Evert Knutsson

Plasma and cerebrospinal fluid levels of baclofen (lioresal®) at optimal therapeutic responses in spastic paresis

Abstract Eleven patients with spastic paresis and marked muscular hypertonus were treated with the GABA derivative, baclofen (Lioresal®), given in 3 oral daily does (30–90 mg per day). After a period of unchanged medication (3 days-1 year) at doses yielding an optimal therapeutic response, determinations were made of the concentrations of unchanged baclofen in plasma and CSF at predetermined intervals after medication. The plasma and CSF levels were compared to the therapeutic responses in patients with α- and γ-spasticity, the type of spasticity being differentiated with cryotests. The concentrations of the drug in plasma showed levels and half-lives corresponding to those observed after the administration of single oral doses to healthy volunteers. Thus, there were no findings indicating an accumulation of the drug in plasma during long-term medication. Confirming previous studies 7 patients with γ-spasticity responded well to the therapy, whereas deterioration or lack of functional improvement was seen in 3 out of 4 patients with α-spasticity. Optimal therapeutic responses in patients with γ-spasticity were obtained at very different levels of the drug in plasma and CSF. In patients with α-spasticity in whom no antispastic effects were observed, the levels of baclofen in plasma and CSF were within the same range as in several functionally improved patients with γ-spasticity. The results are in accordance with the concept that the type of spasticity is crucial in reaching an improvement from baclofen treatment in patients with spastic pareses.

Physical work capacity and physical conditioning in paraplegic patients

In a group of patients with chronic spinal cord injury at the C5-L1 level, the total amount of haemoglobin (THb), the blood volume and the arm work capacity were measured. In 10 of the patients with clinically complete transections at C5-L1, the effects of conditioning exercises with the upper limbs were estimated.THb in the male patients was 9.46 ± 1.63 (mean, S.D., n = 13) g./kg. body weight which is less than normal (P < 0.05). In the female patients it was 7.57 ± 1.47 (n = 4) g./kg. body weight. Eight patients had significantly lower THb than expected from their body weight and length.The blood volume in male patients was 5.15 ± 0.82 (n = 13) litres; in females, it was 3.68 (range 3.0-4.2, n = 4) litres. In 11 of the 17 patients the blood volume was significantly less than expected from the body weight and length.The maximal arm work capacity, as estimated from an exercise test using arm cycling in the sitting posture, was low as compared with that of healthy individuals. In two patients with spinal injury at cervical levels, the heart rate increased to 100-130 beats/minute during maximal effort. In the rest (T4-L1), heart rates of 145-180 beats/minute were reached.After the training, four or five times a week for six weeks, THb and blood volumes were not changed significantly but the mean arm work performance (arm-PWC170, 150 or max.) increased from 40.2 ± 27.3 watts to 56.5 ± 30.6 watts, which is significant (P < 0.02). There was no improvement in the three patients with lesions at C5-T6. All the others (T6-L1) increased their work performance; the mean increase was 50 per cent.

Antiparetic and antispastic effects induced by tizanidine in patients with spastic paresis

The effects of tizanidine were studied in patients with spastic paresis. The study consisted of 4 parts: I, double-blind cross-over trial at maximal dosage 10 mg/day in 13 patients; II, open trial at maximal dosage 32 mg/day in 10 patients; III, long-term medication at dosage 32 mg/day for 6-15 months in 4 patients; IV, single dose (12 mg) administration in 3 patients. The effects were evaluated from clinical examinations, subjective assessments, EMG, gait analysis and quantitative determinations of passive resistance and voluntary strength in isokinetic extensions and flexions of the knee and plantar and dorsal flexions of the ankle at different speeds of motion. At 3-10 mg/day, no effects were observed except for increased prime mover EMG activity in voluntary knee flexions. At 12-32 mg/day, passive resistance decreased significantly in 3 of the movements tested. The maximal voluntary strength increased significantly in 3 movements, frequently associated with enlarged activation of prime mover muscles, less frequently with reduced antagonist co-activation. Functional disability was subjectively reduced and verified by improved gait capacity in 4 patients. Sustained effects on motor performance during long-term medication were verified by withdrawal in 3 patients. Single dose administration resulted in reduced passive resistance and increased voluntary strength, associated with an increased activation of the prime mover muscles. The results indicate that tizanidine exerts its effects in part by reducing spastic restraint, in part by enhancing the capacity to activate paretic muscles.

Treatment of spasticity in children with low dose benzodiazepine

In an attempt to investigate whether benzodiazepines at low dosage have a significant effect in reducing spasticity among children with cerebral palsy, we carried out a double-blind, placebo-controlled, cross-over study. Twelve children with either spastic diplegia or hemiplegia participated in this study. The mean age was 14 years. The restraint of passive knee movements was determined with a dynamic dynamometer and spastic stretch reflexes were measured as EMG activity in muscles stretched. Clonazepam was given at low dosage (0.02 mg/kg body weight). In each child measurements of passive restraint were made on 2 different days immediately before and 3 h after an i.m. injection of either clonazepam or placebo in randomized order. Clonazepam significantly reduced spastic restraint (P < 0.001) compared to non-significant reduction with placebo. The mean plasma concentration of clonazepam at time of spasticity evaluation was 21 mmol/l which is in the low dose range, far below conventional doses. The study thus shows a positive effect of low dose clonazepam in reducing spasticity in children when given as a single dose.

Reduction of Epileptiform Activity in Response to Low-Dose Clonazepam in Children with Epilepsy: A Randomized Double-Blind Study

Summary: Purpose: To evaluate the effect of low‐dose clonazepam (CZP) on the amount of epileptiform activity in children with focal and generalized epilepsy.

Action of dantrolene sodium in spasticity with low dependence on fusimotor drive.

The effects of dantrolene sodium, an anti-spasticity drug with a site of action within the muscle fibres, were studied in 19 patients with spastic paresis. Oral doses were successively increased from 100 mg/day to a maximal tolerated level or up to 800 mg/day. Trial periods were 8-13 weeks. The responses of stretch reflexes to local cooling over the spastic muscles were used to differentiate alpha and gamma spasticity. In the knee extensor and flexor muscle groups, cryo-negative alpha-spasticity was seen in 25 and cryo-positive gamma-spasticity in 4 muscle groups. Ankle clonus was cryo-positive in 14 of 15 cases. Resistance to passive knee joint movements, ankle clonus and isometric or isokinetic muscle strength was determined quantitatively. The gait was recorded by intermittent-light photography and the muscle activation patterns in gait were studied in recordings of the average EMG from limb muscles. Functional disability and spasms were assessed from clinical examinations and interviews. Passive resistance at slow (6%/sec) and fast (30 degrees/sec) knee joint movements decreased by 32% in the extensor muscles (p = 0.005 resp. 0.001) and by 23-26% in the flexor muscles (not significant). Reduced passive resistance was observed in 16 of the muscles with alpha-spasticity and in all 4 of the muscle groups with gamma-spasticity. Clonus was diminished or abolished in 14 of 15 patients with this sign. Maximal isometric or isokinetic muscle strength was unaltered in the majority of the patients. In a few the strength was increased, in some it was decreased. The averaged EMG activity during walking as studied in 10 patients were increased in 35 of the 57 muscle groups examined. In some muscle groups, exaggerated activity attributable to spastic reflexes was reduced. Motor disability was decreased significantly in 10 patients. It was not significantly changed in 5 and deteriorated in 4 patients. Drowsiness and subjective muscle weakness were the most frequent side-effects. SGOT and SGPT were increased in 3 cases.

Effects of skin cooling on stretch reflex activity in triceps surae of the decerebrate cat

Abstract The effects of selective skin stimulation by cooling on the stretch reflexes in triceps surae were studied in the midcollicularly decerebrated cat. Stretch reflexes were elicited with a muscle puller allowing the determination of responses to dynamic and static stretch. The skin overlying the lateral gastrocnemius was freed into a flap, and 8.6 cm 2 of this cooled with a thermoelectric cooling module. Lowering temperature to 10 ± 2 C produced an 11% decrease in the tonic component of the triceps surae stretch reflex, without significantly altering the amplitude of the phasic component. Cooling by applying ice cubes to the skin flap, a procedure involving mechanical stimulation, augmented both the tonic (11%) and the phasic (15%) stretch responses. The removal of the ice cubes depressed both responses for 30 sec. It is concluded that selective cooling of the skin receptors can depress tonic stretch reflexes of underlying muscle in the decerebrated cat. This effect differs from the facilitatory effect on phasic and tonic stretch reflexes characteristic of less selective forms of cutaneous stimulation.

Variability of epileptiform activity in long-term EEGs with short and long intervals in children with epilepsy

OBJECTIVE To evaluate the impact of the time factor on the amount of epileptiform activity in long-term EEG recordings in children with epilepsy. METHODS Ten children with epilepsy of different types underwent three 24 h EEG examinations during two consecutive days and with a months interval. The number of epileptiform discharges during selected corresponding periods of time was counted. RESULTS The number of epileptiform discharges on three repeated examination days showed no significant difference (ANOVA P = 0.88) as intraindividual increases and decreases on different days counterbalanced each other within the group. However the standard deviations of the relative changes were larger between recordings with a months interval compared to those for consecutive days (86% and 33%). The mean magnitude of change was 55% between days separated by a month compared to 24% on consecutive days. The difference was non-significant but showed a trend towards larger changes with a longer interval (P = 0.07). CONCLUSIONS The variability of epileptiform activity was larger when the interval between recordings was 1 month compared to consecutive days. The magnitude of the relative changes between intervals of 1 and 30 days showed a trend towards a difference although not statistically significant. When evaluating repeated long-term EEGs in relation to therapy in children, these variations should be considered.

Impulse discharges from the low pressure side varying with the central blood volume

SummaryAfferent impulse discharges via the communicating branch between the superior and inferior laryngeal nerves were recorded in the superior laryngeal nerve after cutting all its branches to the larynx. Two types of nerve discharges that varied with the blood volume, and the venous return were observed. One was a repetitive burst of impulses discharging synchronously with the inflow of blood to the heart. The impulses within a burst increased in response to blood transfusion and disappeared after blood loss or occlusion of the inferior caval vein. The impulse discharges apparently emanate from atrial receptors of type B. The other type was a tonic impulse discharge that decreased on an increase of the blood volume and increased when the blood volume was reduced. The corresponding receptors were stimulated also by occlusion of the inferior caval vein (impulses in right and left nerves) and the pulmonary veins (impulses in the left nerve). The discharges on caval occlusion appeared in the right nerve 0.75±0.23 sec (mean, S.D.,n=22) and in the left nerve 0.50±0.13 sec (n=33) before the drop of the aortic pressure. It is assumed that these discharges emanate from receptors in the walls of the central veins.