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Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease. IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude. Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / − 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain. Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression.

Pain is a major matter for patients with multiple sclerosis; treatment response is frequently inadequate, with a significant impact on quality of life. The estimated prevalence of pain in multiple sclerosis ranges widely (26-86%), and different subtypes of pain, mediated by specific pathophysiological mechanisms, are described. The aim of this narrative review, performed using a systematic search methodology, was to provide current, evidence-based, knowledge about the pharmacological treatment of the different kinds of pain in multiple sclerosis. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Clinical Trials database (ClinicalTrials.gov), considering publications up to November 2019. Two authors independently selected studies for inclusion, data extraction, and bias assessment. A total of 27 randomized controlled trials were identified, but in only a few cases, patients with different pain qualities were stratified. Following a mechanism-based approach, treatment of paroxysmal pain and painful tonic spasms should be based on sodium-channel blockers, whereas treatment of ongoing extremity pain should be based on gabapentinoids and antidepressants.

Diabetic neuropathy is among the most frequent complications of both type 1 (T1DM) and type 2 diabetes (T2DM) and commonly manifests as a distal symmetrical polyneuropathy (DSPN). Despite evidence that T1DM- and T2DM-related DSPN are separate entities, most of our knowledge on diabetic DSPN derives from studies focused on type 2 diabetes. This systematic review provides an overview of current evidence on DSPN in T1DM, including its epidemiological, pathophysiological and clinical features, along with principal diagnostic tests findings. This review included 182 clinical and preclinical studies. The results indicate that DSPN is a less frequent complication in T1DM compared with T2DM and that distinctive pathophysiological mechanisms underlie T1DM-related DSPN development, with hyperglycemia as a major determinant. T1DM-related DSPN more frequently manifests with non-painful than painful symptoms, with lower neuropathic pain prevalence compared with T2DM-associated DSPN. The overt clinical picture seems characterized by a higher prevalence of large fiber-related clinical signs (e.g., ankle reflexes reduction and vibration hypoesthesia) and to a lesser extent small fiber damage (e.g., thermal or pinprick hypoesthesia). These findings as a whole suggest that large fibers impairment plays a dominant role in the clinical picture of symptomatic T1DM-related DSPN. Nevertheless, small fiber diagnostic testing shows high diagnostic accuracy in detecting early nerve damage and may be an appropriate diagnostic tool for disease monitoring and screening.

Introduction Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) remains a diagnostic challenge due to clinical, neurophysiological, and laboratory findings suggestive of other diagnoses, particularly chronic inflammatory demyelinating polyneuropathy (CIDP). In this cross-sectional prospective study, we aimed to investigate the utility of high-resolution ultrasonography of peripheral nerves as a diagnostic tool to differentiate ATTRv-PN from CIDP. Methods In 11 treatment-naive patients with genetically confirmed late-onset ATTRv-PN and 25 patients with CIDP, we collected clinical, electrodiagnostic, and high-resolution ultrasonography data of the peripheral nerves. In each patient, we used high-resolution ultrasonography to assess 26 nerve sites. Results Of the 11 patients with ATTRv-PN, two had electrodiagnostic study data compatible with a CIDP diagnosis. High-resolution ultrasonography showed that the cross-sectional area of the brachial plexus, median nerve at the axilla, arm, and forearm, ulnar nerve at the forearm, and peroneal nerve at the popliteal fossa were significantly smaller in the 11 ATTRv-PN patients than in CIDP patients. However, in the two patients with electrodiagnostic study data compatible with a CIDP diagnosis, high-resolution nerve ultrasonography data were comparable to those in patients with CIDP. Conclusion Although high-resolution ultrasonography of peripheral nerves provides reliable information in patients with ATTRv-PN, its usefulness as a standalone diagnostic tool to differentiate ATTRv-PN from CIDP might be limited.

In Parkinson's disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients' health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.

