Colin J. Andrews

The action of a GABA derivative in human spasticity

Abstract The action of β-(4-chlorophenyl)-γ-aminobutyric acid has been investigated in spastic patients. It was found to be effective in patients with complete and incomplete spinal lesions, depressing the dynamic response to muscle stretch in doses that had little effect on tendon jerks or voluntary muscle power. It was also found to modify the response to increasing muscle stretch, abolishing the inhibitory effect of increased muscle length on the quadriceps stretch reflex so that in 4 patients a facilitatory effect was unmasked. It is suggested that this drug has a non-specific depressant action on spinal synapses, its effect therefore being manifested in polysynaptic pathways, possibly by activation of “presynaptic” inhibitory mechanisms.

Tonic vibration reflex in spasticity, Parkinson's disease, and normal subjects

The tonic vibration reflex (TVR) has been studied in the quadriceps and triceps surae muscles of 34 spastic, 15 Parkinsonism, and 10 normal subjects. The TVR of spasticity develops rapidly, reaching a plateau level within 2-4 sec of the onset of vibration. The tonic contraction was often preceded by a phasic spike which appeared to be a vibration-induced equivalent of the tendon jerk. The initial phasic spike was usually followed by a silent period, and induced clonus in some patients. No correlation was found between the shape of the TVR and the site of the lesion in the central nervous system. The TVR of normal subjects and patients with Parkinsonism developed slowly, starting some seconds after the onset of vibration, and reaching a plateau level in 20-60 sec. A phasic spike was recorded occasionally in these subjects, but the subsequent tonic contraction followed the usual time course. Muscle stretch increased the quadriceps TVR of all subjects, including those with spasticity in whom the quadriceps stretch reflex decreased with increasing stretch. It is suggested that this difference between the tonic vibration reflex and the tonic stretch reflex arises from the selective activation of spindle primary endings by vibration, while both the primary and the secondary endings are responsive to muscle stretch. The TVR could be potentiated by reinforcement in some subjects. Potentiation outlasted the reinforcing manoeuvre, and was most apparent at short muscle lengths. As muscle stretch increased, thus producing a larger TVR, the degree of potentiation decreased. It is therefore suggested that the effects of reinforcement result at least partially from the activation of the fusimotor system. Since reinforcement potentiated the TVR of patients with spinal spasticity in whom a prominent clasp-knife phenomenon could be demonstrated, it is suggested that the effects of reinforcement are mediated by a descending pathway that traverses the anterior quadrant of the spinal cord.

Comparison of stretch reflexes and shortening reactions in activated normal subjects with those in Parkinson's disease

The stretch reflexes and shortening reactions evoked in six normal subjects during reinforcement were compared with those recorded from patients with Parkinsons disease. Although the responses to stretch and shortening of triceps were similar in both groups, they differed in the biceps muscle. In Parkinsons disease increasing muscle stretch of biceps was associated with increasing reflex activity, whereas the reverse relationship occurred in the activated normal subjects. The biceps EMG during sinusoidal stretching comprised two peaks in the activated normal group, a phenomenon not seen in Parkinsons disease. It is postulated that this response in the activated normal group is due to activation or reinforcement engaging long-loop reflexes. It is concluded that the rigidity of Parkinsons disease is not simply an exaggeration of the stretch reflexes found in normal man but differs in that the effects of flexor reflex afferent nerve fibres are submerged by group Ia afferent activity, and that some long-loop reflex pathways are no longer operative in Parkinsons disease.

Control of the tonic vibration reflex by the brain stem reticular formation in the cat

Abstract The tonic vibration reflex (TVR) has been used to investigate the areas in the brain stem which influence tone in flexor and extensor muscles in the hind limb of the cat. Tonic contraction of triceps surae and tibialis anterior was inhibited by stimulation of the medial medullary reticular formation and facilitated by lateral medullary stimulation. Between the inhibitory and facilitatory areas, a mixed area was found which produced facilitation on direct stimulation which was altered to inhibition when the contralateral motor cortex or internal capsule was stimulated simultaneously. A small area in the caudal medulla reciprocally enhanced and suppressed the TVR in flexors and extensors respectively.

Corticoreticulospinal control of the tonic vibration reflex in the cat

Abstract The cortico-reticulospinal system has been investigated using vibration to produce a tonic reflex in an intact cat. Stimulation of the motor cortex potentiated the effects of medial medullary inhibition but not the facilitation evoked from the lateral medulla. The cortico-bulboreticular pathways were found to project bilaterally to the medulla. Medullary stimulation produced bilateral facilitation or inhibition of the tonic vibration reflex (TVR). Although the cortico-bulboreticular pathway projected bilaterally the effect evoked from the motor cortex was clearly contralateral in its end result. The cortico-reticulospinal system usually inhibits the tonic vibration reflex of both triceps surae and tibialis anterior, but on occasions inhibition of triceps surae was accompanied by a phasic contraction of the tibialis anterior. Stimulation of the contralateral caudate nucleus failed to influence the TVR directly or the response evoked by medullary stimulation. Stimulation of the contralateral red nucleus evoked a facilitation of the TVR which continued several seconds after red nucleus stimulation ceased. It was concluded that those medullary neurones which inhibit tone in flexor and extensor hind limb muscles of the cat are controlled directly by the motor cortex and are uninfluenced by caudate nucleus or red nucleus. The facilitatory neurones in the lateral medulla appear to be independent of cortical control.

The comparison of tremors in normal, parkinsonian and athetotic man ☆

Abstract A comparison has been made of physiological tremor, athetotic tremor, and the resting and action tremors of Parkinsons disease by electromyographic (EMG) and accelerometer recordings. Physiological tremor was characterised by beats which were synchronous in antagonistic muscle pairs and which persisted in the EMG after the abolition of the tendon jerk by ischaemia, indicating that the mechanism does not depend upon the integrity of the stretch reflex arc. Of 22 patients with Parkinsons disease exaggerated physiological tremor (synchronous tremor of frequency greater than 6 cycles/sec) was recorded in 20 and dictated the frequency of the cogwheel phenomenon in 18. The classical alternating tremor of 4–6 cycles/sec was recorded at rest in 8 patients and persisted during activity in only 3, in which patients it was responsible for the frequency of cogwheeling. The tremor of athetosis was found to be similar to “red nucleus tremor” in that its frequency is approximately 3 cycles/sec; it tends to alternate between antagonistic muscle pairs and only becomes apparent during muscular activity.

Comparison of the tonic stretch reflex in athetotic patients during rest and voluntary activity

An electromyographic technique was used to record the tonic stretch reflex (TSR) responses to passive sinusoidal stretching of biceps brachii muscle in athetotic patients. The TSR transmission characteristics measured while the patient was in a relaxed state were compared with those measured while the patient was voluntarily active. The resting TSR and action TSR were found to differ markedly. Sensitivity, pattern, duration, and timing of the TSR responses were all changed during voluntary activity. The results suggest that the TSR in athetosis is functionally reorganized by supraspinal influences during voluntary activity. It is proposed that athetoid movements and action tremor may be a manifestation of abnormal action TSR caused by faulty supra-spinal control during activity.

Quantitative study of the effect of L-dopa and phenoxybenzamine on the rigidity of Parkinson's disease

The static and dynamic components of the tonic stretch reflex and shortening reactions have been studied in biceps brachii, triceps, hamstrings, and quadriceps muscles of 19 patients with Parkinsons disease before and during L-dopa therapy. Clinical improvement during L-dopa administration correlated with a reduction in the dynamic component of the tonic stretch reflex in biceps, triceps, and quadriceps but not the hamstrings muscle, and with the static component of the tonic stretch reflex in biceps and triceps but not quadriceps and hamstrings muscles. The only shortening reaction consistently reduced during the L-dopa treatment period was the dynamic shortening reaction of the triceps muscle. The responses of the stretch reflexes to changes in muscle length were not altered by L-dopa therapy. In severely disabled patients the hamstrings and quadriceps stretch reflexes were maximal in a position of partial flexion of the knee joint and this response to muscle length was not altered in these patients despite a dramatic lessening of rigidity in some patients. Shortening reactions commonly remained in some patients after the stretch reflex of the antagonistic muscle was abolished by L-dopa therapy. The administration of phenoxybenzamine to patients being treated with L-dopa reduced the different components of rigidity more than L-dopa alone, and the responses were consistent with phenoxybenzamine suppressing predominantly the descending noradrenergic pathway.

The real-world efficacy of botulinum toxin type a (botox®) for the prophylaxis of headaches in adult patients with chronic migraine in australian clinical practice: a retrospective chart review

Objectives To determine the real world efficacy of BOTOX for the prophylaxis of headaches in adult patients with chronic migraine (CM) treated through the Pharmaceutical Benefits Scheme (PBS). Methods The medical charts of CM patients treated consecutively by seven clinicians in 5 Australian states/territories were reviewed. Patients who received BOTOX treatment for CM following PBS listing March 2014 and had headache data recorded after the 2nd treatment cycle were included. The primary response measure was the PBS continuation criterion: a≥50% reduction in the number of headache days per month (HDPM) following two BOTOX treatment cycles. Other data collected included demographics, clinical characteristics, headache frequency and medication use. Results Data for 211 patients (89% females) were included in the analysis. Mean age was 45 years old; mean time since diagnosis with CM was 13.5 years and patients had failed a mean of four oral headache prophylactics; most commonly amitriptyline, topiramate, propranolol and pizotifen. At baseline the majority used acute migraine medicines, mostly simple analgesics and triptans but also opioids and 61% had a management plan in place for medication overuse headache. Following two BOTOX treatment cycles (median dose 155U, mean time of assessment 27 weeks), 74% had obtained a≥50% reduction in HDPM; from 25±5 HDPM (mean±SD) to 11±8 HDPM. Acute medication intake was reduced from 19±8 days to 7±6 days per month and there were reductions in the proportions of patients using opioids (over the counter codeine from 44% to 28%; prescribed opioids from 23% to 13%). Conclusions In an Australian clinical practice review, almost three-quarters of CM patients obtained a meaningful reduction in headache days following two BOTOX treatments, fulfilling PBS continuation criterion. Additionally, the use of acute migraine medicines, including opioids, was reduced.