Drug-induced peripheral neuropathies.

Review of the various drugs in current clinical use showed that over 50 of them may cause a purely sensory or mixed sensorimotor neuropathy. These include antimicrobials, such as isoniazid, ethambutol, ethionamide, nitrofurantoin, and metronidazole; antineoplastic agents, particularly vinca alkaloids; cardiovascular drugs, such as perhexiline and hydrallazine; hypnotics and psychotropics, notable methaqualone; antirheumatics, such as gold, indomethacin, and chloroquine; anticonvulsants, particularly phenytoin; and other drugs, including disulfiram, calcium carbimide, and dapsone. Patients receiving drug treatment who complain of paraesthesie, pain, muscle cramps, or other abnormal sensations and those without symptoms who are receiving drugs that are known or suspected to be neurotoxic should undergo neurological examination and studies of motor and sensory nerve conduction. This will allow the incidence of drug-induced peripheral neuropathy to be determined more precisely.     

Experimental models of peripheral neuropathies

BACKGROUND AND PURPOSE: Peripheral neuropathies, disorders of peripheral nerves, result from genetic alterations or from metabolic, inflammatory, infectious, or chemical insults. Experimental animal models, spontaneous or induced, exist for many of the common human peripheral neuropathies. Recent advances in human genetics have led to identification of several specific gene defects involved in heritable neuropathies and have allowed reproduction of the molecular defects in experimental animals. METHODS: Genetic modifications in mice and rats, similar to those seen in humans, along with animal models of specific gene defects are presented and discussed. RESULTS AND CONCLUSION: Chemotherapeutic agents administered to affected animals mimic the dose-dependent neuropathies similar to those seen in humans. Availability of the experimental animal models has been invaluable to an understanding of the pathogenesis of disease and the development of new treatments.     

Nerve conduction in childhood diabetes

Sixty-nine diabetic children were studied with respect to the motor nerve conduction velocities, duration of illness and adequacy of control.As a group there was a trend for children with diabetes to have slower MNCV than non-diabetic children, and for the slowing to become progressive as the duration of their disease increased. Poorer quality of diabetes control was also associated with progressive slowing of conduction but the exact relationship is uncertain, since no patient who had diabetes for more than four years was well controlled.Theories of causation of peripheral neuropathy in diabetic patients are reviewed; metabolic changes, rather than other factors, are thought most likely in children.     

Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies

Peripheral neuropathies are characterized by asymmetrical slowly progressive weakness with no upper motor neuron signs, and can occur either with or without pain. Due to poor knowledge of the disease mechanisms, available pain treatment is very limited. Because of the difficulties and invasiveness involved when performing direct analysis on peripheral and CNS, pathological markers can be searched for in the cerebrospinal fluid (CSF) as an alternative. To investigate pain mechanisms in peripheral neuropathy and find diagnostic markers, CSF samples were analyzed by a differential expression proteomic approach. We studied CSF from: neuropathic patients with pain (PN), without pain (NPN) and healthy controls (CN). 2-DE analysis showed ten protein spots differentially expressed, and six of these were identified by MS. In NPN patients we found an expression level decrease of three pigment epithelium-derived factor (PEDF) protein isoforms. Immunoblot with a specific antibody revealed the presence of additional PEDF isoforms not highlighted by differential expression analysis. Fucose residues on the oligosaccharide chain were found only in the isoforms down regulated in NPN patients. Considered as PEDF has important neurobiological effects, it might be considered an interesting pathology marker.     

Nerve conduction theory: Some mathematical consequences of Bernstein's model

The generally accepted permeability theory of nerve conduction is presented in mathematical form. The resulting velocity formula is found to agree well with data on squid giant axon, but predicts velocities considerably too high in the case ofNitella. The dependence of velocity on fiber diameter is discussed for both medullated and non-medullated nerve, it being shown theoretically that velocity is proportional to the square root of diameter for non-medullated and to the diameter for medullated nerve. The equations relating the shape of the action spike to the observed permeability changes are given but are not solved.     

Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects

We examine the utility of the action potential (AP) duration (APD) restitution curve slope in predicting the onset of electrical alternans when electrotonic and memory effects are considered. We develop and use two ionic cell models without memory that have the same restitution curve with slope >1 but different AP shapes and, therefore, different electrotonic effects. We also study a third cell model that incorporates short-term memory of previous cycle lengths, so that it has a family of S1-S2 restitution curves as well as a dynamic restitution curve with slope >1. Our results indicate that both electrotonic and memory effects can suppress alternans, even when the APD restitution curve is steep. In the absence of memory, electrotonic currents related to the shape of the AP, as well as conduction velocity restitution, can affect how alternans develops in tissue and, in some cases, can prevent its induction entirely, even when isolated cells exhibit alternans. When short-term memory is included, alternans may not occur in isolated cells, despite a steep APD restitution curve, and may or may not occur in tissue, depending on conduction velocity restitution. We show for the first time that electrotonic and memory effects can prevent conduction blocks and stabilize reentrant waves in two and three dimensions. Thus we find that the slope of the APD restitution curve alone does not always well predict the onset of alternans and that incorporating electrotonic and memory effects may provide a more useful alternans criterion.     

The heme precursor delta-aminolevulinate blocks peripheral myelin formation

Delta-aminolevulinic acid (δ-ALA) is a heme precursor implicated in neurological complications associated with porphyria and tyrosinemia type I. Delta-ALA is also elevated in the urine of animals and patients treated with the investigational drug dichloroacetate (DCA). We postulated that δ-ALA may be responsible, in part, for the peripheral neuropathy observed in subjects receiving DCA. To test this hypothesis, myelinating cocultures of Schwann cells and sensory neurons were exposed to δ-ALA (0.1–1 mM) and analyzed for the expression of neural proteins and lipids and markers of oxidative stress. Exposure of myelinating samples to δ-ALA is associated with a pronounced reduction in the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22. We also observed an increase in protein carbonylation and the formation of hydroxynonenal and malondialdehyde after treatment with δ-ALA. Studies of isolated Schwann cells and neurons indicate that glial cells are more vulnerable to this pro-oxidant than neurons, based on a selective decrease in the expression of mitochondrial respiratory chain proteins in glial, but not in neuronal, cells. These results suggest that the neuropathic effects of δ-ALA are attributable, at least in part, to its pro-oxidant properties which damage myelinating Schwann cells.     

The therapeutic potential of gene transfer for the treatment of peripheral neuropathies

Peripheral neuropathy is a common medical problem with numerous aetiologies. Unfortunately, for the majority of cases there is no available medical solution for the underlying cause, and the only option is to try to treat the resulting symptoms. Treatment options exist when neuropathy results in positive symptoms such as pain, but there is a significant lack of treatments for negative symptoms such as numbness and weakness. Systemic application of growth factor peptides has shown promise in protecting nerves from neuropathic insults in preclinical animal studies, but translation into human trials has been problematic and disappointing. Significant advancements have been made in the past few years in utilising gene therapy approaches to treat peripheral neuropathy by expressing neuroprotective gene products either systemically or in specific nervous tissues. For example, plasmids expressing vascular endothelial growth factor injected into muscle, or herpes-simplex-virus-based vectors expressing neurotrophin gene products delivered to dorsal root ganglion neurons, have been used to protect peripheral nerve function in animal models of diabetes-associated peripheral neuropathy. Many published studies support the feasibility of this approach, although several questions still need to be addressed as gene therapy to treat peripheral neuropathy moves out of the laboratory and into the clinic.     

Spectrum of peripheral neuropathies associated with surgical interventions; A neurophysiological assessment

Background

We hypothesized that a wide range of surgical procedures may be complicated by neuropathies, not just in close proximity but also remote from procedural sites. The aim of this study was to classify post-operative neuropathies and the procedures associated with them.

Methods

We retrospectively identified 66 patients diagnosed with post-procedure neuropathies between January 2005 and June 2008. We reviewed their referral cards and medical records for patient demographics, information on procedures, symptoms, as well as clinical and neurophysiological findings.

Results

Thirty patients (45.4%) had neuropathies remote from procedural sites and 36 patients (54.5%) had neuropathies in close proximity to procedural sites. Half of the remote neuropathies (15/30) developed following relatively short procedures. In 27% of cases (8/30) remote neuropathies were bilateral. Seven patients developed neuropathies remote from operative sites following hip arthroplasties (7/30: 23.3%), making hip arthroplasty the most common procedure associated with remote neuropathies. Sciatic neuropathies due to hip arthroplasty (12/36, 33.3%) accounted for the majority of neuropathies occurring in close proximity to operative sites. Five medial cutaneous nerve of forearm neuropathies occurred following arterio-venous fistula (AVF) formation.

Conclusions

An array of surgical procedures may be complicated by neuropathy. Almost half of post-procedure neuropathies occur remote from the site of procedure, emphasizing the need to try to prevent not just local, but also remote neuropathies. Mechanical factors and patient positioning should be considered in the prevention of post-operative neuropathies. There is a possible association between AVF formation and medial cutaneous nerve of forearm neuropathy, which requires further study for validation.     

