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International audience; We report on a two-flavour lattice QCD determination of the $B_s\to D_s$ and $B_s\to D_s^*$ transitions, which in the heavy quark limit can be parameterised by the form factors $\mathcal{G}$, and $h_{\text A_1}$, $h_{\text A_2}$ and $h_{\text A_3}$. In the search of New Physics through tests of lepton-flavour universality, $B_s$ decay channels are complementary to $B$ decays and widely studied at $B$ factories and LHCb. The purpose of our study is to explore a suitable method to extract form factors associated with $b\to c$ currents from lattice QCD. In particular, we present numerical results for $\mathcal{G}$ and $h_{\text A_1}$.

Objectives We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans. Methods Using a cold stimulator consisting of micro-Peltier elements that was able to produce steep cooling ramps up to -300°C/s, we recorded cold-evoked potentials after stimulation of the dorsal midline at C5, T2, T6 and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ-fibres-mediated) and warm (C-fibres-mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways. Results Cold stimulation evoked large-amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s. Discussion This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans that may be useful in the assessment of spinal cord lesions as well as in intraoperative monitoring during spinal surgery. Significance This neurophysiological study provides previously unreported findings on cold spinal pathway conduction velocity in healthy humans. Cold-evoked potentials may represent an alternative to laser-evoked potential recording, useful to assess spinothalamic tract in patients with spinal cord lesions and monitor patients during spinal surgery.

BACKGROUND In this neurophysiological study, we aimed at verifying the nociceptive selectivity of the new, micropatterned electrode (150IDE), recently designed to generate an electric field limited to the intraepidermal free nerve endings. METHODS Using the new 150IDE, we recorded evoked potentials after stimulation of the face and hand dorsum in 22 healthy participants and in patients with exemplary conditions selectively affecting the nociceptive system. We also measured the peripheral conduction velocity at the upper arm and verified the nociceptive selectivity of 150IDE assessing the effect of a selective block of nociceptive nerve fibres of radial nerve with local anaesthetic infiltration. In healthy participants and in patients, we have also compared the 150IDE-evoked potentials with laser-evoked potentials. RESULTS In healthy participants, the 150IDE-evoked pinprick sensation and reproducible scalp potentials, with latency similar to laser-evoked potentials. The mean peripheral conduction velocity, estimated at the upper arm, was 12 m/s. The selective nociceptive fibre block of the radial nerve abolished the scalp potentials elicited by the 150IDE stimulation. In patients, the 150IDE-evoked potentials reliably detected the selective damage of the nociceptive system. CONCLUSIONS Our neurophysiological study shows that this new 150IDE provides selective information on nociceptive system. SIGNIFICANCE 150IDE is a promising new tool for investigating nociceptive system in patients with neuropathic pain.

We report on a two-flavor lattice QCD study of the Bs→Ds and Bs→Ds* transitions parametrized, in the heavy quark limit, by the form factors G, and hA1, hA2, and hA3, respectively. In the search for New Physics through tests of lepton flavor universality, Bs decay channels are complementary to the B decays widely studied at B factories and LHCb, while on the theory side they can be better controlled than the Bc and Λb decays. The purpose of this exploratory two-flavor study is, in preparation for future analyses of lattice QCD simulations with Nf>2 and physical quark masses, to gain experience on a suitable method for a lattice extraction of form factors associated with b→c currents that may yield tighter control over systematic effects like contamination from excited states and cutoff effects. We obtain the zero-recoil values GBs→Ds(1)=1.03(14) and hBs→Ds*(1)=0.85(16).

We report on a two-flavour lattice QCD study of the $B_s \to D_s$ and $B_s \to D^*_s$ transitions parameterized, in the heavy quark limit, by the form factors ${\cal G}$, and $h_{A_1}$, $h_{A_2}$ and $h_{A_3}$, respectively. In the search for New Physics through tests of lepton flavour universality, $B_s$ decay channels are complementary to the $B$ decays widely studied at $B$ factories and LHCb, while on the theory side they can be better controlled than the $B_c$ and $\Lambda_b$ decays. The purpose of this exploratory two-flavour study is, in preparation for future analyses of lattice QCD simulations with ${N_f>2}$ and physical quark-masses, to gain experience on a suitable method for a lattice extraction of form factors associated with $b \to c$ currents that may yield tighter control over systematic effects like contamination from excited states and cut-off effects. We obtain the zero-recoil values ${\cal G}^{B_s \to D_s}(1)=1.03(14)$ and $h^{B_s \to D^*_s}(1)=0.85(16)$.

