Demyelination Of Nerve Fibers Research Articles

The Effects of 4-Aminopyridine on Neurological Deficits in Chronic Cases of Traumatic Spinal Cord Injury in Dogs: A Phase I Clinical Trial

A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77%) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36%) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis.

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

The changes in the excitability of the reorganized axonal membrane in myelinated and demyelinated nerve fibres as well as the causes conditioning such changes have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The variations of the action potential parameters (amplitude and velocity) are traced also. The simulation of the conduction along the normal fiber is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while the demyelination is considered to be an elongation of the nodes of Ranvier. The axonal membrane reorganization is achieved by means of potassium channel blocking and increase of the sodium-channel permeability. It is shown that potassium channels block decreases membrane excitability for the myelinated and demyelinated fibres in the cases of initial and paired stimulation. With increasing sodium-channel permeability on the background of the blocked potassium channels, the membrane excitability is increased. For the fibres with a reorganized membrane, a supernormality of the membrane excitability is obtained, the latter remaining unrecovered during the 30 ms cycle under investigation. The supernormality of the excitability grows from the demyelinated fibre without reorganized membrane to the demyelinated fibre with reorganized one. For short interstimulus intervals, the second action potential propagates along the fibres with a reduced velocity and a decreased amplitude. No supernormality of the potential parameters (amplitude, velocity) is observed during the cycle up to 30 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

Intraoperative Radiation of Canine Carotid Artery, Internal Jugular Vein, and Vagus Nerve: Therapeutic Applications in the Management of Advanced Head and Neck Cancers

As a step in the application of intraoperative radiotherapy (IORT) for treating advanced head and neck cancers, preliminary information was obtained on the radiation tolerance of the canine common carotid artery, internal jugular vein, and vagus nerve to a single, high-dose electron beam. Both sides of the neck of eight mongrel dogs were operated on to expose an 8-cm segment of common carotid artery, internal jugular vein, and vagus nerve. One side of the neck was irradiated, using escalating doses of 2500, 3500, 4500, and 5500 cGy. The contralateral side of the neck served as the unirradiated control. At 3 and 6 months after IORT, one dog at each dose level was killed. None of the dogs developed carotid bleeding at any time after IORT. Light microscopic investigations using hematoxylin-eosin staining on the common carotid artery and internal jugular vein showed no consistent changes that suggested radiation damage; however, the Masson trichrome stain and hydroxyproline concentration of irradiated common carotid artery indicated an increase in the collagen content of the tunica media. Marked changes in the irradiated vagus nerve were seen, indicating severe demyelination and loss of nerve fibers, which appeared to be radiation-dose dependent. Four patients with advanced recurrent head and neck cancer were treated with surgical resection and IORT without any acute or subacute complications. The role of IORT as a supplement to surgery, external beam irradiation, and chemotherapy in selected patients with advanced head and neck cancer needs further exploration.

Effect of digitals on clinical symptoms and conduction variables in patients with multiple sclerosis

Digitalis has been shown to reverse conduction block in demyelinated nerve fibers in experimental animals. In the search for a symptomatic treatment of multiple sclerosis, digoxin (0.02 mg per kilogram of body weight) was given intravenously to 7 patients with probable or clinically definite multiple sclerosis. All of these patients had temperature-dependent symptoms. In 3 patients, improvement of clinical deficits was observed concurrent with significant changes in evoked potential findings. Digitalis derivatives may be useful in ameliorating symptoms in selected patients with multiple sclerosis.

Electrophysiologic study of experimental demyelination induced by serum of patients with IgM M proteins and neuropathy

We induced progressive conduction block in feline sciatic nerve by endoneurial injection of serum from 2 patients with demyelinating neuropathy and an anti-myelin-associated glycoprotein (MAG) IgM M protein. The block was longlasting (up to 4 days) and affected about half the motor nerve fibers. Control serum from patients with an IgM M protein that did not react with MAG produced a transient block (less than 48 hours) that affected an average of 25% of motor fibers. Nerves with sustained block showed widespread demyelination of many nerve fibers, exceeding controls. The findings support the view that chronic demyelinating neuropathy in these patients is caused by the anti-MAG M protein.

