REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES

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A.- Botulinum Toxin Type A: Adverse Events and Management (2022).

B.- Serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin (2015).

C. Ophthalmic adverse events following facial injections of botulinum toxin A: A systemic literature review (2021).

D.- Adverse events with botulinum toxin treatment in cervical dystonia: How much should we blame placebo? (2018).

E.- A Review of Complications Due to the Use of Botulinum Toxin A for Cosmetic Indications (2021).

F. - Adverse Events of Botulinum Toxin Type A in Facial Rejuvenation: A Systematic Review and Meta-Analysis (2016).

G. - Adverse events after botulinum A toxin injection for neurogenic voiding disorders (2005).

 H .- Literature review of the adverse events associated with botulinum toxin injection for the masseter muscle hypertrophy (2018).

I. - Botulinum toxin: did the black box warning change how we treat children with cerebral palsy? (2018).

J.- Botulinum Toxin Deaths: What is the Fact? (2008).

42.) A review of 5 years' experience in the use of botulinium toxin A in the treatment of sixth cranial nerve palsy at the Singapore National Eye Centre. 

43.) The role of botulinum toxin A in acute-onset esotropia. 

44.) Long-term botulinum toxin treatment of cervical dystonia--EMG changes in injected and noninjected muscles. 

45.) Botulinum toxin for amelioration of knee contracture in Duchenne muscular dystrophy. 

46.) Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. 

47.) Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade. 

48.) Botox for hyperadduction of the false vocal folds: a case report. 

49.) The use of botulinum toxin for the treatment of temporomandibular disorders: preliminary findings. 

50.) Achalasia: diagnosis and management. 

51.) Cosmetic indications for botulinum A toxin. 

52.) [Botulinum toxin type A treatment of cosmetically disturbing masseteric hypertrophy]. 

53.) Botulinum toxin type A for Frey's syndrome: a preliminary prospective study. 

54.) Complications of botulinum A exotoxin for hyperfunctional lines. 

55.) The adjunctive usage of botulinum toxin. 

56.) [Writer's cramp treated with botulinum injections]. 

57.) Clinical indications and injection technique for the cosmetic use of botulinum A exotoxin. 

59.) Botulinum toxin for the correction of hyperkinetic facial lines. 

60.) Cosmetic use of botulinum A exotoxin for the aging neck. 

61.) Axillary hyperhidrosis: treatment with botulinum toxin A. 

62.) Treatment of hyperfunctional lines of the face with botulinum toxin A. 

63.) Treatment of cerebral palsy with botulinum toxin A: functional benefit and reduction of disability. Three case reports. 

64.) Understanding botulinum toxin. Surgical anatomy of the frown, forehead, and periocular region. 

65.) Efficacy of repeated botulinum toxin injections as a function of timing. 

66.) Counterparalysis for treatment of paralytic scoliosis with botulinum toxin type A. 

67.)Has botulinum toxin type A a place in the treatment of spasticity in spinal cord injury patients? 

68.) Use of botulinum A toxin in patients at risk of wound complications following eyelid reconstruction. 

69.) Botox for the treatment of dynamic and hyperkinetic facial lines and furrows: adjunctive use in facial aesthetic surgery. 

70.) Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. 

71.) The role of botulinus toxin type A in treatment--with special reference to children. 

72.) Botulinum toxin type A injection for the treatment of frown lines. 

73.) Dilution and storage of botulinum toxin. 

74.) Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome. 

75.) [Oromandibular dystonia and botulinum toxins]. 

76.) Treatment of gustatory sweating with botulinum toxin. 

77.) Diplopia following subcutaneous injections of botulinum A toxin for facial spasms. 

78.) Prevalence of periocular depigmentation after repeated botulinum toxin A injections 

in African American patients. 

79.) Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical dystonia. 

80.) Acute anxiety and depression induced by loss of sensation and muscle control after botulinum toxin A injection. 

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42.) A review of 5 years' experience in the use of botulinium toxin A in the treatment of  sixth cranial nerve palsy at the Singapore National Eye Centre. 

