Small fiber neuropathy: expanding diagnosis with unsettled etiology

Abstract

Purpose of review

Small fiber neuropathies (SFN) are a heterogeneous group of disorders affecting the thinly myelinated Aδ and unmyelinated C-fibers. The clinical picture is dominated by neuropathic pain, often accompanied by autonomic symptoms of variable severity. The underlying causes encompass metabolic conditions like diabetes mellitus, immuno-mediated disorders, infection, exposure to toxins, and gain-of-function variants in the genes encoding the Nav1.7, Nav1.8, and Nav1.9 sodium channel subunits, though the list of associated diseases continues to grow. Recently, increased attention has focused on immune-mediated forms, which led to the identification of potentially treatable subgroups. These discoveries have advanced our understanding of pathophysiological mechanisms.

Recent findings

Recent studies have broadened the spectrum of underlying conditions associated with SFN, including immune-mediated forms and links to SARS-CoV-2 infection and vaccines. Studies on genetic variants linked to unique clinical presentations have also yielded new insights. Furthermore, emerging perspectives highlighted disorders involving small fiber pathology that lacks typical clinical features of neuropathic pain, challenging traditional diagnostic criteria.

Summary

Deepening our understanding of the causes underlying SFN advances the identification of potential therapeutic targets. The clinical presentation of SFN can vary significantly and may not consistently correlate with specific underlying conditions. Therefore, a systematic investigation of possible causes through a structured diagnostic assessment is critical to unveil additional contributing factors.

INTRODUCTION

Small fiber neuropathy (SFN) predominantly affects the peripheral afferent thinly myelinated Aδ fibers and unmyelinated C-fibers, mostly sparing large myelinated fibers. It typically presents with a combination of positive (e.g. burning, sharp and/or deep pain, allodynia, hyperalgesia) and negative (e.g. thermal and pinprick hypoesthesia) symptoms and signs, which often begin in the feet and progress with a length-dependent distribution. However, a nonlength-dependent pattern can occur, including patchy, asymmetric – mononeuritis multiplex-like [1,2], or diffuse involvement [3] (Fig. 1). Autonomic impairment is common, impacting patients’ quality of life [3]. 

FIGURE 1.

Clinical phenotypes in small fiber neuropathy and syndromic small fiber pathology: (a) length-dependent symptoms and signs distribution; (b) patchy pattern in nonlength-dependent distribution; (c) focal/multifocal patterns; (d) predominant autonomic phenotype; (e) diffuse widespread sensory symptoms, and (f) atypical pattern.

Box 1.

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A large variety of underlying conditions have been linked to SFN, including metabolic, immune-mediated, neurotoxic, infectious, iatrogenic, and genetic disorders [4] (Table 1). Identifying these causes is critical to provide patients with specific management and targeted therapy, when available [3,4].

Table 1.

Associated conditions in small fiber neuropathy

Category	Conditions
Acquired
Metabolic	Diabetes mellitus, impaired glucose tolerance, hyperlipidemia, hypothyroidism, vitamin b12 deficiency, folate deficiency, metabolic syndrome
Immune-mediated	Sarcoidosis, Sjögren syndrome, celiac disease, systemic lupus erythematosus, monoclonal gammopathy, inflammatory bowel disease, post-infectious, post-vaccination Paraneoplastic (ANNA-1, CRMP-5-IgG, P/Q VGCC, NMDA, PCA-2), Auto-antibodies (TS-HDS, FGFR3, Plexin D1, MX1, DBNL, KRT8, AGO, CASPR2, and LGI1)
Infectious	HIV, hepatitis C, Lyme neuroborreliosis, Chagas disease, SARS-CoV-2
Toxic and drug-related	Metronidazole, Nitrofurantoin, linezolid, statins, flecainide, bortezomib, TNF inhibitor, alcohol, thallium, hypervitaminosis B6
Hereditary/genetic	Sodium channelopathies (SCN9A, SCN10, and SCN11A), TRPs (TRPA1), COL6A5 mutations, Fabry disease, familial amyloidosis, hemochromatosis, tangier disease, Friedreich ataxia, hereditary sensory autonomic neuropathies HSAN* I, II, III, and IV
Syndromic	Pain syndromes (fibromyalgia, chronic pelvic and bladder pain, irritable bowel syndrome, complex regional pain syndrome type I), Elhers–Danlos syndrome, myalgic encephalomyelitis/chronic fatigue syndrome
Neurodegenerative disorders	Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis

Recent literature findings of the conditions in bold are discussed in the current review.

