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Understanding Small Fiber Neuropathy: The Long and Short of It

Understanding Small Fiber Neuropathy: The Long and Short of It Sensory predominant peripheral neuropathy is a common disorder, affecting as many as 10% of individuals older than 40 years.1 Many of these patients have small fiber neuropathy (SFN). Despite 3 decades of intense study, SFN remains an enigmatic condition that is often difficult to diagnose and manage successfully. In addition, SFN is extremely frustrating for patients who experience pain, disrupted sleep, gait imbalance, autonomic disturbances, and fall-related injuries, all of which lead to a profoundly reduced quality of life. The precise diagnostic criteria for SFN are debated, and the relative role of specific symptoms, signs, specialized investigations (eg, quantitative sensory testing and quantitative sudomotor axon reflex testing), and skin biopsy for measurement of intraepidermal nerve fiber density (IENFD) is uncertain and somewhat controversial.2,3 Approximately half of patients with SFN have diabetic neuropathy, and most of the remainder have cryptogenic sensory peripheral neuropathy (CSPN). Although half of patients with CSPN also have prediabetes and even more are obese,4-6 the lack of a specific cause is difficult for many patients to accept, especially when they learn that treatment often involves only diet and exercise, which they find difficult to sustain, and symptomatic pain management, which is often only modestly effective.6 An uncertain prognosis increases frustration, with many patients experiencing relatively stable symptoms for many years and others progressing to involvement of large nerve fibers. Perhaps most frustrating for physicians and patients is the lack of information concerning the pathogenesis of SFN. There have been several interesting observations that suggest that genetic variations in the Nav1.7 voltage-gated sodium channel may be linked to SFN in some cases.7 The clinical similarities of CSPN to early diabetic neuropathy have led several groups to suggest that the metabolic syndrome (obesity, dyslipidemia, and insulin resistance or prediabetes) is pathogenically linked to SFN, with the metabolic derangements resulting in preferential injury or dysfunction of small distal terminal axons with resultant pain and sensory loss.3 However, regardless of its cause, SFN is characterized clinically by distal, symmetric sensory symptoms and signs and pathologically by reduced IENFD in samples taken at the foot or ankle, with relative preservation at more proximal sites. Over time, patients may experience progression of symptoms from distal to proximal locations and eventually into the hands. This clinical and pathologic pattern has led to the conclusion that SFN is owing to a length-dependent degeneration of the longest axons. In this issue of JAMA Neurology, Khoshnoodi et al8 challenge the assumption of length dependency of axonal degeneration in SFN by examining the differential change in IENFD at 3 biopsy sites (distal leg, distal thigh, and proximal thigh) over time in cohorts of patients with idiopathic SFN (iSFN), impaired glucose tolerance–associated SFN (IGT-SFN), and diabetes mellitus–associated SFN (DM-SFN). They observed a similar decrease in IENFD over time at each anatomical site. The study is interesting and notable from a number of perspectives. The duration of material collection (8 years) is impressive, and the duration between the first and last assessments (ie, at least 2 years) is long enough to permit their cautious conclusions. The inclusion of a comparison group of healthy control participants with no decrease in IENFD is also notable. Their main conclusion is that axon loss over time is not length dependent given the uniform rate of IENFD decrease among the different anatomical locations. This study is potentially an important one because its results suggest that the classic dying-back mechanism (slowly progressive distal to proximal axonal degeneration), presumed to underlie most toxic, degenerative, metabolic, and genetic neuropathies, may not be a primary mechanistic process in many patients with SFN. As the authors note, this in turn raises the possibility that terminal axon processes, perhaps involving local cutaneous interactions, retrograde axonal transport, mitochondrial dysfunction, or other factors, may cause the fundamental pathologic insult in SFN. These results also highlight potential differences in the degenerative process in large myelinated vs small unmyelinated axons. It has been suggested that among patients with DM, individual metabolic factors differentially drive axon loss, with hyperglycemia related to large myelinated axon injury and dyslipidemia and obesity related to small axon loss.9 This difference may explain why early diabetic neuropathy and CSPN, which are linked to obesity and metabolic syndrome, are characterized by greater small fiber injury.10 The apparent discrepancy between decrease in nerve conduction values, which is more clearly length dependent, and IENFD may be consistent with such differences among fiber classes. These data are also significant in their support of the use of IENFD as a biomarker for SFN and will prove extremely useful in the design of future disease-altering therapeutic trials. The report by Khoshnoodi et al8 must be interpreted with caution, however, because there are a number of important limitations in the study. Most obvious are the small sample size, particularly relative to the disease prevalence, and the fact that the data were collected at a single major peripheral nerve center. How these particular participants were selected from the many probably seen at that institution is not clear, which is important given other more substantive concerns. The numbers of patients with DM-SFN and IGT-SFN seem particularly small, especially because approximately 50% of patients with iSFN have glucose intolerance.5,6 A minor but nevertheless