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Singapore Med J 1999 Jun;40(6):405-9 

Quah BL, Ling YL, Cheong PY, Balakrishnan V 

Singapore National Eye Centre, Singapore. 

INTRODUCTION: This retrospective study reports our experience on the use of  botulinum toxin A (BTXA) in the treatment of sixth cranial nerve palsy at the Singapore  National Eye Centre. BTXA is derived from clostridium botulinum; it causes temporary  paralysis of the extraocular muscle (medial rectus) into which it is injected, thus preventing  its contracture and allows the antagonist lateral rectus muscle to take up the slack and  reduce or correct the ocular misalignment.

METHODS: Nineteen patients had BTXA  injection for estropia due to sixth cranial nerve palsy during the period September 1992 to  August 1997. The sixth cranial nerve palsy was related to nasopharyngeal carcinoma in  76.7% of cases. Follow-up after the last injection ranged from zero (defaulted) to 21  months (mean 8, median 6 months).

RESULTS: A total of 25 injections were given to 19  patients. Seven patients (36.8%) had final ocular alignment within 10 prism dioptres of  orthotropia of which six achieved fusion at primary gaze position. There was no  correlation between the number of injections per patient and the size of strabismus or  grade of lateral rectus muscle function. The incidence of ptosis was 48%, subconjunctival  haemorrhage 16% and hypertropia 16%.

DISCUSSION: Our results suggest that those  patients with smaller strabismus and a shorter time interval between onset of strabismus  and botulinum injection tend to achieve better outcome in terms of fusion or ocular  alignment within 10 prism dioptres of orthotropia.

The treatment of strabismus with  BTXA is an acceptable approach in selected patients. The procedure is simple, safe,  cheap, effective, and avoids the risks of general anaesthesia. It can substitute for or  eliminate the need for strabismus surgery in some cases of sixth nerve palsy. 

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43.) The role of botulinum toxin A in acute-onset esotropia. 

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Ophthalmology 1999 Sep;106(9):1727-30 

Dawson EL, Marshman WE, Adams GG 

Department of Orthoptics, Moorfields Eye Hospital, London, England. 

OBJECTIVE: To establish the effectiveness of botulinum toxin A (BTXA) in the  treatment of patients with acute acquired concomitant esotropia.

DESIGN: Retrospective,  interventional, noncomparative case series.

PARTICIPANTS: Fourteen patients  presenting to the Strabismus and Pediatric Service at Moorfields Eye Hospital with  acute-onset esotropia over a 6-year period (1991-1997).

INTERVENTION: 2.5 units  of BTXA injected into the unilateral medial rectus muscle of the deviating eye under  electromyographic control.

MAIN OUTCOME MEASURES: Pre- and postinjection  angle of deviation, pre- and postinjection stereopsis, final level of stereopsis achieved, and  whether corrective squint surgery was later required. RESULTS: Fourteen patients were  identified, of whom eight were male and six female. The mean age at presentation was 5.4  years, and the average time from onset to attending the clinic was 18 weeks. The mean  time from onset of acute esotropia to injection was 32.5 weeks. All patients, except one,  showed considerable improvement in their manifest deviation after one injection of  BTXA. Eight patients (57%) maintained high-grade stereopsis of 120 seconds of arc or  better and long-term ocular alignment with toxin treatment alone.

In total, 11 patients  (79%) gained improved stereopsis and maintained satisfactory ocular alignment with toxin  therapy and did not require squint surgery. Two patients (14%) did not maintain a stable  ocular position after toxin treatment and later required squint surgery, gaining good ocular  alignment and high-grade stereopsis. The one patient who did not respond to the initial  BTXA injection refused all further treatment. The mean follow-up time was 22 months. 

CONCLUSIONS: Botulinum toxin therapy has a definite role in the treatment of children  with acute-onset esotropia. It may well obviate the need for squint surgery. The safety  and ease of administration of this treatment add to its merits. 

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44.) Long-term botulinum toxin treatment of cervical dystonia--EMG changes in injected  and noninjected muscles. 

