Potential risks of iatrogenic complications of nerve conduction studies (NCS) and electromyography (EMG).

Nerve conduction and electromyography studies are generally well tolerated and pose little risk to patients of serious adverse events in the hands of a well-trained competent practitioner. However, some patients and certain examinations do carry a higher risk of potential complications. It is good medical practice to inform patients of any risks, their potential severity and relative frequency. In order to obtain informed consent a dialogue should take place about the nature, purpose and effects of the studies, so patients can decide if they wish to undergo the proposed investigation. In this educational review we identify those procedures and patients at risk, and provide pragmatic practice recommendations for managing these material risks.

Skeletal muscle MRI magnetisation transfer ratio reflects clinical severity in peripheral neuropathies.

MRI may provide treatment outcome measures in neuromuscular conditions. The authors assessed MRI magnetisation transfer ratios (MTRs) in lower-limb musculature as markers of pathology in peripheral neuropathies and compared the findings with associated clinical data. Ten patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were compared with 10 healthy subjects. The MTR in the calf muscles was significantly lower than controls in the two patient groups (both p<0.001). The median MTRs (IQR) were 50.5(1.6) percentage units (p.u.) (control), 41.5(10.6) p.u. (CMT1A) and 39.3(8.7) p.u. (CIDP). Moreover, anterior lower leg MTR correlated strongly with strength of ankle dorsiflexion, measured with the Medical Research Council scale, in CIDP (ρ=0.88, p<0.001) and also in CMT1A (ρ=0.50, p<0.05), where MTR also showed an association with disease duration (ρ=-0.86, p<0.001). Short tau inversion recovery MRI of the same muscles showed abnormalities associated with regions of reduced MTR (p<0.001), and MTR was also reduced in other muscles otherwise deemed normal appearing (p<0.001), indicating that MTR may be more sensitive to muscle damaged by denervation than conventional MRI. The significant reductions in muscle MTR in peripheral neuropathies and the associated correlations with clinical measures indicate that MTR has potential as an imaging outcome measure in future therapeutic trials.

Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems.

Signaling downstream of receptor tyrosine kinases controls cell differentiation and survival. How signals from different receptors are integrated is, however, still poorly understood. In this work, we have identified Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin repeat-rich membrane spanning) as a main player in the modulation of neurotrophin and vascular endothelial growth factor (VEGF) signaling in vivo, and a primary determinant for neuronal and cardiovascular development. Kidins220(-/-) embryos die at late stages of gestation, and show extensive cell death in the central and peripheral nervous systems. Primary neurons from Kidins220(-/-) mice exhibit reduced responsiveness to brain-derived neurotrophic factor, in terms of activation of mitogen-activated protein kinase signaling, neurite outgrowth and potentiation of excitatory postsynaptic currents. In addition, mice lacking Kidins220 display striking cardiovascular abnormalities, possibly due to impaired VEGF signaling. In support of this hypothesis, we demonstrate that Kidins220 constitutively interacts with VEGFR2. These findings, together with the data presented in the accompanying paper, indicate that Kidins220 mediates the integration of several growth factor receptor pathways during development, and mediates the activation of distinct downstream cascades according to the location and timing of stimulation.

Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development.

The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75(NTR). Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain.

MRI shows increased sciatic nerve cross sectional area in inherited and inflammatory neuropathies.

Measurements of the cross sectional area of the sciatic nerve are described in a group of 10 patients with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A), nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 10 healthy controls using MRI. One mid-thigh of each individual was imaged using a short tau inversion recovery sequence and the nerve appearance evaluated radiologically with respect to the signal intensity and visibility of the internal neural structure. The cross sectional area of the sciatic nerve of each individual was measured by defining irregular enclosing regions of interest on the MRI images. The sciatic nerve area was enlarged in both CMT1A (p<0.001) and CIDP (p=0.008) compared with controls and in CMT1A compared with CIDP (p<0.001). Median (interquartile range) areas were 67.6 (16.2) mm(2) for the CIDP group, 135.9 (46.5) mm(2) for the CMT1A group and 43.3 (19.9) mm(2) for the control group. The critical upper value for discriminating pathologically enlarged nerves from normal controls with p<0.05 was 64.4 mm(2). Quantification of sciatic nerve hypertrophy on MRI may be of assistance in cases where the diagnosis is still in doubt, providing an objective pathological marker complimenting other clinical investigations.