Acetyl-L-carnitine (ALC) has shown a neuroprotective effect in patients with peripheral neuropathies of different etiologies. Preclinical studies demonstrated a central anti-nociceptive action, both in neuropathic and nociceptive pain models. The present review aims to provide the knowledge on the efficacy of ALC in patients with painful peripheral neuropathy, based on the evidence. Consistent with the PRISMA statement, authors searched PubMed, Embase and the Cochrane Database of Systematic Reviews for relevant papers, including those issued before April 2018. Two authors independently selected studies for inclusion and data extraction: only trials including patients with a diagnosis of peripheral neuropathy and involving at least 10 patients were considered for the purposes of this review. Fourteen clinical trials were revised, to provide the level of evidence for neuropathy. To assess the global efficacy of ALC in painful peripheral neuropathy, a meta-analysis of four randomized controlled trials was performed. Mean difference in pain reduction as measured on a 10-cm VAS, and 95% CIs were used for pooling continuous data from each trial. Four randomized controlled trials tested ALC in patients with neuropathy secondary to diabetes and to antiretroviral therapy for HIV. Compared to placebo, ALC produced a significant pain reduction equal to 20.2% (95% CI: 8.3%-32.1%, P

ObjectiveTo assess the functional effects of a variant, c.89 G > A (p.Arg30Gln), in the transient receptor potential melastatin 8 (TRPM8) cold-sensing, nonselective cation channel, which we have previously identified in a patient with familial trigeminal neuralgia.MethodsWe carried out Ca2+ imaging and whole-cell patch-clamp recording.ResultsThe TRPM8 mutation enhances channel activation, increases basal current amplitude and intracellular [Ca2+] in cells carrying the mutant channel, and enhances the response to menthol.ConclusionsWe propose that Arg30Gln confers gain-of-function attributes on TRPM8, which contribute to pathogenesis of trigeminal neuralgia in patients carrying this mutation.

BACKGROUND It is widely agreed that carbamazepine and oxcarbazepine are highly effective in the long-term treatment of trigeminal neuralgia. However, the tolerability of these drugs across the different aetiologies of trigeminal neuralgia is still undetermined. METHODS In this retrospective, real-world study, we assessed the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical (254 patients), secondary (60 patients) and idiopathic (40 patients) trigeminal neuralgia. We analysed data using a propensity score analysis to account for selection bias; frequencies of side effects associated with carbamazepine and oxcarbazepine were calculated by adjusting data with the inverse probability of treatment weighting. RESULTS The initial proportion of responders was 88.3% with carbamazepine, and 90.9% with oxcarbazepine. The number of refractory patients was significantly higher in idiopathic (15%) and secondary forms (27%) than in classical trigeminal neuralgia (6%; p

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system. Neuropathic pain represents a broad category of pain conditions, common complications of peripheral neuropathies, which are characterized by a combination of positive symptoms, including paresthesia and/or dysesthesia and sensory deficits in the painful area. In the present paper, we aimed to assess neuropathic pain frequency and clinical characteristics of peripheral neuropathies due to different aetiologies according to grading system criteria of the International Association for the Study of Pain for a definitive diagnosis of neuropathic pain. Epidemiological studies applying these criteria have been conducted in patients with diabetes, brachial plexus injury, and other traumatic nerve injuries. Neuropathic pain was diagnosed in 37–42% of patients with diabetic peripheral neuropathy, 56% of patients with brachial plexus injury, and 22% of patients with intercostobrachial neuropathy. The most frequent neuropathic pain type was ongoing pain (described as burning or pressing), followed by paroxysmal pain (electric shock-like sensations) and allodynia (pain evoked by brushing and pressure). By providing information on the frequency, clinical signs, and variables associated with neuropathic pain due to different aetiologies, these studies contribute to improving the clinical management of this condition.

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.

