Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I-IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. RESULTS: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). RECOMMENDATIONS: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Clenbuterol in the prevention of muscle atrophy: a study of hindlimb-unweighted rats.

OBJECTIVE: To determine whether the administration of clenbuterol, a beta2-adrenergic agonist, prevents loss of muscle mass during a period of imposed inactivity. DESIGN: Randomized trial. SETTING: Basic laboratory research. ANIMALS: Thirty Fischer 344 Brown Norway F1 Hybrid rats, 12 and 30 months of age. INTERVENTIONS: The rats were randomly assigned to a control group, or to 1 of 2 experimental groups: hindlimb unweighted for 2 weeks (HU-2), or hindlimb unweighted with daily injections of clenbuterol for 2 weeks (HU-2Cl). MAIN OUTCOME MEASURES: Muscle mass weighed in milligrams and single fiber cross-sectional area histochemically evaluated. RESULTS: In both age groups, the HU-2 animals had greater muscle atrophy (decrease in muscle mass) in the soleus muscle than the extensor digitorum longus (EDL) muscle. In the HU-2Cl groups, the decline in muscle mass of both the soleus and EDL muscles was attenuated by about 4% to 20%. In the HU-2 group, single fiber cross-sectional area decreased for both fiber types (type I, 20%-40%; type II, 37%-50%) in both age groups. Clenbuterol retarded the inactivity-induced decline in single fiber cross-sectional area by 12% to 50%. In the EDL muscles of the HU-2Cl group, we found hypertrophy in both fiber types in the 30-month-old animals and in type I fibers in the 12-month-old animals. CONCLUSIONS: Clenbuterol attenuated the decrease in muscle mass and single fiber cross-sectional area in both age groups. By preventing the loss of muscle mass, clenbuterol administered early in rehabilitation may benefit severely debilitated patients imposed by inactivity. The attenuated muscle atrophy found with clenbuterol in the present study provides cellular evidence for the reported change in muscle strength after its administration after knee surgery. Thus, the administration of clenbuterol may lead to a more rapid rate of rehabilitation.

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). BACKGROUND: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. METHODS: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. RESULTS: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. CONCLUSION: Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.

Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

Central nervous system ischemia after varicella infection and desmopressin therapy for enuresis.

A 7-year-old boy had a left-sided cerebrovascular accident 48 hours after beginning intranasal desmopressin acetate (DDAVP) therapy for persistent secondary nocturnal enuresis and approximately 2 weeks after varicella infection. A possible connection between desmopressin therapy or varicella infection (or both) and the patients neurologic symptoms is discussed, as is the relationship of desmopressin with hypercoagulability, Suggestions for patient/parent education, medical history taking, and patient surveillance are offered to prescribing physicians.

A functional electric stimulation system using an electrode garment.

A functional electric stimulation system for standing and ambulating that uses a commercially available electrode garment has been developed. The garment allows electrodes to be applied rapidly and securely. Two channels of a four-channel stimulator are used to stimulate the quadriceps muscles and permit the user to stand. The other two channels are used to stimulate the peroneal nerve, which causes a flexor withdrawal reflex and permits stepping. The user controls stepping by hand-held switches. The system provides a means for standing, exercising, and limited ambulation.

Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study.

The ability of botulinum A toxin to denervate and relax a spastic external urethral sphincter was evaluated in a double-blind study involving five men with high spinal cord injuries and detrusor-sphincter dyssynergia. The sphincter was injected with either a low dose of botulinum A toxin or normal saline once per week for three weeks. Electromyography of the external urethral sphincter indicated denervation in the three patients who received toxin injections. The urethral pressure profile decreased an average of 25cm of water, postvoiding residual volume of urine decreased an average of 125cc, and bladder pressure during voiding decreased to an average of 30cm of water. Bulbosphincteric reflexes were more difficult to obtain, and they showed a decreased amplitude with normal latency. In the two patients who received normal saline injections, parameters were unchanged from baseline values until subsequent injection with botulinum A toxin once per week for three weeks when their responses were similar to those of the other three patients. Mild generalized weakness lasting two to three weeks was noted by three patients after initial toxin injections. The duration of the toxin's effect averaged two months. The results suggest that botulinum A toxin, an inhibitor of acetylcholine release at the neuromuscular junction, may be useful in the treatment of detrusor-sphincter dyssynergia.

Augmentation enterocystoplasty for the management of voiding dysfunction in spinal cord injury patients.