Calcium signalling in sensory neurones and peripheral glia in the context of diabetic neuropathies

Peripheral sensory nervous system is comprised of neurones with their axons and neuroglia that includes satellite glial cells in sensory ganglia, myelinating, non-myelinating and perisynaptic Schwann cells. Pathogenesis of peripheral diabetic polyneuropathies is associated with aberrant function of both neurones and glia. Deregulated Ca²⁺ homoeostasis and aberrant Ca²⁺ signalling in neuronal and glial elements contributes to many forms of neuropathology and is fundamental to neurodegenerative diseases. In diabetes both neurones and glia experience metabolic stress and mitochondrial dysfunction which lead to deregulation of Ca²⁺ homeostasis and Ca²⁺ signalling, which in their turn lead to pathological cellular reactions contributing to development of diabetic neuropathies. Molecular cascades responsible for Ca²⁺ homeostasis and signalling, therefore, can be regarded as potential therapeutic targets.     

Temperature-dependent conduction properties in Arctic fish peripheral nerves

The conduction properties of peripheral nerves from the Arctic fish species Arctic eelpouts (Lycodes sp.), snake blenny (Lumpenus lampretaeformis) and polar cod (Boreogadus saida), permanently adapted to low temperatures, were studied. Nerves of these fishes have two types of fibres, characterised by extracellular compound action potentials with fast (7 m/s) and slow (4 m/s) conduction velocities, as measured at 12 °C. The temperature dependence of the conduction velocity was bimodal, changing its slope at about 16 °C. The Q ₁₀ above 16 °C was 1.12–1.49, while below 16 °C it was 1.82–2.16. Irreversible deterioration of the nerve was observed at temperatures around 19–27 °C. A comparison with data previously obtained from Mediterranean fishes indicates that Arctic fishes have similar temperature sensitivity of nerve conduction and a slight vertical displacement on the conduction velocity-temperature curves, which is insufficient to compensate the decrease of the conduction velocity at their physiological temperature, the conduction velocity of Arctic fishes being about one-half of that of temperate fishes. This suggests that this neurophysiological function is not fully cold-adapted in these Arctic fish species. Accepted: 3 June 2000     

Continuous conduction of impulses in peripheral myelinated nerve fibers

1. Conduction of impulses in peripheral myelinated fibers of a nerve trunk is a continuous process, since with uninjured nerve fibers: (a) within each internodal segment the conduction time increases continuously and linearly with increasing conduction distance; (b) the presence of nodes of Ranvier does not result in any detectable discontinuity in the conduction of the impulse; (c) the ascending phase of the spike always has an S shape and never presents signs of fractionation; (d) the shape and magnitude of the spike are constant at all points of each internodal segment. 2. Records have been presented of the external logitudinal current that flows during propagation of an impulse in undissected single nerve fiber (Fig. 6). 3. Propagation of impulses across a conduction block occurs with a readily demonstrable discontinuity.     

Purification and initiation of structural characterization of human peripheral myelin protein 22, an integral membrane protein linked to peripheral neuropathies

Gene duplications, deletions, and point mutations in peripheral myelin protein 22 (PMP22) are linked to several inherited peripheral neuropathies. However, the structural and biochemical properties of this very hydrophobic putative tetraspan integral membrane protein have received little attention, in part because of difficulties in obtaining milligram quantities of wild type and disease-linked mutant forms of the protein. In this study a fusion protein was constructed consisting of a fragment of lambda repressor, a decahistidine tag, an intervening TEV protease cleavage site, a Strep tag, and the human PMP22 sequence. This fusion protein was expressed in Escherichia coli at a level of 10-20 mg/L of protein. Following TEV cleavage of the fusion partner, PMP22 was purified and its structural properties were examined in several different types of detergent micelles using cross-linking, near and far-UV circular dichroism, and nuclear magnetic resonance (NMR) spectroscopy. PMP22 is highly helical and, in certain detergents, shows evidence of stable tertiary structure. The protein exhibits a strong tendency to dimerize. The 1H-15N TROSY NMR spectrum is well dispersed and contains signals from all regions of the protein. It appears that detergent-solubilized PMP22 is amenable to detailed structural characterization via crystallography or NMR. This work sets the stage for more detailed studies of the structure, folding, and misfolding of wild type and disease-linked mutants in order to unravel the molecular defects underlying peripheral neuropathies.