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

AIMS/HYPOTHESIS: Our 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. METHODS: Skin 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. RESULTS: There 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/INTERPRETATION: Cutaneous 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.

The characteristics of pain and dysesthesia in patients with diabetic polyneuropathy.

INTRODUCTION/AIMS: Patients with diabetic polyneuropathy (DPN) may experience paresthesia, dysesthesia, and pain. We aimed to characterize the predictors, symptoms, somatosensory profile, neuropathy severity, and impact of painful DPN and dysesthetic DPN. METHODS: This study was a cross-sectional study of type 2 diabetes patients with confirmed DPN, diagnosed using widely accepted methods including a clinical examination, skin biopsy, and nerve conduction studies. FINDINGS: Of 126 patients with confirmed DPN, 52 had DPN without pain or dysesthesia, 21 had dysesthetic DPN, and 53 painful DPN. Patients with painful DPN were less physically active and suffered from more pain elsewhere than in the feet compared to patients with DPN without pain. Patients with painful DPN had the largest loss of small and large sensory fiber function, and there was a gradient of larger spatial distribution of sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. This could indicate that patients with dysesthesia had more severe neuropathy than patients without dysesthesia but less than patients with painful DPN. Patients with dysesthetic and painful DPN had higher symptom scores for depression and fatigue than those without dysesthesia/pain with no difference between dysesthetic and painful DPN. CONCLUSIONS: There was a gradient of increasing sensory loss from DPN without dysesthesia/pain to dysesthetic DPN and to painful DPN. Pain and dysesthesia are common in DPN and both interfere with daily life. It is therefore important to consider dysesthesia when diagnosing and treating patients with neuropathy.

Analysis of Macrophages and Peptidergic Fibers in the Skin of Patients With Painful Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: The mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP). METHODS: The participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy-30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)-and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers. RESULTS: There was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm-2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm-2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm-2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients. DISCUSSION: The findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

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

ABSTRACT: 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.

Neuropathic Pain: From Mechanisms to Treatment.

Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a common chronic pain condition with major impact on quality of life. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain. Most patients complain of an ongoing or intermittent spontaneous pain of, for example, burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, for example, nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Evoked pain may spread to neighboring areas, and the underlying pathophysiology involves peripheral and central sensitization. Maladaptive structural changes and a number of cell-cell interactions and molecular signaling underlie the sensitization of nociceptive pathways. These include alteration in ion channels, activation of immune cells, glial-derived mediators, and epigenetic regulation. The major classes of therapeutics include drugs acting on α2δ subunits of calcium channels, sodium channels, and descending modulatory inhibitory pathways.

Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes.

Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥4 on the MNSI questionnaire determined possible DPN, whereas pain presence in both feet together with a score ≥3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, body mass index, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (odds ratio 1.52 [95% confidence interval: 1.20-1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality of life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.

Painful and non-painful diabetic polyneuropathy: Clinical characteristics and diagnostic issues.

Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non-painful. It is challenging to diagnose this complication, as no biomarker or clear consensus on the clinical definition of either painful or non-painful DN exists. Hence, a hierarchical classification has been developed categorizing the probability of the diagnosis into: possible, probable or definite, based on the clinical presentation of symptoms and signs. Pain is a warning signal of tissue damage, and non-painful DN therefore represents a clinical and diagnostic challenge because it often goes unnoticed until irreversible nerve damage has occurred. Simple clinical tests seem to be the best for evaluation of DN in the general care for diabetes. Screening programs at regular intervals might be the most optimal strategy for early detection and interventions to possibly prevent further neuronal damage and to lower the economic burden of this complication.

Can diabetic polyneuropathy and foot ulcers in patients with type 2 diabetes be accurately identified based on ICD-10 hospital diagnoses and drug prescriptions?

Purpose: We examined whether diabetic polyneuropathy (DPN) and diabetic foot ulcers in type 2 diabetes can be accurately identified using International Classification of Diseases, 10th revision discharge diagnosis codes, surgery codes, and drug prescription codes. Methods: We identified all type 2 diabetes patients in the Central Denmark region, 2009-2016, who had ≥1 primary/secondary diagnosis code of "diabetes with neurological complication" (E10.4-E14.4), "diabetic polyneuropathy" (G63.2), or "polyneuropathy, unspecified" (G62.9). Patients with potential painful DPN and non-painful DPN were identified based on prescription history for serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, or gabapentinoids. Likewise, type 2 diabetes patients with potential foot ulcers were identified based on diagnosis or surgery codes. We used medical record review as the reference standard and calculated positive predictive values (PPVs). Results: Of 53 randomly selected patients with potential painful DPN, 38 were classified as having DPN when validated against medical records; of these, 18 also had neuropathic pain, yielding a PPV of 72% (95% CI: 58-83%) for DPN and 34% (95% CI: 22-48%) for painful DPN. Likewise, among 54 randomly selected patients with potential non-painful DPN, 30 had DPN based on medical record data; of these, 27 had non-painful DPN, yielding PPVs of 56% (95% CI: 41-69%) and 50% (95% CI: 36-64%), respectively. Secondary E-chapter codes often denoted stroke or mononeuropathies, rather than DPN. Excluding secondary E-chapter codes from the algorithm increased the PPV for DPN to 78% (95% CI: 63-89%) for the painful DPN cohort and to 74% (95% CI: 56-87%) for the non-painful DPN cohort. Of 53 randomly selected patients with potential diabetic foot ulcer, only 18 diagnoses were confirmed; PPV=34% (95% CI: 22-48%). Conclusion: G-chapter and primary E-chapter diagnosis codes can detect type 2 diabetes patients with hospital-diagnosed DPN, and may be useful in epidemiological research. In contrast, our diabetic foot ulcer algorithm did not perform well.

