Peripheral Nerve Disease Research Articles

Molecular evolution of the CMT1A-REP region: a human- and chimpanzee-specific repeat.

The CMT1A-REP repeat consists of two copies of a 24-kb sequence on human chromosome 17p11.2-12 that flank a 1.5-Mb region containing a dosage-sensitive gene, peripheral nerve protein-22 (PMP22). Unequal meiotic crossover mediated by misalignment of proximal and distal copies of the CMT1A-REP in humans leads to a 1.5-Mb duplication or deletion associated with two common peripheral nerve diseases, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). Previous molecular hybridization studies with CMT1A-REP sequences suggested that two copies of the repeat are also found in the chimpanzee, raising the possibility that this unique repeat arose during primate evolution. To further characterize the structure and evolutionary synthesis of the CMT1A-REP repeat, fluorescent in situ hybridization (FISH) analysis and heterologous PCR-based assays were carried out for a series of primates. Genomic DNA was analyzed with primers selected to differentially amplify the centromeric and telomeric ends of the human proximal and distal CMT1A-REP elements and an associated mariner (MLE) sequence. All primate species examined (common chimpanzee, pygmy chimpanzee, gorilla, orangutan, gibbon, baboon, rhesus monkey, green monkey, owl monkey, and galago) tested positive for a copy of the distal element. In addition to humans, only the chimpanzee was found to have a copy of the proximal CMT1A-REP element. All but one primate species (galago) tested positive for the MLE located within the CMT1A-REP sequence. These observations confirm the hypothesis that the distal CMT1A-REP element is the ancestral sequence which was duplicated during primate evolution, provide support for a human-chimpanzee clade, and suggest that insertion of the MLE into the CMT1A-REP sequence occurred in the ancestor of anthropoid primates.

Immunological and infectious diseases of the peripheral nerves

Immunological and infectious diseases of the peripheral nerves

Neurological Complications of HIV and AIDS

edited by G. Said, A.G. Saimont, C. Lacroix, and M. Tardieu, 224 pp., ill., Philadelphia, W.B. Saunders, 1998, $89.00 The AIDS epidemic has touched all aspects of medicine. Neurologic involvement is common in the HIV-infected patient, and occurs at all stages of the disease. Our educational efforts have not always kept pace with the demand for neurologic expertise in its management. This book goes a long way to help remedy this in a practical and straightforward way. The book consists of eight chapters, written by a team of experts who practice in France. The first chapter consists of an overall introduction to HIV infection. The other chapters discuss various more specialized topics including the HIV-associated dementia complex, opportunistic infections and neoplasms of the CNS, spinal cord disease, peripheral nerve and muscle disease, and the neurology of pediatric HIV disease. There are many practical details on the diagnosis and management of the various aspects of the disease, in addition to good discussions of the current understanding of the underlying pathogenesis. The book is …

A skin blister method to study epidermal nerves in peripheral nerve disease.

Skin is a reservoir of sensory and autonomic nerve fibers that are potential indicators of peripheral nerve disease. Biopsies of skin have shown that sensory nerves in the most superficial layer of skin, the epidermal nerve fibers (ENFs), are reduced in patients with polyneuropathy. This report describes a minimally invasive skin blister method to isolate, image, and obtain quantitative analysis of ENFs. Blisters are made by applying a suction capsule to skin. The epidermal roof of the blister is excised, immunostained, whole mounted, and analyzed for ENF number and distribution. A reduction in number and abnormal distribution of ENFs are early indicators of peripheral nerve disease. Illustrations of skin blister and skin biopsy specimens from patients with different types of peripheral nerve disorders are included. These patients were chosen because their findings demonstrate the complementary information obtained by the blister and biopsy methods and the potential of the blister procedure to evaluate single nerve lesions and polyneuropathy and to follow the progress of ENF degeneration and regeneration.

Epidermal nerve fiber density: normative reference range and diagnostic efficiency.

