A. Pepe

Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS

AbstractWe aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.

Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain

Summary In patients with peripheral neuropathy, epidermal innervation and axonal abnormalities, as assessed with skin biopsy, are associated with provoked but not ongoing burning pain. ABSTRACT 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.

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

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.

Diagnostic accuracy of laser-evoked potentials in diabetic neuropathy

Abstract 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.

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

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.

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

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.

13. Which is the best evoked potential technique for assessing the nociceptive system? Preliminary results of a neurophysiological study in healthy humans

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

43. Pain-related cortex function in patients with Alzheimer’s disease. Preliminary results

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

67. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain

The different neuropathic pain types (e.g. 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.

57. An observational study assessing definitively diagnosed peripheral neuropathy and neuropathic pain in patients with multiple myeloma

Patients with multiple myeloma commonly suffer from peripheral neuropathy often accompanied by neuropathic pain. In this observational study we assessed prevalence rates and variables associated with these common complications related to multiple myeloma. We collected 255 consecutive patients with multiple myeloma. All patients underwent periodic neurological examination, the total neuropathy score, nerve conduction study, and the DN4 screening tool for detecting neuropathic pain. In 68% of the patients clinical examination and nerve conduction studies disclosed a predominantly sensory axonal distal symmetric peripheral neuropathy, unrelated to age, but associated with the duration of disease, medications and diabetes. In 25% of patients the DN4 disclosed neuropathic pain unrelated to the severity of peripheral neuropathy. Our detailed diagnostic information on prevalence rates and variables associated with peripheral neuropathy and neuropathic pain in patients with multiple myeloma should help clinical pain management thus improving their quality of life.