Over the past decade, the discovery of potentially pathogenic genetic variants in voltage-gated sodium channel (SCN) genes, primarily expressed in small-size nociceptors, has deepened our understanding of the pathophysiology of SFN and led to the identification of new potentially druggable targets [5,6].

However, despite extensive screening, a significant proportion of cases remain idiopathic. Efforts are increasingly focused on identifying additional underlying causes [7], particularly autoantibodies, the role of SARS-CoV2 infection, and vaccine-related mechanisms, to widen possibilities for targeted therapeutic approaches [8^▪,9]. Finally, an emerging category of disorders, such as fibromyalgia (FMS), synucleinopathies, and amyotrophic lateral sclerosis (ALS) [10], includes those related to small fiber pathology in the absence of clinical features consistent with peripheral neuropathy.

This review provides an update of the advancements on SFN etiologies over the past 18 months.

IMMUNE-MEDIATED SMALL FIBER NEUROPATHY

Up to 21% of SFN patients have underlying immune-mediated diseases [4,11,12], including Sjogren syndrome, sarcoidosis, lupus erythematosus, or harbor potentially pathogenetic autoantibodies. Clinical presentation, which is often characterized by acute onset and nonlength-dependent pattern of symptom distribution [13,14], can be challenging and requires a multimodal diagnostic approach [11,13]. In a small cohort of 20 patients presenting with acute-onset SFN, symptoms occurred mostly after a precipitating event, with a nonlength-dependent pattern and median progression of 2 weeks. Notably, 85% of patients complained of pain and 60% of dysautonomic symptoms. Antifibroblast growth factor 3 (FGFR3) antibodies have been identified in about one-fourth of patients, while in-vitro studies detected IgG immunoreactivity against nerve tissue in 70% of the patients, supporting the hypothesis of an immune-mediated pathophysiology [15^▪▪].

Sjogren's syndrome and sarcoidosis are frequently associated with SFN [11,16^▪,17^▪]. In sarcoidosis, the occurrence of SFN is related to higher prevalence of other symptoms beyond pain, including fatigue, restless leg syndrome, and cognitive impairment [16^▪]. SFN in Sjogren's syndrome presents mostly with nonlength-dependent distribution of symptoms and rarely progresses to large fiber neuropathy [11].

Autoantibodies

The presence of autoantibodies potentially related to immuno-mediated SFN has been investigated in patients with otherwise idiopathic etiology. Autoantibodies against trisulfated heparin disaccharide (TS-HDS), FGFR3, and Plexin D1 have been found in 37–44% of patients [18,19]. Their presence was significantly associated with female sex, a nonlength-dependent distribution, and acute onset [20]. TS-HDS is expressed on the outer surface of peripheral nerves, through its interaction with extracellular proteins such as FGF and VEGF, modulates multiple signaling pathways, involved in neurotrophic support, angiogenic balance, and repair mechanism that are essential for peripheral nerve homeostasis [21].

FGFR3 is a transmembrane tyrosine kinase involved in nerve regeneration, axon development, and cell death signaling [22]. The pathogenic role of anti-FGFR3 antibodies remains uncertain because they mainly recognize intracellular epitopes, casting doubt on both target accessibility and functional relevance [23]. Other immune-mediated mechanisms, such as FGFR3-specific T-cell responses or cross-reactivity with related antigens, should, therefore, be explored. In addition, the selective sensory phenotype is puzzling, given the wider FGFR3 expression in small and large sensory neurons [24] and motor terminals [25].