The sensitivity of neuron-specific antibodies permit the identification of the small unmyelinated nerve fibers within the skin. To develop a reference range of epidermal nerve fiber density in humans, and to evaluate their diagnostic efficiency for sensory neuropathies. Ninety-eight normal controls (age range, 13-82 years) were examined with both directed neurologic examinations and quantitative sensory testing. The diagnostic utility was examined in 20 patients with sensory neuropathies. Each subject had 2 punch biopsies performed at each site in the thigh and distal part of the leg (total of 392 biopsies). After formalin fixation, 50-microm-thick free-floating sections were stained with a polyclonal antibody to neuron-specific ubiquitin hydrolase, anti-protein gene product 9.5. We enumerated intraepidermal nerve fibers per millimeter to derive a "linear density." The linear density technique was validated against a stereological technique that used the fractionator to measure the total length of intraepidermal nerve fibers per 3-mm punch. The biopsy technique was well tolerated, with no notable complications. The linear density quantitation was rapid and had high intraobserver and interobserver reliability. We determined that the density of intraepidermal fibers in normal controls was 21.1+/-10.4 per millimeter (mean +/- SD) in the thigh (fifth percentile, 5.2 per millimeter), and was 13.8+/-6.7 per millimeter at the distal part of the leg (fifth percentile, 3.8 per millimeter). Significantly higher intraepidermal fiber densities were seen in the youngest group (P = .004), and we observed no significant effect of race, sex, height, or weight. The density at the thigh was significantly correlated with that at the distal part of the leg (P = .01) and was consistently higher by about 60%, a reflection of the normal proximal-distal gradient. The results obtained with stereology and the linear density correlated significantly (P=.001), providing internal validation for the technique. Epidermal nerve fiber density was significantly reduced (P = .001) in patients with sensory neuropathies. With a cutoff derived from the fifth percentile of the normative range for the distal part of the leg, the technique had a positive predictive value of 75%, a negative predictive value of 90%, and a diagnostic efficiency of 88%. We have established a reference range for intraepidermal nerve fiber density in normal humans by means of a simple quantitation method based on enumeration of individual intraepidermal nerve fibers on vertical sections of punch skin biopsy specimens stained with the sensitive panaxonal marker anti-protein gene product 9.5. The utility of the density measurement was confirmed for sensory neuropathy with a diagnostic efficiency of 88%. Skin biopsies may be useful to assess the spatial distribution of involvement in peripheral nerve disease and the response to neurotrophic and other restorative therapies.

Direct convective delivery of macromolecules to peripheral nerves.

Although many macromolecules have treatment potential for peripheral nerve disease, clinical use of these agents has been restricted because of limitations of delivery including systemic toxicity, heterogeneous dispersion, and inadequate distribution. In an effort to overcome these obstacles, the authors examined the use of convection to deliver and distribute macromolecules into peripheral nerves. For convective delivery, the authors used a gas-tight, noncompliant system that provided continuous flow through a small silica cannula (inner diameter 100 microm, outer diameter 170 microm) inserted into a peripheral nerve. Increases in the volume of infusion (Vi) (10, 20, 30, 40, and 80 microl) of 14C-labeled (nine nerves) or gadolinium-labeled (two nerves) albumin were infused unilaterally or bilaterally into the tibial nerves of six primates (Macaca mulatta) at 0.5 microl/minute. The volume of distribution (Vd), percentage recovery, and delivery homogeneity were determined using quantitative autoradiography, an imaging program developed by the National Institutes of Health, magnetic resonance (MR) imaging, scintillation counting, and kurtosis (K) analysis. One animal that was infused bilaterally with gadolinium-bound albumin (40 microl to each nerve) underwent MR imaging and was observed for 16 weeks after infusion. The Vd increased with the Vi in a logarithmic fashion. The mean Vd/Vi ratio over all Vi was 3.7+/-0.8 (mean+/-standard deviation). The concentration across the perfused region was homogeneous (K=-1.07). The infusate, which was limited circumferentially by the epineurium, followed the parallel arrangement of axonal fibers and filled long segments of nerve (up to 6.8 cm). Recovery of radioactivity was 75.8+/-9%. No neurological deficits arose from infusion. Convective delivery of macromolecules to peripheral nerves is safe and reliable. It overcomes obstacles associated with current delivery methods and allows selective regional delivery of putative therapeutic agents to long sections of nerve. This technique should permit the development of new treatments for numerous types of peripheral nerve lesions.

Recovery from Guillain–Barré Syndrome Is Associated with Increased Levels of Neutralizing Autoantibodies to Interferon-γ

Guillain–Barré syndrome (GBS) is an immune-mediated demyelinating disease of peripheral nerves that is often preceded by an infection and is usually self-restricted. The Th1 cytokine interferon-γ (IFN-γ) is thought to be disease-promoting in organ-specific autoimmune diseases. We report the spontaneous induction of IFN-γ and a mechanism involving the generation of neutralizing autoantibodies (Aabs) to IFN-γ that may regulate the disease. Numbers of cells spontaneously secreting IFN-γ in peripheral blood were augmented in GBS, in particular at the peak of clinical disease, and decreased during recovery. This decrease was associated with elevated serum concentrations of IgG Aabs to IFN-γ. These Aabs specifically bound to IFN-γ and neutralized its effects in a biological assay. Aabs to IFN-γ are proposed to be another important regulatory mechanism in IFN-γ-driven GBS.