In this clinical and neurophysiological study using a novel cold stimulator, we aim at investigating whether cold-evoked potentials (CEPs) may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function. Using a novel device consisting of micro-Peltier elements, we recorded CEPs after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in 2 patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared CEPs with laser-evoked potentials. In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, although with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/seconds. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorsolateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital, and hand dorsum stimulation. In patients with facial neuropathic pain, CEP recording showed the selective damage of cold pathways providing complementary information to laser-evoked potential recording. Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small fibres mediating cold sensation and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres.

BACKGROUND We aimed at evaluating the differential involvement of large myelinated Aβ-, small myelinated Aδ-, and unmyelinated C-fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. METHODS We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aβ-fiber mediated nerve conduction study, Aδ-fiber mediated laser-evoked potentials and skin biopsy mainly assessing unmyelinated C-fibers. RESULTS Pure large-fiber and small-fiber polyneuropathy were relatively uncommon; conversely mixed-fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small-fiber related variables. CONCLUSIONS Diabetic polyneuropathy mainly manifests as a mixed-fiber polyneuropathy, simultaneously involving Aβ-, Aδ-, and C-fibers. In most patients, neuropathic pain is distinctly associated with small-fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large-, pure small-, and mixed-fiber polyneuropathy, raises the possibility that in patients with pure large-fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques.

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.

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy. Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy.

In human epidermal growth factor receptor 2 (HER2+) expressing breast cancer subtype, the incidence of brain metastases is common and patients often die due to uncontrolled cranial disease. This is a case report of a HER2+ breast cancer woman with diffuse brain metastases that experienced long survival and clinical benefit from multiple radiotherapy treatments and combined systemic therapy, without increased toxicity.

Background: In order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) aimed to collate the evidence available across these topics. Objectives: To determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. Methods: Two reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation. Results: The first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies, and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy, and conditions associated with complex disability with regards to the psychological aspects that are involved. The second PUBMED search yielded 252 studies, which were all evaluated. Anxiety, depression, pain catastrophizing, coping strategies, and pain beliefs were found to be associated to different degrees with the outcomes of multidisciplinary programs, surgery, physical therapies, and psychological interventions. Finally, sense of presence was found to be related to the effectiveness of virtual reality as a distraction tool. Conclusions: Several psychological factors are associated with pain secondary to neurological conditions and should be acknowledged and addressed in order to effectively treat this condition. These factors also predict the therapeutic response to the neurorehabilitative interventions. Background: In order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) aimed to collate the evidence available across these topics. Objectives: To determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. Methods: Two reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation. Results: The first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies, and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy, and conditions associated with complex disability with regards to the psychological aspects that are involved. The second PUBMED search yielded 252 studies, which were all evaluated. Anxiety, depression, pain catastrophizing, coping strategies, and pain beliefs were found to be associated to different degrees with the outcomes of multidisciplinary programs, surgery, physical therapies, and psychological interventions. Finally, sense of presence was found to be related to the effectiveness of virtual reality as a distraction tool. Conclusions: Several psychological factors are associated with pain secondary to neurological conditions and should be acknowledged and addressed in order to effectively treat this condition. These factors also predict the therapeutic response to the neurorehabilitative interventions.

Background Patients with joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia. Methods In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. Results Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. Conclusions While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. What does this study add? In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain.

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.

Background In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. Methods In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. Results We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. Conclusion The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. Significance Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system.

