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Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and in vitro and in vivo studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.
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[This corrects the article DOI: 10.3389/fnmol.2023.1254854.].
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The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen's syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.
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Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several pore-forming voltage-gated sodium channel α subunits (NaV) in a subset of patients with SFN, but the auxiliary sodium channel ß subunits have been less implicated in the development of the disease. ß subunits modulate NaV trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the ß2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel ß subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the ß2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the ß2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of ß2 subunits in SFN and strengthens the link between sodium channel ß subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel α subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary ß2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel ß2 subunit mutations and human pain disorders.
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Mutación con Ganancia de Función , Neuropatía de Fibras Pequeñas/genética , Subunidad beta-2 de Canal de Sodio Activado por Voltaje/genética , Potenciales de Acción , Animales , Células Cultivadas , Ganglios Espinales/citología , Células HEK293 , Humanos , Mutación Missense , Neuronas/metabolismo , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Neuropatía de Fibras Pequeñas/metabolismo , Subunidad beta-2 de Canal de Sodio Activado por Voltaje/metabolismoRESUMEN
Chronic pain may affect 30-50% of the world's population and an important cause is small fiber neuropathy (SFN). Recent research suggests that autoimmune diseases may be one of the most common causes of small nerve fiber damage. There is low awareness of SFN among patients and clinicians and it is difficult to diagnose as routine electrophysiological methods only detect large fiber abnormalities, and specialized small fiber tests, like skin biopsy and quantitative sensory testing, are not routinely available. Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible method for quantifying small nerve fiber degeneration and regeneration, and could be an important tool for diagnosing SFN. This review considers the advantages and disadvantages of CCM and highlights the evolution of this technique from a research tool to a diagnostic test for small fiber damage, which can be a valuable contribution to the study and management of autoimmune disease.
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Introduction: Small fiber neuropathies (SFN) induce pain and/or autonomic symptoms. The diagnosis of SFN poses a challenge because the role of skin biopsy as a reference method and of each neurophysiological test remain to be discussed. This study compares six methods evaluating small sensory and autonomic nerve fibers: skin biopsy, Quantitative Sensory Testing (QST), quantitative sweat measurement system (Q-Sweat), Laser Evoked Potentials (LEP), Electrochemical Skin Conductance (ESC) measurement and Autonomic CardioVascular Tests (ACVT). Methods: This is a single center, retrospective study including patients tested for symptoms compatible with SFN between 2013 and 2016 using the afore-mentioned tests. Patients were ultimately classified according to the results and clinical features as "definite SFN," "possible SFN" or "no SFN." The sensitivity (Se) and specificity (Sp) of each test were calculated based on the final diagnosis and the best diagnostic strategy was then evaluated. Results: Two hundred and forty-five patients were enrolled (164 females (66.9%), age: 50.4 ± 15 years). The results are as follows: skin biopsy: Se = 58%, Sp = 91%; QST: Se = 72%, Sp = 39%; Q-Sweat: Se = 53%, Sp = 69%; LEP: Se = 66%, Sp = 89%; ESC: Se = 60%, Sp = 89%; Cardiovascular tests: Se = 15%, Sp = 99%. The combination of skin biopsy, LEP, QST and ESC has a Se of 90% and a Sp of 87%. Conclusion: Our study outlines the benefits of combining skin biopsy, ESC, LEP and QST in the diagnosis of SFN.
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Small fibers function was evaluated by the electrochemical skin conductance (ESC) in 67 consecutive PD patients and 66 age-matched controls using sudoscan technology. There is no significant reduction in ESC in PD patients compared with controls. We found a weak correlation between feet ESC and modified Hoehn and Yahr Scale.
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Respuesta Galvánica de la Piel/fisiología , Iontoforesis/métodos , Enfermedad de Parkinson/complicaciones , Neuropatía de Fibras Pequeñas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/etiología , Neuropatía de Fibras Pequeñas/fisiopatologíaRESUMEN
PURPOSE: The clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. Hence, sarcoidosis patients may suffer from a great variety of symptoms. The aim of this study was to compare the self-reported burden of sarcoidosis patients in Denmark, Germany and the Netherlands, especially the prevalence of fatigue and small fiber neuropathy (SFN)-related symptoms, as well as differences in treatment strategies. METHODS: A cross-sectional web-based anonymous survey about complaints was conducted among sarcoidosis patients. Patients were invited to take part through the sarcoidosis patient societies as well as through outpatient sarcoidosis clinics in these countries. RESULTS: The questionnaire was completed by 1072 sarcoidosis patients (152 Danish, 532 German and 388 Dutch). Almost all patients reported having sarcoidosis-associated symptoms (organ-related as well as non-specific, non-organ related). Fatigue was reported by almost all respondents (90%), followed by pulmonary symptoms (72.4%). More than 50% of the respondents were being treated with prednisone, which was comparable in all three countries. In contrast, second- and third-line treatment differed substantially between Denmark, Germany and the Netherlands. CONCLUSION: Sarcoidosis patients in Denmark, Germany and the Netherlands present with similar self-reported symptoms, organ-related as well as non-specific, non-organ related. Fatigue (90%) and symptoms associated with SFN (86%) were highly prevalent in all three countries.
