Outcome of small fibre pathology in fibromyalgia: a real life longitudinal observational study.

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.

Laser evoked potentials in fibromyalgia with peripheral small fiber involvement.

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.

Effect of single dose Erenumab on cortical responses evoked by cutaneous a-delta fibers: A pilot study in migraine patients.

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.

Peripheral and central nervous system correlates in fibromyalgia.

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.

Failure of preventive treatments in migraine: an observational retrospective study in a tertiary headache center.

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.

A Simple Pattern of Movement is not Able to Inhibit Experimental Pain in FM Patients and Controls: an sLORETA Study.

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.

Pain Catastrophizing in Childhood Migraine: An Observational Study in a Tertiary Headache Center.

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.

Pain Processing and Vegetative Dysfunction in Fibromyalgia: A Study by Sympathetic Skin Response and Laser Evoked Potentials.

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.

Laser evoked potentials in carpal tunnel syndrome.

OBJECTIVES: The aim of this study was to evaluate the function of Adelta fibers at the hand level in patients with clinical symptoms of Carpal Tunnel Syndrome (CTS) using CO(2) 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 Adelta 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.

Effects of remote cutaneous pain on trigeminal laser-evoked potentials in migraine patients.

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.

Habituation of single CO2 laser-evoked responses during interictal phase of migraine.

A reduced habituation of averaged laser-evoked potential (LEP) amplitudes was previously found in migraine patients. The aim of the present study was to assess the habituation of single LEP responses and pain sensation during the interictal phase in migraine patients. Fourteen migraine patients were compared with ten control subjects. The pain stimulus was laser pulses, generated by CO2 laser, delivered to right supraorbital zone. Patients were evaluated during attack-free conditions. The LEP habituation was studied by measuring the changes of LEP amplitudes across and within three consecutive repetitions of 21 non-averaged trials. In migraine patients the N2-P2 wave amplitudes did not show a tendency toward habituation across and, above all, within the three repetitions. Anomalous behaviour of nociceptive cortex during the interictal phase of migraine may predispose patients to headache occurrence and persistence.

Changes in cortical processing of pain in chronic migraine.

OBJECTIVE: The aim of this study was to perform a topographic and dipolar analysis of nociceptive-evoked responses obtained by laser stimulus under basal conditions in a cohort of chronic migraine (CM) patients, compared with migraine without aura (MWA) patients and noncraniofacial pain controls. BACKGROUND: An increased activation of cortical areas devoted to the emotional and attentive components of pain was previously found during the course of the migraine attack; it was more pronounced in patients reporting higher frequency of migraine. METHODS: Twenty-six outpatients were enrolled in the study; 16 fulfilled the criteria of CM, and 10 were affected by MWA. Fifteen noncraniofacial pain subjects were also selected. The pain stimulus was a CO2 laser pulses. The right-supraorbital zone was stimulated. Source localization analysis was performed on the most prominent laser-evoked potentials (LEPs) peak (P2) for each data set. The anatomical locations of the P2 sources were projected onto a standard normalized 3D MRI model. RESULTS: The CM group differed significantly from both MWA patients and controls for the x coordinate and from controls for the z coordinates. The P2 dipole localized in the rostral cingulate cortex in CM patients, lying in a more posterior location within the anterior cingulate cortex (ACC) in both controls and MWA patients. The x coordinate of the P2 dipole, expressing the postero-anterior location, was significantly correlated with frequency of headache. CONCLUSIONS: CM seems to be characterized by a distinctive pattern of cortical elaboration of pain, with a prevalent activation of the rostral portion of the ACC: our results suggest that this may be a predisposing factor to migraine chronicity.

Visually evoked phase synchronization changes of alpha rhythm in migraine: correlations with clinical features.

OBJECTIVE: This study aimed to compute phase synchronization of the alpha band from a multichannel electroencephalogram (EEG) recorded under repetitive flash stimulation from migraine patients without aura. This allowed examination of ongoing EEG activity during visual stimulation in the pain-free phase of migraine. METHODS: Flash stimuli at frequencies of 3, 6, 9, 12, 15, 18, 21, 24, and 27 Hz were delivered to 15 migraine patients without aura and 15 controls, with the EEG recorded from 18 scalp electrodes, referred to the linked earlobes. The EEG signals were filtered in the alpha (7.5-13 Hz) band. For all stimulus frequencies that we evaluated, the phase synchronization index was based on the Hilbert transformation. RESULTS: Phase synchronization separated the patients and controls for the 9, 24 and 27 Hz stimulus frequencies; hyper phase synchronization was observed in patients, whereas healthy subjects were characterized by a reduced phase synchronization. These differences were found in all regions of the scalp. CONCLUSIONS: During migraine, the brain synchronizes to the idling rhythm of the visual areas under certain photic stimulations; in normal subjects however, brain regions involved in the processing of sensory information demonstrate desynchronized activity. Hypersynchronization of the alpha rhythm may suggest a state of cortical hypoexcitability during the interictal phase of migraine. SIGNIFICANCE: The employment of non-linear EEG analysis may identify subtle functional changes in the migraine brain.

Capsaicin failed in suppressing cortical processing of CO2 laser pain in migraine patients.

