Functional outcomes of intramuscular botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial

OBJECTIVE: To describe the functional and family-centered assessment protocol and outcomes of a phase II trial evaluating upper-limb function after botulinum toxin injections in children with cerebral palsy (CP). DESIGN: Intervention study, case series, phase II trial, follow-up at 2 weeks and 3 and 6 months. SETTING: Specialist outpatient physical disabilities clinic within a public pediatric teaching hospital. PARTICIPANTS: Convenience sample of 16 children with CP (age range, 2-12y). INTERVENTIONS: Botulinum toxin type A (Botox) injections after electrical stimulation localization of appropriate muscle. MAIN OUTCOME MEASURES: The Canadian Occupational Performance Measure (COPM), Goal Attainment Scale (GAS), Melbourne Assessment of Unilateral Upper Limb Function, Child Health Questionnaire (CHQ), parent questionnaire, Modified Ashworth Scale (MAS), Tardieu scale, and active (AROM) and passive (PROM) range of motion. RESULTS: On the COPM, there was significant improvement at 3 months and 6 months. On the GAS, the T-scores were 42 and 47 at 3 and 6 months, respectively. On the Melbourne Assessment and CHQ, there was no significant change. The parent questionnaire indicated acceptability of injections and positive outcomes. On the MAS, there was a significant reduction in tone at 2 weeks, with a return to baseline by 6 months. On the Tardieu scale, there was a significant increase in angle of first catch at 2 weeks, but only the elbow maintained a significant difference at 3 and 6 months. No significant change was found for AROM or PROM. CONCLUSIONS: Sustained functional outcomes occurred after botulinum toxin injections despite increasing muscle tone after an initial reduction in tone. Randomized controlled trials are required.     

Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study

Sixty patients with headaches of more than 15 days per month were recruited for this double-blind, placebo-controlled, parallel study of botulinum toxin type A (BTX) for chronic tension type and chronic migraine headaches. The primary efficacy point was the number of headache-free days as assessed by diary for 12 weeks after BTX injection. Secondary efficacy points included global impressions, the use of abortive headache medications, and palpation. After recruitment, subjects kept diaries for 4 weeks prior to randomization, at which time they received either 200 U of BTX or matching placebo and were followed. After the week-12 evaluation, patients were offered 200 U of BTX (open label), and were similarly followed for another 12 weeks. The mean days with headache of the 60 subjects (49 female, mean age 47 +/- 11 years) was 23 +/- 7 out of 30. Both groups were demographically similar (58 completed). Over a 12-week period after injections, headache-free days had improved in the BTX group from week 8 to 12 (P < 0.05), and strongly tended to improve over the entire 12-week period, 33 +/- 23 vs. 24 +/- 16 days without headache (P = 0.07), but did not meet the a priori significance criteria. The subject global impressions (P < 0.05), subject change in headache impressions (P < 0.005), and investigator global impressions (P < 0.001) all improved in the BTX group compared with placebo. Adverse events were mild and did not differ between groups. At week 24 (open label), headache-free days were less in the twice BTX injected group compared with the once injected group, 40 +/- 26 vs. 26 +/- 19 (P < 0.05). BTX may help chronic daily headache and appears to have a cumulative effect with subsequent injections. The treatment was very well tolerated.     

Botulinum toxin as an effective treatment of clozapine-induced hypersalivation

Hypersalivation is a common and frequently disabling side effect of atypical neuroleptics such as clozapine. Current treatment options of this adverse advent are limited by lack of efficacy or additional side effects. Botulinum toxin (BTX) injections into the parotid glands have been shown to be very effective in treating sialorrhea in the context of various neurological disorders, such as Parkinsons and motor neuron disease. Surprisingly, BTX treatment of drug-induced sialorrhea has not yet been described. We here report a patient with clozapine-induced hypersalivation and a good response to BTX injections lasting for more than 12 weeks, resulting in a marked reduction of the hypersalivation and consequently of his social withdrawal. Our patient serves to alert clinicians to the frequent problem of drug-induced sialorrhea and suggests that BTX injections should be considered as an effective and safe treatment for hypersalivation in psychiatric patients treated with clozapine.The first two authors contributed equally to this work.     

