Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group.

BACKGROUND: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. AIM: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. METHODS: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). RESULTS: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. CONCLUSIONS: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

A longitudinal study of painless and painful intercostobrachial neuropathy after breast cancer surgery.

Intercostobrachial neuropathy, often resulting in neuropathic pain, is a common complication of breast cancer surgery. In this 1-year longitudinal study, we aimed at seeking information on the frequency, clinical features, and course of painless and painful intercostobrachial neuropathy. We enrolled 40 women previously undergoing breast cancer surgery. In these patients, we collected, at 3, 6 and 12 months after surgery, clinical and quantitative sensory testing (QST) variables to diagnose intercostobrachial neuropathy, DN4 questionnaire to identify neuropathic pain, Neuropathic Pain Symptom Inventory to assess the different neuropathic pain symptoms, the Beck Depression Inventory to assess depressive symptoms, and SF36 to assess quality of life and Patient Global Impression of Change. Clinical and QST examination showed an intercostobrachial neuropathy in 23 patients (57.5%). Out of the 23 patients, five experienced neuropathic pain, as assessed with clinical examination and DN4. Axillary surgery clearance was associated with an increased risk of intercostobrachial neuropathy. Whereas sensory disturbances improved during the 1-year observation, neuropathic pain did not. Nevertheless, Beck Depression Inventory, SF36, and the Patient Global Impression of Change scores significantly improved over time. Our study shows that although intercostobrachial neuropathy is a common complication of breast cancer surgery, neuropathic pain affects only a minor proportion of patients. After 1 year, sensory disturbances partially improve and have only a mild impact on mood and quality of life.

EAN guidelines on central neurostimulation therapy in chronic pain conditions.

BACKGROUND AND PURPOSE: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. METHODS: A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. RESULTS: The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. CONCLUSIONS: Given the poor to moderate quality of evidence identified by this review, future large-scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended.

An observational study assessing peripheral neuropathy related to multiple myeloma.

We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naïve patients with multiple myeloma. We enrolled 153 patients with multiple myeloma at initial diagnosis. All patients underwent neurological examination and nerve conduction study. Patients with suspected pure small fiber neuropathy underwent skin biopsy. Of the 153 patients included in this study, 7.2 % had a multiple myeloma-related neuropathy. All patients suffered from a distal symmetric sensory peripheral neuropathy, associated with age (P = 0.04). Our study on prevalence rate of multiple myeloma-related peripheral neuropathy might provide a basis for improving the clinical management of this condition.

Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors.

Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single-agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.

Role of microRNAs in malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9-12 months and latency between exposure and diagnosis ranging from 20-50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17-22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests.

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.

Heat-evoked experimental pain induces long-term potentiation-like plasticity in human primary motor cortex.

We designed a new paired associative stimulation (PAS) protocol that combines experimental pain evoked by laser stimuli and transcranial magnetic stimulation (TMS) (Laser-PAS) to primary motor cortex (M1). We tested in healthy subjects whether Laser-PAS elicits cortical plasticity as reflected by long-term changes in motor-evoked potentials (MEPs) (after-effects). In separate experiments, we examined numerous variables including changes induced by varying the interstimulus intervals (ISIs) and Laser-PAS-induced changes in target and non-target muscle MEPs. We measured MEPs after repetitive laser or TMS (rTMS) pulses, and compared magnetic- and electric (TES)-induced MEPs. We tested MEPs after applying Laser-PAS with laser pulses ipsilaterally to M1. Finally, we studied subjects receiving an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) or placebo (α-lipoic acid). During Laser-PAS at the 50 ms ISI MEPs decreased, thereafter they increased for 60 min; other ISIs induced no after-effects. The after-effects remained restricted to the target muscle. Repetitive laser pulses and rTMS induced no after-effects. After Laser-PAS, TMS-induced MEPs increased, whereas TES-induced MEPs did not. Laser-PAS with laser pulses ipsilaterally to M1 left MEPs unchanged. Memantine, but not α-lipoic acid, abolished the after-effects. In conclusion, Laser-PAS elicits NMDA-dependent cortical plasticity and provides new insights into human pain-motor integration.

Nerve ultrasound in Friedreich's Ataxia: enlarged nerves as a biomarker of disease severity.

