Lack of hemispheric dominance for consciousness in acute ischaemic stroke.

BACKGROUND: Previous reports have suggested left hemispheric dominance for maintaining consciousness, although there is controversy over this claim. OBJECTIVE: To compare early impairment of level of consciousness between patients with right and left hemispheric stroke. METHODS: Data from 564 patients with ischaemic stroke enrolled in the placebo arm of a trial of a putative neuroprotectant were analysed. All patients had major hemispheric stroke with cortical dysfunction, visual field deficit, and limb weakness, with symptom onset within 12 hours of enrolment. Patients were prospectively evaluated on a predefined scale (1-6; 1 = fully awake, higher scores representing greater impairment) to measure level of consciousness at multiple time points over the initial 24 hours after presentation. The National Institutes of Health (NIH) stroke scale score at presentation and infarct volume at 30 days were determined. RESULTS: Some degree of impairment in level of consciousness was observed in 409 of the 564 patients (73%). Median maximum sedation score was 2 for both right and left hemispheric stroke (p = 0.91). Mean sedation score over 24 hours was 1.5 for both right and left stroke (p = 0.75). There was no difference between level of consciousness scores in right and left stroke at any individual time point during the 24 hour monitoring period. No association between side and impairment in level of consciousness was seen after adjustment for stroke severity and infarct volume. CONCLUSIONS: In contrast to previous reports, there was no evidence for hemispheric dominance for consciousness in the setting of a major hemispheric stroke.

Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.

BACKGROUND AND PURPOSE: NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. RESULTS: One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.

Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results.

BACKGROUND AND PURPOSE: A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. METHODS: A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index > or =60 at last follow-up as the primary outcome measure. RESULTS: The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9+/-5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of > or =60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P=0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. CONCLUSIONS: The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results.

OBJECTIVE: To assess the safety of tissue-type plasminogen activator (t-PA) plus clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy. BACKGROUND: Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS-t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke. METHODS: In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index. RESULTS: The number of serious adverse event reports was 47 in the clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23). CONCLUSION: In this pilot study, there were no safety concerns related to the combination of t-PA and clomethiazole. The combination paradigm proved feasible, although many patients received clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and clomethiazole.

Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke.

BACKGROUND AND PURPOSE: Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. RESULTS: One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.

Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus.

AIMS: Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. METHODS: Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. RESULTS: Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). CONCLUSION: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Cerebral and cerebellar activation in correlation to the action-induced dystonia in writer's cramp.

The pattern of brain perfusion of four patients with writer's cramp and four control subjects were examined using positron emission tomography scans after [(15)O] butanol injections. Each subject was scanned 12 times to cover three repetitions of four different motor tasks with the right hand. Drawing of horizontal lines and variable durations of the writing of a prelearned text were performed in a pseudorandom order, the latter task commencing either simultaneously with or 30 sec or 120 sec before the tracer injection. The perceived difficulty and signs of dystonia progressed in correlation to the duration of writing. Statistical parametric maps were calculated to test hypotheses of regional specific effects dependent on the performed motor tasks. The patients with writer's cramp had progressively increased activity in the left primary sensorimotor and premotor cortices, the left thalamus, and the cerebellum with a right-side predominance in correlation to the duration of writing. The regions with activity increases thus corresponded to a cerebrocerebellar motor circuit. The duration of writing correlated to a progressive reduction of activity in the patients' left supramarginal and angular gyri (Brodmann areas 40 and 39) and an inferior part of the left temporal lobe (area 20). The control subjects had neither a significant increase or decrease of activity in correlation to the duration of writing. Group-specific differences were confirmed statistically in split-plot interaction analyses.

A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia.

OBJECTIVE: This study was designed to establish whether a ratio of three units of Dysport is equivalent to one unit of Botox for the treatment of cervical dystonia. METHODS: Patients with predominantly rotational cervical dystonia, and a minimum of four previous Botox treatments, were randomised to receive either the clinically indicated dose of Botox or three times that dose in Dysport units. Study botulinum toxin was administered in a double blind fashion, to one or more clinically indicated muscles, at one or more sites per muscle. Patients returned for assessment two, four, eight, and 12 weeks after treatment. RESULTS: A total of 73 patients (Dysport, 38; Botox, 35) were entered. The Dysport group received a mean (SD) dose of 477 (131) (range 240-720) Dysport units, and the Botox group received a mean (SD) dose of 152 (45) (range 70-240) Botox units. The mean (SEM) post-treatment Tsui scores for the Dysport group (4.8 (0.3)) and the Botox group (5.0 (0.3)) were not statistically different (p=0.66). The study had 91% power to detect a clinically significant difference of two points. Both groups showed substantial improvement in Tsui score by week 2 (mean (SD); Dysport, 46 (28)%; Botox, 37 (28)%), with a peak effect at week 4 (mean (SD); Dysport, 49 (29)%; Botox, 44 (28)%). A similar response profile was seen for other assessments of efficacy. The duration of effect, assessed by time to retreatment, was also similar (mean (SD); Dysport, 83.9 (13.6) days; Botox, 80.7 (14.4) days; p=0.85). During the study 22 of 38 (58%) Dysport patients reported 39 adverse events, and 24 of 35 (69%) Botox patients reported 56 adverse events (p=0.35). A global assessment of efficacy and safety considered that 29 of 38 (76%) Dysport patients and 23 of 35 (66%) Botox patients were treatment successes (p=0.32). CONCLUSION: Patients with predominantly rotational cervical dystonia treated with the clinically indicated dose of Botox or three times that dose in Dysport units show similar improvements and do not have significantly different safety profiles.

The clomethiazole acute stroke study in ischemic, hemorrhagic, and t-PA treated stroke: Design of a phase III trial in the united states and canada.

Clomethiazole is a drug with sedative properties effective in laboratory studies of brain ischemia. A large European multicenter trial of clomethiazole in acute stroke patients showed no benefit overall, but subgroup analysis indicated that patients with large infarctions may have benefited from treatment. To confirm this preliminary finding, we have designed CLASS-IHT, the Clomethiazole for Acute Stroke Study in Ischemic, Hemorrhagic and TPA Treated Patients, to be conducted in North America. Patients who suffer large cerebral infarctions and present within 12 hours of symptom onset are eligible. Patients will be randomized to receive clomethiazole 68 mg/kg over 24 hours or vehicle, using a dosing scheme based on the pharmacokinetics measured in the first trial. Outcome assessments include stroke scales, the Barthel Index, and lesion volume. An additional study of health economic outcomes is planned. The primary endpoint for CLASS-I will be the Barthel Index 90 days after stroke. A total of 1,200 patients will be randomized to CLASS-I, and in safety-only trials, 200 patients with cerebral hemorrhage will be randomized into CLASS-H and another 100 to 200 patients will be randomized into CLASS-T. The details of the protocols for all three studies are presented.

Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical dystonia.

Previous electrophysiologic studies on the effects of local injections of botulinum toxin type A (BTX-A) have indicated impaired neuromuscular transmission in distant muscles. To further study possible distant effects of repeated BTX-A injections, we obtained percutaneous muscle biopsies of the vastus lateralis muscle from 11 patients with cervical dystonia. We examined the biopsies with histopathology and morphometry, and compared them with age-matched healthy controls. There was an increased frequency of angular atrophic type IIB fibers in the patient group, and the mean size of IIB fibers was significantly smaller (p < 0.05). In addition, there was a negative correlation between accumulated dose of botulinum toxin and relative size of type IIA fibers (p < 0.05). We postulate that the observed atrophy is due to distant effects of botulinum toxin causing progressive denervation-like changes in non-treated muscle. This observation calls for further, prospective studies of the long-term effects of the treatment.

