Dennis D. Dykstra

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.

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.

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.

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.

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.

Long Term Effects of Intra-articular Botulinum Toxin A for Refractory Joint Pain

The purpose of this case series review is to describe our 12 month clinical experience with intra-articular injections of Botulinum toxin Type A (BoNT/A) for refractory joint pain. Eleven patients with chronic arthritis who had failed treatment with oral and/or intra-articular medications and were not surgical candidates were referred to us for management of moderate to severe refractory joint pain in 15 joints. The use of BoNT/A to treat joint pain is a non-FDA approved “off label” treatment with potential side effects. After a detailed explanation of the joint injection procedure, signed informed consent was obtained for the procedure. Fifteen joints were injected with BoNT/A (Allergan, Inc): six lower extremity joints (3 knees, 3 ankles) with 25-50 units and nine shoulders with 50-100 units. Patients were followed for one year or longer. Maximum relief of pain was measured by comparing baseline pain on a numeric rating scale (0-10) to pain at the time of maximum relief (paired t-test). Maximum improvement in function was assessed using paired t-tests for improvement in active flexion and abduction for the shoulder joint, and by the time to perform sit to stand ten times (the timed stands test, TST) for the lower extremity joints.Results: Two patients were female and nine were male, aged 42-82 years. Five had osteoarthritis (OA), five had rheumatoid arthritis (RA) and one had psoriatic arthritis. All patients were on analgesic and/or anti-inflammatory medications and all joints had previous intra-articular steroid or viscosupplement injections with inadequate or unsatisfactory benefit. A clinically and statistically significant improvement was noted after IA-BoNT/ A injections. The mean maximum decrease in lower extremity joint pain was 55% (p =0.02) and the 36% (p =0.044) improvement in the Timed Stands Test was noted at four to ten weeks after injection. There was a 71% mean maximum reduction in shoulder pain severity from 8.2 ± 1.1 to 2.4 ± 1.9 (p <0.001). Active range of motion increased 67% in flexion (from 67.8 ± 27.6 to 113.3 ± 46.6 degrees, p =0.001) and 42% in abduction (from 50 18.5 degrees to 71.1 ± 23.1 degrees p =0.01). No immediate or delayed adverse effects related to BoNT/A were noted after the injection. Duration of pain relief was variable and ranged from 3 to 12 months. Five joints were re-injected with IA-BoNT/A and had a similar decrease in joint pain that lasted 3 to 12 months. Conclusions: This is the first report of the long term effects of intra-articular BoNT/A injections to treat chronic joint pain and the efficacy of repeated injections. Although this study was small, and uncontrolled the results suggest that IA-BoNT/ A injections are an effective and safe treatment for chronic joint pain disorders.

The Effect of Nifedipine on Cystoscopy-Induced Autonomic Hyperreflexia in Patients with High Spinal Cord Injuries

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

Efficacy of Intra-Articular Botulinum Toxin Type A in Painful Knee Osteoarthritis: A Pilot Study

To evaluate the efficacy and safety of botulinum toxin type A (BoNT‐A) injected intra‐articularly in 60 subjects with moderate pain and functional impairment secondary to knee osteoarthritis. The study investigators hypothesized that intra‐articular BoNT‐A would result in statistically significant improvements in pain and function at 8 weeks.

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.

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.