The external anal sphincter operates at short sarcomere length in humans.

BACKGROUND: The length at which a muscle/sarcomere operates in vivo (operational length) and the length at which it generates maximal stress (optimal length) can be quite different. In a previous study, we found that the rabbit external anal sphincter (EAS) operates on the ascending limb of the length-tension curve, in other words at lengths shorter than its optimal length (short sarcomere length). In this study, we tested whether the human EAS muscle also operates at a short sarcomere length. METHODS: The length-tension relationship of the EAS muscle was studied in vivo in 10 healthy nullipara women. EAS muscle length was altered by anal distension using custom-designed probes of 5, 10, 15, and 20mm diameter. Probes were equipped with a sleeve sensor to measure anal canal pressure. The EAS muscle electromyograph (EMG) was recorded using wire electrodes. Ultrasound images of anal canal were obtained to measure EAS muscle thickness and anal canal diameter. EAS muscle stress was calculated from the anal canal pressure, inner radius, and thickness of the EAS muscle. KEY RESULTS: Rest and squeeze stress of the anal canal increased with the increase in probe size. Similarly, the change in anal canal stress, i.e. the difference between the rest and the squeeze, which represents the active contribution of EAS to the anal canal stress, increased with the increase in probe size. However, increase in probe size was not associated with an increase in the external anal sphincter EMG activity. CONCLUSIONS & INFERENCES: Increase in EAS muscle stress with the increase in probe size, in the presence of constant EMG (neural input), demonstrates that the human EAS muscle operates on the ascending limb of the length-tension curve or at low sarcomere lengths. We propose that surgically adjusting EAS sarcomere length may represent a novel strategy to treat fecal incontinence in humans.

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.

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 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.

The pathophysiology of spasticity.

Spasticity is only one of several components of the upper motor neurone (UMN) syndrome, known collectively as the 'positive' phenomena, that are characterized by muscle overactivity. Other components include tendon hyper-reflexia, clonus, the clasp-knife phenomenon, flexor and extensor spasms, a Babinski sign, and spastic dystonia. Spasticity is a form of hypertonia due to hyperexcitable tonic stretch reflexes. It is distinguished from rigidity by its dependence upon the speed of the muscle stretch and by the presence of other positive UMN signs. Hyperactive spinal reflexes mediate most of these positive phenomena, while others are due to disordered control of voluntary movement or abnormal efferent drive. An UMN lesion disturbs the balance of supraspinal inhibitory and excitatory inputs, producing a state of net disinhibition of the spinal reflexes. These include proprioceptive (stretch) and nociceptive (flexor withdrawal and extensor) reflexes. The clinical syndrome resulting from an UMN lesion depends more upon its location and extent, and the time since it occurred, than on the pathology of the lesion. However, the change in spinal reflex excitability cannot simply be due to an imbalance in supraspinal control. The delayed onset after the lesion and the frequent reduction in reflex excitability over time, suggests plasticity in the central nervous system. Knowledge of the electrophysiology and neurochemistry of spinal reflexes, together with the action of antispasticity drugs, helps us to understand the pathophysiology of spasticity.

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.

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.

Evaluating the role of botulinum toxin in the management of focal hypertonia in adults.

OBJECTIVES: To investigate the effects of EMG guided botulinum toxin (BTX-A) on impairment and focal disability in adults presenting with focal hypertonia. METHODS: A prospective, randomised, double blind, placebo controlled, parallel group trial was carried out with standardised assessment before and at 3 week intervals until 12 weeks after injection, in patients with focal hypertonia affecting upper or lower limbs. Botulinum toxin or placebo was injected with EMG guidance after multidisciplinary assessment. The modified Ashworth scale of spasticity, percentage passive range of joint motion, subjective rating of problem severity, the Rivermead motor assessment scale, a timed 10 metre walk (lower limb patients), nine hole peg test (upper limb patients), and a modified goal attainment scale were used as outcome measures. The patients were 52 adults; 34 male, 18 female; mean age 40.31, range 16-79 years; mean duration of symptoms 35 months (range 3 months to 22 years). Diagnoses included cerebrovascular accidents (23), head injury (12), incomplete spinal cord injury (six), tumour (five), cerebral palsy (three), and anoxic episodes (three). RESULTS: For each variable an overall score for the treatment period was computed by summing the scores from the 3, 6, 9, and 12 week assessments. These overall scores were significantly better in the treated group for the Ashworth scale, percentage passive range of movement, Rivermead lower limb, and subjective rating of problem severity. The significant treatment effect on the Ashworth scale was seen on analysis of variance (ANOVA) at 3 weeks and the subjective rating of problem severity at 3 and 6 weeks. The goal attainment scale score in both groups was similar at 12 weeks. CONCLUSION: Selective use of botulinum toxin to weaken muscles can lead to a reduction in resistance to passive movement about a distal limb joint. This allows for improvements in passive range of movement and focal disability, particularly in patients presenting with focal spasticity of the lower limb.