Plexin D1 is a transmembrane glycoprotein that mediates signal transduction and axon guidance. Anti-Plexin D1 IgG antibodies have been linked to neuropathic pain associated with musculoskeletal pain [26^▪]. Several clues suggest a pathogenic role, such as patient-derived IgG binding to C-fiber nociceptors and cutaneous nerve fibers in mouse dorsal root ganglia. Additionally, mice injected with IgG from patients who tested positive for plexin D1-IgG, but not with IgG from D1-IgG-negative individuals, showed a transient increase in mechanical and thermal sensitivity [20]. Autoantibodies against Leucine-Rich Glioma-Inactivated 1 (LGI1) and Contactin-Associated Protein-like 2 (CASPR2), commonly associated with autoimmune encephalitis, can also be linked to conditions characterized by peripheral nerve hyperexcitability, dysautonomia and neuropathic pain, and reduced intraepidermal nerve fiber density (IENFD), suggesting a potential pathogenic role in SFN [27]. Other promising autoantibodies identified in idiopathic SFN include the interferon-induced GTP-binding protein Mx1 (MX1), drebrin-like protein (DBNL), cytokeratin 8 (KRT8), and Argonaute (AGO) antibodies [23].

Collectively, these findings warrant confirmatory studies in larger cohorts of patients, while provide a rationale for exploring disease-modifying immunomodulatory treatments. Case reports and series suggested possible efficacy of treatment with intravenous immunoglobulins (IVIg), high-dose steroids or biologicals. In a retrospective study [28^▪] involving 91 patients with pure SFN, 11 out of 12 patients treated with IVIg showed IENFD recovery, especially those carrying Plexin D1 autoantibodies. Another study [29] investigated 54 idiopathic SFN patients and found that 44.4% had antibodies against TS-HDS, FGFR-3, or Plexin D1. Patients who completed IVIg treatment demonstrated improvement in clinical examination, questionnaires scores, and IENFD. However, to date, the only double-blind, placebo-controlled trial in SFN associated with TS-HDS and FGFR-3 autoantibodies showed no benefit of IVIg on pain, clinical examination, and IENFD over 6 months [30]. A recent study proposed treating antibody-associated SFN with a B-cell-depleting monoclonal antibody, particularly for patients who do not respond to IVIg or corticosteroids [8^▪]. However, further randomized controlled trials are necessary to define the effectiveness of immune-modulating and immune-suppressant treatments and the development of standardized protocols [30].

SARS-CoV2 infections

SFN has been associated with several infectious diseases, including HIV, hepatitis C virus and, most recently, SARS-CoV2. A broad range of neurological manifestations, including peripheral neuropathies and autonomic dysfunction has been associated to acute infection of SARS-CoV-2 [31]. Reports of autonomic dysfunction in Guillain–Barré syndrome have raised the possibility that SFN could also arise after SARS-CoV-2 infection, either through direct viral neurotoxicity or postinfectious immune mechanisms. Sensory and autonomic symptoms have been reported in at least half of the cases following SARS-CoV2 infection [32]. Nevertheless, most research to date has examined SFN primarily as a manifestation of long-COVID sequelae. Among patients with painful long COVID, nearly half showed a nonlength-dependent pattern of denervation at skin biopsy [33^▪]. The underlying pathophysiology of long COVID-related SFN remains poorly understood. Indirect mechanisms such as neurovascular dysregulation, systemic inflammation, or autoimmunity rather than direct viral damage to sensory neurons have been suggested [34].

Recently, an association with natural killer (NK) cell genetic variants and long COVID-associated and prepandemic SFN has been reported [35^▪▪]. Among autonomic symptoms, postural orthostatic tachycardia syndrome (POTS) characterized by intolerance to standing and exaggerated rise in heart rate have been reported [33^▪,36,37].

Furthermore, SFN has also been linked to SARS-CoV-2 vaccination. Several case reports have described patients who developed burning pain and dysesthesias after receiving SARS-CoV-2 vaccine, some including skin biopsy confirmation [38^▪,39^▪]. The temporal correlation between symptom onset and vaccination could suggest a possible connection in some cases, but a definitive causal link remains unproven, especially considering the exceptionally high number of vaccinations during the pandemic.

VOLTAGE-GATED SODIUM CHANNELOPATHIES AND OTHER GENETIC DISORDERS

Sodium channel genes

Voltage-gated sodium (Nav) channels, encoded by SCN genes, play a crucial role in generating and propagating action potentials in excitable cells, including neurons. Among them, SCN9A (Nav1.7), SCN10A (Nav1.8), and SCN11A (Nav1.9) are particularly relevant to SFN due to their predominant expression in peripheral nociceptors. SCN9A mutations can cause Mendelian pain disorders, ranging from congenital insensitivity to pain [40] to extreme pain syndromes [41,42]. Association studies suggested that SCN9A variants can contribute to increased pain sensitivity [43] and SFN [5], indicating that other genetic variants in the same gene may also act as risk factors for common neuropathic conditions, including idiopathic SFN (Table 2) [44].

