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.
Our current understanding of brainstem reflex physiology comes chiefly from the classic anatomical-functional correlation studies that traced the central circuits underlying brainstem reflexes and establishing reflex abnormalities as markers for specific areas of lesion. These studies nevertheless had the disadvantage of deriving from post-mortem findings in only a few patients. We developed a voxel-based model of the human brainstem designed to import and normalize MRIs, select groups of patients with or without a given dysfunction, compare their MRIs statistically, and construct three-plane maps showing the statistical probability of lesion. Using this method, we studied 180 patients with focal brainstem infarction. All subjects underwent a dedicated MRI study of the brainstem and the whole series of brainstem tests currently used in clinical neurophysiology: early (R1) and late (R2) blink reflex, early (SP1) and late (SP2) masseter inhibitory reflex, and the jaw jerk to chin tapping. Significance levels were highest for R1, SP1 and R2 afferent abnormalities. Patients with abnormalities in all three reflexes had lesions involving the primary sensory neurons in the ventral pons, before the afferents directed to the respective reflex circuits diverge. Patients with an isolated abnormality of R1 and SP1 responses had lesions that involved the ipsilateral dorsal pons, near the fourth ventricle floor, and lay close to each other. The area with the highest probabilities of lesion for the R2-afferent abnormality was in the ipsilateral dorsal-lateral medulla at the inferior olive level. SP2 abnormalities reached a low level of significance, in the same region as R2. Only few patients had a crossed-type abnormality of SP1, SP2 or R2; that of SP1 reached significance in the median pontine tegmentum rostral to the main trigeminal nucleus. Although abnormal in 38 patients, the jaw jerk appeared to have no cluster location. Because our voxel-based model quantitatively compares lesions in patients with or without a given reflex abnormality, it minimizes the risk that the significant areas depict vascular territories rather than common spots within the territory housing the reflex circuit. By analysing statistical data for a large cohort of patients, it also identifies the most frequent lesion location for each response. The finding of multireflex abnormalities reflects damage of the primary afferent neurons; hence it provides no evidence of an intra-axial lesion. The jaw jerk, perhaps the brainstem reflex most widely used in clinical neurophysiology, had no apparent topodiagnostic value, probably because it depends strongly on peripheral variables, including dental occlusion.
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.
Postherpetic neuralgia is an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated Abeta-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Adelta- and unmyelinated C-fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P<0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Adelta- and C-LEP amplitude reduction correlated with the intensity of constant pain (P<0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Abeta-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.
Evidence of a specific spinal pathway for the sense of warmth in humans. J Neurophysiol 89: 562-570, 2003; 10.1152/jn.00393.2002. While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting A␦ nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO 2 -laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with highresolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470 -540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by A␦ nociceptive input (290 -320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the A␦ input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slowconducting second-order neurons specific for the sense of warmth.
Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Aδ nociceptors. LEPs are to date the reference standard technique for studying nociceptive pathway function in patients with neuropathic pain. To find out whether LEPs also provide a useful neurophysiological tool for assessing antinociceptive drug efficacy, in this doubleblind placebo-controlled study we measured changes induced by the analgesic tramadol on LEPs in 12 healthy subjects. We found that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease. We conclude that LEPs may be reliably used in clinical practice and research for assessing the efficacy of antinociceptive drugs.
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