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Clin Neurophysiol 1999 Sep;110(9):1650-4 

Erdal J, Ostergaard L, Fuglsang-Frederiksen A, Werdelin L, Dalager T, Sjo O, Regeur  L 

Department of Neurology, Copenhagen Hospital Corporation, University of Copenhagen,  Denmark. 

OBJECTIVE: To evaluate changes in quantitative EMG of injected and noninjected  sternocleidomastoid muscles following long-term unilateral botulinum toxin treatment of  cervical dystonia.

METHODS: We investigated 27 patients with cervical dystonia, who  received repeated unilateral botulinum toxin injections of the sternocleidomastoid muscle,  with quantitative EMG at rest and at maximal voluntary contraction. The patients had on  the average 7.1 botulinum toxin treatments and the follow-up period was on the average  31 months (SD 16).

RESULTS: After the first treatment, the injected sternocleidomastoid  muscles showed a significant decrease in turns/s (mean 45%) and amplitude (mean 52%)  at rest, and in amplitude at maximal flexion (mean 24%) and rotation (mean 39%). Except  for a reduction in turns/s at rotation (mean 19%) no further reductions in EMG  parameters were seen after long-term treatment. The contralateral noninjected  sternocleidomastoid muscles showed no significant change in EMG activity after the first  BT treatment, but after long-term treatment a significant reduction in turns/s and amplitude  at both maximal flexion (turns: mean 28%; amplitude: mean 25%) and rotation (turns/s:  mean 32%; amplitude: mean 25%) were seen as compared to pretreatment values. 

CONCLUSION: The results indicate that there seems to be no cumulative  chemodenervation by repeated botulinum toxin injections of sternocleidomastoid muscles  measured by quantitative EMG. Contralateral noninjected sternocleidomastoid muscles  however, seem to be affected following long-term treatment. The mechanism behind this  finding is unknown. 

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45.) Botulinum toxin for amelioration of knee contracture in Duchenne muscular  dystrophy. 

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Europ J Paediatr Neurol 1999;3(4):175-6 

von Wendt LO, Autti-Ramo IS 

University of Helsinki, Hospital for Children and Adolescents, Neurology, Finland. 

An 11-year-old non-ambulant boy with Duchenne muscular dystrophy developed  tightness in his left knee flexors, which caused difficulties in standing exercises. Botulinum  toxin A (BTX-A) was injected into the medial and lateral hamstring muscles and the range  of motion increased by 20 degrees but after 5 months, when the pharmacological effect of  BTX-A had vanished, an increase of only 5 degrees in range compared with the initial  finding was left.

It is concluded that there may be a role for BTX-A in controlling  contractures in Duchenne muscular dystrophy. 

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46.) Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in  patients with cerebral palsy. 

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Gait Posture 1999 Sep;10(1):1-9 

Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ 

Motion Analysis Lab, Children's Hospital, 3020 Children's Way, 5054, San Diego, CA  92123, USA. dsutherland@chsd.org 

The purpose of this study was to quantify the gait of subjects receiving two injections of  either botulinum A toxin or saline vehicle into the gastrocnemius muscle(s). The study  group consisted of cerebral palsy patients who walked with an equinus gait pattern. This  study was a randomized, double-blinded, parallel clinical trial of 20 subjects.

All were  studied by gait analysis before and after the injections. There were no adverse effects.  Peak ankle dorsiflexion in stance and swing significantly improved in subjects who  received the drug and not in controls.

Results of this double blind study give support to  the short term efficacy of botulinum toxin A to improve gait in selected patients with  cerebral palsy. 

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47.) Pure botulinum neurotoxin is absorbed from the stomach and small intestine and  produces peripheral neuromuscular blockade. 

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Infect Immun 1999 Sep;67(9):4708-12 

Maksymowych AB, Reinhard M, Malizio CJ, Goodnough MC, Johnson EA, Simpson  LL 

Departments of Medicine and of Biochemistry and Molecular Pharmacology, Jefferson  Medical College, Philadelphia, Pennsylvania 19107, USA. 