A total of 12 spinal cord injury adults underwent augmentation enterocystoplasty for treatment of a high pressure neurogenic bladder. These patients suffered from urinary incontinence, recurrent urinary tract infection, upper tract deterioration and severe autonomic dysreflexia. A sigmoid colon segment fashioned into a cup-patch was used in 11 patients and detubularized cecum was used in 1. The artificial urinary sphincter was implanted in 3 patients at augmentation enterocystoplasty and in 1 after enterocystoplasty. After a mean followup of 15 months all patients were continent on clean intermittent self-catheterization, the upper tract had remained stable or had improved and the symptoms of autonomic dysreflexia had disappeared. A third of the patients are on maintenance antibiotic therapy to control bacteriuria.

Pediatric rehabilitation. 1. General principles and special considerations.

This self-directed learning module addresses core concepts in the assessment of any child with disability, including physical growth and development, evolution of reflexes, and cognitive and personality development. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. The rehabilitation perspective is emphasized, especially as it changes to accommodate the developing child, with a focus on specific chronic disorders such as respiratory disease, congenital heart disease, and malignancy. These types of disorders serve as a model for the management of problems that require special medical, rehabilitative, and psychosocial consideration.

Pediatric rehabilitation. 2. Brain damage causing disability.

This self-directed learning module addresses rehabilitation issues in the child with brain damage. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. In addition to the motor manifestations, intellectual, social, and emotional impairment are addressed. Problems vary with developmental stage. Emphasis is on the etiology, severity, and combination of deficits in order to develop a plan of management, including physical, occupational, and speech therapy, recreational and social milieu, and family and community resources.

Pediatric rehabilitation. 3. Disorders of the spinal cord: spinal cord injury, myelodysplasia.

This self-directed learning module provides review and references for the basic concepts of, and highlights new advances in, disorders of the spinal cord in children. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. For spinal cord injury, only data pertinent to the pediatric age group are discussed. Myelodysplasia is presented in detail to include genetic implications, early intervention, long-term management planning, psychosocial impact, and quality-of-life considerations.

Pediatric rehabilitation. 4. Disorders of the motor unit.

This self-directed learning module addresses diagnostic and rehabilitation issues in children with the most common disorders of the motor unit. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. Conditions occurring only in infancy or childhood and differences in diagnostic and rehabilitation approaches as compared with those used in adults are highlighted.

Pediatric rehabilitation. 5. Joint and connective tissue diseases.

This self-directed learning module presents pertinent information about rehabilitation management of specific joint and connective tissue diseases affecting children. This section highlights juvenile rheumatoid arthritis, Lyme disease, rheumatic fever, hemophilia, dermatomyositis, polymyositis, systemic lupus erythematosus, and other forms of arthritis. It is a section of the chapter of pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation.

Pediatric rehabilitation. 6. Musculoskeletal and soft tissue disorders.

This self-directed learning module highlights advances in evaluation and treatment of congenital and acquired musculoskeletal disorders in the child. It is a section of the chapter on pediatric rehabilitation for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This section contains information on alterations of limb structure and gait, scoliosis, torticollis, sports injuries and overuse syndromes, and unexplained pain in children.

Bethanechol supersensitivity test, rhabdosphincter electromyography and bulbocavernosus reflex latency in the diagnosis of neuropathic detrusor areflexia.

A total of 57 patients with neuropathic or nonneuropathic detrusor areflexia was studied with the bethanechol supersensitivity test, electromyography of the urethral rhabdosphincter and bulbocavernosus reflex latency. The sensitivity of these tests in detecting neuropathic areflexia was 90, 87.5 and 78.1 per cent, respectively, and the specificity was 95.6, 76 and 80 per cent, respectively. When all 3 tests were performed together the combined accuracy approached 100 per cent. These combined tests are useful in the diagnosis of patients with equivocal bladder neuropathic conditions and in those with subtle neurological lesions.

Increased current delivery and sperm collection using nifedipine during electroejaculation in men with high spinal cord injuries.

Elevated blood pressure associated with autonomic hyperreflexia during electroejaculation in persons with high spinal cord injuries often prevents successful sperm retrieval. The ability of the calcium channel blocker nifedipine to reduce the effects of autonomic hyperreflexia, to facilitate greater current delivery, and to increase sperm collection was evaluated in six persons with spinal cord injuries. Ten milligrams of nifedipine given sublingually ten to 15 minutes before electroejaculation attempts helped to moderate autonomic hyperreflexia and the associated blood pressure elevations. These effects of nifedipine allowed greater current delivery and ultimately increased the chances of successful sperm retrieval in the six men. No adverse drug effects were observed.

Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients.

We evaluated the ability of low doses of botulinum A toxin, an inhibitor of acetylcholine release at the neuromuscular junction, to denervate and relax the spastic rhabdosphincter in 11 men with spinal cord injury and detrusor-sphincter dyssynergia. Toxin concentration, injection volume, percutaneous versus cystoscopic injection of the sphincter and number of injections were evaluated in 3 treatment protocols. All 10 patients evaluated by electromyography after injection showed signs of sphincter denervation. Bulbosphincteric reflexes in the 10 patients evaluated after injection were more difficult to obtain, and they showed a decreased amplitude and normal latency. The urethral pressure profile in the 7 patients in whom it was measured before and after treatment decreased an average of 27 cm. water after toxin injections. Post-void residual urine volume decreased by an average of 146 cc after the toxin injections in 8 patients. In the 8 patients for whom it could be determined toxin effects lasted an average of 50 days. The toxin also decreased autonomic dysreflexia in 5 patients.

The effect of nifedipine on cystoscopy-induced autonomic hyperreflexia in patients with high spinal cord injuries.

We evaluated the ability of the calcium channel blocker nifedipine to control autonomic hyperreflexia during cystoscopy in 7 patients with cervical spinal cord injuries. Nifedipine (10 mg.) alleviated autonomic hyperreflexia when given sublingually during cystoscopy and prevented autonomic hyperreflexia when given orally 30 minutes before cystoscopy. No adverse drug effects were observed.

Vasoactive intracavernous pharmacotherapy for the treatment of erectile impotence in men with spinal cord injury.

A total of 66 spinal cord injury patients with erectile dysfunction entered a protocol of penile intracavernous pharmacotherapy with papaverine hydrochloride (30 mg. per ml.) or a combination of papaverine (25 mg. per ml.) and phentolamine mesylate (0.83 mg. per ml.) in an attempt to restore erectile function. Of the patients 52 completed the protocol and all achieved transient functional penile erections after administration of the drug. Of the 52 responders 71 per cent currently practice self-injection as a method to restore erectile function. Sustained erections that required irrigation of the cavernous bodies with alpha-adrenergic agents developed in 4 patients and 1 suffered localized intracorporeal induration. If the long-term followup shows that complications remain relatively minor, undoubtedly vasoactive intracavernous pharmacotherapy will have a major role in the restoration of erectile function in the motivated man with spinal cord injury. However, in view of the unknown long-term effects and potential dangers of this approach it is important that patients adhere to a strict drug injection protocol under the supervision of qualified urologists who are familiar with the potential risks and complications.

The value of urodynamic testing in the management of neonates with myelodysplasia: a prospective study.

We report the results of a prospective study conducted to identify neonates with myelomeningocele at risk for changes in the upper urinary tract. Thirty newborns underwent full urological evaluation and were followed for a mean period of 18.2 months. The initial studies included voiding cystourethrography, excretory urography and urodynamic tests. Followup consisted of periodic radiographic studies and repeat urodynamic testing if any changes were observed. According to urodynamic findings the patients were divided into 2 groups: group 1 consisted of 9 neonates (30 per cent) with detrusor-sphincter dyssynergia and high pressure, decreased-compliance bladders, and group 2 consisted of 21 children (70 per cent) with atonic bladders and low pressure, reduced-compliance bladders without dyssynergia. In group 1, 55 per cent of the patients had initially abnormal radiographic findings in contrast with 28.5 per cent in group 2. Anticholinergic drugs and clean intermittent catheterization or vesicostomy reversed the changes in 40 per cent of the children in group 1, 40 per cent remained stable and 20 per cent showed signs of deterioration. Four children in group 1 with normal neonatal radiographs were treated expectantly and at followup they all showed signs of deterioration. The neonates in group 2 with normal radiographic findings remained normal at followup. Of those who initially had changes 67 per cent reversed to normal without treatment, 17 per cent remained stable and 17 per cent had deterioration. Newborns with detrusor-sphincter dyssynergia or high pressure, reduced-compliance bladders are at high risk of having upper urinary tract changes and require preventive decompressive treatment. Children with atonic or low pressure, reduced-compliance bladders and those with a coordinated bladder and sphincter are at low risk and need only close followup.