RESUMEN
OBJECTIVES: Small fiber neuropathy presents a significant diagnostic and therapeutic challenge. To solve this challenge, efforts have been made to identify autoantibodies associated with this condition. Previous literature has often considered tri-sulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR3) as a singular seropositive group and/or focused primarily on symptomatic associations. METHODS: One hundred seventy-two small fiber neuropathy patients with a Washington University Sensory Neuropathy panel were selected for TS-HDS seropositivity, FGFR-3 seropositivity, and seronegative controls. Data were collected to on the demographic, symptomatic, and laboratory profiles of each subgroup. RESULTS: Percent female (P = 0.0043), frequency of neuropathic pain symptoms (P = 0.0074), and erythrocyte sedimentation rate (P = 0.0293), vitamin D (P < 0.0001), and vitamin B12 (P = 0.0033) differed between the groups. Skin biopsy was more frequently normal within both the FGFR-3 and the TS-HDS cohort (P = 0.0253). CONCLUSIONS: TS-HDS and FGFR-3 display a distinct phenotype from both controls and one another. Immunoglobulin M (IgM) against FGFR-3 and IgM against TS-HDS may be individually valuable markers for the development of distinct clinical phenotypes.
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Autoanticuerpos , Conducción Nerviosa , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Neuropatía de Fibras Pequeñas , Humanos , Femenino , Neuropatía de Fibras Pequeñas/diagnóstico , Persona de Mediana Edad , Masculino , Conducción Nerviosa/fisiología , Anciano , Adulto , Autoanticuerpos/sangre , Heparina/análogos & derivados , Inmunoglobulina M/sangre , Heparitina Sulfato/sangre , Estudios de Conducción Nerviosa , DisacáridosRESUMEN
Practical yet reliable diagnostic tools for small-fiber neuropathy are needed. We aimed to establish a histopathologic protocol for estimating intraepidermal nerve fiber density (eIENFD) on formalin-fixed, paraffin-embedded tissue (FFPE), evaluate its reliability through intraobserver and interobserver analyses, and provide normative reference values for clinical use. Sixty-eight healthy participants underwent nerve conduction studies and quantitative sensory testing. Skin biopsies from the distal and proximal leg were taken and processed using routine immunohistochemistry (anti-PGP9.5 antibodies) on thin 5 µm sections. eIENFD was assessed with a modified counting protocol. Interobserver and intraobserver reliabilities were excellent (ICC=0.9). eIENFD was higher in females than males (fibers/mm, 14.3±4.4 vs. 11.6±5.8, P <0.05), decreased with age ( r s =-0.47, P <0.001), and was higher proximally than distally (15.0±5.5 vs. 13.0±5.3, P =0.002). Quantile regression equations for the fifth percentile of distal and proximal eIENFD were presented: 13.125-0.161×age (y)-0.932×sex (male=1; female=0) and 17.204-0.192×age (y)-3.313×sex (male=1; female=0), respectively. This study introduces a reliable and reproducible method for estimating epidermal nerve fiber density through immunostaining on 5-µm thin FFPE tissue samples. Normative data on eIENFD is provided. Regression equations help identify abnormal decreases in small nerve fiber density.
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Epidermis , Fibras Nerviosas , Neuropatía de Fibras Pequeñas , Humanos , Masculino , Femenino , Epidermis/patología , Epidermis/metabolismo , Fibras Nerviosas/patología , Fibras Nerviosas/metabolismo , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/patología , Adulto , Persona de Mediana Edad , Anciano , InmunohistoquímicaRESUMEN
OBJECTIVES: Small fiber neuropathy (SFN) is a subtype of painful neuropathies defined by dysfunction of the Aδ and unmyelinated C fibers. It presents with both neuropathic pain and dysautonomia symptoms, posing a significant diagnostic and therapeutic challenge. To address this challenge, research has been conducted to identify autoantibodies and define their association with phenotypes. METHODS: Eleven cases of anti-plexin-D1 seropositive SFN were reviewed, along with relevant literature, in attempt to better define anti-plexin-D1 SFN demographics, symptoms, associated medical conditions, and therapeutics. RESULTS: Anti-plexin-D1 SFN typically presents in female patients, with neuropathic pain, normal skin biopsy findings, and normal nerve conduction studies. Anti-plexin-D1 shows an association with concurrent chronic pain, with almost half of the patients undergoing an interventional procedure. CONCLUSIONS: Anti-plexin-D1 represents a unique subgroup of SFN, defined by distinct demographics, phenotype, biopsy findings, and therapeutic management.