The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice.

A local elevation of H+-ion concentrations often occurs in inflammation and usually evokes pain by excitation of primary nociceptive neurons. Expression patterns and functional properties of the capsaicin receptor and acid-sensing ion channels suggest that they may be the main molecular substrates underlying this proton sensitivity. Here, we asked how the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) contribute to the proton response in subpopulations of nociceptive neurons from adult rats and mice (wildtype C57/Bl6, Balb/C and TRPV1-null). In cultured dorsal root ganglion neurons, whole cell patch clamp recordings showed that the majority of capsaicin-sensitive rat dorsal root ganglion neurons displayed large proton-evoked inward currents with transient ASIC-like properties. In contrast, the prevalence of ASIC-like currents was smaller in both mouse wildtype strains and more frequent in capsaicin-insensitive neurons. Transient ASIC-like currents were more frequent in both species among isolectin B4-negative neurons. A significantly reduced proton response was observed for dissociated dorsal root ganglion neurons in TRPV1 deficient mice. Unmyelinated, but not thin myelinated nociceptors recorded extracellularly from TRPV1-null mutants showed a profound reduction of proton sensitivity. Together these findings indicate that there are significant differences between rat and mouse in the contribution of TRPV1 and ASIC subunits to proton sensitivity of sensory neurons. In both species ASIC subunits are more prevalent in the isolectin B4-negative neurons, some of which may represent thin myelinated nociceptors. However, the main acid-sensor in isolectin B4-positive and isolectin B4-negative unmyelinated nociceptors in mice is TRPV1.

Painful vascular compression syndrome of the sciatic nerve caused by gluteal varicosities.

The authors report three patients with chronic sciatic pain without focal neurologic deficit. Sitting or lying on the affected side provoked pain, and standing and walking relieved it. MRI revealed varicotic gluteal vessels compressing the sciatic nerve. Decompression of the nerve resulted in complete and permanent pain relief. Sciatic or buttock pain in patients with varicosities and pain provocation in the sitting or lying position suggests this neurovascular compression syndrome.

Peroneal nerve palsy caused by thrombosis of crural veins.

Acute palsies of the peroneal nerve may have a variety of causes. In many patients, the cause remains undetermined. The authors report a patient with a thrombosis of a crural vein causing an acute peroneal nerve palsy. If the clinical history of patients with an acute peroneal nerve lesion is suggestive of venous thrombosis an appropriate diagnostic workup should be considered.

Predominant neuronal B-cell loss in L5 DRG of p75 receptor-deficient mice.

The significance of the p75 low-affinity neurotrophin receptor, for the maintenance and survival of DRG cells, was studied in p75-deficient mice. Perikarya of the L5 DRG of 12-week-old p75 receptor-deficient mice and healthy Balb C mice were compared using stereological techniques. Following systematic sampling, the optical fractionator and the planar vertical rotator were used to estimate the number and mean volume of the cell bodies of the two neuronal subpopulations. The loss of B-cells was 57% (P < 0.00001), numbers being 7300 (CV = 0.12) in controls and 3100 in p75 receptor-deficient mice (CV = 0.18). Also, A-cells showed a significant loss of 39% (P < 0.0001), numbers being 2600 (CV = 0.12) in control mice and 1500 (CV = 0.16) in p75 receptor-deficient mice. The volume of A-cells was reduced by 30% (P<0.01), from 24.700 microm3 (CV=0.17) perikarya in p75 knock-out mice to 15.100 microm3 (CV=0.17) in controls. B-cell volume did not change significantly. It is concluded that the p75 receptor plays a major role in the survival of DRG cells. The predominant loss of small B-cells indicates that the effect of neurotrophins is dependent upon the presence of the p75 low-affinity receptor.