Objective This cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients. Methods We recorded familial occurrence by systematically interviewing all patients with a definite diagnosis of classical or idiopathic trigeminal neuralgia. We found 12 occurrences of trigeminal neuralgia with positive family history out of 88 enrolled patients. Whole-exome sequencing was carried out in 11 patients. We concentrated on the genetic variants within a 173-gene panel, comprising channel genes encoding sodium, potassium, calcium, chloride, transient receptor potential channels, and gap junction channels. Gene expression profiles were based on published RNA sequencing datasets of rodent/human trigeminal ganglia tissues, with a focus on genes related to neuronal excitability. Results In patients with familial trigeminal neuralgia, pain was more often located in the right, second division. All patients reported triggers. Four patients experienced concomitant continuous pain. Whole-exome sequencing analysis within the trigeminal ganglion electrogenisome identified 41 rare variants in ion channels, consisting of variants in sodium channels (6), potassium channels (10), chloride channels (5), calcium channels (7), transient receptor potential channels (12), and gap junction channels (1). In one patient, a previously profiled gain-of-function mutation in SCN10A (Nav1.8 p.Ala1304Thr), previously reported in painful neuropathy, was found; this variant was not present in unaffected siblings. Conclusions Our results suggest that familial occurrence of trigeminal neuralgia is more common than previously considered. Although our results demonstrate variants in genes encoding voltage-gated ion channels and transient receptor potential channels within these patients, further study will be needed to determine their roles in the pathogenesis of trigeminal neuralgia.

Introduction Trigeminal neuralgia is an exemplary neuropathic pain condition characterized by paroxysmal electric-shock-like pain. However, up to 50% of patients also experiences concomitant continuous pain. In this neuroimaging study, we aimed to identify the specific anatomical features of trigeminal nerve root in patients with concomitant continuous pain. Methods We enrolled 73 patients with a definitive diagnosis of classical and idiopathic trigeminal neuralgia and 40 healthy participants. The diagnosis of trigeminal neuralgia was independently confirmed by two clinicians. Patients were grouped as patients with purely paroxysmal pain (45 patients) and patients also with concomitant continuous pain (28 patients). All participants underwent a structured clinical examination and a 3T MRI with sequences dedicated to the anatomical study of the trigeminal nerve root, including volumetric study. Images analysis was independently performed by two investigators, blinded to any clinical data. Results In most patients with concomitant continuous pain, this type of pain, described as burning, throbbing or aching, manifested at the disease onset. Demographic and clinical variables did not differ between the two groups of patients; the frequency of neurovascular compression and nerve dislocation were similar. Conversely, trigeminal nerve root atrophy was more severe in patients with concomitant continuous pain than in those with purely paroxysmal pain ( p = 0.006). Conclusions Our clinical and neuroimaging study found that in patients with trigeminal neuralgia, concomitant continuous pain was associated with trigeminal nerve root atrophy, therefore suggesting that this type of pain is likely related to axonal loss and abnormal activity in denervated trigeminal second-order neurons.

We aimed to investigate whether small-fibre pathology, a common skin biopsy finding in patients with fibromyalgia, implies clinically important abnormalities of somatosensory system function and verify whether it is associated with voltage-gated sodium channel variants. In 57 consecutively enrolled patients with fibromyalgia, we used skin biopsy to distinguish patients with and without small-fibre pathology. In all patients, we assessed somatosensory system function using quantitative sensory testing (QST) and laser-evoked potentials and investigated voltage-gated sodium channel genotyping. We then compared these variables in patients with and without small-fibre pathology. We found that clinical measures, QST, and laser-evoked potential variables did not differ between patients with and without small-fibre pathology. In most patients with small-fibre pathology, QST and laser-evoked potential variables fell within normative ranges commonly used in clinical practice. Of the 57 patients, one patient without small-fibre pathology and 2 patients with small-fibre pathology had rare variants of voltage-gated sodium channels, namely SCN11A, SCN9A, and SCN1A variants. The SCN9A variant, found in a patient with small-fibre pathology, was an already profiled gain-of-function mutation, previously reported in small-fibre neuropathy. Our findings suggest that small-fibre pathology has a negligible impact on somatosensory system function in fibromyalgia. The genetic analysis suggests that patients with rare small-fibre neuropathy due to voltage-gated sodium channel variants may be misdiagnosed as patients with fibromyalgia.

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. Electronic supplementary material The online version of this article (10.1007/s40265-018-0964-9) contains supplementary material, which is available to authorized users.

