Peripheral Nerve Disease Research Articles

C-polymodal nociceptors activated by noxious low temperature in human skin.

1. Fifty-five C-polymodal nociceptors innervating hairy skin in human volunteers were tested for discrete stimulus-response properties through microneurography. 2. All fifty-five units were responsive to mechanical and heat stimuli. Twenty-two (40%) of these exhibited an additional response to noxious low temperature. The twenty-two mechano-heat-cold nociceptors displayed similar receptor responses to heat and mechanical stimuli, and conduction velocity, as those of the pure mechano-heat C-polymodal nociceptors. 3. Low temperature stimuli between 19 and 0 degree C evoked responses at low discharge frequency (0.4 +/- 0.22 impulses s-1, mean +/- S.E.M.) in the twenty-two units sensitive to such energy. These units displayed a tendency to decrease their discharge after a few seconds of steady stimulation. 4. Three units tested with a freezing stimulus responded with relatively vigorous discharge, which never exceeded the maximal discharge frequency elicited by either mechanical or heat stimuli. One of these units became sensitized to heat after the freezing challenge. 5. It is concluded that a subpopulation of C-polymodal nociceptors is sensitive to noxious low temperature and may thus contribute to the determination of cold pain. The same type of primary afferent is probably one mediator of the symptom cold hyperalgesia in peripheral nerve disease.

Tumor necrosis factor α and interleukin-6 mRNA expression in neonatal Lewis rat Schwann cells and a neonatal rat Schwann cell line following interferon γ stimulation

There is increasing evidence that Schwann cells play an important role in the pathogenesis of autoimmune inflammatory peripheral nerve disease. Schwann cells have been reported to express major histocompatibility complex class I and II (MHC I and II) and intercellular adhesion molecule-1 (ICAM-1), and to produce interleukin-1 (IL-1), prostaglandin E2 and thromboxane A2. In this study we investigated freshly dissociated neonatal Lewis rat Schwann cells and a SV40 transfected neonatal rat Schwann cell line (Schwann cell line) for production of mRNA for the immunomodulatory cytokines IL-2, IL-4, IL-6, IL-10, interferon-gamma (IFNγ), and tumor necrosis factor-alpha (TNFα) employing RT-PCR. Primary Schwann cells and Schwann cell line were examined following IFNγ stimulation and were found to express TNFα and IL-6 mRNA. These results further support a role for Schwann cell participation in inflammatory responses within the peripheral nervous system (PNS).

Isolation and characterization of a novel oligodendrocyte-specific protein.

Myelin plays a critical role in nervous system function and alterations in myelin-specific proteins cause a variety of neurologic disorders. We isolated a novel cDNA from the CNS that shares little nucleotide sequence homology with previously reported genes but appears to encode a protein related to peripheral myelin protein-22 (PMP-22) based on its amino acid sequence, predicted structure, and cellular localization. PMP-22 is important in peripheral myelination and Schwann cell proliferation, and mutations in its gene cause diseases of peripheral nerves. The isolated cDNA is 1.8 kb in length with an open reading frame of 621 bp. Northern blot analysis detected hybridization of labeled cDNA with a single 2.1-kb transcript only in the CNS. In situ hybridization revealed expression of this cDNA in oligodendrocytes of brain and spinal cord as well as in oligodendrocyte-enriched cultures; therefore we have named it oligodendrocyte-specific protein (OSP) cDNA. An OSP-specific polyclonal antibody reacted with a single 22-kd protein present in CNS myelin and oligodendrocytes. Developmental expression of OSP mRNA in the spinal cord was similar to that of the mRNA for a major myelin protein, proteolipid protein (PLP), and similar to PMP-22 in peripheral nerves. Since OSP is localized to oligodendrocytes and myelin, has a similar structure with PMP-22, and has a developmental pattern of expression like other myelin proteins, it probably has an important role in CNS myelinogenesis.

