Distal symmetric polyneuropathy (DSP) is most often explained by length-dependent metabolic or toxic axonal injury, with typical Wallerian and distal axonopathy patterns. Clinically, it presents as symmetric, length-dependent sensory more than motor deficits, usually chronic in course. Electrodiagnostic testing reveals reduced compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes with relatively preserved conduction velocities and latencies. Common causes include diabetes and other dysglycemic states, alcohol use, toxins and medications, nutritional deficiencies, and renal or hepatic disease, though many cases remain idiopathic and axonal in nature [4].

Sensory neuronopathies arise from injury to the dorsal root ganglion, or less commonly the anterior horn cell, and differ from typical peripheral neuropathies by their non–length-dependent and often asymmetric distribution. Clinically, they present with sensory loss and marked sensory ataxia while motor strength is relatively preserved early in the disease course. Electrodiagnostic studies show diffusely reduced or absent sensory responses with relatively preserved motor conduction. These disorders are most often associated with autoimmune conditions such as Sjögren syndrome, paraneoplastic syndromes, and certain toxins including platinum-based chemotherapeutic agents [5].

Demyelinating neuropathies are caused by injury to the myelin sheath, resulting in conduction slowing and block, and may occur as acquired immune-mediated or hereditary disorders. They typically present with proximal and distal weakness and areflexia, with a tempo that ranges from acute onset, as in Guillain–Barré syndrome, to chronic progression, as seen in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Electrodiagnostic studies reveal slowed conduction velocities, prolonged distal latencies, temporal dispersion, conduction block, and abnormal or absent F-waves. Etiologies include the CIDP spectrum and other immune-mediated neuropathies, paraproteinemic forms, and hereditary demyelinating conditions such as Charcot–Marie–Tooth type 1. This category includes both acquired demyelinating neuropathies and hereditary demyelinating neuropathies (e.g., Charcot–Marie–Tooth disease [CMT], hereditary neuropathy with liability to pressure palsies [HNPP]) [6].

Small-fiber neuropathy arises from selective injury to nociceptive and autonomic fibers, producing a clinical pattern dominated by burning pain, allodynia, thermal dysesthesias, and frequent autonomic symptoms, while examination and standard nerve conduction studies may remain normal. Diagnosis relies on specialized testing, most notably skin biopsy to assess intraepidermal nerve fiber density and autonomic evaluations such as the quantitative sudomotor axon reflex test (QSART) or heart rate variability. Common etiologies include dysglycemia and diabetes, amyloidosis, sarcoidosis, Sjögren syndrome, various toxins, and idiopathic causes [7].

Autonomic neuropathy involves injury to sympathetic and parasympathetic fibers, often overlapping with small-fiber disease, and is characterized clinically by orthostatic hypotension, gastrointestinal dysmotility, genitourinary dysfunction, and sudomotor abnormalities, with diabetes frequently amplifying morbidity. Diagnosis relies on standardized autonomic function testing performed in conjunction with somatic nerve assessments. The most recognized context is diabetic cardiovascular autonomic neuropathy, along with other diabetic autonomic syndromes [8].

Vasculitic neuropathy results from ischemic infarction of the vasa nervorum and typically presents as a subacute, painful, asymmetric mononeuropathy multiplex, where urgent recognition and treatment can alter outcomes. Amyloid and other infiltrative neuropathies arise from extracellular deposition, often producing a length-dependent phenotype with prominent small-fiber and autonomic features. Toxic–inflammatory neuropathies, such as those induced by chemotherapy, usually manifest as axonal, length-dependent sensorimotor involvement [9].

Entrapment neuropathies arise from mechanical compression and ischemia at common entrapment sites, producing early demyelination with potential axonal loss if injury is severe or prolonged. Clinically, they present with focal territorial deficits, such as median neuropathy at the wrist, and may coexist with systemic polyneuropathies, particularly in the context of diabetes [10].

Overlap among neuropathic disorders is common, as many conditions evolve to produce mixed axonal and demyelinating features over time, while autonomic and small-fiber involvement frequently coexist and contribute to the overall clinical presentation.