Sternocleidomastoid muscle responses to transcranial magnetic stimulation in patients with cervical dystonia.

Ten cervical dystonia (CD) patients, with involuntary head rotation to one side and contralateral sternocleidomastoid muscle (SCM) hypertrophy, were investigated with transcranial magnetic stimulation, and the results were compared to those of 10 healthy subjects. Monopolar needle electrodes with isolated shafts were used for bilateral electromyographic recordings in the SCMs of the motor evoked potentials (MEPs) elicited by the magnetic stimulator. The latencies of ipsilateral SCM MEPs were shorter in the CD patients than in the control subjects (P < 0.001). The latencies of SCM activity suppression by TMS were longer in the CD patients than in the control group when stimuli were given on the contralateral side (P < 0.05). Both the clinically dystonic and the contralateral SCM of the CD patients exhibited significantly abnormal latencies of the ipsilateral SCM MEPs (P < 0.01) and of the SCM suppression (P < 0.05). Three CD patients also had consistent activity in the SCM counteracting the direction of head rotation during the suppression experiments. The latencies of the suppression of this abnormal activation were shorter (P < 0.05), than the latencies of the suppression in the SCM during normal voluntary activation by these CD patients (i.e. rotation of the head in the contrary direction). The results suggest bilaterally enhanced motoneuronal excitability and disturbed inhibitory regulation in patients with CD.

C-peptide improves autonomic nerve function in IDDM patients.

In order to determine the possible influence of C-peptide on nerve function, 12 insulin-dependent diabetic (IDDM) patients with symptoms of diabetic polyneuropathy were studied twice under euglycaemic conditions. Tests of autonomic nerve function (respiratory heart rate variability, acceleration and brake index during tilting), quantitative sensory threshold determinations, nerve conduction studies and clinical neurological examination were carried out before and during a 3-h i.v. infusion of either C-peptide (6 pmol.kg-1.min-1) or physiological saline solution in a double-blind study. Plasma C-peptide concentrations increased from 0.11 +/- 0.02 to 1.73 +/- 0.04 nmol/l during C-peptide infusion. Clinical neurological examination quantitative sensory threshold evaluations and nerve conduction measurements failed to detect significant changes between C-peptide and saline study periods. Respiratory heart rate variability increased significantly from 13 +/- 1 to 20 +/- 2% during C-peptide infusion (p < 0.001), reaching normal values in five of the subjects; control studies with saline infusion did not alter the heart rate variability (basal, 14 +/- 2; saline, 15 +/- 2%). A reduced brake index value was found in seven patients and increased significantly during the C-peptide infusion period (4.6 +/- 1.0 to 10.3 +/- 2.2%, p < 0.05) but not during saline infusion (5.9 +/- 2 to 4.1 +/- 1.1%, NS). It is concluded that short-term (3-h) infusion of C-peptide in physiological amounts may improve autonomic nerve function in patients with IDDM.

Impaired sensory-motor integration during grasping in writer's cramp.

Six subjects with writer's cramp and six healthy control subjects were examined while lifting a small instrumented object with variable weight and friction using the precision grip. The isometric grip and load forces were sampled at 400 Hz and stored in a flexible laboratory computer system for later analysis. Quantitative measurement of vibration and temperature sensibility showed normal sensory perception in the writer's cramp subjects. They exhibited an impaired programming of the grip-lift force co-ordination, while the ability to generate unimodal force-rate trajectories and to characterize the pattern of the force output according to memory representations of weight and friction of the object were intact. The capacity to terminate quickly the programmed grip force in lifts erroneously programmed too high was impaired. Writer's cramp subjects also employed excessive grip force during the static phase of the lift, and some patients had a short grip force latency after sudden unpredicted load increases, indicating a disinhibited spinal reflex response. The results indicate an impaired capacity in writer's cramp subjects to integrate sensory information in the motor programming and force regulation during precision grip tasks, despite a normal sensibility.

