Keywords
small fiber neuropathy - skin biopsy - neuropathic pain
Small fiber neuropathy (SFN) is a condition that selectively or predominantly affects the peripheral afferent thinly myelinated Aδ fibers and unmyelinated C-fibers, leaving the larger myelinated fibers relatively spared. It is clinically characterized by sensory symptoms and neuropathic pain that significantly impact quality of life. Autonomic complaints can also occur and worsen the clinical picture.[1] Most cases present with a length-dependent distribution, although a non–length-dependent pattern of symptoms can also occur. SFN complicates several common diseases, such as diabetes and impaired glucose tolerance; however, almost half of the cases remain idiopathic. Limited epidemiological data are available, and the prevalence is estimated between 13.3 and 52.8 per 100,000.[2]
[3]
In the last two decades, the availability of diagnostic tools, particularly skin biopsy, has advanced our understanding of SFN and provided significant insight into the nociceptive pathways and mechanisms of neuropathic pain. A valuable example is the discovery of pathogenic genetic variants in voltage-gated sodium channel genes and TRPA1, which has expanded our knowledge of the pathophysiology in SFN, leading to the identification of new molecular target sites, with the opportunity to develop more effective, personalized treatments.[4] However, there are aspects still debated and not fully understood. First, although diagnostic criteria for the classical symmetric length-dependent SFN are available,[5]
[6] those for non–length-dependent distribution as well as focal or multifocal SFN have not been established. Second, only a few natural history studies have been designed to evaluate the clinical course and progression of the disease. Finally, the significance of small nerve fiber loss in conditions not included among classical SFN, such as fibromyalgia,[7] Parkinson disease,[8]
[9] and other neurodegenerative disorders, is uncertain.
This review aims to provide an overview of the clinical assessment, diagnosis, and treatment of this disorder.
What Are Small Nerve Fibers?
What Are Small Nerve Fibers?
Small fibers are the peripheral branches of small- and medium-sized dorsal root ganglia (DRG) and trigeminal ganglia neurons extending into the skin and internal organs, where they detect potential noxious stimuli.[10] They convey the information to the spinal cord and eventually the supraspinal structures and brain ([Fig. 1]). Small fibers are classified into thinly myelinated Aδ-fibers, with intermediate conduction velocities, transducing pinprick and rapid pain, and unmyelinated C-type fibers, with the slowest conduction velocity, conveying burning and slow pain sensations. C-fibers arise from multimodal nociceptors, activated by thermal, chemical, and mechanical stimuli. In the skin, the terminal branches eventually enter the epidermis, where they run close to keratinocytes, forming a functional interaction through synaptic-like contacts.[11] A subgroup of C-nociceptors is that of peptidergic fibers containing and releasing neuropeptides such as CGRP and substance P, to actively mediate vasoactive, trophic, and proinflammatory effects ([Fig. 2]).
Fig. 1 Representation of small nerve fiber-mediated perception of thermal and painful stimuli. They are transduced by peripheral receptors expressed on terminal endings of first-order sensory neurons and conveyed to the spinal cord and eventually the supraspinal structures and brain.
Fig. 2 Illustration of the sensory somatic cutaneous innervation showing normal nerve fiber in a healthy subject and degeneration of the terminal endings of small nerve fibers populating the epidermis in a patient with small fiber neuropathy. LTMR, low-threshold mechanosensitive receptors; HTMR, high-threshold mechanosensitive receptors.
Small fibers also innervate autonomic structures such as dermal vessels, sweat glands, and hair follicles, with Aδ-fibers contributing to preganglionic sympathetic and parasympathetic fibers, and C fibers to postganglionic fibers.
Clinical Features and Phenotypes
Clinical Features and Phenotypes
SFN can present with different patterns, among which the most common is a length-dependent distribution of symptoms also defined as the classic SFN. Some patients present with a non–length-dependent distribution of symptoms or focal symptoms involving selectively a specific area, that is, burning mouth syndrome (BMS; [Fig. 3]).
Fig. 3 Clinical phenotypes in small fiber neuropathy patients. (A) Length-dependent symptoms distribution; (B) patchy pattern in non–length-dependent distribution; (C) focal patterns; (D) diffuse widespread sensory symptoms and pain. Different phenotypes may suggest possible associated conditions (see text for details).
