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.

Neurophysiologic assessment of small fibre damage in chemotherapy-induced peripheral neuropathy.

OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.

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.

Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case-Control Study.

OBJECTIVE: Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs). DESIGN: Case-control study. SETTING: A single medical center in Belgium. SUBJECTS: The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study. METHODS: All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs. RESULTS: No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time-frequency maps of EEG oscillation amplitude between HCs and both patient populations. CONCLUSIONS: EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.

Fibromyalgia syndrome-A laser-evoked potentials study unsupportive of small nerve fibre involvement.

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain and a variety of non-pain symptoms. Central sensitivity phenomena are found consistently in FMS. Additionally, several researchers proclaimed that a subgroup of FMS patients may present with unrecognized peripheral small fibre neuropathy (SFN). Laser-evoked brain potentials (LEP) are considered as a reliable method for the functional assessment of the thermo-nociceptive system, including the evaluation of SFN. OBJECTIVES: The aim of this retrospective study was to estimate the prevalence of thermo-nociceptive system dysfunction based on LEPs in FMS. METHODS: LEP recordings of 92 FMS patients and 39 age and gender-matched healthy controls were selected from a database collected between 2003 and 2012 with standardized settings for laser stimulation and EEG recording. The N1, N2 and P2 LEP components were identified and characterized by peak latency and amplitude. RESULTS: None of the FMS patients showed signs of loss of function of the nociceptive responses evoked by A δ-nociceptor activation, compared to healthy controls. 6.5% of the FMS patients had N2-P2 peak-to-peak amplitudes above the upper limit of the 99%-confidence interval. N2-P2 peak-to-peak amplitudes were negatively correlated with age, without age-related differences between groups. CONCLUSIONS: The characteristic signs of a damaged thermo-nociceptive system as revealed by LEPs were absent in this large cohort of FMS patients. SIGNIFICANCE: The present research does not support the hypothesis that small fibre neuropathy is a significant contributor to the pathophysiology of FMS.

Motor cortex function in fibromyalgia: a pilot study involving near-infrared spectroscopy and co-recording of laser-evoked potentials.

Interaction between the motor and nociceptive systems seems to play an important role in chronic pain. In this pilot study we used a combination of functional near-infrared spectroscopy (FNIRS) and laserevoked potentials (LEPs) during concurrent finger tapping task and noxious laser stimulation in fibromyalgia (FM) patients and controls. The study included 9 healthy subjects and 15 FM patients. During concurrent FNIRS and LEP recording, participants were required either to remain in resting relaxed condition or to execute a finger tapping task with the right hand. In the control group, the left motor cortex showed increased oxyhaemoglobin levels, while the early N1 LEP component was reduced, during the finger tapping task. In FM patients, motor cortex oxyhaemoglobin concentrations were lower during movement, which did not reduce LEPs. The left motor cortex oxyhaemoglobin concentrations had 79.2% diagnostic accuracy. The interplay between motor and pain-related circuits seems to be dysfunctional in FM patients. These results may support a role for motor cortex modulation in the treatment of this disabling disease.

[Small fiber neuropathy]. / La neuropathie des petites fibres.

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

Skin denervation does not alter cortical potentials to surface concentric electrode stimulation: A comparison with laser evoked potentials and contact heat evoked potentials.

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

Diagnostic accuracy of laser-evoked potentials in diabetic neuropathy.

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.

Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients.

BACKGROUND: Repetitive painful laser stimuli lead to physiological laser-evoked potential (LEP) habituation, measurable by a decrement of the N2/P2 amplitude. The time course of LEP-habituation is reduced in the capsaicin model for peripheral and central sensitization and in patients with migraine and fibromyalgia. In the present investigation, we aimed to assess the time course of LEP-habituation in a neuropathic pain syndrome, i.e. painful radiculopathy. METHODS: At the side of radiating pain, four blocks of 25 painful laser stimuli each were applied to the ventral thigh at the L3 dermatome in 27 patients with painful radiculopathy. Inclusion criteria were (1) at least one neurological finding of radiculopathy, (2) low back pain with radiation into the foot and (3) a positive one-sided compression of the L5 and/or S1 root in the MRI. The time course of LEP-habituation was compared to 20 healthy height and age matched controls. Signs of peripheral (heat hyperalgesia) and central sensitization (dynamic mechanical allodynia and hyperalgesia) at the affected L5 or S1 dermatome were assessed with quantitative sensory testing. RESULTS: Painful radiculopathy patients showed decreased LEP-habituation compared to controls. Patients with signs of central sensitization showed a more prominent LEP-habituation decrease within the radiculopathy patient group. CONCLUSIONS: Laser-evoked potential habituation is reduced in painful radiculopathy patients, which indicates an abnormal central pain processing. Central sensitization seems to be a major contributor to abnormal LEP habituation. The LEP habituation paradigm might be useful as a clinical tool to assess central pain processing alterations in nociceptive and neuropathic pain conditions. SIGNIFICANCE: Abnormal central pain processing in neuropathic pain conditions may be revealed with the laser-evoked potential habituation paradigm. In painful radiculopathy patients, LEP-habituation is reduced compared to healthy controls.

Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

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.

Robot-guided neuronavigated rTMS as an alternative therapy for central (neuropathic) pain: Clinical experience and long-term follow-up.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) appears as a useful tool to alleviate neuropathic pain but only few data are available for the long-term benefit of this treatment. METHODS: Here we report the effects of rTMS sessions, considered as a possible therapy for pain relief after a failure of different medications in patients with central (neuropathic) pain. We review here the prospectively collected data of the first forty patients treated as follow: 20 Hz stimulation delivered over the contralateral primary motor cortex (M1), each 3-4 weeks. RESULTS: A total of 440 rTMS sessions was collected (mean sessions number: 11, range: 1-37, follow-up 312 days on average, maximum 2.8 years). After four sessions, nine patients (22.5%) discontinued rTMS because of a lack of efficiency (<10% pain-relief). The other 31 patients (77.5%) had a cumulative effect across sessions leading to a mean pain relief of 41% for a duration of 15.6 days. A correlation was observed between pain relief in the first session and long-term pain relief (R = 0.649. p = 5.6*10(-6) ). Both intensity and duration of pain relief were significantly better for patients with persistent laser evoked potentials (LEPs, p = 0.049 and 0.0018). We did not observe any adverse-effects. CONCLUSION: These results suggest that repeated sessions of 20 Hz rTMS over M1 are interesting in clinical practice for the treatment of selected patients with central pain. Both the cumulative effects across the first sessions and the long duration of pain-relief should impact further randomized trials that are warranted to conclude formally on rTMS efficiency in central pain.

Hyperexcitability in pain matrices in patients with fibromyalgia.

OBJECTIVES: Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM. METHODS: In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Aδ- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Aδ-LEP conditioned by a preceding C-LEP. RESULTS: No difference was found in control LEP amplitudes for Aδ- or C-fibres between patients and healthy subjects. Conversely, the Aδ-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001). CONCLUSIONS: Objective evidence from increased conditioned Aδ-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches.

Trigeminal laser-evoked potentials: a neurophysiological tool to detect post-surgical outcome in trigeminovascular contact neuralgia.

BACKGROUND: The aim of this study was to explore the nociceptive system of patients affected by trigeminal neuralgia (TN) secondary to documented vascular contact who underwent microvascular decompression. For that purpose, we used the classical trigeminal reflexes and the trigeminal laser-evoked potentials (tLEPs) before and after surgery, in order to verify any possible change after decompression and determine if there was any correlation between the neurophysiological parameters and the clinical outcome. METHODS: Eleven patients affected by TN caused by trigeminovascular contact and 10 age-matched controls underwent conventional trigeminal reflexes (bilateral Blink Reflex/BR and Masseter Inhibitory Reflex stimulating infraorbital and mental nerves/MIR V2 and V3) and tLEPs. Patients repeated neurophysiological tests one week after surgery. RESULTS: Short-latency BR and MIR were normal in all patients before surgery and there was no statistical difference before and after surgery. Conversely, in patients before surgery, tLEPs' amplitudes were significantly lower in the affected than in the healthy side (p = 0.017 for V2 and 0.037 for V3 branches). After surgery, on the affected side, tLEP amplitude increased and the pre/post-operative difference was significant (p = 0.017 for V2 and 0.028 for V3 divisions). Nine patients referred satisfactory pain relief and the favourable clinical outcome correlated with the neurophysiological recovery. CONCLUSIONS: This study demonstrates that TN caused by trigeminovascular compression may be related to Aδ fibres impairment, and tLEPs are more sensitive than conventional trigeminal reflexes to reveal small fibre dysfunction and to monitor the post-surgical outcome in these patients.

Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features.

In fibromyalgia (FM), reduced habituation of laser-evoked potentials (LEPs) suggests a dysfunction of pain processing at a central level. In this study, we aimed to further examine the nociceptive pathways at the peripheral to the central level in a large group of FM patients by means of LEPs and skin biopsy, in light of healthy controls findings and main clinical features. One hundred and ninety-nine FM patients and 109 age- and sex-matched controls were submitted to LEPs by the dorsum of the right hand and the skin over the right chest and knee tender point stimulation. Skin biopsy was performed in 21 randomly selected FM patients and 60 age- and sex-matched controls. The mean N2-P2 amplitude was reduced in the whole FM group, with normal or even increased values in patients with migraine as comorbidity and reduced values in other patients including those presenting with distal sensory deficits. All patients had reduced N2-P2 habituation in respect to controls. In the FM group, LEPs habituation was correlated with pain at tender points and bad quality of life. Epidermal fiber density was significantly reduced in FM patients versus controls, and correlated with N2-P2 amplitude by the hand and chest tender-point stimulation. Dysfunction in the nociceptive system at both the central and peripheral levels may concur to explain phenotypical eterogeneity and clinical symptom complexity in fibromyalgia.