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Neuralgia , Neuropatía de Fibras Pequeñas , Humanos , Femenino , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/epidemiología , Neuralgia/diagnóstico , Neuralgia/epidemiología , Autoanticuerpos , Fenotipo , DemografíaRESUMEN
OBJECTIVES: Small fiber neuropathy (SFN) affects the fibers involved in cutaneous and visceral pain and temperature sensation and are a crucial part of the autonomic nervous system. Autonomic dysfunction secondary to SFN and autoimmune receptor antibodies is being increasingly recognized, and gastrointestinal (GI) manifestations include constipation, early satiety, nausea, vomiting, and diarrhea. Enteric nervous system involvement may be a possible explanation of abnormal GI motility patterns seen in these patients. METHODS: Children suspected to have SFN based on symptoms underwent skin biopsy at the Child Neurology clinic at Arnold Palmer Hospital for Children, which was processed at Therapath™ Neuropathology. SFN was diagnosed using epidermal nerve fiber density values that were below 5th percentile from the left distal leg (calf) as reported per Therapath™ laboratory. RESULTS: Twenty-six patients were diagnosed with SFN. Retrospective chart review was performed, including demographic data, clinical characteristics, and evaluation. A majority of patients were white adolescent females. Autonomic dysfunction, including orthostasis and temperature dysregulation were seen in 61.5% of patients (p = 0.124). Somatosensory symptoms, including pain or numbness were seen in 85% of patients (p < 0.001). GI symptoms were present in 85% of patients (p < 0.001) with constipation being the most common symptom seen in 50% of patients. This correlated with the motility testing results. CONCLUSIONS: Pediatric patients with SFN commonly have GI symptoms, which may be the main presenting symptom. It is important to recognize and look for symptoms of small fiber neuropathy in children with refractory GI symptoms that may explain multisystemic complaints often seen in these patients.
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Enfermedades Gastrointestinales , Neuropatía de Fibras Pequeñas , Femenino , Adolescente , Humanos , Niño , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/etiología , Estudios Retrospectivos , Fibras Nerviosas/patología , Piel/patología , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/patología , Biopsia , Estreñimiento/diagnóstico , Estreñimiento/etiología , Estreñimiento/patologíaRESUMEN
A proportion of people with fibromyalgia demonstrate small fibre pathology (SFP). However, it is unclear how SFP directly relates to pain phenomenology. Thirty-three individuals with FMS and ten healthy volunteers underwent assessment of SFP and sensory phenotyping using corneal confocal microscopy, validated questionnaires and quantitative sensory testing (QST). Corneal nerve fibre length was used to stratify participants with fibromyalgia into with SFP [SFP+] and without SFP [SFP-]. SFP was detected in 50% of the fibromyalgia cohort. Current pain score and QST parameters did not differ between SFP+ and SFP-. Mechanical pain sensitivity (MPS) demonstrated a significant gain-of-function in the SFP- cohort compared to healthy-volunteers (p = 0.014, F = 4.806, η2 = 0.22). Further stratification revealed a cohort without structural SFP but with symptoms compatible with small fibre neuropathy symptoms and a significant gain in function in MPS (p = 0.020 Chi-square). Additionally, this cohort reported higher scores for both depression (p = 0.039, H = 8.483, η2 = 0.312) and anxiety (p = 0.022, F = 3.587, η2 = 0.293). This study confirms that SFP is present in a proportion of people with fibromyalgia. We also show that in a proportion of people with fibromyalgia, small fibre neuropathy symptoms are present in the absence of structural SFP. Greater mechanical pain sensitivity, depression and anxiety are seen in these individuals.
