Department of Neurology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
Correspondence to Jiwon Yang Department of Neurology, Gil Medical Center, Gachon University College of Medicine, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea Tel: +82-32-460-3346 Fax: +82-32-460-3344 E-mail: jiwonyang@gachon.ac.kr
• Received: September 22, 2025 • Revised: December 30, 2025 • Accepted: April 2, 2026
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Distal symmetric polyneuropathy (DSPN) is the most common form of diabetic neuropathy and a major cause of morbidity in patients with diabetes. Despite extensive research, diagnostic advances have been incremental rather than transformative, and accurate diagnoses in clinical practice still rely on careful clinical assessments. This review focuses on diagnostic approaches for DSPN that can be applied in routine neurological practice. We summarize the evolving definition and diagnostic criteria of DSPN, including the graded classification proposed by the Toronto consensus panel. Core diagnostic elements such as detailed history-taking, bedside neurological examinations, and validated clinical scoring systems are reviewed. We also discuss the role and limitations of nerve conduction studies, skin biopsy, corneal confocal microscopy, and tests of small-fiber function. Laboratory evaluations for differential diagnoses and current American Diabetes Association screening recommendations are also discussed.
Diabetic neuropathy is the most common form of peripheral neuropathy encountered in neurological practice and its burden is expected to increase with the increasing global prevalence of diabetes.1 Despite extensive research, the multifactorial pathogenesis of diabetic neuropathy remains incompletely understood, and advances in both diagnosis and treatment have been incremental rather than transformative.2,3
While distal symmetric polyneuropathy (DSPN) is the prototypical manifestation, diabetic neuropathy has a broad clinical spectrum, necessitating careful neurological assessments and clinical judgments for accurate diagnoses. This review primarily addresses diagnostic approaches for DSPN, spanning methods from conventional clinical assessments to recently developed techniques.
CLINICAL CLASSIFICATION OF DIABETIC NEUROPATHY
The clinical spectrum of diabetic neuropathy is initially classified according to the distribution of involvement into diffuse, focal, or multifocal forms. Diffuse neuropathy is the most prevalent, with an estimated lifetime risk of approximately 50% in patients with diabetes. Based on the predominant fiber type affected, the condition can be further divided into large-fiber, small-fiber, and mixed-fiber neuropathies. The most common subtype is mixed-fiber DSPN, which typically presents in a stocking-glove distribution and may be accompanied by neuropathic pain or features of autonomic neuropathy.2,4
Focal neuropathies may present as cranial neuropathies involving cranial nerves III, IV, VI, and VII, with an incidence estimated at 1%,5 or as peripheral mononeuropathies affecting nerves such as the median, ulnar, or peroneal nerves, with an incidence of up to 10% among all patients with diabetes.6 Multifocal mononeuropathy is characterized by the asymmetric, noncontiguous involvement of multiple nerves and usually exhibits stepwise progression. In patients with long-standing diabetes, multifocal involvement may eventually become difficult to distinguish clinically from DSPN.
Distinct from these patterns, diabetic radiculoplexus neuropathy represents a rare and atypical entity characterized by the acute or subacute onset of asymmetric pain and weakness, most commonly affecting the lumbosacral plexus, and is generally considered distinct from DSPN. Autonomic neuropathy may coexist with DSPN or occur independently, and has been reported to occur in 20-40% of individuals with diabetes.7 Depending on the organs involved, manifestations may include resting tachycardia, orthostatic hypotension, gastroparesis, enteropathy, esophageal dysmotility, urinary retention, recurrent urinary tract infections, incontinence, and sudomotor dysfunction.8
Given the heterogeneity of diabetic neuropathy, the following sections focus primarily on diagnostic approaches for the most common form; that is, DSPN.
