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Objectives We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans. Methods Using a cold stimulator consisting of micro-Peltier elements that was able to produce steep cooling ramps up to -300°C/s, we recorded cold-evoked potentials after stimulation of the dorsal midline at C5, T2, T6 and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ-fibres-mediated) and warm (C-fibres-mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways. Results Cold stimulation evoked large-amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s. Discussion This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans that may be useful in the assessment of spinal cord lesions as well as in intraoperative monitoring during spinal surgery. Significance This neurophysiological study provides previously unreported findings on cold spinal pathway conduction velocity in healthy humans. Cold-evoked potentials may represent an alternative to laser-evoked potential recording, useful to assess spinothalamic tract in patients with spinal cord lesions and monitor patients during spinal surgery.

BACKGROUND In this neurophysiological study, we aimed at verifying the nociceptive selectivity of the new, micropatterned electrode (150IDE), recently designed to generate an electric field limited to the intraepidermal free nerve endings. METHODS Using the new 150IDE, we recorded evoked potentials after stimulation of the face and hand dorsum in 22 healthy participants and in patients with exemplary conditions selectively affecting the nociceptive system. We also measured the peripheral conduction velocity at the upper arm and verified the nociceptive selectivity of 150IDE assessing the effect of a selective block of nociceptive nerve fibres of radial nerve with local anaesthetic infiltration. In healthy participants and in patients, we have also compared the 150IDE-evoked potentials with laser-evoked potentials. RESULTS In healthy participants, the 150IDE-evoked pinprick sensation and reproducible scalp potentials, with latency similar to laser-evoked potentials. The mean peripheral conduction velocity, estimated at the upper arm, was 12 m/s. The selective nociceptive fibre block of the radial nerve abolished the scalp potentials elicited by the 150IDE stimulation. In patients, the 150IDE-evoked potentials reliably detected the selective damage of the nociceptive system. CONCLUSIONS Our neurophysiological study shows that this new 150IDE provides selective information on nociceptive system. SIGNIFICANCE 150IDE is a promising new tool for investigating nociceptive system in patients with neuropathic pain.

BACKGROUND We aimed at evaluating the differential involvement of large myelinated Aβ-, small myelinated Aδ-, and unmyelinated C-fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain. METHODS We collected clinical and diagnostic test variables in 133 consecutive patients with diabetic polyneuropathy. All patients underwent Aβ-fiber mediated nerve conduction study, Aδ-fiber mediated laser-evoked potentials and skin biopsy mainly assessing unmyelinated C-fibers. RESULTS Pure large-fiber and small-fiber polyneuropathy were relatively uncommon; conversely mixed-fiber polyneuropathy was the most common type of diabetic polyneuropathy (74%). The frequency of neuropathic pain was similar in the three different polyneuropathies. Ongoing burning pain and dynamic mechanical allodynia were similarly associated with specific small-fiber related variables. CONCLUSIONS Diabetic polyneuropathy mainly manifests as a mixed-fiber polyneuropathy, simultaneously involving Aβ-, Aδ-, and C-fibers. In most patients, neuropathic pain is distinctly associated with small-fiber damage. The evidence that the frequency of neuropathic pain does not differ across pure large-, pure small-, and mixed-fiber polyneuropathy, raises the possibility that in patients with pure large-fiber polyneuropathy nociceptive nerve terminal involvement might be undetected by standard diagnostic techniques.

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.

Neuropathic pain is a common problem in clinical practice and one that adversely affects patients’ quality of life. Converging evidence from animal and human studies demonstrates that neuropathic pain arises from a lesion in the somatosensory system. Injured peripheral nerve fibers give rise to an intense and prolonged ectopic input to the CNS and, in some cases, also to secondary changes in dorsal horn neuronal excitability. Convincing evidence now suggests that classifying neuropathic pain according to a mechanism-based rather than an etiology-based approach might help in targeting therapy to the individual patient and would be useful in testing new drugs. This article summarizes our current understanding of the peripheral and central pathophysiological mechanisms underlying neuropathic pain and focuses on how symptoms translate into mechanisms.

Background: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.

Background The guidelines on trigeminal neuralgia management that have been agreed and jointly published by the American Academy of Neurology and the European Federation of Neurological Societies recommend carbamazepine (CBZ) and oxcarbazepine (OXC) as the first-choice medical treatments in patients with trigeminal neuralgia (TN). The aim of this retrospective study was to analyze the natural history of classical trigeminal neuralgia in a large cohort of patients, focusing on drug responsiveness, side effects related to CBZ and OXC, and changes in pain characteristics during the course of disease. Findings We selected the last 100 consecutive patients with typical TN who began treatment with CBZ and the last 100 with OXC. All had MRI scans and a complete neurophysiological study of trigeminal reflexes. Among them, 22 were excluded on the basis of neuroradiological or neurophysiological investigations, to avoid the inclusion of patients with possible secondary TN. The initial number of responders was 98% with CBZ with a median dose of 600 mg (range 200–1200), and of 94% with OXC, with a median dose of 1200 mg (range 600–1800). In a mean period of 8.6 months, 27% of responders to CBZ incurred in undesired effects to a level that caused interruption of treatment or a dosage reduction to an unsatisfactory level. In a mean period of 13 months, the same occurred to 18% of responders to OXC. Among patients who had a good initial response, only 3 patients with CBZ and 2 with OXC developed late resistance. During the course of disease, paroxysms worsened in intensity in 3% of patients, and paroxysms duration increased in 2%. We did not observe the onset of a clinically manifest sensory deficit at any time in any patient. Conclusions Unlike common notion, in our large patient sample the worsening of pain with time and the development of late resistance only occurred in a very small minority of patients. CBZ and OXC were confirmed to be efficacious in a large majority of patients, but the side effects caused withdrawal from treatment in an important percentage of patients. These results suggest the opportunity to develop a better tolerated drug.

Objective To investigate the cutaneous silent period (CSP), a spinal inhibitory reflex mainly mediated by A-delta fibres, in demyelinating and axonal polyneuropathy (PNP) and evaluate whether CSP parameters differ between patients with and without neuropathic pain. Methods Eighty-four patients with demyelinating PNP, 178 patients with axonal PNP and 265 controls underwent clinical examination, DN4 questionnaire, standard nerve conduction study, motor-root stimulation and CSP recordings from abductor digiti minimi. We calculated the afferent conduction time of CSP (a-CSP time) with the formula: CSP latency − root motor evoked potential latency. Results In the demyelinating PNP group the a-CSP time was significantly longer; in the axonal PNP group, CSP duration was shorter than the demyelinating group ( p = 0.010) and controls ( p = 0.001). CSP parameters were not different between patients with and without neuropathic pain. Conclusions The abnormality of a-CSP time in the demyelinating PNP group suggests the crucial role of A-delta fibres in the mechanism of CSP; the shorter CSP duration in the axonal PNP group supports the strong influence of the number of axons on this parameter. Our study suggests that neuropathic pain could be related to pathophysiological mechanisms differing from mere A-delta fibre loss. Significance CSP evaluation is effective in detecting A-delta fibre dysfunction in axonal as well as demyelinating PNP.

Neuropathic pain, i.e. pain arising as a direct consequence of a lesion or disease of the somatosensory system, affects about the 7 % of the general population. In this short review, we describe the most reliable laboratory tools for assessing neuropathic pain, such as quantitative sensory testing, laser-evoked potential recordings and skin biopsy, procedures that selectively assess nociceptive pathways.