Background

An unknown disease that caused excessive production of sweet urine was first described in historical records from Ancient Egypt, India, and China [1, 2]. Clinical experiences of numerous physicians and scientists including the Greek physician Aretaeus of Cappadocia (second century AD), the English anatomist and physician Thomas Willis (seventeenth century AD), and the English physician and physiologist Matthew Dobson (eighteenth century AD) subsequently contributed to widespread recognition of the disease, which is today known as diabetes mellitus (DM) [1].

DM has three microvascular complications: neuropathy, retinopathy, and nephropathy [3, 4]. Neuropathy can occur in patients with type 1 (T1DM) or type 2 DM (T2DM). The estimated prevalence of diabetic neuropathy among youth and adults is 2.4–75.1% according to data from cohort studies [5,6,7]. Diabetic neuropathy represents a clinically heterogeneous group of neurological disorders characterized by dysfunction of the peripheral nervous system attributed to DM after excluding other causes [8]. According to the pattern of neurological deficits, diabetic peripheral neuropathy can be painful or non-painful [9] and is classified into four types: diffuse neuropathy, mononeuropathy, radiculopathy, and other neuropathies [10]. Diffuse neuropathy is the most commonly encountered type and 75–90% of all diabetic peripheral neuropathy cases present with typical length-dependent sensorimotor symptoms characteristic of distal symmetrical polyneuropathy (DSPN) [10, 11]. Diabetic peripheral neuropathy is a major risk factor for lower-extremity complications such as ulceration, infection, deformity, and amputation. Research on diabetic peripheral neuropathy may help elucidate the complex pathogenetic mechanisms involved, thereby improving diagnosis and management [12].

Table 1 shows a chronology of important events in the history of diabetic peripheral neuropathy. Generally, the events can be grouped into two periods: foundation (second century AD—nineteenth century AD) and expansion (twentieth century AD—present).

Table 1 Milestones in the history of diabetic peripheral neuropathy
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In the foundation period, major discoveries made by John Rollo in 1798, Charles-Jacob Marchal de Calvi in 1864, and Thomas Pryce in 1887 firmly established the relationship between DM, peripheral nerve dysfunction, and foot ulceration. Frederick Pavy described the signs and symptoms of diabetic peripheral neuropathy in 1885, while Ernst Viktor von Leyden proposed an early classification system that distinguished hyperesthetic, motor, and ataxic forms in 1887.

The expansion period is characterized by various advancements that are currently ongoing including: long-term population-based research on DM and its complications; use of objective approaches such as electrophysiological testing to detect nerve dysfunction in patients with diabetic peripheral neuropathy; refinement of diagnostic criteria and classification systems for diabetic peripheral neuropathy; and widespread implementation of structured foot screening programs for early detection of diabetic peripheral neuropathy and prevention of complications.

Aims, material, and method

Neuropathy is an important risk factor for diabetes-related lower-extremity complications, which collectively contribute to the increasing global disability burden, especially among adults aged 50–69 years [38, 39]. Due to the public health implications of DM and its complications in resource-limited settings [40, 41], this narrative review aims to summarize the general principles of screening for diabetic peripheral neuropathy based on established and emerging evidence in order to delineate a practical approach to identifying adult patients at risk for diabetes-related foot disease and its complications.

Medical literature published in English between 1770 and 2023 was identified and considered for the review. The primary search strategy involved retrieval of relevant literature from health sciences databases (EMBASE, CINAHL, Cochrane library, and PubMed) and grey literature (Google Scholar, Opengrey, Scopus, Virtual Health Library, Web of Science Core Collection, and organization websites) using a combination of keywords and Boolean operators: “comprehensive foot examination” AND “diabetic foot”; diabetes AND “microvascular complications”; (“diabetic foot” OR “diabetic foot syndrome”); (“diabetic peripheral neuropathy” OR “distal symmetrical polyneuropathy”); “diabetic peripheral neuropathy” AND guideline; epidemiology AND “diabetic peripheral neuropathy”; (“non-painful diabetic neuropathy” OR “painless diabetic neuropathy”); “painful diabetic neuropathy” AND treatment; “diabetic peripheral neuropathy” AND “risk factors”; prevention AND “diabetic peripheral neuropathy”; and Screening AND “diabetic peripheral neuropathy”. The secondary search strategy involved citation searching in order to retrieve additional relevant literature.

Epidemiological data, screening practices, and management strategies were extracted from the retrieved literature. Comprehensive findings were summarized and reported qualitatively.

