NEUROPHYSIOLOGIC SIGNS OF LOWER MOTOR NEURON IMPAIRMENT FOLLOWING LESIONS OF THE UPPER ONES. Ph.D. Thesis. Miklós Lukács M.D. - PDF

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NEUROPHYSIOLOGIC SIGNS OF LOWER MOTOR NEURON IMPAIRMENT FOLLOWING LESIONS OF THE UPPER ONES Ph.D. Thesis Miklós Lukács M.D. Department of Neurology University of Szeged, Szeged, Hungary LIST OF

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NEUROPHYSIOLOGIC SIGNS OF LOWER MOTOR NEURON IMPAIRMENT FOLLOWING LESIONS OF THE UPPER ONES Ph.D. Thesis Miklós Lukács M.D. Department of Neurology University of Szeged, Szeged, Hungary LIST OF FULL PAPERS THE THESIS BASED UPON I. Lukács M. Motoros egységek szerkezeti változásai cerebralis ischaemiás kórfolyamatokban elektrofiziológiai adatok. Ideggyógyászati Szemle 2005; 58(7-8): II. Lukács M. Electrophysiological signs of changes in motor units after ischaemic stroke. Clin Neurophysiol 2005; 116: IF: 2.54 III. Lukács M. F wave measurements detecting changes in motor neuron excitability after ischaemic stroke. Electromyogr Clin Neurophysiol 2007; 47: IV. Lukács M, Vécsei L, Beniczky S. Large motor units are selectively affected following a stroke. Clin Neurophysiol 2008; 119: IF: 2.45 V. Lukács M, Vécsei L, Beniczky S. Fiber density of the motor units recruited at high and low force output. (accepted for publication) Muscle Nerve 2009 IF: 2.50 VI. Lukács M, Vécsei L, Beniczky S. Changes in muscle fiber density following a stroke. (submitted manuscript) Clin Neurophysiol Sum of impact factors (IF) for references: IF:7,49 2 LIST OF ABBREVIATIONS ADM ANOVA CMAP CSAP CT EMG FD ISI MUNE MUP NCS SD SE SFEMG abductor digiti minimi analysis of variance compound muscle action potential compound sensory action potential computer tomography electromyography fiber density interstimulus interval motor unit number estimation motor unit potential nerve conduction study standard deviation standard error single-fiber electromyography 3 TABLE OF CONTENTS I. SUMMARY...5 II. INTRODUCTION... 9 III. OBJECTIVES IV. SUBJECTS AND METHODS Changes in the motor unit potentials and nerve conduction studies Changes in fiber density at low force output Changes in fiber density at high force output Fiber density at low and high force output in healthy subjects Macro electromyography at high and low force output F wave measurements V. RESULTS Changes in the motor unit potentials and compound motor action potentials Changes in fiber density at low force output Changes in fiber density at high force output Fiber density at low and high force output in healthy subjects Macro electromyography at high and low force-output F wave measurements VI. DISCUSSION VII. NEW RESULTS ESTABLISHED IN THE THESIS IX. ACKNOWLEDGEMENTS X. REFERENCES XI. ANNEXES I. SUMMARY BACKGROUND: Loss of lower motor neurons caused by upper motor neuron lesion following stroke has been recently suggested by neurophysiological data. Needle electromyographic studies have revealed pathological spontaneous activity in paretic muscles after a cerebrovascular insult and MUNE studies reported loss of functioning motor units on the hemiparetic side of stroke patients (3, 4, 25, 26, 31, 40, 46, 47, 56). These changes might be due to trans-synaptic degeneration that occurs secondarily to the lesion of the upper motor neurons (25, 26). Alternatively the lower motor neurons could have been inactivated due to the lack of efferent impulses. However, these changes could have been caused by compression neuropathy in or inactivation of the paretic limb. Therefore, the concept about lower motor neuron injury with upper motor neuron lesion remained controversial. The armamentarium of the clinical neurophysiologist enables him to assess specific aspects of the pathophysiologic changes in the nerves and muscles. Each lower motor neuron innervates many muscle fibers. The lower motor neuron and all the muscle fibers innervated by it constitute the motor unit. The number of muscle fibers inervated by large (high-threshold) motor neurons is higher than the number of mucle fibers innerveted by smaller (low-threshold) motor neurons (28, 29). Judicious selection of appropriate neurphysiologic techniques can yield a significant amount of complementary information about the function (or dysfunction) of these structures. Motor nerve conduction studies are informative about the number of functionning lower motor neurons. Concentric needle EMG detects the spontaneous muscle electric activity following denervation, and also the reorganisation of the motor units in the subsequent, chronic stage after denervation (51). Using single-fiber EMG one can determine the FD, a sensitive measure of motor unit reorganisation already in the early, subacute stage (48). Macro EMG records from large territories in the muscle, making it possible to identify the different subpopulations of motor units (17, 49, 52). Recording F waves after conditioning stimuli yields valuable information about the changes in the excitability of the lower motor neurons (19, 20, 39). Thus various neurophysiologic methods are suitable to investigate the possible pathophysiologic changes in the lower motor neurons following the lesions of the upper ones. 5 OBJECTIVES: The objective of our studies was to assess specific aspects of the lower motor neuron affection following stroke: - How do the different neurophysiological changes progress in time? - Is there a selective loss of a fiber-subpopulation? - Is there any change in the excitability of the remaining lower motor neurons? - What is the clinical significance of these finding (i.e. correlation of the neurophysiological changes with the clinical severity of the symptoms)? SUBJECTS AND METHODS: Changes in the motor unit potentials and compound motor action potentials: The subjects in the study were 48 hospitalized patients with a unilateral ischaemic stroke in the territory of the middle cerebral artery as the first episode. The duration of hemiparesis ranged from one week to one year. Motor nerve conduction studies of the ulnar nerve and concentric needle EMG of the abductor digiti minimi muscle were performed on both sides, and hemiparetic side mean and extreme parameter values were compared with the unaffected side mean and extreme parameter values using non-parametric tests. Changes in muscle fiber density: Fiber density was determined using single-fiber electromyography, in the abductor digiti minimi muscle. At first, we determined fiber density at low force output on the hemiparetic and the unaffected side of 59 patients with unilateral ischemic stroke in the territory of the middle cerebral artery, and 42 healthy controls. Duration of hemiparesis ranged from 2 weeks to 48 months. In order to survey a larger population of motor units, we measured the fiber density at high force output too. The subjects were 45 consecutively hospitalized patients (31 male, 14 female), aged years (mean 59.0 years, median 62 years). To asses if the recruitment of larger motor units at higher force affects the fiber density we compared fiber density values recruited at low and high force output in 48 healthy subjects (32 male, 16 female) aged years (mean 60 years). Comparing the affection of high-threshold and low-threshold motor units: Forty-five stroke patients and 40 healthy controls participated in the study. The duration of the symptoms ranged from 8 months to 4 years. Macro EMG was recorded from the abductor digiti minimi muscle at two levels of force output (low and high). The median macro motor unit potential amplitudes on the paretic side were compared with those on the unaffected side and in the controls. Changes in the excitability of motor neurons: F waves from 44 hospitalized stroke patients and 35 healthy controls were recorded from abductor pollicis brevis muscles in the course of 6 two experiments: (1) single stimuli following high-intensity ipsilateral cutaneous conditioning were used to stimulate the median nerve; (2) paired stimuli were given to the median nerve at gradually increasing interstimulus intervals to assess recovery curves. All patients had hemiparesis with the duration of the symptoms ranging from 2 weeks to 2 years. Mean F-wave amplitudes elicited by the conditioning stimuli were compared with mean F-wave amplitudes elicited by the test stimuli on both the hemiparetic and the unaffected side. RESULTS: Changes in motor unit potentials and compound motor action potential (M wave): The mean M wave amplitude was significantly lower, while the spontaneous activity and the mean number of motor unit potential phases and turns were significantly higher on the hemiparetic side. The outliers above maximum for motor unit potential duration and amplitude on the hemiparetic side were significantly higher than those on the unaffected side. Correlations were found between the hemiparetic side parameter values and time after stroke onset and hemiparetic severity. Changes in muscle fiber density: In stroke patients the fiber density measured at low and at high force output was significantly increased on the hemiparetic side compared to the unaffected side and controls. This change was correlated with the severity of the clinical signs. The fiber density gradually increased during the first 10 months following the stroke and thereafter remained constant. The mean fiber density did not depend on the force output levels in healthy subjects either. Selective injury of high-threshold motor units: In the control group and on the unaffected side, the macro motor unit potentials were significantly larger at the high force output than at the lower one. However, on the paretic side the macro motor unit potentials at the high force output had the same amplitude as those recorded at the low force output. These changes correlated with the severity of the paresis. Changes in the excitability of motor neurons: The amplitude of the F waves was increased on the hemiparetic side. The recovery curve of mean F-wave amplitude after conditioning stimulation was prolonged on the hemiparetic side. A correlation was found between this delay of recovery and hemiparetic severity. There was no reduction of mean F-wave amplitudes elicited following high-intensity ipsilateral cutaneous stimulation on the hemiparetic side, as opposed to the controls. 7 CONCLUSIONS: Shortly after ischaemic stroke trans-synaptic degeneration of the lower motor neurons occurs. The large, high-threshold lower motor neurons are selectively lost. Subsequently collateral reinnervation starts: the remaining lower motor neurons reinnervate the denervated muscle fibers, leading to changes in the structure of the motor units. The remaining lower motor units show pathophysiological changes: hyperexcitability, prolonged depolarisation, decreased inhibition from spinal interneurons. The abnormities of the lower motor neurons following stroke are correlated with the clinical severity. Fiber density is a robust EMG parameter independent from the force output at which it is measured. Our findings furnish further insight into a rarely investigated aspect of stroke: the transsynaptic affection of the lower motor neurons. 8 I. INTRODUCTION The circulatory disturbances of the central nervous system often involve motor structures, causing negative signs such as loss of muscle strength, incapacity for selective innervation, and poor contraction modulation. The cerebrovascular lesion primarily affects the territory of the upper motor neurons, but the clinical signs manifest by means of the striated muscles controlled by the lower motor neurons. There is mounting evidence that the impairment of the lower motor neurons associated with lesions of the upper motor neurons is more than just a signal deprivation/decentralization. The concept of lower motor neuron injury following a stroke has been suggested recently by electrophysiological data. Needle electromyographic studies have revealed pathological spontaneous activity in paretic muscles after a cerebrovascular insult (3, 4, 30, 46, 47, 56). Hara (25, 26) and McComas (40) reported loss of functioning motor units on the hemiparetic side of stroke patients. Datolla (11) has found that there is morphological muscle rearrangement after a stroke. These findings suggest drop-out of lower motor neurons together with an axonal lesion and may indicate both functional disturbances and changes in the microanatomy of the motor units. These changes could play a role in the pathomechanisms of the motor deficit of stroke patients. Howewer, few data have been published on changes in motor units in the case of upper motor neuron lesion, as in stroke. Moreover, it is unclear whether these changes would affect the motor units randomly or in some specific pattern. Different types of motor units can be distinguished on the basis of various interrelated properties: recruitment threshold, size, and histochemical and biomechanical characteristics (44, 51). Clarifying this issue might furnish further insight into the pathophysiology of lower motor neuron injury following a stroke. Alterations in the muscle fiber topography within the motor unit territory reflect events during degeneration and collateral sprouting. The study of the focal distribution of muscle fibers in the paretic muscles of stroke patients could provide additional information about lower motor neuron involvement in the case of upper motor neuron lesion (8). Needle electromyography allows assessment of structural alterations of motor units. Alterations in muscle membrane function, in motor unit organization, or in the number of fibers in a motor unit cause changes in the electrical signals. Several methods using different types of needle electrodes focus on different aspects of the changes in pathology of the motor unit. Concentric needle EMG detects the spontaneous muscle electric activity following 9 denervation, and also the reorganisation of the motor units in the subsequent, chronic stage after denervation (51). Using single-fiber EMG one can determine the FD, a sensitive measure of motor unit reorganisation already in the early, subacute stage (48). Macro EMG records from large territories in the muscle, making it possible to identify the different subpopulations of motor units (17, 49, 52). Individual electromyographic methods present different sensitivity and specificity for certain specific changes in disease. Judicious selection of appropriate needle electromyographic techniques can yield a significant amount of complementary information about the state of motor units in the case of upper motor neuron lesion, and about the relationship between lower motor neuron injury and the severity of the hemiparesis. In addition to muscle weakness, spasticity contributes to the motor disability following ischaemic lesions of the central nervous system. It was showed that spastic muscle tone has a significant neuronal component, resulting mostly from hyperexcitability of lower motor neurons. Electrophysiological studies in patients with spastic hemiparesis have found no specific patterns of abnormalities and no correlations with severity of spasticity. One possible explanation for this lack of correlation is that the studies employed the H reflex which involves an afferent loop of the Ia fibers and therefore may not be ideal for monitoring segmental spinal motor neuron excitability. Changes in F waves have been reported valuable for evaluating motor neuron inhibition (35). F waves are generated by backfiring of motor neurons and therefore could be used to explore altered lower motor neuron excitability in patients with spastic muscle tone. II. OBJECTIVES With these premises as starting-point, we investigated the controversial concept of lower motor neuron injury following stroke, using parameters and methods previously not reported. Our objectives were: 1. To assess the progression in time of the possible degeneration of the motor units following stroke, as reflected by the neurophysiologic changes. 2. To explore whether a subpopulation of motor units is selectively affected following stroke. 3. To investigate the pathophysiology of the remaining lower motor neurons. 10 4. To assess the clinical significance of these neurophysiological changes (i.e. correlation with the clinical severity). III. SUBJECTS AND METHODS 1. Changes in the motor unit potentials and compound motor action potentials Subjects in the study were 48 hospitalized patients with a unilateral ischaemic stroke in the territory of the middle cerebral artery as the first clinical episode. The exclusion criteria were age above 65 years, and any sign or data indicating peripheral nerve and muscle disease or predisposing pathological states such as diabetes mellitus, malignant tumors, immunological disease, critical state, or toxic damage. The age range of the 34 male and 14 female patients was years (mean 55 years, median 59 years). The ischaemic lesion developed in 29 patients in the right, and in 19 patients in the left hemisphere. The process proved to be atherothrombotic in 31 and thromboembolic in 17 patients. In every subject, the CT examination showed a unilateral hypodensity characteristic of ischaemic transformation in the territory of the middle cerebral artery. The maximal diameter of the lesion was depending on the patient between 2 and 6 cm and there were no radiological signs of intracranial hypertension. The duration of hemiparesis ranged from one week to one year (mean value 5.3 months, median value 4.9 months). A total of 37 healthy subjects aged years (mean 50.5 years, median 54 years) were similarly investigated to establish the reference values of the study. After a detailed explanation, all selected patients and controls gave their consent. The study was carried out with the approval of the authorized Ethical Comittee of the Medical Chamber. The clinical status of the patient was evaluated using the long term items of the Scandinavian Stroke Scale ranging from 0 (no active movements) to 30 (full muscle strength) points (12). Our subjects had scores between 7 and 22 points. Nerve conduction studies were carried out in our laboratory using Neuropack MEB 2200A equipment (Nihon Kohden Corporation, Tokyo, Japan). The nerve conduction studies (NCSs) were performed using surface electrodes. In the case of motor NCSs, the frequency band of the filters were 2 Hz-3 khz, and maximum M-potentials 11 were evoked with supramaximal stimulation using single square pulses of 0.2 ms duration. Averaged sensory potentials were elicited using sequences of supramaximal stimuli with duration of 0.2 ms and a frequency of 2 Hz at the band pass 20 Hz to 3 khz. Distal motor latency to the standardized distance of 80 mm and the amplitude of the motor (CMAP) and sensory (CSAP) potential were determinated, and motor and sensory conduction velocity was calculated for the ulnar nerve on both sides. The active electrode was positioned over the belly of the abductor digiti minimi muscle (ADM). A ground reference electrode was positioned between the recording and stimulus sites, and the reference electrode was placed over the nearest metacarpal-phalangeal joint. The antidromic method was used for sensory neurography, the recording interelectrode distance being 23 mm. The values for conduction velocities were corrected to 34 0 C skin temperature. Concentric needle electromyography Concentric needle (NM-131T/330T, Nihon Kohden Corporation, Tokyo, Japan) EMG was performed on both sides on the ADM muscle during inactivity and during voluntary contraction. Using 20 different needle positions, spontaneous electrical activity was examined. At least 20 MUPs were recorded from each investigated muscle and quantitatively analysed using multimup method (51). The signals were recorded at the band pass of 2 Hz to 5 khz, using a 50 mikrov/cm gain for the spontaneous activity and 200 mikrov/cm gain for the multimup analysis. The sweep speed in the edit mode was 3 ms/div. Different depths were studied at 3-4 skin insertions in the middle part of the muscle. The recorded MUAPs were checked visually. Those with a noisy baseline were rejected, and the duration markers were corrected. The following MUP parameters were measured: amplitude, duration, number of phases and turns. For each subject the mean values and standard deviation of
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