Changes of somatosensory evoked potentials preceding rapid voluntary movement in Go/No-go choice reaction time task.

To elucidate the sensorimotor mechanisms in preparation of voluntary movement, we examined the changes of the somatosensory evoked potentials (SEPs) following median nerve stimulation in Go/No-go choice-reaction time task. Eleven normal subjects performed extension of the middle finger according to the Go signal while they did not make any movement and relaxed on the No-go and Control signals, respectively. Each signal was randomly presented on a computer screen in front of the subject. Single pulse stimulation was applied to the right median nerve at 150 ms after the response signal in each Go/No-go and Control sequence so as to be just before the voluntary movement in the Go sequence. The SEPs were recorded from F3, C3' (midpoint between P3 and C3) and P3 on the left hemisphere. In comparison with the Control sequence, the amplitude of N20 and P25 recorded from C3' and P3 was significantly attenuated before movement in the Go sequence (P<0.02, ANOVA with Bonferroni-Dunn post hoc procedure). On the other hand, the parietal N33 and frontal N30 were attenuated in both Go and No-go sequences (P<0.02). None of the SEP components were changed when the stimulus was delivered before the response signal. We speculate that the attenuation of N20 was linked with the activation of the motor cortex followed by the actual movement. The attenuation of other components up to 33 ms after stimulus were considered to be more related to the preparation or the attention to the voluntary movement than to the movement itself.

Abnormal motor unit synchronization of antagonist muscles underlies pathological co-contraction in upper limb dystonia.

The aim of this study was to examine the pathophysiological mechanisms underlying co-contraction in patients with dystonia (n = 6) and writer's cramp (n = 5). Multi-unit needle and surface EMGs were recorded from extensor carpi radialis (ECR) and flexor carpi radialis (FCR) muscles during motor tasks that elicited dystonia or writer's cramp. The EMGs from ECR and FCR were recorded simultaneously and analysed using cross-correlation analysis. Similar recordings were obtained from healthy age- and sex-matched control subjects (n = 8). Despite co-contraction of the muscles, cross-correlograms from the healthy subjects did not reveal evidence of motor unit synchronization. Cross-correlograms from the dystonic subjects revealed a central peak with a median duration of 37 ms, indicating broad-peak motor unit synchronization. Cross-correlograms from patients with writer's cramp were either flat or modulated by a 11-12-Hz tremor. Frequency-domain analysis of ECR and FCR EMGs demonstrated significant coherence in the patients with dystonia and writer's cramp. These results indicate that co-contraction in dystonia is neurophysiologically distinct from voluntary co-contraction and is produced by abnormal synchronization of presynaptic inputs to antagonist motor neuron pools. ECR and FCR co-contraction in writer's cramp may be a compensatory process under voluntary control.

An open-labelled clinical and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple sclerosis.

We studied the electrophysiological parameters of motor performance in eight patients with multiple sclerosis and troublesome fatigue, before and after treatment with 3,4-diaminopyridine. Symptomatic fatigue was evaluated by the Krupp Fatigue Severity Score and motor performance of adductor pollicis by transcranial magnetic stimulation, rapid voluntary movements and a fatiguing exercise test of a sustained 45-s isometric contraction. The motor tests revealed baseline abnormal motor function and substantial central fatigue. After a 3-week course of 3,4-diaminopyridine (25-60 mg/day), six out of the eight patients reported substantial improvement in fatigue and the group showed slightly less fatigue on the exercise test. Other electrophysiological tests of motor function were unchanged. The findings suggest that 3,4-diaminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. However, the mechanism behind such a benefit in fatigue remains unclear and the discrepancy between subjective and more objective responses underlines the probable multifactorial nature of the pathogenesis of this symptom in multiple sclerosis.

Further studies using higher doses of botulinum toxin type F for torticollis resistant to botulinum toxin type A.

OBJECTIVE: A previous study of botulinum toxin type F (BTX-F) treatment for torticollis had shown a dose of 520 MU to be effective, but for a much shorter duration than is usual with botulinum toxin type A (BTX-A). The objective was to assess the effect of a higher dose of BTX-F. METHODS: Four of the previously treated patients, plus an additional patient, were treated with a higher dose of 780 MU BTX-F. All were secondary nonresponders to BTX-A due to neutralising antibodies. A test injection of 40 MU BTX-F was also given into the extensor digitorum brevis muscle (EDB), to examine the time course of the biological effect of the toxin electrophysiologically. Patients were followed up at two, four, eight, and 12 weeks. RESULTS: All patients reported subjective improvement lasting from seven to 11 (mean 8.6) weeks accompanied by a significant reduction in mean clinical severity scores at two weeks. Four patients had pain which was substantially reduced. The electrophysiological studies confirmed biological sensitivity to the toxin in all patients, showing a significant change beginning at two weeks and returning to baseline at 12 weeks. The time course of this effect paralleled roughly that of the clinical response. The four patients who had previously received 520 MU BTX-F reported that the response was better and longer in duration with 780 MU. Dysphagia was more common than reported with the lower dose. CONCLUSION: Better results are possible with higher doses of BTX-F but the duration of benefit is still shorter than with BTX-A, seemingly due to a shorter duration of neuromuscular junction blockade.