OBJECTIVE: In Friedreich's ataxia research, the focus is on discovering treatments and biomarkers to assess disease severity and treatment effects. Our study examines high-resolution nerve ultrasound in these patients, seeking correlations with established clinical markers of disease severity. METHOD: Ten patients with Friedreich's Ataxia underwent a comprehensive clinical assessment with established scales (SARA, FARS, mFARS, INCAT, ADL 0-36, IADL). Additionally, they underwent nerve conduction studies and high-resolution nerve ultrasound. Quantitative evaluation of nerve cross-sectional area, conducted at 24 nerve sites using high-resolution nerve ultrasound, was compared with data obtained from 20 healthy volunteers. RESULTS: All the patients had a severe sensory axonal neuropathy. High-resolution nerve ultrasound showed significant increase, in cross sectional area, of median and ulnar nerves at the axilla and arm. The cumulative count of affected nerve sites was directly associated with clinical disability, as determined by SARA, FARS, mFARS, ADL 0-36, and INCAT score, while displaying an inverse correlation with IADL. CONCLUSIONS: Our study shows that high-resolution ultrasound reveals notable nerve abnormalities, primarily in the upper limbs of patients diagnosed with Friedreich's Ataxia. The observed correlation between these nerve abnormalities and clinical disability scales indicates the potential use of this technique as a biomarker for evaluating disease severity and treatment effects. SIGNIFICANCE: Nerve Ultrasound is a potential biomarker of disease severity in Friedreich's Ataxia.

Predicting value for incomplete recovery in Bell's palsy of facial nerve ultrasound versus nerve conduction study.

OBJECTIVE: This longitudinal study aims at assessing the predictive value of facial nerve high-resolution ultrasound (HRUS) for incomplete clinical recovery in patients with Bell's palsy, the most common facial nerve disease. METHODS: We prospectively enrolled 34 consecutive patients with Bell's palsy. All patients underwent neurophysiological testing (including facial nerve conduction study) and HRUS evaluations 10-15 days (T1), one month (T2), and three months (T3) after the onset of Bell's palsy. Patients who did not experience complete recovery within three months were also evaluated after six months (T4). We have then compared the accuracy of HRUS with that of the facial nerve conduction study in predicting incomplete clinical recovery at three and six months. RESULTS: At T1, the facial nerve diameter, as assessed with HRUS, was larger on the affected side than on the normal side, particularly in patients with incomplete recovery at T2, T3 and T4. ROC curve analysis, however, showed that the facial nerve diameter at T1 had a lower predictive value than the facial nerve conduction study for an incomplete clinical recovery at three (T3) and six (T4) months. Still, the facial nerve diameter asymmetry, as assessed with HRUS, had a relatively high negative predictive value (thus indicating a strong association between normal HRUS examination and a good prognosis). CONCLUSIONS: Although HRUS shows abnormally increased facial nerve diameter in patients in the acute phase of Bell's palsy, the predictive value of this technique for incomplete clinical recovery at three and six months is lower than that of the nerve conduction study. SIGNIFICANCE: Nerve ultrasound has a low predictive value for incomplete clinical recovery in patients with Bell's Palsy.

Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain.

Pain is a subjective condition that cannot be objectively measured; for this reason, self patient-perspective is crucial. Recently, several screening tools to discriminate between nociceptive and neuropathic pain have been developed. We aimed at assessing the consistence and discrepancy of two widely used screening tools, The Douleur Neuropathique 4 (DN4) and the 6-item questionnaire (ID-Pain), by comparing their ability in discriminating neuropathic from nociceptive pain. DN4 and ID-Pain were administered to 392 Italian patients attending 16 outpatient services for peripheral nerve diseases. Based on medical history, clinical findings and diagnostic tools, patients were divided into two groups (neuropathic and nociceptive). Globally, ID-Pain identified neuropathic pain in 60 % of patients (38 % probable, 22 % likely). Interestingly also DN4 diagnosed neuropathic pain in 60 % of cases. A discrepancy was observed in 16 % of cases. DN4 and ID-Pain resulted to be highly interrelated in the identification of neuropathic pain. Sensitivity of DN4 was 82 % and specificity was 81 %, while ID-Pain (considering both probable and likely groups) showed sensitivity 78 % and specificity 74 %. Reliable screening tools for neuropathic pain are well related between them; hence, they are available for researchers and clinicians who may choose the most appropriate for their activity. Since the gold standard for the diagnosis and treatment of neuropathic pain cannot do without a neurological evaluation, perhaps DN4, that includes physician objective measures, may help reducing the percentage of dubious cases. Conversely, when needing a more agile tool (not needing a physician) ID-Pain may be adopted.

Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter.

OBJECTIVE: The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization. In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). METHODS: In 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16-64-256-mN pinprick probes. RESULTS: Although both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. CONCLUSIONS: These findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SIGNIFICANCE: Our results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Cutaneous innervation and trigeminal pathway function in a patient with facial pain associated with Parry-Romberg syndrome.