Symmetric, predominantly motor weakness that evolves over $\le$4 weeks with reduced/absent reflexes may prompt consideration of Guillain–Barré syndrome (GBS) and expedited decisions regarding intravenous immunoglobulin (IVIg) or plasma exchange (PE) [11]. Dysphagia, respiratory compromise, or rapidly evolving autonomic instability warrants intensive care unit (ICU)-level monitoring [11]. By contrast, a painful, asymmetric mononeuritis multiplex–like picture with systemic inflammatory features should raise concern for vasculitis or paraneoplastic disease and trigger early specialty referral for electrodiagnostics, serology, and—when appropriate—biopsy.

A symmetric, length-dependent, sensory-predominant presentation points first to metabolic/toxic causes such as DPN or chemotherapy-induced peripheral neuropathy (CIPN) [12, 13]. Non–length-dependent or multifocal patterns raise the likelihood of immune-mediated neuropathies (e.g., CIDP or autoimmune nodopathies), vasculitis, or paraneoplastic etiologies [14]. A small-fiber–predominant syndrome—burning pain with thermal/pinprick loss and relatively preserved vibration—suggests early DPN, CIPN, or amyloid and should prompt small-fiber testing [12, 13]. Chronic ($\ge$8 weeks) symmetric sensorimotor deficits with reduced reflexes keep CIDP or nodopathy high on the list [14].

Bedside screening remains valuable: thermal/pinprick for small- fibers; 128-Hz tuning fork and joint-position sense for large fibers; and 10-g monofilament for protective sensation. For DPN, at least annual neuropathy assessment is advised (type 2: from diagnosis; type 1: from 5 years after onset) [12].

Clinicians are encouraged to ensure that laboratory testing and electrodiagnostic studies are pattern-driven rather than ordered as a “shotgun” panel. When DPN is likely, prioritize optimization of metabolic control; when immune disease is suspected, EDX and targeted inflammatory/immune labs. In CIPN, document the drug history, dose, and cumulative exposure [12, 13].

EDX, including NCS and EMG, are pivotal to define (1) demyelinating vs axonal physiology; (2) length-dependent vs non–length-dependent involvement; (3) the presence of conduction block (CB) and temporal dispersion; and (4) anatomic localization. In CIDP, typical demyelinating features include prolonged distal latencies, slowed conduction velocities, CB/temporal dispersion, and prolonged F-waves, findings that directly inform treatment decisions. In autoimmune nodopathies, watch for prominent CB with little or no temporal dispersion, consistent with reversible conduction failure at the node/paranode [14]. CIPN most often shows a sensory-predominant axonal pattern [13].

For carpal tunnel syndrome (CTS) as a focal confirmation scenario, a paired-accuracy meta-analysis indicates similar diagnostic performance for nerve-muscle US and EDX (sensitivity 86% vs 92%, specificity 79% vs 82%); shared decision-making can weigh patient preference, cost, and availability [15].

US and MRN serve complementary roles; selecting the modality based on its specific strengths enhances diagnostic yield. US is favored for superficial nerves, small branches, dynamic compression, and metal-adjacent regions (e.g., near postoperative hardware or devices). It visualizes extrinsic compression, gliding impairment, cysts/foreign bodies in real time, and is rapid, bedside-capable, and cost-effective [16, 17]. MRN is central for deep nerves, brachial/lumbosacral plexus, tumors, and extensive trauma. When available, use higher field strength and optimized 3D isotropic protocols with robust fat suppression and suppression of intravascular signal to improve conspicuity of nerve fascicles and perineural pathology [18, 19]. In the presence of metal, artifact mitigation can include using lower field strength and metal artifact–reduction techniques with appropriate bandwidth adjustments [16, 18].