important source of possible bias is that although the technician determining IENFD was masked, it is not clear whether there was sufficient masking for visit (baseline vs follow-up), which could bias toward a decrease in IENFD among those with neuropathy. Of greater concern are several observations relative to the IENFD values and the apparent neuropathy progression. The absolute IENFD values are surprisingly high. The fifth percentile cutoff for the mean age of the studied population was 4.3 fibers per millimeter for women and 3.5 fibers per millimeter for men.11 Even if nerve fragments were counted, these numbers are surprisingly high for a neuropathy population. This observation is particularly striking given the dramatic decrease in nerve conduction parameters. Recent clinical trials and natural history studies12,13 have failed to report a significant decrease in nerve conduction or clinical measures, such as the Neuropathy Impairment Score of the Lower Limb, over the observed timeframe in diabetic neuropathy. In that context, the magnitude of decrease in sural sensory amplitude from 12 to 4 μV in the IGT-SFN cohort and 9 to 4 μV in the DM-SFN cohort suggests this population had greater disease severity, was uniquely vulnerable to progression, or that there was some unrecognized bias in the sample. The magnitude of IENFD decrease was also greater than that reported in another natural history study,14 and the finding of a uniform decrease at proximal and distal sites stands in contrast to observations in other forms of peripheral neuropathy, which share clinical similarities to CSPN and diabetic neuropathy.15,16 It is also evident that these data preclude a linear IENFD decrease because most patients would have absent distal innervation in several years and absent proximal innervation within several more. However, from a clinical perspective, epidermal fibers are absent distally in a significantly few patients with neuropathy, but they are only rarely absent proximally. This observation strongly suggests that the cohort in this sample is indeed different from others reported or that the long-term temporal profile of IENFD decrease must be different proximally, calling into question the central conclusion that SFN may not be length dependent. In the end, it is important to recognize that neurologic localization and diagnosis are founded in clinical phenomenology. Even if skin biopsy is not a length-dependent biomarker, the clinical scenario remains almost uniformly a length-dependent process. Thus, although provocative and deserving of interest and careful thought, these results are not sufficient to set aside clinical terms such as length dependent or stocking and glove. They hint at a more complex underlying pathophysiologic mechanism with potential differential effects on specific axon populations. They also serve to emphasize the vulnerability of small unmyelinated axons to metabolic injury and their promise as a biomarker of disease progression and response to therapy. Broader application of IENFD as a biomarker and surrogate measure in neuropathy clinical trials will help address these fundamentally important questions while supporting therapeutic development. Back to top Article Information Corresponding Author: John T. Kissel, MD, Department of Neurology, The Ohio State University Wexner Medical Center, 395 W 12th Ave, 7th Floor, Columbus, OH 43210 (john.kissel@osumc.edu). Published Online: April 11, 2016. doi:10.1001/jamaneurol.2016.0256. Conflict of Interest Disclosures: None reported. References 1. Gregg EW, Sorlie P, Paulose-Ram R, et al; 1999-2000 national health and nutrition examination survey. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care. 2004;27(7):1591-1597.PubMedGoogle ScholarCrossref 2. Gibbons CH. Small fiber neuropathies. Continuum (Minneap Minn). 2014;20(5 Peripheral Nervous System Disorders):1398-1412.PubMedGoogle Scholar 3. Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med. 2004;164(9):1021-1025.PubMedGoogle ScholarCrossref 4. Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist. 2008;14(1):23-29.PubMedGoogle ScholarCrossref 5. Kissel JT. Peripheral neuropathy with impaired glucose tolerance: a sweet smell of success? Arch Neurol. 2006;63(8):1055-1056.PubMedGoogle ScholarCrossref 6. Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. J Peripher Nerv Syst. 2012;17(suppl 2):15-21.PubMedGoogle ScholarCrossref 7. Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26-39.PubMedGoogle ScholarCrossref 8. Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal assessment of small fiber neuropathy: evidence of a non–length-dependent distal axonopathy [published April 11, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.0057.Google Scholar 9. Smith AG, Singleton JR. Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications. 2013;27(5):436-442.PubMedGoogle ScholarCrossref 10. Guy RJ, Clark CA, Malcolm PN, Watkins PJ. Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia. 1985;28(3):131-137.PubMedGoogle Scholar 11. Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15(3):202-207.PubMedGoogle ScholarCrossref 12. Dyck PJ, Dyck PJ, Klein CJ, Weigand SD. Does impaired glucose metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study. Muscle Nerve. 2007;36(4):536-541.PubMedGoogle ScholarCrossref 13. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054-2060.PubMedGoogle ScholarCrossref 14. Dyck PJ, Davies JL, Litchy WJ, O’Brien PC. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology. 1997;49(1):229-239.PubMedGoogle ScholarCrossref 15. Løseth S, Stålberg EV, Lindal S, Olsen E, Jorde R, Mellgren SI. Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5 year follow-up study [published online December 15, 2015]. J Peripher Nerv Syst. doi:10.1111/jns.12154.Google Scholar 16. Burakgazi AZ, Messersmith W, Vaidya D, Hauer P, Hoke A, Polydefkis M. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77(10):980-986.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

