Separating motor neuron diseases from pure motor neuropathies. Multifocal motor neuropathy with persistent conduction block.
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Antibodies↗
Biomedical subjects
A J Sumner
Publications and source records attributed to A J Sumner.
A computer simulation of conduction block: effects produced by actual block versus interphase cancellation.
A reduction in compound muscle action potential (CMAP) amplitude and area following proximal versus distal stimulation is the accepted clinical hallmark of conduction block; however, quantitative criteria for determining conduction block remain ambiguous. In this study, digitized records of individual motor unit action potentials (MUAPs) elicited by incremental stimulation in vivo were arithmetically combined in a computer simulation of CMAP generation. Through simulation of possible phase interaction patterns of individual MUAPs, we have shown that abnormal temporal dispersion alone can produce reductions in CMAP area of up to 50%, values that are commonly thought to represent conduction block. Furthermore, by simulating conduction block without excessive temporal dispersion in defined subpopulations of axons, we have demonstrated the importance of the fastest conducting (largest MUAP) axons in determining CMAP amplitude and area. In conclusion, measurements of CMAP amplitude and area in determining conduction block may be misleading if there is significant abnormal temporal dispersion, and quantitation of the degree of conduction block is difficult without knowledge of which subpopulations of axons are affected.
Action Potentials↗
Effect of digitalis 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.
Adult↗
Aberrant reinnervation.
Although great emphasis is placed on providing a satisfactory conduit for regeneration of peripheral axons after nerve repair, the quality of functional restoration is influenced as much by the quality as the quantity of axonal regeneration. Misdirected regeneration is so commonly encountered that motor axons appear to enter and regenerate to muscles in an almost random manner. Thus, when there are several choices, as usually is the case with more proximal nerve or plexus repairs, misdirected reinnervation accounts in many incidences for a poor quality of functional restoration. The regenerative capacities of type I and type II motor axons appear to differ. Proprioceptors and other sensory axons have been shown to reinnervate inappropriate end organs. Consequently, deranged central reflex modulation and disturbed orderly recruitment of motor units according to the size principle also contributes to this problem. Central re-education or adaptation to misdirected regeneration does not occur to any appreciable extent.
Electromyography↗
Vector short-latency somatosensory-evoked potentials after median nerve stimulation.
A new method has been developed for recording short-latency somatosensory-evoked potentials after median nerve stimulation. Negative electrical forces recorded with three orthodiagonal bipolar electrodes in the neck had a direction opposite to that of impulse conduction in the proximal peripheral and cervical somatosensory pathway. Sequential tracings of vectors opposite the electrical forces were made in three-dimensional display, thus reproducing the actual time sequence of electrical events in those structures. Fixed generators such as the subcortical nuclei were also analyzed with this technique, and multiple generators of N13 potential (N13a and N13b) were visualized. This technique may be useful in the functional evaluation of the somatosensory pathway in the cervical cord.
Adult↗
A syndrome of asymmetric limb weakness with motor conduction block.
We describe 3 patients with asymmetric limb weakness, fasciculations (2 patients), relatively preserved reflexes, normal cranial nerves, and few or no sensory abnormalities. The symptoms had been progressive over 1 to 15 years. Detailed motor nerve conduction studies showed conduction block and slowing localized to sharply circumscribed areas 30 to 100 mm long in several nerves in each patient. By contrast, the sensory conduction studies over the same nerve segments were normal, indicating very selective involvement of motor fibers. Sural nerve biopsies showed minor changes that varied among the patients. One patient had high levels of anti-GM1 antibodies, 1 had mildly elevated levels, and 1 had high levels of only asialo-GM1 antibodies. Treatment with immune suppressive therapy has produced minimal improvement in 1 patient.
Electrophysiology↗
Mitomycin C induces a delayed and prolonged demyelination and conduction block due to Schwann cell destruction.
The intraneural injection of 25 micrograms/ml of mitomycin C produced a prolonged conduction block of delayed onset within the injected nerve. No change in electrophysiological parameters was seen for 6 days after injection, but thereafter a marked drop in the compound muscle action potential (CMAP) amplitude from stimulation proximal to the site of injection occurred, with recovery not being complete until day 97. CMAP amplitude from stimulation distal to the injection site remained unchanged. The reason for this prolonged period of conduction block was apparent from histological examination of the nerve. Light and electron microscope studies demonstrated Schwann cell death, clearly evident at day 8 and followed by subsequent macrophage removal of myelin and Schwann cell debris. Remyelination was not seen until day 40. Hence for periods of about 30 days naked axons persisted through the area of injection. Schwann cells associated with unmyelinated fibres were relatively unaffected, suggesting that myelinating Schwann cells were vulnerable to this agent by virtue of the metabolic processes associated with their myelin maintenance and renewal. These findings indicate that mitomycin C injected intraneurally provides an excellent model to study the effects of Schwann cell disease.
