Safety of Botulinum Toxin A in Children and Adolescents with Cerebral Palsy in a Pragmatic Setting

This retrospective study aimed to examine the safety of botulinum toxin A (BoNT-A) treatment in a paediatric multidisciplinary cerebral palsy clinic. In a sample of 454 patients who had 1515 BoNT-A sessions, data on adverse events were available in 356 patients and 1382 sessions; 51 non-fatal adverse events were reported (3.3% of the total injections number, 8.7% of the patients). On five occasions, the adverse reactions observed in GMFCS V children were attributed to the sedation used (rectal midazolam plus pethidine; buccal midazolam) and resulted in prolongation of hospitalization. Of the reactions attributed to the toxin, 23 involved an excessive reduction of the muscle tone either of the injected limb(s) or generalized; others included local pain, restlessness, lethargy with pallor, disturbance in swallowing and speech production, seizures, strabismus, excessive sweating, constipation, vomiting, a flu-like syndrome and emerging hypertonus in adjacent muscles. Their incidence was associated with GMFCS level and with the presence of epilepsy (Odds ratio (OR) = 2.74 − p = 0.016 and OR = 2.35 − p = 0.046, respectively) but not with BoNT-A dose (either total or per kilogram). In conclusion, treatment with BoNT-A was safe; adverse reactions were mostly mild even for severely affected patients. Their appearance did not necessitate major changes in our practice.     

Best Clinical Practice in Botulinum Toxin Treatment for Children with Cerebral Palsy

Botulinum toxin A (BoNT-A) is considered a safe and effective therapy for children with cerebral palsy (CP), especially in the hands of experienced injectors and for the majority of children. Recently, some risks have been noted for children with Gross Motor Classification Scale (GMFCS) of IV and the risks are substantial for level V. Recommendations for treatment with BoNT-A have been published since 1993, with continuous optimisation and development of new treatment concepts. This leads to modifications in the clinical decision making process, indications, injection techniques, assessments, and evaluations. This article summarises the state of the art of BoNT-A treatment in children with CP, based mainly on the literature and expert opinions by an international paediatric orthopaedic user group. BoNT-A is an important part of multimodal management, to support motor development and improve function when the targeted management of spasticity in specific muscle groups is clinically indicated. Individualised assessment and treatment are essential, and should be part of an integrated approach chosen to support the achievement of motor milestones. To this end, goals should be set for both the long term and for each injection cycle. The correct choice of target muscles is also important; not all spastic muscles need to be injected. A more focused approach needs to be established to improve function and motor development, and to prevent adverse compensations and contractures. Furthermore, the timeline of BoNT-A treatment extends from infancy to adulthood, and treatment should take into account the change in indications with age.     

Changes in Muscle Mass after Botulinum Toxin Injection in Children with Spastic Hemiplegic Cerebral Palsy

We aimed to evaluate muscle mass changes after injection of botulinum toxin (BoNT) in children with spastic hemiplegic cerebral palsy (CP). Children aged between 2 and 12 years who were diagnosed with hemiplegic CP with spastic equinus foot were prospectively recruited and administered BoNT in the affected leg. Lean body mass (LBM) of both legs and total limbs was measured by dual-energy X-ray absorptiometry (DXA) preinjection and 4 and 12 weeks after injection. A total of 15 children were enrolled into the study. LBM of both legs and total limbs increased significantly over 12 weeks of growth. The ratio of LBM of the affected leg to total limbs and to the unaffected leg significantly reduced at 4 weeks after injection compared with preinjection but significantly increased at 12 weeks after injection compared with 4 weeks after injection. In conclusion, the muscle mass of the affected leg after BoNT injection in children with hemiplegic spastic CP decreased at 4 weeks after BoNT injection but significantly recovered after 12 weeks after injection.     