Understanding Small Fiber Neuropathy: The Long and Short of It

JAMA Neurology , Volume 73 (6) – Jun 1, 2016

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American Medical Association
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Copyright © 2016 American Medical Association. All Rights Reserved.
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2168-6149
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DOI
10.1001/jamaneurol.2016.0256
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Abstract

Sensory predominant peripheral neuropathy is a common disorder, affecting as many as 10% of individuals older than 40 years.1 Many of these patients have small fiber neuropathy (SFN). Despite 3 decades of intense study, SFN remains an enigmatic condition that is often difficult to diagnose and manage successfully. In addition, SFN is extremely frustrating for patients who experience pain, disrupted sleep, gait imbalance, autonomic disturbances, and fall-related injuries, all of which lead to a profoundly reduced quality of life. The precise diagnostic criteria for SFN are debated, and the relative role of specific symptoms, signs, specialized investigations (eg, quantitative sensory testing and quantitative sudomotor axon reflex testing), and skin biopsy for measurement of intraepidermal nerve fiber density (IENFD) is uncertain and somewhat controversial.2,3 Approximately half of patients with SFN have diabetic neuropathy, and most of the remainder have cryptogenic sensory peripheral neuropathy (CSPN). Although half of patients with CSPN also have prediabetes and even more are obese,4-6 the lack of a specific cause is difficult for many patients to accept, especially when they learn that treatment often involves only diet and exercise, which they find difficult to sustain, and symptomatic pain management, which is often only modestly effective.6 An uncertain prognosis increases frustration, with many patients experiencing relatively stable symptoms for many years and others progressing to involvement of large nerve fibers. Perhaps most frustrating for physicians and patients is the lack of information concerning the pathogenesis of SFN. There have been several interesting observations that suggest that genetic variations in the Nav1.7 voltage-gated sodium channel may be linked to SFN in some cases.7 The clinical similarities of CSPN to early diabetic neuropathy have led several groups to suggest that the metabolic syndrome (obesity, dyslipidemia, and insulin resistance or prediabetes) is pathogenically linked to SFN, with the metabolic derangements resulting in preferential injury or dysfunction of small distal terminal axons with resultant pain and sensory loss.3 However, regardless of its cause, SFN is characterized clinically by distal, symmetric sensory symptoms and signs and pathologically by reduced IENFD in samples taken at the foot or ankle, with relative preservation at more proximal sites. Over time, patients may experience progression of symptoms from distal to proximal locations and eventually into the hands. This clinical and pathologic pattern has led to the conclusion that SFN is owing to a length-dependent degeneration of the longest axons. In this issue of JAMA Neurology, Khoshnoodi et al8 challenge the assumption of length dependency of axonal degeneration in SFN by examining the differential change in IENFD at 3 biopsy sites (distal leg, distal thigh, and proximal thigh) over time in cohorts of patients with idiopathic SFN (iSFN), impaired glucose tolerance–associated SFN (IGT-SFN), and diabetes mellitus–associated SFN (DM-SFN). They observed a similar decrease in IENFD over time at each anatomical site. The study is interesting and notable from a number of perspectives. The duration of material collection (8 years) is impressive, and the duration between the first and last assessments (ie, at least 2 years) is long enough to permit their cautious conclusions. The inclusion of a comparison group of healthy control participants with no decrease in IENFD is also notable. Their main conclusion is that axon loss over time is not length dependent given the uniform rate of IENFD decrease among the different