Ep. 182: Small Fibre Neuropathy

00:00:00: Welcome to EANcast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:15: Hello everyone and welcome to the EANcast Weekly Neurology.

00:00:21: My name is Katerina Leone from Sapienza University and I'm part of the EAN Clinical Neurophysiology Pundit.

00:00:29: I'm indeed a clinical neurophysiologist and I also work in the field of pain and today I have the pleasure of moderating a conversation at the crossroads of these two worlds.

00:00:41: Small fiber neuropathy.

00:00:43: Small fiber neuropathy is an emergent and complex topic.

00:00:46: It is often subtle, sometimes difficult to diagnose and it can have a strong impact on patient's quality of life.

00:00:54: To explore it properly, I really wanted to have with us someone who has played a key role in improving our understanding of this foundation, bringing together deep expertise both in neuropathic pain and in peripheral neuropathies.

00:01:09: We have with us Professor Andrea Truini from Sapienza University of Rome.

00:01:14: Andrea, welcome and thank you for joining us today.

00:01:18: Thank you.

00:01:19: Hello everyone, my name is Andrea Truini.

00:01:22: I'm an urologist working in Sapienza University with many years of experience in neuropathy pain, especially in the diagnostic evaluation of small fiber disorders.

00:01:33: Okay, so Andrea, let's go and let's start from the basics.

00:01:38: When we say small fiber neuropathy, what exactly do we mean?

00:01:42: What makes it different from the more classic large fiber polyneuropathies?

00:01:49: When we talk about small fiber neuropathy, we are referring to a condition that affects the peripheral nervous system and more specifically targets a very particular group of nerve fibers, the small nerve fibers.

00:02:03: These small fibers include the adiastal fibers, which are small millimeter fibers and unminimated C fibers.

00:02:11: They are labeled small simply because their axons have a smaller diameter compared with the larger sensory fibers, like the abeta fibers, which are responsible for things like touch and vibration.

00:02:25: Now, these small fibers have a very specific job.

00:02:29: Adels and C fibers mainly carry information about temperature, like feeling cold and warm, pain and heat sensation.

00:02:39: C fibers are also involved in autonomic functions, meaning things like heart rate, sweating, and other activities we don't consciously control.

00:02:51: It's important to mention that there is some ambiguity in the literature when it comes to defining small fiber neuropathy.

00:02:58: Some authors use the term to describe cases where symptoms may point to small fiber involvement, even if large nerve fibers are involved at the same time.

00:03:12: Because of that, we often separate the small fiber neuropathy into two categories.

00:03:17: There is the pure small fiber neuropathy, where only the small fibers are affected, and that's actually quite rare.

00:03:25: And then there's the predominately small fiber neuropathy, which is much more common and is what we usually see in clinical practice.

00:03:34: Okay, so... In short, small fiber neuropathy basically affects the smallest nerve fibers responsible for pain, temperature, itch, and autonomic body functions.

00:03:49: The term is sometimes used broadly, but in everyday practice we most often deal with the so-called predominantly small fiber neuropathy rather than the rare pu one, okay?

00:04:03: That helps explain why patients frequently presents with puzzling symptoms like burning pain, dysesthesia, or autonomic symptoms altogether.

00:04:15: From your clinical experience, what are the key features that should make a clinician suspect small fiber neurotomy?

00:04:24: Well, so when patients have small fiber damage, they typically develop symptoms that affect temperature and pain perception.

00:04:34: autonomic functions as well.

00:04:36: Sensory symptoms can often be described as negative symptoms, meaning a loss of sensation.

00:04:43: So, for example, I once had a patient who, without realizing it, dropped vegetables into the boiling water with his bare hands because he couldn't feel the heat.

00:04:55: But it's not just about losing sensations.

00:04:59: A lot of patients also report let's say positive symptoms, which reflect the abnormal activity in the ADALT and C fibers.

00:05:09: These positive symptoms can include things like spontaneous pain, frequently described as burning pain or deep aching pain, or pain provoked by normally harmless stimuli, even the lightest touch, which is a sensory symptom called dynamic mechanical aludinia.