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 Trigeminal neuralgia is one of the most characteristic and difficult to treat neuropathic pain conditions in patients with multiple sclerosis. The present narrative review addresses the current evidence on diagnostic tests and treatment of trigeminal neuralgia secondary to multiple sclerosis. Methods We searched for relevant papers within PubMed, EMBASE and the Cochrane Database of Systematic Reviews, taking into account publications up to December 2018. Results Trigeminal neuralgia secondary to multiple sclerosis manifests with facial paroxysmal pain triggered by typical manoeuvres; neurophysiological investigations and MRI support the diagnosis, providing the definite evidence of trigeminal pathway damage. A dedicated MRI is required to identify pontine demyelinating plaques. In many patients with multiple sclerosis, neuroimaging and surgical evidence suggests that neurovascular compression might act in concert with the pontine plaque through a double-crush mechanism. Although no placebo-controlled trials have been conducted in these patients, according to expert opinion the first-line therapy for trigeminal neuralgia secondary to multiple sclerosis relies on sodium-channel blockers, i.e. carbamazepine and oxcarbazepine. The sedative and motor side effects of these drugs frequently warrant an early consideration for neurosurgery. Surgical procedures include Gasserian ganglion percutaneous techniques, gamma knife radiosurgery and microvascular decompression in the posterior fossa. Conclusions The relatively poor tolerability of the centrally-acting drugs carbamazepine and oxcarbazepine highlights the need to develop new selective and better-tolerated sodium-channel blockers. Prospective studies based on more advanced neuroimaging techniques should focus on how trigeminal anatomical abnormalities may be able to predict the efficacy of microvascular decompression.

Objectives Overlapping neural system dysfunctions, mainly involving the secondary somatosensory cortex (S2), the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC), seem to be related to both pain-perception abnormalities and psychotic symptoms in schizophrenia (SCZ) and bipolar disorder (BD). Laser-evoked potentials (LEPs) were used to investigate pain-perception and central pain-processing abnormalities in SCZ, bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and to evaluate their relationship with history of psychosis, and social-cognitive and functional impairments. Methods Twenty patients with SCZ, 17 patients with BD-I, and 21 patients with BD-II who were all under similar pharmacological treatment underwent clinical, functional, and neuro-psychological assessment. LEPs were analyzed in patients and 19 healthy subjects (HS). LEPs elicit responses reflecting the activity of the S2 (N1 wave) and the ACC/AIC cortices (N2/P2 complex). A four-group ANOVA was conducted between patients and HS to compare pain-perceptive thresholds (PThs), N1, and N2/P2-LEP components. Results Compared to HS: (i) patients with SCZ showed pain-processing and pain-perception abnormalities, as revealed by significantly higher PTh (P

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.

Although several reports have indicated that trigeminal neuralgia related to multiple sclerosis may occur bilaterally in the orofacial region, trigeminal neuralgia pain usually involves the two sides in different time lapses, and the simultaneous involvement of trigeminal territories on both sides is commonly considered incompatible with its diagnosis. This case report describes a patient with bilateral trigeminal neuralgia related to multiple sclerosis that started simultaneously on both sides of the orofacial region. A 55-year-old man presented with a 16-year history of relapsing/remitting multiple sclerosis. For 1 year, the patient had been complaining of electric shock-like, paroxysmal pain of severe intensity that lasted from a fraction of a second to a few minutes and involved the first and second trigeminal divisions of both sides simultaneously. The neurophysiologic testing of trigeminal reflexes showed bilateral delayed latencies of reflex responses compatible with a trigeminal afferent pathway impairment related to multiple sclerosis. A dedicated 3T magnetic resonance imaging scan revealed pontine demyelinating plaque and a bilateral neurovascular conflict at the trigeminal root entry zone. The finding of an unusual case of simultaneous bilateral trigeminal neuralgia due to multiple sclerosis should prompt neurologists to consider a diagnosis of trigeminal neuralgia in patients with multiple sclerosis in cases of simultaneous involvement of trigeminal territories on both sides.

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: Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. Materials and methods: After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. Results: We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. Conclusions: Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication.

L-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action.Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy.In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve.The primary endpoint was met, with significant improvement of the SCV (P 0.0001). All sensory neurophysiological measures also significantly improved. BCTQ score changed significantly (P 0.0001), with a greater improvement in the symptom component. Nine of the NPSI types of pain, particularly squeezing and pressure pain and pain evoked by pressure, showed a significant reduction (P 0.0001).Our clinical and neurophysiological study indicated that 4 months of treatment with LAC exerted a neuroprotective effect. LAC reduced pain in patients with mild and moderate CTS, a result that is possibly due to both its neuroprotective action and its central anti-nociceptive properties. Clinical Trials Registration code: EudraCT 2014-002289-62.

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.

Objective Prevalence and clinical characteristics of neuropathic pain due to traumatic brachial plexus injury. Design Observational epidemiological study. Setting Hospital-based multicenter study. Subjects One hundred seven prospectively enrolled patients with brachial plexus injury. Methods All the patients underwent clinical examination and neurophysiological testing for a definitive diagnosis of the brachial plexus lesion. The DN4 questionnaire was used to identify neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to evaluate the different symptoms of neuropathic pain. The SF36 questionnaire and the Beck Depression Inventory (BDI) were used to assess quality of life and mood disturbances in patients with neuropathic pain. Results Of the 107 enrolled patients, 74 had pain (69%); neuropathic pain, as assessed by means of the DN4, was identified in 60 (56%) of these patients. According to the NPSI, the most frequent and severe pain type was the spontaneous burning pain. Clinical and neurophysiological findings showed that pain is unrelated to age but is associated with the severity of peripheral nerve damage. The SF36 questionnaire and BDI showed that neuropathic pain impairs quality of life and causes depression. Conclusions Our study provides information on the prevalence, characteristics, and variables associated with neuropathic pain due to traumatic brachial plexus injuries that might provide a basis for improving the clinical management of this condition.

Introduction Although it is widely accepted that facial pain paroxysms triggered by innocuous stimuli constitute a hallmark sign of trigeminal neuralgia, very few studies to date have systematically investigated the role of the triggers involved. In the recently published diagnostic classification, triggered pain is an essential criterion for the diagnosis of trigeminal neuralgia but no study to date has been designed to address this issue directly. In this study, we set out to determine, in patients with trigeminal neuralgia, how frequently triggers are present, which manoeuvres activate them and where cutaneous and mucosal trigger zones are located. Methods Clinical characteristics focusing on trigger factors were collected from 140 patients with trigeminal neuralgia, in a cross-sectional study design. Results Provocation of paroxysmal pain by various trigger manoeuvres was reported by 136 of the 140 patients. The most frequent manoeuvres were gentle touching of the face (79%) and talking (54%). Trigger zones were predominantly reported in the perioral and nasal region. Conclusion This study confirms that in trigeminal neuralgia, paroxysmal pain is associated with triggers in virtually all patients and supports the use of triggers as an essential diagnostic feature of trigeminal neuralgia.

Background Although secondary trigeminal neuralgia is usually due to tumors or multiple sclerosis, other major neurologic diseases, such as aneurysms, should be taken into account when the history or the symptoms suggest a secondary origin. Case Description A 67-year-old lady presented with a 6-month history of trigeminal neuralgia involving exclusively the right ophthalmic division. A dedicated 3-dimensional–magnetic resonance imaging–magnetic resonance angiography study documented rare contact with a wide-necked aneurysm of the superior cerebellar artery, which distorted the trigeminal root. The patient underwent an endovascular treatment by stent-assisted coiling with the complete disappearance of neuralgic pain attacks within 24 hours. Conclusion The complete relief from the neuralgic paroxysms immediately after endovascular stent-assisted occlusion of a superior cerebellar artery aneurysm demonstrates the crucial role of a pulsating stimulus on the demyelinated nerve fibers in evoking the ectopically generated discharges.