anatomical locations. This study is potentially an important one because its results suggest that the classic dying-back mechanism (slowly progressive distal to proximal axonal degeneration), presumed to underlie most toxic, degenerative, metabolic, and genetic neuropathies, may not be a primary mechanistic process in many patients with SFN. As the authors note, this in turn raises the possibility that terminal axon processes, perhaps involving local cutaneous interactions, retrograde axonal transport, mitochondrial dysfunction, or other factors, may cause the fundamental pathologic insult in SFN. These results also highlight potential differences in the degenerative process in large myelinated vs small unmyelinated axons. It has been suggested that among patients with DM, individual metabolic factors differentially drive axon loss, with hyperglycemia related to large myelinated axon injury and dyslipidemia and obesity related to small axon loss.9 This difference may explain why early diabetic neuropathy and CSPN, which are linked to obesity and metabolic syndrome, are characterized by greater small fiber injury.10 The apparent discrepancy between decrease in nerve conduction values, which is more clearly length dependent, and IENFD may be consistent with such differences among fiber classes. These data are also significant in their support of the use of IENFD as a biomarker for SFN and will prove extremely useful in the design of future disease-altering therapeutic trials. The report by Khoshnoodi et al8 must be interpreted with caution, however, because there are a number of important limitations in the study. Most obvious are the small sample size, particularly relative to the disease prevalence, and the fact that the data were collected at a single major peripheral nerve center. How these particular participants were selected from the many probably seen at that institution is not clear, which is important given other more substantive concerns. The numbers of patients with DM-SFN and IGT-SFN seem particularly small, especially because approximately 50% of patients with iSFN have glucose intolerance.5,6 A minor but nevertheless important source of possible bias is that although the technician determining IENFD was masked, it is not clear whether there was sufficient masking for visit (baseline vs follow-up), which could bias toward a decrease in IENFD among those with neuropathy. Of greater concern are several observations relative to the IENFD values and the apparent neuropathy progression. The absolute IENFD values are surprisingly high. The fifth percentile cutoff for the mean age of the studied population was 4.3 fibers per millimeter for women and 3.5 fibers per millimeter for men.11 Even if nerve fragments were counted, these numbers are surprisingly high for a neuropathy population. This observation is particularly striking given the dramatic decrease in nerve conduction parameters. Recent clinical trials and natural history studies12,13 have failed to report a significant decrease in nerve conduction or clinical measures, such as the Neuropathy Impairment Score of the Lower Limb, over the observed timeframe in diabetic neuropathy. In that context, the magnitude of decrease in sural sensory amplitude from 12 to 4 μV in the IGT-SFN cohort and 9 to 4 μV in the DM-SFN cohort suggests this population had greater disease severity, was uniquely vulnerable to progression, or that there was some unrecognized bias in the sample. The magnitude of IENFD decrease was also greater than that reported in another natural history study,14 and the finding of a uniform decrease at proximal and distal sites stands in contrast to observations in other forms of peripheral neuropathy, which share clinical similarities to CSPN and diabetic neuropathy.15,16 It is also evident that these data preclude a linear IENFD decrease because most patients would have absent distal innervation in several years and absent proximal innervation within several more. However, from a clinical perspective, epidermal fibers are absent distally in a significantly few patients with neuropathy, but they are only rarely absent proximally. This observation strongly suggests