Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests.

The diagnosis of small fiber neuropathy (SFN) is a challenge for clinical neurophysiology. Conventional nerve conduction studies are inappropriate for this purpose and therefore various neurophysiological tests have been proposed. In this study, we compared the diagnostic value of five of these tests in 87 patients with clinically definite (n=33) or possible (n=54) SFN related to amyloid neuropathy secondary to transthyretin gene mutation or monoclonal gammopathy (n=30), primary Sjögren's syndrome (n=20), Fabry's disease (n=2), or unknown cause (n=35). Neurophysiological tests included quantitative sensory testing with determination of warm and cold detection thresholds (WDT, CDT), recording of laser-evoked potentials (LEP) and sympathetic skin responses (SSRs), and measurement of electrochemical skin conductance (ESC) using Sudoscan(®) device. All tests were performed at the four extremities (hands and feet). All patients with clinically definite SFN and 70% of the patients with possible SFN had at least one abnormal test. The LEP was the most sensitive test (altered in 79% of the patients with at least one abnormal test), followed by ESC (61%), WDT (55%), SSR (41%), and CDT (32%). The combination of LEP, assessing A-delta sensory fibers, WDT, assessing sensory C fibers, and ESC, assessing autonomic C fibers, appears a relevant approach for the diagnosis of SFN. Compared to SSR and CDT, these three tests, LEP, WDT, and ESC, had a significantly better diagnostic sensitivity and their combination further improved diagnostic accuracy.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming.

BACKGROUND: 'Conventional' protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than 'conventional' protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of 'conventional' 10 Hz-rTMS. METHODS: In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10 Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. RESULTS: Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. CONCLUSIONS: The present results show that the analgesic effects of 'conventional' 10 Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

Motor cortex rTMS in chronic neuropathic pain: pain relief is associated with thermal sensory perception improvement.

BACKGROUND: Improvement in sensory detection thresholds was found to be associated with neuropathic pain relief produced by epidural motor cortex stimulation with surgically implanted electrodes. OBJECTIVE: To determine the ability of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex to produce similar sensory changes. METHODS: In 46 patients with chronic neuropathic pain of various origins, first-perception thresholds for thermal (cold, warm) and mechanical (vibration, pressure) sensations were quantified in the painful zone and in the painless homologue contralateral territory, before and after rTMS of the motor cortex corresponding to the painful side. Ongoing pain level was also scored before and after rTMS. Three types of rTMS session, performed at 1 Hz or 10 Hz using an active coil, or at 10 Hz using a sham coil, were compared. The relationships between rTMS-induced changes in sensory thresholds and in pain scores were studied. RESULTS: Subthreshold rTMS applied at 10 Hz significantly lowered pain scores and thermal sensory thresholds in the painful zone but did not lower mechanical sensory thresholds. Pain relief correlated with post-rTMS improvement of warm sensory thresholds in the painful zone. CONCLUSIONS: Thermal sensory relays are potentially dysfunctioning in chronic neuropathic pain secondary to sensitisation or deafferentation-induced disinhibition. By acting on these structures, motor cortex stimulation could relieve pain and concomitantly improve innocuous thermal sensory discrimination.

The value of navigation-guided rTMS for the treatment of depression: an illustrative case.

Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has been thought to have great potential to treat refractory depression since the first studies published ten years ago. However, one of the potential limitations of rTMS is the poor definition of the localization of the prefrontal cortical target, which is based on a rather simplistic anatomical approach, i.e., 5cm anterior to the primary motor cortical representation of the hand. This "standard procedure" does not take into consideration interindividual variations in brain morphology. We report the case of a 40-year-old woman who underwent two weeks of 10Hz-rTMS for the treatment of a major, drug-resistant depressive episode. The rTMS target was determined with the "standard procedure" for the first week and with a dedicated navigation system as the left Brodmann area 46 for the second week. The clinical assessment of antidepressant effects was performed before and after each week of stimulation. Following the first week of stimulation, the patient improved, in particular regarding speech production. Using the navigation system, the location of the target stimulated during the first week was found to correspond to Broca's area, and not to the prefrontal area as intended. Antidepressant effects were more marked after the second week of navigated rTMS. In the present case, the prefrontal target was situated 8.3cm anterior to hand motor cortex. This illustrates that the "standard procedure" may inaccurately target the prefrontal cortex, although resulting in antidepressant-like effects. The use of navigation systems should limit the variability of the results reported so far in the treatment of depression by rTMS.

Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain.

BACKGROUND: Motor cortex repetitive transcranial magnetic stimulation (rTMS) was found to relieve chronic neuropathic pain, but the optimal parameters of stimulation remain to be determined, including the site of stimulation. OBJECTIVE: To determine the relationship between cortical stimulation site and pain site regarding the analgesic efficacy of rTMS of motor cortex in chronic neuropathic pain. METHODS: Thirty-six patients with unilateral chronic neuropathic pain located at the face or the hand were enrolled. Motor cortex rTMS was applied at 10 Hz over the area corresponding to the face, hand, or arm of the painful side, whatever pain location. Analgesic effects were daily assessed on visual analogue scale for the week that followed each rTMS session. RESULTS: All types of rTMS session, whatever the target, significantly relieved pain, compared with baseline. However, analgesic effects were significantly better after hand than face area stimulation in patients with facial pain and after face than hand or arm area stimulation in patients with hand pain. CONCLUSION: Repetitive transcranial magnetic stimulation was more effective for pain relief when the stimulation was applied to an area adjacent to the cortical representation of the painful zone rather than to the motor cortical area corresponding to the painful zone itself. This result contradicts the somatotopic efficacy observed for chronic epidural motor cortex stimulation with surgically implanted electrodes.