Activation and suppression of the sternocleidomastoid muscle induced by transcranial magnetic stimulation.

Responses in the stemocleidomastoid muscle (SCM) induced by transcranial magnetic stimulation (TMS) were investigated in 10 healthy subjects. Stimuli were given with the Dantec MagLiteTM magnetic stimulator using a 12.5 cm circular coil with counter-clockwise current direction. Monopolar needle electrodes with isolated shafts were used for simultaneous bilateral electromyographic (EMG) recordings of the SCM. TMS given on either side invariably induced an ipsilateral motor evoked potential of the SCM (SCM-MEP), whereas a contralateral SCM-MEP was just seen in 25% of the performed stimulation series also when maximal intensity was used. The SCM-MEPs recorded ipsilaterally to the side of stimulation had significantly higher maximal amplitudes (P < 0.05) compared to the SCM-MEPs recorded contralaterally (mean +/- S.D.: 1.0 +/- 0.5 and 0.2 +/- 0.1 mV, respectively). These results support the concept of a predominantly ipsilateral control of SCM activation. The contralateral SCM-MEPs tended to have a shorter latency than the ipsilateral SCM-MEPs. The thresholds of the ipsilateral SCM-MEPs were significantly higher (P < 0.01) on the left side than on the right side (mean +/- S.D.: 78 +/- 18 and 60 +/- 16 A/microseconds, respectively), which could be due to the consistent use of counter-clockwise coil current direction. TMS given on either side induced suppression of voluntary SCM activity in all investigated subjects. Responses induced by TMS given ipsilaterally and contralaterally to the voluntary activated muscle did not differ significantly (P > or = 0.05) regarding threshold or latency of the suppression.

Efficacy of botulinum toxin for cervical dystonia. A comparison of methods for evaluation.

Twenty patients with cervical dystonia were treated during one year with repeated intramuscular injections of botulinum toxin. The outcome was evaluated comparing subjective global rating with relative changes in degree of pain on the Visual analogue scale (VAS), degree of dysfunction due to dystonia, and quality of life according to the Nottingham health profile (NHP). Objective measurement of dystonic position and movement ability was performed using a goniometer, semiquantitatively noted as scores according to Fahn and Tsui. Before treatment, the degree of impaired life quality on the NHP did not correlate with the Tsui score of dystonic posture, but significantly with the Fahn score (p < 0.01) which also includes data on pain. Significant improvement after treatment was seen for all parameters (p < 0.05). Global subjective rating correlated significantly with improved posture according to the Tsui score (p < 0.05), but not with reduced pain or degree of dysfunction. The results suggest that the efficacy of botulinum toxin in cervical dystonia is best evaluated using a combination of the VAS for pain and the Tsui score for dystonic posture and movement ability.

Electromyographic single motor unit potentials after repeated botulinum toxin treatments in cervical dystonia.

Electromyographic (EMG) single motor unit potentials (MUPs) of the sternomastoid muscles (STM) were made before and after repeated treatment with botulinum type A toxin (Bx) for cervical dystonia. Post-treatment examinations were 6-25 weeks after the latest injection, when symptoms and EMG interference pattern had recurred and signs of denervation were scarce. Concentric needle EMG records of 200 motor unit potentials in 10 patients showed reduced durations and areas after treatment (P < 0.05). Increased polyphasia or satellite potentials were not observed. Macro-EMG records of 110 MUPs in 6 patients showed reduced amplitudes and areas in the injected STM when compared to the untreated side (P < 0.05). Fibre density was within the same range (1.0-1.2). The results indicate that the pattern of the terminal innervation is mainly restored even after repeated Bx treatments, but the number or size of active muscle fibres within the motor unit is reduced. The clinical relapse could be due to recovery of the original nerve terminals, or to nerve sprouts closely imitating the blocked terminal nerve twigs or both.