Operationally, in entrapment neuropathies, start with US to detect swelling/flattening, hyperemia, and dynamic signs; add MRN when needed to map the full extent and denervation changes [16, 19]. In trauma/postoperative settings, US is advantageous near sutures and hardware, whereas MRN best captures the overall extent of plexus or long-segment injuries [16, 18]. For tumor/infiltration, MRN depicts features of peripheral nerve sheath tumors (PNST) (e.g., fascicular sign/target sign) and can suggest malignancy (e.g., lower apparent diffusion coefficient (ADC)); consider fluorodeoxyglucose positron emission tomography (FDG-PET) when appropriate [16].

When small-fiber–predominant involvement is suspected (burning pain, thermal hypoalgesia, prominent paresthesia with largely normal EDX), combine intraepidermal nerve fiber density (IENFD) from skin biopsy (invasive but standardized histologic metric), quantitative sensory testing (QST) (functional but subject-dependent), and corneal confocal microscopy (CCM) (noninvasive quantitative imaging). Of these, CCM has shown early sensitivity to regeneration, detecting significant increases in corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) as soon as 1–8 months after pharmacologic or surgical interventions, with effects sustained longer term—supporting its role as a biomarker of early small-fiber recovery and a bridge between trials and practice [20].

Mechanistic evidence suggests that hyperglycemia/metabolic stress can alter exosome release and cargo (e.g., miRNA/protein/lipid profiles), thereby amplifying neuroinflammation, Schwann-cell dysfunction, impaired axonal regeneration, and microvascular injury—processes central to diabetic neuropathy pathogenesis. In contrast, clinical evidence remains preliminary: circulating exosomal signatures (including candidate miRNAs proposed in early studies) may serve as minimally invasive biomarkers for early detection, phenotyping (painful vs painless), and longitudinal monitoring, but require standardized isolation/assays and prospective validation across cohorts. Therapeutically, most data are preclinical, where Schwann cell–derived or mesenchymal stromal cell–derived exosomes have been reported to support neuroprotection and repair (mitochondrial support, inflammation modulation, axonal regeneration), and engineered exosomes are being explored as targeted delivery vehicles for therapeutic nucleic acids or drugs; however, translation is limited by manufacturing scale-up, cargo consistency, dosing/route optimization, and safety/efficacy confirmation in human trials [21].

Despite its promise, CCM (and other specialized small-fiber assessments) has limited availability in routine practice, requires dedicated equipment and trained expertise, and demonstrates variability in normative values and diagnostic thresholds across devices, acquisition protocols, and reference populations [22].

Testing for nodal/paranodal antibodies should be guided by specific clinical triggers. Evaluation is warranted in patients with CIDP-like disease who demonstrate a poor or early-relapsing response to IVIg; prominent ataxia, coarse tremor, or marked sensory ataxia; cranial, ocular, or respiratory muscle involvement; electrodiagnostic studies showing prominent conduction block with minimal temporal dispersion suggestive of nodal dysfunction; or magnetic resonance imaging (MRI)/MRN evidence of nerve root or plexus hypertrophy [14].

Recommended testing includes antibodies to neurofascin-155 (NF155), neurofascin-186 (NF186), neurofascin-140 (NF140), contactin-1 (CNTN1), and contactin-associated protein 1 (CASPR1) (including pan-neurofascin). Cell-based assays (CBA) are preferred, as ELISA alone may yield false-positive or false-negative results; accordingly, CBA-focused diagnostic strategies are advised [14]. IgG subclass may have therapeutic implications. Immunoglobulin G (IgG) -predominant responses (e.g., against NF155, CNTN1, or CASPR1) are often less responsive to IVIg and may respond better to B-cell–targeted therapies such as rituximab. In contrast, acute IgG3-predominant cases may initially respond to IVIg but can later switch to an IgG4 profile and become treatment-refractory [14].

Fig. 1 summarizes a pragmatic diagnostic algorithm for peripheral neuropathy, and Table 1 outlines the core initial and conditional tests used in this review.