Patients with classic length-dependent SFN ([Fig. 3A]) typically complain of neuropathic pain along with various degrees of loss of thermal and nociceptive sensation in the feet. Pain is usually ongoing and spontaneous, frequently described as burning, prickling, shooting, aching, or, less commonly, cold and itching,[6] and it worsens during the night. Some patients also report intolerance to socks and sheets. Pain is frequently exacerbated by warm and, less commonly, cold exposure, as in oxaliplatin-induced neuropathy. Some patients can also suffer from restless legs syndrome,[12] fatigue,[13] and cramps,[14] whereas others report unpleasant paresthesias.[15] Symptoms often remain confined to the feet for years,[16] although they can gradually extend to the legs, with a distal-to-proximal gradient. When symptoms reach the knees, the hands and distal forearms can also be involved, starting from the fingertips ([Fig. 3]).
The progression may also involve large fibers, especially in metabolic-related SFN (i.e., in diabetic neuropathy and impaired glucose intolerance IGT)[6]
[17]; in those cases, the clinical picture is defined as mixed fiber neuropathy.
Less frequently, SFN shows a non–length-dependent pattern, characterized by symptoms and signs with a patchy distribution, involving at the onset preferably proximal sites including the upper limbs, face, and trunk, with a variable distribution that is not strictly symmetrical. Symptoms can progress simultaneously in proximal and distal areas of the limbs. This clinical picture may be caused by a primary ganglionopathy, namely, the involvement of the dorsal root sensory ganglia,[18] or less frequently of multiple sensory nerves, with the most commonly recognized causes being immune-mediated, paraneoplastic, and genetic disorders.[19]
[20]
Patients are diagnosed with focal SFN when there is evidence of SFN degeneration in isolated regions of the body, such as BMS,[21] or notalgia paresthetica.[22]
Another subgroup consists of individuals in whom widespread pain symptoms correlate with SFN diagnosed by skin biopsy and/or quantitative sensory testing (QST), like in fibromyalgia[23] and Ehler-Danlos syndrome,[24]
[25] also defined as small fiber pathology or syndromic SFN.[26]
Autonomic symptoms may be serious manifestations of SFN, occurring in amyloidotic, diabetic autonomic, and paraneoplastic neuropathies, and in patients carrying specific mutations of sodium channel genes.[27] Dysautonomia can present with focal, segmental, or generalized autonomic neuropathy affecting cardiovascular, gastrointestinal, urogenital, sudomotor, and pupillomotor functions. Autonomic symptoms include dry mouth and eyes, blurry vision, orthostatic dizziness, palpitations, hypo- or anhidrosis, as well as hyperhidrosis. Cardiac disturbances include palpitations, orthostatic intolerance, and orthostatic hypotension (OH). In some cases, SFN may be related to the neuropathic subgroup of postural orthostatic tachycardia syndrome (POTS).[28] When the gastrointestinal tract is involved, symptoms include gastroparesis, constipation, or diarrhea due to small intestinal bacterial overgrowth caused by intestinal dysmotility. Genitourinary dysfunction encompasses several symptoms, typically occurring early and including impotence, reduced urinary sensation, hesitation, nocturia, urinary retention, and incontinence.
A comprehensive assessment of autonomic function and clinical examination is essential to correctly interpret the symptoms, which are often not specific and can pose diagnostic challenges.
Diagnostic Assessment
Bedside Clinical Examination
A thorough clinical evaluation including family and personal medical history, medications, and potential toxic and chemotherapeutic agents should be performed. Clinical scales and questionnaires can support the collection of symptoms, scoring pain intensity for different types of pain qualities, and drawing body maps for distribution. Among the most frequently used, the Small Fiber Neuropathy and Symptoms Inventory Questionnaire is specifically designed for SFN.[29]
At the bedside, the standardized somatosensory evaluation should encompass all sensory modalities, including negative and positive sensory signs, also using clinical scales and questionnaires. Tests should include the evaluation of light touch sensation to a cotton swab or 10 gr monofilament, finger pressure, pinprick, flat brush, and, for cold and warm stimuli, thermorollers kept at 20 and 40 °C.[30] Positive sensory signs include the assessment of hyperalgesia, which is increased, and abnormal pain sensation after painful stimuli, and allodynia, which is an abnormal painful perception of nonpainful stimuli. Notably, given the subjective nature of pain perception, allodynia and hyperalgesia should be first tested in a nonaffected area and then within the neuropathic area. Other positive signs are the “aftersensation,” defined as the persistent sensation of pain abnormally lasting after the stimulus ends, and the “wind-up” phenomenon, defined as a progressive and frequency-dependent increase of pain after high-intensity repetitive pinprick stimuli.[30] The distribution of sensory signs within a cutaneous map drawn with a pencil could be important to quantify the extent of involvement and monitor changes after treatment or clinical progression. Large fiber assessment includes vibratory sensation assessment to a 128-Hz tuning fork, joint proprioception, deep tendon reflexes, muscle tone, trophism, and strength.