Action Potentials↗
Effect of digitalis on central demyelinative conduction block in vivo.
In searching for agents effective in treating multiple sclerosis, we studied the effect of a short-acting digitalis, ouabain, on conduction block in an animal model of central nervous system demyelination. The electrogenic sodium/potassium pump, which digitalis specifically inhibits, is responsible for part of the resting membrane potential and also the activity-related membrane hyperpolarization following high-frequency impulses. The latter causes intermittent conduction block in demyelinated fibers. Therefore, digitalis might be expected to reverse demyelinative conduction blocks by reducing the threshold at the blocking node. Somatosensory evoked potentials were monitored in 11 rats with spinal cord demyelination before and after systemic administration of ouabain (0.1-0.6 mg or 0.21-1.58 mg/kg IP). In all rats, slowed conduction velocity of the compound action potential through the lesion was significantly reversed, and failure to transmit high-frequency impulses was improved upon. The amplitude of the cortical somatosensory evoked potentials also increased significantly. Digitalis is a promising therapeutic agent for trial in patients with multiple sclerosis.
Afferent Pathways↗
Slow recovery of central axons in acrylamide neuropathy.
To study the differential vulnerability of central versus peripheral axons, we observed serial changes in conduction over comparable segments of central and peripheral axons of the primary sensory neuron in 17 rats with acrylamide neuropathy using somatosensory evoked potentials. Central conduction abnormalities persisted even after peripheral conduction and clinical abnormalities had recovered. Morphometric studies showed prompt restoration of the largest-diameter fibers in the peripheral nerve after clinical recovery but persistent or even more severe loss of large- and medium-sized fibers in the cervical gracile tract. This finding suggests that recovery from central-peripheral distal axonopathy begins in the largest peripheral axons, perhaps even at the expense of central axons, and that clinical recovery can occur at a time when central conduction remains abnormal. The selective central axonopathy found in certain chronic degenerative disorders may be a consequence of this slow central recovery process associated with chronic or intermittent metabolic derangements.
Acrylamides↗
Analysis of the feline immune response to human myelin-associated glycoprotein.
Elucidation of the pathogenesis of demyelinating peripheral neuropathy associated with myelin-associated glycoprotein (MAG) binding IgM paraproteins requires an in vivo animal model of the syndrome. Multiple immunizations of cats with MAG in Freund's adjuvant did not produce an antibody response but four immunizations with MAG-iscom (Morein, B. et al. (1984) Nature, 308: 457-460) did induce IgM antibodies which bound to human MAG and cat peripheral nerve myelin. Despite the presence of antibody for a 13-month period, no neuropathy developed. At necropsy, the peripheral nerves were ultrastructurally normal and no antibody was detectable in the endoneurium. A competitive ELISA indicated that the cat and human IgM antibodies recognized different epitopes.
Animals↗
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.
Animals↗
Tellurium-induced demyelination: an electrophysiological and morphological study.
Tellurium (Te) is a naturally occurring element with many industrial uses. Microinjection of 0.3 micrograms of potassium tellurite [K(2)TeO(3)] into the endoneurial space of rat tibial nerve causes a rapidly progressing focal conduction block as measured by the disappearance of the evoked compound muscle action potential (CMAP) of the intrinsic foot muscles following stimulation proximal to the injection site. Conduction block was fully established within 6 hours and persisted for approximately 7 days, followed by the appearance of low amplitude, long latency, temporally dispersed potentials. The proximal CMAPs increased in amplitude and decreased in latency and temporal dispersion until normalization by 28 days after injection. The distal CMAP showed a minimal decline in amplitude. Morphological observations showed splitting of myelin, especially in the paranodal regions, followed by accumulation of myelin debris in Schwann cells and macrophages. Although the exact mechanism remains unknown, this in vivo model provides a unique opportunity to study the electrophysiological and morphological correlates of an acutely evolving demyelinative process.
Animals↗
Physiological consequences of antiserum-mediated experimental demyelination in CNS.
To study the pathophysiology of immunologically mediated demyelination in the central nervous system (CNS), we injected 20 to 30 microliters of polyclonal antigalactocerebroside serum (AGC) into the lower thoracic dorsal column of the spinal cord in 20 Wistar rats. AGC-injected spinal cords contained areas of fascicular demyelination adjacent to the focus of axonal degeneration at the injection site. Somatosensory evoked potentials were recorded serially after tibial nerve stimulation. In 85% of AGC-injected animals, the following characteristics were observed by 3 days after injection: (1) decreased amplitude of the cortically generated potential (P15); (2) failure of transmission of high-frequency (50 Hz) impulses (rate-dependent block); (3) delayed conduction velocity of the compound action potentials through the lesion. None of these changes was seen in 90% of 20 rats injected with normal saline or control rabbit sera. In 7 rats with acrylamide-induced axonopathy or wallerian degeneration, the rate-dependent block was not observed. The onset of clinical symptoms (hindlimb ataxia) in AGC-injected rats was best correlated with development of the rate-dependent block. Clinical recovery was observed by 14 days after injection concurrent with restoration of P15 amplitude, when the rate-dependent block and decreased conduction velocities were unchanged. High-frequency-resistant conduction was re-established much later than clinical recovery in 3 rats. These findings suggest that failure of high-frequency impulse transmission may produce clinical symptoms and that a central adaptive mechanism to remodulated trains of impulses plays a role in clinical recovery from CNS demyelination.
Acrylamide↗
Schwann cell degeneration induced by doxorubicin (adriamycin).
Doxorubicin is an anthracycline antineoplastic antibiotic that acts at the cell nucleus by intercalating between base pairs of DNA, thus inhibiting DNA-directed mRNA synthesis. Intraneural micro-injection of 0.19-0.38 micrograms of this substance into rat sciatic nerve results in a delayed subacute demyelination that is secondary to focal Schwann cell degeneration. Remyelination eventually occurs but is not complete until at least days 60-75 postinjection. Toxic Schwann cell disorders produced by agents such as doxorubicin may serve as useful models in understanding the pathogenesis of human demyelinative neuropathies.
Action Potentials↗
Lethal retrograde axoplasmic transport of doxorubicin (adriamycin) to motor neurons. A toxic motor neuronopathy.
Doxorubicin (Adriamycin) is an autofluorescent anthracycline antibiotic that acts as a DNA intercalator. Following intraneural microinjection of 3 micrograms of doxorubicin into rat tibial nerve, fluorescence microscopy indicated that it is transported retrogradely to anterior horn cell bodies. Subsequently, these motor neurons underwent a progressive subacute degeneration that occurred over a period of 35-39 days. Combined electrophysiological and neuropathological methods indicated that dorsal root ganglion cells were relatively unaffected by this dose of toxin. The selective motor neuron degeneration produced by this agent raises the possibility that abnormalities of nucleic acid metabolism may be involved in the aetiology of motor neuron diseases.
Action Potentials↗
Effects of 4-aminopyridine in experimental CNS demyelination.
We studied the effect of systemically administered 4-aminopyridine in a model of CNS demyelination. In five rats with demyelination, slowed conduction velocity through the lesion was partially reversed at dose levels of 5.6 to 7.2 mg/kg. All rats developed convulsion at this dosage, and impaired conduction of high-frequency impulses was unchanged. These findings suggest certain limitations of 4-aminopyridine as a therapeutic agent.
4-Aminopyridine↗
Neuralgic amyotrophy: an increasingly diverse entity.
We describe nine cases of neuralgic amyotrophy whose clinical and electrophysiologic findings suggest lesions of individual peripheral nerves or peripheral nerve branches occurring singly (mononeuropathy) or in various combinations (mononeuropathy multiplex). There were four occurrences of isolated denervation of the pronator teres muscle; four occurrences of anterior interosseous nerve lesions; three occurrences of lateral antebrachial cutaneous nerve lesions; two occurrences of long thoracic nerve lesions; and one occurrence each of a median nerve trunk lesion, a median palmar cutaneous branch lesion, a suprascapular nerve lesion, and an axillary nerve lesion. "Neuralgic" pain was a prominent feature in all cases, and the location of the pain correlated with the location of the nerve lesions. We hypothesize that the specific course of certain nerves (especially their location across joints) selectively exposes them to mild focal trauma that increases their susceptibility to this disease. Whatever the etiology, this entity is considerably more diverse than generally appreciated.
Adult↗
Prosthetic nerve grafts: a resorbable tube as an alternative to autogenous nerve grafting.
The use of a prosthetic nerve graft, composed of a resorbable polyorthoester tube, as an alternative to free autogenous nerve grafting for the treatment of a gap in a peripheral nerve was studied, with a cat sciatic nerve as the model. The results demonstrate that regeneration will occur through a resorbable tube spanning a 1.5 cm gap and reinnervate end organ muscle. In those muscles showing evidence of reinnervation, nerve regeneration through the tubes as assayed by electrophysiologic examination demonstrated no difference compared with autogenous nerve grafts, with the exception that the initial rate of regeneration was delayed by 4 to 6 weeks.
Animals↗