The effect of botulinum toxin on hand function after incomplete spinal cord injury at the level of C5/6: a case report.

OBJECTIVE: To investigate the benefits of the focal use of botulinum toxin in spasticity in the forearm seen after incomplete spinal cord injury. DESIGN: A single case study with standardized assessment before and at three-week intervals after injection. INTERVENTION: EMG-guided selective injection of botulinum toxin. SUBJECT: A 23-year-old man, 18 months post injury. MEASURES: Rivermead Motor Assessment; grip strength; Jebsen hand tests; visual analogue scale; Ashworth spasticity scale. RESULTS: Weakness was seen as expected with some functional losses, but the patient made gains in the areas of concern: shaking hands, typing, using the hand to drink. These gains were sustained at 12 weeks. CONCLUSION: Selective use of botulinum toxin to weaken muscles can lead to functional benefit.

Botulinum toxin does not reverse the cortical dysfunction associated with writer's cramp. A PET study.

Previous H2(15)O PET activation studies on patients with idiopathic torsion dystonia (ITD) have shown overactive striatum and frontal accessory areas and underactivity of the primary motor cortex and caudal supplementary motor area (SMA) during volitional movement. We have now examined activation of the motor system in healthy control subjects and patients with writer's cramp while they write a stereotyped word repetitively at a paced rate before and after treatment with botulinum toxin to see if these patients showed a similar pattern of abnormalities and whether they were reversible. As in ITD, our patients with writer's cramp showed impaired activation of the contralateral primary motor cortex, but enhanced activation of frontal association cortex. Botulinum-toxin treatment improved writing and increased activation in parietal cortex and caudal SMA. This may represent either a change in movement strategy or associated cortical reorganization secondary to deefferentation of alpha motor neurons. However, botulinum toxin failed to improve the impaired activation of the primary motor cortex. We conclude that, while botulinum toxin is clinically effective in writer's cramp, it does not reverse the associated dysfunction of primary motor and premotor cortex.

An electrophysiological study of the mechanism of fatigue in multiple sclerosis.

Fatigue is a common and disabling symptom in multiple sclerosis but is poorly understood. We investigated 'physiological' fatigue in 21 patients with multiple sclerosis who complained of disabling fatigue by measuring the decline in strength during a 45 s maximal contraction of the adductor pollicis muscle. The results were compared with those from a control group of 19 healthy subjects. The strength of control subjects declined by approximately 20% during the contraction; twitch interpolation showed central drive remained almost maximal throughout, and therefore that the fatigue was peripheral in origin. Patients had normal baseline strength, but developed greater fatigue (approximately 45%), which was central in origin. In both cases, the decline in strength followed a roughly linear time course suggesting that the patients, like the normals, were trying to maintain a maximum voluntary effort. Evidence for frequency-dependent conduction block (FDCB) in the patients' central motor pathways was sought by measuring the EMG responses to single and paired transcranial magnetic stimuli. Fatigue had no effect on the latency or size of EMG responses to transcranial magnetic stimulation, suggesting that FDCB was unlikely to have occurred. This was supported by measurements of the maximum speed of voluntary muscle contraction; although the patients showed relatively slow speeds before exercise, the decline in speed after fatigue was no greater than in normal subjects. We conclude that excessive 'physiological' fatigue contributes to the symptom of fatigue in multiple sclerosis and is central in origin. However, since the degree of exercise-induced fatigue did not correlate with the baseline complaint of fatigue, other factors must also be operating to produce the full range of clinical symptoms. We found no conclusive evidence that central fatigue is related to increased dysfunction in the primary central motor pathways and no evidence that FDCB is the pathophysiological mechanism. We postulate that central fatigue in multiple sclerosis is due to impaired drive to the primary motor cortex and several lines of evidence strongly suggest that this is not due to a lack of motivation.

A double-blind, placebo-controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures.

The efficacy and tolerability of vigabatrin as add-on therapy was assessed in patients with uncontrolled partial seizures. Ninety-seven patients entered this seven-centre, double-blind, placebo-crossover study. Vigabatrin (2 g or 3 g) or placebo was administered daily. Vigabatrin was well-tolerated and did not cause clinically significant adverse drug effects when added to established anticonvulsant therapy. No significant differences were observed between dose groups for the overall incidence of adverse events, although drowsiness and visual disturbances (diplopia, ataxia, visual abnormalities) showed a dose-related increase with vigabatrin treatment. The results of this study indicate that vigabatrin, given in a daily dose of either 2 g or 3 g is significantly more effective than placebo in reducing seizure frequency among patients with partial seizures.