The clinical significance of a single abnormal immunoglobulin band in cerebrospinal fluid electrophoresis

The finding of oligoclonal immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is considered a cornerstone in the diagnosis of multiple sclerosis, but can be observed in other diseases as well. In a small subset of patients only a single Ig band, confined to the CSF, is identified. We evaluated the possible diagnostic significance of such a finding. Agarose gels of 6000 CSF samples were re-examined. In 1013 samples (16.8%) there were oligoclonal bands, and in 33 additional samples (0.55%) a single band was found (without a correlating band in the serum). Full data was available for 20 single band patients. Seven patients had clinical definite multiple sclerosis. Of these, 6 had a typically prominent affective disorder and 5 had a relatively malignant course of disease. Seven additional patients had other white matter diseases of the central nervous system (CNS). The remaining patients had inflammatory diseases of peripheral nerves or CNS gray matter and non-inflammatory brain diseases. The frequency of demyelinating diseases of the CNS in patients with a single abnormal Ig band in the CSF was significantly less than in a control group of patients with oligoclonal bands. In conclusion, the finding of a single Ig band confined to the CSF may hint for a disease other than multiple sclerosis, and mark an aggressive course with affective disorder in those who do have multiple sclerosis.

Intrathecal synthesis of anti-sulfatide IgG is associated with peripheral nerve disease in acquired immunodeficiency syndrome.

Peripheral nervous system involvement in the acquired immunodeficiency syndrome (AIDS) can take the form of an acute or chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, mononeuropathy multiplex, or autonomic neuropathy. There is no widely held consensus on the etiology of PNS or other neurological complications associated with HIV infection. We report here that PNS disease in HIV-infected individuals is associated with intrathecal synthesis of an antibody directed against sulfatide, a major component of myelin. The anti-sulfatide antibody is also present nonspecifically in serum. The antibody requires the presence of the 3-O-sulfogalactosyl residue for binding and recognizes preferentially the hydroxy fatty acid-containing form of sulfatide. Anti-sulfatide antibodies are therefore one of the humoral factors responsible for demyelinating diseases in AIDS patients.

Cutaneous innervation in sensory neuropathies

To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-microns free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean +/- SEM) was 17.84 +/- 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p = 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 +/- 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 +/- 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.

SS-9-6 Motor reorganization in central and peripheral nervous diseases

SS-9-6 Motor reorganization in central and peripheral nervous diseases

PS-3-9 Relationship between conduction velocity distribution and morphological fiber diameter analysis in peripheral nerve diseases

PS-3-9 Relationship between conduction velocity distribution and morphological fiber diameter analysis in peripheral nerve diseases

HLA-DR expression in peripheral neuropathies: the role of Schwann cells, resident and hematogenous macrophages, and endoneurial fibroblasts.

The expression of HLA-DR and the macrophage marker CD 68 was studied in 44 sural nerve biopsies from patients with inflammatory and non-inflammatory neuropathies and controls using immunohistochemistry on non-osmicated semithin sections, a technique that has not been used before in such a biopsy study. Most HLA-DR-immunoreactive (ir) cells were fibroblasts, macrophages or perineural cells, some were perivascular and endothelial cells, and only few were Schwann cells. Counts of immunoreactive cells revealed (a) increased HLA-DR expression in severe as compared to less severe neuropathies and to controls, (b) no correlation between the numbers of HLA-DR-ir cells and CD 68-ir macrophages, and (c) no close correlation between diagnostic groups and the number of HLA-DR-ir cells, but higher numbers in inflammatory neuropathies. We conclude that endoneurial fibroblasts and macrophages as antigen-presenting cells may be mediators in various peripheral nerve diseases, not only in inflammatory disorders.