Background and Aim l-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action. Objective Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy. Methods In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120 days after treatment with LAC 500 mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve. Results The primary endpoint was met, with significant improvement of the SCV (P

We aimed at verifying whether widespread pain due to Ehlers Danlos syndrome, hypermobile type (hEDS) is associated with deficit of the endogenous pain-inhibitory control. In 22 patients with pain due to hEDS and in 22 healthy participants, matched for age and sex, we investigated function of the endogenous pain-inhibitory control using the Conditioned Pain Modulation(CPM) protocol.CPM protocol consisted of two heat painful stimuli, i.e. a test stimulus and a conditioning stimulus; no change or an increase in the test stimulus rating during conditioning stimulation is compatible with a deficit in the descending inhibitory pain control. In healthy participants the CPM protocol showed that the test stimulus rating was significantly reduced during conditioning (P

Background Migraine is a neurovascular disorder in which altered functional connectivity between pain-modulating circuits and the limbic system may play a role. Cortical spreading depression (CSD), which underlies migraine aura (MWA), induces C-fos expression in the amygdala. The role of CSD and amygdala connectivity in migraine without aura (MwoA) is less clear and may differentiate migraine from other chronic pain disorders. Methods Using resting-state functional MRI, we compared functional connectivity between the amygdala and the cortex in MWA and MWoA patients as well as in healthy subjects and in two other chronic pain conditions not associated with CSD: trigeminal neuralgia (TGN) and carpal tunnel syndrome (CTS). Results Amygdala connectivity in both MWA and MWoA was increased to the visceroceptive insula relative to all other groups examined. Conclusion The observed increased connectivity within the limbic/viscerosensory network, present only in migraineurs, adds to the evidence of a neurolimbic pain network dysfunction and may reflect repetitive episodes of CSD leading to the development of migraine pain.

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.

TN is a relatively rare condition defined as “a sudden unilateral severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve” IASP [1].

Background Depression occurs in about 50% of patients with multiple sclerosis. The aims of this study was to investigate the prevalence of depressive symptoms in a multicenter MS population using the Beck Depression Inventory II (BDI II) and to identify possible correlations between the BDI II score and demographic and clinical variables. Methods Data were collected in a multi-center, cross-sectional study over a period of six months in six MS centers in Italy using BDI II. Results 1,011 MS patients participated in the study. 676 subjects were female, with a mean age of 34 years (SD 10.8), mean EDSS of 3.3 (0–8.5) and mean disease duration of 10.3 years (range 1–50 years). 668 (%) subjects scored lower than 14 on the BDI II and 343 (33.9%) scored greater than 14 (14 cut-off score). For patients with BDI>14 multivariate analysis showed a significant difference between EDSS and disease course. BDI II scores for subjects with secondary progressive (SP) MS were significantly different from primary progressive (PP) patients (p < 0.001) but similar to relapsing-remitting (RR) patients. Considering subjects with moderate to severe depressive symptoms (BDI II score from 20–63), in relation to disease course, 11.7% (83/710) had RR MS, 40.7% (96/236) SP and 13.6% (6/44) PP. Conclusions Using the BDI II, 30% of the current sample had depressive symptoms. BDI II score correlates with disability and disease course, particularly in subjects with SP MS. The BDI II scale can be a useful tool in clinical practice to screen depressive symptoms in people with MS.

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.

In this review we summarize progress in research on Parkinson's disease-related pain as reported in articles published in the Journal of Neurology in the years 2011 and 2012.

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.

Trigeminal Neuralgia (TN) is a clinical condition characterized by a sudden, usually unilateral, brief, stabbing, recurrent pain with a distribution consistent with one or more divisions of the fifth cranial nerve. In the classical form, the genesis of paroxysmal pain has been attributed to areas of focal demyelination due to vascular compression on the nerve. The 20–50% of patients with TN have an atypical form characterized by the presence of constant pain, often described as burning continuous or sub-continuous, as well as paroxysmal pain. We hypothesize an axonal damage underlying the constant pain component. We enrolled 55 patients with typical (n = 36) and atypical (n = 19) TN according to the criteria of the 3rd edition of the International Classification of Headache Disorders (ICHD-3). Each patient underwent magnetic resonance imaging (MRI), laser evoked potentials (LEPs) and trigeminal reflexes. The comparison between the duration of disease between the two groups showed no significant differences. We found a greater asymmetry of amplitude (healthy side vs affected side) of N2-P2 component from thermal stimulation in the group with atypical TN (p The atypical form has an axonal damage and is not a time-bound phenomenon. The involvement of C-fibers could be the mechanism behind continuous pain.