00:05:27: Some patients also describe are really intense each.

00:05:32: The thing with these positive symptoms is that it's not about a total loss of these fibers or the small fibers.

00:05:40: It's more than these fibers are still there, but they've become hyper excitable.

00:05:46: This can make ordinary sensations feel way more intense or even generate pain when there's no obvious trigger at all.

00:05:56: On top of sensory issues, A lot of patients also experience autonomic dysfunction.

00:06:01: A really common symptom here is the orthostatic intolerance, so people might feel lightheaded or dizzy when they stand.

00:06:09: Genitourinary symptoms are also very common, and there are also issues with sweating.

00:06:15: A lot of times, however, sweating problems go under-reported, since patients might not notice them unless you ask.

00:06:23: But when you do, many described changes nowadays wet.

00:06:27: for example, sweating less in some areas, but more in others.

00:06:32: And some patients may even present with changes in skin color due to impaired blood flow and dysregulation of the autonomic control of circulation.

00:06:43: I think that this shows how small fibroenteropathy can present with such a wide range of symptoms and why it can sometimes be hard to pin down exactly what's going on.

00:06:55: In most patients, these symptoms, the sensory and the autonomic symptoms tend to follow a length-dependent distribution with the classical symmetric stocking glove presentation, but there are cases where the symptoms don't follow this pattern.

00:07:11: One big example is with the genetically determined small fiber neuropathies like Erythromeralgia and the Taroxima Extreme Pain Disorders, which are linked to mutations in the one point seven volt-educated sodium channel.

00:07:25: In children, this condition can even manifest in a really dramatic way with the early kind like patterns of pain or color changes in the skin.

00:07:36: Okay, well, so you provided a lot of information about the clinical features, so let me just briefly summarize.

00:07:45: In short, we have damage to small fibers that can cause both a loss of sensation, and this is true especially for pain and temperature, or abnormal exaggerated sensation like burning pain, pain from light touch, intense itch, And we have to keep in mind also that patients have autonomic symptoms, particularly dizziness when standing, sweating, abnormalities, or even changes in color.

00:08:14: You also mentioned that the classical symptoms follow a stalking and growth pattern, but we have to acknowledge that especially in some genetics, more fiber neuropathies, the pattern can look very different and this might help explain why this condition can be so valid.

00:08:36: Okay, so that's very helpful.

00:08:38: And why

00:08:39: is the diagnosis considered tricky and what should clinician keep in mind?

00:08:46: Well, I have to say, I'm not entirely convinced that diagnosing small fibroinuropathy is always as difficult as it is often represented to be, as long as the clinician is actually aware of the condition.

00:09:01: Neurologists in particular should know that small fibroinuropathy exists, that it typically manifests with disturbances in pain and temporal sensation often together with autonomic symptoms, and that As you told us, in some cases it can have an atypical distribution.

00:09:18: Maybe where things really get tricky is with the diagnostic tests we commonly rely on.

00:09:25: One of the biggest challenges is the limited usefulness of nerve conduction studies.

00:09:30: By definition, in patients with use more fiber neuropathy, nerve conduction studies are expected to be completely normal.

00:09:40: That's because these tests use electrical stimulation that mainly activate large mediated nerve fibers.

00:09:47: So if the problem is limited to small fibers, the nerve conduction study will remain normal.

00:09:54: And that's where clinicians can easily be falsely reassured.

00:09:58: A normal test result might suggest everything is fine when in reality the patient is still very much affected.

00:10:06: Okay, since you mentioned it, and speaking of diagnostic tool, we often hear about skin biopsy for interpidermal fiber density or quantitative sensory testing, laser evoked potential.

00:10:22: Could you give us a clear and practical overview of each of these techniques?

00:10:28: When do they help?

00:10:29: What are their limitations?

00:10:32: Before getting into diagnostic tests, it's important to take a step back and remember that the diagnosis of small fibroenuropathy starts with a clinical picture.

00:10:46: First and foremost, it relies on recognizing the typical symptoms.