OXALOSIS: STRATIFYING DISEASE SEVERITY AND THE ROLE OF ORGAN TRANSPLANTATION.

202 Aim: To develop a clinical staging strategy in an effort to determine the indications and timing of multi-organ transplantation in patients diagnosed with primary hyperoxaluria (PH1). Method: A clinical staging strategy divided our patients into four categories. Stage 1: patients with PH1 and normal renal function; Stage 2: patients with PH1, normal renal function, but with nephrocalcinosis and/or urolithiasis; Stage 3: patients with PH1, end stage renal disease, and no evidence of extrarenal disease; and Stage 4: patients with PH1, end stage renal disease, and evidence of extrarenal disease (i.e. osteosclerosis, cardiomyopathy, or peripheral nerve disease). Results: Over a six year period 11 patients with PH1 underwent liver transplantation (OLTx). There were six males and five females with a mean age of 13.8 ± 9 years (range 1.5 - 35). Two patients were in Stage 2, two patients were in Stage 3 and seven patients were in Stage 4. Both Stage 2 patients received isolated OLTx, one is alive and well without evidence of oxalosis five years after transplantation, and the other patient died secondary to graft versus host disease (GVHD) five months after OLTx. Both Stage 3 patients received simultaneous liver/kidney transplants and are alive and well > 5 yrs. after transplantation. In the Stage 4 group, two patients received simultaneous liver/kidney transplants (OLTx/KTx). Both of these patients died secondary to infection within six months after transplantation. The remaining five patients underwent staged OLTx/KTx with four patients receiving kidney transplants at a later date (range: 9 months - 23 months). Three of these four patients are alive and well, with excellent graft function in both their kidney and liver. The fourth patient died secondary to infection two months after undergoing KTx. The fifth patient is well and listed for a kidney transplant eighteen months after successfully undergoing OLTx. To analyze patient survival after transplantation we have grouped the patients into those diagnosed with extrarenal disease (Stage 4) and those without extrarenal disease (Stages 2 and 3). Based on this strategy there is a 75% patient survival in patients without evidence of extrarenal disease, compared with a 43% patient survival when there is evidence of extrarenal disease at the time of OLTx. If we further subdivide the Stage 4 patients into those undergoing simultaneous OLTx/KTx versus staged OLTx/KTx, there is a 0% patient survival in the former group and an 80% patient survival in the second group. Conclusion: This clinical staging strategy suggests that patients diagnosed with Stage 4 disease should undergo staged KTx following successful OLTx while combined OLTx/KTx remains an acceptable and preferred approach to patients with Stage 3 disease.

Human autoimmune neuropathies.

Peripheral nerve diseases are among the most prevalent disorders of the nervous system. Because of the accessibility of the peripheral nervous system (PNS) to direct physiological and pathological study, neuropathies have traditionally played a unique role in developing our understanding of basic mechanism of nervous system injury and repair. At present they are providing new insight into the mechanisms of immune injury to the nervous system. A rapidly growing catalogue of PNS disorders are now suspected to be immune-mediated, and in the best understood of these disorders, the molecular and cellular targets of immune attack are known, and the pathophysiology follows directly from the specific immune injury. This review summarizes the immunologically relevant features of the PNS, then considers selected immune-mediated neuropathies, focusing on pathogenetic mechanisms. Finally, the PNS is providing a testing ground for new immunotherapies and approaches to protection and regeneration, including the use of trophic factors. The current status of treatment and implications for future approaches is reviewed.

Antiganglioside GM1 Antibodies and Their Complement Activating Capacity in Central and Peripheral Nervous System Disorders and in Controls