Parry-Romberg syndrome (PRS) is a rare condition manifesting with progressive hemifacial atrophy. Although reported PRS clinical disturbances include facial pain and recent studies raised the possibility that PRS-related pain is a neuropathic pain condition due to the trigeminal nerve damage, no studies have directly investigated cutaneous innervation and trigeminal pathway function in patients with this rare condition. In a 50-year-old woman presenting with a 10-year history of slowly progressive hemifacial atrophy and facial pain, we investigated large myelinated fibres with masticatory muscle electromyography and trigeminal reflexes, and tested small myelinated and unmyelinated fibres with laser-evoked potentials. We also investigated cutaneous innervation by measuring the intraepidermal nerve fibre (IENF) density after skin biopsy of the supraorbital regions. We found that neurophysiological data and IENF density came within normal ranges, with no differences between normal and affected side. Our study showing that the standard reference techniques for assessing cutaneous innervation and trigeminal pathway function disclosed no abnormalities in this patient with PRS suggest that this rare and disabling condition is not associated with trigeminal system damage. These findings indicate that in this patient PRS-related pain is not a neuropathic pain condition, rather it probably arises from the musculoskeletal abnormalities.

Iatrogenic damage to the mandibular nerves as assessed by the masseter inhibitory reflex.

Iatrogenic injury of the inferior alveolar or lingual nerves frequently leads to legal actions for damage and compensation for personal suffering. The masseter inhibitory reflex (MIR) is the most used neurophysiological tool for the functional assessment of the trigeminal mandibular division. Aiming at measuring the MIR sensitivity and specificity, we recorded this reflex after mental and tongue stimulations in a controlled, blinded study in 160 consecutive patients with sensory disturbances following dental procedures. The MIR latency was longer on the affected than the contralateral side (P < 0.0001). The overall specificity and sensitivity were 99 and 51%. Our findings indicate that MIR testing, showing an almost absolute specificity, reliably demonstrates nerve damage beyond doubt, whereas the relatively low sensitivity makes the finding of a normal MIR by no means sufficient to exclude nerve damage. Probably, the dysfunction of a small number of nerve fibres, insufficient to produce a MIR abnormality, may still engender important sensory disturbances. We propose that MIR testing, when used for legal purposes, be considered reliable in one direction only, i.e. abnormality does prove nerve damage, normality does not disprove it.

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex.

OBJECTIVE: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. METHODS: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. RESULTS: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. CONCLUSIONS: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. SIGNIFICANCE: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans.

Laser evoked potentials in patients with trigeminal disease: the absence of Adelta potentials does not unmask C-fibre potentials.

OBJECTIVE: Although laser stimuli activate both Adelta- and C-fibres, the corresponding laser evoked potentials (LEPs) remain restricted to the Adelta-fibre input. Previous studies found C-LEPs after limb stimulation only in subjects with block or clinical impairment of Adelta-fibres. In this study, we aimed at verifying whether in the trigeminal territory the impairment of Adelta-fibres unmasks the C-LEP. METHODS: By collecting retrospectively LEPs recorded in 370 patients, we analyzed the results from 150 trigeminal divisions with absent Adelta-LEPs. RESULTS: We found signals that were consistent with the C-fibre input in three patients only. In most patients with absent Adelta-LEPs, however, laser stimuli still elicited the Adelta-conveyed pinprick sensation. CONCLUSIONS: The preserved pinprick sensation suggests that the Adelta-fibre volley, though weakened, reached the cortex. The C-LEP absence may be explained according to the first come first served hypothesis: the evoked potential related to an afferent volley reaching the cortex shortly after a preceding input (i.e. a C-fibre volley coming after an Adelta-fibre) will be suppressed. SIGNIFICANCE: In clinical studies using the standard laser pulses to evoke the Adelta-LEPs, the finding of absent signals does not indicate a concomitant impairment of C-fibres.

Current and Innovative Pharmacological Options to Treat Typical and Atypical Trigeminal Neuralgia.

Trigeminal neuralgia is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. A subgroup of patients with trigeminal neuralgia [TN (previously defined as atypical TN)] also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The aim of this review is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), taking into account publications up to February 2018. Two authors independently selected studies for inclusions, data extraction, and bias assessment. Carbamazepine and oxcarbazepine are the first-choice drugs for paroxysmal pain. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment with lamotrigine or baclofen should be considered. In patients with atypical TN, both gabapentin and antidepressants are expected to be efficacious and should be tried as an add-on to oxcarbazepine or carbamazepine. Although carbamazepine and oxcarbazepine are effective in virtually the totality of patients, they are responsible for side effects causing withdrawal from treatment in an important percentage of cases. A new, better tolerated, Nav1.7 selective state-dependent, sodium channel blocker (vixotrigine) is under development. Future trials testing the effect of combination therapy in patients with TN are needed, especially in patients with concomitant continuous pain and in TN secondary to multiple sclerosis.

Author Correction to: L-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain.

In the original publication the name of third author was incorrectly published.

A pain in the skin. Regenerating nerve sprouts are distinctly associated with ongoing burning pain in patients with diabetes.

BACKGROUNDS: Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how intraepidermal regenerating nerve sprouts are associated with these two types of pain. METHODS: We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti-protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth-associated protein 43 (GAP43) to quantify regenerating nerve sprouts. RESULTS: We found that the GAP43-stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance. CONCLUSION: Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts. SIGNIFICANCE: Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43-staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes.