Michael J Leathley

Prevalence of spasticity post stroke

Objectives: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. Design: A cohort study of prevalence of spasticity at 12 months post stroke. Setting: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. Subjects: One hundred and six consecutively presenting stroke patients surviving to 12 months. Main outcome measures: Muscle tone measured at the elbow using the Modi”ed Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modi”ed Barthel Index. Results: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modi”ed Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had signi”cantly lower Barthel scores at 12 months (p < 0.0001). Conclusion: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.

Reliability of the tone assessment scale and the modified ashworth scale as clinical tools for assessing poststroke spasticity

OBJECTIVES To establish reliability of the Tone Assessment Scale and modified Ashworth scale in acute stroke patients. SETTING A North Liverpool university hospital. PATIENTS Eighteen men and 14 women admitted with acute stroke and still in hospital at the study start date (median age, 74 yrs; median Barthel score, 8). MAIN OUTCOME MEASURES The modified Ashworth scale and the Tone Assessment Scale. STUDY DESIGN The 32 patients were examined with both scales on the same occasion by two raters (interrater comparison) and on two occasions by one rater (intrarater comparison). RESULTS The reliability of the modified Ashworth scale was very good (kappa = .84 for interrater and .83 for intrarater comparisons). The reliability of the Tone Assessment Scale was not as strong as the modified Ashworth scale, with marked variability in the assessment of posture (kappa = .22 to .50 for interrater and .29 to .55 for intrarater comparisons) and associated reaction (kappa/kappaW = -.05 to .79 for interrater and .19 to .83 for intrarater comparisons). However, those aspects of the Tone Assessment Scale that addressed response to passive movement and that are scored similarly to the modified Ashworth scale showed good to very good interrater reliability (kappaW = .79 to .92) and good to very good intrarater reliability (kappaW = .72 to .86), except for the question related to movement at the ankle where agreement was only moderate (kappaW = .59). CONCLUSIONS The modified Ashworth scale is reliable. The section of the Tone Assessment Scale relating to response to passive movement is reliable at various joints, except the ankle. It may assist in studies on the prevalence of spasticity after stroke and the relationship between tone and function. Further development of a measure of spasticity at the ankle is required. The Tone Assessment Scale is not reliable for measuring posture and associated reactions.

Effects of the 5-HT3 antagonist GR38032F (ondansetron) on benzodiazepine withdrawal in rats

Effects of the 5-HT3 receptor antagonist GR38032F (ondansetron) on chlordiazepoxide withdrawal were assessed in rats which received chlordiazepoxide b.i.d. for 21 days at doses up to 40 mg/kg per injection. Withdrawal signs recorded were: body weight and food intake, which fell and then recovered over 9 days. Saline or GR38032F (1.0, 0.1 or 0.01 mg/kg) were administered b.i.d. during withdrawal. Clear withdrawal signs were seen in rats treated with saline after chronic chlordiazepoxide. However, GR38032F at 0.1 mg/kg reduced the severity of withdrawal. At 0.01 mg/kg GR38032F shortened withdrawal duration, but did not diminish peak withdrawal signs. At 1.0 mg/kg GR38032F, did not attenuate withdrawal signs at all. GR38032F (0.01-1.0 mg/kg) had no effect on ad lib food intake, therefore the attenuation of withdrawal was probably not simply due to stimulation of appetite. These data support recent claims that GR38032F attenuates benzodiazepine withdrawal, and they indicate that this effect shows an inverted U-shaped dose-response curve.

Evaluation of the dependence potential of the selective 5-H1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal

Two initial studies investigated: i) the effects of withdrawal from ipsapirone [a putative non-benzodiazepine (BZ) anxiolytic] and chlordiazepoxide (CDP); and ii) effects of ipsapirone in animals withdrawn from CDP. Rats were injected b.i.d. for 21 days with saline, ipsapirone or CDP at doses up to 40 mg/kg/injection. Subsequently, controls received the treatment administered previously, other subjects received saline during withdrawal from ipsapirone or CDP. Further subjects received ipsapirone (3, 10 or 30 mg/kg b.i.d.) during CDP withdrawal. Withdrawal indices recorded were body weight and food intake. Withdrawal signs were absent after ipsapirone treatment but present after CDP treatment, when food intake and bodyweight measures fell and then recovered. At the high dose of 30 mg/kg (b.i.d.) ipsapirone potentiated CDP withdrawal signs. Potentiation of withdrawal wasnot seen in animals treated with ipsapirone at lower doses (3 and 10 mg/kg, b.i.d.). In a subsequent study we found that ipsapirone conditioned a taste aversion, a possible index of drug-induced “malaise”, at doses as low as 7.5 mg/kg. Therefore a possible explanation for the potentiation of BZ withdrawal in subjects treated with high doses of ipsapirone was that drug-induced “malaise” reduced food intake and body weight, rather than ipsapirone causing true potentiation of BZ withdrawal. However, in a further study we showed that the ipsapirone treatment regime which potentiated BZ withdrawal didnot significantly reduce food intake or body weight, suggesting that high doses of ipsapirone potentiate BZ withdrawal by a mechanism that does not simply involve “malaise”. The most plausible account of the observed potentiation of withdrawal by ipsapirone involves actions of the ipsapirone metabolite (1-(2-pyrimidinyl)-piperazine) on alpha2-adrenoceptors, which are known to be implicated in BZ withdrawal. However, the precise mechanism involved remains unclear. Collectively, the studies reported show that ipsapirone does not induce the type of withdrawal signs seen with BZs. However, there was no evidence that ipsapirone attenuated BZ withdrawal. It is therefore likely that patients withdrawn from BZs will experience withdrawal if treated with ipsapirone, and that if treated with high doses withdrawal may be exacerbated.