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Fibromialgia , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/diagnóstico , Dolor , Umbral del Dolor , Fibras Nerviosas/patologíaRESUMEN
OBJECTIVE: Small fiber neuropathy (SFN) is a well-defined chronic painful condition causing severe individual and societal burden. While mood disorders have been described, cognitive and behavioral profiles of SFN patients has not been investigated. METHODS: Thirty-four painful SFN patients underwent comprehensive cognitive, behavioral, psychological, quality of life (QoL), and personality assessment using validated questionnaires. As control samples, we enrolled 36 patients with painful peripheral neuropathy (PPN) of mixed etiology and 30 healthy controls (HC). Clinical measures of neuropathic pain, duration, frequency, and intensity of pain at the time of assessment were recorded. Between-group and correlation analyses were performed and corrected for multiple comparisons. RESULTS: No differences in clinical measures were found between SFN and PPN, and all groups had similar cognitive profiles. SFN patients showed higher levels of anxiety and alexithymia (p < .005) compared to PPN and HC, considering also pain intensity. Maladaptive coping strategies characterized both patient groups, but only SFN revealed higher levels of acceptance of pain (p < .05). Pain intensity and neuropathic symptoms were associated with mood, low QoL and catastrophism (p < .001), particularly, the higher the perceived pain intensity, the higher the use of maladaptive coping strategies (p < .001). The personality assessment revealed significant feelings of worthlessness and somatization traits both in SFN and PPN (p < .002 vs HC). DISCUSSIONS: our results suggest that SFN patients had a normal-like cognitive profile, while their behavioral profile is characterized by mood disorders, alexithymia, maladaptive coping strategies, and poor QoL, as other chronic pain conditions, possibly related to pain intensity. Personality assessment suggests that somatization and feelings of worthlessness, which may worsen the neuropsychological profile, deserve clinical attention when considering patients' therapeutic approaches. At the same time, the high level of acceptance of pain is promising for therapeutic approaches based on psychological support.
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Neuralgia , Dolor , Enfermedades del Sistema Nervioso Periférico , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/complicaciones , Neuropatía de Fibras Pequeñas/diagnóstico , Calidad de Vida , Estudios de Casos y Controles , Neuralgia/diagnóstico , Neuralgia/etiología , Neuralgia/terapia , Fenotipo , CogniciónRESUMEN
OBJECTIVES: Corneal confocal microscopy (CCM) is a non-invasive technique that examines the corneal cellular structure. Its use in the detection of small fiber neuropathy is being researched. In our study, we examined the role of CCM in the detection of small fiber neuropathy in diabetic patients, as well as the differences between CCM findings in diabetic patients with and without overt polyneuropathy with neuropathic symptoms. METHODS: 56 Diabetes Mellitus (DM) patients and 18 healthy controls were included in the study. The individuals included in the study were divided into three groups. Patients with diabetes who were found to have polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 1, patients with diabetes and neuropathic symptoms without overt polyneuropathy according to electrophysiological diagnostic criteria were classified as Group 2, and healthy individuals were classified as Group 3. Electrophysiological examination and corneal imaging with CCM were performed in all groups. RESULTS: The CNFD and CNFL values of individuals in the diabetic group were discovered to be lower. CNFD values differ statistically between the groups (p = 0.047). Group 1-Group 3 differs from Group 2-Group 3 (respectively; p = 0.018, p = 0.048). CONCLUSION: Our study demonstrates that CCM can be used in patients with neuropathic symptoms and no polyneuropathy detected in EMG and thought to have small fiber neuropathy. CCM provides an opportunity for early diagnosis in small fiber neuropathy.
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Córnea , Neuropatías Diabéticas , Microscopía Confocal , Neuropatía de Fibras Pequeñas , Humanos , Microscopía Confocal/métodos , Masculino , Córnea/diagnóstico por imagen , Córnea/patología , Córnea/inervación , Femenino , Persona de Mediana Edad , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/diagnóstico por imagen , Neuropatías Diabéticas/fisiopatología , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/fisiopatología , Adulto , Anciano , Diabetes Mellitus/fisiopatologíaRESUMEN
OBJECTIVES: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. METHODS: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. RESULTS: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3â¯% had reduced IENFD, 43.2â¯% of the females and 50.9â¯% of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50â¯% of the patients (48.9â¯% in females and 52.9â¯% in males). In the low IENFD group 45 cases out of 90 (50â¯%) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50â¯%) showed abnormal QST. CONCLUSIONS: Less than half of these patients had reduced IENFD, and 50â¯% had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).