Lionfish envenomation

Lionfish (Pterois volitans) are venomous fish most often found as aquarium pets throughout the United States. Lionfish envenomations frequently occur on the upper extremities, with pain as the predominant symptom. Immersing the injured part in warm (45°C) water is considered the first and foremost important treatment as it is reported to relieve pain and inactivate the venom. Other methods of analgesia are discussed. We present a case of lionfish envenomation that failed to respond to warm water immersion.     

Effect of stimulation intensity and botulinum toxin isoform on rat bladder strip contractions

The present experiments compared the inhibitory effects of botulinum toxin A (BoNT-A) and botulinum toxin D (BoNT-D) on neurally evoked contractions of rat bladder strips. We examined the effect of fatigue (trains of 100 shocks at 20Hz every 20s for 10min) followed by non-fatigue stimulation (trains of 100 shocks at 20Hz every 100s for 20min) on the onset of effect and potency of the two toxins. For non-fatigue experiments, strips were untreated (n=4); or incubated with 1.36nM BoNT-A (n=4). During fatigue experiments, strips were untreated (n=5); or treated with either 1.36nM BoNT-A (n=6) or 0.8nM BoNT-D (n=6). In non-fatigue experiments, BoNT-A produced significant decreases in contractile area after 1h of stimulation compared to untreated strips (P<0.05). After three series of fatigue stimulation, differences in recovery amplitude and area between untreated versus BoNT-A, and untreated versus BoNT-D bladder strips, were statistically significant (P<0.05). The onset of inhibitory effect was quicker in BoNT-D-treated strips, as a significant reduction (P<0.05) in recovery of contractile area was observed after 1h of stimulation compared to both untreated and BoNT-A-treated preparations. In addition, treated (BoNT-A and BoNT-D) and untreated bladder strips responded similarly to atropine, suggesting that the effects of BoNT result from inhibition of both acetylcholine and ATP release. Our results demonstrate that BoNT-D may be a more effective agent to inhibit transmitter release from autonomic nerves of the rat lower urinary tract. Moreover, in our hands, non-fatigue stimulation is as effective as fatigue stimulation in inhibiting bladder strip contractions.     

The treatment of drooling by ultrasound-guided intraglandular injections of botulinum toxin type A into the salivary glands

OBJECTIVE: The aim of the study was to present the background, procedure, and technique of bilateral ultrasound-guided, single-dose injections of botulinum toxin type A (BTX) into the salivary glands in patients with severe drooling. STUDY DESIGN: Clinical trial. METHODS: Initially, an in vitro study was performed to determine the volume of the dilution of BTX required for optimal spreading and to gain insight in the spreading pattern of the fluid in the submandibular gland. Subsequently, patients with severe drooling were included in a clinical study. Salivary flow was measured under standardized conditions, and BTX was injected into the submandibular glands with the patient under general anesthesia and with ultrasound guidance as an outpatient procedure or during a short stay at the daytime care unit. RESULTS: BTX for each gland should be diluted in a volume of 1 to 1.5 mL saline to achieve adequate spreading within the gland and to diminish the risk of diffusion into surrounding structures. With ultrasound guidance, separate structures surrounding the glands and structures within the glandular parenchyma are well recognized and injection errors can be avoided. CONCLUSIONS: With the procedure described, it is possible to accurately inject BTX directly into the glandular parenchyma and to visualize spreading of the fluid in the glandular parenchyma. It is found to be a safe method that guarantees an optimal clinical effect and avoids potentially harmful side effects. We recommend ultrasound guidance if injections of BTX into the salivary glands are considered.     

