the only pediatric neurologist in this whole city I'm a generalist. I do not do EMGs. I have a Partner who sees about 5% pediatrics in his practice. So when I do get an EMG, I'll send I'll send them to him But I do want to thank you guys for coming. I hope you had a great week. Thanks for the cold weather Maybe it'll stay One question. How did you treat your teenager? And what how did you help her? She went on a celiac free or a gluten-free diet, yeah and Then the wrinkle test that you do on the fingers How is it how wrinkled I couldn't tell on the picture. Is it a lack of wrinkling? Is it? excessive wrinkling So the smoother the more significant yeah, okay That was it. Have you guys had a great week. Thanks for coming they have more opinion. pre-diabetic state in adults is one of the most common causes brought quickly, you know, the kids who have 15 hemoglobin A1Cs and people just sort of jump on them and get them back to seven overnight. A lot of those kids get a very bad small fiber neuropathy that takes a long time to recover. So be aware of that. But all the things you're saying are appropriate. I mean, all of us who are EMGers have seen snap, crackle, pop, you know, in muscles for a long time. I was always taught that that was just a normal variant. Whether that's gonna turn out to be something related to degrees of small fiber, fibromyalgia, I don't know. I mean, I think that we have to just live and learn, yeah? So with regards to like ultrasound, I know that for at least involvement of the autonomic portion, like Guillain-Barre or so, there were some studies measuring the cross-sectional area of the vagus nerve. But again, I don't think that was ever done in pediatric population with small fiber neuropathy. So, you know, that's something that people are looking for any, basically, conditions with the autonomic involvement.

small fiber neuropathy

pediatric cases

diagnosis

autonomic dysfunction

symptoms

skin biopsies

nerve fiber density

thermoregulatory sweat tests

pharmacological therapies

cognitive behavioral therapy

rehabilitation programs

treatment protocols

pediatric health

research