Painless Diabetic Polyneuropathy Research Articles

Structural changes in Schwann cells and nerve fibres in type 1 diabetes: relationship with diabetic polyneuropathy

Aims/hypothesisOur aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes.MethodsSkin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres.ResultsThere was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures.Conclusions/interpretationCutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes.Graphical

Structural Changes of Cutaneous Immune Cells in Patients With Type 1 Diabetes and Their Relationship With Diabetic Polyneuropathy.

Diabetic polyneuropathy (DPN) is a complication of diabetes characterized by pain or lack of peripheral sensation, but the underlying mechanisms are not yet fully understood. Recent evidence showed increased cutaneous macrophage infiltration in patients with type 2 diabetes and painful DPN, and this study aimed to understand whether the same applies to type 1 diabetes. The study included 104 participants: 26 healthy controls and 78 participants with type 1 diabetes (participants without DPN [n = 24], participants with painless DPN [n = 29], and participants with painful DPN [n = 25]). Two immune cells, dermal IBA1+ macrophages and epidermal Langerhans cells (LCs, CD207+), were visualized and quantified using immunohistological labeling and stereological counting methods on skin biopsies from the participants. The IBA1+ macrophage infiltration, LC number density, LC soma cross-sectional area, and LC processes were measured in this study. Significant difference in IBA1+ macrophage expression was seen between the groups (p = 0.003), with lower expression of IBA1 in participants with DPN. No differences in LC morphologies (LC number density, soma cross-sectional area, and process level) were found between the groups (all p > 0.05). In addition, IBA1+ macrophages, but not LCs, correlated with intraepidermal nerve fiber density, Michigan neuropathy symptom inventory, (questionnaire and total score), severity of neuropathy as assessed by the Toronto clinical neuropathy score, and vibration detection threshold in the whole study cohort. This study showed expressional differences of cutaneous IBA1+ macrophages but not LC in participants with type 1 diabetes-induced DPN compared with those in controls. The study suggests that a reduction in macrophages may play a role in the development and progression of autoimmune-induced diabetic neuropathy.

Difficult patient with polyneuropathy: CIDP associated with type 1 diabetes mellitus

Polyneuropathies are a heterogeneous group of diseases that can be caused both by a primary lesion of peripheral nerves, and secondarily, against the background of various somatic diseases. The most common cause of chronic polyneuropathy is distal symmetrical diabetic polyneuropathy. In clinical practice, it is important to be aware of dysimmune polyneuropathy, such as Guillain Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and paraproteinemic polyneuropathy, which lead to severe motor impairment and disability in patients. Identification of the cause of polyneuropathy requires real art, which includes knowledge of the clinical, electrophysiological picture and variants of the course of the disease, as well as a wide range of conditions leading to their development. Timely diagnosis of polyneuropathies and early assignment of etiological and pathogenetic therapy reduce the risk of developing irreversible changes in peripheral nerves caused by axonal degeneration. In the treatment of polyneuropathy of various origins, a special place is occupied by B vitamins, which have a neurotropic effect. Cyanocobalamin is a pathogenetic therapy in patients with diabetes who take metformin for a long time and who developed polyneuropathy due to vitamin B12 deficiency. In one patient, a combination of several variants of polyneuropathies is possible. The article presents a clinical case of a patient with type 1 diabetes mellitus (DM) who developed dysimmune chronic inflammatory demyelinating polyneuropathy (CIDP) associated with DM on the background of distal symmetrical painless diabetic polyneuropathy after a COVID- 19 infection. A feature of the development of CIDP was the acute onset of the disease. Variants of the clinical picture, ENMG criteria, as well as features of treatment, the effectiveness of therapy and the prognosis of CIDP in patients with DM are discussed.

Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy-Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study.

ObjectiveAxonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy‐induced distal symmetrical polyneuropathy.MethodsTwo hundred thirty‐nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy‐induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies).ResultsParticipants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength–duration time constant, and current–threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy‐induced polyneuropathy.InterpretationAxonal excitability did not significantly differ between painful and painless diabetic or chemotherapy‐induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506–520