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Neuropatía de Fibras Pequeñas , Masculino , Femenino , Humanos , Estudios Retrospectivos , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/patología , Fibras Nerviosas/patología , Fibras Nerviosas/fisiología , Piel/inervación , BiopsiaRESUMEN
BACKGROUND: Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies. OBJECTIVES: The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differential diagnoses. They conclude that autonomic symptoms are frequently associated, often presenting with diverse symptoms. METHODS: A selective literature research to present SFN symptoms as well as differential diagnostic and therapeutic steps in the context of SFN and rare diseases focusing on the autonomic nervous system. RESULTS: Neuropathic pain significantly reduces quality of life. To shorten the time until diagnosis and to initiate therapy, the authors recommend a structured patient history including sensory plus and minus symptoms and non-specific autonomic signs. If the initial search for the cause is not successful, rare causes such as treatable transthyretin (ATTR) amyloidosis and Fabry's disease or autoimmune causes should be considered, particularly in the case of progressive and/or autonomic symptoms. CONCLUSION: The diagnosis and therapy of rare SFN requires interdisciplinary collaboration and, in many cases, a referral to specialized centers to achieve the best patient care.
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Neuralgia , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/terapia , Calidad de Vida , Enfermedades Raras/complicaciones , Neuralgia/diagnóstico , Neuralgia/etiología , Neuralgia/terapia , Sistema Nervioso AutónomoRESUMEN
BACKGROUND AND OBJECTIVES: Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. METHODS: We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. RESULTS: Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. DISCUSSION: AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.
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Enfermedades del Sistema Nervioso Periférico , Neuropatía de Fibras Pequeñas , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Anticuerpos , Axones , Fibras Nerviosas , Dolor , Neuropatía de Fibras Pequeñas/diagnóstico , Persona de Mediana EdadRESUMEN
The current study aims to characterize brain morphology of pain as reported by small fiber neuropathy (SFN) patients with or without a gain-of-function variant involving the SCN9A gene and compare these with findings in healthy controls without pain. The Neuropathic Pain Scale was used in patients with idiopathic SFN (N = 20) and SCN9A-associated SFN (N = 12) to capture pain phenotype. T1-weighted, structural magnetic resonance imaging (MRI) data were collected in patients and healthy controls (N = 21) to 1) compare cortical thickness and subcortical volumes and 2) quantify the association between severity, quality, and duration of pain with morphological properties. SCN9A-associated SFN patients showed significant (P < .017, Bonferroni corrected) higher cortical thickness in sensorimotor regions, compared to idiopathic SFN patients, while lower cortical thickness was found in more functionally diverse regions (eg, posterior cingulate cortex). SFN patient groups combined demonstrated a significant (Spearman's ρ = .44-.55, P = .005-.049) correlation among itch sensations (Neuropathic Pain Scale-7) and thickness of the left precentral gyrus, and midcingulate cortices. Significant associations were found between thalamic volumes and duration of pain (left: ρ = -.37, P = .043; right: ρ = -.40, P = .025). No associations were found between morphological properties and other pain qualities. In conclusion, in SCN9A-associated SFN, profound morphological alterations anchored within the pain matrix are present. The association between itch sensations of pain and sensorimotor and midcingulate structures provides a novel basis for further examining neurobiological underpinnings of itch in SFN. PERSPECTIVE: Cortical thickness and subcortical volume alterations in SFN patients were found in pain hubs, more profound in SCN9A-associated neuropathy, and correlated with itch and durations of pain. These findings contribute to our understanding of the pathophysiological pathways underlying chronic neuropathic pain and symptoms of itch in SFN.
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Neuralgia , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/diagnóstico , Neuralgia/diagnóstico por imagen , Neuralgia/genética , Neuralgia/complicaciones , Imagen por Resonancia Magnética , Giro del Cíngulo , Canal de Sodio Activado por Voltaje NAV1.7/genéticaRESUMEN
INTRODUCTION/AIMS: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non-invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis. METHODS: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods. RESULTS: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [rs ], 0.58; p < .002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (rs , 0.52; p < .001), the Neuropathy Impairment Score (rs , -0.45; p < .01), the heat-pain detection threshold (rs , -0.62; p < .0001), and the autonomic section of the Kumamoto ATTRv clinical score (rs , -0.53; p < .0001). DISCUSSION: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease.