The COSTAR wheelchair study: a two-centre pilot study of self-propulsion in a wheelchair in early stroke rehabilitation

Objective: It is uncertain whether self-propulsion in a wheelchair should be encouraged or discouraged in the early stages of stroke rehabilitation. Design: A two-centre pilot study to assess the feasibility of performing a multicentre randomized controlled trial on this subject. Setting: Clatterbridge and Aintree Stroke Rehabilitation Units, Merseyside, UK. Subjects: Forty early stroke patients (mean age 67 years) in whom it was uncertain whether self-propulsion in a wheelchair should be encouraged were studied. Intervention: A central randomization service at Newcastle University was used to determine the policy about wheelchair provision and use for each patient. They were allocated to either an ‘encouraged to self-propel’ or a ‘discouraged from self-propulsion group’. Outcome measures used: Independent outcome assessment was performed by postal questionnaire and telephone interview using the Barthel ADL Scale, Nottingham Extended ADL Scales and the shortened General Health Questionnaire (GHQ-12) at 3 and 12 months. Patients length of stay and their Ashworth tone score were also measured either at three months or when they were discharged from hospital. Results: After considerable preparation time it was possible to conduct a trial on self-propulsion in early stroke rehabilitation in the two-pilot centres. No major differences were found between the pilot groups for any of the outcome measures. Conclusions: A multicentre randomized controlled trial to assess this question is feasible but further work is being conducted before proceeding, to satisfy the concerns expressed to our group regarding the appropriateness of the intervention and the outcome measures. Address for correspondence: JA Barrett, Clatterbridge Hospital, Wirral, Merseyside CH69 4JY, UK. e-mail: jabarrett@clatterbridgesru.freeserve.co.uk

In vivo interactions of NAN-190, a putative selective 5-HT1A antagonist, with ipsapirone

The actions of NAN-190, a putative 5-HT1A antagonist, were assessed in rats. The selective 5-HT1A agent ipsapirone suppressed operant responding, but this effect was not antagonised by NAN-190, which suppressed responding itself in a dose-related manner, and had additive effects when administered with ipsapirone. These data do not support suggestions that NAN-190 is a 5-HT1A antagonist. NAN-190 may be a 5-HT1A partial agonist which can antagonise effects of full 5-HT1A agonists.

Evidence for a dissociation between benzodiazepine withdrawal signs

The relationship between benzodiazepine-withdrawal induced weight loss and conditioned taste aversion was studied. Rats were treated with chlordiazepoxide (CDP) for 10 days (n = 37) or with vehicle (n = 39). Significant withdrawal-induced weight loss was observed. On day 11 all animals received an intra-oral infusion of saccharin. In a subsequent saccharin vs water choice test significant withdrawal-induced conditioned taste aversion was observed, as CDP pretreated animals drank less saccharin than controls. The two withdrawal indices were not correlated in the CDP pretreated animals [r = + 0.05], despite the fact that we studied a large group of rats. These data are in agreement with suggestions that drug withdrawal syndromes may be heterogeneous phenomena with a number of different underlying neural mechanisms.

Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats

This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal—so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT3 antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at deses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT3 antagonist ondansetron (0.01–0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT3 antagonists may have relatively limited utility in treating some signs of BZ dependence.

Effects of the CCKB antagonist L-365, 260 on benzodiazepine withdrawal-induced hypophagia in rats.

The effect of the selective CCKB antagonist L-365, 260 on chlordiazepoxide (CDP) withdrawal-induced hypophagia was assessed in two related studies in rats pretreated for 21 days with CDP at doses escalated from 10 to 30 mg/kg per day (b.i.d.). L-365, 260 was studied at doses from 0.001 to 10 mg/kg (b.i.d.). There was no evidence that L-365, 260 at any dose alleviated CDP withdrawal-induced hypophagia. These data contrast with reports that CCKB antagonists alleviate behavioural benzodiazepine (BZ) withdrawal symptoms considered to be indicative of “anxiogenesis”. Presumably, such positive effects of CCKB antagonists are due to “functional antagonism”, with enhanced anxiety during BZ withdrawal being attenuated by anxiolytic actions of CCKB antagonists. Collectively, studies with CCKB antagonists and other agents involving a number of different BZ withdrawal signs suggest that BZ withdrawal is a heterogeneous syndrome, with various different underlying mechanisms. CCKB antagonists appear to alleviate only a subset of possible BZ withdrawal signs.

Assessment of the dependence potential of the potent high-efficacy 5-HT1A agonist S-14506 in rats.

This study assessed the dependence potential of S-14506 [ 1- [ 2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy napthyl) piperazine], a novel, potent 5-HT1A full agonist with anxiolytic and antidepressant actions in animal models. The dependence potential of S-14506 was compared with that of the benzodiazepine (BZ) chlordiazepoxide (CDP). BZ withdrawal caused weight loss, aphagia and hyperthermia after chronic b.i.d. treatment for 21 days. None of these withdrawal effects were seen after similar b.i.d. S-14506 treatment at high doses. However, the acute pharmacological actions of CDP and S-14506 differed on a number of indices. Specifically, CDP increased food intake and body weight, whilst S-14506 decreased these measures, possibly due to the induction of the serotonin syndrome. Of particular interest was the observation that S-14506 induced marked hypothermia, to which complete tolerance developed very rapidly (after only 1 day). The observation of marked, rapid tolerance to S-14506-induced hypothermia, in conjunction with the absence of withdrawal hyperthermia after prolonged chronic treatment at high doses, suggests that tolerance to this effect of S-14506 can be dissociated from dependence. Collectively, the data reported suggest that the full 5-HT1A agonist S-14506 is devoid of dependence potential, other human and animal studies having previously suggested that partial 5-HT1A agonists typically induce no, or minimal, dependence.