Migraine is a common comorbidity with fibromyalgia (FM). CGRP is a potent inflammatory neuropeptide that may play a role in somatic and visceral pain either inflammatory or neuropathic. Previous studies have reported a significant number of migraine patients with FM responding to anti-CGRP therapies. The potential impact on diffuse pain and global disability associated with fibromyalgia is still unclear. In this retrospective, observational, cross-sectional study, we aimed to analyze the effects of a monoclonal antibody therapy in a subpopulation of migraineurs with FM compared to patients without this comorbidity by assessing the headache frequency and disability as well as the severity of FM (assessed by the Fibromyalgia Impact Questionnaire (FIQ). Among 1088 patients came for the first visit to our headache Center between January 1, 2021, and December 31, 2022, we examined six-month outcomes of 148 migraine patients prescribed various monoclonal antibodies to CGRP, erenumab, galcanezumab, and fremanezumab. One hundred and twenty-two patients were selected, 26 of whom suffered from FM. We retrospectively evaluated the following characteristics at baseline (T0) and after 6 months (T1),headache frequency and severity, number of days with symptomatic medication, and MIDAS score. In the FM patients, we evaluated the FIQ and the intensity of somatic pain using a numerical rating scale from 0 to 10. Headache characteristics improved similarly in patients with and without FM comorbidity. The number of patients in whom headache frequency decreased by at least 50

BACKGROUND:Plasma neurofilament light chain (NFL) has been measured as a biomarker of neuronal damage in various neurological disorders. Elevated tau and β-amyloid levels have been found in patients with fibromyalgia (FM). The aim of the present study was to compare plasma neurofilament levels in fibromyalgia patients with normal controls and to investigate the correlation with clinical features and cognitive tests. METHODS:Plasma NFL levels were assessed in 33 FM patients and compared with 22 age-matched controls. All patients were also assessed with clinical scales examining fibromyalgia disability, sleep quality and duration, fatigue, anxiety, and depression, and a neuropsychological battery examining executive function, verbal short-term memory, and working memory, as well as attentional executive function and selective attention, interference sensitivity, and inhibition of automatic responses. RESULTS:NFL levels were higher in FM patients (controls 6.19± 1.92; FM 17.28± 15.94 pg/mL ANOVA p 0.002). Working memory was the most impaired cognitive function significantly correlated with high NFL scores (Pearson p 0.034). Short sleep times also correlated with higher NFL scores (Pearson p 0.02) and poorer working memory performance (Pearson p 0.02). No correlation was found with indices of disease severity and duration. CONCLUSIONS:Plasma NFL levels are elevated in fibromyalgia patients, suggesting neuronal damage and correlating with a slight decrease in working memory and short sleep duration. SIGNIFICANCE STATEMENT:Plasma neurofilament levels are elevated in patients with fibromyalgia, regardless of disease severity and duration. Neurofilament levels are higher in patients with mild working memory impairment and sleep disorders. Subgroups of patients with primary neuronal damage phenomena could be individualized for prospective evaluation with regard to the possible development of cognitive decline and sleep disturbances, which would justify a tailored therapeutic approach.

OBJECTIVES:Small fibre pathology is frequently described in fibromyalgia (FM), but its evolution and its role in clinical outcome of the disease are unclear. This longitudinal observational real-life study aimed to monitor the evolution of skin nerve fibre density in FM, in view of the clinical data. METHODS:Sixty-two FM patients were controlled by means of skin biopsy and clinical assessment after 18 months of follow-up. RESULTS:At T0 intraepidermal nerve fibre density (IENFD) was normal in 10 patients, reduced at thigh-proximal-site in 46 cases and decreased at proximal and foot-distal-site in 6 patients. At follow up-T1-the IENFD was unchanged, while Brief Pain Inventory-BPI-pain sub score, DN4 and fatigue were improved. Reduced IENFD at proximal and distal sites, together with fatigue and BPI-motor and work sub scores were predictors of more severe disability measured with Fibromyalgia Impact Questionnaire (FIQ) at T1. Reduced IENFD influenced a minor effect of drugs-antiepileptics and/or antidepressants, and physical exercise on fatigue. CONCLUSIONS:Small fibre impairment seems stable in medium term in FM. A possible influence of small fibre dysfunction on motor performance could have a role in FM evolution. The beneficial effect of physical exercise could be limited in patients with reduced IENFD.