Autosomal dominant cerebellar phenotypes

The dominantly inherited ataxias comprise a series of clinical phenotypes that include ataxia, dysarthria, dysmetria, and intention tremor resulting from the involvement of the cerebellum and its afferent and efferent pathways. These inherited ataxias occur commonly throughout the world and represent an area of intense neurologic research. Although the clinical manifestations and neuropathologic findings of cerebellar disease are predominant, there may be characteristic changes in the basal ganglia, brainstem, spinal cord, optic nerves, retina, and peripheral nerve. In large families with dominantly inherited disease, there are many gradations, from pure cerebellar manifestations to mixed cerebellar and brainstem disorders, cerebellar and basal ganglia syndromes, and spinal cord or peripheral nerve disease. Rarely, dementia may be present as well. The clinical picture may be consistent within a family with dominantly inherited ataxia, but on occasion there is a characteristic syndrome in the majority of affected family members and an entirely different phenotype in one or several members. For these reasons, I suggested in 1990 [1] that for the autosomal dominant phenotypes, the genotype would be required to settle the issue of disease assignment and classification. Neurologists have written extensively as to the appropriateness of various classifications and have debated, often passionately at meetings, the uniqueness and placement of newly evaluated families with inherited cerebellar disease. Categories of disease abound, therein satisfying the needs of selective investigators to be either unifiers or splitters, often based on quite arbitrary factors [1]. Scholarly, yet divergent, classifications of dominantly inherited syndromes have been formulated by Greenfield, [2] Konigsmark and Weiner, [3] Harding, [4] and the World Federation of Neurology Study Group on Cerebellar Ataxias (unpublished, 1993). Harding [4] separates the autosomal dominant cerebellar ataxias (ADCAs) into type I and type II, in which ataxia is combined to a varying degree with pyramidal and extrapyramidal signs …

Partial structure and mapping of the human myelin P2 protein gene.

The myelin P2 protein, a 14,800-Da cytosolic protein found primarily in peripheral nerves, belongs to a family of fatty acid binding proteins. Although it is similar in amino acid sequence and tertiary structure to fatty acid binding proteins found in the liver, adipocytes, and intestine, its expression is limited to the nervous system. It is detected only in myelin-producing cells of the central and peripheral nervous systems, i.e., the oligodendrocytes and Schwann cells, respectively. As part of a program to understand the regulation of expression of this gene, to determine its function in myelin-producing cells, and to study its role in peripheral nerve disease, we have isolated and characterized overlapping human genomic clones encoding the P2 protein. We report here on the partial structure of this gene, and on its localization within the genome. By using a panel of human-hamster somatic cell hybrids and by in situ hybridization, we have mapped the human P2 gene to segment q21 on the long arm of chromosome 8. This result identifies the myelin P2 gene as a candidate gene for autosomal recessive Charcot-Marie-Tooth disease type 4A.

Sympathetic skin response.

The sympathetic skin response (SSR) is the potential generated by sweat in response to different stimuli. This potential has a waveform that habituates with closely repeated stimuli and a latency of 1.3-1.5 s at the hand and 1.9-2.1 s at the foot. It has been used to study the peripheral sympathetic system in peripheral nerve diseases. The response is absent in many cases of peripheral neuropathy, often in the presence of autonomic symptoms. SSR has also been used to study a few diseases that may affect the central sympathetic system. This review outlines the history, physiopathogenesis, and analysis of SSR as well as general techniques used in its study. The reported association of SSR with peripheral and central nervous system diseases is also presented.

Early detection of distal symmetrical polyneuropathy during HIV infection by paired stimulation of sural nerve

In 203 HIV infected patients in various clinical stages neurological examination, paired stimulation (LPSS), nerve conduction velocity (NCVS) and amplitude (AMPS) of the sural nerve, distal latency (DLP), nerve conduction velocity (NCVP), amplitude (AMPP) and F waves of the peroneal nerve were recorded. Neurological examination revealed symptoms and clinical of polyneuropathy in 67 (33%) (WR 1–6) of the patients. LPSS after paired stimulation was abnormal in 25.5%, NCVS in 14.2%, AMPS in 9.8%, NCVP in 11.8%, DLP in 11.2%, AMPP in 5.9% and FWP in 14.6%. Our findings indicate a high incidence of peripheral nerve system involvement during HIV infection. In 11.5% of all patients only LPSS proved polyneuropathy. Neurophysiological results from HIV infected patients with symptoms and clinical signs of polyneuropathy were statistically significantly different from HIV infected patients without symptoms and clinical signs of polyneuropathy. The delay of LPSS represents the most sensitive neurophysiological indicator of polyneuropathy during HIV infection and announces the onset of peripheral nerve disease even in early stages of infection, according to Walter Reed staging classification 1 and 2 (approx. 20%).