Clostridium botulinum serotype A produces a neurotoxin composed of a 100-kDa heavy  chain and a 50-kDa light chain linked by a disulfide bond. This neurotoxin is part of a ca.  900-kDa complex, formed by noncovalent association with a single nontoxin,  nonhemagglutinin subunit and a family of hemagglutinating proteins. Previous work has  suggested, although never conclusively demonstrated, that neurotoxin alone cannot survive  passage through the stomach and/or cannot be absorbed from the gut without the  involvement of auxiliary proteins in the complex.

Therefore, this study compared the  relative absorption and toxicity of three preparations of neurotoxin in an in vivo mouse  model. Equimolar amounts of serotype A complex with hemagglutinins, complex without  hemagglutinins, and purified neurotoxin were surgically introduced into the stomach or into  the small intestine.

In some experiments, movement of neurotoxin from the site of  administration was restricted by ligation of the pylorus. Comparison of relative toxicities  demonstrated that at adequate doses, complex with hemagglutinins, complex without  hemagglutinins, and pure neurotoxin can be absorbed from the stomach. The potency of  neurotoxin in complex was greater than that of pure neurotoxin, but the magnitude of this  difference diminished as the dosage of neurotoxin increased. Qualitatively similar results  were obtained when complex with hemagglutinins, complex without hemagglutinins, and  pure neurotoxin were placed directly into the intestine.

This work establishes that pure  botulinum neurotoxin serotype A is toxic when administered orally. This means that pure  neurotoxin does not require hemagglutinins or other auxiliary proteins for absorption from  the gastrointestinal system into the general circulation. 

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48.) Botox for hyperadduction of the false vocal folds: a case report. 

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J Voice 1999 Jun;13(2):234-9 

Rosen CA, Murry T 

Department of Otolaryngology, University of Pittsburgh, School of Medicine, PA, USA. 

We present a patient with severe hyperadduction of the false vocal folds (FVF) treated  with Botulinum Toxin injections to each FVF. This patient presented with severe  dysphonia and was found to demonstrate severe hyperadduction of the FVF's with all  phonatory tasks.

The patient was treated with extensive speech therapy without  improvement in voice quality nor FVF motion pattern. He was then injected with Botox A  bilaterally using a peroral approach to the FVFs. Shortly after treatment the patient  experienced dramatic improvement in voice quality.

Videolaryngoscopy revealed no  adduction of the FVFs with phonation and essentially normal true vocal fold motion. He  remained with normal voice quality one year after treatment without any further treatment.  Possible mechanism of action of this type of treatment are discussed. 

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49.) The use of botulinum toxin for the treatment of temporomandibular disorders:  preliminary findings. 

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J Oral Maxillofac Surg 1999 Aug;57(8):916-20; discussion 920-1 

Freund B, Schwartz M, Symington JM 

Faculty of Dentistry, University of Toronto, Ontario, Canada.

brian@max-facial.com 

PURPOSE: The aim of this study was to evaluate the response of patients with  temporomandibular disorders to Botulinum toxin A (BTX-A) therapy.

METHODS: The  15 subjects enrolled in this uncontrolled study were diagnostically categorized and treated  with 150 units of BTX-A. Both masseter muscles received 50 units each under  eletromyographic (EMG) guidance.

Similarly, both temporalis muscles were injected with  25 units each. Subjects were assessed at 2-week intervals for 8 weeks. Outcome  measures included subjective pain by visual analog scale (VAS), measurement of bite  force, interincisal opening, tenderness to palpation, and a functional index based on  multiple VAS.

RESULTS: All mean outcome measures, with the exception of bite force,  showed a significant (P = .05) difference between the preinjection assessment and the  four follow-up assessments. No side effects were reported.

CONCLUSIONS: BTX-A  injections produced a statistically significant improvement in four of five measured  outcomes, specifically pain, function, mouth opening, and tenderness. No statistically  significant changes were found in mean maximum voluntary contraction or in paired  correlation of factors such as age, sex, diagnosis, depression index, or time of onset. 

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50.) Achalasia: diagnosis and management. 