EVOLVING DEFINITION OF DSPN
The definition of DSPN has evolved over time. The 2004 joint report of the American Academy of Neurology (AAN), the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation identified the combination of neuropathic symptoms, signs, and abnormal findings in nerve conduction (NC) NC studies (NCSs) as the most-valid diagnostic approach.9 The European Federation of Neurological Societies subsequently recommended measuring the intraepidermal nerve fiber (IENF) density using a skin biopsy as the standard for small-fiber neuropathy (SFN).10 In 2010 the Toronto consensus panel proposed a graded diagnostic classification of DSPN, ranging from possible to confirmed and subclinical disease states (Table 1). This framework has since been widely adopted in both clinical research and practice.11
DIAGNOSTIC APPROACHES FOR DSPN
Detailed history-taking and neurological examination
The typical clinical features of DSPN reflect length-dependent axonal metabolic dysfunction with a “dying-back” pattern, whereby symptoms such as distal paresthesia, aching, and numbness gradually appear in the longest nerves, typically those innervating the distal lower extremities, before subsequently progressing proximally.3 The risk factors for neuropathic progression that should be assessed include diabetes duration, glycemic control, smoking, alcohol consumption, obesity, hypertension, and dyslipidemia.2,3
Neurological examinations play a central role in regular screening and the early detection of neuropathy (Fig. 1). The function of large sensory fibers is typically evaluated by testing vibration sensations using a 128-Hz tuning fork, pressure sensations with a 10-g monofilament, and light-touch sensations with a cotton swab. Diminished or absent ankle deep tendon reflexes are also suggestive of large-fiber dysfunction. The function of small sensory fibers is assessed by testing pain sensations with sharp disposable pins (e.g., Neurotips®; Owen Mumford Ltd, Woodstock, UK) and temperature sensations with a cold tuning fork.
For the 10-g monofilament test, the patient is instructed to close their eyes while the filament tip is applied perpendicularly to predefined plantar sites until it bends, held for 1-3 seconds, and then lifted carefully to avoid any sliding or rubbing sensation. The patient is asked to respond “yes” whenever they perceive the stimulus, without promoting questions such as “Do you feel it?”. If no response is given at a particular site, the filament is applied to a different site. Mandatory test locations include the plantar surface of the distal hallux and the first, third, and fifth metatarsal heads, with optional sites such as the midsole, calcaneus, and plantar surface of the third and fifth toes at the examiner’s discretion. Failure to detect the stimulus in at least 7 of 10 applications indicates an increased risk of painless injury.12,13
For vibration testing, a 128-Hz tuning fork is applied with minimal pressure to the distal phalanx of the great toe to assess whether the patient perceives the vibrations when the tuning fork is applied for more than 10 seconds, whether there is a discrepancy compared with the examiner, and whether the perception is symmetric in both great toes. If abnormalities are detected, the examination is extended proximally to the medial malleolus, tibial tuberosity, and iliac crest.14
Validated questionnaires and composite scoring systems
Composite scales combining questionnaires and physical examinations have been developed and validated for diagnosing diabetic neuropathy and they are widely used in both research and clinical practice. These instruments typically include assessments of sensory function and reflexes as described above. Among them, the most widely used and well-validated is the Michigan neuropathy screening instrument, which integrates a questionnaire with a structured physical examination and has been found to exhibit a sensitivity of 50% and a specificity of 92%.15 The Michigan diabetic neuropathy score provides a more-detailed evaluation incorporating NCS findings.16 Other established scales include the Toronto clinical neuropathy score,17 the neuropathy impairment score in the lower limbs,18 and the neuropathy disability score.19 The Utah early neuropathy scale was developed to detect early SFN by assessing pinprick sensation in six lower-limb segments and evaluating allodynia, hyperesthesia, motor function, vibration perception, joint position, and reflexes, thus covering both small- and large-fiber involvement.14
Diagnostic tests
NC studies
NCSs are the most reliable noninvasive method for evaluating peripheral nerve function and they are highly recommended for diagnosing DSPN. Both the AAN and the Toronto consensus panel recognize NC abormalities as essential for diagnosing DSPN. The AAN specifies that the minimum requirement is for unilateral sural, ulnar, and median sensory studies together with peroneal, tibial, median, and ulnar motor studies (including F-waves) to be performed, with DSPN defined when at least two nerves (including the sural nerve) show abnormalities below the first percentile.9 In contrast, the Toronto consensus panel does not prescribe explicit cut-offs.11 Notably, Dyck et al.20 found that the diagnostic accuracy was higher for composite scores integrating multiple NC attributes than for criteria based on single-nerve abnormalities or a small set of selected parameters, supporting their use in both clinical and research settings. However, NCSs are not diagnostic for pure SFN and entail additional healthcare costs.