Visualization of denervated muscle by gadolinium-enhanced MRI.

Thirty patients presenting with foot drop due to lesions of the peroneal nerve or L5 spinal root were investigated with gadolinium (Gd)-enhanced MRI of the lower leg. Significant enhancement was only seen in the denervated muscles in a pattern appropriate for the distribution of the nerve or root. In a rat model, identical changes in the denervated muscle were reproduced and seen as early as 24 hours after sciatic nerve transection. Thus, Gd-enhanced MRI is a new and sensitive technique to visualize denervated muscle.

MRI in isolated sixth nerve palsies.

In previous studies the origin of the majority of isolated sixth nerve palsies was not clear or was ascribed to vascular disease. Our purpose was determine how frequently a causative lesion was demonstrated on MRI in patients with an acute unilateral sixth nerve palsy. We performed a prospective study of 43 patients using a standardised protocol. In 27 patients (63%) a lesion was identified on the initial MRI relevant to the sixth nerve palsy; 21 (49%) were found to have a tumour or tumour-like lesion; the frequency of presumed vasculopathy in this group was 15%. There were 16 patients (37%) with an initially normal MRI, of whom 10 (62%) had a history of vasculopathy, a significantly different proportion from the group of patients with a visible causative lesion. MRI after 3-6 months was normal in all patients with a normal initial MRI. We suggest that MRI should routinely be performed in patients presenting with an acute sixth nerve palsy, even those with evidence of a vasculopathy. If the symptoms regress spontaneously and there is a history of vasculopathy, follow-up MRI is not necessary.

Neuropathic pain.

Damage to peripheral nerves triggers a cascade of events in axotomized sensory neurones that are generally believed to be responsible for the generation of neuropathic pain. Recent data in animal models show that alterations in the properties of undamaged neurones that project into a damaged nerve can also play an important role. These new findings could explain some of the enigmatic clinical signs and symptoms of pain following nerve injury such as the spread of symptoms into areas not affected by the primary lesion. The basis by which uninjured nerves could be affected is a reduced supply of neurotrophic factors, an abnormal interaction in the Remak bundles of partially denervated Schwann cells and unmyelinated axons, or the byproducts of Wallerian degeneration.

Glutamate-induced excitation and sensitization of nociceptors in rat glabrous skin.

Anatomical studies demonstrate the presence of glutamate receptors on unmyelinated axons in peripheral cutaneous nerves. Pharmacological studies show that intraplantar injection of glutamate or glutamate agonists in the glabrous skin results in nociceptive behaviors. The present study describes a novel in vitro skin-nerve preparation using the glabrous skin from the rat hindpaw. In the first series of experiments, recordings were obtained from 141 fibers that responded to a strong mechanical search stimulus. Based on their conduction velocity they were classified as C (27%), A delta (28%) and A beta (45%) fibers. The C and A delta fibers typically exhibited sustained firing during suprathreshold mechanical stimuli whereas both rapidly (66%) and slowly (34%) adapting responses were obtained from A beta fibers. Noxious heat excited 46% of the C fibers but only 12% of the A delta units. In another series of experiments application of an ascending series of glutamate concentrations (10, 100, 300, and 1000 microM) to A delta (n=14) and C (n=19) nociceptors resulted in a significant excitation of 43% (6/14) A delta fibers and 68% (13/19) C fibers. At these concentrations, there was no excitation of A beta units (n=13). Superfusion of the receptive fields of either mechanoheat-sensitive A (AMH, n=10) or C fibers (CMH, n=12) for 2 min with 300 microM glutamate resulted in sensitization of 90% (9/10) AMH and 92% (11/12) CMH fibers to subsequent thermal stimulation. This was evidenced by a significant (1) decrease in thermal threshold for activation, (2) increase in discharge rate, and (3) increase in peak instantaneous frequencies during the second heat trial. Glutamate-induced sensitization to heat occurred in the absence of either a glutamate-induced excitation or an initial heat response. Exposure of A delta or C fibers to glutamate did not result in a decrease in von Frey thresholds. These data provide a physiological basis for the nociceptive behaviors that arise following intraplantar injection of glutamate or glutamate agonists. Furthermore, demonstration of glutamate-induced excitation and heat sensitization of nociceptors indicates that local or topical administration of glutamate receptor antagonists may have therapeutic potential for the treatment of pain.