Objective: To evaluate multichannel laser evoked potentials (LEPs) in patients with fibromyalgia (FM) and small fiber impairment. Methods: We recorded LEPs using 65 electrodes in 22 patients with FM and proximal denervation, 18 with normal skin biopsy, and 7 with proximal and distal intraepidermal nerve fiber density (IENFD) reduction. We considered the amplitude and topographical distribution of N1, N2 and P2 components, and habituation of N2 and P2 waves. The sLORETA dipolar analysis was also applied. We evaluated 15 healthy subjects as controls. Results: We observed reduced amplitude of the P2 component in FM group, without a topographic correspondence with the prevalent site of denervation. Decreased habituation of P2 prevailed in patients with reduced IENFD. The cingulate cortex and prefrontal cortex, were activated in the FM group, without correlation between the degree of denervation and the strength of late wave dipoles. A correlation was noted between anxiety, depression, fibromyalgia invalidity, and pain diffusion. Conclusions: The amplitude and topography of LEPs were not coherent with epidermal nerve fiber density loss. They supposedly reflected the clinical expression of pain and psychopathological factors. Significance: Multichannel LEPs are not the expression of small fiber impairment in FM. Rather, they reflect the complexity of the disease. (C) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Background Erenumab is a monoclonal antibody against calcitonin gene-related peptide receptors, which showed efficacy in migraine attack prevention. The aims of the present pilot study were to i) evaluate the effect of single dose of Erenumab 70 mg on laser evoked potentials from trigeminal and brachial stimulation in a cohort of migraine patients; ii) correlate the neurophysiological changes with clinical outcome after 3 months’ treatment. Methods Laser evoked potentials were recorded by 61 electroencephalogram channels before (T0), 1 h (T1) and 7 days after (T2) Erenumab 70 mg injection, stimulating the left and right forehead and the right hand. Laser evoked potential control 1 h after the injection served as placebo session. Results Seventeen migraine patients were evaluated. The N1 and N2 component obtained from the right and left trigeminal stimulation diminished in amplitude at T2, compared to T0 and T1 conditions. N2 habituation reduction slightly recovered at T2. Laser evoked potential changes did not correlate with clinical improvement after 3 months of Erenumab treatment. Conclusions A single dose of Erenumab has a mild inhibitory effect on cortical responses evoked from trigeminal cutaneous a-delta fibers. Though this phenomenon was not predictive of the clinical outcome, it confirms a wide representation of calcitonin gene-related peptide receptors on trigeminal afferents.

Research on Fibromyalgia (FM) is currently based on interesting pathogenetic hypothesis based on the involvement of the central and peripheral nervous system. Recent studies have shown an altered central processing of nociceptive inputs as well as a small fibers neuropathy (SFN) in a large number of fibromyalgic patients. Objectives: 1) to evaluate Laser Evoked Potentials (LEPs) in FM patients, taking into consideration skin innervation and comparison with control group 2) to identify cortical sources of LEPs in consideration of skin biopsy results.

Abstract Background Although the criteria for acute migraine treatment and prevention have been well described, there are still unmet needs, general underuse and low benefits of preventive drugs. The aim of the present study was to retrospectively observe the short-term effect of preventive treatment in a cohort of migraine patients attending a tertiary headache center, using data from electronic medical records. Methods This was an observational retrospective cohort study based on data collected in a tertiary headache center. Data were extracted from an electronic dataset collected from January 2009 to December 2019. The main selection criteria were as follows: age of 18–75 years; diagnosis of migraine without aura (MO), migraine with aura (MA) or chronic migraine (CM); a control visit 3 months after the first access; and prescription of preventive treatment with level of evidence 1 as reported by Italian guidelines. As the primary outcome, we considered the change in the frequency of headache at the follow-up visit. Then, as secondary outcome measures, we used disability scores, intensity of headache, and allodynia. As predictive factors, we considered age, migraine duration, sex, headache frequency, allodynia, anxiety and depression at baseline, and comorbidity with fibromyalgia. Results Among the 6430 patients screened, 2800 met the selection criteria, 1800 returned to the follow-up visit, 550 withdrew because of adverse events, and 1100 were included the analysis. One hundred thirty-four patients had a frequency reduction of 50% or more. Flunarizine was used for less severe migraine, with a better effect compared to those of other drugs (odds ratio: 1.48; p: 0.022). Low headache frequency and absent or mild allodynia predicted a better outcome. Conclusions The mild effect of preventive drugs on migraine features and even the number of patients who were lost to follow-up or dropped out because of adverse events confirm that in severe and chronic patients, the first line of prevention can only delay a more focused therapeutic approach.