Skin biopsy
A skin biopsy is currently regarded as the most reliable technique for diagnosing SFN.11,21 The density of IENFs crossing the dermal-epidermal junction-quantified as the number of fibers per millimeter-is reduced in SFN. Interpreting the density requires consideration of age- and sex-related effects, and normative reference values have been established. For length-dependent SFN, a punch biopsy is typically performed at the distal leg (10 cm above the lateral malleolus), with an additional specimen obtained from the thigh when a non-length-dependent process is suspected.10 The IENF density is correlated with other neuropathy measures such as clinical questionnaires, sensory NC, and quantitative sensory testing (QST), although the strengths and consistency of these correlations vary.22,23 The IENF density may also serve as a marker of treatment outcome, as it has been proposed to reflect neuropathy progression or nerve regeneration.10,24 However, the risk of bleeding and infection as well as the requirement for specialized laboratories and equipment represent hurdles to its widespread application as a screening method.
Corneal confocal microscopy (CCM)
CCM is a noninvasive in vivo imaging technique used to visualize corneal small unmyelinated C-fibers that has revealed small-fiber degeneration not only in diabetic neuropathy but also in human immunodeficiency virus, idiopathic neuropathies, Charcot-Marie-Tooth disease, and chemotherapy-induced neuropathy.25-28 Unlike skin biopsies, CCM is simple and permits longitudinal follow-up, making it an emerging tool for the evaluation of small-fiber pathology.29 CCM typically provides the three quantitative parameters of corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and corneal nerve branch density, with CNFL and CNFD showing the greatest utility in identifying DSPN. However, a more-recent study of patients with DSPN and obesity found that CCM parameters showed only weak correlations with the IENF density and cold or warm detection thresholds and demonstrated lower diagnostic accuracy than these established tests.30-32 These findings suggest that CCM cannot yet be considered a complete substitute for the IENF density or thermal QST in diagnosing SFN due to limitations in standardization and interpretation.
Other tests for small-fiber function
The quantitative sudomotor axonal reflex test (QSART) is a noninvasive method for evaluating postganglionic sympathetic sudomotor function mediated by small nerve fibers, which cannot be assessed by conventional NCSs. The QSART enables quantitative assessments of sweat production and demonstrates moderate diagnostic sensitivity for SFN, particularly in length-dependent patterns. The QSART offers practical advantages over skin biopsies in clinical settings where invasive tests are not possible. However, variability in protocols, reference values, and susceptibility to medications restrict its standardization, and the QSART should therefore only be regarded as a complementary diagnostic tool for identifying small-fiber and autonomic involvement in DSPN.33
The SUDOSCAN® (Impeto Medical, Paris, France) device tests sudomotor function by measuring the electrochemical conductance, in which low-voltage electrodes are placed on the palms and soles to induce chloride ion secretion through sweat glands, thereby measuring the skin conductance. This test takes only 3 minutes, is noninvasive, and reflects C-fiber function, and provides reasonable sensitivity and specificity in detecting SFN.34
The Neuropad® (TRIGOcare International GmbH, Wiehl, Germany) device is used to perform a simple sudomotor function test, in which a cobalt chloride-containing patch is applied to the sole of the foot and observed for a color change from blue to pink within 10 minutes in response to sweating. It has advantages as a screening tool due to its low intra- and interobserver variability and minimal training requirements, although its sensitivity and specificity have varied considerably across studies.2,35
While tests such as microneurography and laser-evoked potentials can also be used to assess small-fiber function, their low availability and lack of standardization currently restrict their use to specialized centers and research settings.