Interleukin-6 Levels in Patients With Diabetic Polyneuropathy

IntroductionDiabetic polyneuropathy (DPN) is a common chronic complication of type 2 diabetes. The pathogenesis of DPN is still debated, but proinflammatory cytokine mediators like interleukin-6 (IL-6) are possibly involved. We conducted this cross-sectional observational study to assess whether IL-6 levels increase in patients with DPN.Materials and methodsThis study was conducted at the Institute of Post Graduate Medical Education and Research Hospital in Kolkata, India, from 2016 to 2017. The study included 57 patients aged 30 to 60 years diagnosed with type 2 diabetes with neuropathy on clinical examination and nerve conduction study. Patients with neuropathy due to other causes were excluded. The study participants were assigned into one of four groups. Group 1 (n=15) served as healthy control patients, Group 2 (n=12) contained patients with type 2 diabetes without neuropathy, Group 3 (n=20) contained patients with type 2 diabetes with painful neuropathy, and Group 4 (n=10) contained patients with type 2 diabetes with painless neuropathy. We compared IL-6 levels between each group. ResultsThere was no significant difference in serum IL-6 levels between healthy controls (Group 1) and patients with type 2 diabetes without neuropathy (Group 2). However, we noted a significant increase in serum IL-6 levels among patients with painful DPN (Group 3) compared to control groups. Interestingly, serum IL-6 levels were higher in patients with painful DPN (Group 3) than patients with painless DPN (Group 4).ConclusionsIL-6 increases significantly in painful diabetic neuropathy patients compared to patients with diabetes with painless neuropathy and thus may have a role in the pathogenesis of pain in DPN. Serum IL6 level can be a potential noninvasive marker of painful DPN, and it can help distinguish painful DPN from other causes of pain in patients with diabetes.

Risk factors for depression and anxiety in painful and painless diabetic polyneuropathy: A multicentre observational cross-sectional study.

BackgroundDespite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited.MethodsThis observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State‐Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain‐free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes‐, neuropathy‐ and pain‐related), the socio‐economic and the cognitive factors (catastrophizing).ResultsThe study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety.ConclusionsIn addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals.SignificanceIn large cohorts of well‐defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain.

The role of tropomyosin receptor kinase type B in modulation of neuropathic pain in diabetic polyneuropathy

It is well known that brain derived neurotrophic factor (BDNF) can modulate pain symptoms in diabetic polyneuropathy (DPN). It is still not known which type of receptor mediates its hyperalgesic effects. Aim: to compare serum levels of BDNF and tropomyosin receptor kinase type B (trkB) in patients with a painful and painless forms DPN.

Tropomyosin receptor kinase B-mediated signaling in integration of neuropathic pain and obesity in diabetic polyneuropathy.

ABSTRACTObjective:To assess the quantitative serum levels of tropomyosin receptor kinase receptor B, and to estimate its association with serum concentration of brain-derived neurotrophic factor and obesity in patients with painful and painless forms of diabetic polyneuropathy.Methods:We examined 70 patients with diabetic polyneuropathy with confirming peripheral nerve dysfunction by electroneuromyography and measuring of serum levels tropomyosin receptor kinase receptor B and brain-derived neurotrophic factor by enzyme immunoassay. Diabetic polyneuropathy was diagnosed using the modified Toronto Consensus (2011) criteria, while neuropathic pain was assessed using an 11-point Numerical Pain Rating Scale. The patients were divided into two groups according to presence or absence of neuropathic pain. Control Group consisted of 14 healthy persons.Results:The serum levels of tropomyosin receptor kinase receptor B and brain-derived neurotrophic factor in patients with diabetic polyneuropathy are significantly higher than healthy controls (p=0.000). Hyperexpression of brain-derived neurotrophic factor in serum was associated with painful form of diabetic polyneuropathy (R=0.392, p=0.012) and obesity (R=0.412, p=0.001). On the contrary high concentration of tropomyosin receptor kinase receptor B in serum associated with painless diabetic polyneuropathy by Pain DETECT (R=-0.354, p=0.015), low body weight (R=-0.354, p=0.015) and severe demyelization of nerve fibers (R=-0.574, p=0.001), indicated “non-working” receptor detected in serum.Conclusion:Tropomyosin receptor kinase receptor B signaling is involved in the modulation of neuropathic pain and obesity in diabetic polyneuropathy.

Long Noncoding RNA MALAT-1 and Mirna-9 Expression Profile Levels in Patients with Diabetic Polyneuropathy (DPN) and Their Correlations with The Severity of Painful DPN