Bedside assessment of the autonomic nervous system can provide useful information. It should include a thorough inspection to detect skin discoloration, trophic changes, loss of hair/nails, atrophic or dry skin, hyperhidrosis, and the assessment of pupillary light reflex and response to accommodation. Postural variability of blood pressure (BP) and heart rate (HR) is assessed by the measurement of BP and HR after at least 5 minutes of rest and again after 1, 3, and 5 minutes of standing up. OH is defined when a sustained reduction of systolic BP of > 20 mm Hg and diastolic BP of >10 mm Hg is recorded. Notably, if OH is accompanied by a lack of HR increase after 3 minutes of standing (ΔHR/Δ systolic BP of < 0.5 beats/min), a neurogenic origin should be suspected.[31]
Skin Biopsy
The first demonstration of the staining of intraepidermal nerve fibers using the gene product of protein 9.5, a cytoplasmic carboxyl-terminal ubiquitin hydrolase, was in 1989.[32]
[33] The quantification of intraepidermal nerve fiber density (IENFD) with skin biopsy, as standardized in the EFNS/PNS guideline, proved to have the highest sensitivity and specificity for diagnosing SFN,[34] while responding to the need to identify a lesion of the somatosensory system in the context of a neuropathic pain condition. Briefly, linear IENFD, expressed as the number of fibers per millimeter (IENF/mm), is obtained by counting the number of nerve fibers crossing the dermal–epidermal junction in three nonconsecutive 50-μm-thick slices, then dividing by the length of the epidermis. Skin biopsy could be performed at any location; however, since the classical clinical picture of SFN is characterized by sensory complaints mainly involving distal lower limbs, IENFD quantification has been standardized for the lower leg, where biopsy is taken 10 cm proximal from the lateral malleolus within the territory of the sural nerve.[22] Proximal sites, such as the thigh, can also be investigated to address non–length-dependent distribution; however, as opposed to the distal site, a large dataset of normal values is not yet available. An additional biopsy from the proximal thigh can also provide information on the proximal distribution of the neuropathy.[22]
Sex- and age-matched normal reference values for IENFD at the distal leg site have been provided for bright field[35] ([Fig. 4]) and immunofluorescence[36] microscopy, both reporting comparable diagnostic accuracy.[37] In patients with normal IENFD, axonal swelling can represent pre-degenerative pathology.[38] This finding should suggest the need to repeat the biopsy over time, especially if the diagnostic suspicion is supported by the clinical picture. Small nerve fiber-mediated autonomic function innervating sweat glands, pilomotor muscles, and vessels can also be investigated in the skin ([Fig. 5]). Quantification methods have been proposed[39]
[40] to increase the diagnostic yield. Overall, skin biopsy is a minimally invasive procedure that can be repeated for longitudinal assessments. It can cause rare and usually mild complications such as bleeding, infection, or keloid formation. Anticoagulant and antiplatelet therapy should not be considered an absolute contraindication since it can be managed by applying a compression dressing.
Fig. 4 Bright field immunostaining with antiprotein gene product 9.5 antibody (PGP9.5) in 50-μm-thick section from the distal leg of skin biopsy comparing cutaneous innervation in a patient with small fiber neuropathy (SFN) and a healthy control. In the patient with SFN, the density of intraepidermal nerve fibers is reduced (scale bar: 50 μm).