So far, the pathogenic significance and use for diagnosis of antiganglioside GM1 antibodies (anti-GM1) are unclear. We therefore compared serum IgM and IgG antimonosialo ganglioside GM1 levels of 33 patients with presumed immune-mediated neuropathies, 100 patients with various other central or peripheral neurological disorders, and 110 controls by ELISA. We also measured the complement-activating capacity of anti-GM1 by C5b-9-GM1-ELISA to evaluate its value to distinguish between pathogenic and nonpathogenic autoantibodies. Low levels of anti-GM1 were observed in all disease categories and in controls (healthy blood donors). Twenty-four of the controls including the 10 with the highest serum IgM or IgG anti-GM1 were examined for neurological disorders in a double-blind checkup study. In the patients, elevated IgM anti-GM1 levels were predominantly found in those with neuropathies (NP), but barely in patients with central nervous system disease (CNSD). We found elevated IgG anti-GM1 levels predominantly in patients with NP of inflammatory origin (multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome), rarely in patients with NP of noninflammatory origin or CNSD, but not in the control disease group myasthenia gravis (MG). Median levels of IgM-, IgG-, (IgM+IgG)-, and C5b-9-binding anti-GM1 were significantly higher in patients with inflammatory NP as compared to the controls (p < 0.025). In addition, median levels of IgG- and (IgM+IgG)-anti-GM1 were significantly higher in inflammatory NP versus CNSD. Elevated complement-binding activity was associated with low or elevated IgM and/or IgG anti-GM1. Nevertheless, there was a significant correlation between anti-GM1 level (IgM+IgG) and the respective complement-activating capacity (r = 0.758; n = 243). Estimation of anti-GM1 and their respective complement-activating capacity may be helpful in the diagnosis of inflammatory neuropathies. However, neither an elevated anti-GM1 level nor an increased C5b-9 binding seems specific for a given disease category (e.g. peripheral nerve disease) nor a disease process (e.g. demyelination or inflammation).

Immunity neurologic disease. Peripheral nerve disease. Mechanism of pathogenesis and treatment of the Guillain-Barre syndrome. Precedence of the Campylobacter jejuni enteritis and antiganglioside antibody.

Immunity neurologic disease. Peripheral nerve disease. Mechanism of pathogenesis and treatment of the Guillain-Barre syndrome. Precedence of the Campylobacter jejuni enteritis and antiganglioside antibody.

Charcot-Marie-Tooth neuropathies and related disorders.

As a group, the Charcot-Marie-Tooth (CMT) neuropathies represent the most common inherited peripheral nerve diseases. Estimates of the prevalence rate are 1 in 2500 but the exact numbers are difficult to ascertain because of the heterogeneity of the syndrome(s). The classification of CMT has undergone change coincident with chromosomal localization and gene identification. Table 1 summarizes the diseases and genetic defects discussed in this review.

Peripheral Nerve and Muscle Diseases I

Brain PathologyVolume 7, Issue 4 p. 1117-1121 Free Access Peripheral Nerve and Muscle Diseases I First published: 28 January 2008 https://doi.org/10.1111/j.1750-3639.1997.tb00990.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume7, Issue4October 1997Pages 1117-1121 RelatedInformation

Peripheral Nerve and Muscle Diseases II

Brain PathologyVolume 7, Issue 4 p. 1219-1223 Free Access Peripheral Nerve and Muscle Diseases II First published: 28 January 2008 https://doi.org/10.1111/j.1750-3639.1997.tb01013.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume7, Issue4October 1997Pages 1219-1223 RelatedInformation

5-30-23 Moving toes and fingers and peripheral nerve disease: Etiology, varieties and associations

5-30-23 Moving toes and fingers and peripheral nerve disease: Etiology, varieties and associations

Glucose: a continuous risk factor for cardiovascular disease.

The glucose level that defines diabetes mellitus is that level above which patients have a high risk of eye, kidney, and neuronal disease. The risk of these complications rises as glucose levels increase, and decreases as therapy brings the glucose level down. Thus, in patients with diabetes, glucose is a continuous, modifiable risk factor for eye, kidney and peripheral nerve disease. Plasma glucose concentrations in the diabetic range are also a continuous risk factor for cardiovascular disease (CVD). Moreover, epidemiological evidence shows that the relationship between plasma glucose concentration and CVD extends well below the glucose level defined for diabetes and even impaired glucose tolerance. This continuous relationship between glucose and CVD exists in all people, not just in those with a defined metabolic disease, and is therefore similar to the relationship between cholesterol or blood pressure and CVD. It may be secondary to either a direct effect of elevated glucose or to some underlying metabolic abnormality that raises both glucose and cardiovascular risk. Whether interventions that lower glucose will also lower the risk of CVD is still unknown; the results of clinical trials are awaited.

Local human sural nerve blood flow in diabetic and other polyneuropathies.