Effect of Botulinum Toxin Injection on the Progression of Hip Dislocation in Patients with Spastic Cerebral Palsy: A Pilot Study

Hip adductor spasticity is a contributing factor to hip dislocation in patients with cerebral palsy (CP). We hypothesized that botulinum toxin injected into the hip adductor muscles would reduce spasticity and help prevent hip dislocation. Twenty patients with bilateral spastic CP aged 2 to 10 years with gross motor function classification system level IV or V were included. Botulinum toxin was injected into the hip adductor muscles at baseline and at 6-month follow-up. Muscle tone was measured with an eight-channel surface electromyography (EMG) recorder. A hip X-ray was performed, and Reimer’s hip migration index (MI) was measured. The Wilcoxon signed-rank test was used to compare the surface EMG values of the hip muscles at baseline and follow-up. The mean root mean square surface EMG value of the hip adductor muscles was significantly reduced at 1, 2, 3, and 7 months after the first injection, up to approximately 53% of the baseline. The 1-year progression of the hip MI was −0.04%. Repeated sessions of botulinum toxin injections at the hip adductor muscles significantly reduced muscle tone and hip displacement. A botulinum toxin injection may be used as an adjunctive treatment in the prevention of hip dislocation.     

High Doses of Botulinum Toxin Type A for the Treatment of Post-Stroke Spasticity: Rationale for a Real Benefit for the Patients

In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with the employment of incobotulinum toxin up to 800 U has been published, and the authors investigated safety and tolerability. Other researches showed efficacy in spasticity reduction, but there is a lack of evidence about the reasons to use high doses of botulinum toxin. This short communication highlights the benefits of higher doses for subjects with upper and lower limb spasticity.     

小剂量A型肉毒毒素治疗痉挛型脑瘫

目的 观察小剂量A型肉毒毒素（BTX—A）治疗痉挛型脑瘫的疗效。方法 选择65例痉挛型脑瘫患儿，进行小剂量A型肉毒毒素注射．再进行家庭康复治疗及配带矫形器进行步态训练治疗3—6个月，并设对照组对比观察。结果 经BTX—A注射后患儿肌张力降低，关节活动度扩大，继续康复治疗及配带足踝矫形器训练，肌张力、关节活动度、步态得到进一步改善。BTX—A组显效41侧，有效16例，无效8例，总有效率87．69％。对照组显效12例，有效8例，无效35例，总有效率46.16％。两组对比差异有显著性（P〈0．001）。结论 小剂量BTX—A神经阻滞术治疗痉挛型脑瘫具有解痉快，不良反应小，操作方便。安全可靠，费用低等优点．     

Cost-Effectiveness of Treating Upper Limb Spasticity Due to Stroke with Botulinum Toxin Type A: Results from the Botulinum Toxin for the Upper Limb after Stroke (BoTULS) Trial

Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was £93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of £20,000 per QALY was 0.36. The point estimates of the ICER remained above £20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost-effective at the threshold value did not exceed 0.39, regardless of the assumptions made.     

Reduced Cross-Sectional Muscle Growth Six Months after Botulinum Toxin Type-A Injection in Children with Spastic Cerebral Palsy

Botulinum Neurotoxin type-A (BoNT-A) injections are widely used as first-line spasticity treatment in spastic cerebral palsy (SCP). Despite improved clinical outcomes, concerns regarding harmful effects on muscle morphology have been raised. Yet, the risk of initiating BoNT-A to reduce muscle growth remains unclear. This study investigated medial gastrocnemius (MG) morphological muscle growth in children with SCP (n = 26, median age of 5.2 years (3.5)), assessed by 3D-freehand ultrasound prior to and six months post-BoNT-A injections. Post-BoNT-A MG muscle growth of BoNT-A naive children (n = 11) was compared to (a) muscle growth of children who remained BoNT-A naive after six months (n = 11) and (b) post-BoNT-A follow-up data of children with a history of BoNT-A treatment (n = 15). Six months after initiating BoNT-A injection, 17% decrease in mid-belly cross-sectional area normalized to skeletal growth and 5% increase in echo-intensity were illustrated. These muscle outcomes were only significantly altered when compared with children who remained BoNT-A naive (+4% and −3%, respectively, p < 0.01). Muscle length growth persevered over time. This study showed reduced cross-sectional growth post-BoNT-A treatment suggesting that re-injections should be postponed at least beyond six months. Future research should extend follow-up periods investigating muscle recovery in the long-term and should include microscopic analysis.     