Motor cortex rTMS restores defective intracortical inhibition in chronic neuropathic pain.

OBJECTIVE: To assess cortical excitability changes in patients with chronic neuropathic pain at baseline and after repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. METHODS: In 22 patients with unilateral hand pain of various neurologic origins and 22 age-matched healthy controls, we studied the following parameters of cortical excitability: motor threshold at rest, motor evoked potential amplitude ratio at two intensities, cortical silent period (CSP), and intracortical inhibition (ICI) and intracortical facilitation. We compared these parameters between healthy subjects and patients at baseline. We also studied excitability changes in the motor cortex corresponding to the painful hand of patients after active or sham rTMS of this cortical region at 1 or 10 Hz. RESULTS: At baseline, CSP was shortened for the both hemispheres of patients vs healthy subjects, in correlation with pain score, while ICI was reduced only for the motor cortex corresponding to the painful hand. Regarding rTMS effects, the single significant change was ICI increase in the motor cortex corresponding to the painful hand, after active 10-Hz rTMS, in correlation with pain relief. CONCLUSION: Chronic neuropathic pain was associated with motor cortex disinhibition, suggesting impaired GABAergic neurotransmission related to some aspects of pain or to underlying sensory or motor disturbances. The analgesic effects produced by motor cortex stimulation could result, at least partly, from the restoration of defective intracortical inhibitory processes.

Low-frequency repetitive TMS of premotor cortex can reduce painful axial spasms in generalized secondary dystonia: a pilot study of three patients.

Dystonia is associated with excessive corticospinal motor output. Motor cortex excitability may be reduced by low-frequency repetitive transcranial magnetic stimulation (rTMS) of premotor cortical areas. We report the effects of 1 Hz rTMS applied at 90% of resting motor threshold over the left premotor cortex in an open pilot study of three patients with severe, generalized, secondary dystonia including painful spasms in the proximal and axial musculature. A 20-min session of premotor rTMS was daily performed during 5 consecutive days. The series of rTMS sessions dramatically reduced the painful spasms, for 3-8 days after the last session, without any other significant beneficial effects. However, a slight reduction of the Movement score of the Burke, Fahn and Marsden rating scale was observed for two patients, and of the Disability score for the third one. Low-frequency rTMS of the premotor cortex may improve some specific motor symptoms in severe, generalized dystonia. These results should prompt confirmation in a larger placebo-controlled study.

Neuropathic pain controlled for more than a year by monthly sessions of repetitive transcranial magnetic stimulation of the motor cortex.

Neuropathic pain can be controlled by motor cortex stimulation using surgically-implanted electrodes in a majority of selected patients. Analgesic effects were also found to result from repetitive transcranial magnetic stimulation (rTMS) of the cortex. We report the case of a woman, in whom drug-resistant peripheral pain was controlled for 16 months by monthly sessions of motor cortex rTMS until a durable pain relief was obtained after surgical implantation of a cortical stimulator. This case illustrates the value of rTMS in helping patients to wait for surgery.

Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain.

OBJECTIVE: Drug resistant neurogenic pain can be relieved by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. This study was designed to assess the influence of pain origin, pain site, and sensory loss on rTMS efficacy. PATIENTS AND METHODS: Sixty right handed patients were included, suffering from intractable pain secondary to one of the following types of lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the face, the upper limb, or the lower limb. The thermal sensory thresholds were measured within the painful zone and were found to be highly or moderately elevated. Finally, the pain level was scored on a visual analogue scale before and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the motor cortex corresponding to the hand on the painful side, even if the pain was not experienced in the hand itself. RESULTS: and discussion: The percentage pain reduction was significantly greater following real than sham rTMS (-22.9% v -7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic effects. These effects were significantly influenced by the origin and the site of pain. For pain origin, results were worse in patients with brainstem stroke, whatever the site of pain. This was consistent with a descending modulation within the brainstem, triggered by the motor corticothalamic output. For pain site, better results were obtained for facial pain, although stimulation was targeted on the hand cortical area. Thus, in contrast to implanted stimulation, the target for rTMS procedure in pain control may not be the area corresponding to the painful zone but an adjacent one. Across representation plasticity of cortical areas resulting from deafferentation could explain this discrepancy. Finally, the degree of sensory loss did not interfere with pain origin or pain site regarding rTMS effects. CONCLUSION: Motor cortex rTMS was found to result in a significant but transient relief of chronic pain, influenced by pain origin and pain site. These parameters should be taken into account in any further study of rTMS application in chronic pain control.