Fig. 5 Confocal analysis of total (PGP9.5-ir; green), cholinergic (VIP-ir; red), and noradrenergic (TH-ir; blue) fibers in a skin biopsy comparing healthy subjects and patients with small fiber neuropathy (SFN). (A, B) Healthy arteriovenous anastomosis shows an abundant noradrenergic innervation (A″′) and less dense cholinergic network (A″), whereas degeneration of both the TH and the VIP-positive fibers is found in SFN (B-B″′). (C, D) Healthy secretory coils of the sweat glands (C–C″′) are characterized by a dense intertwining of fibers, mainly cholinergic (C″) with a small amount of noradrenergic fibers (C″′). In SFN, we observe a marked degeneration of both cholinergic and noradrenergic fibers (D–D″′). Scale bar: 20 µm. AVA, arteriovenous anastomosis; SFN, small fiber neuropathy.
Quantitative Sensory Testing
QST is a noninvasive psychophysical assessment used to measure the threshold of sensory perception related to the function of large and small nerve fibers. Various sensory modalities can be tested, including light touch, vibration, warmth, cooling, and sensitivity to heat and cold pain. Individuals are tasked with recognizing these sensations, and using different methods, the functional impairment of sensory nerve fibers can be quantified.[41] The method of levels, which gauges a patient's ability to detect a specific change in temperature, offers an advantage over reaction time-dependent methods, as it reduces biases related to cognitive impairment or use in pediatric patients.[42] Conversely, the method of limits requires patients to respond to temperature changes promptly by pressing a button. QST serves as a confirmatory tool for diagnosing SFN, with recommendations provided for its clinical use, outlining applications and result interpretation.[43] In particular, the use of QST is recommended for screening for small and large fiber neuropathies, and monitoring of somatosensory deficits, evoked pain, allodynia, and hyperalgesia. However, QST is not recommended as a standalone test for the diagnosis of neuropathic pain.
Normative values for QST vary depending on factors such as age, gender, and the body site being tested, with parameters adjusted accordingly.[44] In a recent study comparing different diagnostic tests in patients with SFN, QST was abnormal in 28% of patients, whereas distal leg IENFD was reduced in 70%, and neurological examination was abnormal in 62%.[45] Application and interpretation of QST imply considering some limitations inherent to the method: it relies on patient cooperation, making it susceptible to bias; it cannot differentiate between involvement of the central and peripheral somatosensory pathways; and it is time-demanding and requires specialized equipment. In view of the above, QST alone is not recommended as a sole diagnostic tool for diagnosing SFN; however, it can provide detailed information about the involvement of specific sensory modalities that could be used for phenotyping and stratification into subgroups, potentially reflecting different underlying pathophysiological backgrounds.
Corneal Confocal Microscopy
Corneal confocal microscopy (CCM) is a noninvasive method able to visualize unmyelinated C fibers innervating the cornea in vivo. The evaluation of corneal innervation has been standardized, with normative values for four different parameters, including nerve fiber density, branch density, nerve fiber length, and tortuosity.[46] Its main strength is that it is a repeatable noninvasive examination and can be used for follow-up evaluations. Its utility as a diagnostic tool is supported by the evidence of reduced corneal nerve fiber density in patients with length-dependent and non–length-dependent SFN patients,[47]
[48] and these findings are supported by a systematic review and meta-analysis.[49] However, a recent study comparing the diagnostic yield of CCM with IENFD and cold and warm detection thresholds in patients with type 2 diabetes showed a lower sensitivity of CCM in the diagnosis of diabetic neuropathy compared with skin biopsy and QST.[50]
Autonomic Testing
Autonomic testing can recognize the presence, distribution, and severity of autonomic dysfunction, which can be particularly important in some conditions such as diabetic neuropathy and amyloidosis.[51]
[52]
[53] Cardiovascular autonomic tests assess heart rate variability (HRV) and BP changes at rest and after various standardized maneuvers, enabling exploration of cardiovagal and adrenergic function. In addition, HRV can be used to assess the activity of central oscillators, parasympathetic and sympathetic efferents, the baroreflex pathway, and the sinus node. Time and frequency domain HRV measures are the mathematical methods commonly used to determine HRV.