A型肉毒毒素治疗肌张力过强

目的：探讨Ａ型肉毒毒素局部注射治疗面肌痉挛、各型头颈肌张力障碍的临床疗效和安全性。方法：采用Ａ型肉毒毒素局部多点注射痉挛肌肉,治疗前后对照。结果：治疗面肌痉挛２５０例（１０２８轮次）,有效率１００％,作用持续１６ｗｋ±ｓ４ｗｋ;睑痉挛７８例（２６０轮次）,有效率９３．９％,作用持续１５ｗｋ±４ｗｋ;口颌肌痉挛５３例（１８１轮次）,有效率８５．１％,作用持续１４ｗｋ±４ｗｋ;痉挛性斜颈２８例（７９轮次）,有效率８１％,作用持续１４ｗｋ±４ｗｋ。副作用轻微、可逆。结论：该疗法安全、有效,可作为面肌痉挛及各型头颈部肌张力障碍的首选治疗。     

康复训练结合药物治疗儿童脑瘫的疗效观察

目的：探讨A型肉毒毒素辅助治疗儿童脑瘫的临床价值。方法：将86例双下肢痉挛脑瘫患儿随机分为两组：对照组43例,采用Vojta训练治疗;实验组43例,采用Vojta训练与肌肉注射A型肉毒毒素治疗。观察比较两组患儿的痉挛状况、运动功能及日常生活活动能力。结果：实验组治疗后的综合痉挛评分明显低于对照组（P〈0．05）,实验组治疗后的粗大运动功能D区、E区分值均明显高于对照组（P〈0．05）,实验组治疗后的日常生活活动能力评分明显高于对照组（P〈0．05）。结论：A型肉毒毒素能有效缓解脑瘫患儿的肢体肌肉痉挛,促进运动功能恢复。     

A型肉毒毒素治疗肌张力障碍

A型肉毒毒素因用于高兴奋性肌肉疾病的有效性而倍受神经内科医生的关注,治疗的方法越来越多,治疗的病种不断扩展,被认为是近几年来神经内科领域重要进展之一.本文从A型肉毒毒素历史、药理、方法与剂量、适应证(偏侧面肌痉挛与单纯眼肌痉挛、痉挛性斜颈、Meige综合征、祛皱美容)、毒副作用、禁忌证等几个方面进行综述.     

The Role of Botulinum Toxin Type A in the Clinical Management of Refractory Anterior Knee Pain

Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention. Evidence for long term benefit of most conservative treatments or surgical approaches is currently lacking. Injection of Botulinum toxin type A to the distal region of vastus lateralis muscle causes a short term functional “denervation” which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle. Initial data suggest that, compared with other interventions for anterior knee pain, Botulinum toxin type A injection, in combination with an active exercise programme, can lead to sustained relief of symptoms, reduced health care utilisation and increased activity participation. The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective. Further studies, including larger randomized placebo-controlled trials, are required to confirm the effectiveness of Botulinum toxin type A injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief.     

Influence of Botulinum Toxin Therapy on Postural Control and Lower Limb Intersegmental Coordination in Children with Spastic Cerebral Palsy

Botulinum toxin injections may significantly improve lower limb kinematics in gait of children with spastic forms of cerebral palsy. Here we aimed to analyze the effect of lower limb botulinum toxin injections on trunk postural control and lower limb intralimb (intersegmental) coordination in children with spastic diplegia or spastic hemiplegia (GMFCS I or II). We recorded tridimensional trunk kinematics and thigh, shank and foot elevation angles in fourteen 3–12 year-old children with spastic diplegia and 14 with spastic hemiplegia while walking either barefoot or with ankle-foot orthoses (AFO) before and after botulinum toxin infiltration according to a management protocol. We found significantly greater trunk excursions in the transverse plane (barefoot condition) and in the frontal plane (AFO condition). Intralimb coordination showed significant differences only in the barefoot condition, suggesting that reducing the degrees of freedom may limit the emergence of selective coordination. Minimal relative phase analysis showed differences between the groups (diplegia and hemiplegia) but there were no significant alterations unless the children wore AFO. We conclude that botulinum toxin injection in lower limb spastic muscles leads to changes in motor planning, including through interference with trunk stability, but a combination of therapies (orthoses and physical therapy) is needed in order to learn new motor strategies.     