A practical approach is to: (1) triage red flags first (GBS, autonomic/respiratory compromise) [11]; (2) apply pattern recognition (length-dependent vs non–length-dependent; symmetric vs asymmetric; small- vs large-fiber); (3) use core labs and EDX to establish axonal vs demyelinating vs nodal physiology [12, 13, 14]; (4) select imaging appropriately—US for superficial/dynamic/metal-adjacent scenarios, MRN for deep nerves, plexus, tumors, and extensive trauma—with optimized protocols for the clinical question and metal artifact–reduction strategies when needed [16, 18, 19]; (5) when small-fiber involvement is likely, incorporate CCM/IENFD/QST, noting CCM’s sensitivity to early regeneration [20]; and (6) if IVIg-refractory CIDP-like disease or nodal signatures are present, test by CBA for NF155/CNTN1/CASPR1 ($\pm$ pan-neurofascin (pan-NF)) and align treatment accordingly [14]. For focal entrapment (e.g., CTS), US and EDX offer comparable accuracy, so shared decision-making based on preference, cost, and access is appropriate [15].

Clinicians may consider escalating the diagnostic workup to EDX (NCS/EMG) when large-fiber involvement is suspected (objective sensory loss, weakness, areflexia), when the pattern is asymmetric, non–length-dependent, or rapidly progressive, when an immune-mediated neuropathy is suspected, or when the diagnosis remains unclear after core laboratory testing (and before initiating immunotherapy). Proceed to US when symptoms suggest focal entrapment/structural pathology, when dynamic compression is suspected, when evaluation is needed near metal/hardware, or when pre-procedural planning is required (e.g., for targeted injection or surgical planning). Proceed to MRN when deep nerves or plexus are suspected to be involved, when tumor/trauma or extensive postoperative injury is suspected, when symptoms remain unexplained despite EDX/US, or when whole-course mapping is required for management decisions. Proceed to genetic testing when onset is in childhood/early adulthood, when there is a family history or characteristic skeletal deformity (e.g., pes cavus), or when EDX suggests a hereditary pattern (e.g., diffuse uniform demyelination without clear conduction block or recurrent pressure palsies). Proceed to biopsy when results are likely to change management—particularly in suspected vasculitic neuropathy (painful, asymmetric mononeuritis multiplex with systemic inflammatory features), suspected amyloidosis/infiltrative neuropathy, or suspected small-fiber neuropathy with normal EDX (skin biopsy for IENFD as appropriate) [9].

In children, the algorithm requires several pediatric-specific safeguards. Red flags include delayed motor milestones, gait clumsiness, pes cavus, scapular winging, and unexplained pain crises or autonomic instability. Time course still guides the differential—acute/subacute patterns often reflect infectious or post-infectious causes (including pediatric GBS variants), whereas chronic courses suggest toxic/metabolic or hereditary etiologies. Initial testing mirrors adults but prioritizes potentially reversible causes (e.g., B12 deficiency, thyroid disease, inflammatory screens) and a careful drug/toxin review; when phenotype or family history points to a genetic disorder, early targeted genetics is appropriate. Electrodiagnostic testing should use age-adjusted norms, and imaging (US or MRN) helps exclude structural entrapment and can inform biopsy decisions [11, 23]. Management emphasizes physiotherapy and orthotics, child-appropriate analgesic dosing, and family genetic counseling; immunotherapy follows established pediatric GBS/CIDP frameworks when indicated. Overall, apply the same stepwise logic, but lower the threshold for genetics, adjust EDX interpretation for age, and focus on reversible causes early.

For painful diabetic peripheral neuropathy (PDN) and other neuropathic pain syndromes, first-line pharmacologic options include serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), gabapentinoids, and sodium channel blockers, all supported by moderate-quality evidence [27, 28]. Across high-quality guidelines and meta-analyses, SNRIs (e.g., duloxetine), gabapentinoids (gabapentin/pregabalin), and sodium-channel blockers (e.g., mexiletine, carbamazepine; lamotrigine for selected phenotypes) achieve broadly similar small-to-moderate average pain reductions in painful neuropathy; in practice, between-class differences are driven more by adverse-event profiles and comorbidities than by efficacy per se. Duloxetine often suits patients with co-existing depression/anxiety or fatigue; gabapentinoids warrant caution for sedation, dizziness/falls, weight gain, and the need for renal dosing; Na⁺ blockers require electrocardiogram (ECG)/QTc vigilance and drug–drug interaction review.