00:10:51: Disturbance is in pain and temperature sensation often associated with autonomic dysfunction.

00:10:57: When this characteristic presentation is present, A definite diagnosis then requires objective tests that specifically assess small fiber involvement.

00:11:07: And this approach is actually very consistent across all widely accepted diagnostic criteria, whether we are talking about the action criteria or the best criteria.

00:11:16: All of these criteria agree on one key point.

00:11:20: The diagnosis of small fiber enopathy is based on a combination of compatible symptoms and signs and objective evidence of small fiber damage.

00:11:29: most commonly obtained through tests like skin biopsy.

00:11:33: So, let's start with the skin biopsy.

00:11:36: This technique investigates epidermal innervation, which is mainly composed of a million of a million ADC fiber terminals, with a smaller contribution from mainly needed ADATA fibers.

00:11:48: Although skin biopsy can technically be performed at different body sites, in clinical practice To diagnose more fiber neuropathy, it is usually done at a distal site on the leg and a proximal site on the thigh.

00:12:02: This allows clinicians to assess whether the neuropathy follows a length-dependent pattern.

00:12:07: To visualize the nerve fibers, we use a panneuronal mark, the protein gene product, nine point five.

00:12:15: Skin biopsy has been extensively studied, is more.

00:12:19: fiber neuropathy is generally considered the gold standard for diagnosis.

00:12:24: That said, it's its overall diagnostic accuracy is still debated.

00:12:29: According to the European Academy of Neurology recommendations for neuropathy pain assessment, skin biopsy has an estimated sensitivity in a specificity of about eighty percent.

00:12:39: I think that one of the main limitations with skin biopsy is that it provides structural information only.

00:12:46: It's a more formative technique.

00:12:48: In other words, it quantifies the number of fibers, but not how well they work.

00:12:54: At this point, I think that functional tests are really needed.

00:12:59: And regarding functional tests, well, several tests are commonly used to assess small fiber function.

00:13:06: One of them is the quantitative sensory testing.

00:13:09: This is a psychophysical technique that uses standardized stimuli to measure sensory threshold, including pain and temperature.

00:13:17: It allows relatively selective assessment of small fiber mediated sensations.

00:13:22: However, its main limitation is that is not objective, since it depends on patient responses.

00:13:30: Another group of tests includes nociceptive op potentials, such as laser op potentials and counter-tative op potentials.

00:13:39: These are objective tests.

00:13:41: These neurophysiological techniques directly assess small fiber pathways.

00:13:45: In patients with a very small fiber neuropathy, for instance, their diagnostic accuracy is comparable to that of the skin biopsy.

00:13:54: Then we have also cardiovascular reflex tests which evaluate autonomic small fiber function.

00:14:00: These tests assess heart rate and blood pressure responses during standardized maneuvers like the breathing, the balsama maneuver and the standing up.

00:14:10: They provide information on both parasympathetic and sympathetic function and can detect abnormalities in autonomic regulation, which is mediated by the small fibers.

00:14:20: Regarding the diagnosis overall, my general recommendation of whether is to combine skin biopsy with one of these functional assessments in order to improve diagnostic accuracy.

00:14:33: This is particularly important because abnormalities on skin biopsy have also been reported in conditions that are not primarily peripheral anaeropathies.

00:14:44: Finally, it's important also to acknowledge that access to these diagnostic tools differs widely around the world.

00:14:54: In resource-limited settings, the diagnosis of homophobic neuropathy often relies mainly on a very careful clinical examination focusing on pain and temperature disturbances and automatic symptoms.

00:15:08: And when a blunt test like skin biopsy or quantitative sensory testing are not available, a typical clinical presentation, the exclusion of alternative diagnosis and the identification of common causes, for instance diabetes, infections, can support a probable diagnosis.

00:15:28: So, okay, you mentioned something very important.

00:15:32: First of all, thanks for this clear picture of all the diagnostic tools available.

00:15:39: What I wanted to point out is that even though it is long being considered the gold standard you said that skin biopsy on its own is not enough to diagnose more fiber neuropathy, is it correct?