Conduction along myelinated and demyelinated nerve fibres during the recovery cycle: Model investigations

The membrane excitability changes as well as the underlying mechanisms of these changes in a normal and in a systematically paranodally demyelinated nerve fibre have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The ionic current kinetics determining the observed changes in the action potential parameters are presented also. The simulation of the conduction in the normal fibre is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while in the case of a demyelinated fibre according to the same equations modified by Stephanova (1988a). It has been shown for the demyelinated membrane that increased demyelination increases both the threshold current for the second potential as well as the absolute refractory period. With increasing interpulse interval, the subnormality of the membrane excitability is followed by supernormality in the case of the demyelinated membrane. For the recovery cycle of 30 ms under consideration no supernormality of the normal membrane excitability is obtained. With interpulse interval from 8.8 to 10.9 ms, the highest degree of demyelination (l = 30 microns) is accompanied by a refractory period of transmission. The membrane properties of the normal and demyelinated fibres recover 20 ms after the first pulse. For short interpulse intervals, the amplitude of the second action potential is decreased, and a slower propagation velocity is obtained. The most sensitive phenomenon is the excitability of the demyelinated membrane, which remains unrecovered 30 ms after the first pulses has been applied.

Ouabain reverses conduction disturbances in single demyelinated nerve fibers.

Symptoms in patients with demyelinating disorders are associated with 3 important conduction abnormalities: complete conduction block, rate-dependent conduction block, and slowed impulse conduction. The recent observation that the electrogenic Na/K pump causes the nerve membrane hyperpolarization responsible for rate-dependent conduction block in demyelinated axons raises the possibility that focal inhibition of the pump may reverse the rate-dependent block. Since the pump is also responsible for maintaining part of the resting membrane potential, pump inhibition might have an additional effect of reversing the complete conduction block by reducing the threshold. We have demonstrated that inhibition of the pump by topical application of ouabain, a short-acting cardiac glycoside, reverses the conduction abnormalities in acutely demyelinated single rat ventral root axons by reducing the threshold of transmission. Ouabain or other cardiac glycosides show potential promise as agents for trial in the symptomatic treatment of patients with MS and other demyelinating disorders.

A differential diagnostic test for optic neuritis

A temporary lowering of body temperature by means of cold drinks, tried on a group of 18 patients with acute optic neuritis, led in 14 cases to a significant improvement in the 30 degree visual field, which the authors tested with the Octopus 201 automatic perimeter. In a group of 11 patients (17 eyes) who had previously had optic neuritis an improvement in the visual field was only seen in 8 eyes; in the other 9 eyes there was a deterioration. A slight deterioration in the 30 degree visual field after lowering body temperature was demonstrated in a group of 7 patients (12 eyes) with various diseases of the optic nerve as well as in 5 other healthy subjects. The temporary improvement in the patients with acute optic neuritis was probably caused by a reversible increase in the conductivity of the demyelinated nerve fibers as a result of lowering body temperature.

Galactose neuropathy: impact of chronic endoneurial edema on nerve blood flow.

Peripheral neuropathy induced by galactose feeding results in endoneurial edema with increased tissue pressure and ultimate demyelination of nerve fibers. To assess the role of ischemia in the pathogenesis of this neuropathy, nerve blood flow was measured 6 months after the start of galactose ingestion, between the onset of edema and nerve fiber changes. Measurement was carried out by a noninvasive technique involving the use of [14C]iodoantipyrine as a radioactive tracer of tissue perfusion. A significant decline in nerve blood flow was found, which correlated positively with increased nerve water content as quantified by a microgravimetric technique. We sought to establish the pathogenic role of nerve edema in the development of schwannopathy and demyelination by morphological examination. It was found that Schwann cells appeared normal in areas of the peripheral nervous system in which edema does not occur, such as spinal ganglia and roots, whereas in regions in which there was edema, massive glycogen accumulation in Schwann cells and demyelination occurred. These findings suggest that edema, rather than hyperactivity in the sorbitol pathway, is responsible for the pathological changes in galactosemic neuropathy and that ischemia resulting from edema and increased endoneurial fluid pressure is the mechanism responsible for fiber injury.