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Semin Gastrointest Dis 1999 Jul;10(3):103-12 

Vaezi MF 

Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, OH  44195, USA. 

Achalasia is a primary esophageal motor disorder of unknown cause that produces  complaints of dysphagia, regurgitation, and chest pain. The current treatments for  achalasia involve the reduction of lower esophageal sphincter (LES) pressure, resulting in  improved esophageal emptying. Calcium channel blockers and nitrates, once used as an  initial treatment strategy for early achalasia, are now used only in patients who are not  candidates for pneumatic dilation or surgery, and in patients who do not respond to  botulinum toxin injections.

Because of the more rigid balloons, the current pneumatic  dilators are more effective than the older, more compliant balloons. The graded approach  to pneumatic dilation, using the Rigiflex (Boston Scientific Corp, Boston, MA) balloons  (3.0, 3.5, and 4.0 cm) is now the most commonly used nonsurgical means of treating  patients with achalasia, resulting in symptom improvement in up to 90% of patients. 

Surgical myotomy, once plagued by high morbidity and long hospital stay, can now be  performed laparoscopically, with similar efficacy to the open surgical approach (94%  versus 84%, respectively), reduced morbidity, and reduced hospitalization time. Because  of the advances in both balloon dilation and laparoscopic myotomy, most patients with  achalasia can now choose between these two equally efficacious treatment options. 

Botulinum toxin injection of the LES should be reserved for patients who can not undergo  balloon dilation and are not surgical candidates. 

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51.) Cosmetic indications for botulinum A toxin. 

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Semin Ophthalmol 1998 Sep;13(3):142-8 

Foster JA, Wulc AE, Holck DE 

The Cleveland Clinic Foundation, Cleveland, OH, USA. 

This article describes the use of botulinum toxin type A in the cosmetic treatment of facial  wrinkles. Injection techniques, volumes, and concentration of the botulinum A toxin are  described for various types of facial wrinkles. 

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52.) [Botulinum toxin type A treatment of cosmetically disturbing masseteric  hypertrophy]. 

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Ned Tijdschr Geneeskd 1998 Mar 7;142(10):529-32 

Rijsdijk BA, van ES RJ, Zonneveld FW, Steenks MH, Koole R 

Academisch Ziekenhuis, Utrecht. 

Two patients, a woman aged 21 and a man aged 29, with asymmetrical swellings of both  mandibular angles and a painful, heavy sensation in the masticatory muscles (and in the  woman also round the maxillary joint), were diagnosed as having hypertrophy of the  masseter muscles.

Both had the habit of jaw clenching and tooth grinding. Treatment  consisted not of the traditional surgical debulking which also allows correction of  overdeveloped osseous mandibular angles, but of injections with botulinum toxin type A.  Injection of 40-60 IU (product: Botox) per muscle was followed by some atrophy;  cosmetically satisfactory results were achieved after repetition of the treatment a few  months later.

Reduction of muscle volume was confirmed by a quantitative volumetric  assessment of MRI scans. In the female patient, the pain also abated. 

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53.) Botulinum toxin type A for Frey's syndrome: a preliminary prospective study. 

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Ann Otol Rhinol Laryngol 1998 Jan;107(1):52-5 

Laccourreye O, Muscatelo L, Naude C, Bonan B, Brasnu D 

Department of Otorhinolaryngology-Head and Neck Surgery, Laennec Hospital,  Assistance Publique des Hopitaux de Paris, University Paris V, France. 

Fourteen patients with severe Frey's syndrome (occurring after conservative  parotidectomy) managed with intracutaneous injection of botulinum toxin type A were  prospectively evaluated. Results were analyzed for effectiveness, complications, and  adverse effects.

Complications were not encountered. The only adverse effect noted was  a temporary and slight partial paresis of the upper lip of 3 months' duration in 2 patients.  Permanent paresis was not encountered. Frey's syndrome was always controlled within 2  days following the intracutaneous injection of botulinum toxin A. Frey's syndrome  recurrence was not encountered with a follow-up duration that varied from 3 to 9 months  (mean follow-up 7 months).