In a cohort of patients with idiopathic SFN, about one-third complained of OH symptoms but none had OH when tested.[54] Another study reported a significant reduction of HRV both in the frequency and time domain.[55] The absence of a nocturnal fall in BP, termed a “non-dipping” profile, was also described.[56]
The postganglionic sudomotor and vasomotor function can be assessed by several standardized quantitative methods that share the same principle of delivering a cholinergic stimulation (i.e., acetylcholine or pilocarpine) by iontophoresis within a small skin area, then recording sweating through different techniques, allowing a quantitative determination of the innervated sweat glands density. One of the most widely used is the Quantitative Sudomotor Axon Reflex test (QSART), which measures axon-reflex-mediated sweating as the total sweat output. It has been standardized in different sites including the forearm, proximal leg, distal leg, and foot, allowing the detection of length-dependent or generalized postganglionic sudomotor impairment. However, the sensitivity differs significantly between studies, ranging from 2 to 80% in SFN,[57]
[58]
[59] making it a complementary test to assess autonomic SFN. Sudomotor tests can also be performed using the Neuropad,[60] a semiquantitative and not highly sensitive method, the Dynamic Sweat Test (DST),[61] and the Quantitative Direct and Indirect axon Reflex Testing (QDIRT).[62]
The stimulated skin wrinkling test has been described as an additional test. This is based on the principle that immersion in water or the application of an anesthetic cream on the fingertips activates the sympathetic nerve fibers in the skin, causing vasoconstriction and consequently cutaneous wrinkling. One study used this test to demonstrate the impaired postganglionic sympathetic function in SFN patients.[63]
Finally, vasomotor responses can be tested using laser Doppler flowmetry and other laser Doppler-based techniques that assess peripheral vasoconstriction and vasodilatation responses quantifying the change of microvascular blood flow.[64]
[65] They provide valuable additional information about the integrity of axonal reflexes, although they have yet to be widely used in clinical practice. Even though the microvascular blood flow is regulated both by neurogenic and nonneurogenic factors, rapid vasoconstriction responses are mediated only by sympathetic nerve fibers and are a valuable method to test the integrity of autonomic SFN.[64]
[65]
Diagnostic Criteria
Different diagnostic criteria for SFN have been proposed ([Table 1]) based on symptoms, signs, and diagnostic tests aiming to address small nerve fiber involvement. The combination of clinical signs, abnormal QST, and/or reduced IENFD can more reliably lead to the diagnosis of SFN than the combination of abnormal QST and IENFD in the absence of clinical signs. In addition, IENFD reduction showed a higher diagnostic accuracy compared with QST.[66] These findings are further supported by the results of a recent study that addressed the diagnostic yield of six different tests in SFN.[45]
Table 1
Diagnostic criteria for SFN
|
Besta criteria[6]
|
|
Combination of two out of three of the following abnormal findings:
1. Neurological examination revealing clinical signs of loss of sensory modalities mediated by somatic small nerve fibers (i.e., thermal and pinprick sensation).
2. Abnormal thermal threshold assessed at dorsal foot by QST.
3. Reduced IENFD at skin biopsy collected at distal leg.
A recent revision of these criteria
[66]
emphasized the importance of clinical signs in improving the diagnostic accuracy of SFN
|
|
NEURODIAB criteria
[5]
|
|
Presence of length-dependent symptoms and/or clinical signs of small fiber damage
|
Possible SFN
|
|
Presence of length-dependent symptoms, clinical signs of small-fiber damage, and normal sural nerve conduction study
|
Probable SFN
|
|
Presence of length-dependent symptoms, clinical signs of small-fiber damage, normal sural NCS, and demonstration of small nerve fiber impairment by confirmatory test including skin biopsy and QST
|
Definite SFN
|
Abbreviations: NCS, nerve conduction study; QST, quantitative sensory testing; SFN, small fiber neuropathy.
