Geoffrey Sheean

Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: Results of the first US randomized, double-blind, placebo-controlled study

Botulinum toxin type A (Dysport) has been shown in European studies to be a safe and effective treatment for cervical dystonia. This multicenter, double‐blind, randomized, controlled trial assessed the safety and efficacy of Dysport in cervical dystonia patients in the United States. Eighty patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo. Participants were followed up for 4 to 20 weeks, until they needed further treatment. They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment. Dysport was significantly more efficacious than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10‐point vs. 3.8‐point reduction in total score, respectively, at week 4; P ≤ 0.013). Of participants in the Dysport group, 38% showed positive treatment response, compared to 16% in the placebo group (95% confidence interval, 0.02–0.41). The median duration of response to Dysport was 18.5 weeks. Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport. No participants in the Dysport group converted from negative to positive antibodies after treatment. These results confirm previous reports that Dysport (500 units) is safe, effective, and well‐tolerated in patients with cervical dystonia.

Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement

Upper limb spasticity affecting elbow, wrist, and finger flexors can be safely and effectively reduced with injections of botulinum toxin type‐A (BoNT‐A). It has been best studied in adults in the context of post‐stroke spasticity. The clinical benefits include reduction in pain and deformity, improvement in washing and dressing the upper limb, and a reduction in caregiver burden (Class I evidence, recommendation level A). Some patients show improvement in function performed by active movement of the affected upper limb (Class III evidence, recommendation C), but predicting and measuring this is difficult, and further research is needed. An individually based approach to treatment and outcome measurement is preferred (Class IV, recommendation U). More research is needed to resolve many unknown issues of assessment and treatment, using research methods appropriate to the question.

Botulinum treatment of spasticity: why is it so difficult to show a functional benefit?

Clinical experience seems to indicate that botulinum toxin injections can, in selected patients with upper motor neurone syndrome, reduce spasticity and improve voluntary movement and active function. However, double-blind placebo-controlled trials have had difficulty showing active functional improvement, despite the clear ability of botulinum toxin to reduce spasticity. This prompts a re-analysis of the basic assumption that spasticity impairs voluntary movement and a review of the methodology of the clinical trials. Motor dysfunction is usually caused by weakness and the other ‘negative’ features of upper motor neurone syndrome, rather than muscle overactivity. Recent research has explored the pathophysiological basis of the voluntary movement disorder, in particular the role of the various forms of motor overactivity, which might be amenable to botulinum toxin treatment. The failure of double-blind placebo-controlled clinical trials to show improvement in active function is, to a large extent, a result of their methodology, especially patient selection, injection protocols, and the choice of outcome measures. Clinical trials need to be re-designed and based upon expert experience and a better understanding of the pathophysiology of the motor disorder.

Spastic Hypertonia and Movement Disorders: Pathophysiology, Clinical Presentation, and Quantification

A delayed consequence of a lesion affecting the upper motor neuron pathways is the appearance of some forms of motor overactivity, including spasticity. Many of these are caused by hyperexcitability of spinal reflexes, such as stretch reflexes (spasticity, tendon hyperreflexia) or flexor withdrawal reflexes (flexor spasms), and are elicited at rest by sensory stimulation. Spastic co‐contraction is probably attributable to failure of reciprocal inhibition; it occurs only during active voluntary movement and constrains such movement. The basic underlying mechanism of these changes is not clear, although a change in the balance between the inhibitory and excitatory supraspinal upper motor neuron pathways toward net excitation most likely contributes. Increased intrinsic excitability of the alpha motor neurons is another possible factor. Spastic dystonia is most often seen as the presence of tonic muscle contraction in the absence of voluntary movement or spinal reflex activation, and the underlying mechanisms are obscure. Prolonged shortening of tissues, either because of weakness or muscle contraction, leads to stiffness of the soft tissues, which contributes to hypertonia and is thus self‐perpetuating, and ultimately to contracture with fixed shortening. Some of these forms of motor overactivity produce involuntary movements (hyperkinetic), eg, flexor spasms, whereas others impair movement (hypokinetic), either voluntary movement, eg, spastic co‐contraction, or passive movement, eg, spasticity. Quantification has mostly focused on hypertonia, that is, increased resistance at rest to passive movement. In the upper motor neuron syndrome, hypertonia could be caused by a combination of spasticity, spastic dystonia, and soft tissue stiffness (rheologic changes). Some measures, such as the Ashworth or Modified Ashworth Scales, quantify hypertonia but are very poor at distinguishing between spasticity and soft tissue stiffness. Another, the Tardieu Scale, is better at making this distinction, but quantification of the spasticity portion of hypertonia remains difficult, at least in a clinical setting.

Botulinum toxin treatment of adult spasticity : a benefit-risk assessment.

Injections of botulinum toxin have revolutionised the treatment of focal spasticity. Before their advent, the medical treatment for focal spasticity involved oral antispasticity drugs, which had decidedly non-focal adverse effects, and phenol injections. Phenol injections could be difficult to perform, could cause sensory complications and had effects that were of uncertain duration and magnitude. Furthermore, few neurologists knew how to perform them as they were mostly the province of rehabilitation specialists. Botulinum toxin can produce focal, controllable muscle weakness of predictable duration, without sensory adverse effects.Randomised clinical trials (RCTs) involving patients with spasticity resulting f r om a variety of diseases (mainly stroke and multiple sclerosis) have clearly shown that botulinum toxin type A (Dysport® and Botox®) can temporarily (for approximately 3 months) reduce spastic hypertonia in the elbow, wrist and finger flexors of the upper limbs, and the hip adductors and ankle plantarflexors in the lower limbs. The clinical benefits from this reduction of neurological impairment are best shown in the upper limb, with less disability of passive function and reduced caregiver burden. In the lower limbs, there is improved perineal hygiene from hip adductor injections. The benefits of reducing ankle plantarflexor tone are less well established. Pain is also reduced, possibly by mechanisms other than muscle weakness. Improved active function has not yet been clearly demonstrated in RCTs, only in open-label trials. The safety of botulinum toxin-A is impressive, with minimal (mainly local) adverse effects.There are little data on the use of botulinum toxin type B (Myobloc® or Neurobloc®) in spasticity and the only RCT that has examined this did not show tone reduction; dry mouth appeared to be a very common adverse effect. There are also very little data to allow a benefit-risk comparison of phenol and botulinum toxin injections; each have their clinical and technical advantages and disadvantages, and phenol is much less costly than botulinum toxin.