In this study we investigate whether the cutaneous silent period (CSP)-an inhibitory response evoked in hand muscles by painful digital nerve stimulation-is useful for assessing nociceptive pathway function in patients with neuropathic pain. In 40 patients with peripheral neuropathy (21 without and 19 with neuropathic pain) we recorded the CSP in the abductor digiti minimi after fifth digit stimulation and also recorded laser evoked potentials (LEPs) after stimulation applied to the ulnar territory of the hand. Although the LEP amplitude was significantly lower in patients with pain than in those without (P 0.50). Pain intensity correlated significantly with LEP amplitudes (P 0.5). Our findings indicate that the CSP is not useful for assessing nociceptive pathway function in patients with neuropathic pain.

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.

Objective: In this clinical and neuroimaging study, we sought information on the possible role of neurovascular compression in multiple sclerosis (MS)–related trigeminal neuralgia (TN). Methods: After screening 1,628 consecutive patients with MS, we enrolled 28 patients with definite unilateral MS-related TN. In these patients, we acquired dedicated 3T MRI scans, identified pontine demyelinating plaques, and, using highly specific diagnostic criteria, distinguished possible neurovascular compression. Results: MRI scans in most patients showed a demyelinating plaque in the pontine trigeminal root entry zone on the affected side. The frequency of the neurovascular compression and its association with the pontine demyelinating plaque were higher on the affected than on the unaffected side (54% vs 0%; p = 0.0001). Conclusions: Our observation that in many patients with MS-related TN a pontine demyelinating plaque and neurovascular compression coexist should prompt neurologists to seek possible neurovascular compression in patients with MS-related TN.

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.

This review deals with the diagnostic usefulness of neurophysiological testing in patients with craniofacial pain. Neurophysiological testing of trigeminal nerve function relies on trigeminal reflexes and laser-evoked potentials (LEPs). This review briefly describes the physiology of trigeminal reflexes and LEPs, reports normal values and highlights the neurophysiological abnormalities in the main clinical conditions.

Aims of the study. - Nerve conduction studies have demonstrated that carbamazepine (CBZ), as well as other antiepileptic drugs (AEDs), can affect peripheral nerve conduction; reports on conventional somatosensory evoked potentials and CBZ are controversial. In a previous study, assessing laser-evoked potentials (LEPs) in CBZ-treated patients with idiopathic trigeminal neuralgia, we found that LEPs were dampened even after stimutation of the non-painful side, with a strong correlation between LEP latency and daily CBZ dose. No other study investigated the influence of AEDs on LEPs. In order to clarify the effect of CBZ on LEPs we sought possible LEP changes in epileptic patients taking CBZ.Materials and methods. - We studied LEPs after trigeminal and hand CO2-laser stimutation in 20 patients with epilepsy taking CBZ and 20 age-matched controls.Results. - Although the trigeminal LEP mean latency was slightly longer in epileptic patients (P = 0.11), we did not find significant differences between epileptic patients and controls for any LEP data. LEP data did not correlate with the daily CBZ dose, CBZ blood concentration, or duration of therapy (P > 0.3).Conclusion. - The tack of a CBZ-induced dampening of LEPs suggests that small-fibre pathways, compared to large-fibre, might be less susceptible to AED's toxic effect. Although the TN patients in our previous study were older than the epileptic patients in the present study, a possible combined effect induced by drug and age in patients with TN is unlikely because LEP latency is reportedly unaffected by age. The CBZ-induced effect in patients with trigeminal neuralgia is possibly related to pathophysiological changes specific to this disease. (c) 2005 Elsevier SAS. All rights reserved.