[Neurogenic autonomic dysfunction in adults].

Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions.

[Neurogenic autonomic dysfunction in primary amyliodosis].

Neurogenic autonomic dysfunction (NAD) and polyneuropathy occur in common conditions like diabetes and alcoholism. However, it can also be seen in rare diseases like in this case report of amyloid light-chain amyloidosis: primary amyloidosis. A 56-year-old man presented with polyneuropathy, a sympathetic dysfunction causing orthostatic intolerance, syncope, parasympathetic dysfunction and involvement of the enteric nervous system. The report illustrates, that routine screening can be insufficient in diagnosing amyloidosis. NAD and polyneuropathy without clear aetiology may require a multidisciplinary elucidation of more rare diseases.

[Skin biopsy and quantitative sensory testing can contribute to small fibre neuropathy diagnostics].

Nerve conduction studies are normal in small fibre neuropathy and special methods such as skin biopsies or quantitative sensory testing are required for diagnosis. In skin biopsies, nerve fibres are stained immunohistochemically and loss of distal nerve endings can be quantified directly. Assessment of thermal detection thresholds is used to evaluate the function of the sensory thermal pathways, but cannot discriminate between central and peripheral lesions. Small fibre neuropathy is often associated with potentially treatable diseases, and treatment of neuropathic pain may be required.

Fibromyalgia and Chronic Pain Syndromes: A White Paper Detailing Current Challenges in the Field.

This manuscript, developed by a group of chronic pain researchers and clinicians from around the world, aims to address the state of knowledge about fibromyalgia (FM) and identify ongoing challenges in the field of FM and other chronic pain syndromes that may be characterized by pain centralization/amplification/hypersensitivity. There have been many exciting developments in research studies of the pathophysiology and treatment of FM and related syndromes that have the potential to improve the recognition and management of patients with FM and other conditions with FM-like pain. However, much of the new information has not reached all clinicians, especially primary care clinicians, who have the greatest potential to use this new knowledge to positively impact their patients' lives. Furthermore, there are persistent misconceptions about FM and a lack of consensus regarding the diagnosis and treatment of FM. This paper presents a framework for future global efforts to improve the understanding and treatment of FM and other associated chronic pain syndromes, disseminate research findings, identify ways to enhance advocacy for these patients, and improve global efforts to collaborate and reach consensus about key issues related to FM and chronic pain in general.

Chronic pain in the pelvic area or lower extremities after rectal cancer treatment and its impact on quality of life: a population-based cross-sectional study.

The aim of this investigation was to examine the prevalence of and factors associated with chronic pain in the pelvic area or lower extremities after rectal cancer treatment and its impact on quality of life (QoL). This is a population-based cross-sectional study of chronic pain and QoL in patients treated for rectal cancer from 2001 to 2007. A modified version of the Brief Descriptive Danish Pain Questionnaire and the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire were mailed to 1713 Danish patients. Informative answers were obtained from 1369 patients (80%). A total of 426 patients (31%) reported chronic pain in the pelvic area or lower extremities, 173 (41%) of whom had daily pain. Pain in other parts of the body was associated with the presence of pain in the pelvic region (odds ratio [OR] 4.81 [3.63-6.38], P < 0.001). Multivariate logistic regression analysis showed an association with chronic pain in female patients (OR 1.91 [1.51-2.43], P < 0.001) and in those who received radio(chemo)therapy (OR 1.31 [1.01-1.7], P = 0.041) or underwent abdominoperineal excision (OR 1.71 [1.19-2.44], P = 0.003), total mesorectal excision (OR 1.39 [1.01-1.90], P = 0.041), and Hartmann procedure (OR 1.72 [1.04-2.84], P = 0.33) compared with partial mesorectal excision. Ordinal regression analysis showed a strong association between all QoL subgroups and pelvic pain. Chronic pain in the pelvic region or lower extremities after rectal cancer treatment is a common but largely neglected problem that is associated with female gender, type of surgery, radio(chemo)therapy, and young age, all of which impact the patient's QoL.

Specifying the nonspecific components of acupuncture analgesia.

