In patients with distal symmetric polyneuropathy we assessed non-nociceptive Aβ- and nociceptive Aδ-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Aβ-fibre function, and laser-evoked potentials (LEPs) to assess Aδ-fibre function. Patients with pain had the same age (P > 0.50), but a longer delay since symptom onset than those without (P < 0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P < 0.0001), NCS data did not differ between groups (P > 0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P < 0.0001). Our findings indicate that the impairment of Aβ-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.
Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS. We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Abeta-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Adelta-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Adelta-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Abeta-fibres, spontaneous constant pain arises from damage to nociceptive Adelta-fibres.
Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face- and foot-laser evoked potentials (LEPs) and foot-cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot-LEPs (P<0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS (P<0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions. Our data suggest that anodal tsDCS over the thoracic spinal cord might impair conduction in the ascending nociceptive spinal pathways, thus modulating LEPs and increasing pain tolerance in healthy subjects.
Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P<0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P<0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex.
Contact heat stimuli have been reported to excite mechano-thermal nociceptors and to evoke brain potentials (CHEPs) from the limbs. We investigated whether contact heat evokes reproducible CHEPs from the trigeminal territory and may prove a reliable diagnostic tool in facial neuropathic pain. We applied contact heat stimuli to the perioral and supraorbital regions; CHEPs were recorded from the vertex in 20 controls and 2 patients with facial neuropathic pains, and reflex responses from the orbicularis oculi and masticatory muscles in 5 controls. We studied the correlation between CHEP data and perceptive ratings, site of stimulation, and age. Finally, we compared CHEPs with laser evoked potentials (LEPs). Contact heat stimuli at 51 degrees C evoked vertex potentials consisting of an NP complex similar to that elicited by laser pulses, though with a latency some 100-ms longer. Perioral stimulation yielded higher pain intensity ratings, shorter latency and larger amplitude CHEPs than supraorbital stimulation. CHEP data correlated significantly with age. Contact heat stimuli at 53 degrees C evoked a blink-like response in the relaxed orbicularis oculi muscle and a silent period in the contracted masseter muscle. In patients with facial neuropathic pain the CHEP abnormalities paralleled those seen with LEPs. We were unable to achieve reproducible signals related to C-receptor stimulation by contact heat stimuli at 41 degrees C in the ten subjects in whom they were tested. Contact heat stimulation, as well as laser stimulation, easily yields large-amplitude brain potentials and nociceptive reflexes, both related to the Adelta input. However CHEPs are not suitable for C-fibres potentials recording.
Iatrogenic injury of the inferior alveolar or lingual nerves frequently leads to legal actions for damage and compensation for personal suffering. The masseter inhibitory reflex (MIR) is the most used neurophysiological tool for the functional assessment of the trigeminal mandibular division. Aiming at measuring the MIR sensitivity and specificity, we recorded this reflex after mental and tongue stimulations in a controlled, blinded study in 160 consecutive patients with sensory disturbances following dental procedures. The MIR latency was longer on the affected than the contralateral side (P < 0.0001). The overall specificity and sensitivity were 99 and 51%. Our findings indicate that MIR testing, showing an almost absolute specificity, reliably demonstrates nerve damage beyond doubt, whereas the relatively low sensitivity makes the finding of a normal MIR by no means sufficient to exclude nerve damage. Probably, the dysfunction of a small number of nerve fibres, insufficient to produce a MIR abnormality, may still engender important sensory disturbances. We propose that MIR testing, when used for legal purposes, be considered reliable in one direction only, i.e. abnormality does prove nerve damage, normality does not disprove it.
Tangier disease is an autosomal recessive disorder characterized by severe reduction in high-density lipoprotein cholesterol and peripheral lipid storage. We describe a family with c.5094C > A p.Tyr1698* mutation in the ABCA1 gene, clinically characterized by syringomyelic-like anesthesia, demyelinating multineuropathy, and reduction in intraepidermal small fibers innervation. In the proband patient, cardiac involvement determined a myocardial infarction; lipid storage was demonstrated in gut, cornea, and aortic wall. The reported ABCA1 mutation has never been described before in a Tangier family.
Postherpetic neuralgia (PHN) is a common and exceptionally drug-resistant neuropathic pain condition. In this cross-sectional skin biopsy study, seeking information on the responsible pathophysiological mechanisms we assessed how ophthalmic PHN affects sensory and autonomic skin innervation. We took 2-mm supraorbital punch skin biopsies from the affected and unaffected sides in 10 patients with ophthalmic PHN. Using indirect immunofluorescence and a large panel of antibodies including protein gene product (PGP) 9.5 we quantified epidermal unmyelinated, dermal myelinated and autonomic nerve fibers. Although skin biopsy showed reduced epidermal and dermal myelinated fiber density in specimens from the affected side, the epidermal/dermal myelinated nerve fiber ratio was lower in the affected than in the unaffected side (p < 0.001), thus suggesting a predominant epidermal unmyelinated nerve fiber loss. Conversely, autonomic skin innervation was spared. Our study showing that ophthalmic PHN predominantly affects unmyelinated nerve fiber and spares autonomic nerve fiber might help to understand the pathophysiological mechanisms underlying this difficult-to-treat condition.
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