International consensus statement for the use of botulinum toxin treatment in adults and children with neurological impairments – introduction

Botulinum neurotoxin (BoNT) is most commonly used to reduce focal over‐activity in skeletal muscle, although newer indications such as management of drooling, pain and tremor are emerging. Treatment of spasticity incorporating BoNT is usually part of an integrated multidisciplinary rehabilitation programme. Prior to initiating this therapy, specific functional limitations, goals and expected outcomes of treatment should be discussed with the patient/carers. Muscle selection and the order/priority of treatment should be agreed. Treatment goals may involve increasing active or passive function or the avoidance of secondary complications or impairment progression. This paper describes the basic science mechanisms of the action of BoNT and subsequent nerve recovery and introduces a supplement comprising the best available evidence and expert opinion from international panels on questions of assessment, indications, BoNT regimen, adjunctive therapy, expected outcomes and recommended monitoring. Speciality areas reviewed include Paediatric Lower Limb Hypertonicity, Paediatric Upper Limb Hypertonicity, Adult Lower Limb Hypertonicity, Adult Upper Limb Hypertonicity, Cervical Dystonia, Drooling and Pain and Niche Indications. There is good quality scientific evidence to support the efficacy of BoNT to reduce muscle over‐activity in the limbs secondary to central nervous system disorders in adults and children, to address primary or secondary cervical dystonia, to reduce saliva flow and to treat some pain syndromes. There is emergent evidence for the efficacy of BoNT to reduce focal tremor, to treat other types of pain including neuropathic pain and also to improve function following treatment of focal muscle over‐activity.

Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate

Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment.

Response of the dropped head/bent spine syndrome to treatment with intravenous immunoglobulin.

Weakness of neck extension causing a dropped head may result from many neuromuscular disorders. One etiology is isolated neck extensor myopathy. A similar focal myopathy of the lower axial muscles may cause the bent spine syndrome, which manifests as flexion of the trunk and inability to stand upright. Combination of both dropped head and bent spine myopathies is uncommon. Inflammation is usually not pronounced in these conditions and response to immunosuppressive treatment is rare. We present an 81‐year‐old man who developed progressive weakness of neck and trunk extension over several months, with a prominent inflammatory process in the thoracic paraspinal muscles, which responded dramatically to treatment with intravenous immunoglobulin (IVIg). This case, together with other rare reports, suggests that the presence of inflammation in the biopsy of an affected muscle may predict treatment response. Muscle Nerve, 2006

Botulinum toxin assessment, intervention and aftercare for paediatric and adult niche indications including pain: international consensus statement

Evidence is emerging for the use of botulinum neurotoxin type‐A (BoNT‐A) for niche indications including pain independent of spasticity. Pain indications such as chronic nociceptive back pain, piriformis syndrome, chronic myofascial pain, pelvic pain, complex regional pain syndrome, facial pain and neuropathic pain are outlined in this paper. Of these, class I evidence is available for the treatment of chronic nociceptive low back pain, piriformis syndrome, myofascial pain, facial pain, neuropathic pain and plantar fasciitis. Peri‐operative use of BoNT‐A is emerging, with indications including planning for surgery and facilitating surgery, as well as healing and improving analgesia post‐operatively. Evidence is limited, although there are some reports that clinicians are successfully using BoNT‐A peri‐operatively. There is class I evidence showing pre‐operative use of BoNT‐A has a beneficial effect on outcomes following adductor‐release surgery. The use of BoNT for treatment of tremor, other than neck tremor in the setting of cervical dystonia, including evidence for upper limb tremor, cranial tremor and non‐dystonic neck tremor is reviewed. The evidence is variable at this stage, and further study is required to develop definitive recommendations for the clinical utility of BoNT‐A for these indications.

Quantification of motor unit action potential energy

OBJECTIVE Motor unit action potentials (MUAPs) recorded by needle electrode reflect the functional state of the motor unit and its force-generating capacity, and are usually described morphologically (e.g. amplitude, duration). However, since the purpose of motor unit activation is force generation, MUAP energy seems a more physically meaningful measurement. METHODS MUAPs were obtained by multi-MUAP decomposition of real interference patterns taken from human patients with neurological diseases. The energy content of each MUAP was measured from a time-frequency representation (TFR), specifically the Choi-Williams distribution, and compared with the standard MUAP morphological measure, the Size Index. The sample included normal, neurogenic, and myopathic MUAPs, from 11 patients. RESULTS There is an exponential distribution of energy within a sample of MUAPs and a strong exponential relationship between the Size Index and MUAP energy was observed. CONCLUSIONS The energy content of a MUAP can be quantified and corresponds very well with the current quantitative standard. Energy is a possible addition to MUAP quantification. SIGNIFICANCE MUAPs could be classified as having normal, large (neurogenic), or low (myopathic) energy. MUAP energy has direct physical and physiological meaning that reflects the force-generating capacity of the motor unit. Time-frequency analysis could also be used to study the specific frequency content of MUAPs and the energy of MUAPs within an interference pattern, without the need for decomposition.