Ultrasound-Guided Injection of Botulinum Toxin Type A for Piriformis Muscle Syndrome: A Case Report and Review of the Literature

Piriformis muscle syndrome (PMS) is caused by prolonged or excessive contraction of the piriformis muscle associated with pain in the buttocks, hips, and lower limbs because of the close proximity to the sciatic nerve. Botulinum toxin type A (BoNT-A) reduces muscle hypertonia as well as muscle contracture and pain inhibiting substance P release and other inflammatory factors. BoNT-A injection technique is important considering the difficult access of the needle for deep location, the small size of the muscle, and the proximity to neurovascular structures. Ultrasound guidance is easy to use and painless and several studies describe its use during BoNT-A administration in PMS. In the present review article, we briefly updated current knowledge regarding the BoNT therapy of PMS, describing also a case report in which this syndrome was treated with an ultrasound-guided injection of incobotulinumtoxin A. Pain reduction with an increase of hip articular range of motion in this patient with PMS confirmed the effectiveness of BoNT-A injection for the management of this syndrome.     

Pain in Patients with Post Paralytic Hemifacial Spasm: Before,during and after Botulinum Toxin Injections

It is well-established that botulinum toxin (BT) injections improve quality of life in patients with postparalytic hemifacial spasm. Nevertheless, injection-related pain and contracture-related pain have not yet been studied. The primary objective of our study was to evaluate injection-related pain in patients with facial palsy sequelae, and to compare the standard technique (syringe) with the Juvapen device. The secondary objective was to evaluate the improvement of contracture-related pain one month after BT injection. Methods: We conducted an observational, prospective, monocentric study based on 60 patients with facial palsy sequelae who received BT injections in our university ENT (ear, nose throat) department. There were 30 patients in the Juvapen group (J) and 30 in the standard technique group (ST). All patients completed Numerical Rating Scale (NRS) questionnaires immediately after the injections and one month later. Results: The average NRS score was 1.33/10 with Juvapen and 2.24/10 with the standard technique (p = 0.0058; Z = 2.75). In patients with contracture-related pain, the average NRS score was 3.53 before BT injection, and 0.41 one month after BT injection (p = 0.0001). Conclusions: Juvapen is a less-painful injection technique than the standard one. BT reduces contracture-related pain one month after injection.     

Measuring Effects on Pain and Quality of Life after Abobotulinum Toxin A Injections in Children with Cerebral Palsy

Sixty-seven percent of children with cerebral palsy (CCP) experience pain. Pain is closely interrelated to diminished quality of life. Despite this, pain is an overlooked and undertreated clinical problem. The objective of this study was to examine the analgesic effect of a single lower extremity intramuscular injection of Abobotulinum toxin A/Dysport in CCP. Twenty-five CCP with at least moderate pain (r-FLACC ≥ 4) during passive range of motion were included. Localized pain and pain in everyday living were measured by r-FLACC and the Paediatric Pain Profile (PPP), respectively. Functional improvements were evaluated by the goal attainment scale (SMART GAS). Quality of life was evaluated by either the CPCHILD or the CP-QOL. The subjects were evaluated at baseline before injection, then after 4, 12, and 28 weeks. Twenty-two subjects had a significant mean and maximum localized pain reduction (p < 0.001) at four weeks post-treatment in 96% (21/22). The reduction was maintained at 12 (19/19) and 28 weeks (12/15). Daily pain evaluated by the PPP was significantly reduced and functional SMART GAS goals were significantly achieved from 4 to 28 weeks. Quality of life improved significantly at four weeks (CPCHILD). Significant functional gains and localized and daily pain reduction were seen from 4 to 28 weeks.     