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Costo de Enfermedad , Sarcoidosis/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios Transversales , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Glucocorticoides/uso terapéutico , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Prevalencia , Pronóstico , Sarcoidosis/diagnóstico , Sarcoidosis/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: Cognitive failure is associated with memory and concentration problems. Previously, a prevalence of one third was found in a general sarcoidosis population. The aim of this study was to assess if neurosarcoidosis patients are at higher risk for developing everyday cognitive failure using the Cognitive Failure Questionnaire (CFQ) and to determine what factors were associated with cognitive failure. METHODS: A cross-sectional web-based survey was conducted from April to May 2017 in a national sample of neurosarcoidosis patients. The survey asked about complaints and included 3 questionnaires (Fatigue Assessment Scale [FAS], Small Fiber Neuropathy Screening List [SFNSL] and CFQ. Data were compared to a general sarcoidosis population. RESULTS: Of the 152 patients who completed the survey, 131 had neurosarcoidosis. The mean CFQ score was significantly higher in the neurosarcoidosis (45.6±20.7) compared to the general sarcoidosis population (36.2±15.9; p< 0.0001). High CFQ scores (≥43) were found in 55.7% and 33.9%, respectively (p<0.0001). The FAS score (OR 21.4) and SFNSL score (OR 4.3) were the strongest positive predictors of a high CFQ score. CONCLUSION: Cognitive failure is a significant problem in neurosarcoidosis. More than half of the patients reported cognitive deficits, compared to one third of a general sarcoidosis population. Fatigue and small fiber neuropathy play a role in cognitive failure.
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Enfermedades del Sistema Nervioso Central/epidemiología , Cognición , Disfunción Cognitiva/epidemiología , Trastornos de la Memoria/epidemiología , Memoria , Sarcoidosis/epidemiología , Adulto , Anciano , Atención , Estudios de Casos y Controles , Enfermedades del Sistema Nervioso Central/diagnóstico , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Estudios Transversales , Fatiga/epidemiología , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Países Bajos/epidemiología , Prevalencia , Pronóstico , Factores de Riesgo , Sarcoidosis/diagnóstico , Neuropatía de Fibras Pequeñas/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Fatigue is a major and disabling problem in sarcoidosis. Knowledge concerning correlates of the development of fatigue and possible interrelationships is lacking. OBJECTIVE: A conceptual model of fatigue was developed and tested. METHODS: Sarcoidosis outpatients (n = 292) of Maastricht University Medical Center completed questionnaires regarding trait anxiety, depressive symptoms, cognitive failure, dyspnea, social support, and small fiber neuropathy (SFN) at baseline. Fatigue was assessed at 6 and 12 months. Sex, age, and time since diagnosis were taken from medical records. Pathways were estimated by means of path analyses in AMOS. RESULTS: Everyday cognitive failure, depressive symptoms, symptoms suggestive of SFN, and dyspnea were positive predictors of fatigue. Fit indices of the model were good. CONCLUSIONS: The model validly explains variation in fatigue. Everyday cognitive failure and depressive symptoms were the most important predictors of fatigue. In addition to physical functioning, cognitive and psychological aspects should be included in the management of sarcoidosis patients.
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Disfunción Cognitiva/psicología , Depresión/psicología , Fatiga/psicología , Sarcoidosis/psicología , Neuropatía de Fibras Pequeñas/fisiopatología , Adulto , Ansiedad/epidemiología , Ansiedad/psicología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/fisiopatología , Depresión/epidemiología , Disnea/epidemiología , Disnea/fisiopatología , Fatiga/epidemiología , Fatiga/fisiopatología , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Capacidad de Difusión Pulmonar , Calidad de Vida , Sarcoidosis/epidemiología , Sarcoidosis/fisiopatología , Neuropatía de Fibras Pequeñas/epidemiología , Apoyo Social , Encuestas y Cuestionarios , Capacidad VitalRESUMEN
BACKGROUND: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients. METHODS: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch. RESULTS: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038). CONCLUSIONS: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired - as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.