Background: Diabetic polyneuropathy (DPN) is the major microvascular complication of type 2 diabetes mellitus (T2DM). Painful-DPN is a major cause of mortality as well as morbidity. Long non-coding RNAs (lncRNAs) and microRNAs (miRNA) have emerged as critical regulators of many diseases, however, little is known about their expression patterns and functions in T2DM and its complications. Objective: To investigate the expression profile levels of lncRNA MALAT-1 and miRNA-9 in Egyptian patients with T2DM and to explore their associations with clinical and electrophysiological tests of both painful and painless DPN. Patients and Methods: This cross-sectional controlled study enrolled 55 patients with DPN and 40 controls. All participants were subjected to a complete neurological examination and electrophysiological tests involving nerve conduction studies. The expression levels of lncRNA MALAT-1 and miRNA-9 were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with DPN (0.219±0.061, 0.006454±0.0018, respectively) compared to controls (0.111±0.013, 0.0033±0.004, respectively). Interestingly, the relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with painful DPN (0.206±0.037, 0.0045±0.0008, respectively) compared to patients with painless DPN 0.219±0.083, 0.0058±0.0017, respectively). Patients with DPN had sensory-motor axonal polyneuropathy which was affecting both lower limbs more than upper limbs. P<0.001*. Conclusions: The relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with DPN more specifically in patients with painful DPN groups, hence, MALAT-1 and miRNA-9 could be used as useful and reliable diagnostic biomarkers of DPN.

Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy.

Diabetic polyneuropathy (DPN) is a common complication of diabetes and is often associated with neuropathic pain. The mechanisms underlying development and maintenance of painful DPN are largely unknown, and quantification of intraepidermal nerve fiber density from skin biopsy, one of the neuropathological gold standard when diagnosing DPN, does not differentiate between patients with and without pain. Identification of possible pain pathophysiological biomarkers in patients with painful DPN may increase our knowledge of mechanisms behind neuropathic pain. Animal models of painful DPN have been shown to have an increased density of peptidergic nerve fibers (substance P and calcitonin gene-related peptide). In this study, we performed a detailed skin biopsy analysis in a well-characterized group of DPN patients with primarily small fiber involvement, with and without pain, and in healthy controls and test for correlation between skin biopsy findings and pain intensity and quantitative sensory testing. We found that although there was no difference in intraepidermal nerve fiber density using protein gene product 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing substance P and calcitonin gene-related peptide compared with patients with painless DPN and healthy controls. Peptidergic nerve fiber density correlated with pain ratings in patients with pain (R = 0.33; P = 0.019), but not with quantitative sensory testing results. In this article, we show, for the first time in humans, an increased density of dermal peptidergic fibers in painful DPN. These findings provide new insight in the pathophysiological mechanisms of pain in diabetes and open the research towards new therapeutic targets.

Structural Nerve Remodeling at 3-T MR Neurography Differs between Painful and Painless Diabetic Polyneuropathy in Type 1 or 2 Diabetes.

Background The pathophysiologic mechanisms underlying painful symptoms in diabetic polyneuropathy (DPN) are poorly understood. They may be associated with MRI characteristics, which have not yet been investigated. Purpose To investigate correlations between nerve structure, load and spatial distribution of nerve lesions, and pain in patients with DPN. Materials and Methods In this prospective single-center cross-sectional study, participants with type 1 or 2 diabetes volunteered between June 2015 and March 2018. Participants underwent 3-T MR neurography of the sciatic nerve with a T2-weighed fat-suppressed sequence, which was preceded by clinical and electrophysiologic tests. For group comparisons, analysis of variance or the Kruskal-Wallis test was performed depending on Gaussian or non-Gaussian distribution of data. Spearman correlation coefficients were calculated for correlation analysis. Results A total of 131 participants (mean age, 62 years ± 11 [standard deviation]; 82 men) with either type 1 (n = 45) or type 2 (n = 86) diabetes were evaluated with painful (n = 64), painless (n = 37), or no (n = 30) DPN. Participants who had painful diabetic neuropathy had a higher percentage of nerve lesions in the full nerve volume (15.2% ± 1.6) than did participants with nonpainful DPN (10.4% ± 1.7, P = .03) or no DPN (8.3% ± 1.7; P < .001). The amount and extension of T2-weighted hyperintense nerve lesions correlated positively with the neuropathy disability score (r = 0.37; 95% confidence interval [CI]: 0.21, 0.52; r = 0.37; 95% CI: 0.20, 0.52, respectively) and the neuropathy symptom score (r = 0.41; 95% CI: 0.25, 0.55; r = 0.34; 95% CI: 0.17, 0.49, respectively). Negative correlations were found for the tibial nerve conduction velocity (r = -0.23; 95% CI: -0.44, -0.01; r = -0.37; 95% CI: -0.55, -0.15, respectively). The cross-sectional area of the nerve was positively correlated with the neuropathy disability score (r = 0.23; 95% CI: 0.03, 0.36). Negative correlations were found for the tibial nerve conduction velocity (r = -0.24; 95% CI: -0.45, -0.01). Conclusion The amount and extension of T2-weighted hyperintense fascicular nerve lesions were greater in patients with painful diabetic neuropathy than in those with painless diabetic neuropathy. These results suggest that proximal fascicular damage is associated with the evolution of painful sensory symptoms in diabetic polyneuropathy. © RSNA, 2019 Online supplemental material is available for this article.