This preliminary report confirmed that in patients who have  Frey's syndrome after conservative parotidectomy, the intracutaneous injection of  botulinum toxin is a valuable treatment option that should be further investigated. 

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54.) Complications of botulinum A exotoxin for hyperfunctional lines. 

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Dermatol Surg 1998 Nov;24(11):1249-54 

Matarasso SL 

Department of Dermatology, University of California School of Medicine, San Francisco,  USA. 

Clostridium botulinum type A exotoxin is one of the recent advances for treatment of the  aging face. Due to the sudden and exponential surge in popularity, there is little precise  consensus regarding its safety and efficacy.

Many of the reported complications  associated with its aesthetic use are few and anecdotal. As we gain more experience and  long-term follow-up with this procedure, complications and their treatment can be better  documented. As most of the salutary effects of Botulinum toxin are temporary,  fortunately, so too are the complications associated with this form of therapy. 

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55.) The adjunctive usage of botulinum toxin. 

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Dermatol Surg 1998 Nov;24(11):1244-7 

Carruthers J, Carruthers A 

Department of Ophthalmology, University of British Columbia, Vancouver, Canada. 

BACKGROUND: Botulinum toxin is a safe, helpful adjunct to many other treatments for  facial rejuvenation. Used together, the final result is more polished and refined. In  addition, botulinum toxin can be used to maintain the surgical laser results by preventing  dynamic facial muscular action re-establishing expressive wrinkles and folds. 

OBJECTIVES: We describe the facial areas best treated with botulinum toxin and our  adjunctive techniques so that the cosmetic physician can easily incorporate these into their  practice.

RESULTS: The aesthetic results are improved with the combination of  botulinum toxin and the surgical or laser procedure over either modality alone. 

CONCLUSIONS: We believe that there are many new treatment options for combined  therapy with botulinum toxin, laser resurfacing, and surgical procedure in periocular and  facial rejuvenation that the aesthetic physician can easily incorporate into their practice. 

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56.) [Writer's cramp treated with botulinum injections]. 

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Ned Tijdschr Geneeskd 1998 Aug 1;142(31):1768-71 

Koelman JH, Struys MA, Ongerboer de Visser BW, Speelman JD 

Academisch Medisch Centrum, Amsterdam. 

OBJECTIVE: To evaluate the first clinical experience with local botulinum toxin A (BTA)  injections in patients with writer's cramp.

DESIGN: Descriptive. SETTING: Academic  Medical Centre, Amsterdam, the Netherlands.

METHOD: In May 1993-January 1996  ten patients with writer's cramp were treated with BTA (Dysport). Age of the patients  varied from 28 to 68 years, the duration of complaints from 1 to 29 years. Muscles for  injections were selected by observation, sometimes combined with electromyography.  BTA was administered under electromyographic guidance.

RESULTS: The amount of  BTA administered per treatment session ranged from 15 to 400 IU. In three patients the  BTA-induced weakness necessary to reach a beneficial effect on writing was  unacceptable. In seven patients the response was satisfactory or good and lasted 2 to 15  months (mean: 3.5 months).

CONCLUSION: The results confirm the efficacy of BTA in  writer's cramp. 

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57.) Clinical indications and injection technique for the cosmetic use of botulinum A  exotoxin. 

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Dermatol Surg 1998 Nov;24(11):1189-94 

Carruthers A, Carruthers J 

Division of Dermatology, University of British Columbia, Vancouver, Canada. 

BACKGROUND: Some wrinkles and unsightly facial expressions are due to overactivity  of the underlying facial musculature. Botulinum A exotoxin reversably paralyses selected  muscles. Botulinum toxin has been used to correct facial cosmetic concerns. 

OBJECTIVES: This paper describes the authors' experience with the cosmetic use of  botulinum toxin. The areas that can be treated, the appropriate technique for each area  and special considerations such as dose, dilution, and relevant anatomy are discussed. 

RESULTS: Our results have been published previously and are referenced in this paper. 