The aim of this study was to compare the properties of the nociceptive system in eight migraine without aura patients in the pain-free phase with 10 healthy controls, by evaluating the topography and the source of the CO2 laser-evoked potentials (LEPs) obtained by the right supraorbital skin, during and after capsaicin topical application. In healthy subjects the acute cutaneous pain induced by capsaicin reduced the amplitude of the vertex LEPs and induced a posterior shifting of the P2 wave dipolar source within the anterior cingulate cortex. These functional changes seemed significantly reduced in migraine patients, for a disturbed pattern of pain modulation at the cortical level, which may subtend the onset and persistence of migraine.

Topographic and dipolar analysis of laser-evoked potentials during migraine attack.

OBJECTIVE: The aim of this study was to perform further evaluation of laser-evoked potentials (LEPs) during migraine attacks using multichannel recording and topographic analysis. Specifically, this study aimed to confirm the pattern previously observed in acute migraine, while also defining the components of LEPs that are mainly modified during headache, as well as the correlation between features of LEPs and clinical variables. In addition, we aimed to conduct a dipolar source analysis of the main LEP waves in migraine patients to check the variability in the source location of LEPs during acute migraine. BACKGROUND: An amplitude enhancement of LEPs was previously detected during migraine attack using a single scalp derivation on the vertex; hyperalgesia to heat stimuli was also detected for both the face and hand. METHODS: Eighteen patients suffering from migraine without aura were analyzed. The supraorbital zones and the dorsum of the hand were stimulated on both the symptomatic and nonsymptomatic sides in all patients. The LEPs were recorded via 25 scalp electrodes. Dipolar source analysis of the P2 components was performed using a spherical model in all patients and using a realistic Magnetic Resonance model in four patients. RESULTS: During attacks, the later waves, and particularly the P2 component, were significantly enhanced; the amplitude of the P2 component obtained during the attack by stimulation of the supraorbital zone on the side of the headache was significantly correlated with the intensity of pain and the frequency of headache. In our patients, the P2 wave was generated in the anterior cingulate cortex, with a shift toward its rostrocaudal portion, and was mainly devoted to elaboration of the emotive compound of pain during migraine attack. CONCLUSIONS: Cortical activation by laser stimuli during migraine attack was confirmed. This effect was more pronounced in patients with a higher frequency of migraine attacks. This may be due to a lack of inhibitory control over the transmission of pain to the cortex. The increased activation of cortical areas devoted to attention and emotion may be linked to headache.

Nitroglycerin induces migraine headache and central sensitization phenomena in patients with migraine without aura: a study of laser evoked potentials.

In migraineurs nitroglycerin (NTG) induces severe delayed headache, resembling spontaneous migraine attacks. The aim of the present study was to evaluate NTG laser evoked potentials (LEP) features amplitude and pain sensation to laser stimuli during NTG-induced headache. Nine patients were selected. Headache was induced by oral administration of 0.6 mg of NTG; signals were recorded through disk electrodes placed at the vertex and referred to linked earlobes. CO(2)-LEPs delivered by stimulation of the dorsum of both hands and the right and left supraorbital zones were evaluated after the onset of moderate or severe headache resembling spontaneous migraine and at least 72 h after the end of the headache phase. Patients exhibited a significant heat pain threshold reduction and an LEPs amplitude increment during headache when both the supraorbital zones were stimulated. NTG appeared to support a reliable experimental model of migraine, based on the neuronal effects on the integrative-nociceptive structures. The LEPs facilitation during NTG-induced headache may be subtended by a hyperactivity of nociceptive cortex as well as by a failure of pain-inhibitory control.

Steady-state visual evoked potentials in the low frequency range in migraine: a study of habituation and variability phenomena.

Previous studies have revealed that migraine patients display an increased photic driving to flash stimuli in the medium frequency range. The aim of this study was to perform a topographic analysis of steady-state visual evoked potentials (SVEPs) in the low frequency range (3-9 Hz), evaluating the temporal behaviour of the F1 amplitude by investigating habituation and variability phenomena. The main component of SVEPs, the F1, demonstrated an increased amplitude in several channels at 3 Hz. Behaviour of F1 amplitude was rather variable over time, and the wavelet-transform standard deviation was increased in migraine patients at a low stimulus rate. The discriminative value of the F1 mean amplitude and variability index, tested by both an artificial neural network classifier and a support vector machine, were high according to both methods. The increased photic driving in migraine should be subtended by a more generic abnormality of visual reactivity instead of a selective impairment of a visual subsystem. Temporal behaviour of SVEPs is not influenced by a clear tendency to habituation, but the F1 amplitude seemed to change in a complex way, which is better described by variability phenomena. An increased variability in response to flicker stimuli in migraine patients could be interpreted as an overactive regulation mechanism, prone to instability and consequently to headache attacks, whether spontaneous or triggered.

Heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in chronic tension-type headache.

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.

High and low frequency transcutaneous electrical nerve stimulation inhibits nociceptive responses induced by CO2 laser stimulation in humans.

The aim of the study was to evaluate the effects of transcutaneous electric nerve stimulation (TENS) on CO(2) laser evoked potentials (LEPs) in 16 normal subjects. The volar side of the forearm was stimulated by 10 Hz TENS in eight subjects and by 100 Hz TENS in the remainder; the skin of the forearm was stimulated by CO(2) laser and the LEPs were recorded in basal conditions and soon after and 15 min after TENS. Both low and high frequency TENS significantly reduced the subjective rating of heat stimuli and the LEPs amplitude, although high frequency TENS appeared more efficacious. TENS seemed to exert a mild inhibition of the perception and processing of pain induced by laser Adelta fibres activation; the implications of these effects in the clinical employment of TENS remain to be clarified.