It is well known that acupuncture has pain-relieving effects, but the contribution of specific and especially nonspecific factors to acupuncture analgesia is less clear. One hundred one patients who developed pain of ≥ 3 on a visual analog scale (VAS, 0 to 10) after third molar surgery were randomized to receive active acupuncture, placebo acupuncture, or no treatment for 30 min with acupuncture needles with potential for double-blinding. Patients' perception of the treatment (active or placebo) and expected pain levels (VAS) were assessed before and halfway through the treatment. Looking at actual treatment allocation, there was no specific effect of active acupuncture (P=.240), but there was a large and significant nonspecific effect of placebo acupuncture (P<.001), which increased over time. Interestingly, however, looking at perceived treatment allocation, there was a significant effect of acupuncture (P<.001), indicating that patients who believed they received active acupuncture had significantly lower pain levels than those who believed they received placebo acupuncture. Expected pain levels accounted for significant and progressively larger amounts of the variance in pain ratings after both active and placebo acupuncture (up to 69.8%). This is the first study to show that under optimized blinding conditions, nonspecific factors such as patients' perception of and expectations toward treatment are central to the efficacy of acupuncture analgesia and that these factors may contribute to self-reinforcing effects in acupuncture treatment. To obtain an effect of acupuncture in clinical practice, it may therefore be important to incorporate and optimize these factors.

Epidermal nerve fiber length density estimation using global spatial sampling in healthy subjects and neuropathy patients.

Assessment of intraepidermal nerve fiber density (IENFD) has become a useful tool for the investigation of patients with suspected small-fiber neuropathy (SFN). Here, we estimate epidermal nerve fiber lengths in 12 patients with SFN and 36 healthy controls using global spatial sampling and compare the lengths with IENFD and axonal swelling ratios. Skin biopsies were analyzed on 50-µm-thick free-floating sections immunostained for the neuronal cytoplasmic marker PGP 9.5. Mean IENFD in SFN patients was 2.22 ± 1.63 mm versus 7.51 ± 2.17 mm in controls; mean length density was 112 ± 82.6 mm in SFN patients versus 565 ± 240 mm in controls (p < 0.001 for both). The correlation between the nerve fiber length and the IENFD was r = 0.16 for healthy subjects and r = 0.39 for patients, suggesting that these variables provide different quantitative information. There were significant differences in axonal swelling ratios between healthy subjects and patients, that is, per IENFD and per nerve fiber length. Together, these results suggest that, although length estimation requires more time and additional equipment, it is as effective as IENFD in differentiating SFN patients from healthy subjects. Estimating nerve fiber length may increase mechanistic understanding beyond IENFD estimation and improve efficiency in diagnosing SFN.

The neuropathic component in persistent postsurgical pain: a systematic literature review.

Persistent postsurgical pain (PPSP) is a frequent and often disabling complication of many surgical procedures. Nerve injury-induced neuropathic pain (NeuP) has repeatedly been proposed as a major cause of PPSP. However, there is a lack of uniformity in NeuP assessment across studies, and the prevalence of NeuP may differ after various surgeries. We performed a systematic search of the PubMed, CENTRAL, and Embase databases and assessed 281 studies that investigated PPSP after 11 types of surgery. The prevalence of PPSP in each surgical group was examined. The prevalence of NeuP was determined by applying the recently published NeuP probability grading system. The prevalence of probable or definite NeuP was high in patients with persistent pain after thoracic and breast surgeries-66% and 68%, respectively. In patients with PPSP after groin hernia repair, the prevalence of NeuP was 31%, and after total hip or knee arthroplasty it was 6%. The results suggest that the prevalence of NeuP among PPSP cases differs in various types of surgery, probably depending on the likelihood of surgical iatrogenic nerve injury. Because of large methodological variability across studies, a more uniform approach is desirable in future studies for evaluating persistent postsurgical NeuP.

Persistent pain after surgery for cutaneous melanoma.

OBJECTIVES: Chronic pain is a well-known complication after surgery, but the prevalence of persistent pain after melanoma surgery is unknown. This study examined the prevalence and predictors of persistent pain after melanoma surgery. METHODS: Between September 2005 and June 2009, 448 patients underwent surgery for cutaneous melanoma at the Department of Plastic Surgery, Aalborg Hospital. A questionnaire was sent to all 402 survivors, and 350 (87.1%) responded. In addition, all patients with pain and a control group of sex-matched and age-matched patients without pain were invited to a clinical examination. RESULTS: Thirty-four patients (9.7%) reported pain in the scar area within the last month, and 8.6% reported chronic pain. The pain was mostly mild with little impact on daily life, but 1.7% reported moderate to severe pain, and 3.4% reported at least moderate impact of pain on daily life. Sensory changes were reported by 108 patients (31.5%); 25% of these had pain compared with 3% of patients with normal sensation [P<0.001, 10.8 (4.5 to 25.8)]. Young age was a predictor for persistent pain. A small group of patients (10 with and 22 without pain in the questionnaire) were clinically examined, suggesting that the areas of sensory disturbances were larger in patients reporting persistent pain or dysesthesia. DISCUSSION: The results support previous findings that persistent postoperative pain is a complication of almost any surgical intervention. Persistent pain was related to abnormal sensation, and neuropathic pain should be considered in these patients.