Although the most widely agreed neurophysiological tool for investigating small fiber damage is laser-evoked potential (LEP) recording, no study has documented its diagnostic accuracy. In this clinical, neurophysiological, and skin biopsy study, we collected age-corrected LEP normative ranges, verified the association of LEPs with pinprick sensory disturbances in the typical diabetic mixed fiber polyneuropathy, and assessed the sensitivity and specificity of LEPs in diabetic small fiber neuropathy. From 288 LEP recordings from the face, hand, and foot in 73 healthy subjects, we collected age-corrected normative ranges for LEPs. We then selected 100 patients with mixed-fiber diabetic neuropathy and 25 patients with possible small-fiber diabetic neuropathy. In the 100 patients with mixed fiber neuropathy, we verified how LEP abnormalities were associated with clinically evident pinprick sensory disturbances. In the 25 patients with possible pure small fiber neuropathy, using the skin biopsy for assessing the intraepidermal nerve fiber density as a reference standard, we calculated LEP sensitivity and specificity. In healthy participants, age strongly influenced normative ranges for all LEP variables. By applying age-corrected normative ranges for LEPs, we found that LEPs were strongly associated with pinprick sensory disturbances. In relation to the skin biopsy findings, LEPs yielded 78% sensitivity and 81% specificity in the diagnosis of diabetic small fiber neuropathy. Our study, providing age-corrected normative ranges for the main LEP data and their diagnostic accuracy, helps to make LEPs more reliable as a clinical diagnostic tool, and proposes this technique as a less invasive alternative to skin biopsy for diagnosing diabetic small fiber neuropathy.

Background: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. Objectives: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. Methods: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. Results: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. Conclusions: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the paper. Background: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. Objectives: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. Methods: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. Results: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. Conclusions: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the paper.

Cardioembolic stroke is generally caused by intracranial artery occlusion. Clots may be identified in the intracranial vessels by means of conventional neuroimaging in the acute phase. High-resolution ultrasonography may show some features suggestive of cardiac emboli when occluding extracranial carotid arteries. We describe a patient with cardioembolic ischemic stroke in the right hemisphere in whom a left internal carotid artery stenosis paradoxically protected the ipsilateral hemisphere from distal intracranial embolism. The patient also presented multiple acute ischemic embolic lesions in the right middle cerebral artery territory and in the right occipital lobe, which was fed by the posterior cerebral artery, anomally originating from the right carotid siphon. Interestingly, the left internal carotid artery--which showed a severe preexisting stenosis--was occluded by the cardiac clot, whereas the right internal carotid artery only presented a moderate stenosis that had probably allowed the clots to pass. Therefore, the severe left internal carotid artery stenosis may have blocked the cardiac embolus, preventing it from reaching the ipsilateral hemisphere.

Background In Parkinson's disease (PD), the influence of chronic pain on motor features has never been investigated. We have recently designed a technique that combines nociceptive system activation by laser stimuli and primary motor cortex (M1) activation through transcranial magnetic stimulation (TMS), in a laser-paired associative stimulation design (Laser-PAS). In controls, Laser-PAS induces long-term changes in motor evoked potentials reflecting M1 long-term potentiation-like plasticity, arising from pain-motor integration. Objective We here examined the possible influence of chronic pain on motor responses to Laser-PAS in patients with PD, with and without chronic pain. Methods We compared motor responses to Laser-PAS in healthy subjects and in patients with PD, with and without chronic pain. Results Unlike controls, we found reduced responses to Laser-PAS in patients with PD, with and without pain. Patients off and on dopaminergic therapy had similar responses to Laser-PAS. When comparing responses to Laser-PAS in patients with and without pain, the two patients' subgroups had similar abnormalities. When we compared patients with pain in the body region investigated with Laser-PAS, with those with pain in other body regions, we found prominent changes in patients with homotopic pain. Finally, when comparing Laser-PAS with the original PAS protocol, which combines electric peripheral nerve stimuli and TMS, in patients without pain and those with homotopic pain, we found similar responses to both techniques in patients without pain, whereas Laser-PAS induced greater abnormalities than PAS in patients with pain. Conclusions In PD, chronic pain degrades response to Laser-PAS through abnormal pain-motor integration.

Emerging evidence associates chronic pain syndrome, such as fibromyalgia, with endogenous pain modulatory system dysfunction, leading to an impaired descending pain inhibition. In this study, using resting-state functional magnetic resonance imaging (fMRI), we aimed at seeking possible functional connectivity changes of the periaqueductal gray (PAG), a brainstem area that belongs to the endogenous pain modulatory system, in patients with fibromyalgia.In 20 patients with fibromyalgia and 15 healthy subjects, we investigated PAG functional connectivity using resting-state fMRI. We also analysed the correlation between clinical variables, such as pain severity, disease duration, and depressive personality traits with PAG functional connectivity.Compared with control subjects, we identified that patients with fibromyalgia had an increased PAG connectivity with insula, anterior cingulate cortex, and anterior prefrontal cortex. The functional connectivity between PAG and the rostral ventral medulla, however, was not concordantly increased. PAG functional connectivity correlated with pain severity, disease duration, and the depressive personality trait rating.Our fMRI study showing abnormal resting state functional connectivity of the PAG suggests that patients with fibromyalgia have an endogenous pain modulatory system dysfunction, possibly causing an impaired descending pain inhibition. This abnormal PAG functioning might underlay the chronic pain these patients suffer from.

Patients with painful neuropathy frequently complain of pain in response to normally non-painful brushing, namely dynamic mechanical allodynia. Despite many animal studies suggesting that allodynia arises when the spontaneous firing in damaged nociceptive afferents sensitise second-order nociceptive neurons to Aβ-fibre input, no studies have sought to confirm this mechanism by investigating Aβ-fibre sparing in human patients with allodynia. In this study we compared data from Aβ-fibre-mediated nerve conduction studies and nociceptive-fibre-mediated laser-evoked potentials (LEPs) in 200 patients with distal symmetric polyneuropathy (114 with neuropathic pain, 86 without). Of the 114 patients with painful neuropathy studied, 44 suffered from allodynia. Whereas no statistical difference was found in nerve conduction study data between patients with and without allodynia, LEP amplitudes were larger in patients with allodynia than in those without (P

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.

Neuropathic pain is a common problem in clinical practice and one that adversely affects patients’ quality of life. Converging evidence from animal and human studies demonstrates that neuropathic pain arises from a lesion in the somatosensory system. Injured peripheral nerve fibers give rise to an intense and prolonged ectopic input to the CNS and, in some cases, also to secondary changes in dorsal horn neuronal excitability. Convincing evidence now suggests that classifying neuropathic pain according to a mechanism-based rather than an etiology-based approach might help in targeting therapy to the individual patient and would be useful in testing new drugs. This article summarizes our current understanding of the peripheral and central pathophysiological mechanisms underlying neuropathic pain and focuses on how symptoms translate into mechanisms.

To gain information on the topographical distribution of warmth, burning and itch sensations in healthy humans, we delivered laser stimuli to elicit sensations of warmth, applied capsaicin cream for burning, and pricked histamine for itch on the skin of the face, shoulder, hand, thigh and foot in 12 healthy subjects. We found that whereas warm and burning sensations progressively increased from foot to face, itch sensation increased from face to foot (P0.0001). Hence our findings indicate that unlike thermal and pain receptors, itch receptors are denser at distal than at proximal body sites. Our psychophysical study provides new information supporting the idea that specific unmyelinated neuronal pathways mediate sensations of warmth, burning and itch.

Background Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Methods Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. Results A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%–56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 – 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 – 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 – 11.82). Conclusion OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

Pain is very common in neurorehabilitation, where it may be a target for treatment and have a negative effect on rehabilitation procedures and outcomes. Promising preliminary preclinical data support certain therapeutic approaches to pain, but there is a strong need of adequate preclinical models, experimental settings, outcome measures, and biomarkers that are more relevant for pain within the neurorehabilitation field. Data on the diagnosis and assessment of nociceptive and neuropathic pain (NP) are very scanty in neurorehabilitation, but those from other contexts can be adapted and translated to this specific setting. The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) has searched and evaluated existing evidence on animal models for the treatment of pain, definition and diagnostic criteria for nociceptive and NP, screening tools and questionnaires, along with diagnostic, clinical and instrumental techniques to distinguish nociceptive from NP and, more generally, to assess pain in the field of neurorehabilitation. The present ICCPN recommendations provide information on the relevance of current preclinical models, and may be helpful in ameliorating pain diagnosis and assessment, which are prerequisites for better application and tailoring of current pharmacological and non-pharmacological treatments. They may also be useful for future studies aimed at filling the gaps in the current knowledge of these topics.

We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naive 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.

Capecitabine is converted to 5-fluorouracil by thymidine phosphorylase, and mitomycin C is capable of upregulating the expression of thymidine phosphorylase suggesting a synergistic effect. Fifty-three patients (median age 62 years) with anthracycline- and taxane-resistant, metastatic breast cancer received mitomycin C 6 mg/m2 on day 1, and capecitabine (Xeloda) 2,000 mg/m2/day from day 1 to day 14 with cycles repeated every 4 weeks. Overall, 77.4% had visceral metastases and 33 were pretreated with ≧3 chemotherapy lines. A median of 6 cycles were given (range 1–19) with a complete response observed in 2 patients (3.9%), partial response in 17 (33.3%) and stable disease in 19 (37.2%). Overall response rate was 37.2% (95% CI, 24.0–50.5%), with a median duration of 10.4 months. Median time to progression was 8.1 months and median survival was 17.4 months (1- and 2-year survival rates of 60 and 28%, respectively). Toxicity was mild. The most frequent grade 3/4 events were neutropenia (5.7% of patients), diarrhea (3.8%), and deep venous thrombosis (3.8%). Capecitabine plus mitomycin C may represent an effective and manageable treatment option for advanced breast cancer patients resistant to anthracyclines and taxanes. This approach provides an alternative for pretreated patients with advanced breast cancer.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

Objectives: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. Methods: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. Treatment: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1–14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. Results: Most frequent related G3–4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3–4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0–15.7 months), the median response duration 2.8 months (95% confidence interval 1.2–5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7–6.3 months). The 1-year survival rate was 53.8%. Conclusions: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC.

Colorectal cancer represents a major health problem in the western world. A lot of drugs have been employed in treatment of this disease, but only few data are available about predictive factors for response to anticancer treatments in colorectal cancer. Aim of this paper is to review the main data about this investigation field. Using a Medline database search (1966–2003) we reviewed all the relevant papers that investigate clinical and molecular predictors for response to the main drugs used in the treatment of colorectal cancer patients, both in adjuvant and in advanced setting. Moreover we comprehensively reviewed all the data published in abstract form during the most significant international meetings. Our review put in evidence the most important predictive factors for response in colorectal cancer patients treated with anticancer chemotherapy both in adjuvant and in advanced setting. The predictive factors are clustered on the basis of the different anticancer drugs. The results of this review provide the rationale basis for personalizing anticancer treatment in colorectal cancer patients by molecular and clinical features, aiming to improve response rate and reduce toxicities.

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion, invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.

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.

Background: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.

Background The guidelines on trigeminal neuralgia management that have been agreed and jointly published by the American Academy of Neurology and the European Federation of Neurological Societies recommend carbamazepine (CBZ) and oxcarbazepine (OXC) as the first-choice medical treatments in patients with trigeminal neuralgia (TN). The aim of this retrospective study was to analyze the natural history of classical trigeminal neuralgia in a large cohort of patients, focusing on drug responsiveness, side effects related to CBZ and OXC, and changes in pain characteristics during the course of disease. Findings We selected the last 100 consecutive patients with typical TN who began treatment with CBZ and the last 100 with OXC. All had MRI scans and a complete neurophysiological study of trigeminal reflexes. Among them, 22 were excluded on the basis of neuroradiological or neurophysiological investigations, to avoid the inclusion of patients with possible secondary TN. The initial number of responders was 98% with CBZ with a median dose of 600 mg (range 200–1200), and of 94% with OXC, with a median dose of 1200 mg (range 600–1800). In a mean period of 8.6 months, 27% of responders to CBZ incurred in undesired effects to a level that caused interruption of treatment or a dosage reduction to an unsatisfactory level. In a mean period of 13 months, the same occurred to 18% of responders to OXC. Among patients who had a good initial response, only 3 patients with CBZ and 2 with OXC developed late resistance. During the course of disease, paroxysms worsened in intensity in 3% of patients, and paroxysms duration increased in 2%. We did not observe the onset of a clinically manifest sensory deficit at any time in any patient. Conclusions Unlike common notion, in our large patient sample the worsening of pain with time and the development of late resistance only occurred in a very small minority of patients. CBZ and OXC were confirmed to be efficacious in a large majority of patients, but the side effects caused withdrawal from treatment in an important percentage of patients. These results suggest the opportunity to develop a better tolerated drug.