Neural mechanisms of cutaneous nociceptive pain.

Acute mechanical, thermal, and chemically induced pains in the skin are signalled by a set of specific nociceptive afferents, which encode the magnitude of the perceived pain by their discharge intensity. After tissue injury or inflammation, a number of changes in the properties of the primary afferent occur parallel to profound changes in the central nervous system. Primary hyperalgesia (within the area of tissue injury) is best explained by changes of the properties of primary nociceptive afferents, whereas secondary hyperalgesia (increased pain sensitivity outside the area of tissue injury) critically requires functional changes in the central nervous system. Collectively, these changes are the basis for the many forms of hyperalgesia that can present clinically as incident pain. Knowledge of the various types of hyperalgesia and their underlying mechanisms is required for better treatment of this challenging aspect of chronic pain.

Changes of copper-transporting proteins and ceruloplasmin in the lentiform nuclei in primary adult-onset dystonia.

A recent study reported an increase of brain tissue copper content in the lentiform nuclei of patients with primary adult-onset dystonia. In this study we analyze copper-metabolizing proteins (Menkes protein, Wilson protein, ceruloplasmin) by Western blot analysis in frozen brain tissue (lentiform nuclei) of 3 patients with primary dystonia. Menkes protein was reduced in all patients, while Wilson protein and ceruloplasmin were increased in the 2 patients with focal dystonia and reduced in the patient with generalized dystonia. Our data provides further evidence for a disturbance of copper metabolism in primary dystonia.

Impaired nociception and pain sensation in mice lacking the capsaicin receptor.

The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.

Localization of ionotropic glutamate receptors in peripheral axons of human skin.

Recent observations suggest that glutamate is important in sensory transduction in the periphery, contributing to peripheral sensitization of nociceptors and the hyperalgesia that accompanies inflammation. This study examined the presence of ionotropic glutamate receptors N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazolone-4-propionic acid (AMPA) and kainate (KA) in normal human hairy skin (n=6) using immunohistochemistry at the electron microscopic level. Analysis of labeled axons at the dermal-epidermal junction demonstrated that 26. 9+/-2, 19.5+/-3 and 18.5+/-1% of the axons analyzed were labeled for subunits of the NMDA, AMPA or KA receptors, respectively. An occasional Schwann cell process was labeled for either NMDA or KA receptors. The findings support the hypothesis that glutamate and its ionotropic receptors may play a role in the periphery in sensory processing in humans.

Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75.

Merkel cells are specialized epidermal cells which are abundantly found in touch-sensitive areas and which are innervated by slowly adapting mechanosensitive afferent fibres with large myelinated (Abeta) axons. The role of Merkel cells in mechanosensation, their developmental regulation and their influence on sensory neuron function are, however, incompletely understood. Here, we used mice lacking the neurotrophin receptor p75 which is expressed on Merkel cells to investigate their postnatal development and that of their innervating sensory neurons. Using morphological studies we now show that Merkel cells develop normally in both hairy and glabrous skin in these animals until 2 weeks old, but are progressively lost thereafter and have almost completely disappeared 2 months after birth. Using standard extracellular electrophysiological recording techniques we find that despite the profound loss of Merkel cells there is no corresponding reduction in the number of myelinated slowly adapting afferent fibres. Moreover, the mean mechanical threshold of these neurons and their average stimulus response function to suprathreshold mechanical stimuli does not change during the time period when more than 99% of Merkel cells are lost. We conclude that Merkel cells require p75 during the late postnatal development. However, neither the survival nor the mechanical sensitivity of slowly adapting mechanoreceptive Abeta-fibres depends on the presence of Merkel cells.