Pain Reduction in Adults with Limb Spasticity Following Treatment with IncobotulinumtoxinA: A Pooled Analysis

Some studies have shown that incobotulinumtoxinA reduces spasticity-associated pain, but further evidence is needed. This exploratory analysis pooled pain-relief data from six Phase 2 or 3 studies of incobotulinumtoxinA (four placebo-controlled studies) for treating upper limb spasticity in adults. Spasticity-associated pain was assessed at baseline and 4 weeks post incobotulinumtoxinA injection using the disability assessment scale (DAS) for pain. Only data for patients with pain at baseline were analysed. Overall, 544 (incobotulinumtoxinA, N = 415; placebo, N = 129) of 937 patients (58.1%) experienced pain at baseline. At Week 4, a significantly greater proportion of incobotulinumtoxinA- (52.1%) than placebo-treated patients (28.7%; Chi-square p < 0.0001) showed a response (≥1-point improvement in DAS pain score). In logistic regression analysis, incobotulinumtoxinA-treated patients were 2.6 times more likely to achieve this endpoint than placebo-treated patients. A significant difference between incobotulinumtoxinA and placebo was observed regardless of baseline pain severity. Additionally, 27.1% of incobotulinumtoxinA- versus 12.4% of placebo-treated patients reported complete pain relief at Week 4 (p = 0.0006). Pain relief increased with multiple injection cycles. To achieve patient-centred care, pain relief may be considered a treatment goal in adults with spasticity-associated pain regardless of pain severity. This study contributes to understanding the benefits of incobotulinumtoxinA in treating limb spasticity-associated pain.     

小剂量A型肉毒毒素治疗面肌痉挛

目的 :探讨小剂量 (2 .0U )A型肉毒毒素局部注射治疗面肌痉挛的临床疗效和安全性。方法 :面肌痉挛病人 5 8例 (男性 2 4例 ,女性 34例 ;年龄 4 7a±s 13a)采用A型肉毒毒素 (2 .0U )局部多点注射痉挛肌肉 ,治疗前后对照。结果 :治疗面肌痉挛 5 8例 ,有效率 97% (5 6 /5 8) ,作用持续 15wk± 4wk。副作用轻微、可逆。结论 :小剂量A型肉毒毒素治疗面肌痉挛疗效肯定 ,副作用少     

Ultrasound-Guided Nerve Block with Botulinum Toxin Type A for Intractable Neuropathic Pain

Neuropathic pain includes postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and trigeminal neuralgia, and so on. Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself. Botulinum toxin type A (BoNT-A) has been known for its analgesic effect in various pain conditions. Nevertheless, there are no data of nerve block in PHN and PDN. Here, we report two patients successfully treated with ultrasound-guided peripheral nerve block using BoNT-A for intractable PHN and PDN. One patient had PHN on the left upper extremity and the other patient had PDN on a lower extremity. Due to side effects of drugs, escalation of the drug dose could not be made. We injected 50 Botox units (BOTOX^®, Allergan Inc., Irvine, CA, USA) into brachial plexus and lumbar plexus, respectively, under ultrasound. Their pain was significantly decreased for about 4–5 months. Ultrasound-guided nerve block with BoNT-A may be an effective analgesic modality in a chronic intractable neuropathic pain especially when conventional treatment failed to achieve adequate pain relief.     

Liposome-Encapsulated Botulinum Toxin A in Treatment of Functional Bladder Disorders

Botulinum toxin A (BoNT-A) intravesical injections have been used to treat patients with refractory functional bladder disorders such as overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), but the risk of adverse events and the need for repeated injections continue to prevent widespread application of this treatment. Liposomes are vesicles that comprise concentric phospholipid layers and an aqueous core; their flexible compositions enable them to adsorb and fuse with cell membranes and to deliver drugs or proteins into cells. Therefore, liposomes have been considered as promising vehicles for the less invasive delivery of BoNT-A. In previous placebo-controlled trials including patients with OAB refractory to medical treatment, it was shown that liposomal BoNT-A could significantly decrease the frequency and urgency of urination. In patients with IC/BPS, it was shown that liposomal BoNT-A could also improve bladder pain, but the therapeutic efficacy was not superior to that of the placebo. As the therapeutic mechanisms of BoNT-A include the decreased expression of nerve growth factors, P2X3 receptors, and vanilloid receptors on C-fibers, liposomal BoNT-A might play a more promising role in the treatment of bladder oversensitivity. This article features the contemporary literature regarding BoNT-A, liposomes, and liposomal BoNT-A treatment for functional bladder disorders and potential clinical applications in the future.