Findings

Epidemiology of diabetic peripheral neuropathy

Epidemiological data for diabetic peripheral neuropathy is heterogeneous. The reasons for heterogeneity include: large proportion of asymptomatic patients [8]; few population-based studies reported in the literature [42,43,44,45,46]; differences in the burden of neuropathy in patients with T1DM compared to T2DM [47,48,49]; limited research on painful and non-painful variants of neuropathy [9, 50, 51]; and lack of a standardized approach to screening.

The prevalence of diabetic peripheral neuropathy is known to increase with age and is estimated to be 6–60% among adult patients [47, 52]. Painful diabetic neuropathy (PDN) is particularly common in adults and has an estimated prevalence of 10–68% among diverse patient cohorts [53,54,55,56]. Therefore, screening for diabetic peripheral neuropathy is an important preventive care practice that may lead to a substantial reduction in disease burden.

Screening for diabetic peripheral neuropathy

Principle 1: multiphasic approach

It is beyond the scope of the present article to discuss the various methods used to detect diabetic peripheral neuropathy. The methods have been comprehensively reviewed in various publications [57,58,59,60,61].

Current screening practices are region specific, but the position statement by the American Diabetes Association (ADA) and the ADA evidence-based standards of care in diabetes guideline provide comprehensive guidance [8, 62]. The ADA recommends that medical history and comprehensive foot examination be used to screen for diabetic peripheral neuropathy at time of diagnosis for patients with T2DM and five years after diagnosis for patients with T1DM. Furthermore, patients should be reassessed at least annually regardless of DM type using 10-g Semmes–Weinstein monofilament evaluation (SWME) and at least one other clinical assessment such as vibration perception, pinprick, temperature perception, or ankle reflexes [62].

The ADA does not recommend assessment of sudomotor function during clinical evaluation of diabetic peripheral neuropathy [62]. Instead, pinprick and temperature sensation are recommended for assessment of small nerve fiber function. However, sudomotor dysfunction is a critical pathophysiological process in the pathogenesis of diabetes-related foot disease, especially in the early stages [63,64,65]. Research suggests that evaluation of sudomotor function helps identify individuals at risk for foot ulceration [66, 67], but whether such evaluation should be conducted routinely is unclear. Neuropad is an accurate, sensitive, and cost-effective point-of-care test that is used to evaluate sudomotor function [65, 68,69,70,71]. Since Neuropad has high sensitivity and negative predictive value for detecting small nerve fiber dysfunction [72, 73], it may be used as an adjunct clinical test during diabetic foot screening. However, further validation of Neuropad is needed to support its widespread use during foot screening.

Lack of a standardized methodology for the screening of DM or its microvascular complications in resource-limited settings is an unmet medical need [74]. Additionally, there is no single tool that can be used to objectively evaluate sensory, motor, and autonomic deficits associated with diabetic peripheral neuropathy [58]. Evidence suggests that combining multiple assessments increases sensitivity, specificity, and accuracy of detecting diabetic peripheral neuropathy [8, 75,76,77,78]. Therefore, multiphasic screening—where one or more tools for assessing the signs and symptoms of diabetic peripheral neuropathy are used concurrently or sequentially—may detect a greater proportion of deficits, thereby aiding clinical decision-making. Through the multiphasic approach, both small and large nerve fiber function can be evaluated using objective measures of diabetic peripheral neuropathy [79]. In resource-limited settings, a practical combination of assessments could be focused medical history, Michigan Neuropathy Screening Instrument (MNSI), and a simple point-of-care test such as Neuropad.

The MNSI is comprised of a questionnaire (MNSIQ) and physical examination (MNSIE). Both components are sensitive, specific, and easy to administer [80, 81]. MNSIQ scores  ≥ 4 and MNSIE scores  ≥ 2 are abnormal and suggest diabetic peripheral neuropathy in patients with T1DM [82] while MNSIQ  ≥ 7 and MNSIE  ≥ 2 are suggestive of diabetic peripheral neuropathy in patients with T2DM [83].

The Neuropad test involves placing a blue plaster impregnated with anhydrous cobalt-II-chloride on the plantar aspect of the foot and observing for a change in color over 10–15 min [84,85,86]. If the plaster remains blue or turns patchy blue/pink there is inadequate sweat production due to sudomotor dysfunction, which indicates increased risk for foot ulceration [84,85,86,87].

Recently, the combinations of MNSI and SUDOSCAN [88, 89] or MNSI, Neuropad, and Vibratip have been used to rapidly and non-invasively detect diabetic peripheral neuropathy [90]. Overall, evidence from such studies and current guideline recommendations support the use of various combinations of assessments during screening for diabetic peripheral neuropathy.

