Chronic Peripheral Neuropathy Research Articles

Disease management for chronic pain: barriers of program implementation with primary care physicians.

This study investigated the implementation of a disease management (DM) program for chronic pain among primary care physicians. Its aim was the dissemination of guidelines for the treatment of chronic pain to help primary care physicians identify, treat, and manage patients highly impaired by pain. The goals of the program were: 1) To identify those pain patients who are at greatest disability due to pain; 2) To assess the impact of a DM program for pain on clinical practice; and 3) To evaluate the effect of the program on physician's use, compliance, and satisfaction with guidelines. Thirty primary care physicians followed 82 patients who were identified as having chronic migraine headaches, back pain, or painful peripheral neuropathy. All patients were categorized according to their level of disability based on ratings of pain intensity, activity interference, emotional distress, perceived support, and work disability. Treatment algorithms developed for this study were placed in the charts of those patients considered to have moderate or high disability. Physicians completed pre- and poststudy questionnaires. Chronic pain patients could be successfully classified according to the disability from their pain and physicians were open to accepting guidelines for treatment. By the end of the study, primary care physicians reported improved confidence in treating chronic pain. Most felt that chronic pain management was a problem in their practice, and they recognized the benefit of treatment algorithms. Many of the physicians, however, expressed reluctance to regularly consult the algorithms when treating chronic pain. The identification of barriers for implementation of DM programs for pain is presented, and recommendations for future implementation are discussed.

The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy.

Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies caused by aberration of the intimate relationship between the myelin sheath and the axon; disorders causing demyelination are classified as CMT1 and those causing axonal loss as CMT2. The mechanisms by which mutations disturb the relationship of the myelin sheath and axon are not fully understood; however, we hypothesize that some mutations affect this relationship more profoundly than others, and thus account for the paradox that mutation of a "myelin gene" can present with electrophysiologic features of CMT2 and vice versa. Also, contrary to popular understanding, inherited neuropathies account for a substantial number of chronic peripheral neuropathies. Because of this observation, we propose that molecular diagnosis is a necessary adjunct for differentiating genetic and acquired peripheral neuropathies, even in sporadic chronic neuropathy.

An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers

OBJECTIVESTo investigate the hypothesis that chronic low level exposure to organophosphates (OPs) in sheep dips is related to clinically detectable measures of polyneuropathy.METHODSThe design was a cross sectional exposure-response study...

Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis

Painful sensory neuropathy is a common and debilitating consequence of human immunodeficiency virus (HIV). The underlying causes of neuropathic pain are most likely not due to direct infection of the nervous system by active virus. The goal of this study was to determine whether epineural exposure to the HIV-1 envelope protein gp120 could lead to chronic painful peripheral neuropathy. Two doses of gp120 or BSA control were transiently delivered epineurally via oxidized cellulose wrapped around the rat sciatic nerve. Animals were assessed for neuropathic pain behaviors at several intervals from 1–30 days following nerve surgery. Allodynia and hyperalgesia were observed within 1–3 days following gp120 and sustained throughout the testing period. The gp120-exposed sciatic nerve exhibited early but transient pathology, notably axonal swelling and increased tumor necrosis factor alpha (TNF-α) within the nerve trunk. In contrast, intense astrocytic and microglial activation was observed in the spinal cord, and this gliosis persisted for at least 30 days following epineural gp120, in parallel with neuropathic pain behaviors. These findings demonstrate that limited peripheral nerve exposure to HIV protein can induce persistent painful sensory neuropathy that may be sustained and magnified by long-term spinal neuropathology.

Management of Chronic Peripheral Neuropathy

Management of Chronic Peripheral Neuropathy

Determination of platinum by radiochemical neutron activation analysis in neural tissues from rats, monkeys and patients treated with cisplatin

Cisplatin is one of the most used antineoplastic drugs, essential for the treatment of germ cell tumours. Its use in medical treatment of cancer patients often causes chronic peripheral neuropathy in these patients. The distribution of cisplatin in neural tissues is, therefore, of great interest. Rats and monkeys were used as animal models for the study of sensory changes in different neural tissues, like spinal cord (ventral and dorsal part), dorsal root ganglia and sural nerve. The study was combined with quantitative measurements of the content of platinum in the neural tissues of the animals mentioned and in the neural tissues of human patients. For the determination of platinum in the tissues radiochemical neutron activation analysis has been used. The detection limit is 1 ng Pt g −1. The platinum results indicate that platinum becomes accumulated in the dorsal root ganglia and in the sural nerve.

Localization of survival motor neuron protein in human apoptotic-like and regenerating muscle fibers, and neuromuscular junctions.