Causes of Small Fiber Neuropathy
Causes of Small Fiber Neuropathy
An increasing number of conditions have been identified in association with SFN, and this number is likely to keep growing. The identification of the underlying cause remains essential for considering disease-modifying treatments. The diagnostic workup of SFN patients should include screening for any potentially treatable metabolic, immune-mediated, infectious, or genetic diseases ([Table 2]). Nevertheless, up to 50% of cases remain idiopathic.[4] Among acquired conditions, diabetes and impaired glucose tolerance are the leading causes of SFN. It is estimated that 1 in 10 adults aged 20 to 79 years worldwide have diabetes,[67] and painful peripheral neuropathy is reported to occur in up to 25% of diabetic patients.[68] Glucose overload triggers the dysregulation of different metabolic pathways in diabetes, eventually causing nerve damage with a dying-back pathological pattern, resulting in a classical length-dependent distribution of symptoms. However, the pathogenic role of diabetic neuropathy is not limited to hyperglycemia. Dyslipidemia and metabolic syndrome have been associated with neuropathy[69]
[70] and a higher incidence in type 2 diabetes patients,[71]
[72] independent of glycemic status.[73]
Table 2
Diagnostic screening tests for clinical practice
|
Condition
|
Diagnostic tests
|
|
Diabetes[a]
|
Fasting blood glucose
|
|
Glucose tolerance test
|
|
Hb1Ac
|
|
Immune-mediated diseases
|
Antinuclear antibody (ANA)
|
|
Extractable nuclear antigen (ENA), anti-RO (SSA), anti-La (SSB)—(Sjogren syndrome)
|
|
Antineutrophil cytoplasmic antibody screening (ANCA)
|
|
Rheumatoid factor
|
|
Antibodies for celiac disease (gliadin, transglutaminase, and endomysial)
|
|
Cryoglobulin
|
|
C-reactive protein
|
|
Infectious disease
|
Serology for hepatitis B and C[a]
|
|
Testing for HIV[a]
|
|
Hematological disease
|
Serum electrophoresis
|
|
Serum and urine immunofixation
|
|
Complete blood count
|
|
Other metabolic conditions
|
Renal function
|
|
Thyroid function
|
|
Liver function
|
|
Vitamin B12
|
|
Folate
|
|
Antibodies related[a]
|
CASPR2, LGI1
|
|
Paraneoplastic[a]
|
ANNA-1, CRMP-5-IgG, P/Q VGCC, NMDA, PCA-2[134]
|
|
Drug or toxic[a]
|
Levels of lead, mercury, thallium, zinc, and arsenic
|
|
Genetic disease
|
Transthyretin (TTR) gene testing—familial amyloid polyneuropathy[a]
|
|
α-Galactosidase A enzyme activity/alpha-Gal A (GLA) gene testing—Fabry disease (testing is indicated when systemic features are present)[135]
|
|
SCN9A, SCN10A, and SCN11A[b]
|
|
HSAN[a] I, II, III, and IV
|
Note: Tests suggested to be included in the initial screening are reported in bold.
a To consider in the presence of autonomic function involvement.
b To consider in familial idiopathic cases.
Immune Mediated
Immune-mediated diseases are found in up to 21% of SFN patients, more likely presenting with non–length-dependent pattern[74] and often acute onset.[75] Such distribution of symptoms, which can be proximal, patchy, asymmetrical, or diffuse, suggests a probable ganglionopathy primarily affecting small-size sensory neurons. Sarcoidosis and Sjogren syndrome have been described in SFN,[76]
[77]
[78]
[79] and available evidence does not report an evolution through mixed neuropathy with large sensory and motor fiber involvement.[77]
There is a growing interest in antibodies associated with SFN in the absence of systemic diseases. Autoantibodies against trisulfated heparin disaccharide (TS-HDS-Abs) and fibroblast growth factor receptor 3 (FGFR3-Abs) have been found in patients with sensory neuropathy and idiopathic SFN.[80]
[81]
[82]
[83] TS-HDS sits on the outer surface of cells in peripheral nerves and plays a role in cell growth and angiogenesis. FGFR3 belongs to the tyrosine kinase receptor family and is involved in nerve regeneration, axon development, and cell death signaling.[84] In a cohort of 155 SFN patients with no identified cause, 37% had immunoglobulin M (IgM) antibodies against TS-HDS, and 15% with IgG antibodies against FGFR3. Both were significantly associated with female sex and a non–length-dependent distribution of neuropathy. Interestingly, the presence of IgM against TS-HDS was closely associated with an acute onset, recalling what is observed in other neuropathies sustained by an immune-mediated pathological mechanism.[80] However, it is not yet known whether these antibodies have a clear pathogenetic significance in SFN.