BACKGROUND:Fibromyalgia (FM) is a syndrome characterized by altered pain processing at central and peripheral level, whose pathophysiologic mechanisms remain obscure. We aimed at exploring the structural changes of peripheral nociceptor measured by skin biopsy, the functional changes of central nociceptive pathway assessed by laser-evoked potentials (LEP), and their correlation with clinical features and comorbidities.METHODS:In all, 81 patients diagnosed with FM underwent skin biopsies with quantification of intraepidermal nerve fibre density (IENFD) at the thigh and distal leg, and LEP recording by stimulating hand, thigh and foot. Nerve conduction study (NCS), clinical features, comorbidity with migraine and mood disorders, and previous, non-active immune-mediated disorders were recorded.RESULTS:Intraepidermal nerve fibre density was reduced in 85% of patients at the thigh and in 12.3% of patients at the distal leg, whereas it was normal in 14.8% of patients. N2P2 habituation index from laser stimulation at the thigh was altered in 97.5% of patients and correlated with reduced IENFD at the thigh. LEP latencies and amplitudes did not differ among groups. No association was found between IENFD, LEP, clinical features and comorbidities.CONCLUSIONS:Fibromyalgia patients most commonly showed a mild loss of peripheral nociceptors at the thigh rather than distal small fibre neuropathy. This finding was associated with an altered habituation index and strengthened the hypothesis that central sensitization plays a key role in the pathogenesis of the disease.SIGNIFICANCE:Central impairment of pain processing likely underlies FM, which in most patients is associated with mild proximal small fibre pathology.

Motor cortex activation seems to induce an analgesic effect on pain that would be different between patients with fibromyalgia (FM) and control subjects. This study was conducted to analyze the changes of the laser-evoked potentials (LEPs) induced during a finger tapping task in the FM patients and the controls employing a multi-dipolar analysis according to Standardized low resolution brain electromagnetic tomography (sLORETA) method. The LEPs from 38 FM patients and 21 controls were analyzed. The LEPs were recorded while subjects performed a slow and a fast finger tapping task. We confirmed that the difference between N1, N2 and P2 wave amplitudes between conditions and groups was not significant. In control subjects, the fast finger tapping task induced a modification of cortical source activation in the main areas processing laser stimulation from the moving hand independently from the movement speed. In summary, a simple and repetitive movement is not able to induce consistent inhibition of experimental pain evoked by the moving and the not moving hand in each group. It could interfere with LEP sources within the limbic area at least in control subjects, without inhibit cortical responses or explain the different pattern of motor and pain interaction in FM patients.

Objectives.In episodic migraine patients between attacks we previously found reduced lateral inhibition and habituation, but normal sensitization, mechanisms within the somatosensory cortex.During the attacks, after an initial transient sensitization, both delayed habituation and lateral inhibition normalized [1].Here, we have studied lateral inhibition and habituation/sensitization in the somatosensory cortex of patients evolved from episodic to chronic migraine (CM), and we searched for possible correlations with clinical features.Methods.Sixteen patients with CM without medication overuse, and 17 healthy volunteers (HV) underwent SSEPs elicited by electrical stimulation of the right median (M) and ulnar (U) nerve at the wrist separately and simultaneously (MU).We measured parietal N20-P25 amplitudes and we calculated the percentage of lateral inhibition by using the formula 100-(MU/(M+U)*100).Sensitization and habituation were calculated on the median nerve responses as the 1st N20-P25 amplitude block and as the slope of the linear regression between the 1st and the 2nd block of 100 averaged sweeps respectively.Results.In CM patients, percentage of somatosensory lateral inhibition was comparable to that of HV.Patients had a generalized increase of SSEP amplitudes than HV and habituated normally.Percentage of lateral inhibition negatively correlated with monthly days with headache, and positively with severity of headache attacks.Conclusions.In CM patients, we show a pattern of somatosensory response similar to that found in episodic migraine patients during a migraine attack.Moreover, in the transformation process between episodic and chronic migraine, lateral inhibition may contribute to clinical characteristics of CM.