00:15:54: Well, this is the point.

00:15:57: It's worth noting that abnormalities on skin biopsy... have also been reported in people with conditions that are not primarily peripheral neuropathies like fibromyalgia, for instance.

00:16:08: This can sometimes make it challenging to distinguish between the two.

00:16:13: However, there is an important difference.

00:16:16: Unlike patients with morphine neuropathy, patients with fibromyalgia generally do not have thermal pain sensory deficits.

00:16:24: And when it comes to functional tests like for instance, not exactly bulk potentials, these tests do not show abnormalities in patients with fibromyalgia.

00:16:34: Then, the correct definition for skin biopsy findings for skin biopsy abnormalities in patient fibromyalgia is small-fibre pathology rather than small-fibre neuropathy.

00:16:49: This is why a combination approach, a detailed clinical examination, together with skin biopsy and functional testing, provides the best accuracy for correctly diagnosing small-fibre neuropathy.

00:17:03: Okay, fine.

00:17:05: Thank you very much for this important clarification.

00:17:08: So, summing up, we have to take in mind that diagnosing small-fibre neuropathy always starts from the clinical picture, but it cannot rely just on symptoms.

00:17:21: We have a skin biopsy, which remains an important tool, yet... It only provides structural information and is not specific by itself.

00:17:33: That's why you said combining clinical evaluation with structure and functional test gives the most accurate diagnosis and helps us distinguish between the two small fiber neuropathy from other conditions.

00:17:50: Okay, that's very, very clear.

00:17:52: But once we identify small fiber neuropathy, We still have to understand why it happened.

00:18:00: What are the most common causes clinicians should screen for?

00:18:06: Well, regarding causes of small fibroenuropathy, some are very well established.

00:18:11: The most common one maybe is diabetes.

00:18:15: Autoimmune diseases are also very important, for example, children's syndrome, as well as some infectious diseases.

00:18:22: like HIV and, more recently, COVID-IX.

00:18:27: Genetic disorders are another key group, of course, these include classic monogenic conditions, like redatory sensory and atomic muropathies, phabrid disease, or familial and melodotic muropathy.

00:18:41: In the last few years, there has also been growing recognition of mutations in voltage-adjacated sodium channels as a cause of small fibroin muropathy.

00:18:51: this mutation can modify, can alter how small net fibers fire, leading to pain and sensory symptoms.

00:19:00: However, that said, a significant number of people still fall into the idiopathic category, meaning that, despite a comprehensive evaluation, no clear etiology can be identified.

00:19:15: In literature, there's still an ongoing debate about whether In at least some of these idiopathic cases, inflammation autoimmunity may play a significant role.

00:19:29: Okay, so we should always think of diabetes or even pre-diabetes, I guess.

00:19:37: Immune mediated causes, genetic condition, infections, and if you cannot find anything, then we have to conclude for an idiopathic form.

00:19:47: Okay, thank you.

00:19:49: So now I think we can move to treatment, which is very interesting in clinical practice.

00:19:55: Management, I know that can be challenging because structural damage and symptoms do not always correlate.

00:20:04: So how do you approach therapy?

00:20:07: And more importantly, what is realistic to expect for patients?

00:20:14: Well, when we have to treat small fibroin neuropathy, One very important priority is often symptom control, especially in neuropathy pain, and there are a few treatment options available.

00:20:27: The drug most commonly used are antidepressants and gabapantinoids.

00:20:32: That said, it's important to be realistic about what these treatments can actually achieve.

00:20:38: It's well recognized that their effectiveness is often limited.

00:20:42: Most studies show that a large proportion of patients do not achieve satisfactory pain relief even with treatment and even when patients do benefit.

00:20:53: That improvement is usually modest, typically around a thirty to fifty percent reduction in pain.

00:21:01: For this reason, I think it's very important to be transparent with patients and to set realistic goals when treating pain.

00:21:09: And finally, it's worth remembering that medications, drugs are only one part of the overall approach.

00:21:17: other strategies might also be considered, including physical therapy, psychological support, and non-invasive neuromodulation.