Table 2.

Genes and mechanisms involved in small-fiber neuropathy

Gene	Product	Mechanism	SFN phenotype	References
SCN9A	Voltage-gated sodium channel alpha subunit Nav1.7	Gain-of-function mutations increase neuronal excitability	Painful SFN, idiopathic SFN, diabetic SFN, inherited erythromelalgia, paroxysmal extreme pain disorder	[5,42–44,49,46,48]
SCN10A	Voltage-gated sodium channel alpha subunit Nav1.8	Gain-of-function mutations; increased nociceptor activity	Painful SFN	[5,48,49]
SCN11A	Voltage-gated sodium channel alpha subunit Nav1.9	Gain-of-function mutations alter resting potential and neuronal excitability	Painful SFN	[48,49]
SCN3A	Voltage-gated sodium channel alpha subunit Nav1.3	Variants in sodium alpha and beta subunits modulating excitability	Mutations found in painful and painless SFN	[49,53]
SCN7A	Osmosensitive sodium channel alpha subunit Nav2.1 (NaX)	direct sensor of extracellular Na+ in central and postganglionic sympathetic neurons	No direct link	[62]
SCN1B–SCN4B	Voltage-gated sodium channel beta subunits			[49]
TRPA1	Transient Receptor Potential Cation Channel Subfamily A Member 1	Variants affecting chemosensation, thermosensation and oxidative stress response	Familial episodic pain syndrome, cram-fasciculation syndrome, idiopathic painful SFN	[46,51–53,54▪▪]
TRPV1, TRPV3, TRPM8	Transient Receptor Potential cation Channels	Altered thermosensation	Painful SFN	[53,54▪▪]
KCNQ3, KCNA2, KCNA4, KCNK18	Potassium Voltage-gated channels	Disrupted potassium channel function affecting excitability	Painful SFN	[55,53,56]
HCN1	Hyperpolarization-activated cyclic nucleotide-gated potassium channel	Hyperpolarization-activated current alterations	Painful SFN	[53]
ANK2	Ankyrin 2	Irritable nociceptor	Irritable phenotype in diabetic polyneuropathy	[58▪]
OPRM1	Opioid receptor Mu 1	Opioid receptor variant linked to neuropathic pain susceptibility	Neuropathic pain including SFN	[58▪]
TTR	Transthyretin	Amyloidogenic variants cause nerve fiber degeneration	SFN with autonomic dysfunction, early hATTR	[63]

A recent study based on paleogenetic findings identified a Neanderthal introgression in SCN9A gene, showing that individuals with native American ancestry and carrying the archaic haplotype (M932L, V991L, and D1908G) exhibited lower mechanical pain thresholds after sensitization with mustard oil [45]. This supports the hypothesis that genetic influence on pain sensitivity may be evolutionarily conserved and additive across Nav1.7 variants. However, a study on patients with different chronic pain conditions, revealed that the variant W1538R, topologically included in the Neanderthal introgressed genomic region, was significantly enriched in patients in association to the archaic haplotype, suggesting that the impact of the haplotype could be related to the presence of the W1538R, frequently inherited together [46]. This finding has important implication for guiding targeted treatments. Indeed, the efficacy of lacosamide, a sodium channel blocker, demonstrated in a randomized clinical trial in SFN patients carrying SCN9A variants [6], was influenced by variants, which can inhibit its pharmacological effect [47].

Advancements in sequencing technologies improved the assessment of the mutational burden. Recent findings revealed gain-of-function variants in SCN9A, SCN10A, or SCN11A in 12% of pure SFN patients [48], rising to 18% when SCN7A and SCN3A, and beta-subunits (SCN1B–SCN4B) were included [49].

However, the frequency of SCN gene variants was reported to be similar in painful (18.5%) and painless (18.8%) SFN [49]. This finding highlighted the need to shift from single-variant analysis to an aggregate analysis approach, capable of revealing significant differential enrichment of rare variants between patients and healthy controls. This approach, using the unified sequence kernel association test (SKAT-O) was recently applied to patients affected by chronic pain syndromes [46,50]. Notably, in the SKAT-O analysis, which included healthy elderly participants as controls, SCN genes were less enriched in rare variants as compared to other genes, such as TRPA1 and PTPRZ1[46].