A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.

(230) StEPS: a novel tool to phenotype and rate the severity of painful polyneuropathy

Patients with peripheral neuropathic pain typically present with a combination of pain and somatosensory deficits. Pain may occur spontaneously or manifest as increased sensitivity to external stimuli (allodynia, hyperalgesia). These symptoms and signs often vary between patients, indicating differences in the pathophysiological mechanisms responsible for nerve damage, loss of sensory function or pain that are likely to have therapeutic relevance. We investigated the variance in symptoms and signs associated with diabetic polyneuropathy (DPN). DPN is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Our aim was to develop a tool for the assessment of painful peripheral neuropathies such as DPN that captures differences and commonalities of clinical phenotypes in a simple standardized bedside evaluation. The study included 25 patients with type 2 diabetes (DM2) but no clinical evidence of DPN, 61 patients with DPN and chronic neuropathic pain, 19 patients with painless DPN and 20 healthy subjects. Study participants completed a structured interview (47 items) and a standardized physical examination (39 items). We determined principal components of the phenotypic variance by analyzing the temporal characteristics, stimulus-dependence and sensory character of pain, the presence of paresthesia, clinical signs of autonomic nervous system involvement, and the outcome of physical tests of sensory function. Correlation patterns of symptoms and signs were examined for features discriminating between DPN phenotypes. We combined interview questions and physical tests identifying these features in an abridged assessment tool that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). StEPS generates a phenotypic profile of painful neuropathy without requiring quantitative sensory testing. The profile includes separate intensity ratings of spontaneous or evoked pain to allow recording the response to analgesic treatment with greater specificity than conventional global pain scores. Supported by an unrestricted research grant from GlaxoSmithKline.

ID 321 – Is intraepidermal nerve fiber density a reliable biomarker of progression in painful and painless diabetic polyneuropathy?

We aimed to confirm usefulness of intraepidermal nerve fiber density (IENFD) as a marker of progression of diabetic polyneuropathy (DPN) in patients with early type 2 diabetes mellitus (DM2). In a group of 23 healthy subjects (median age 57 years, 14 men) and 30 DM2 patients (median age 60 years, 17 men) we serially evaluated skin biopsies from distal leg. Eighteen DM2 patients complied with the criteria of symptomatic diabetic polyneuropathy (DPN) and 12 had no neuropathy (nDPN). Time interval between biopsies were >2 years (median, range: 29.6, 24.7–58.4, and 33.8, 25.5–54.1 months in controls and DM2 patients, respectively). At first skin biopsy, the IENFD was normal in all controls and nDPN patients compared to abnormal IENFD in 77.8% of DPN patients. Drop in IENFD expressed as a proportion of the 1st IENFD value in % per year in both painful and painless DPN patients was significantly higher (11.95[3.82]%/year, p In conclusion, decrease in IENFD values in early DM2 patients is about 12% of the initial IENFD value irrespective of symptoms and/or signs of DPN at initial evaluation and several times quicker compared to healthy subjects.

A novel association between nondipping and painful diabetic polyneuropathy.

We hypothesized the meaningful coexistence of neuropathic pain and nondipping in painful diabetic polyneuropathy (PDPN). In 113 patients with PDPN, with painless diabetic polyneuropathy (DPN(+)) and without DPN (DPN(-)), neuropathic pain, sleep, risk for obstructive sleep apnea (OSA), autonomic function, and blood pressure (BP) circadian pattern were assessed using the Douleur Neuropathique en 4 Questions (DN4), the Medical Outcomes Study Sleep Scale, the Berlin Questionnaire, cardiovascular reflex tests, and ambulatory BP monitoring. Patients with PDPN showed higher nighttime systolic BP (130.4 ± 15.6 mmHg) than both DPN(-) (119.9 ± 10.6 mmHg; P < 0.0001) and DPN(+) patients (124.2 ± 12.3 mmHg; P < 0.05), and lower day-night difference (∆) in systolic BP (5.5 ± 6.5 vs. 8.6 ± 7.7%; P < 0.05) and diastolic BP than DPN(-) patients. In a stepwise regression analysis, orthostatic hypotension, high risk for OSA, and PDPN (DN4 interview) were independent determinants of ∆ in systolic BP (r = 0.46; P = 0.0001), ∆ in diastolic BP, and nighttime systolic BP. PDPN is associated with higher nocturnal systolic BP and impaired BP circadian pattern independent of pain-related comorbidities, suggesting a condition of high cardiovascular risk.