00:21:26: However, symptom management is only one part of the picture.

00:21:31: Whenever possible, we also need to address the underlying cause of the small fibroenteropathy.

00:21:37: This is particularly important in acquired conditions such as diabetes or other immune diseases like children's syndrome, and the same applies to some genetic disorders, including fibroid disease and familial amyloidotic neuropathy, where disease-specific therapies are now available and can significantly modify the course of the disease.

00:22:00: There is also some interest in the role of a new mechanism in small fibroid neuropathy, as I told you before, based on some evidence in the literature suggesting a possible link.

00:22:12: with immune dysregulation, some others have proposed the use of intravenous immunoglobulin.

00:22:18: However, I think it's fair to say that this area remains far from being very well settled.

00:22:26: In fact, at least one randomized control trial comparing intravenous immunoglobulin with placebo in patients with more fibromuropathy failed to show any significant benefit.

00:22:40: Okay, so whenever possible, we have to focus on the underlying cause, why neuropathic pain is managed with the common standard medications, but we have to remember to keep expectation realistic and that is very important.

00:23:00: As it often happens, of course, with chronic pain condition, the biopsychosocial approach is essential.

00:23:09: It is as well a clear communication with patients about possible goals and outcomes that really matters.

00:23:18: Now, since many of our listeners are residents or early career neurologists, if you had to give them three practical tips on recognizing and managing small fibroenteropathy, what would they be?

00:23:34: First of all, a careful clinical examination is really essential.

00:23:38: This means paying close attention to pain and temperature sensation, and especially looking for deficits in thermal pain perception.

00:23:49: Just as important is the evaluation of the autonomic symptoms, this shouldn't be treated as an utter thought.

00:23:56: they need to be actively asked about and when appropriate, objectively tested.

00:24:02: And it's also worth remembering that although it's uncommon few small fiber neuropathy can occasionally present with non-length dependent sensory disturbances.

00:24:14: The next step is choosing the right diagnostic test.

00:24:18: Net conduction studies are always useful, mainly because many patients also had some degree or large fiber involvement, but when small fiber neuropathy is suspected, particularly few small fiber neuropathy, net conduction studies are not sufficient on their own.

00:24:36: They need to be complemented with a skin biopsy along with functional tests such as quantitative sensory testing, nociceptive rock potentials, or cardiovascular reflex testing.

00:24:47: It's important to keep in mind that abethic diagnosis osmophibia neuropathy does not rely on a single test.

00:24:54: It requires the right clinical presentation, together with objective evidence of osmophibia damage.

00:25:02: And we know that in practice, combining skin biopsy with functional testing significantly improves the accuracy of the diagnosis.

00:25:12: Finally, once the diagnosis is established, it's really crucial to look for the underlying cause.

00:25:18: Both common and less common etiologies should be considered, including diabetes, infectious diseases, and genetic conditions like familial and melodotic polyneuropathy for instance.

00:25:30: And in selected cases, testing for mutations in voltage-garry solute channels may also be appropriate.

00:25:38: Okay, thank you, Andrea.

00:25:39: I think you have already done it, but let me briefly summarize the key messages from today.

00:25:46: Small fiber neuropathy mainly affects pain, terminal and autonomic fiber, which is why patients often present with burning pain, dysesthesia and autonomic symptoms.

00:25:58: Routine nerve conduction studies are usually normal, so maintaining a high level of clinical suspicion is essential.

00:26:07: Diagnosis relies on complementary tools, including skin biopsy, quantitative sensory testing, and laser report potential.

00:26:15: No single test is sufficient on its own.

00:26:18: We always have to look for the underlying cause, management focus on treating the cause when possible, and controlling neuropathic pain.

00:26:27: but with realistic expectation and also a multidisciplinary approach.

00:26:32: Andrea, thank you again for being with us and for sharing your expertise.

00:26:37: I think that was a very, very helpful conversation.

00:26:40: And thank you to you all, our listeners, for joining us today.

00:26:45: Bye, everyone.

00:26:47: Thank you.

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