Transient receptor potential channels

Among transient receptor potential (TRP) channels acting as molecular sensors for temperature, mechanical stimuli, and chemical irritants, TRPA1 has recently drawn particular interest due to its role in neuropathic pain. Two pathogenic variants resulting in a missense change and in a premature protein truncation, have been described associated with familial episodic pain syndrome and cramp-fasciculation syndrome, respectively [51,52].

A recent study linked the TRPA1 p.Ala172Val variant with episodic widespread chronic pain phenotype, resembling the familial episodic pain syndrome linked to the p.Asn855Ser variant [51]. Functional studies revealed that p.Ala172Val causes a gain-of-function of the channel in response to agonists, resulting in altered nociceptive afferent functioning [50].

In addition to syndromic conditions, in a cohort of patients with painful SFN carrying no variants in candidate SCN genes, the screening of rare mutations revealed most commonly variants in the TRP genes [53]. Additionally, a whole-exome sequencing (WES) analysis in early-onset (<45 years) cases of painful SFN showed an enrichment of variants in TRP genes, suggesting their role in pain modulation alongside sodium channels [54^▪▪].

A gene-wise aggregation analysis identified TRPA1 as significantly enriched with rare variants in patients with idiopathic chronic pain conditions, including SFN, compared to healthy controls [46].

Other genetic and epigenetic associations

Potassium channels regulate neuronal excitability by maintaining resting membrane potential and modulating action potential firing. Recent studies suggest that rare genetic variants in genes encoding potassium channels can play a role in the pathophysiology of painful SFN [53,55,56] inducing changes in resting membrane potential, Na-K-pump functioning, channel conductance, and hyperpolarization-activated current [57]. Gene burden analysis of candidate pain genes revealed significant associations between rare OPRM1 variants and neuropathic pain, likely due to abnormal mu-opioid receptor signaling. Additionally, a variant in the ANK2 gene, involved in cytoskeletal anchoring, was linked to the ‘irritable nociceptor’ phenotype [58^▪].

Exploring epigenetic mechanisms can provide valuable insights. A recent study identified four miRNAs (miR-30a-5p, miR-30d-5p, miR-181a-2–3p, and miR-203a-5p) expressed in keratinocytes of patients with SCN-related SFN, correlating with NEDD4 transcription level, further implicating NEDD4 in the regulation of Nav1.7 [59]. Further evidence suggested that epigenetic modifications are involved in the development and maintenance of neuropathic pain. Recently, distinct DNA methylation signatures discriminated painful and painless neuropathy phenotypes in type 2 diabetes patients, and GCH1, MYT1L, and MED16 emerged as most promising therapeutic targets amongst differentially methylated genes [60^▪▪]. Furthermore, a pioneering study demonstrates that patients with painful diabetic neuropathy exhibit accelerated epigenetic aging, assessed by DNA methylation clocks, telomere length, immune cell composition, and methylation-based plasma protein surrogates, compared to those with painless phenotype and healthy controls. These findings suggest that neuropathic pain reflects and potentially promotes biological aging. Applying similar approaches to idiopathic SFN could uncover diagnostic and stratification biomarkers and clarify whether epigenetic alterations influence disease severity and the progression of neuropathic pain of unknown origin [61^▪▪,62,63].

SYNDROMIC SMALL FIBER PATHOLOGY

Over the past decade, small nerve fiber involvement has been increasingly associated with conditions lacking the typical clinical features of classic SFN, which have been referred to as syndromic small fiber pathology[4,64,65^▪▪]. They included fibromyalgia (FMS), chronic visceral pain, irritable bowel disease (IBD) [66^▪], bladder pain syndrome [67], and complex regional pain syndrome type 1 [68^▪▪] among the most commonly reported. Although there is a general agreement that FMS is primarily a disorder of central pain processing [65^▪▪], some studies showed a coexisting involvement of peripheral small nerve fibers, as demonstrated by skin denervation [64,69^▪], abnormalities of C-fiber function at microneurography [70] and increased thermal thresholds at quantitative sensory testing [71,72]. In FMS, skin denervation typically shows a nonlength-dependent pattern [66^▪] that can be accompanied by morphological abnormalities (73), such as thinner nerve fibers and increased peptidergic innervation of glabrous skin arteriole-venule shunts [73].