Microangiopathy is considered relevant to the pathogenesis of several forms of peripheral nerve disease, particularly diabetic polyneuropathy. In diabetes, however, it is uncertain whether reductions in mixed nerve trunk blood flow account for early features of polyneuropathy in contrast to later disease, where microvascular changes have been described. To address this issue, we measured local sural nerve blood flow in patients with mild diabetic polyneuropathy who were enrolled in a clinical trial (n = 26), patients with other polyneuropathies being studied by diagnostic sural nerve biopsy (n = 17), patients with vasculitic polyneuropathy (n = 3) and one patient with rapidly progressive severe diabetic polyneuropathy and lumbosacral plexopathies. Standardized measurements were made at 10 sites along the sural nerve of each patient prior to sural nerve resection for biopsy. We used a laser Doppler flowmetry probe sensitive to red blood cell flux to measure sural nerve blood flow. This was slightly higher in patients with mild diabetes compared with those with other polyneuropathies, but was reduced in patients with vasculitis. In patients with mild diabetes, there was no relationship between sural nerve blood flow and prebiopsy sural nerve action-potential amplitude, sural myelinated fibre density, haemoglobin A1C, duration of diabetes or age of the patient. Ten diabetic patients entered in the clinical trial had sural nerve blood flow recorded in one sural nerve, followed 1 year later by a second sural nerve blood flow measurement prior to biopsy of the contralateral sural nerve. Despite a mild trend toward decline in fibre density between the nerves over this period of time, sural nerve blood flow was similar. The patient with severe diabetic polyneuropathy and lumbosacral plexopathies had reduced sural nerve blood flow. Our findings do not provide evidence that reductions in sural nerve blood flow are associated with early peripheral neuropathy in diabetes, unlike vasculitis. The early trend toward slight rises in sural nerve blood flow may be a result of early functional microangiopathy that accompanies nerve dysfunction but does not cause it.

Survey of inherited peripheral nerve diseases

Survey of inherited peripheral nerve diseases

Thrombin and Its Precursor in Human Cerebrospinal Fluid

The blood coagulation cascade proteolytic enzyme, thrombin, affects many cell types, including neurons and astrocytes, in which it prevents process outgrowth and induces significant morphological degeneration and even cell death. Since thrombin may contribute significantly to pathological conditions in the central nervous system (CNS), where it is synthesized locally, we measured the levels of thrombin and its precursor, prothrombin, in the cerebrospinal fluid (CSF) of 67 individuals from 6 groups: non-neurologic controls (NNC); spinal degenerative disease (SDD); peripheral nerve disease (PND); cerebrovascular, neuroimmune and seizure disorders and tumor (CNSD); traumatic brain injury (TBI) and neurodegenerative disorders (NDD). We employed a sensitive chromogenic assay utilizing the thrombin specific tripeptide substrate, S-2238, to evaluate CSF levels of thrombin and prothrombin. The latter estimated after its conversion to active enzyme by the snake venom prothrombinase, ecarin. No measurable active thrombin was detected in these CSF samples. However, activatable prothrombin was measured in all groups. The mean activatable prothrombin concentrations (in nM) were 7.26 +/- 3.39 (NNC); 8.85 +/- 3.09 (SDD); 6.78 +/- 2.58 (PND); 6.33 +/- 3.87 (CNSD); 5.10 +/- 1.86 (TBI), and 7.80 +/- 3.27 (NDD). Duncan's multiple comparison test showed significant reduction (p <0.05) in prothrombin levels of the TBI group. Our data suggests that the prothrombin zymogen gains access to the CSF, likely across either an intact or compromised blood-brain barrier (BBB), in increased amounts with age. Reduced levels in TBI patients may have diagnostic and/or prognostic value.

Office Practice of Neurology

Part 1 Principles of ambulatory neurology and the approach to clinical problems: principles of diagnosis - the general approach to neurologic diagnosis principles of diagnosis - common presenting symptoms and findings principles of diagnosis - special tests principles of treatment. Part 2: general aspects of cerebrovascular disease common pathogenesis of stroke less common causes of stroke management of cerebrovascular disease. Part 3 Infectious diseases: diseases of the spinal cord motor neuron diseases diseases of peripheral nerve diseases of neuromuscular transmission diseases of muscle. Part 4: Parkinson's Disease and Parkinson-like syndromes non-Parkinsonian movement disorders. Part 5: behavioural neurology epilepsy disorders of sleep psychiatric issues in neurologic practice. Part 6: brain tumours - specific tumour types spinal cord tumours neurologic complications of systemic cancer. Part 7: cardiology and cardiac surgery pulmonary disorders nephrology and urology gastronenterology and hepatology haematology endocrinology and metabolism toxins and drug effects organ transplantation rheumatology. Part 8: general aspects of headache headache syndromes and their treatment special headache problems general aspects of pain generalized pain syndromes regional pain syndromes.