Experimental demyelinating optic neuropathy induced by intra-neural injection of galactocerebroside antiserum

The morphological changes induced by microinjection of galactocerebroside (Gal-C) antiserum into the rat optic nerve are described. Light and electron microscopic observations were made 2 – 20 days post-injection. The severity and extent of the lesion varied according to the volume of antiserum injected and the depth of penetration into the nerve. With small volumes of antiserum (1–3 μl), primary demyelination was the principal change found from 2 days onwards and by 10 days there was evidence of remyelination by oligodendroglia. Some fibres undergoing Wallerian-type degeneration were also found. The injection of larger volumes of antiserum (5–10 μl) produced a more extensive lesion with marked axonal degeneration in addition to demyelination at the periphery of the lesion. These findings show that Gal-C antiserum can cause demyelination of central nerve fibres when the blood-brain barrier is bypassed.

Psychological aspects of multiple sclerosis and its treatment: toward a biopsychosocial perspective.

Multiple sclerosis (MS) is a chronic, progressive neurological disease that produces demyelination of the CNS nerve fibers. With onset most often in young adulthood, the disease produces a variety of neurological symptoms and follows an unpredictable course characterized by exacerbations and remissions. This article reviews the literature on psychological aspects of MS including early psychoanalytic studies and more current psychosocial research. Literature on the relationship between stress and symptoms, and the extent of cognitive impairment experienced is reviewed. A view of psychosocial adjustment to MS based upon an adaptive coping model, and a psychological treatment approach suited to the special needs of individuals with MS are discussed. Finally, a biopsychosocial research model is recommended due to the complex, interactive nature of MS and unique research difficulties it presents.

Unidimensional latency — topograph applied to normal and demyelinated nerve fibers of rats

Unidimensional latency — topograph applied to normal and demyelinated nerve fibers of rats

Multiple exercise-related mononeuropathy with abdominal colic

Hereditary neuropathy with liability to pressure palsies (NLPP) is a rare disease characterized by recurrent sensory-motor deficits precipitated by exposure to minor pressure. This report describes a variant of this neuropathy in 5 siblings suffering from painful palsies after strenuous work with concurrent episodes of abdominal colic resembling that of acute intermittent porphyria. Electrophysiological studies of the index case showed the typical abnormalities of motor and sensory nerve conduction, including clinically non-affected nerves. Light and electron-microscopic examination showed the characteristic lesions of the NLPP with sausage-like swelling of the myelin sheaths. In addition, non-compacted, “loose” myelin lamellae were frequently observed in association with distended Schmidt-Lantermann incisures. Non-compacted myelin was a prominent finding in this type of demyelinating neuropathy. We suggest that an unknown metabolic factor may induce both demyelination of peripheral nerve fibers and functional disturbance in autonomic nerves leading to attacks of abdominal pain.

The optic nerve in multiple sclerosis: A morphological study with retrospective clinico-pathological correlations

We examined both optic nerves in 18 cases of chronic multiple sclerosis histologically. Thirty-five of these 36 nerves showed demyelination. In only eight patients had a history of unilateral or bilateral optic neuritis been recorded. The visual acuity of 15 of these patients had been recorded. In statistical analysis the loss of visual acuity correlated with the extent of demyelination in the optic nerves. In some cases, however, useful visual acuity proved to be compatible with the complete demyelination of the total cross section of the nerves over a length of 1 cm and more. These findings are considered to be evidence that conduction can take place in demyelinated nerve fibers running through relatively large demyelinated areas. At the same time the correlation between functional impairment and demyelination points to a crucial role played by demyelination in chronic multiple sclerosis.

Trigeminal neuralgia treated by the injection of glycerol into the trigeminal cistern.

Seventy-five patients with trigeminal neuralgia were treated by the injection of 0.2 to 0.4 ml of glycerol by the anterior percutaneous route into the trigeminal cistern, which was visualized by the aid of contrast medium (metrizamide). Eighty-six per cent of the patients were completely free from pain after the treatment, which produced only minimal disturbance of facial sensitivity. No complications have been observed. It is suggested that glycerol acts mainly on partly demyelinated nerve fibers, which are assumed to be involved in the trigger mechanism.

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.

