Early botulinum toxin treatment for spastic pes equinovarus--a randomized double-blind placebo-controlled study.

BACKGROUND AND PURPOSE: Spastic pes equinovarus is a frequent pathological posture of the lower extremity. Botulinum toxin (BoNT/A) has been successfully applied to treat lower limb spasticity. However, the best time to initiate treatment remains unclear. A beneficial effect of an early treatment has been suggested in previous studies. METHODS: A single-centre double-blind randomized placebo-controlled trial was performed to investigate the efficacy of BoNT/A to reduce muscle hypertonicity at the ankle. Fifty-two patients with unilateral or bilateral spastic pes equinovarus with a modified Ashworth score (mAS) of at least 1+ after stroke, traumatic brain injury or hypoxic encephalopathy were allocated to receive either BoNT/A or placebo treatment. A second, open injection was optional at week 12. Patients received unilateral or bilateral injections with 230 or 460 U onabotulinumtoxinA, respectively. The course of the mAS was explored during the open study phase. RESULTS: Patients who had received BoNT/A treatment had lower mAS compared with placebo at week 12 (P < 0.01). During the open label phase, patients from the placebo group showed further deterioration of muscle tone despite starting from a similar baseline and receiving BoNT treatment. Spastic feet that had received BoNT/A in the first cycle had comparatively lower mAS scores over all follow-up data and at week 24 (P < 0.01). CONCLUSIONS: The study demonstrates a reduction of muscular hypertonicity in spastic pes equines with BoNT/A treatment given during the first 3 months after the lesion. Exploratory analyses of the course of muscular hypertonicity during the open phase favour earlier to later treatment.

An open-label cohort study of the improvement of quality of life and pain in de novo cervical dystonia patients after injections with 500 U botulinum toxin A (Dysport).

OBJECTIVES: It remains to be determined whether the benefits of botulinum toxin type A (BoNT-A) on cervical dystonia (CD) motor symptoms extend to improvements in patient's quality of life (QoL). This analysis of a large, multicentre study was conducted with the aim of investigating changes in QoL and functioning among de novo patients receiving 500 U BoNT-A (abobotulinumtoxinA; Dysport) for the treatment of the two most frequent forms of CD, predominantly torticollis and laterocollis. DESIGN: A prospective, open-label study of Dysport (500 U; Ipsen Biopharm Ltd) administered according to a defined intramuscular injection algorithm. SETTING: German and Austrian outpatient clinics. PARTICIPANTS: 516 male and female patients (aged ≥18 years) with de novo CD. The majority of patients had torticollis (78.1%). 35 patients had concomitant depression (MedDRA-defined). MAIN OUTCOME MEASURES: Change from baseline to weeks 4 and 12 in Craniocervical Dystonia Questionnaire (CDQ-24) total and subscale scores, patient diary items ('day-to-day capacities and activities', 'pain' and 'duration of pain') and global assessment of pain. RESULTS: Significant improvements were observed in CDQ-24 total and subscale scores at week 4 and were sustained up to week 12 (p<0.001). Changes in CDQ-24 scores did not significantly differ between the torticollis and laterocollis groups or between patients with or without depression. There were also significant reductions in patient diary item scores for activities of daily living, pain and pain duration at weeks 4 and 12 (p<0.001). Pain relief (less or no pain) was reported by 66% and 74.1% of patients at weeks 4 and 12, respectively. Changes in pain parameters demonstrated a positive relationship with change in Tsui score. CONCLUSIONS: After standardised open-label treatment with Dysport 500 U, improvements in QoL and pain intensity up to 12 weeks in patients with CD were observed.

[Botulinum toxin in the treatment of adult spasticity. An interdisciplinary German 10-point consensus 2010]. / Botulinum-Neurotoxin in der Behandlung der Spastizität im Erwachsenenalter. Ein interdisziplinärer deutscher 10-Punkte-Konsensus 2010.

Spasticity is one of the major causes of functional impairment in adults with lesions of the central nervous system. For instance, approximately 30% of post-stroke patients suffer from different degrees of spasticity with possible consecutive impairments. Numerous studies or meta-analyses showed that local injections of botulinum toxin in spastic muscles lead to dose-dependent reduction in muscle tone and improvement of passive movements (e. g. facilitated care), especially following repeated injections.However, country-specific regulations and patient-remote administration in German health care often do not allow adequate provision of this therapy. Thus, the present consensus statement based on the EBM analyses of the published international literature tries to highlight recent advances and the standard in the field of local spasticity treatment, aiming to facilitate communication between the decision makers and German reimbursement institutions in health care. Prior to initiation of BoNT-A injections, patient-oriented goals should be identified in a multiprofessional context to assure realistic goals for this specific treatment and patient expectations. In Germany for the treatment of focal spasticity following stroke three products have been approved: Botox® (Pharm Allergan, Ettlingen), Dysport® (Ipsen Pharma, Ettlingen) and Xeomin® (Merz Pharma, Frankfurt/Main). For all preparations safety has been repeatedly shown. Functional improvements have also been illustrated for selected patients concerning hand/arm function and gait. The dose per muscle and the selection of muscles to be injected have to be individualized according to the patient's symptoms and should be accompanied by modern neurorehabilitative therapies such as redression or repetitive activation of the injected and antagonistic muscles.

Comparison of an intermittent high-intensity vs continuous low-intensity physiotherapy service over 12 months in community-dwelling people with stroke: a randomized trial.

OBJECTIVE: This study compared two modes of physiotherapy service over 12 months in community-dwelling people with stroke, either following a train-wait train paradigm by providing bouts of intense physiotherapy, or a continuous less intense programme. DESIGN: Randomized trial. SETTING: Community-dwelling people with stroke. INTERVENTIONS: Fifty patients, first-time stroke, discharged home, following inpatient rehabilitation, allocated to two groups, A and B. Over 12 months, Group A (n = 25) received three two-month blocks of therapy at home, each block contained four 30 to 45 minute sessions per week, totalling 96 sessions. Group B (n = 25) continuously received two 30 to 45 minute sessions per week, totalling 104 sessions. MAIN OUTCOME MEASURES: Primary Rivermead Mobility Index (0-15), secondary upper- and lower-limb motor functions, Activities of Daily Living competence, tone and number of falls. RESULTS: Both groups were comparable at onset, the mean age in Group A (B) was 62.4 (61.9) years. A and B patients equally improved functions over time, between group differences did not occur. The initial (terminal) Rivermead Mobility Index was 9.4 ± 2.8 (12.2 ± 2.1) in Group A, and 8.5 ± 3.5 (11.2 ± 2.7) in Group B. More Group B patients fell seriously (7 versus 1). CONCLUSIONS: The intermittent high-intensity and continuous low-intensity therapy protocols were equally effective, the sheer intensity seems more important than the time-mode of application. The relatively young patients functionally improved in the first year after stroke, the reduced risk of serious falls in the intermittent high-intensity group should be validated.

Botulinum toxin B increases mouth opening in patients with spastic trismus.

BACKGROUND: Severe generalized spastic movement disorders of various aetiologies often involve the jaw muscles and lead to a spastic trismus with masseter muscle hypertonia. We report a placebo-controlled randomized study on patients with spastic trismus. METHODS: Eleven patients with masseter hypertonia because of stroke, hypoxic encephalopathy or traumatic brain injury were allocated to either botulinum toxin serotype B (BoNT/B) injections into the masseter muscles or placebo treatment. The dental gap, the amount of saliva, salivation scales, and a clinical goal attainment were evaluated. RESULTS: Three weeks after injection the BoNT/B group showed a significantly increased mouth opening compared with placebo treatment (P < 0.05). In addition to the muscle paralysing effect, a goal attainment scale demonstrated a clinical benefit for the BoNT/B group (P < 0.01). CONCLUSIONS: Botulinum toxin serotype B injections into the masseter muscles effectively reduce hypertonia and provide for better mouth opening, thereby contributing to a positive and desired clinical goal.

Cost-effectiveness modeling of intrathecal baclofen therapy versus other interventions for disabling spasticity.

OBJECTIVE: To assess by simulation the cost-effectiveness of intrathecal baclofen (ITB) therapy compared with conventional medical treatments for patients with disabling spasticity and functional dependence caused by any neurological disease. METHODS: Two models were created to simulate therapeutic strategies for managing severe spasticity, one with and one without the use of ITB, to assess various treatment sequences over 2 years based on current medical practices in France. Successful treatment at each evaluation was defined as a combination of: (1) the increased patient and caregiver satisfaction as assessed by goal attainment scaling (GAS), and (2) a decrease of at least 1 point on the Ashworth score. Probabilistic sensitivity analyses were performed using 5000 Monte-Carlo simulations taking into account specific distribution curves for direct costs and effectiveness parameters in each treatment option. RESULTS: The model simulations suggest that including ITB as a first option strategy in the management of function of severely impaired patients with disabling spasticity results in a higher success rate (78.7% vs 59.3%; P < .001). In addition, the ITB therapy model revealed a lower cost (pound 59,391 vs pound 88,272; P < .001) and an overall more favorable cost-effectiveness ratio (pound 75,204/success vs pound 148,822/success; P < .001), compared with conventional medical management without ITB. CONCLUSION: Within the assumptions of our modeling, ITB therapy evaluated by a combination of treatment success criteria at 6-month intervals over a 2-year period may be a cost-effective strategy compared to conventional medical management alone.

[Multidisciplinary therapy for focal spasticity treatment]. / Fokale Therapie der Spastizität im multi- professionellen Team.

For treating focal dystonias and spastic syndromes local intramuscular injections of botulinum toxin type A (BTA) are the method of choice. The therapy aims to reduce disabling dystonic and spastic movement disorders, ease care and personal hygiene, reduce pain, and improve quality of life. With respect to functional improvement from and accuracy of BTA-injection, treatment results in spasticity often profits from electrical or sonographical guidance of BTA injection in addition to active time localized training methods (physio- and occupational therapy). Since we know that only active synapses binds BTA (receptor is located in the acetylcholine vesicle) further therapeutic methods should also be employed to enhance efficacy of BTA, especially casting and splinting electrical stimulation, for muscle activation and regaining of normal length of spastic muscules are recommended. The goals of focal therapy for spasticity should be discussed with the patient and family members to guarantee maximum results from the coordinated multidisciplinary effort of BTA-treatment in disabling spasticity.

Using translational medicine to understand clinical differences between botulinum toxin formulations.

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Craniocervical dystonia questionnaire (CDQ-24): development and validation of a disease-specific quality of life instrument.

OBJECTIVE: To develop and test a questionnaire for measuring quality of life in patients with craniocervical dystonia. METHODS: A 29-item pool was developed based on semi-structured interviews of patients with cervical dystonia (CD) and blepharospasm (BSP). This preliminary questionnaire was administered to 203 consecutive patients with CD and BSP from Austrian dystonia and botulinum toxin outpatient clinics. For scale generation, a combination of exploratory factor and cluster analysis was applied. This resulted in the 24-item version of the instrument (CDQ-24) based on five subscales: Stigma, Emotional wellbeing, Pain, Activities of daily living, and Social/family life. The validity and reliability of the CDQ-24 was assessed in 231 consecutive patients with CD and BSP different from those examined with the preliminary questionnaire. This second survey included the CDQ-24, a generic QoL instrument (SF-36) and clinical rating scales. Sensitivity to change was analysed in 51 previously untreated (de novo) patients four weeks and one year following the first botulinum toxin treatment. RESULTS: Internal consistency reliability was satisfactory for all subscales, with values of Cronbach's alpha ranging from 0.77 to 0.89. The CDQ-24 subscales showed moderate to high correlations with those SF-36 subscales measuring similar aspects (Pearson's correlation r = 0.50-0.73; p<0.001, each). Sensitivity to change was confirmed by highly significant improvements of all CDQ-24 subscores in the de novo patients from baseline to four week follow up. One year follow up data revealed a stable improvement. CONCLUSION: The CDQ-24 is the first fully validated and disease specific questionnaire to evaluate quality of life of patients with cervical dystonia and blepharospasm and we propose its use in clinical trials as well as in daily clinical practice.

The prevalence of primary dystonia in the general community.

The prevalence of primary dystonia was assessed in a random population sample of individuals aged 50 and over in Bruneck, South Tyrol. The diagnosis of primary dystonia was confirmed by videotaped review. Primary dystonia was present in 6 of 707 cases resulting in a prevalence rate of 732 per 100,000 (95% CI 319-1,564) in the general population aged 50 and over. Only two cases (33%) had been previously diagnosed. These results indicate that the true prevalence of primary dystonia is significantly higher than published rates.

The impact of blepharospasm and cervical dystonia on health-related quality of life and depression.

The aim of the study was to evaluate and compare health-related quality of life (HR-QoL) and depression in essential blepharospasm (BSP) and idiopathic cervical dystonia (CD), to identify the clinical and demographic factors associated with poor HR-QoL in both disorders and to analyse the effect of Botulinum Toxin A (BtxA) therapy. Two hundred-twenty consecutive patients with BSP (N = 89, 62 % women, mean age 64 years, mean disease duration 7 years) and CD (N = 131, 64 % women, mean age 53 years, mean disease duration 8 years) recruited from routine referrals to eight Austrian dystonia clinics were included. HR-QoL was measured by the Short Form 36 (SF-36) and depression by the Beck Depression Inventory (BDI). At baseline, patients with CD and BSP scored significantly worse in all eight SF-36 domains compared with an age-matched community sample. In addition, 47 % of patients with CD and 37 % of those with BSP were depressed. Women with BSP scored significantly lower in all SF-36 domains and were more depressed than male patients. In contrast, there was no significant effect of gender on HR-QoL and depression in CD. Neck pain had a significant impact on all SF-36 domains and represented the main determinant of depression in CD. Although BtxA therapy resulted in a significant improvement of clinical symptoms in BSP and CD, HR-QoL did not improve in BSP and only two of the eight SF-36 domains improved significantly in patients with CD. The present study for the first time demonstrated that BSP has a substantial impact on health status emphasizing the need for psychological support with interventions aimed at treating depression in these patients. Our results provide further evidence for the profound impact of CD on HR-QoL and indicate the importance of an adequate management of neck pain in addition to reducing the severity of dystonia in CD. The mismatch between objective BtxA derived improvement of dystonia and lack of change of HR-QoL as determined by the SF-36 illustrates the need for optimized disease specific quality of life rating scales in patients with craniocervical dystonia.

Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia.

We investigated the efficacy of botulinum toxin A (BtxA) therapy in patients with atypical parkinsonian disorders (APD) exhibiting different types of disabling focal dystonia unresponsive to oral drug therapy. Eight patients with functionally disabling focal dystonia out of a series of 60 consecutive patients with APDs regularly treated at our outpatient movement disorders clinic were included. Patients were diagnosed according to established criteria and had disabling limb dystonia (n=4) or craniocervical dystonia (n=4) unresponsive to oral pharmacological treatment. Localization and dose of BtxA injections was determined individually based on clinical examination as well as EMG in patients with limb dystonia. BtxA reduced dystonic symptoms in all patients; only one developed a transient local side-effect. BtxA was particularly effective in the long-term treatment (up to 50 months) of blepharospasm associated with progressive supranuclear palsy (PSP). BtxA also alleviated PSP-associated retrocollis and orofacial dystonia with lower lip retraction associated with PSP and multiple system atrophy. BtxA treatment of limb dystonia in corticobasal degeneration (CBD) temporarily improved hand and arm function in early-disease stages while treatment in advanced stages reduced pain, facilitated hygiene and prevented secondary contractures. Limb dystonia was also alleviated by BtxA therapy in one patient with neuronal multisystem degeneration of undetermined cause. The results suggest that BtxA therapy may represent an effective means of alleviating disabling focal dystonia in different APDs. Particularly in early stage APD with disabling limb dystonia local BtxA injections may result in functional improvement.

Dynamic balance function in phasic cervical dystonia following Botulinum toxin therapy.

Previous research by our group revealed normal dynamic balance function in pure tonic cervical dystonia (CD) with impaired equilibrium in phasic CD patients investigated at least 3 months following Botulinum toxin (BtxA) treatment. The current study was performed to determine whether impaired dynamic equilibrium in phasic CD is influenced by symptomatic treatment with BtxA. Dynamic balance was tested in 20 patients with phasic CD on a dynamic platform with a cylindrical curved base (stabilometer) 4 weeks following BtxA treatment. Balance was assessed by the linear displacement of the platform and the maximum amplitude of platform displacement with open and closed eyes and compared with pre-BtxA data. Despite a clinically significant BtxA-induced reduction of phasic head movements, none of the platform measures improved significantly. In addition, there was no correlation between the BtxA-induced clinical improvement and changes in any of the dynamic balance measures pre- vs. post-BtxA. In conclusion, the persistent dynamic balance impairment after effective BtxA therapy may indicate that disequilibrium in phasic CD does not simply reflect disturbed vestibular input from repetitive head oscillations, but argues in favour of different sensorimotor processing in tonic and phasic CD.

Clinical characteristics of the geste antagoniste in cervical dystonia.

The geste antagoniste (moving an arm to the face or head) is a well-known clinical feature in cervical dystonia (CD) to alleviate the abnormal posture. The clinical phenomenology of these manoeuvres has not so far been assessed systematically. Fifty patients with idiopathic CD aware of at least one geste antagoniste (60% women, mean age at onset 44.1 years, mean disease duration 7.5 years) were subjected to a standardized investigation including a semiquantitative clinical rating scale and polymyographic recordings of six cervical muscles. Twenty-seven patients (54%) demonstrated more than one geste antagoniste (range 2-5). A clinically significant (> or = 30%) reduction of head deviation was observed in 41 patients (82 %). Dystonic head posture improved by a mean of 60 % along all planes by the geste manoeuvre with a complete cessation of head oscillations in nine of 33 patients (27 %) with phasic CD. No significant laterality of the "geste-arm" or the facial target area was found. The duration of geste-effects depended significantly on disease duration and determined the patient's self-rating of the benefit of the manoeuvre. EMG-polygraphy revealed two types of geste-induced polymyographic changes: a decrease in recruitment density and amplitude in at least one dystonic muscle (66%), and an increased tonic muscle activation in the remaining patients. The remarkable efficacy of the geste antagoniste and the considerable variety in performance, duration, and EMG-pattern of these manoeuvres warrant further investigation of the therapeutic use of sensorimotor stimulation, in particular for those CD patients who experience limited or no effect from botulinum toxin therapy.

A study of the paravertebral anatomy for ultrasound-guided posterior lumbar plexus block.

IMPLICATIONS: We investigated the feasibility of posterior paravertebral sonography as a basis for ultrasound-guided posterior lumbar plexus blockades. Posterior paravertebral sonography proved to be a reliable as well as accurate imaging procedure for visualization of the lumbar paravertebral region except the lumbar plexus.

Modulation of upper extremity motor evoked potentials by cutaneous afferents in humans.

The excitability of motoneurons controlling upper limb muscles in humans may vary with cutaneous nerve stimulation. We investigated the effect of noxious and non-noxious conditioning stimuli applied to right and left digit II and right digit V on motor evoked potentials (MEPs) recorded from right thenar eminence, abductor digiti minimi, biceps and triceps brachii muscles in twelve healthy subjects. Transcranial magnetic stimulation (TMS) was applied at interstimulus intervals (ISI) ranging from 40 to 160 ms following conditioning distal digital stimulation. TMS and transcranial electrical stimulation (TES) were compared at ISI 80 ms. Painful digital stimulation caused differential MEP amplitude modulation with an early maximum inhibition in hand muscles and triceps brachii followed by a maximum facilitation in arm muscles. Stimulation of different digits elicited a similar pattern of MEP modulation, which largely paralleled the behavior of cutaneous silent periods in the same muscles. Contralateral digital stimulation was less effective. MEPs following TMS and TES did not differ in their response to noxious digital stimulation. MEP latencies were shortened by cutaneous stimuli. The observed effects were stimulus intensity dependent. We conclude that activation of A-alpha and A-delta fibers gives rise to complex modulatory effects on upper limb motoneuron pools. A-delta fibers initiate a spinal reflex resulting in MEP amplitude reduction in muscles involved in reaching and grasping, and MEP amplitude facilitation in muscles involved in withdrawal. These findings suggest a protective reflex mediated by A-delta fibers that protects the hand from harm. A-alpha fibers induce MEP latency shortening possibly via a transcortical excitatory loop.