Epidemiology of Stroke in Blacks in Africa

I reviewed the literature on epidemiology of Stroke in Blacks in Africa. Stroke, said to be rare in Black Africans some four decades ago, has become increasingly common now accounting for 4% to 9% of deaths and 6.5% to 41% of neurological admissions in hospital populations. In community-based studies, it is the third or fourth commonest non-infective neurological disease, after headache, epilepsy and diseases of peripheral nerves. In both hospitals and communities, males are more afflicted than females. The age specific incidence rates are similar to those found in Caucasians and Japanese. Occlusive stroke is the commonest type accounting for about 60%, followed by cerebral haemorrhage (20%) subarachnoid haemorrhage (10%). The major risk factor is hypertension which is present in 80% or more in patients with cerebral haemorrhage and subarachnoid haemorrhage, and in 60% in those with occlusive stroke. Other risk factors are age, sickle cell disease, diabetes mellitus, non-ischaemic heart disease (including cardiomyopathies, infective endocarditis, atrial fibrillation mitral valve prolapse) infections, arteritis, smoking, alcohol consumption and cocaine use (in the young people), Transient ischaemic attracts are relatively uncommon reflecting the rarity of large vessel atherosclerotic disease. Case fatality rate is higher than in the developed countries. About 15% of young people (below age of 40 years) with stroke have no identifiable risk factor. Studies are needed on the effectiveness of population-based control of hypertension (which afflicts 10% to 30% of African communities) to reduce the incidence of stroke, especially as atherosclerotic ischaemic heart disease, although emerging is still relatively uncommon in Sub-Saharan African communities. (Hypertens Res 1994; 17 Suppl. I: S1-S10)

Diabetic neuropathy, nerve growth factor and other neurotrophic factors

Diabetic neuropathy typically presents as an insidious symmetrical distal degenerative disease of peripheral nerves. A failure of neurotrophic factors to regulate neuronal phenotype might be expected to result in such a clinical picture. Experimentally, diabetic rats show reduced expression of target-derived nerve growth factor as well as reduced expression of neuronal genes that are responsive to nerve growth factor. The latter is corrected by administration of exogenous nerve growth factor. Thus, deficient neurotrophic support might contribute to the pathogenesis of diabetic neuropathy, and any successful treatment might include exogenous neurotrophins or other strategies to correct their deficiency of action.

Production of prostanoids by Lewis rat Schwann cells in vitro

Schwann cells may play a role in the pathogenesis of autoimmune inflammatory diseases of peripheral nerve. They are the targets of autoimmune attack but may also act as antigen presenting cells. Here we investigate the possibility that Schwann cells may be able to modulate T-cell mediated immunity via prostanoid production. The results show that Lewis rat Schwann cells in vitro generate significant amounts of the pro-inflammatory and immunoregulatory mediators, prostaglandin E 2 and throm☐ane A 2 and so may influence autoimmune inflammatory reactions within the peripheral nervous system.

The neurotrophic analogue of ACTH(4–9) reduces the perineuronal microglial reaction after rat facial nerve crush

Following peripheral nerve crush, microglial cells proliferate and migrate to motoneuron cell bodies of the injured nerves. Newly formed glial processes displace nerve terminals from the cell bodies. This process is known as synaptic stripping. In animal models of peripheral nerve diseases, the ACTH(4-9) analogue, ORG2766, was shown to facilitate axonal regeneration and to protect against experimental neuropathy. In the present study we examined the effect of ORG2766 on the microglial reaction. After facial nerve crush, rats were treated with either ORG2766 (75 micrograms/kg/48 h) or saline and were killed on day 2-6 after operation. Blind counting of the number of perineuronal glial cells in the facial nucleus was used to assess the effect of ORG2766 treatment on the microglial reaction. In the saline-treated animals the number of perineuronal glial cells per motoneuron cell body on the crushed side increased significantly. This number increased up to day 5 after operation and decreased significantly from day 5 to 6. After an initial increase in the peptide-treated animals, however, the number of perineuronal glial cells remained constant from day 3 onwards. Hence, on post-operation days 4 and 5, this number was significantly less than that seen in saline-treated animals. Microglial cells proliferate, presumably through signalling by injured motoneurons. It is suggested that the decrease in the number of perineuronal glial cells in the ORG2766-treated animals is the result of a peptide-induced reduction in the release of mediating signals/cytokines or, alternatively, increased protection of motoneurons by stress proteins. Further research should address the mechanism of action of ORG2766 in animal models of motoneuron disease.

Stimulation of rat Schwann cell proliferation by estradiol: synergism between the estrogen and cAMP

Schwann cells dissociated from sciatic nerves of 4- to 5-day-old rats were established in long-term primary cultures. After treatment with anti-Thy-1.1 and complement, pure Schwann cell cultures were obtained as confirmed by indirect immunofluorescence staining of the S-100 antigen. The effect of estradiol on Schwann cell proliferation was tested. The estrogen alone had no effect on cell multiplication, but in the presence of forskolin (5 μM) or dibutyryl cyclic AMP (dbcAMP, 1 μM), estradiol (100 nM) became a potent mitogen. This effect was specific since when the anti-estrogen ICI-164,384 (200 nM) was added to the cultures, it completely inhibited the mitogenic effect of estradiol. In the absence of the estrogen, ICI-164,384 did not inhibit dbcAMP-induced cell growth. The effect of progesterone was also tested in the presence of forskolin, and no influence on cell multiplication was seen. Specific and saturable binding sites for estradiol were measured in Schwann cells by whole cell assay after labeling cells at 37°C with [ 3H]estradiol and about 3000 specific binding sites per cell were found. Treatment of the cultures with forskolin (5 μM) for 48 or 72 h, but not for shorter times, resulted in a two-fold increase in estradiol binding. Estrogen receptors were visualized inside Schwann cells with a monoclonal anti-ER antibody by indirect immunofluorescence staining. Double-label immunofluorescence of ER and S-100 showed that ER immunostaining was restricted to spindle-shaped Schwann cells expressing the S-100 antigen. The finding that Schwann cells are a target for estrogen has important implications for understanding the development, regeneration and disease of peripheral nerves.

Sensory and sympathetic ganglia in HIV-1 infection: Immunocytochemical demonstration of HIV-1 viral antigens, increased MHC class II antigen expression and mild reactive inflammation

Sensory and sympathetic ganglia from 12 cases of human immunodeficiency virus type 1 (HIV-1) infection, all but one without clinical evidence of peripheral nerve disease, were studied immunocytochemically for their content of lymphocytes, macrophages, MHC Class II antigens and HIV-1 and cytomegalovirus antigens. They were compared with ganglia from 7 normal and peripheral nerve disease control cases. Compared with normal controls, many of the ganglia from the majority of HIV-1-infected subjects contained more T lymphocytes and macrophages and enhanced MHC class II expression. A few also showed occasional neuronal degeneration which was not present in the normal controls. In 7 cases HIV-1 gp41 envelope protein and/or p24 core protein antigens were detected in intraganglionic macrophages. Sensory ganglia contained more gp41 HIV-1 antigen than sympathetic ganglia. There was no clear correlation between detection of HIV-1 antigens in ganglia and in the CNS. Detection of HIV-1 antigens in ganglia was more common in cases of HIV-1 infection that had progressed to clinical AIDS by the time of death (71%) than in those that had not done so (40%). It is concluded that there is commonly a mild ganglionitis which is asymptomatic in the absence of detailed clinical testing and frequently associated with local presence of HIV-1 antigens in sensory and sympathetic ganglia in AIDS.

Effects of Desipramine, Amitriptyline and Fluoxetine on Pain in Diabetic Neuropathy

Abstract Background. Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective. Methods. We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. Results. After individual dose titration, the mean daily doses of the drugs were as follows: amitript...