Aims : There is considerable evidence that links COX-2 to the development of cancer. The aim of our study was to assess, by immunohistochemistry, COX-2 expression in ductal carcinoma in situ (DCIS) and its possible correlation with HER-2/neu, vascular endothelial growth factor (VEGF) expression and other common immunohistochemical parameters (p53, ER, PGR, Ki67). Methods and results : Tissue samples of 49 archival cases of DCIS without any invasive component were analysed for COX-2, HER-2/neu, VEGF, oestrogen and progesterone receptors, Ki67 and p53 by immunohistochemistry using specific antibodies. COX-2 expression was detected in 43 (87.8%) tissue samples, of which 12 (24.5%) were graded as weak, 22 (44.9%) as moderate and nine (8.4%) as high expression. Only six (12.2%) lesions were negative for COX-2 expression. VEGF expression was detected in 93.8% of samples; 66.7% of lesions were found to be positive for HER-2/neu expression. Furthermore, COX-2 expression was significantly correlated with VEGF expression (P = 0.003). A significant positive correlation was also observed between COX-2 and HER-2/neu expression (P

Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aβ-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without (P0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection (P0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit (P0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection (P0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain (P0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings (P0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications.

Objective To investigate the cutaneous silent period (CSP), a spinal inhibitory reflex mainly mediated by A-delta fibres, in demyelinating and axonal polyneuropathy (PNP) and evaluate whether CSP parameters differ between patients with and without neuropathic pain. Methods Eighty-four patients with demyelinating PNP, 178 patients with axonal PNP and 265 controls underwent clinical examination, DN4 questionnaire, standard nerve conduction study, motor-root stimulation and CSP recordings from abductor digiti minimi. We calculated the afferent conduction time of CSP (a-CSP time) with the formula: CSP latency − root motor evoked potential latency. Results In the demyelinating PNP group the a-CSP time was significantly longer; in the axonal PNP group, CSP duration was shorter than the demyelinating group ( p = 0.010) and controls ( p = 0.001). CSP parameters were not different between patients with and without neuropathic pain. Conclusions The abnormality of a-CSP time in the demyelinating PNP group suggests the crucial role of A-delta fibres in the mechanism of CSP; the shorter CSP duration in the axonal PNP group supports the strong influence of the number of axons on this parameter. Our study suggests that neuropathic pain could be related to pathophysiological mechanisms differing from mere A-delta fibre loss. Significance CSP evaluation is effective in detecting A-delta fibre dysfunction in axonal as well as demyelinating PNP.

The different neuropathic pain types (eg, ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small-fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.

The periaqueductal gray (PAG), a brain area belonging to the descending pain modulatory system, plays a crucial role in pain perception. Little information is available on the relationship between PAG activation and perceived pain intensity. In this study, we acquired functional magnetic resonance imaging (fMRI) scans from the PAG during the cold pressor test, a model for tonic pain, in 12 healthy volunteers. fMRI data were acquired with a 12-channel head-coil and a 3-Tesla scanner and analyzed with Statistical Parametric Mapping (SPM8) software. During the cold pressor test, fMRI showed significant activation clusters in pain-related brain areas: bilateral middle and superior frontal gyrus, anterior cingulate cortex and thalamus, left insula, right inferior frontal gyrus, left inferior temporal gyrus and in the bilateral PAG (cluster level corrected threshold p

Cardioembolic stroke is generally caused by intracranial artery occlusion. Clots may be identified in the intracranial vessels by means of conventional neuroimaging in the acute phase. High-resolution ultrasonography may show some features suggestive of cardiac emboli when occluding extracranial carotid arteries. We describe a patient with cardioembolic ischemic stroke in the right hemisphere in whom a left internal carotid artery stenosis paradoxically protected the ipsilateral hemisphere from distal intracranial embolism. The patient also presented multiple acute ischemic embolic lesions in the right middle cerebral artery territory and in the right occipital lobe, which was fed by the posterior cerebral artery, anomally originating from the right carotid siphon. Interestingly, the left internal carotid artery--which showed a severe preexisting stenosis--was occluded by the cardiac clot, whereas the right internal carotid artery only presented a moderate stenosis that had probably allowed the clots to pass. Therefore, the severe left internal carotid artery stenosis may have blocked the cardiac embolus, preventing it from reaching the ipsilateral hemisphere.

Laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs) are widely agreed method for investigating the nociceptive system. Concentric electrodes (CE) have also recently been introduced to measure pain-related evoked potentials (PREPs) and, thereby, to assess the nociceptive system in patients. Although some authors have reported that low intensity CE stimulation, evoking pinprick sensation, selectively activates nociceptive fibres, the CE reliability in the assessment of nociceptive system is still unclear. In this study we aimed to verify whether low and high intensity CE stimulations selectively activates nociceptive fibres. To do so we recorded LEPs, CHEPs and PREPs before and after capsaicin-induced skin denervation. To date, we have enrolled 6 healthy subjects. All subjects underwent a baseline recording of LEPs, CHEPs and PREPs after stimulation of the right forearm. For PREP recording we used both low intensity stimulation, evoking a distinct pinprick sensation and high intensity stimulation, evoking an electrical painless sensation. After the baseline evoked potential recordings, we applied an 8% capsaicin plaster on the right forearm. After one-two weeks, we recorded LEPs, CHEPs and PREPs after stimulation of the capsaicin-induced denervated forearm skin. In a small skin area spared by evoked potential stimulations we have also collected a skin biopsy for assessing the skin denervation. While LEPs and CHEPs were suppressed after topical application of capsaicin, low and high intensity PREPs did not differ before and after capsaicin-induced skin denervation. The skin biopsy documented the skin denervation induced by the capsaicin plaster. Our data indicate that both low and high intensity CE stimulation elicit PREPs after skin denervation, thus suggesting that the CE stimulation probably coactivates non-nociceptive fibres.

Patients with joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia. In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain.

Introduction Previous studies found that patients with Alzheimer’s disease (AD) have increased pain threshold and pain tolerance. Nevertheless it is still unclear whether these findings are explained by communication problems, or rather they are associated with degenerative processes affecting pain-related cortex. In this neurophysiological study we aimed at assessing pain-related cortex function, by recording laser evoked potentials (LEPs) after hand stimulation in patients with AD. Methods We enrolled 10 patients with a diagnosis of probable mild-to-moderate AD, recruited from the Alzheimer Evaluation Unit of “Sapienza” University of Rome. In all patients we recorded the SII-generated N1-LEP, and the N2–P2 complex of LEPs, generated in the insula and cingulate cortex. All patients also underwent the recording of Ab-fibre mediated somatosensory evoked potentials (SEP), after median nerve stimulation. LEP and SEP variables were compared with normative reference ranges, matched for age and gender. Results Whereas SEP variables, and the N1-LEP component came within reference values in all patients, the N2–P2 complex of LEP was dampened or absent in 7 patients. Conclusions Our findings suggest that in patients with AD the degenerative processes affect pain-related cortex. This damage predominantly involves the insular cortex and the anterior cingulate cortex.

Cannabinoids proved to be effective in several experimental neuropathic pain models, and there is increasing evidence for their use in human neuropathic pain conditions. In this study we aimed at testing whether dronabinol inhibits nociceptive transmission in humans. To do so we verified whether dronabinol modulates the nociceptive-mediated laser evoked potentials (LEPS). We conducted a double blind randomized controlled trial in fourteen healthy volunteers. All subjects underwent two separate sessions: one with 5 mg of dronabinol and the other with 1.5 mg of bromazepam as control drug. The two sessions were randomly alternated among subjects. In each session LEPs were recorded from 32 scalp electrodes after hand stimulation. Each session consisted of two recording blocks: before oral administration of dronabinol or bromazepam and 60 min after dronabinol or bromazepam. Both the dronabinol and the bromazepam left the LEP latency unchanged. While the dronabinol reduced the N1-, N2-, P2-LEP components ( P