Mario Campero

Slowly conducting afferents activated by innocuous low temperature in human skin

1 Microneurography was used to search for primary afferents responsive to innocuous low temperature in human nerves supplying the hairy skin of the hand or foot. Eighteen units were identified as cold‐specific units: they displayed a steady‐state discharge at skin temperatures in the range 28‐30 °C, they were sensitive to small changes in temperature, and they responded vigorously when a cool metal probe touched their receptive fields (RFs). They were insensitive to mechanical stimuli and sympathetic activation. Their RFs comprised one, or at most two, spots less than 5 mm in diameter. 2 Nine units were characterised in detail by a series of 10 s cooling and warming pulses from a holding temperature of 35 °C. The threshold temperature for activation by cooling was 29.4 ± 2.0 °C (mean ±s.d.). Adaptation of the responses to supra‐threshold cooling pulses was partial: mean peak and plateau firing rates were maximal on steps to 15 °C (35.9 and 19.9 impulses s−1, respectively). Three of these units also displayed a paradoxical response to warming, with a mean threshold of 42.3 °C. 3 Sixteen of the eighteen cold‐specific units were also studied by electrical stimulation of their RFs. They conducted in the velocity range 0.8‐3.0 m s−1. When stimulated at 2 Hz, their latency increased according to a characteristic time course, reaching a plateau within 3 min (mean slowing (±s.d.) 5.2 ± 1.1 %) and recovering quickly (50 % recovery in 17.8 ± 4.5 s). 4 To reconcile these findings with previous studies of reaction times and the effects of nerve compression on sensation, it is concluded that either human cold‐specific afferent fibres are incompletely myelinated ‘BC’ fibres, or else there are C as well as Aδ cold fibres, with the C fibre group contributing little to sensation.

Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy

Six patients with chronic pain, mechanical and thermal hyperalgesia/allodynia, and cutaneous vasodilatation starting distally in their extremities, were evaluated using clinical and neurophysiological methods and microneurography. Evidence of small‐fiber polyneuropathy was documented in all, but the etiology remained cryptogenic in several. Different forms of hyperexcitability were detected by microneurography in both common polymodal and mechanically insensitive C nociceptors, which explain all the somatosensory abnormalities. Signs of hyperexcitability included reduced receptor threshold (accounting for mechanical and heat allodynias), spontaneous C nociceptor discharge (explaining spontaneous “burning” pain and antidromic vasodilatation), and multiplied nociceptor responses to stimulation (accounting for hyperalgesia). The clinical and electrophysiological profiles of these patients resemble the experimental syndrome evoked by application of capsaicin to the skin. This similarity, and the striking heat dependence of the spontaneous pain, suggest that a common feature may be altered expression or modulation of vanilloid 1 receptor, provoking abnormal nociceptor discharges. Muscle Nerve, 2005

Phentolamine sympathetic block in painful polyneuropathies II. Further questioning of the concept of ‘sympathetically maintained pain’

To test for the presence of “sympathetically maintained pain” (SMP), we administered placebo-controlled phentolamine sympathetic blocks to 14 patients with painful polyneuropathies. Six received IV infusion of saline for 30 minutes, followed by phentolamine (35 mg). In eight patients, the saline phase was followed by double-blind infusion of phentolamine or phenylephrine (500 μg), a second saline phase, and then the other active drug. We measured magnitudes of spontaneous pain and mechanical hyperalgesias on a 0-to-10 pain scale every 5 minutes and monitored sensory and sympathetic effects clinically and through quantitative thermotest and thermography. Five patients reported significant diminution of pain (> 50%), all in response to placebo. Neither phentolamine nor phenylephrine provided relief, although all patients had signs of physiologic abnormalities reputed to be determinants or predictors of SMP. These results complement previous studies demonstrating the nonexistence of SMP among “reflex sympathetic dystrophy” patients and further question the concept of SMP.

Velocity recovery cycles of C fibres innervating human skin.

Velocity changes following single and double conditioning impulses were studied by microneurography in single human C fibres to provide information about axonal membrane properties. C units were identified as mechano‐responsive (n= 19) or mechano‐insensitive (12) nociceptors, cold‐sensitive (8) or sympathetic fibres (9), and excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25–2 Hz. The interval between single or paired (20 ms apart) conditioning stimuli and test stimulus was then varied between 500 and 2 ms, and recovery curves of velocity change against inter‐spike interval constructed, allowing for changes in these variables with distance. All fibres exhibited an initial (4–24 ms) relative refractory phase, and a long‐lasting (>500 ms) ‘H2’ phase of reduced velocity, attributed to activation of Na+/K+‐ATPase. Mechano‐responsive nociceptors exhibited an intermediate phase of either supernormality or subnormality, depending on stimulation rate. Mechano‐insensitive nociceptors behaved similarly, but all were supernormal at 1 Hz. Sympathetic units exhibited only a long‐lasting supernormality, while cold fibres exhibited a briefer supernormal and a late subnormal phase (H1), similar to A fibres. A pre‐conditioning impulse doubled H2 and increased H1, but did not augment supernormality or the subnormality of similar time course. Like A fibre supernormality, these phenomena were explained by a passive cable model, so that they provide an estimate of membrane time constant. Nociceptor membrane time constants (median 110 ms, n= 17) were rather insensitive to membrane potential, indicating few active voltage‐dependent potassium channels, whereas sympathetic time constants were longer and reduced by activity‐dependent hyperpolarisation.