Background: Migraine is the most common cause of primary headache in children leading to a decrease in the quality of life. During the last decade, pain catastrophizing construct became a major focus of interest in the study and treatment of pain. Aim of the study: To evaluate pain catastrophizing in episodic and chronic migraine children and adolescents selected in a tertiary headache Center. To test whether the children's pain catastrophizing might be associated (a) with the frequency of attacks and disability (b) with psychopathological aspects (c) with allodynia and total tenderness score as symptom of central sensitization. To test the best discriminating clinical variables and scores between episodic and chronic migraine, including pain catastrophizing. Methods: We conducted a cross sectional observational study on consecutive pediatric patients affected by migraine. We selected 190 headache patients who met the diagnostic criteria for Migraine without aura, Migraine with aura and Chronic migraine. We submitted all children to the Child version of the Pain Catastrophizing Scale (PCS-C), and to the disability scale for migraine (PedMIDAS), general quality of life estimated by children (PedsQL) and parents (PedsQL-P), anxiety and depression (SAFA-A; SAFA-D) scales. We also evaluated headache frequency and the presence and severity of allodynia and pericranial tenderness. Results: No difference was detected in Total Pain Catastrophizing score (PCS-C) between chronic and episodic migraine groups (ANOVA F = 0.59, p = 0.70); the PedMIDAS, the PedsQL-P for physical functioning and the Total Tenderness Score were discriminant variables between episodic and chronic migraine. The PCS-C was not correlated with migraine related disability as expressed by Ped MIDAS, but it was significantly correlated with general low quality of life, allodynia, pericranial tenderness, anxiety, and depression. Conclusion: Pain catastrophizing seems a mental characteristic of a clinical phenotype with psychopathological traits and enhanced expression of central sensitization symptoms. This clinical profile causes general decline in quality of life in the child judgment, with a probable parents' underestimation. In childhood age, it would not be a feature of chronic migraine, but the possibility that it could predict this evolution is consistent and worthy of further prospective evaluation.

BACKGROUND:A dysfunction of pain processing at central and peripheral levels was reported in fibromyalgia (FM). We aimed to correlate laser evoked potentials (LEPs), Sympathetic Skin Response (SSR), and clinical features in FM patients.METHODS:Fifty FM patients and 30 age-matched controls underwent LEPs and SSR by the right hand and foot. The clinical evaluation included FM disability (FIQ) and severity scores (WPI), anxiety (SAS) and depression (SDS) scales, and questionnaires for neuropathic pain (DN4).RESULTS:The LEP P2 latency and amplitude and the SSR latency were increased in FM group. This latter feature was more evident in anxious patients. The LEPs habituation was reduced in FM patients and correlated to pain severity scores. In a significant number of patients (32%) with higher DN4 and FIQ scores, SSR or LEP responses were absent.CONCLUSIONS:LEPs and SSR might contribute to clarifying the peripheral and central nervous system involvement in FM patients.

Objectives: The aim of this study was to evaluate the function of A delta fibers at the hand level in patients with clinical symptoms of Carpal Tunnel Syndrome (CTS) using CO2 laser evoked potentials (LEPs), in light of the intensity and distribution of sensory symptoms and pain.Methods: Thirty-four CTS outpatients (62 hands) were compared to 23 sex- and age-matched control subjects (46 hands). The periungueal skin of the first, second, third and fifth fingers, and the dorsum of the hands were stimulated in random order. The latency and amplitude of the N2, P2 and N1 components were evaluated with respect to the Nerve Conduction Study (NCS) data, clinical scales, pain intensity and glove-like symptoms distribution.Results: The amplitude of the N2-P2 complex was significantly reduced in CTS hands compared to normal hands after stimulation of the second and third fingers, even in patients with mild nerve conduction impairment. No significant fifth finger LEP abnormalities were found in patients with glove-like distribution symptoms. The N2-P2 amplitude at the second and third fingers was positively correlated with the severity of sensory symptoms.Conclusions: The involvement of median nerve A delta fibers in CTS seems to be an early phenomenon, which concurs with the impairment of large motor and sensory afferents and is linked to the severity of the disease.Significance: The finding of reduced sensory symptoms in patients with severe thin afferents damage, may suggest a slight expression of central sensitisation phenomena in the advanced stage of CTS syndrome. (C) 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The present study aimed to evaluate heat pain thresholds and evoked potentials following CO(2) laser thermal stimulation (laser-evoked potentials, LEPs), during remote application of capsaicin, in migraine patients vs. non-migraine healthy controls. Twelve outpatients suffering from migraine without aura were compared with 10 healthy controls. The LEPs were recorded by 6 scalp electrodes, stimulating the dorsum of the right hand and the right supraorbital zone in basal condition, during the application of 3% capsaicin on the dorsum of the left hand and after capsaicin removal. In normal subjects, the laser pain and the N2-P2 vertex complex obtained by the hand and face stimulation were significantly reduced during remote capsaicin application, with respect to pre-and post-capsaicin conditions, while in migraine LEPs and laser pain were not significantly modified during remote painful stimulation. In migraine a defective brainstem inhibiting control may coexist with cognitive factors of focalised attention to facial pain, less sensitive to distraction by a second pain.