Although skin biopsy should not be used to assimilate FMS with SFN, which has different clinical features and pathophysiology [69^▪,74^▪], a possible co-existence of the two conditions has been suggested [71,75^▪]. These findings emphasize the importance of correlating clinical symptoms with diagnostic tests to establish the diagnosis of SFN [7,71,75^▪]. FMS symptoms can overlap those of other clinical entities, such as IBD, particularly in cases with multisystem involvement, including dyshidrosis and urogenital dysfunction [75^▪].

Recent studies linked SFN with myalgic encephalomyelitis/chronic fatigue syndrome [76^▪], which is characterized by a plethora of symptoms including fatigue, cognitive impairment, muscle pain, headache, and tachycardia. The onset can be triggered by an infection or a stressful event, and the potential mechanisms comprise immune dysregulation, chronic inflammation, gut dysbiosis, and genetic susceptibility [77]. About half of these patients experience pain and dysautonomia, and higher thermal thresholds and small fiber morphological abnormalities, including fiber tortuosity at CCM, have been reported [76^▪].

Among the syndromic forms of SFN, there are also conditions not associated with chronic pain. These include both nonpain-related systemic conditions and neurodegenerative diseases. Recently described examples are POTS [78^▪] and myotonic dystrophy type 1 [79^▪], as well as several neurodegenerative disorders such as Parkinson's disease [80^▪▪,81^▪▪] and ALS [10].

DIAGNOSTIC AND THERAPEUTIC APPROACH

Diagnostic assessment

The diagnostic approach of SFN is often challenging, as conventional nerve conduction studies are typically normal. According to current diagnostic criteria, diagnosis requires the combination of compatible clinical symptoms and signs, and evidences of small fiber involvement assessed by skin biopsy and/or quantitative sensory testing (QST) [82]. Skin biopsy with quantification of IENFD is considered the gold standard, providing structural confirmation of small fiber loss. Beyond quantification, the distribution pattern of fiber loss, morphological features consistent with predegenerative changes, or regenerative sprouting can provide additional information [3]. Increasing attention has also been directed toward emerging molecular markers [59], resident skin cells, and activated immune cells [68^▪▪,83], which may offer additional insights into disease mechanisms and diagnostic refinement.

QST, although a psychophysical method, allows functional assessment of thermal and pain thresholds, contributing to defining clinical patterns as an extension of the neurological examination. Its diagnostic accuracy in SFN is significantly enhanced when using combined limit and level-methods [82], particularly combined cold and warm detection thresholds [84^▪]. Further diagnostic tools may complement conventional assessments in SFN. Corneal confocal microscopy (CCM), in particular, has emerged as a validated and noninvasive structural marker of small fiber damage, with strong diagnostic and prognostic value in diabetic forms. It enables quantification of small fiber degeneration and regeneration, allows longitudinal monitoring to identify disease progression or recovery, and provides markers of systemic inflammation through analysis of decreased corneal nerve fiber density, increased tortuosity, and increased dendritic cells [85]. Its diagnostic yield, however, appears lower than of skin biopsy in idiopathic SFN [86^▪].

Perception threshold tracking (PTT), a recently introduced psychophysical method in diabetic neuropathy, has shown high diagnostic concordance with both CCM and thermal detection thresholds, suggesting its potential value as an additional functional marker [87^▪].

Autonomic testing, particularly heart rate variability analysis, quantitative sudomotor axon reflex testing (QSART), and thermoregulatory sweat testing, provide valuable information on autonomic fiber integrity. These techniques are especially recommended in cases with prominent autonomic symptoms or when the first-line investigations yield inconclusive results.