Mutations in the gene encoding survival motor neuron (SMN) protein are found in > 98% of patients with autosomal-recessive spinal muscular atrophy. We investigated the possible role of SMN in normal and abnormal human muscle by immunostaining biopsies of 20 patients with various neuromuscular diseases using monoclonal antibodies against SMN. SMN was strongly expressed cytoplasmically in chronic peripheral neuropathies, in about 80% of chronically denervated, very atrophic muscle fibers containing clumps of TUNEL-positive pyknotic nuclei: about 60% of those fibers also had cytoplasmic Bcl-2 and Bax immunoreactivity. In regenerating muscle fibers of various myopathies SMN co-localized with desmin, Bcl-2 and Bax; it was also present at the postsynaptic domain of normal human neuromuscular junctions. Thus, SMN may play a role in normal and pathological processes of adult human muscle fibers.

Diabetic peripheral neuropathy and quality of life.

The quality of life (QOL) of 79 people with type 1 and type 2 diabetes and 37 non-diabetic controls was assessed using the Nottingham Health Profile (NHP). The NHP consists of six domains assessing energy, sleep, pain, physical mobility, emotional reactions and social isolation. Symptomatic diabetic neuropathy was present in 41 of the patients. The neuropathy patients had significantly higher scores (impaired QOL) in 5/6 NHP domains than either the other diabetic patients (p < 0.01) or the non-diabetic (p < 0.001) controls. These were: emotional reaction, energy, pain, physical mobility and sleep. The diabetic patients without neuropathy also had significantly impaired QOL for 4/6 NHP domains compared with the non-diabetic control group (p < 0.05) (energy, pain, physical mobility and sleep). This quantification of the detrimental effect on QOL of diabetes, and in particular of chronic symptomatic peripheral diabetic neuropathy, emphasizes the need for further research into effective management of these patients.

Antiglycolipid antibodies in motor neuropathies.

In peripheral neuropathies with monoclonal gammopathy, mainly IgM, it appears clear from clinical, electrophysiological, and experimental data, that the target glycolipid or glycolipid epitope for the IgM is related to the type of neuropathy--purely sensory, predominantly sensory, or uniquely motor. Investigations have focused on chronic peripheral neuropathies associated with polyclonal IgM reactivity to glycolipids. Although IgM anti-GM1 antibodies are present in normal controls, there is a subgroup of motor neuropathies with high titer anti-GM1 antibodies, mainly multifocal neuropathies with conduction blocks (MMNCB). Another subgroup of MMNCB may include IgM anti-SGPG antibodies that do not cross-react with MAG. The importance of the fine structure of the epitope has to be considered in view of the pathogenicity of the antibody. It may bear consequences on its binding properties on the neuronal surfaces and on its biological implications.

Neural architecture in transected rabbit sciatic nerve after prolonged nonreinnervation.

Observations have been made on the rabbit sciatic nerve distal to a transection, with survival periods of up to 26 mo and prevention of reinnervation. It was confirmed that the nerve becomes compartmented by fibroblast processes and that a zone of fine collagen fibrils develops around the Schwann cell columns that constitute the Büngner bands. The Schwann cells become progressively more atrophic but after 6 mo of denervation still expressed low affinity p75 nerve growth factor receptor (NGFR), the latest stage at which this was examined. NGFR was also expressed by the processes of the fibroblasts producing the endoneurial compartmentation. By 26 mo after transection the site of previous nerve fibres was indicated by sharply demarcated domains of approximately circular outline in transverse section consisting of densely packed longitudinally oriented collagen fibrils. Some of these domains still possessed centrally situated Schwann cells or residual basal lamina but many were acellular. The central collagen fibrils in these domains were of smaller diameter than those situated peripherally but were of larger size than those that form around the Büngner bands during wallerian degeneration. The peripherally located fibrils in the domains were of the same calibre as for normal endoneurial collagen. The collagen domains were encircled by fibroblast processes or at times enclosed in a perineurial cell ensheathment. Long-standing axonal loss therefore leads to a striking reorganisation of the internal architecture of peripheral nerve trunks. The findings may be relevant for the interpretation of the appearances in chronic peripheral neuropathies in man.

Autoantibodies in Neurodegenerative Diseases: Antigen-Specific Frequencies and Intrathecal Analysis

The frequency of autoantibodies (AAbs) was surveyed in several neurodegenerative diseases, other neurological diseases, and controls using antigen-specific EIAs for neurofilament heavy subunit, tubulin, glial fibrillary acidic protein, S100 protein, tau, β-amyloid peptide, myelin basic protein, and heparan sulfate proteoglycan. High frequencies of sera and cerebrospinal fluid tubulin AAbs were found in Alzheimer disease (62% and 69%, respectively), Parkinson disease (27% and 70%), amyotrophic lateral sclerosis (54% and 67%), and in sera from multiple sclerosis (50% and 67%), optic neuritis (85%), Guillain-Barré syndrome (88%), and vascular dementia (52%). High frequencies of neurofilament heavy subunit AAbs were detected in Guillain-Barré syndrome, chronic peripheral neuropathy (88%) and optic neuritis (62%); whereas, some Alzheimer’s disease (33%) and vascular dementia (44%) patients had glial fibrillary acidic protein AAbs. Lower frequencies of other AAbs were found in patient groups. AAb results were also compared to functional assessment of blood-brain barrier integrity in Parkinson’s disease and Alzheimer’s disease. The relevance of these AAbs to pathogenesis and/or course of neurologic diseases merits further study with particular reference to subgrouping and prognosis.

Mixed cryoglobulinaemia: a cross-road between autoimmune and lymphoproliferative disorders.

Mixed cryoglobulinaemia (MC) is a systemic vasculitis, secondary to the deposition in small and medium-sized blood vessels of circulating immune complexes, mainly the cryoglobulins, and complement. MC is characterised by a typical clinical triad (purpura, weakness, arthralgias) and by one or more organ involvement: chronic hepatitis, glomerulonephritis, peripheral neuropathy, skin ulcers and diffuse vasculitis. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Hepatitis C virus (HCV) infection has been found in the majority of patients with MC; the frequency of HCV markers (91%) was significantly higher than other rheumatic diseases (6.4%), namely systemic lupus, Sjögren's syndrome, rheumatoid arthritis and systemic sclerosis, or healthy controls (1.2%). The HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production. In a similar way, HCV infection may also be involved in the pathogenesis of other autoimmune (glomerulonephritis, thyroiditis, lung fibrosis, autoimmune hepatitis, porphyria cutanea tarda) and lymphoproliferative disorders (monoclonal gammopathies, B-cell lymphomas). MC shares numerous clinico-serological and pathological features with the above disorders. HCV seems to be their common etiological agent; however, a variable combination of unknown co-factors (infectious, genetic, environmental) should be determinant for the appearance of different clinical patterns.

Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study

Forty-six diabetic patients with chronic painful peripheral neuropathy were treated with acupuncture analgesia to determine its efficacy and long-term effectiveness. Twenty-nine (63%) patients were already on standard medical treatment for painful neuropathy. Patients initially received up to six courses of classical acupuncture analgesia over a period of 10 weeks, using traditional Chinese Medicine acupuncture points. Forty-four patients completed the study with 34 (77%) showing significant improvement in their primary and/or secondary symptoms ( P<0.01). These patients were followed up for a period of 18–52 weeks with 67% were able to stop or reduce their medications significantly. During the follow-up period only eight (24%) patients required further acupuncture treatment. Although 34 (77%) patients noted significant improvement in their symptoms, only seven (21%) noted that their symptoms cleared completely. All the patients but one finished the full course of acupuncture treatment without reported or observed side effects. There were no significant changes either in the peripheral neurological examination scores, VPT or in HbA1c during the course of treatment. These data suggest that acupuncture is a safe and effective therapy for the long-term management of painful diabetic neuropathy, although its mechanism of action remains speculative.

Mechanisms of action of anti-GM1 and anti-GQ1b ganglioside antibodies in Guillain-Barré syndrome.

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

Pharmacological characterization of N-methyl-D-Aspartate receptors in spinal cord of rats with a chronic peripheral mononeuropathy

N-Methyl-D-aspartate (NMDA) receptor antagonists, acting in the spinal cord, are analgesic. However, the clinical utility of these antagonists is diminished by their adverse effects on cognition and behavior. To facilitate the development of spinal cord-selective NMDA receptor antagonists, we characterized ligand interactions at NMDA receptors in spinal cord of normal rats and rats with a chronic peripheral neuropathy. NMDA receptors in spinal cord were distinguished from those in cerebral cortex on the basis of differences in the potencies of competitive and noncompetitive antagonists and on the basis of differences in their response to spermidine. D(-)-2-Amino-5-phosphonopentanoic acid (AP-5) and (+)-(1-hydroxy-3-aminopyrrolidine-2-one) (HA-966) were more potent in inhibiting NMDA-dependent [ 3H]TCP binding in spinal cord while, conversely, MK-801 was more potent in inhibiting [ 3H]TCP binding to NMDA receptors in cerebral cortex. Spermidine increased [ 3H]TCP binding to NMDA receptors in cerebral cortex (39 ± 8%) but not spinal cord (2 ± 1%). Based on these properties, NMDA receptors in spinal cord more closely resembled those in cerebellum than those in cerebral cortex. Generation of a chronic neuropathy had no effect on the density of NMDA receptors in lumbar spinal cord. There were also no major changes in the potencies of competitive antagonists or channel blocking ligands, although there was a trend for kynurenic acid and d-CPP to be more potent in the spinal cords of neuropathic animals. These findings indicate that, in both normal and neuropathic pain states, NMDA receptors in spinal cord can be distinguished pharmacologically from those in cerebral cortex. These findings underscore the feasibility of developing spinal cord-selective NMDA receptor antagonists as novel analgesics.