Sensory neuropathy usually impairs tactile sensations related to large myelinated afferents (Abeta) as well as thermal-pain sense related to small myelinated (Adelta) and unmyelinated (C) afferents. By selectively affecting large or small fibres, some sensory neuropathies may also provoke a dissociated sensory loss. Standard nerve conduction studies and somatosensory evoked potentials assess Abeta-fibre function only. Laser pulses selectively excite free nerve endings in the superficial skin layers and evoke Adelta-related brain potentials (LEPs). From earlier studies and new cases we collected data on 270 patients with sensory neuropathy. LEPs often disclosed subclinical dysfunction of Adelta fibres and proved a sensitive and reliable diagnostic tool for assessing small-fibre function in sensory neuropathy.

Editors' Note: In WriteClick this week, Dr. Tenser, referencing “A dual concurrent mechanism explains trigeminal neuralgia in patients with multiple sclerosis,” argues that vascular compression has been overemphasized as an etiology in trigeminal neuralgia (TN) and hypothesizes a CNS etiology. Authors Truini and Cruccu disagree with his reasoning and reemphasize the importance of root entry zone demyelination in pathogenesis. In reference to “Neurologic signs and symptoms frequently manifest in acute HIV infection,” Drs. Kamtchum-Tatuene et al. and authors Hellmuth et al. agree that neurologic symptoms in acute HIV infection are typically mild and possibly underestimated. Both groups stress the importance of timely HIV diagnosis and rapid initiation …

The habituation to sensory stimuli of different modalities is reduced in migraine patients. However, the habituation to pain has never been evaluated. Our aim was to assess the nociceptive pathway function and the habituation to experimental pain in patients with migraine. Scalp potentials were evoked by CO(2) laser stimulation (laser evoked potentials, LEPs) of the hand and facial skin in 24 patients with migraine without aura (MO), 19 patients with chronic tension-type headache (CTTH), and 28 control subjects (CS). The habituation was studied by measuring the changes of LEP amplitudes across three consecutive repetitions of 30 trials each (the repetitions lasted 5 min and were separated by 5-min intervals). The slope of the regression line between LEP amplitude and number of repetitions was taken as an index of habituation. The LEPs consisted of middle-latency, low-amplitude responses (N1, contralateral temporal region, and P1, frontal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). The latency and amplitude of these responses were similar in both patients and controls. While CS and CTTH patients showed a significant habituation of the N2/P2 response, in MO patients this LEP component did not develop any habituation at all after face stimulation and showed a significantly lower habituation than in CS after hand stimulation. The habituation index of the vertex N2/P2 complex exceeded the normal limits in 13 out of the 24 MO patients and in none of the 19 CTTH patients (P

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.

Although classical trigeminal neuralgia (CTN) is frequently caused by neurovascular contact (NVC) at the trigeminal root entry zone (REZ), both anatomical and MRI studies have shown that NVC of the trigeminal nerve frequently occurs in individuals without CTN. To assess the accuracy of MRI in distinguishing symptomatic from asymptomatic trigeminal NVC, we submitted to high-definition MRI the series of CTN patients referred to our outpatient service between June 2011 and January 2013 (n=24), and a similar number of age-matched healthy controls. Two neuroradiologists, blinded to the clinical data, evaluated whether the trigeminal nerve displayed NVC in the REZ or non-REZ, whether it was dislocated by the vessel or displayed atrophy at the contact site, and whether the offending vessel was an artery or a vein. Our data were meta-analyzed with those of all similar studies published from January 1970 to June 2013. In our sample, REZ contact, nerve dislocation and nerve atrophy were independently associated with CTN (P=.027; P=.005; P=.035 respectively). Compared to a rather low sensitivity of each of these items (alone or in combination), their specificity was high. When REZ contact and nerve atrophy coexisted, both specificity and positive predictive value rose to 100%. Meta-analysis showed that REZ NVC was detected in 76% of symptomatic and 17% of asymptomatic nerves (P

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.

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.