CONCLUSIONS: Botulinum toxin is safe and effective in the management of some facial  lines and wrinkles. Its use is associated with a high degree of patient and physician  satisfaction. 

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59.) Botulinum toxin for the correction of hyperkinetic facial lines. 

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Australas J Dermatol 1998 Aug;39(3):158-63 

Goodman G 

ggoodman@bluepacific.com.au 

The present article illustrates the effects of low dose botulinum toxin (BTx) injections for  the improvement of hyperkinetic facial lines and presents a grading treatment chart  designed to standardize the reporting of the improvement seen. A questionnaire of patient  acceptance, the patients' impression of therapy and short-term results and complications  are reported.

Twelve patients with 26 injected-paired regions were charted and the  response to injection was graded. Patients had hyperkinetic facial lines in glabella,  periorbital regions or horizontal forehead lines. Diluted BTx type A (1 IU/0.1 mL) was  injected and patients were assessed at 10 days.

A second follow up injection was offered  to patients at this stage if required. Objectively, all patients' hyperkinetic actions and lines  improved or diminished. The degree of improvement was similar in all areas injected and  a symmetry of results was always observed.

In a minority of cases, all movement was lost  (7/26) and in others it was weakened but present (19/26). In some injected areas the  actual expression line that was visible at rest disappeared entirely (11/26): in the others it  was diminished (15/26).

Complications were few. Two patients had temporary brow  ptosis that spontaneously recovered within the first week. No eyelid ptosis was noted.  Bruising and headaches were the most common reported complications. Low dose BTx  is an effective and well-tolerated treatment for hyperkinetic facial lines with few significant  complications in this small pilot study. The grading chart may allow easier comparisons of  results between studies on the effects of BTx therapy. 

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60.) Cosmetic use of botulinum A exotoxin for the aging neck. 

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Dermatol Surg 1998 Nov;24(11):1232-4 

Brandt FS, Bellman B 

Department of Dermatology and Cutaneous Surgery, University of Miami School of  Medicine, Florida, USA. 

BACKGROUND: The use of botulinum toxin for facial rhytides has become more  popular. In the past, plastic surgery was the only choice for rejuvenation of the aging  neck. We discuss the cosmetic use of botulinum toxin for the rejuvenation of the neck and  review the anatomy.

OBJECTIVES: We will review the four age-related neck  degeneration categories and discuss how to inject botulinum A exotoxin into the platysmal  neck bands.

RESULTS: We will discuss how botulinum can tighten neck jowls, eliminate  horizontal neck rhytides, and improve skin laxity.

CONCLUSION: Botulinum A exotoxin  is a safe, effective, alternative treatment for rejuvenation of the aging neck and lower face.  Patients are uniformly satisfied and complications are minimal. 

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61.) Axillary hyperhidrosis: treatment with botulinum toxin A. 

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Arch Phys Med Rehabil 1998 Mar;79(3):350-2 

Odderson IR 

Department of Rehabilitation Medicine, University of Washington, Seattle, USA. 

Hyperhidrosis can be emotionally challenging and socially and professionally disruptive,  and there are few effective treatments. This condition was successfully treated with  botulinum toxin in two men who, since their early teens, had had excessive axillary  sweating, requiring frequent shirt changes.

They received bilateral axillary injections with  100 units of botulinum toxin type A, and within 5 days reported cessation of excessive  sweating.

Quantitative measurements before and 2 to 4 weeks after the injections  demonstrated an average reduction of 71% and 76% (from 11.6 to 3.4 and from 2.5 to  0.6 mL/min m2) in axillary sweating during rest.

A 96% reduction (from 42.9 to 1.7  mL/min m2) was seen in one patient during mental stress. No complications developed.  This study quantitates the reduced axillary sweating achieved through chemodenervation  with botulinum toxin A. 

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62.) Treatment of hyperfunctional lines of the face with botulinum toxin A. 

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Dermatol Surg 1998 Nov;24(11):1198-205 

Binder WJ, Blitzer A, Brin MF 

Department of Head and Neck Surgery, University of California at Los Angeles, USA. 