The effect of botulinum toxin injections to the calf muscles on freezing of gait in parkinsonism: a pilot study

Background Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is poorly understood and responds unsatisfactorily to medical treatment. We recently reported a unique patient with Parkinson's disease (PD) who had significant alleviation of FOG shortly after she was injected with botulinum toxin type A (BTX-A) for foot dystonia (Giladi et al. 1997). Objective To assess the effect of BTX-A injections into the calf muscles of parkinsonian patients on FOG. Method BTX-A was injected in an open fashion into the calf muscles of 10 parkinsonian patients (age 55–75 years) with FOG as a predominant symptom. Response of FOG was assessed subjectively by the patient from worsening (–1) to marked improvement (+3). One patient was injected in a single blind fashion with saline or BTX-A after he had an initial good response. Results Seven patients reported different rates of improvement of FOG severity in 15 out of 17 therapeutic sessions. Four patients (40%) reported marked improvement (+3) of FOG in 5 sessions. Two patients reported no effect in two sessions. The mean duration of improvement was 6 weeks (range 1–12 weeks) with definite deterioration afterwards. The patient who was injected in a single blind fashion did not respond to saline injections but improved significantly with BTX-A treatment. Conclusions We observed a clear temporal relationship between BTX-A injections into the calf muscles of parkinsonian patients and improvement of FOG. A double blind placebo controlled prospective study is needed before any conclusions can be drawn about the role of BTX-A injection in FOG. Received: 31 August 2000 / Received in revised form: 24 October 2000 / Accepted: 19 January 2001     

Histopathological and radiological investigations of the influence of botulinum toxin on the submandibular gland of the rat

The aim of the study was to correlate the sonographic features of Botox A injection in rat submandibular gland with the histopathological changes. Fifteen Wistar albino rats were randomly assigned to 2 groups. Group 1 (control group) consisted of 5 animals not given any substance. Group 2 was divided as “a” and “b” each consisting of 5 animals. A median cervical incision has been performed to the rats in group 2 and 2.5 U Botulinum toxin A reconstituted 0.1 ml physiologic saline was injected into the right gland. Sonograms were obtained before the application, at the first day of the Botox A application, in addition to group 2a on the 14th day, and on 28th day to group 2b. Gland size was lower in group 2a and 2b comparing to control group. The gland size of group 2b was lower than group 2a. There was no change in vascularization. There was no other histopathological change except lymphocytic infiltration in group 2. It was observed that Botox A injection does not have a direct effect on the cells in submandibular gland but it causes a homogenic shrinking in gland size without atrophy.     

The first documented case of true botulinum toxin granuloma

Abstract

We report a unique case of foreign-body granuloma following botulinum neurotoxin type A (BoNTA) injection. A 44-year-old woman was injected with BoNTA by a dermatologist. Within 2 months of treatment, palpable nodules developed on injection site and biopsy revealed foreign-body granuloma.     

Structure and Function of Clostridium Botulinum Progenitor Toxin

Clostridium botulinum strains produce seven immunologically distinct neurotoxins (NTX), type A to G. the NTXs associate with nontoxic components in cultures, and become large complexes with three forms (12S, 16S, and 19S) designated progenitor toxins. the 12S toxin consists of a NTX and a nontoxic component having no hemagglutinin (HA) activity (described here as non-toxic non-HA, NTNH), and the 16S and 19S toxins are formed by conjugation of the 12S toxin with HA. Based on the genetic-and protein chemical-analyses of the progenitor toxins it became clear that 1) the HA consists of four subcomponents namely HA1 (Mr. 33–35 kDa), HA2 (15–17 kDa), HA3a (19–23 kDa), and HA3b (52–53 kDa), 2) the genes coding for NTX (ntx), NTNH (ntnh), and HA (ha) occur as a cluster; ha lies just upstream of ntnh, and ntx lies just downstream of ntnh, 3) ha is in the opposite orientation from that of ntnh and ntx, 4) ha consists of three ORFs (ha1, ha2, and ha3), 5) the gene product (70 kDa) of ha3 is split into HA3a and HA3b after translation, 6) HA3a is cleaved at several different sites of its N-terminal region to form proteins with slightly different Mrs, 7) the 19S toxin is a dimer of 16S toxin crosslinked by HA1, 8) the NTNHs of type A to D 12S toxins have a cleavage(s) on their N-terminal regions. It also became clear that the HA plays an important role when the 16S (and 19S) toxin is absorbed from the small intestine.