Syndromes with chronic daily headache include chronic migraine (CM). The reason for the transformation of migraine into chronic daily headache is still unknown. In this study, we aimed to evaluate heat pain thresholds and event-related potentials following CO(2)-laser thermal stimulation (LEPS) in hand and facial regions in patients with CM, to show changes in nociceptive brain responses related to dysfunction of pain elaboration at the cortical level. The results were compared with findings from normal control subjects and from subjects who suffer from migraine without aura. The effects of stimulus intensity, subjective pain perception and attention were monitored and compared with features of the LEPS. Twenty-five CM patients, 15 subjects suffering from migraine without aura and 15 normal control subjects were enrolled in the study. LEPS amplitude variation was reduced in CM patients with respect to the perceived stimulus intensity, in comparison with migraine without aura patients and control subjects. In both headache groups, the distraction from the painful laser stimulus induced by an arithmetic task failed to suppress the LEPS amplitude, in comparison with control subjects. These results suggest an abnormal cortical processing of nociceptive input in CM patients, which could lead to the chronic state of pain. In both headache groups, an inability to reduce pain elaboration during an alternative cognitive task emerged as an abnormal behaviour probably predisposing to migraine.

Current opinion concerning the pathophysiology of tension-type headache (TTH) and its related pericranial muscle tenderness proposes a primary role of central sensitization at the level of dorsalhorn/trigeminal nucleus as well as the supraspinal level. Investigation of these phenomena can be conducted using laser-evoked potentials (LEPs), which are objective and quantitative neurophysiological tools for the assessment of pain perception. In the present study we examined features of LEPs, as well as cutaneous heat-pain thresholds to laser stimulation, in relation to the tenderness of pericranial muscles in chronic TTH resulting from pericranial muscle disorder, during a pain-free phase. Twelve patients with TTH and 11 healthy controls were examined using the Total Tenderness Scoring (TTS) system. The stimulus was a laser pulse generated by a CO(2) laser. The dorsum of the hand and the cutaneous zones corresponding to pericranial muscles were stimulated. Subjective perception of stimulus intensity was assessed by a visual analogue scale. Two responses, the earlier named N2a and the last named P2, were considered; the absolute latency was measured at the highest peak of each response. The N2a-P2 components' peak-to-peak amplitude was detected. The heat pain threshold was similar in TTH patients and controls at the level of both the hand and pericranial skin. The TTS scores at almost all pericranial sites were higher in TTH patients than in normal controls. The amplitude of the N2a-P2 complex elicited by stimulation of the pericranial zone was greater in TTH patients than in controls; the amplitude increase was significantly associated with the TTS score. Our findings suggest that pericranial tenderness may be a primary phenomenon that precedes headache, and is mediated by a greater pain-specific hypervigilance at the cortical level.

The aims of this study were to assess how stress affects chronic headaches, and in particular to determine whether events play a role in the transformation of an episodic headache into a chronic form. A population of 267 Italian patients with chronic headache (headache present on average more than 15 days per month) was studied. Our results confirm a triggering role of stress on headache. We also found that episodic headache (migraine in most patients, 74.1%) preceded the development of a chronic form in about 90% cases. Among these patients, in 44.8% a stressful event correlated with the transformation. Analysis of these events revealed that minor events played a greater role than major life events, suggesting that patients with transformed headache are characterised by a different way of reacting to stress.

A multicenter study was carried out in 10 Italian headache centers to investigate the prevalence of anxiety and depression in patients with chronic daily headache(CDH). The study investigated 219 patients (171 F; 48 M) including 53 cases of chronic tension-type headache (CTTH), 99 cases of CTTH+ migraine and 67 cases of transformed migraine (TM). The type of headache diagnosed at the beginning was episodic tension-type headache (ETTH, n=32), ETTH + migraine (n=2), CDH ab initio (n=22), migraine with/without aura (n=151), not classifiable migraine (n=7) and not classifiable headache (n=3). The assessment of anxiety and depression was carried out using a Zung self-rating scale for anxiety (Zung A) and for depression (Zung D). The results show that anxiety and depression levels, in each group, were related to sex (F>M). Anxiety, but not depression, was related to the length of chronicization process. Anxiety and depression did not correlate with type of headache at onset, with ongoing headache or, surprisingly, with the abuse of anti-inflammatory drugs. These data suggest the chronicization is a biological and psychological trait.