A pragmatic rule is to begin with one first-line class, reassess at 8–12 weeks using predefined pain and function thresholds, and—if there is partial benefit with good tolerance—either switch classes or consider low-dose combination therapy; prioritize safety and tolerability over theoretical additive efficacy. Their average effect sizes are comparable, and opioids should generally be avoided except as short-term rescue in selected cases [27]. The therapeutic goal should focus on pain reduction and functional improvement rather than complete elimination. Response is typically assessed after 8–12 weeks; partial responders may benefit from class switching or combination therapy [29].

Dosing and titration should be individualized according to sedation, fall risk, weight gain, anticholinergic burden, renal and hepatic function, and potential interactions (e.g., selective serotonin reuptake inhibitors [SSRI]/SNRI coadministration or tricyclic antidepressant (TCA) cardiotoxicity) [28]. A conservative initial dose and slow titration are recommended in elderly or renally impaired patients. When combining agents, safety and tolerance should guide the regimen rather than expecting additive efficacy [29]. As adjunctive options, the 8% capsaicin patch provides modest yet clinically meaningful analgesia with minimal systemic exposure [30].

Transient local burning is common but self-limited. Topical agents, including lidocaine 5% patch, can be used as adjuncts, particularly for patients intolerant of systemic drugs or with focal neuropathic pain [27].

When pharmacotherapy provides insufficient relief, US-guided procedures may be appropriate. These require precise anatomical targeting and risk assessment, including management of anticoagulation, infection, and glycemic control [19, 31].

The use of corticosteroids should be determined on a case-by-case basis, and specific indications are outlined below. Corticosteroids are indicated in selected conditions such as Morton’s neuroma, where injection of local anesthetic combined with a small dose of non-particulate corticosteroid can provide short-term improvement in pain and function [32, 33]. For greater occipital nerve (GON) blocks, evidence is mixed in migraine (no added benefit of steroid in an randomized controlled trial (RCT)) but supportive in cluster headache [34, 35, 36].

Routine use of corticosteroids should be avoided for sympathetic blocks and simple trigger-point injections due to limited demonstrated benefit and the potential for adverse effects. Decisions should be individualized based on patient comorbidities (e.g., diabetes, infection risk) and aligned with local practice protocols [37].

For cases with suspected perineural adhesion or compression, hydrodissection using saline or dilute local anesthetic $\pm$ low-dose steroid may improve nerve mobility and pain in selected patients. Evidence is mainly derived from small observational studies and case series; therefore, short-term improvements have been reported, and hydrodissection can be considered between conservative therapy and surgical decompression on a case-by-case basis [19, 38].

For patients with moderate-to-severe neuropathic pain refractory to optimized conservative therapy, neuromodulation provides a key therapeutic option. Proper patient selection—based on pain distribution, disease mechanism, psychological readiness, and comorbidities—is critical to ensure response. This section covers spinal cord stimulation (SCS) and pulsed radiofrequency (PRF), which modulate pain transmission without nerve destruction [39, 40].

Cannabinoids: evidence for chronic neuropathic pain shows small-to-moderate short-term benefit with frequent dose-limiting adverse effects (sedation, cognitive changes), variable legal access, and uncertain long-term safety; reserve for refractory cases after shared decision-making [52].

Ketamine: intravenous (IV) ketamine can provide short-term analgesia and wind-down central sensitization in highly refractory neuropathic pain; limit to monitored settings with defined protocols and psychological screening; durability and optimal maintenance remain uncertain [53].

Mexiletine: oral Na⁺ channel blocker useful for select sodium-channel–mediated pain and refractory PDN; monitor for gastrointestinal (GI) intolerance and QT-related risk; consider ECG at baseline and dose escalation. These options should not displace first-line agents and should be integrated within multidisciplinary care, with explicit risk–benefit documentation [54].