1. 4-Aminopyridine (4AP) and tetraethylammonium ions (TEA), which block voltage-dependent potassium channels in other nerve membranes, have been used to study nerve conduction in fibres of normal rat spinal roots and those demyelinated with diphtheria toxin. The pharmacological actions have been compared with those of temperature. 2. Both TEA and 4AP increased the amplitude and duration of the monophasically recorded compound action potentials of non-myelinated fibres in normal rat dorsal roots. Enhancement of the action potential amplitude by 4AP was maximal near 1 mM, and was not readily reversed by washing. At concentrations up to 50 mM the action of TEA was weaker and reversible. 3. In normal dorsal and ventral roots TEA (20 mM) and 4AP (5 mM) had only a mildly depressant action on the compound action potentials of myelinated fibres. Whereas the slight reduction in peak amplitude and increase in width was also found in a single fibres treated with TEA, none was discerned in single fibres exposed to 4AP over a wide temperature range. 4. It is concluded that voltage-dependent potassium channels occur in significant numbers in mammalian non-myelinated fibres, but not at nodes of Ranvier. 5. Spinal roots previously treated with diphtheria toxin to cause demyelination were studied by longitudinal current analysis. Fibres affected by diphtheria toxin had a late phase of outward current, either restricted to nodes or, in the case of continuous conduction, distributed along internodes, and this outward current was specifically blocked by 4AP. 6. Both 4AP and TEA increased the temperature at which conduction block occurred in most single demyelinated fibres, so that in some cases fibres blocked at physiological temperatures were enabled to conduct. 4AP was more potent than TEA, but less consistent in its effect. 7. It is concluded that potassium channels are present at widened nodes and in internodal axolemma exposed by demyelination. Their presence enables TEA and 4AP to overcome conduction block in some demyelinated nerve fibres.

Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The use of a potassium-blocking agent to prolong action potentials may seem surprising because we previously found tetraethylammonium chloride (TEA), another potassium blocker, ineffective on normal rat myelinated fibres, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels. On the other hand, 4AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre, might further resemble its unmyelinated terminals by responding to 4AP. In testing this hypothesis, we have found that both TEA and 4AP prolong action potentials of demyelinated and unmyelinated fibres, and both facilitate conduction in fibres blocked by demyelination. 4AP is effective at lower concentrations, and is the more promising for clinical use, as it has already been used with beneficial effects in the treatment of Eaton-Lambert syndrome and myasthenia gravis.

CHRONOLOGICAL STUDY OF ULTRASTRUCTURAL CHANGES IN THE PERIPHERAL NERVES IN MAREK'S DISEASE

A chronological study was made of the ultrastructural changes in peripheral nerves following inoculation of 1-day-old chicks with a neurogenic strain of Marek Disease virus. No virus particles were found in nerves. Cellular infiltration of nerves was detected as early as 5 days after inoculation and by 3 weeks some nerves contained proliferative lesions which possessed many of the ultrastructural features characteristic of normal, reactive lymphoid tissue. About 4 weeks after inoculation, coinciding with the onset of neurological signs, areas of widespread demyelination appeared within these lesions; lymphocytes and macrophages penetrated and destroyed the myelin sheath, but spared Schwann cells and most axons. Later oedematous, sparsely infiltrated B type lesions were observed, some of which contained demyelinated nerve fibres undergoing repair; these were therefore a stage in the regression of the proliferative lesions. Our observations do not favour the hypothesis that cellular infiltration of nerves in Marek's disease is the direct result of auto-sensitization to normal myelin. They are consistent with the hypothesis that demyelination is a secondary feature and that the primary lesions are preferential sites for immune demyelination.

Short-term toxicity and reproduction studies in rats with hexachloro-(1,3)-butadiene

In rats given daily doses of 0. 0.4, 1.0, 2.5, 6.3, and 15.6 mg of hexachloro-(1,3)-buta-diene (HCBD)/kg by gavage for 13 weeks, no effect levels of 1.0 and 2.5 mg/kg were established for females and males, respectively. Inhibition of growth occurred in both sexes at the two highest doses and degeneration of proximal renal tubules occurred at doses of 2.5 and 6.3 mg/kg or more in females and males, respectively. Urine-concentrating ability was significantly reduced in females at doses of 2.5 mg/kg or more and in males at 15 mg/kg. Relative kidney weights were increased at the two highest doses in both sexes. Increased cytoplasmic basophilia of hepatocytes occurred in males at the two highest doses, associated with an increase in liver weight. In females, liver weights were increased only at the 15.6 mg/kg dose. In other studies, nephrotoxicity was noted after 2 weeks of administration of 150 and 450 ppm in the diet, characterized by epithelial hyperplasia of the proximal renal tubules. Ataxia associated with demyelination and fragmentation of femoral nerve fibers also occurred at a dietary level of 1500 ppm. Except for decreased body weights at birth and weaning, no effects on fertility or progeny were found. No porphyrinogenic effects were noted.