Vascular Pathology in CCL Neuropathy: A Quantitative Temporal Study

An experimental neuropathy in rats produced by tying loosely constrictive ligatures around one sciatic nerve evokes pain-related behavior that follows a reproducible time course. We have previously investigated the pathologic changes in the sciatic nerve in this model, and a striking feature was protrusion and proliferation of endoneurial endothelial cells. In the present study, we quantified these changes at time points from 1 day to 12 weeks after surgery. One day after surgery, vessels were distended, shown by an increase of the slope of a graph in which the vessel areas were plotted on the x axis and luminal areas on the y axis. From Day 7, the slope was reduced; i.e., vessel walls had thickened and lumina were smaller. By Day 14, narrowing of lumina was observed in the contralateral (control) nerve also. We suggest that endothelial cell proliferation, known to be induced by cytokines produced by macrophages, indicates increased activity and pathogenic significance of these cytokines in the CCI model.

The Effect of Hyperbaric Oxygenation (HBO) on HIV-Associated Chronic Fatigue and Peripheral Neuropathy

The Effect of Hyperbaric Oxygenation (HBO) on HIV-Associated Chronic Fatigue and Peripheral Neuropathy

Effect of exercise training on acute (crush lesion) and chronic (diabetes mellitus) peripheral neuropathy in the rat

The effect of moderate exercise training on acute and chronic neuropathy in two separate experiments was examined. Acute nerve dysfunction was induced by sciatic nerve crush lesion and chronic neuropathy by streptozotocin-induced diabetes mellitus (experimental diabetic neuropathy; EDN). Moderate exercise training was achieved by placing food and water, separately, at either end of a U-shaped tubular home cage (8 m). Recovery from the crush lesion and the development of EDN were monitored by evaluating the free walking pattern and nerve conduction velocity (NCV), respectively. In the acute neuropathy model, 24 days of exercise after the crush lesion resulted in an enhanced return of motor function in the early phase of recovery (P < 0.01) and an increased sensory NCV after 250 days in the late phase (P < 0.001). Diabetic rats benefited from this exercise training by showing fewer signs of EDN, as evidenced by a superior motor function (toespreading, calculated from the free walking pattern; P < 0.05) and an improvement in both motor and sensory NCV (both P < 0.05). We conclude that moderate exercise training is effective in enhancing recovery from acute peripheral neuropathy and in ameliorating the consequences of experimental chronic neuropathy in diabetic rats.

The natural history of chronic demyelinating neuropathy associated with benign IgM paraproteinaemia. A clinical and neurophysiological study.

Eighteen patients are described, all of whom had chronic demyelinating peripheral neuropathy and benign IgM paraproteinaemia. All patients had serum antibodies against peripheral nerve myelin or myelin-associated glycoprotein. Seventeen were followed up clinically and electrophysiologically for between 1 and 14 years (mean 7.4 years). The presenting symptoms and signs were almost always those of a distal sensory disturbance in the limbs followed by distal weakness. All patients developed tremor or ataxia in the arms, and gait ataxia. The severity of the neuropathy varied greatly between patients at similar stages. Some had a predominantly sensory deficit and others a predominantly motor deficit. All patients eventually developed both motor and sensory signs. The neuropathy became slowly worse over the first 2-5 years and then appeared to stabilize, although long-term follow-up did reveal a very slow progression in the group as a whole. No patient developed evidence of haematological malignancy but two patients died of malignancy involving other systems. On reviewing 75 patients from the literature, non-haematological malignancy was found to be the commonest cause of death.

Case history notes designed as an aid to professional education. Advanced diabetic microvascular disease secondary to impaired glucose tolerance

AbstractA case of advanced diabetic microvascular disease secondary to impaired glucose tolerance (IGT) with server proliferative retinopathy, end‐stage diabetic nephropathy and chronic peripheral neuropathy is described. There was concomitant large vessel disease with Fournier's gangrene and left below‐knee amputation. The diabetic patient had been informed some 20 years earlier that he had a ‘tendency to diabetes’ but no formal treatment was given and no follow‐up arranged. It is important to avoid the term ‘mild diabetes’ and recognise that patients with IGT require proper dietary advice and follow‐up assessment so that the severe microangiopathy (and macroangiopathy) seen in this case may be prevented.