that the cohort in this sample is indeed different from others reported or that the long-term temporal profile of IENFD decrease must be different proximally, calling into question the central conclusion that SFN may not be length dependent. In the end, it is important to recognize that neurologic localization and diagnosis are founded in clinical phenomenology. Even if skin biopsy is not a length-dependent biomarker, the clinical scenario remains almost uniformly a length-dependent process. Thus, although provocative and deserving of interest and careful thought, these results are not sufficient to set aside clinical terms such as length dependent or stocking and glove. They hint at a more complex underlying pathophysiologic mechanism with potential differential effects on specific axon populations. They also serve to emphasize the vulnerability of small unmyelinated axons to metabolic injury and their promise as a biomarker of disease progression and response to therapy. Broader application of IENFD as a biomarker and surrogate measure in neuropathy clinical trials will help address these fundamentally important questions while supporting therapeutic development. Back to top Article Information Corresponding Author: John T. Kissel, MD, Department of Neurology, The Ohio State University Wexner Medical Center, 395 W 12th Ave, 7th Floor, Columbus, OH 43210 (john.kissel@osumc.edu). Published Online: April 11, 2016. doi:10.1001/jamaneurol.2016.0256. Conflict of Interest Disclosures: None reported. References 1. Gregg EW, Sorlie P, Paulose-Ram R, et al; 1999-2000 national health and nutrition examination survey. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care. 2004;27(7):1591-1597.PubMedGoogle ScholarCrossref 2. Gibbons CH. Small fiber neuropathies. Continuum (Minneap Minn). 2014;20(5 Peripheral Nervous System Disorders):1398-1412.PubMedGoogle Scholar 3. Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med. 2004;164(9):1021-1025.PubMedGoogle ScholarCrossref 4. Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist. 2008;14(1):23-29.PubMedGoogle ScholarCrossref 5. Kissel JT. Peripheral neuropathy with impaired glucose tolerance: a sweet smell of success? Arch Neurol. 2006;63(8):1055-1056.PubMedGoogle ScholarCrossref 6. Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. J Peripher Nerv Syst. 2012;17(suppl 2):15-21.PubMedGoogle ScholarCrossref 7. Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26-39.PubMedGoogle ScholarCrossref 8. Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal assessment of small fiber neuropathy: evidence of a non–length-dependent distal axonopathy [published April 11, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.0057.Google Scholar 9. Smith AG, Singleton JR. Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications. 2013;27(5):436-442.PubMedGoogle ScholarCrossref 10. Guy RJ, Clark CA, Malcolm PN, Watkins PJ. Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia. 1985;28(3):131-137.PubMedGoogle Scholar 11. Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15(3):202-207.PubMedGoogle ScholarCrossref 12. Dyck PJ, Dyck PJ, Klein CJ, Weigand SD. Does impaired glucose metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study. Muscle Nerve. 2007;36(4):536-541.PubMedGoogle ScholarCrossref 13. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054-2060.PubMedGoogle ScholarCrossref 14. Dyck PJ, Davies JL, Litchy WJ, O’Brien PC. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology. 1997;49(1):229-239.PubMedGoogle ScholarCrossref 15. Løseth S, Stålberg EV, Lindal S, Olsen E, Jorde R, Mellgren SI. Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5 year follow-up study [published online December 15, 2015]. J Peripher Nerv Syst. doi:10.1111/jns.12154.Google Scholar 16. Burakgazi AZ, Messersmith W, Vaidya D, Hauer P, Hoke A, Polydefkis M. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77(10):980-986.PubMedGoogle ScholarCrossref

Journal

JAMA NeurologyAmerican Medical Association

Published: Jun 1, 2016

Keywords: peripheral neuropathy,diabetic neuropathies,biological markers,disease progression,nerve fibers,neuropathy, sensory,axonal neuropathy,neuropathy, small-fiber

References