Principle 2: risk stratification

The second objective of screening is prevention of diabetic foot syndrome (DFS), which is a complication of diabetic peripheral neuropathy associated with high rates of hospitalization and non-traumatic lower-extremity amputation [91, 92]. DFS is a pathological condition characterized by ulceration, infection, or deformity of the foot due to diabetes-related neurovascular dysfunction. Over 80% of lower-extremity amputations in patients with DM are preceded by foot ulceration [93, 94]. Four pathophysiological processes are implicated in diabetic foot ulceration (DFU): loss of protective sensation (LOPS) secondary to DSPN, ischemia secondary to peripheral arterial disease (PAD), anhidrosis and arteriovenous shunting secondary to peripheral autonomic neuropathy, and repetitive trauma [91]. The lifetime risk of developing DFU is between 19 and 34% [95, 96]. Rates of ulcer recurrence after healing are estimated to be 40% within one year, 60% within three years, and 65% within five years [95]. The corresponding one-, three-, and five-year survival rates associated with DFU are 86.9%, 66.9%, and 50.9%, respectively [97]. The highest risk of mortality related to DFU is reported for patients with end-stage renal disease (ESRD), amputation, chronic kidney disease, PAD, older age, or a history of cardiovascular disease [97]. Despite the public health significance of DFS, very little is known about its true burden in resource-limited settings [98, 99].

Based on current guidelines, there are several criteria for stratifying patients according to their clinical risk for DFS and amputation [100,101,102,103]. The criteria are summarized below.

The International Diabetes Federation (IDF) stratifies patients into four groups:

  • Low risk—normal plantar sensation

  • Moderate risk—presence of LOPS

  • High risk—presence of LOPS ± PAD

  • Very high risk—history of ulceration, amputation, or neuropathic fracture

The International Working Group on the Diabetic Foot (IWGDF) stratifies patients into four categories:

  • Very low risk—absence of LOPS or PAD

  • Low risk— presence of LOPS or PAD

  • Moderate risk— presence of LOPS + PAD; or LOPS + deformity; or PAD + deformity

  • High risk—presence of LOPS or PAD + one or more of the following: previous foot ulceration; or lower-extremity amputation (major or minor); or ESRD

The ADA stratifies patients into five categories:

  • Very low risk—absence of LOPS and PAD

  • Low risk—presence of LOPS ± deformity

  • Moderate risk—presence of PAD ± LOPS; diminished dorsalis pedis or posterior tibial pulse; presence of swelling or edema

  • High risk—presence of DM with previous history of ulceration or lower-extremity amputation; chronic venous insufficiency

  • Urgent—active foot pathology: open wound or ulcerative area ± signs of infection; new neuropathic pain or pain at rest; signs of active Charcot deformity; vascular compromise

The National Institute for Health and Care Excellence (NICE) stratifies patients into four groups:

  • Low risk—presence of callus alone

  • Moderate risk—presence of deformity; or neuropathy; or PAD

  • High risk—previous ulceration; or previous amputation; or on renal replacement therapy; or neuropathy + PAD; or neuropathy + callus ± deformity; or PAD + callus ± deformity

  • Active diabetic foot—presence of ulceration; or foot infection; or chronic limb-threatening ischaemia; or gangrene; or suspicion of acute Charcot arthropathy

Patients at increased risk for DFS and lower-extremity amputation are recommended to undergo SWME, despite concerns about diagnostic accuracy of SWME during screening for diabetes-related foot disease [104,105,106,107] and questions about the number of sites on the foot that must be assessed [106, 107]. In settings where SWME cannot be conducted, the Ipswich Touch Test (IpTT) is a potential substitute assessment that may be used to evaluate LOPS [108,109,110]. However, since no clinical guidelines currently recommend IpTT for risk stratification, more studies are needed to evaluate whether it is an appropriate substitute for SWME.

A recently developed semi-quantitative scoring system stratifies patients according to their risk for developing DFU based on minor criteria (foot or nail fungal infection; ill-fitting socks and footwear; lack of visual or cognitive ability for selfcare; glycated hemoglobin  > 9%; diabetes duration  > 10 years; and male sex), moderate criteria (slight polyneuropathy; pronounced foot deformity; pronounced hyperkeratosis; PAD; and renal insufficiency or dialysis), and major criteria (pronounced polyneuropathy; history of foot ulcer; and history of non-traumatic amputation) [111]. Validation of this new risk assessment system in diverse patients at risk for DFS is needed to determine how to incorporate the system into future screening practices.

Principle 3: individualized treatment and scheduled follow-up

Management of diabetic peripheral neuropathy remains a challenge for health care providers because none of the currently available treatments effectively target underlying pathogenesis [112]. Furthermore, diabetic peripheral neuropathy is a progressive disorder that can cause irreversible nerve damage [113, 114]. Thus, individualized treatment and scheduled follow-up are interdependent. The main objectives of treatment are intensive glycemic control and management of neuropathic pain alongside one or all of the following: diabetes self-management education and support; lifestyle optimization; adequate foot care and proper or therapeutic footwear; and multifactorial control of cardiovascular risk factors [112, 115,116,117].

PDN is particularly difficult to manage and current treatment options include pharmacologic and non-pharmacologic interventions [117, 118]. Four classes of oral pharmacologic interventions are recommended for treatment: gabapentinoids (gabapentin, mirogabalin, and pregabalin); serotonin-norepinephrine reuptake inhibitors (desvenlafaxine, duloxetine, and venlafaxine); tricyclic antidepressants (amitriptyline, imipramine, and nortriptyline); and sodium channel blockers (carbamazepine, lacosamide, lamotrigine, oxcarbazepine, and valproic acid) [118]. Topical treatment with capsaicin may be considered in patients with contraindications to oral pharmacotherapy or a preference for topical pain management [118]. Due to their adverse events profile and high abuse potential, serotonin-norepinephrine reuptake inhibitors/opioid dual mechanism agents (tapentadol and tramadol) are currently not recommended for treating PDN [118]. Unfortunately, pharmacologic intervention seldom achieves complete resolution of neuropathic pain due to limited efficacy, dose-limiting adverse events, or both [119,120,121]. Therefore, a standardized approach to combining pharmacotherapies is an unmet medical need and remains an area of intense study [122,123,124].

Spinal cord stimulation is an emerging therapeutic adjunct for the management of PDN [125]. This type of non-pharmacologic intervention—referred to as neuromodulation—effectively relieves pain, improves neurological function, and enhances quality of life [126, 127]. High-quality evidence supports the use of either invasive or non-invasive neuromodulation for the treatment of patients with PDN that is refractory to pharmacologic intervention [128, 129].

Finally, health care providers should remember that patients with asymmetrical distribution of clinical signs and symptoms or an unclear diagnosis require prompt referral to a neurologist for confirmatory electrophysiological testing [8].

Integrated approach to screening for diabetes-related foot disease

Figure 1 shows a comprehensive algorithm that integrates the general principles of screening for diabetic peripheral neuropathy. This algorithm may assist clinical decision-making in resource-limited settings and contribute to standardization of preventive foot screening practices.

Fig. 1
figure 1

Proposed screening algorithm for diabetic peripheral neuropathy. Screening for diabetic peripheral neuropathy involves multiphasic clinical assessment, stratification according to risk for diabetic foot syndrome and amputation, and individualized treatment and scheduled follow-up. DFS: diabetic foot syndrome; DSPN: distal symmetrical polyneuropathy; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus

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In Sheffield, United Kingdom, a one-stop microvascular complication screening clinic has used a similar algorithm/flow chart to screen patients for diabetic peripheral neuropathy as part of its comprehensive diabetes-related foot, eye, and renal disease assessment [130]. This shift towards integrated screening programs is a potentially transformative development because health care providers may be able to detect individuals at risk or those already affected more efficiently and utilize available healthcare resources more effectively [130,131,132].

Evidence from available studies suggests that concurrent screening for one or more diabetes-related complications is well-received by patients and health care providers and may be more convenient than attending separate screening sessions [133, 134]. The current limitations of clinical guidelines and unique challenges affecting diverse clinical settings must be overcome in order to optimize preventive foot screening practices and facilitate implementation of concurrent screening strategies for microvascular complications of DM [135,136,137].

Conclusions

In conclusion, diabetic peripheral neuropathy represents a clinically heterogeneous group of neurological disorders that are classified according to the pattern of neurological dysfunction. Diabetic peripheral neuropathy is highly prevalent and associated with substantial morbidity and mortality. Regular screening for diabetes-related foot disease using simple assessments may improve patient outcomes. Multiphasic clinical assessment for diabetic peripheral neuropathy, risk stratification, individualized treatment, and scheduled follow-up of patients is a practical approach to preventive foot care in resource-limited settings.

Areas of ongoing research that are expected to have a positive impact on future screening practice include: identification of a single tool that accurately detects sensory, motor, and autonomic nerve dysfunction in diabetic peripheral neuropathy; elucidation of the prevalence of diabetic peripheral neuropathy in diverse patient populations; validation of recently proposed systems for risk stratifying patients with diabetes-related foot disease; and discovery of novel pharmacologic and non-pharmacologic treatments for diabetic peripheral neuropathy.