Unmyelinated afferents in human skin and their responsiveness to low temperature

In humans, there are different types of cutaneous cold-sensitive afferents responsible for cold sensation and cold pain. Innocuous cold is primarily mediated by a population of slow A delta afferents, based on psychophysical and neurophysiological studies. Noxious cold (usually below 15 degrees C) is mediated, at least in part, by polymodal nociceptors. There is also a population of unmyelinated afferents responsive to innocuous low temperature, some of which also respond to heat, whose sensory function has not been completely defined. A paradoxical hot/burning evoked by cooling is unmasked by A-fibre block, and similar sensations are evoked by applying simultaneous cool and warm stimuli to adjacent skin areas. These unmyelinated fibres activated by innocuous cooling (and heating) may contribute to this hot/burning sensation, along with other thermoregulatory functions.

ALS-linked protein disulfide isomerase variants cause motor dysfunction

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS‐linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.

Toward an objective measure of functional disability in dysferlinopathy.

Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales.

Cerebral and Cutaneous Involvements of Xanthoma Disseminatum Successfully Treated with an Interleukin-1 Receptor Antagonist: A Case Report and Minireview.

A young male presented with panhypopituitarism (including diabetes insipidus) and temporal lobe epilepsy. A histology specimen of cutaneous papules was diagnostic of non-Langerhans histiocytosis. The diagnosis of xanthoma granulomata was considered based on the clinical and brain MRI findings. Brain lesions significantly worsened over time despite radiotherapy until anakinra induced a complete clinical and radiological remission of all active lesions. Although a single case, the outcome of this patient with xanthoma disseminatum treated with an interleukin-1 receptor antagonist opens and strengthens new and recent physiopathogenic and treatment perspectives for the otherwise difficult-to-treat non-Langerhans cell histiocytosis. Similar results with anakinra have been observed in patients with Erdheim-Chester disease and in multicentric reticulohistiocytosis.

Nerve Excitability and Structural Changes in Myelinated Axons from Diabetic Mice

OBJECTIVE The mechanisms associated with nerve dysfunction and axonal loss in diabetes has not been fully clarified. Excitability and pathological aspects in nerves from diabetic mice were studied in order to explore the pathophysiology of diabetic neuropathy. METHODS Myelinated nerve fibres from the sciatic nerve of BKS.Cg-m (+/+) Lepr (db) /J mice were studied by registering the CMAP controlled by an automated threshold tracking method. The sciatic nerve was also studied pathologically. RESULTS Diabetic mice displayed longer latencies, higher thresholds and lower amplitudes compared to controls and had a rightward shift in the stimulus response curves. Strength-duration time constant was lower in diabetic mice but not reaching statistical significance (p=0.09). Diabetics displayed an increase in accommodation, with a smaller change in excitability in threshold electrotonus. Refractoriness, mean superexcitability and late subexcitability were reduced in diabetic mice. Diabetic mice had a larger number of myelinated fibres compared to controls (p<0.05), but larger than 9 μm were virtually absent, accounting for near 7% in control animals. CONCLUSIONS Db/db mice develop electrophysiological changes suggestive of membrane depolarization as the result of Na(+)/K(+) pump impairment. Loss of large myelinated fibres might also contribute to the nerve excitability profiles in this model.

Spinal cord infarction with ipsilateral segmental neuropathic pain and flaccid paralysis. A functional role for human afferent ventral root small sensory fibres

This paper illustrates the cases of two patients with an acute onset of right brachial neuropathic pain, flaccid paralysis and contralateral thermal and thermal pain hypoesthesia, without posterior column impairment nor pyramidal signs below the segmental lesion. MRI showed right sided spinal cord infarction, in the anterior spinal artery territory between C1 and C5 in one patient and between C3 and C7 in the other. Contact Heat Evoked Potentials and Quantitative Thermal Sensory testing are consistent with contralateral, but not ipsilateral, spinothalamic tract involvement. Electromyographic results established ipsilateral segmental denervation and somatosensory evoked responses were consistent with dorsal column sparing. Unilateral anterior cervical spinal cord infarction may present with acute ipsilateral segmental neuropathic pain, lower motor neurone-type weakness, contralateral thermoanalgesia and no pyramidal signs. The ipsilateral pain provides novel evidence that in some instances, ventral roots can play a role in nociception in humans. The infarcted territory may result from occlusion of a sulcal commissural artery or a number of more proximal vessels (including a single or duplicated anterior spinal artery, vertebral arteries or feeding radicular arteries).