Antiplexin D1 IgG antibodies in one study were identified in approximately 13% of 63 SFN patients and were absent in healthy controls.[85] Plexin D1 is a transmembrane glycoprotein involved in signal transduction and axon guidance. Patient-derived IgG was shown to bind C-fiber nociceptors on mouse DRG sections and their terminals in the skin. Furthermore, mice injected with plexin D1-IgG-positive patients showed a transient increase in mechanical and thermal sensitivity.[85]
Autoantibodies against leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) described in peripheral and central nervous system disorders have also been described in neuropathic pain associated with reduced IENFD, suggesting a potential pathogenic role in SFN.[86]
[87]
Novel autoantibodies have been identified in idiopathic SFN using a high-throughput protein array technology.[88] They include interferon-induced GTP-binding protein Mx1 (MX1), drebrin-like protein, and cytokeratin 8 (KRT8). Subgroup analysis revealed higher levels of anti-MX1 in idiopathic SFN compared with secondary SFN, proposing anti-MX1 as a potential biomarker. However, although encouraging, these results are preliminary and based on a limited number of patients, and need to be confirmed in future studies.
Infectious Diseases
SFN has been identified in association with infectious diseases, including HIV and hepatitis C virus infection.[89]
[90] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with multisystem postacute sequelae. Persistent neurological symptoms such as fatigue, “brain fog,” headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy are seen in up to one-third of cases, and are referred to as “long COVID (coronavirus disease).”[91]
[92]
[93] In a case series of 13 patients reporting painful paresthesias within 2 months following COVID-19 disease, six had clinical signs of neuropathy and a skin-biopsy-confirmed diagnosis of SFN; of these, two also showed autonomic dysfunction confirmed by autonomic function testing. Six patients reported sensory symptoms, but they had neither clinical signs nor denervation on skin biopsy. No association between the incidence of SFN and the severity of COVID-19 disease was reported.[94] In another case series of 17 long COVID patients with suspected neuropathy, 10 had SFN confirmed by skin biopsy and 4 had autonomic dysfunction.[95] Among autonomic findings associated with SARS-CoV-2 infection, symptoms of POTS with intolerance to standing and exaggerated rise in HR have been reported, more common in females and individuals aged between 15 and 45 years.[92]
[96] In addition, SFN has also been described in association with COVID-19 vaccination,[97] based on the temporal association with the onset of sensory or autonomic symptoms. However, no causal relationship has been demonstrated.
Genetic
The identification of gain-of-function missense mutations in SCN9A,[98]
SCN10A,[99] and SCN11A
[100] genes encoding Nav 1.7, Nav 1.8, and Nav 1.9 sodium channels α-subunit, respectively, in patients with idiopathic SFN led to the definition of the subgroup of sodium-channelopathy-related SFN. More recently, gain-of-function mutations have also been described in the gene encoding the β2-subunit of sodium channel in patients with idiopathic SFN and diabetic painful neuropathy.[101]
[102] Most of these patients presented with a classical length-dependent clinical picture. However, single mutations have been described as being associated with peculiar phenotypes, such as the G856D in SCN9A, identified in kindreds characterized by severe pain, dysautonomia, and acromesomelia.[103] The pathogenicity of some genetic variants has been demonstrated by cell electrophysiology. However, several observations[104] suggest that most should be considered risk factors rather than causative. Recently, a gene-wise aggregation analysis of painful and painless neuropathy patients, chronic widespread pain, and fibromyalgia patients compared healthy individuals identified TRPA1 as the most significant gene enriched of rare variants, giving a 4.8-fold higher risk of chronic pain. Notably, among the patients harboring TRPA1 variants, 25% were diagnosed with painful neuropathy and, irrespective of the clinical diagnosis, about one-third complained of itch and cold-triggered pain, mostly episodic.[105]
SFN can be an early finding in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and has been reported in presymptomatic carriers of TTR gene mutations.[106]
[107] In this context, the identification of small nerve fiber degeneration is pivotal for early diagnosis and disease-modifying treatment. SFN has explained the presence of neuropathic pain symptoms in other genetic conditions, including Fabry disease, Pompe disease,[108] Gaucher disease,[109] Ehlers-Danlos syndrome,[24]
[25] neurofibromatosis,[110]
[111] and CANVAS.[112]
Syndromic Disorders
Small fiber nerve impairment has been observed in several conditions lacking the typical clinical features of SFN. Notably, reduced IENFD has been described in neurodegenerative diseases like Parkinson disease[8] and amyotrophic lateral sclerosis,[113] as well as in chronic pain syndromes primarily characterized by widespread and poorly localized pain like fibromyalgia.[7]
[9]
[23]
[114] The significance of skin denervation in these pathological conditions, defined as small fiber pathology, is still unclear and may represent an epiphenomenon of the pathology. This strengthens the importance of a consistent relationship between clinical symptoms and signs and instrumental investigations to reach a definite diagnosis of SFN.