(Disease-modifying therapy) Whenever an etiology-directed option exists, addressing the underlying cause should be prioritized alongside symptom control (e.g., immune, metabolic, toxic, compressive, or systemic causes), ideally coordinated with neurology and relevant specialty services.

PPNI arises from combined mechanical compression or stretch, ischemia, injection pressure–related fascicular injury, neurotoxicity, and position-related external compression. In anesthesia, intraneural (intrafascicular) injection, excessive injection pressure, prolonged fixed positioning, and tourniquet-induced blood flow interruption are key drivers [57, 58]. Surgical contributors include traction, compression, thermal damage, and ischemia in procedures such as orthopedic (shoulder/elbow), cardiac, urologic/gynecologic, and head & neck surgery [55].

Common perioperative patterns include position-related neuropathies (e.g., lithotomy-associated femoral/obturator compression; prone positioning with axillary/radial compression; brachial plexus stretch with shoulder abduction), tourniquet-related ischemic injury with longer inflation times, block-related injury associated with intrafascicular injection/elevated injection pressure and higher local anesthetic exposure, and direct surgical trauma or traction (e.g., shoulder/elbow fixation or trocar-related injury to the lateral femoral cutaneous nerve) [55, 59, 60, 61] .

Regional anesthesia–associated neuropathy: After peripheral nerve block, most postoperative neurologic symptoms are transient paresthesias; persistent deficits are uncommon (0.02–0.1%). Typical presentations are sensory-predominant and map to the block territory, though motor involvement can occur with intrafascicular injection, high injection pressure, or compressive hematoma [57]. Risk factors include preexisting neuropathy (e.g., diabetes), prolonged/labored needle manipulation, large volumes or high concentrations of local anesthetic, and prolonged fixed positioning [62]. Multifactorial causation is frequent and may involve both anesthesia- and surgery-related mechanisms. During block placement, combine real-time US with low-current nerve stimulation when feasible, avoid injection against high opening pressure or patient-reported severe pain/paresthesia, and stop immediately if fascicular expansion or intraneural spread is suspected. Incorporating injection-pressure monitoring and using fractional, aspiration-interrupted injections reduce the likelihood of intrafascicular delivery. For patients with preexisting neuropathy (e.g., diabetes), adopt the lowest effective dose/volume and document baseline deficits to mitigate “double-crush” confounding.

Prevention can be summarized as (1) optimize technique during regional anesthesia (US-guided needle visualization, avoid injection against high opening pressure or severe paresthesia; consider pressure monitoring as an adjunct), (2) minimize exposure (use the lowest effective dose/volume and avoid incompatible admixtures), and (3) reduce mechanical/ischemic stress (neutral positioning with periodic checks, individualized tourniquet pressure and shortest feasible duration). In selected high-risk procedures, intraoperative neuromonitoring (motor evoked potentials [MEP] and somatosensory evoked potentials [SEP]) may facilitate early detection [16, 55, 58, 59, 60, 61].

When new deficits arise, consider both anesthesia- and surgery-related etiologies. Early US or MRN helps define anatomical localization, while electrodiagnostics differentiate axonal vs. demyelinating patterns [16, 18]. In the acute phase, distinguish reversible edema from irreversible axonal injury; prompt decompression of external sources and early rehabilitation can influence outcomes. If positioning, traction, or block-related mechanisms are implicated, implement recurrence-prevention bundles (positioning protocols, US proficiency training, injection pressure alarms) at the institutional level. For continuous perineural catheters, monitor for unexpectedly prolonged or dense motor block; if present, pause infusion and reassess before resuming at lower concentration. In anticoagulated patients or those with difficult needle passes, maintain a low index of suspicion for bleeding-related compression. Signs of local infection (fever, erythema, discharge) should prompt catheter removal and appropriate cultures and antibiotics.

Although rare, PPNI can be life-altering. Preoperative counseling should state that: (1) injuries are uncommon but not fully preventable; (2) many cases improve over weeks to months; and (3) severe cases may require prolonged rehabilitation or reconstruction. Written consent and documentation are recommended [55, 57].