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Neuropatías Amiloides Familiares , Neuropatía de Fibras Pequeñas , Adulto , Humanos , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/patología , Fenómenos Electrofisiológicos/fisiología , Fibras Nerviosas/fisiología , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/etiología , Recuento de Células , Piel/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , JapónRESUMEN
INTRODUCTION: Peripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available. METHODS: We conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN). RESULTS: Twenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered. CONCLUSION: Our results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy.
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Enfermedad de Fabry , Neuralgia , Neuropatía de Fibras Pequeñas , Masculino , Humanos , Adulto , Persona de Mediana Edad , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Relevancia Clínica , Neuralgia/diagnóstico , Neuralgia/etiología , Neuralgia/terapia , Fibras Nerviosas , Neuropatía de Fibras Pequeñas/diagnóstico , Diagnóstico PrecozRESUMEN
INTRODUCTION: Hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) presymptomatic carriers often show preclinical abnormalities at small fiber-related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic carriers' follow-up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late-onset ATTRv presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO). METHODS: Late-onset ATTRv presymptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fiber density (IENFD) evaluation from a distal and a proximal site. Douleur Neuropathique-4 (DN4) and Small Fiber Neuropathy-Symptoms Inventory (SFN-SIQ) were used to assess painful and small fiber neuropathy-related symptoms. PADO and time-to-PADO (delta-PADO) were estimated for each carrier, and correlations with diagnostic test measures were analyzed. RESULTS: Forty presymptomatic ATTRv subjects were enrolled. Twenty carriers (50%) had distal IENFD reduction, with a non-length-dependent distribution in 73% of cases. Eleven subjects (27.5%) had cold and/or warm detection threshold (CDT and/or WDT) abnormalities at QST. Delta-PADO positively correlated with sural sensory nerve action potential (SNAP) amplitude (r = .416, p = .004), and z-values of QST parameters like CDT (r = .314, p = .028), WDT (r = -.294, p = .034), and mechanical detection threshold (MDT; r = -.382, p = .012). Simple linear regression models showed a linear relation between delta-PADO and sural SAP, CDT, and MDT. CONCLUSIONS: Our findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv presymptomatic carriers, often with a non-length-dependent pattern. However, only sural SAP amplitude and QST parameters correlated with delta-PADO, suggesting that serial combined QST and NCS evaluation could be useful in ATTRv presymptomatic carriers' follow-up.
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Polineuropatías , Neuropatía de Fibras Pequeñas , Humanos , Neuropatía de Fibras Pequeñas/diagnóstico , Piel/patología , Dolor , Polineuropatías/patología , BiopsiaRESUMEN
BACKGROUND AND AIMS: The diagnosis of small fiber neuropathy (SFN) is supported by reduced intraepidermal nerve fiber density (IENFD). The noninvasive method corneal confocal microscopy (CCM) has the potential to be a practical alternative. We aimed to estimate the diagnostic accuracy of CCM compared with IENFD and cold detection thresholds (CDT) in SFN and mixed fiber neuropathy (MFN). METHODS: CCM was performed in an unselected prospective cohort of patients with a clinical suspicion of polyneuropathy. Predefined criteria were used to classify SFN and MFN. Neuropathy scores, including the Utah early neuropathy scale (UENS), were used to describe severity. Patients with established other diagnoses were used for diagnostic specificity calculations. RESULTS: Data were taken from 680 patients, of which 244 had SFN or MFN. There was no significant difference in sensitivities [95%CI] of CCM (0.44 [0.38-0.51]), IEFND (0.43 [0.36-0.49]), and CDT (0.34 [0.29-0.41]). CCM specificity (0.75 [0.69-0.81]) was lower (p = .044) than for IENFD (0.99 [0.96-1.00]) but not than for CDT (0.81 [0.75-0.86]). The AUCs of the ROC curves of 0.63, 0.63 and 0.74 respectively, was lower for corneal nerve fiber density (p = .0012) and corneal nerve fiber length (p = .0015) compared with IENFD. While UENS correlated significantly with IENFD (p = .0016; R2 = .041) and CDT (p = .0002; R2 = .056), it did not correlate with CCM measures. INTERPRETATION: The diagnostic utility of CCM in SNF and MFN is limited by the low specificity compared with skin biopsy. Further, CCM is less suitable than skin biopsy and CDT as a marker for neuropathy severity.