Painful and Painless Diabetic Neuropathy: One Disease or Two?

Painful diabetic polyneuropathy (PDPN) is generally considered a variant of diabetic polyneuropathy (DPN) but the identification of distinctive aspects that characterize painful compared with painless DPN has however been addressed in many studies, mainly with the purpose of better understanding the mechanisms of neuropathic pain in the scenario of peripheral nerve damage of DPN, of determining risk markers for pain development, and also of recognizing who might respond to treatments. This review is aimed at examining available literature dealing with the issue of similarities and differences between painful and painless DPN in an attempt to respond to the question of whether painful and painless DPN are the same disease or not and to address the conundrum of why some people develop the insensate variety of DPN whilst others experience distressing pain. Thus, from the perspective of comparing painful with painless forms of DPN, this review considers the clinical correlates of PDPN, its distinctive framework of symptoms, signs, and nerve functional and structural abnormalities, the question of large and small fiber involvement, the peripheral pain mechanisms, the central processing of pain and some new insights into the pathogenesis of pain in peripheral polyneuropathies and PDPN.

Microvascular Perfusion Abnormalities of the Thalamus in Painful but Not Painless Diabetic Polyneuropathy

OBJECTIVEThe pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN.RESEARCH DESIGN AND METHODSEighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [ttFM]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region.RESULTSSubjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest ttFM(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion.CONCLUSIONSPainful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN.

Cerebrospinal fluid levels of β endorphin in painful and painless diabetic polyneuropathy

β endorphin (β-EP) is an important modulator of central pain pathways. To examine whether changes in central production of β-EP contribute to the pathogenesis of diabetic neuropathic pain, we compared the cerebrospinal fluid (CSF) levels of β-EP and its precursor proopiomelanocortin (POMC) between 15 diabetic patients with chronic painful diabetic polyneuropathy, eight patients with severe painless diabetic neuropathy, and ten nondiabetic controls. Both peptides were measured by specific monoclonal antibody-based two-site immunoradiometric assays (IRMAs). In the diabetic patients with painful neuropathy, mean ± SD CSF β-EP concentrations (5.7 ± 2.2 pmol/L) were comparable to those of the diabetic patients with painless neuropathy (6.0 ± 2.3 pmol/L) and did not correlate with the severity of neuropathic pain. CSF β-EP, but not POMC, concentrations were lower in the diabetic neuropathic patients overall (5.8 ± 1.9 pmol/L) compared to the control subjects (7.6 ± 2.2 pmol/L) ( p < 0.05). CSF POMC showed no intergroup differences. However, POMC levels were 80-fold higher than those of β-EP and should always be considered when interpreting immunoreactive β-EP or other derivative peptide levels in CSF. We conclude that CSF β-EP levels appear to be reduced in diabetic polyneuropathy but they do not relate to the presence of neuropathic pain. This might explain why opioid analgesics are of little, if any, help in alleviating diabetic neuropathic pain.

Association of Painful and Painless Diabetic Polyneuropathy With Different Patterns of Nerve Fiber Degeneration and Regeneration

We evaluated neuropathological abnormalities in sural nerve biopsies from 6 nondiabetic control subjects and 16 age-matched diabetic patients with different syndromes of sensory polyneuropathy (6 with chronic painful neuropathy [CPN], 4 with newly presenting painful neuropathy [NPN], and 6 with painless neuropathy associated with recurrent neurotrophic foot ulcers [RFU]). Although all but one of the evaluated features of myelinated and unmyelinated fiber pathology could be found in every diabetic patient, certain myelinated fiber abnormalities were associated with the clinical characteristics of the neuropathy. Thus, myelinated fiber density was severely reduced, "empty" Schwann tubes (an index of myelinated fiber degeneration) were increased, and early regeneration (bands of Büngner [BB], nonmyelinated axons) was pronounced in the RFU group. Progression from BB to regenerating myelinated fiber cluster (myelination and maturation) was more successful in patients with CPN and NPN than in those with RFU, and the finding of fibers with disproportionately large Schwann cells (cytoplasm and myelin) relative to axon caliber was exclusive to patients with neuropathic pain. We concluded that 1) unequal rates of successful fiber regeneration may underlie the apparent difference in the extent of myelinated fiber loss between painful and painless diabetic polyneuropathy; 2) myelinated and unmyelinated fiber degeneration and regeneration per se are probably not the cause of neuropathic pain in diabetic polyneuropathy, because each occurred in patients with RFU; and 3) axonal atrophy may be involved in neuropathic pain generation.

Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration

Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration