Distinguishing Painful Peripheral Neuropathies From Ischemic Limb Rest Pain in Patients With Diabetes
ISSN: 2694-3026
J CRIT LIMB ISCHEM 2024;4(4). doi:10.25270/jcli/CLIG24-00012
Introduction
The distribution of detectable diabetic peripheral neuropathy (DPN) is estimated to range from 10% within 1 year of diabetes mellitus (DM) diagnosis to up to 60% in patients with DM lasting for more than 25 years.1 Given the increasing prevalence of DM from 425 million (8.6% of the general population) in 2019 to 9.8% of people worldwide, expected in 2045,2,3 a soaring incidence (around 60% in newly diagnosed cases) is anticipated.2,3 DPN is often accompanied by peripheral occlusive arterial disease as a parallel complication of DM, particularly in patients with long-lasting or poorly controlled hyperglycemia.1-3 A contemporary review by Zaffar et al1 revealed that 66% of type 1 and 59% of type 2 DM cases demonstrated evidence of DPN at comparable time intervals.1 Painful DPN (pDPN) represents a frequent clinical subset of DPN, ranging from 35% to 65% of neuropathic patients (owing to specific individual systemic, geographical, and sociocultural influences).1,3,6,7 Chronic limb-threatening ischemia (CLTI)4 has been previously studied as a precarious critical limb ischemia (CLI) condition4,5 associated with the most extreme and terminal type of lower limb occlusive arterial disease.4,5 High amputation rates,4,5 major cardiovascular events, and death (20% mortality within 6 months and 50% at 5 years) have been documented in these patients.3-5 Distinguishing the true origin of pain is not always straightforward,6-8 and the most motivated clinician may be confronted with unexpected hurdles to accurate diagnosis.
Definitions
For more clarity and a practical point of view, the current definitions of the main pathophysiological entities discussed in this paper are reproduced below, according to recent taxonomy publications and reviews.
Neuropathic pain (NP) is defined as pain caused by a lesion or disease of the somatosensory nervous system.6,8 A recognized diagnosis of NP requires the presence of underlying neurological lesions.6,8
The generic diabetic neuropathy embodies the presence of neuropathic symptoms and/or signs of central or peripheral nerve dysfunction in persons with diabetes after ruling out other causes, which may range from hereditary, traumatic, compressive, metabolic, toxic, nutritional, infections, immune-mediated, neoplastic, and secondary to other systemic illness.1
Specific diabetic peripheral neuropathy (DPN) encompasses (according to the Toronto neuropathy expert group meeting)9 a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and perineural microvessel alterations, as a result of chronic hyperglycemia exposure and cardiovascular risk covariates.9
Specific painful diabetic peripheral neuropathy (pDPN), following consensual definitions, represents a frequent subtype of peripheral NP that is correlated with DPN. It is defined as neuropathic pain as a direct consequence of abnormalities in the peripheral somatosensory neural system in people with DM.6,9
In a parallel consensus,4chronic limb-threatening ischemia (CLTI) pain is usually described as affecting unilaterally the ischemic inferior limb, more frequently the forefoot, getting worse at night, and requiring opiate analgesia for management.4 A high probability of CLTI pain is associated with its presence for more than 2 weeks, to specific hemodynamic proofs for severely damaged limb perfusion (eg, absolute ankle pressure (AP) < 50 mm Hg and absolute toe pressure (TP) < 30 mm Hg).4 The ankle-brachial index (ABI) should be typically < 0.4 for this condition, but it may be subject to inadequate analysis,4,5 especially for patients with DM, those presenting with chronic kidney disease, or both subgroups that may exhibit incompressible, calcified crural arteries.4,5
Although the toe-brachial index (TBI) was equally evoked to provide more precise hemodynamic information (in patients with DM and calcified pedal arteries), it remains potentially influenced by below-the-knee and below-the-ankle current arterial stiffness and extended arterial calcifications.4
Classification
Regarding patients having dominant neuropathic painful affectation, the UK screening test score for DPN represents a noninvasive and highly reproducible method for screening and grading diabetic inferior limb chronic denervation.10 Based on sensory and vibration perception thresholds, DPN can be easily detected and scored (0–10 points) as normal (0–1), mild (2–4), moderate (5–6), or severe (7–10 points).7,10
The Toronto Diabetic Neuropathy Expert Panel10 proposes a mainstay diagnostic feasibility stratification that is applied in 4 grades (possible, probable, confirmed, and subclinical DPN). At the same time, a recent study by Scholz et al recommends a specific painful DPN classification structured upon a 3-level clinical diagnostic scale11 featuring NP as the first level, chronic DPN as the second level, and pDPN as the third clinical severity level.11
Figure 1 shows a schematic illustration of the generic classification of DPN (Toronto consensus),9 associated with the 3-level specific pDPN diagnostic scale,11 intentionally focusing on the DM chronic neuropathy diagnostic.
Regarding the individual types of fiber denervation9 and related peripheral neuronal loss,11,12 DPN (containing the pDPN variant) was further subdivided into sensory, motor, and autonomic varieties of limb denervation.1,9,11,12
Reciprocally, considering the contingent nature of patients with a painful ischemic limb, their specific CLTI designation is justified by the presence of clinical signs and symptoms of severe ischemic inferior limb tissue threat.4,5 This partition is currently sustained in the literature by the Rutherford clinical stratification (ie, patient categories 4, 5, and 6),4 adding the recent Global Limb Anatomic Staging System (GLASS) classification4 and parallel to the Society of Vascular Surgery’s Wound, Ischemia, and Foot Infection (WIfI) 3-variable inferior limb ischemia grading system to predict major tissue loss.4
Etiology and Pathophysiology
Although the precise etiological and pathophysiological initiatory mechanisms remain partially unknown, the presence of chronic and persistent hyperglycemia seems to represent a key element in the induction and development of DPN, pDPN, and CLTI, as well as other parallel microcirculatory dysfunctions at the systemic level.1-3,9,11
Nevertheless, pDPN, as a pathogenic entity, seems to add a wide array of multifactorial interactions, such as genetic, biological, clinical, metabolic, and psychosocial individual risk factors.6,8
It was stipulated that NP may result from both central and peripheral nerve damage.6,8,11 Characteristic neural lesions observed in pDPN can provoke persistent structural and functional maladaptive nerve responses in specific somatosensory locations.6,11 Particularly concerning the DM environment, this seems to directly inflict defective peripheral neurotropism and impaired axonal transport1,8,12 by several distinct mechanisms such as a) the sorbitol pathway, the b) advanced glycation end products, by c) protein kinase C, and the d) hexosamine pathways.1,12 Therefore, the persistent progression of all these known deleterious hyperglycemic pathways may increase local oxidative stress products.1,6,12 This process appears to involve further mitochondrial dysfunction and microvascular endothelial cell affliction.1,12
Interestingly, up to this point of pathogenic progress, both DPN and CLTI share a common microvascular pathogenic cascade, unveiling one common unfolding pathway from the basic molecular level until mitochondrial degradation.1,6
It is thought that further on, this initial pathogenic path divides itself into the microvascular vasa nervorum and separate vasa vasorum structural wall and endothelial damage; hence, this dichotomy may induce independent endothelial injuries for both vascular and neural microcirculatory networks.1,6,12 These dichotomic self-unfolding microcirculatory alterations seem responsible for triggering the next characteristic neuropathic vs ischemic individual pain symptoms.1,12
Parallel microvascular manifestations of abnormal capillary blood flow are equally documented in other territories of the human body, at the same level as pDPN (Figure 1) and neuroischemic CLTI foot syndrome.2,3 6 Therefore, the brain, retina, and visceral afflictions, including kidney microvascular disease, may parallel the peripheric neural and arteriolar system microcirculatory decay, joining musculoskeletal structures and skin perfusion disorders, among others.1,9,11,12 The knowledgeable clinician may anticipate these potential concomitant targets of a poorly controlled metabolic syndrome.
Without aggressive hyperglycemic control, the vital perineural and endothelial capillary networks may collapse, inducing severe endoneurial (or arteriolar) hypoxia associated with irreversible nerve dysfunction and depletion; these irrevocable DPN changes may lead to concomitant arterial microcirculatory damage in specific diabetic foot territories.1,9,12
More specifically, this microvascular destruction produces reactive oxygen species (ROS) that exceed local tissue antioxidant defense mechanisms and potentially cause additional capillary damage.11-13 Not surprisingly, this ROS-imbalanced production equally harms the intracellular mitochondrial level of CLTI-exposed tissues, seemingly as hyperglycemia does (via the same ROS) at the peripheral neural fiber level.6,8,11-13 Abnormal oxidative stress also accentuates the damaged capillary bed and neurovascular harm by parallel angiogenesis and arteriogenesis abolition, which connects to muscular mass degradation and timely deconditioning of whole limb tissues (including rising pain originating from both augmented microvascular ischemia and pDPN gram evolution).11-13
Clinical Features and Appropriate Diagnostics
Several reviews have estimated that the prevalence of patients with DM with a proven DPN diagnosis ranges from 20% to approximately 35%, while pDPN has been documented in approximately 35% to 65% of patients with DM.1,2,6,9,13 Particularly concerning pDPN (a severe form of DPN), this seems to be associated with increased mortality (42%) at 5 years,9 and (seemingly for DPN), there are no established current diagnostic gold standards to date.9,13
An important point in the clinical evaluation of patients with probable or definite pDPN (Figure 1) is the precocious recognition and follow-up of each unfolding evocative pDPN symptom.11,13
From a practical perspective, different types of peripheral nerve damage12,13 and their clinical presentations have been described as potentially induced by DM, including distal symmetric polyneuropathy, autonomic neuropathy, radiculoplexopathy, and mononeuropathies, with or without irritative discomfort.1,6,12,13
For all these diabetes-related entities, several diagnostic challenges must be noted first, as the current gold standard diagnostic test for DPN and pDPN is still lacking.1,13 Peripheral nerves are structured as large- and small-diameter fibers, and each group exhibits specific symptoms (Figure 2). Large fiber dysfunction manifests as weakness, numbness, tingling, and loss of balance. In contrast, dysfunction related to small fiber destruction includes sporadic or continuous pain and local anesthesia.1,8,13 Small fiber symptoms may prevail, particularly in the early stages of DPN, and in association with eventual autonomic denervation.1,8,13
Early pDPN symptoms appear to be exacerbated at night and usually include (Figures 1 and 2) bilateral and symmetrical foot pain (usually in a stocking-glove distribution)1,3,8,15 associated with different forms of paresthesia, commonly presented as tingling, burning, prickling, or shooting pain, and the more unusual addition of cold sensations1,13 (Figure 1).
Another challenge in current pDPN assessments is severity appraisal.9,11,13 During the last decade, numerous severity scales and questionnaires were proposed to uncover DPN or pDPN progression.9,11,13,14 A review conducted by Dyck et al14 suggested a coordinated follow-up that progressively added new signs and symptoms related to individual clinical and electrophysiological irregularities (Figure 1). Alternatively, several analogous composite scores, including different scale questionnaires, have been proposed. However, with restricted practical utility, evidence based on prospective and multicenter studies remains scarce.1,3,8,13,14 The most common clinical form of DPN to be suspected is, by far, distal symmetrical polyneuropathy, currently adding pDPN symptoms.1,9,12 Its presence and unfolding symptoms are related to the length of the involved nerves, so it may primarily affect the longest nerves in the feet.1,13 A schematic representation of currently described pDPN signs and symptoms is presented in Figure 1. It assembles several multivariable approaches requested for pDPN diagnostics and schematizes some of the previously proposed schemes in a simplified 3-level diagram.1,8,9,13-15
Specific sensory features of DPN and pDPN
The accurate diagnosis of sensory pDPN characteristics may eventually prove to be demanding. This statement relies on a detailed medical history and a thorough investigation of clinical signs.1,3,8,13 Commonly, sensory affectation shows (Figures 1 and 2) the same specific stocking-glove-like allocation as the sensory symptoms.1,3,8,13
It is also generally accepted that large-fiber evaluation should include the analysis of vibration sensation using a 128 Hz tuning fork and light touch perception by applying a 10-g monofilament on the dorsal aspect of the toes.1,3,8,13-15 The results, however, seem to depend on each clinician’s experience and daily practice.3,13 A study conducted by Dyck et al16 associated 24 patients with DM with and without DPN who were examined in a blind manner by 12 experienced physicians. Interestingly, the results showed that considerable and excessive variability among physician judgment of signs, symptoms, and diagnosis was noted.16
Motor specificities of DPN and pDPN
Motor neuropathy can also be suspected upon meticulous clinical examination;1-3,13 information about muscle strength, tonus, or atrophy should be correlated with eventual bone deformations (Charcot foot) and vicious postures.1,3,13 Global evaluation combines the parallel appraisal of nerve conduction studies to confirm eventual motor nerve dysfunction (Figures 1 and 2). Although there is no uniform level of evidence, motor disabilities seem to appear much later than sensory decay in DPN (sometimes associated with pain onset) and gather a multifactorial neuromyopathic profile.1,3,8,13,14
Autonomic characteristics of DPN and pDPN
Autonomic denervation can occur in the early stages of DPN and is commonly associated with sensory, motor, and painful clinical manifestations.1,8,13 Small neural fiber damage is associated with pain, anesthesia to a pinprick and temperature sensations, and autonomic dysfunction. Regarding diabetic distal symmetrical polyneuropathy, eventual autonomic involvement can be suspected if the patient has abnormalities in sweating and microcirculatory temperature reflexes.1,3,13,15 Several generic tests have been proposed, such as the vagal baroreflex exam, thermoregulatory sweat testing, and skin vasomotor reflex monitoring (which incorporates the use of laser Doppler flowmetry) for evaluating the severity of autonomic fiber damage.1,3,13,15
Pain specificities associated with DPN
The association between small neural fiber involvement and common symmetric and pDPN has been described (Figures 1 and 2) as the current phenotype of distal DPN.9,13,15 Small fiber injuries are usually revealed early in DPN onset and typically induce pain, anesthesia to a pinprick, and temperature changes.1,13,15 In pDPN patients, various types of neuropathic pain have been described that can be assembled in distinct cluster-symptoms groups based on each patient’s pain and sensory profile.13,15 Hence, different clusters may address different pathophysiological pathways (according to the 4 distinct pathways of the hyperglycemic damage previously mentioned) to deliver cluster-specific symptoms.9,13,15 According to global DPN evolution (related to risk factor persistency), the initial pDPN symptomatology may also be subject to continuous changes according to continuously evolving abnormalities in deep tissue somatosensory innervation and microvascularization.11-13
Complementary pDPN Diagnostic Exams
With the hope to improve individual DPN diagnostics and better outline pDPN singularities regarding other painful syndromes of the lower extremities (including CLTI), several quantitative diagnostic exams have been described in the last decade11-13,15 such as:
a). Electrophysiological assessment, with higher sensitivity, which has been applied to sensory nerves and is a key examination for quantitatively evaluating large nerve fiber function.
b) Skin biopsies that add intraepidermal neural fiber density appraisal.
c) Cornea confocal microscopy, which noninvasively estimates corneal small fiber alterations.
d) Point-of-care devices (POCD), which include simultaneous sural nerve conduction velocity analysis, adding plantar sweat evaluation, and parallel measurements of sudomotor reflex activity in both hands.
e) Eleven specific serum proteins, which were significantly correlated with pDPN severity, warranting further complementary investigation as eventual forthcoming biomarkers.17
Despite undeniable technological progress with better DPN and pDPN diagnostics, all the methods still require clinical validation based on larger prospective and multicenter studies.13,15
Noninvasive, Basic Diagnostics for CLTI
Diminished limb perfusion, tissue oxygenation, and nutrition may cause claudication or CLTI rest pain.4,5 However, these typical symptoms of peripheral arterial disease can be altered or absent in certain patients with diabetes who exhibit peripheral denervation by concomitant DPN. Alternatively, chronic CLTI may or may not mask atypical unilateral DPN pain symptoms in patients with neuroischemic diabetic inferior limbs.4,5
More precisely, CLTI ischemic rest pain (Figure 2) is usually unilaterally located; it frequently involves the forefoot and worsens in a decline position,4 and may require opiate analgesia for management.4 If this type of pain is present for more than 2 weeks and is combined with hemodynamic evidence of severely impaired arterial perfusion (AP < 50 mmHg and TP < 30 mmHg), it could represent a thorough argument for CLTI.4
Beyond first-line AP, TP, ABI, and TBI exams previously mentioned, other noninvasive tests for CLTI confirmation have been proposed in recent years (without detailed description in this paragraph), such as the pedal (or plantar) acceleration time, transcutaneous oxygen pressure, laser Doppler flowmetry and laser speckle imaging, near-infrared spectroscopy, hyperspectral imaging, computed tomography (CT) angiography and color-coded CT perfusion, magnetic resonance imaging (MRI) angiography, arterial spin labeling MRI, diffuse speckle contrast analysis, skin micro-oxygen sensors, and nuclear medicine evaluation by single photon emission CT, among others.3-5,18,19