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Enfermedades del Sistema Nervioso Periférico , Neuropatía de Fibras Pequeñas , Humanos , Estudios Prospectivos , Piel/patología , Enfermedades del Sistema Nervioso Periférico/diagnóstico por imagen , Enfermedades del Sistema Nervioso Periférico/patología , Biopsia , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/patología , Microscopía Confocal/métodos , Córnea/diagnóstico por imagen , Córnea/inervaciónRESUMEN
INTRODUCTION: Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN. METHODS: This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA. RESULTS: Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients. DISCUSSION: This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association.
Asunto(s)
Neuropatía de Fibras Pequeñas , Vasculitis , Masculino , Femenino , Humanos , Anticuerpos Anticitoplasma de Neutrófilos/análisis , Neuropatía de Fibras Pequeñas/complicaciones , Neuropatía de Fibras Pequeñas/diagnóstico , Estudios Retrospectivos , Ensayo de Inmunoadsorción Enzimática , PeroxidasaRESUMEN
BACKGROUND: The nociceptive flexion reflex (NFR) is a polysynaptic and multisegmental spinal reflex that develops in response to a noxious stimulus and is characterized by the withdrawal of the affected body part. The NFR possesses two excitatory components: early RII and late RIII. Late RIII is derived from high-threshold cutaneous afferent A-delta fibers, which are prone to injury early in the course of diabetes mellitus (DM) and may lead to neuropathic pain. We investigated NFR in patients with DM with different types of polyneuropathies to analyze the role of NFR in small fiber neuropathy (SFN). METHODS: We included 37 patients with DM and 20 healthy participants of similar age and sex. We performed the Composite Autonomic Neuropathy Scale-31, modified Toronto Neuropathy Scale, and routine nerve conduction studies. We grouped the patients into large fiber neuropathy (LFN), SFN, and no overt neurological symptom/sign groups. In all participants, NFR was recorded on anterior tibial (AT) and biceps femoris (BF) muscles after train stimuli on the sole of the foot, and NFR-RIII findings were compared. RESULTS: We identified 11 patients with LFN, 15 with SFN, and 11 with no overt neurological symptoms or signs. The RIII response on the AT was absent in 22 (60%) patients with DM and 8 (40%) healthy participants. The RIII response on the BF was absent in 31 (73.8%) patients and 7 (35%) healthy participants (P = .001). In DM, the latency of RIII was prolonged, and the magnitude was reduced. Abnormal findings were seen in all subgroups; however, they were more prominent in patients with LFN compared to other groups. CONCLUSIONS: The NFR-RIII was abnormal in patients with DM even before the emergence of the neuropathic symptoms. The pattern of involvement before neuropathic symptoms was possibly related to an earlier loss of A-delta fibers.
Asunto(s)
Neuropatía de Fibras Pequeñas , Humanos , Dimensión del Dolor , Neuropatía de Fibras Pequeñas/diagnóstico , Nocicepción , Reflejo/fisiología , Pie , Umbral del Dolor/fisiología , Estimulación EléctricaRESUMEN
BACKGROUND: Alcohol overconsumption is well known to cause damage to the peripheral nervous system. The aim of this study was the functional and structural evaluation of the small nerve fibers in alcohol-dependent subjects, with or without symptoms of peripheral neuropathy. METHODS: Twenty-six consecutive alcohol-dependent subjects treated for detoxification voluntarily in the specialized unit of the Athens University Psychiatric Clinic were enrolled in this prospective study over 18 months. Every subject was assessed by peripheral nerve evaluation using the Neuropathy Symptoms Score (NSS) and Neuropathy Impairment Score (NIS), followed by nerve conduction studies (NCS), quantitative sensory testing (QST), and skin biopsy. Twenty-nine normal subjects, age- and gender-matched, constituted the control group. RESULTS: Peripheral neuropathy was diagnosed in 16 subjects (61.5%). Among these 16 subjects, pure large fiber neuropathy (LFN) was found in two subjects (12.5%), pure small fiber neuropathy (SFN) was found in eight subjects (50%), and both large and small fiber neuropathy was diagnosed in six patients (37.5%). The intraepidermal nerve fiber density (IENFD) of the patients' skin biopsy was significantly lower than that of the control group. Additionally, QST results showed a statistically significant sensory impairment in the patients. CONCLUSIONS: Our study confirms small fiber neuropathy due to alcohol abuse with a high prevalence of pure SFN that might have remained undetected without QST and IENFD.