Central axons in injured cat spinal cord recover electrophysiological function following remyelination by Schwann cells.

Axonal morphometry of the lesion site was studied at 3 months after standardized weight-drop contusion injury of the thoracic spinal cord in adult cats. From a sample of 25 injured animals, 12 examples were found in which all surviving axons in the dorsal column were remyelinated by Schwann cells, at the level of the lesion. The dorsolateral tracts were also peripherally myelinated in 6 of these cases, and there was no central myelination in complete transverse sections through the lesion in four animals. In these cases, Schwann cell myelination was prevalent for several millimeters on either side of the lesion center. The extent of Schwann cell invasion correlated with the intensity of injury, measured by overall axon loss. Cortical somatosensory evoked potentials (CSEP) were recorded from all animals before and at intervals for 12 weeks after injury. CSEP to hindlimb (tibial nerve) stimulation were lost immediately at injury but some recovery took place during the first month. The extent of CSEP recovery correlated negatively but weakly with overall axon loss. Clear SEP were recorded at 3 months post-injury in 3 of the animals in which the dorsal columns were remyelinated by Schwann cells; in one of these, the dorsolateral funiculi were also peripherally myelinated. In another, oligodendrocyte myelination was absent from the entire transverse section of the lesion site. Thus, abnormal remyelination by cells of the peripheral nervous system, which is known to occur in a variety of central demyelinating conditions, is capable of restoring effective action potential conduction in mammalian spinal cord sensory tracts.

A model for slow axonal transport and its application to neurofilamentous neuropathies.

A model for slow axonal transport is developed in which the essential features are reversible binding of cytoskeletal elements and of soluble cytosolic proteins to each other and to motile elements such as actin microfilaments. Computer simulation of the equations of the model demonstrate that the model can account for many of the features of the SCa and SCb waves observed in pulse experiments. The model also provides a unified explanation for the increase and decrease of neurofilament transport rates observed in various toxicant-induced neuropathies.

Inflammation of rat molar pulp and periodontium causes increased calcitonin gene-related peptide and axonal sprouting.

We have studied the response of nerve fibers containing calcitonin gene-related peptide immunoreactivity (CGRP-IR) to inflammation using a rate dental experimental system. Inflammation was induced by drilling tooth cusps to create pulpal exposures; the induced pulpitis and subsequent periapical lesions were studied 1-35 days later using standard CGRP immunohistochemistry and the avidin-biotin peroxidase method. The injury and resulting inflammation caused a disruption of CGRP-IR nerve fiber location and arborization that varied depending on whether the initial injury was limited to the pulp tip or extended throughout the pulp horn. At shorter survival periods (24 hr, 3 days) nerve fibers were either decreased or bundled into the center of the pulp with sprouting along the wound border. At 6 days necrosis and acute inflammation had advanced to varying degrees, and CGRP-IR fibers were extensively sprouted in the surviving pulp; the pulp also stained specifically for CGRP within 1-2 mm of the inflamed tissue at 6 days. At 35 days, we found total pulp necrosis in most teeth and the development of periapical bone loss, granulomatous tissue, and periapical abscesses. There was also an extensive increase in CGRP-IR nerve fibers in the tissues surrounding sites of severe periodontal inflammation and necrosis. In some cases, macrophage-like cells staining specifically for CGRP were near the abscesses. The results show important interactions between peptidergic nerve fibers and inflammatory cells, and are discussed in terms of the role of nerve fibers containing CGRP in neurogenic inflammation, mechanisms for intensification of CGRP immunoreactivity in affected fibers or neighboring cells, and implications for chronic inflammatory conditions, dental pain, and anesthesia.

Use of exogenous electric current in the treatment of delayed lesions in peripheral nerves.

A commonly observed clinical problem following nerve injury is the incomplete recovery of function associated with the formation of a neuroma in continuity. In the present study, exogenous direct electric current was tested for its ability to promote growth of axons through a neuroma-like lesion. Neuroma-like structures were created by crushing rat sciatic nerves at two sites 4 mm apart and applying phenol to the intermediate region. A bulbous axonally impenetrable structure is formed 3 weeks later. At that time, silicone cuffs were sewn onto the nerve proximal to the phenol application site and 7 mm distally. In experimental groups, cuffs were attached to wires leading to a subcutaneously implanted Traxon power source, the distal cuff being cathodal. In control groups, cuffs were not electrically connected. In electrically active groups, substantial numbers of myelinated axons were seen distal to the cathode 3 weeks after implantation. Four times fewer fibers were observed in control groups. Footprint patterns from electrically active animals revealed a significant improvement over control neuroma preparations, as quantitated using the Sciatic Functional Index.

Multiple transmitter systems contribute neurites to individual senile plaques.