In parallel, neurophysiological techniques are gaining recognition for their ability to provide objective functional data in diagnostically challenging cases. Among this, microneurography, despite its technical demands and limited availability to specialized centers, allows direct recording of spontaneous and evoked activity in individual C-fibers, including C-nociceptors subpopulation not assessable through QST or skin biopsy, thus offering unique access to peripheral nociceptive processing [88^▪▪]. While its clinical use remains restricted, microneurography has proven valuable in clinical trials of peripherally acting analgesics [70,89] and in characterizing peculiar clinical pictures, like sodium channellopathies. Additionally, painful evoked potentials, laser-evoked potentials (LEPs), contact heat-evoked potentials (CHEPs), and the more recently developed cold-evoked potentials (CEPs) are increasingly used to assess Aδ fiber function and spinothalamic pathways. These techniques allow the selective activation of different nociceptive subpopulations based on stimulus modality, allowing targeted exploration of distinct afferent pathways within the Aδ fiber pathways. While CEPs have demonstrated enhanced sensitivity for detecting cold-specific abnormalities [90,91], their use is limited during lower limb recordings, by low signal-to-noise ratios and higher susceptibility to habituation [92]. Notably, none of these modalities reliably activate C-fibers when applied to the lower extremities, reducing their diagnostic value in this context.

Therapeutic approach

The management of SFN aims primarily at treating the underlying cause, when identifiable, for example, optimizing glycemic control in patients with diabetes or impaired glucose tolerance. In cases where autoimmune mechanisms are suspected or confirmed, immunomodulatory treatments such as corticosteroids, intravenous immunoglobulins, or other immunosuppressants may be considered. While evidence is limited, their use may be justified in carefully selected patients.

Over the past two decades, substantial efforts have focused on the development of pharmacological agents targeting ion channels selectively expressed in nociceptive neurons. Nevertheless, the treatment of SFN-related pain remains challenging, similar to other neuropathic pain conditions, with fewer than half of patients achieving clinically meaningful relief, and tolerability often limited by adverse effects. Current guidelines recommend serotonin–norepinephrine reuptake inhibitors (SNRIs; e.g. duloxetine), gabapentinoids (gabapentin and pregabalin), and tricyclic antidepressants as first-line agents. Topical formulations, including 5% lidocaine patches and high-concentration capsaicin plasters, are considered second-line options, supported by moderate-quality evidence. Tramadol and botulinum toxin A may be used in selected cases, although the latter has received only weak recommendations based on limited randomized controlled trials in SFN populations [93^▪,94].

The identification of sodium channel mutations in SFN has revealed novel molecular targets for personalized treatment approaches, spurring particular interest in the development of selective Nav channel blockers. Among available agents, lacosamide – an antiepileptic drug that enhances slow inactivation of voltage-gated sodium channels and modulates collapsing-response mediator protein-2 (CRMP-2), has demonstrated potential in Nav1.7-related SFN, with pain reduction reported in specific subgroups [6].

However, targeting Nav channels remains complex due to rapid gating kinetics, genetic heterogeneity, and the modulatory influence of other ion channel systems and disease states [95]. As a result, alternative strategies are under investigation, including modulation of channel trafficking, enhancement of inactivation over inhibition, and the use of endogenous channel-targeting peptides, subtype-specific monoclonal antibodies, or neurotoxins.

Nonpharmacological interventions are increasingly integrated into multimodal care strategies. Spinal cord stimulation may be considered in refractory cases, although its cost-effectiveness and appropriate patient selection should be carefully assessed within a multidisciplinary context [96,97]. Physical therapy, despite limited supporting data in SFN, remains a useful adjunct to maintain mobility and functionality. Given the complex and multidimensional nature of neuropathic pain, influenced by biological, psychological, and sociocultural factors, a multidisciplinary and multidimensional approach based on the biopsychosocial model is recommended. Finally, emerging precision medicine frameworks incorporating molecular and neurophysiological biomarkers may promote tailored therapeutic strategies for patients with SFN [98^▪▪].

CONCLUSION

Our understanding of the underlying causes of SFN has advanced significantly, with new evidence highlighting autoantibody-mediated mechanisms. The role of genetic and epigenetic modifications has also grown stronger, suggesting they may act as both disease determinants and contributing risk factors. Small fiber pathology observed in clinical presentations lacking typical features of neuropathic pain or SFN warrants further investigation at the molecular level. These studies, along with others, should aim to elucidate the underlying pathophysiological mechanisms to develop tailored treatments for patients.

Acknowledgements

None.

Financial support and sponsorship

This work was supported by funding from the Italian Ministry of Health (RRC).

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest