Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study.

OBJECTIVE: To define a safe and effective dose of Dysport for treating hip adductor spasticity. METHODS: Patients with definite or probable multiple sclerosis, and disabling spasticity affecting the hip adductor muscles of both legs, were randomised to one of four treatment groups. Dysport (500, 1000, or 1500 Units), or placebo was administered by intramuscular injection to these muscles. Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment. RESULTS: A total of 74 patients were recruited. Treatment groups were generally well matched at entry. The primary efficacy variables-passive hip abduction and distance between the knees-improved for all groups. The improvement in distance between the knees for the 1500 Unit group was significantly greater than placebo (p = 0.02). Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only. Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1000 Unit and 1500 Unit groups. Duration of benefit was significantly longer than placebo for all Dysport groups (p<0.05). Adverse events were reported by 32/58 (55%) Dysport patients, and by 10/16 (63%) placebo patients. Compared with the two lower dose groups, twice as many adverse events were reported by the 1500 Unit group (2.7/patient). The incidence of muscle weakness was higher for the 1500 Unit group (36%) than for placebo (6%). The response to treatment was considered positive by two thirds of the patients in the 500 Unit group, and by about half the patients in the other groups. CONCLUSION: Dysport reduced the degree of hip adductor spasticity associated with multiple sclerosis, and this benefit was evident despite the concomitant use of oral antispasticity medication and analgesics. Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport. Dysport treatment was well tolerated, with no major side effects seen at doses up to 1500 Units. The optimal dose for hip adductor spasticity seems to be 500-1000 Units, divided between both legs.

Subcutaneous apomorphine in Parkinson's disease: response to chronic administration for up to five years.

Subcutaneous apomorphine, administered by continuous waking-day infusion with boluses, or by repeated intermittent injection, was given to 71 parkinsonian patients with severe refractory levodopa related on-off fluctuations for 1-5 years. A mean reduction in daily off period time of approximately 50% was maintained, and the incidence of neuropsychiatric toxicity remained low on long-term follow-up. No clinically significant tolerance or loss of therapeutic effect was seen, although increasingly severe on-phase dyskinesias and postural instability marred the long-term therapeutic response in many patients. Despite these drawbacks, apomorphine, when combined with the peripheral dopamine receptor agonist domperidone, represents a significant therapeutic advance in the management of late-stage Parkinson's disease and should certainly be considered before experimental implantation procedures.

The dopaminergic response in multiple system atrophy.

Fifteen of 23 pathologically confirmed cases of multiple system atrophy (MSA) showed some initial response to levodopa and eight of these remained at least partially responsive at the time of death. Eleven developed motor oscillations, and drug-induced dyskinesias, often involving the face and jaw, were also seen in 11 cases. Acute levodopa and apomorphine challenges were administered to 11 patients with clinical MSA who were considered levodopa responsive. A short duration relatively small amplitude response with associated dyskinesias occurred in six and a further three developed dyskinesias without any motor response. Following levodopa withdrawal, a delayed deterioration occurred after three to six days in six patients, five of whom had shown no short duration motor response to the acute challenges. The occurrence of levodopa-induced dyskinesias without a concomitant motor response and delayed deterioration several days after levodopa withdrawal may be more typical of patients with MSA than Parkinson's disease.

Comparative efficacy of two oral sustained-release preparations of L-dopa in fluctuating Parkinson's disease. Preliminary findings in 20 patients.

20 patients with Parkinson's disease and a fluctuating response to chronic treatment with conventional L-dopa preparations participated in an open randomized trial comparing two sustained-release L-dopa preparations (Madopar HBS, Sinemet CR4). While a majority (15 patients, 7 on Madopar HBS and 8 on Sinemet CR4) showed a favourable response after 2 months of slow-release L-dopa treatment the clinical benefit remained stable in only 2 patients on Madopar HBS and 3 patients on Sinemet CR4 over the entire follow-up period of 12 months. Reasons for treatment failure were increased peak-dose or biphasic dyskinesias or prolonged "off"-periods. This preliminary study failed to demonstrate clinically significant advantages of one slow-release principle over the other.

Treatment of spasmodic torticollis with local injections of botulinum toxin. One-year follow-up in 37 patients.

Thirty-seven patients with spasmodic torticollis (cervical dystonia) who received repeated local injections of botulinum toxin have been followed up for a mean period of 12.3 (10-29) months, during which time 138 treatment sessions were performed. Mean doses per muscle averaged 320 mouse units (mu; range 160-1000 mu botulinum toxin A prepared by CAMR, Porton Down, UK). Eighty-six per cent of patients experienced significant improvement of posture and 84% of those with pain had relief following the first injection. Muscular patterns of recurrent torticollis were relatively constant and in most patients efficacy was maintained with subsequent injections, while 15% of all follow-up sessions failed. Only 2 of 37 patients were consistent nonresponders; 22% and 10% of all sessions were complicated by transient dysphagia and weakness of neck muscles, respectively. It is concluded that local botulinum toxin injections can be a safe and efficaceous long-term treatment of spasmodic torticollis and that optimal doses should be between 200 and 400 mu/muscle.

Clinical and polymyographic investigation of spasmodic torticollis.

Polymyographic recordings were used to identify the most dystonic muscles suitable for local injection with botulinum toxin in 100 patients with spasmodic torticollis (TS). Rotating TS (72% of the patients) was due to dystonic activity of the splenius muscle ipsilateral to and/or the sternocleidomastoid muscle contralateral to the side of chin deviation. One-third of these patients had also dystonic activation of the contralateral splenius muscle and, rarely, the contralateral trapezius muscle. Ten patients had laterocollis due to dystonic activation of all recorded muscles on one side of the neck. Nine patients had retrocollis due to activity of both splenius muscles and rarely additional activity in both trapezius muscles. The type of dystonic muscle activity was found to be tonic, phasic or tremulous. Besides the evaluation of spontaneous dystonic EMG activity further examination during the "geste antagoniste" or the muscle activity during rotating head movements can provide additional information. It is concluded that polymyography may provide a rationale for identifying the dystonic muscles underlying the different forms of TS. It may prove to be helpful for the successful therapy with botulinum toxin and may be useful in differentiating tremulous torticollis from other types of head tremor.

Antiparkinsonian activity of a non-ergot dopamine agonist, CV 205-502, in patients with fluctuating Parkinson's disease.

Six patients with fluctuating Parkinson's disease received single rising oral doses of the nonergot dopamine agonist CV 205-502 in an open experimental study. Doses of 0.5 mg produced antiparkinsonian effects of comparable intensity but longer duration than 200 mg of L-DOPA. CV 205-502, which combines structural features common to both ergolines and apomorphine, thus revealed interesting antiparkinsonian properties, but nausea and vomiting were dose-limiting side effects in all patients tested.