Senile plaques (SP), which consist largely of abnormal neuronal processes in proximity to deposits of amyloid, are a characteristic neuropathological feature of Alzheimer's disease. In lesser numbers, SP also occur in the brains of nondemented aged humans and nonhuman primates. To date, it is not known whether neurites in individual SP derive from neurons of one or several neurotransmitter systems. In aged monkeys, two strategies were used to test the hypothesis that individual SP can contain abnormal neurites arising from multiple neuronal systems. First, immunocytochemical methods were used to identify somatostatin-immunoreactive neurites in plaques, and these sections were subsequently stained with silver to visualize other neurites. Numerous plaques contained both somatostatin-positive and somatostatin-negative (i.e. argyrophilic only) neurites, suggesting that more than one transmitter system contributed neurites to each of these plaques. Second, two-color immunocytochemical techniques showed, in a small percentage of plaques, that cholinergic neurites coexist with neuropeptide Y (NPY)-containing neurites or catecholaminergic neurites. These results suggest that the formation of SP may result from events that involve abnormalities of neuronal processes arising from multiple transmitter systems.

Axonal damage in severe traumatic brain injury: an experimental study in cat.

Based upon recent clinical findings, evidence exists that severe traumatic brain injury causes widespread axonal damage. In the clinical setting, it has been assumed that such axonal damage is the immediate consequence of traumatically induced tearing. However, in laboratory studies of minor head injury, evidence for primary traumatically induced axonal tearing has not been found. Rather the traumatic event has been linked to the onset of subtle axonal abnormalities, which become progressively severe over time (i.e., 12-24 h). In the light of these discrepant findings, we investigated, in the present study, whether progressive axonal change other than immediate tearing occurs with severe traumatic brain injury. Anesthetized cats were subjected to high intensity fluid-percussion brain injury. Prior to injury all animals received cortical implants of horseradish peroxidase (HRP) conjugated to what germ agglutinin to anterogradely label the major motor efferent pathways. Such an approach provided a sensitive probe for detecting traumatically induced axonal abnormality via both light microscopy (LM) and transmission electron microscopy (TEM). The animals were followed over a 1- to 6-h posttraumatic course, and processed for the LM and TEM visualization of HRP. Through such an approach no evidence of frank traumatically induced tearing was found. Rather, with LM, an initial intra-axonal peroxidase pooling was observed. With time, unilobular HRP-containing pools increased in size and progressed to bi- or multilobulated profiles. Ultimately, these lobulated configurations separated. Ultrastructurally, the initial unilobular pool was associated with organelle accumulation and focal axolemmal distention without frank disruption. Over time, such organelle accumulations increased in size and sequestered into multiple pools reminiscent of the bi- and multilobulated structures seen with LM. Ultimately, these organelle accumulations became detached, resulting in physically separated proximal and distal organelle-laden swellings surrounded by a distended axolemma and thinned myelin sheath. The findings reject the hypothesis that axons are immediately torn upon impact.

Hypothermia-induced reversible polyneuropathy: electrophysiologic evidence of axonopathy.

A 2 1/2-year-old child developed peripheral polyneuropathy following exposure to hypothermia. Serial electrophysiologic studies over the next 10 months revealed progressive recovery from severe axonopathy. The literature on cold-induced neuropathy is reviewed. The two electrophysiologic studies reported previously in cold-induced polyneuropathy patients are discussed and compared with findings of our patient.

The pathophysiology of proximal neurofilamentous giant axonal swellings: implications for the pathogenesis of amyotrophic lateral sclerosis.

Neurofilamentous giant axonal swellings are observed in a number of human disorders, although they can manifest at different locations (i.e. proximal or distal) along the axon. Recent advances in understanding the pathogenesis of these changes has resulted from correlations of ultrastructural changes with abnormalities in the axonal transport of neurofilament proteins in experimental models produced by toxic chemicals. Using single, high doses of either acrylamide or 2,5-hexanedione, a reduction in neurofilament transport has been shown in the rat sciatic nerve. In contrast to the distal axonal swellings observed upon repeated exposures to these agents, modest proximal axonal swellings containing increased neurofilament content are found following high dose exposures. Thus, regardless of the location of swelling production, a defect in slow transport appears to underlie swelling formation. beta,beta'-Iminodipropionitrile (IDPN) produces proximal neurofilamentous giant axonal swellings which are indistinguishable from those observed in some patients with amyotrophic lateral sclerosis (ALS). Although not a model for ALS, IDPN provides a means to study the functional consequences of proximal giant axonal swellings. Intracellular recordings from IDPN-intoxicated cats reveal a number of abnormalities which may have electrophysiological counterparts in ALS, suggesting that the swellings may be important in the expression of the disease. Although axonal degeneration is rarely observed in the cat, perikaryal recordings reveal a number of alterations which are strikingly similar to those obtained from chromatolytic motor neurons following nerve transection. A perturbation of "trophic" signals from the periphery may be involved in the generation of axotomy-like changes in IDPN-intoxicated cats.

Diagnostic difficulties in infantile neuroaxonal dystrophy. A clinicopathological study of eight cases.

The clinical features of eight children with infantile neuroaxonal dystrophy are presented. Diagnosis was established by brain biopsy (4 cases), conjunctival biopsy (1 case), and the family history (2 cases), while in one case a presumptive diagnosis was made on the combination of clinical and neurophysiological findings without histopathological confirmation. The pleomorphic clinical picture and variable neurophysiological findings make a firm diagnosis difficult without histopathological confirmation. However, in the appropriate clinical context, serial neurophysiological investigations (ERG, VEP, EEG, ENMG) may suggest the diagnosis after the age of 2 years. Conjunctival biopsy is not invariably helpful, and neuroaxonal spheroïds are not always demonstrated in brain biopsies by conventional techniques. However, they were consistently identified using a non-specific esterase stain and by electron microscopy. This technique is described, and the significance of ultrastructural and neuropathological findings in infantile neuroaxonal dystrophy is discussed.

Sensory axonal dysfunction in the upper and lower limb of diabetic patients and its relation to diabetic retinopathy.

We studied the sensory and motor potentials of the median and posterior tibial nerves and sural nerves in 20 insulin-treated diabetic patients, aged 21-71 years, with a known duration of 1 month to 25 years. Individual levels of sensory velocity were within normal range or slightly reduced in diabetic patients. However, the reductions of sensory potential amplitude were obvious in the sural nerve. No relation was found between sensory amplitude and either known diabetic duration or retinal diabetic changes. These results suggest that axonal degeneration of sensory fibers cannot easily be corrected in comparison to the slight changes caused by segmental demyelination.

Peripheral neuropathy associated with high-dose Ara-C therapy.

Central nervous system toxicity associated with high-dose cytosine arabinoside (Ara-C) therapy (HD Ara-C) is well known. The authors report the case of a severe isolated peripheral polyneuropathy due to HD Ara-C. Electrophysiologic changes and histologic observations were consistent with axonal degeneration and scattered destruction of myelin sheaths. This observation emphasizes the need for careful complete neurologic evaluation for patients receiving HD Ara-C treatment.

Capsaicin prevents histamine-induced itching.

The effects of topical treatment with capsaicin or mustard oil on histamine-induced pruritus, wheal formation and flare response were studied in the human skin. Capsaicin pretreatment resulted in a reversible marked reduction or abolition of the axon reflex flare, but did not influence whealing. Itching was also strongly diminished or even abolished, provided that the flare response was completely blocked. The onset of itching was significantly promoted by pretreatment of the skin with mustard oil, inducing axon reflex vasodilatation. It is concluded that, in addition to the axon reflex flare, capsaicin-sensitive peptide-containing primary afferent neurones are also intimately involved in the mediation of the sensation of itching.

Pyridoxine neuropathy in rats: specific degeneration of sensory axons.

When rats received pyridoxine in doses large enough to cause neuropathy in humans, the animals developed gait ataxia that subsided after the toxin was withdrawn. By using quantitative histologic techniques, we found axonal degeneration of sensory system fibers and that the fibers derived from the ventral root were spared. Although the degeneration approached the dorsal root ganglion, neurons in the ganglion did not degenerate. We found no early decrease in oxygen consumption of nerve, suggesting that impaired oxidative metabolism was not the primary event.

Reflex activity and axonal conduction in the L-7 spinal cord segment following experimental compression trauma.

In cats in which the spinal cord was transected at C-1, the exposed L-7 spinal cord segment was compressed with an electromagnetically driven rod applied to the dorsal surface of the segment. With the magnitude of compression constant at 3 mm, the cord was compressed for durations of 50 msec, 0.5 sec, or 1.0 sec. Polysynaptic reflex discharges integrated in the injured segment and action potentials conducted in dorsal column axons traversing the same region were electrophysiologically measured before, during, and for 41/2 hours after trauma. Structural changes were evaluated on frozen serial sections obtained both from compressed segments and from tissue adjacent to the injury. At a compression duration of 50 msec, the amplitude of evoked reflex activity decreased abruptly, and dorsal column axonal conduction was blocked for 1 minute following compression. This early-phase response was followed by partial recovery of both functions which persisted until the end of the experiment. Prolonging compression to 0.5 sec brought about a further decrease of polysynaptic reflex activity. Axonal conduction was also decreased, but not significantly. With compression lasting 1.0 sec, no significant changes in reflex discharges and axonal conduction occurred compared with those measured at 0.5 sec. Neither function was abolished, even after the longest compression time. Prolongation of compression significantly increased both the intensity and the spread of edema, whereas changes in hemorrhage were not significant. Thus, a plateau rather than a progressive increase in severity of functional and structural posttraumatic changes was reached by increasing the duration of compression. This injury model reduces the sources of variability found in other experimental compression trauma models and permits the quantitative assessment of basic spinal cord mechanisms and correlated histopathological changes in the same preparation following trauma.

Evolution of axonal swellings in cats intoxicated with beta,beta'-iminodipropionitrile (IDPN). An electrophysiological and morphological study.

beta,beta'-Iminodipropionitrile (IDPN) causes formation of axonal swellings in the proximal internodes of spinal motor axons. The swellings enlarge and demyelinate with the progression of the neuropathy. The correlation between axonal swellings and electrophysiologic function of motoneurons was examined in cats 2 to 35 days after initial administration of IDPN. Morphologic changes in intraspinal motor axons, occasionally observed 2 days after the first injection, became progressively more evident at later times, with enlargement at the first internode in some axons and appearance of fusiform or balloon-like axonal swellings. At 7 days axonal swellings were infrequently observed and the main structural feature was a reduction in myelin thickness in affected nerve fibers. Despite scant histopathologic changes, motoneuron action potential discharge at this time was significantly altered in latency to onset of spike and rate of rise. Abnormal motoneuron firing patterns were observed at this time. As the neuropathy progressed, both the frequency of occurrence and the size of axonal swellings increased markedly but at no time was there morphologic evidence of chromatolysis. At 14 and 35 days, (after two or five IDPN injections) action potential discharge became further altered in latency to spike onset, rate of rise, initial segment conduction time and somal-dendritic threshold. The incidence of repetitive firing increased and axonal conduction block was observed in several motoneuron recordings. The electrophysiologic changes closely resemble those reported in chromatolytic motoneurons after axotomy. The axonal swellings induced by IDPN may produce an axotomy-like condition which becomes more prominent as the neuropathy progresses but without morphologic evidence of chromatolysis.

Membrane ultrastructure of developing axons in glial cell deficient rat spinal cord.

In order to investigate axolemmal development in a glial cell deficient environment, normal and irradiated dorsal funiculus in rat lumbosacral spinal cord was examined by freeze-fracture electron microscopy. At 3 days of age, normal fibres are all unmyelinated and of small (less than 0.5 micron) diameter. The unmyelinated axons have a moderate density (approximately 850 microns-2) of intramembranous particles (IMPs) on P-fracture faces and a low IMP density (approximately 300 microns-2) on E-faces. IMPs are homogeneously distributed along both fracture faces. By 19 days of age, the normal dorsal funiculus is well populated with myelinated axons and glial cells, as well as a sizable population of unmyelinated fibres. Nearly all of the myelinated fibres have a large (greater than 1.0 micron) diameter; whereas, most unmyelinated axons are of small (less than 0.5 micron) calibre. The axolemma of unmyelinated axons is relatively undifferentiated, with an asymmetrical distribution of IMPs (P-face: approximately 1100 microns-2; E-face: approximately 450 microns-2). Myelinated fibres show nodal and paranodal regions with P-face and E-face ultrastructure similar to previous descriptions. Internodal axolemma appears relatively homogeneous, with P-faces being highly particulate (approximately 2100 microns-2) and a low IMP density (approximately 200 microns-2) on E-faces. Following irradiation of the lumbosacral spinal cord at 3 days of age, there is a severe reduction in the number of glial cells and myelinated fibres in this region when the tissue is examined at 19 days of age. Despite the deficiency of glial cells in this tissue, axonal and axolemmal development continue. Numerous large (greater than 1.0 micron) diameter axons are present in this irradiated tissue. Large diameter axons show a high (approximately 2000 microns-2) density of IMPs on P-faces; E-face IMP density remains at approximately 440 micron-2. Small calibre axons also have an asymmetrical distribution of particles (P-face: approximately 1100 microns-2; E-face: 280 microns-2). The axolemmal E-faces of some glial cell deprived fibres exhibit regions with greater than normal (approximately 750 microns-2) density of IMPs. These results demonstrate that some aspects of axonal and axolemmal development continue in a glial cell deficient environment, and it is suggested that axolemmal ultrastructure is, at least in part, independent of glial cell association.

Acquired oculomotor synkinesis.

Paradoxical patterns of pupillary, lid and eye movement may follow oculomotor nerve palsy or they can develop spontaneously in patients with no known history of oculomotor palsy. The mechanism of this condition, known variously as aberrant regeneration of the third nerve, oculomotor misdirection or acquired oculomotor synkinesis, is not known, although the prevailing opinion has held that it occurs when axons regenerating within an oculomotor nerve become misdirected and innervate muscles for which they were not intended. However, there is evidence against this hypothesis. The authors critically review the various hypotheses and elucidate the controversy concerning the pathogenesis of acquired oculomotor synkinesis.