All these novel technologies have undeniable advantages and inherent limitations for the scrutiny of each flow type. Nevertheless, when associated with clinical observations, they afford a more accurate analysis of macro- and microvascular flow, capillary and tissue oxygenation levels, or potential intracellular hypoxia at the mitochondrial level.4,5,18
Discussion and Differential Diagnostics
The presence of chronic, disabling pain in the inferior limbs, possibly associated with specific risk factors for DPN, pDPN, and CLTI, is always a priority for detailed investigation and treatment. Rapid and irreversible degradation of the exposed extremity leads to severe hypoxia, local tissue decay, bacterial proliferation, increased neuropathic effects, irreversible denervation, and diminished tissue regeneration capacities.1-3,8,9,13-15 The hypothesis of a highly probable CLTI condition (with or without associated DPN)18,19 should always be evoked in the first place (Figure 2); this implies an oriented anamnesis and thoughtful neurovascular clinical examination, adding specific noninvasive screening methods for neuropathic vs vascular diagnostics.2-5,19 In summary, any inferior limb painful syndrome that lasts for more than 2 weeks4 in a patient with DM with positive vascular risk factors needs to be firstly interpreted as ischemia-related unless additional diagnostic exams prove the contrary.2,3 4,13,19 As an aphorism, any clinical suspicion of pDPN may paradoxically require, in the first place, a vascular preamble (ie, segmental pressures and duplex) for ruling out any eventual more urgent vascular hidden pathology. Unlike challenging differential diagnostics in other medical disciplines, the true recognition of painful DPN vs severe CLTI pain relies on meticulous anamnesis, clinical examination, and recommended first-line noninvasive examinations.1-4,15,18,19
The vascular specialist may be confronted with unexpected diagnostic defiance in their daily practice because classical ischemic pain4 can be distorted or excluded in advanced diabetic limb neuropathy.3-6,19 More rarely, independently evolving pDPN (Figure 1) may lead (according to the degree of neuronal loss)9,12 to adjoining central nervous system symptoms of NP that can mimic or even modify previous “true” CLTI rest pain features.3,6,12
Any attempt to standardize the differential diagnosis and prognosis of pDPN vs CLTI rest pain becomes even more delicate because of their mutable appearance according to their divergent evolutions.6,12,13
Because pDPN and CLTI can display a myriad of clinical combinations (Figures 1 and 2) within the same ongoing metabolic syndrome (whether controlled or not), no gold standard examination for timely identification and differential diagnosis has been unanimously recognized.9,11-13
The experienced clinician should be aware of inconsistencies and snares of the initial ischemic rest pain resemblance (by increase of lactate in hypoxic tissue and abnormal oxidative stress), which can change along the duration of CLTI, by adding secondary or complementary novel neuropathic-like appearances.6,12,19
Finally, because some of the multifaceted appearances of pDPN may change over time and with each phenotype, and because no standard pDPN diagnostic has been proven reliable to date,11-13 a parallel and systematic vascular assessment4 appears essential at the patient’s first examination.3-5
Over 20 years ago, a review of the effectiveness of DPN diagnostic was made by England et al,20 who concluded that the DPN and pDPN formal diagnostics remain troublesome and depends on the examiner’s skill for tying together symptoms, signs, and diagnostic test results.20 Unfortunately, without major changes, this assertion seems to remain equally valid in current practice.13,20
Conclusions
The assessment of painful diabetic neuroischemic limbs invariably requires a multispecialty approach. The differential diagnosis of painful DPN relies on thoroughly analyzing each individual’s medical history, clinical evaluation, and noninvasive screening test data. Concomitant ischemic participation should be systematically ruled out by focused arterial flow examination and diagnostic methodology in concordance with the available consensual CLTI vascular recommendations.
Disclosures
Vlad Adrian Alexandrescu, MD, PhD; Arnaud Kerzmann, MD; and Vincent Tchana-Sato, MD, PhD, are from the Cardiovascular and Thoracic Surgery Department, CHU Sart-Tilman University Hospital Center, Liège, Belgium.
The authors report no financial relationships or conflicts of interest regarding the content herein.
Acknowledgments: The corresponding author acknowledges all members of the academic team of Cardiovascular and Thoracic Surgery Department in CHU Sart-Tilman Hospital of Liège, Belgium, for their support and consultancy in supervising and reviewing this paper.
Corresponding author: Vlad Adrian Alexandrescu, MD, PhD, Cardiovascular and Thoracic Surgery Department, CHU Sart-Tilman Hospital, Avenue de l'Hôpital 1, 4000 Liège, Belgium. Email: v.alex@skynet.be