Management
Treatment in SFN is aimed at addressing the underlying cause, if identified, such as improvement of glycemic and metabolic control in diabetes and IGT.[115] Symptomatic treatment includes the management of pain, cognitive behavioral therapy and related approaches, physical activity, lifestyle changes, and the management of dysautonomia when present.
Treatment of neuropathic pain remains challenging, with less than half of patients achieving at least 50% pain relief, and high rates of side effects from medications. General recommendations are provided by guidelines.[116] Gabapentinoids (gabapentin, pregabalin), tricyclic antidepressants, and serotonin–noradrenaline reuptake inhibitors (duloxetine and venlafaxine) are first-line drugs, whereas topical treatment including lidocaine patch and capsaicin high-concentration plasters has a weaker recommendation, as does tramadol. Botulinum toxin A received a weak recommendation for peripheral neuropathic pain, tested in specific RCT in SFN patients.[117] The treatment of neuropathic pain is discussed in more detail in another article in this issue of the journal.
The identification of sodium channel gene mutations prompted the development of new therapeutic drugs, such as Nav1.7 blockers. Efficacy was, however, quite disappointing, with only a trend toward a reduction in the weekly average pain score.[118] Lacosamide, an approved antiseizure drug, has recently shown convincing potential for the treatment of SFN, acting by selective enhancement of slow inactivation of voltage-gated sodium channels and interacting with collapsing-response mediator protein-2. Lacosamide showed its effectiveness in a subgroup of Nav1.7-related SFN patients.[119]
[120]
Immunomodulatory treatment has been explored, especially in cases in which an autoimmune etiology was reported or suspected.[121] Treatment with IVIG in Sjogren syndrome-related SFN,[122] combined with anti-TNF in sarcoidosis-related SFN,[123] showed significant pain relief. However, in other SFNs, including idiopathic SFN and SFN associated with TS-HDS and FGFR-3 antibodies, results were not conclusive.[124]
[125]
Spinal cord stimulation can be considered in selected patients,[126] taking into account the cost–benefit balance within a multidisciplinary context.
Physical therapy and rehabilitation techniques are other valuable options, although there is little data on their efficacy in SFN.[127] Since pain in SFN is a multidimensional and complex symptom influenced by several factors including physical, psychological, neurophysiological, cultural, and socioeconomic, a multidisciplinary approach is recommended.[128] In this view, the biopsychosocial model could help in finding personalized approaches.[129]
Immunotherapy was proposed in the treatment of immune-mediated SFN.[121] Case reports and series showed positive results after treatment with immunomodulating and immunosuppressive drugs, including IVIG, high-dose steroids, and biologicals.[76]
[78]
[84]
[130] However, randomized controlled trials in these patient groups are needed to confirm the therapeutic efficacy and determine the optimal doses for maintenance therapy.
Natural History
There are few longitudinal studies evaluating disease progression in SFN. Progressive skin denervation assessed by skin biopsy did not correlate with clinical disability.[131]
[132] One study of 52 patients with SFN showed progressive skin denervation during 2 to 3 years of follow-up, with a similar rate of IENF loss at proximal and distal sites, suggesting a non–length-dependent pattern of terminal axonopathy.[131] Progression to large fiber neuropathy is considered uncommon, with a low rate of significant long-term disability.[133]
Conclusion
SFNs are a heterogeneous group of disorders dominated by neuropathic pain and dysautonomic symptoms. Several conditions have been associated, including metabolic, genetic, immune-mediated, toxins, and infections, with the list still growing. In clinical practice, the diagnosis is based on personal history, neurological examination, nerve conduction studies, skin biopsy, and other supportive functional tests. Pain treatment remains challenging; however, the lessons from the discovery of channelopathies in SFN not only improved our knowledge of underlying mechanisms but also offered the opportunity to test new drugs. Recent advances suggest that there may be a shift toward an approach to diagnosis and treatment based on individual biomarkers and biological mechanisms, hopefully improving the current limitations.