Laboratory evaluation and screening recommendations
Patients with suspected DSPN must undergo laboratory evaluations in order to exclude alternative or coexisting causes of neuropathy and to identify potentially treatable conditions. Recommended baseline tests include the levels of serum vitamin B12 and thyroid-stimulating hormone, renal function tests, and assessments for paraproteinemia when clinically indicated.2
The American Diabetes Association guidelines recommend annual screening for DSPN starting 5 years after type 1 diabetes is diagnosed and at the time of a diagnosis of type 2 diabetes followed by yearly assessments. Such screening should primarily rely on a combination of symptom assessments and simple bedside neurological examinations, with further diagnostic testing guided by clinical findings.
CONCLUSION
Thorough history-taking, neurological examinations, and composite scores remain fundamental to diagnosing DSPN in clinical practice. Emerging diagnostic techniques are increasingly focused on the early detection of DSPN, but further validation is required. Future efforts should aim to establish robust and reliable measures that accurately reflect disease progression, recovery, and repair.
Notes
Conflicts of Interest
Nothing to declare.
Funding
None.
Acknowledgment
Fig. 1 is based on an original photograph; only the background was modified using AI, without altering the main content.
Fig. 1.
Bedside neurological examinations for sensory modalities: (A) pressure sensations assessed with a 10-g monofilament, (B) mandatory and optional sites for performing the 10-g monofilament test, (C) pain sensations assessed with a pinprick test, (D) sudomotor function assessed with the Neuropad® (TRIGOcare International GmbH, Wiehl, Germany) device, (E) vibration sensations assessed with a 128-Hz tuning fork, and (F) light-touch sensations assessed with a cotton swab.
Table 1.
Graded diagnostic classification of distal symmetric polyneuropathy (DSPN)
Category
Diagnostic criteria
Possible DSPN
Presence of neuropathic symptoms (e.g., decreased sensation, positive neuropathic symptoms) or neuropathic signs (e.g., symmetrically decreased distal sensation, decreased or absent ankle reflexes)
Probable DSPN
Presence of a combination of neuropathic symptoms and clinical signs, including any two or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes
Confirmed DSPN
Presence of neuropathic symptoms or signs plus objective evidence of neuropathy on nerve conduction studies or reduced intraepidermal nerve fiber density on skin biopsy
Subclinical DSPN
Abnormal diagnostic test results (e.g., nerve conduction studies or skin biopsy) in the absence of neuropathic symptoms or signs
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Diagnostic approaches in distal symmetric polyneuropathy in diabetes mellitus
Fig. 1. Bedside neurological examinations for sensory modalities: (A) pressure sensations assessed with a 10-g monofilament, (B) mandatory and optional sites for performing the 10-g monofilament test, (C) pain sensations assessed with a pinprick test, (D) sudomotor function assessed with the Neuropad® (TRIGOcare International GmbH, Wiehl, Germany) device, (E) vibration sensations assessed with a 128-Hz tuning fork, and (F) light-touch sensations assessed with a cotton swab.
Fig. 1.
Diagnostic approaches in distal symmetric polyneuropathy in diabetes mellitus
Category
Diagnostic criteria
Possible DSPN
Presence of neuropathic symptoms (e.g., decreased sensation, positive neuropathic symptoms) or neuropathic signs (e.g., symmetrically decreased distal sensation, decreased or absent ankle reflexes)
Probable DSPN
Presence of a combination of neuropathic symptoms and clinical signs, including any two or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes
Confirmed DSPN
Presence of neuropathic symptoms or signs plus objective evidence of neuropathy on nerve conduction studies or reduced intraepidermal nerve fiber density on skin biopsy
Subclinical DSPN
Abnormal diagnostic test results (e.g., nerve conduction studies or skin biopsy) in the absence of neuropathic symptoms or signs
Table 1. Graded diagnostic classification of distal symmetric polyneuropathy (DSPN)