Since Botulinum toxin A became a mainstay therapy for blepharospasm, its use in treating  other dystonic conditions, spasticity disorders, as well as hyperfunctional lines of the face  has increased exponentially in recent years.

The following article summarizes our  experience in establishing a safe and reliable method of administration of botulinum toxin  A for treating hyperfunctional lines of the face. 

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63.) Treatment of cerebral palsy with botulinum toxin A: functional benefit and reduction  of disability. Three case reports. 

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Pediatr Rehabil 1997 Oct-Dec;1(4):235-7 

Mall V, Heinen F, Linder M, Philipsen A, Korinthenberg R 

Department of Neuropediatrics, Children's Hospital, University of Freiburg, Germany. 

Three patients with cerebral palsy are described suffering, respectively, of pes equinus,  spasm of the m. teres major and flexion spasm of the hand, who were treated with  botulinum toxin A. These patients demonstrate not only the local reduction of the muscular  hyperactivity following treatment with botulinum toxin A but also the potential functional  benefit resulting from such a treatment.

Thus, local intramuscular injection of botulinum  toxin A in children with cerebral palsy should be considered as part of a multidisciplinary  treatment concept, since reduction of the disability and the functional improvements could  have high impact on daily living activities. 

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64.) Understanding botulinum toxin. Surgical anatomy of the frown, forehead, and  periocular region. 

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Dermatol Surg 1998 Nov;24(11):1172-4 

Wieder JM, Moy RL 

Division of Dermatology, UCLA School of Medicine, USA. 

BACKGROUND: Cosmetic denervation of hyperfunctional facial lines using botulinum  toxin (Botox, Allergan, Inc., Irvine, CA) has gained growing popularity over recent years.  Understanding the clinical use and effects of botulinum toxin requires a thorough  understanding of the muscular anatomy of the treatment areas.

OBJECTIVE: The  purpose of this article is to review the anatomy of the frown, forehead, and periocular  regions. Function of individual muscles is discussed to understand proper injection  technique.

CONCLUSIONS: The anatomy of the frown, forehead, and periocular  regions is complex. Individual muscles are tightly intertwined and treatment of one  anatomic region may affect many different muscles.

A complete understanding of the  anatomy of the upper face is essential to ensure proper injection technique, safe and  predictable results as well as anticipating complications. 

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65.) Efficacy of repeated botulinum toxin injections as a function of timing. 

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Ann Otol Rhinol Laryngol 1997 Dec;106(12):1012-9 

Inagi K, Ford CN, Rodriquez AA, Schultz E, Bless DM, Heisey DM 

Department of Surgery, University of Wisconsin Medical School, Madison, USA. 

This pilot study was designed to determine if the interval between repeated botulinum  toxin injections influenced physiologic and histologic effects on laryngeal muscles in a rat  model. The physiologic measurements included digitized videomicroscopic recording of  vocal fold movement and electromyography.

The histologic measurements included  muscle fiber size and digitized optical density of laryngeal muscles after glycogen depletion  by electrical stimulation. The results demonstrated that the effect of timing of the second  injection was strongly correlated to laryngeal changes.

Most notable were results in the  subjects that underwent injections 6 weeks apart. We hypothesize that these findings  might be related to terminal axonal sprouting with reinnervation. The results from this  study help confirm and expand the validity of using the rat laryngeal model to understand  the effect of botulinum toxin. Moreover, we believe that the data might be extrapolated to  prove useful in predicting human responses to botulinum toxin treatment for functional  dystonias such as spasmodic dysphonia. 

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66.) Counterparalysis for treatment of paralytic scoliosis with botulinum toxin type A. 

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Am J Orthop 1997 Mar;26(3):201-7 

Nuzzo RM, Walsh S, Boucherit T, Massood S 

Overlook Hospital, Summit, New Jersey, USA. 

In this study, botulinum toxin was used to treat paralytic scoliosis. Twelve children with  paralytic scoliosis and severe, complicating additional diseases required surgical delay.  Although this use of botulinum toxin is experimental, alternative treatments posed greater  risks. An institutional review board protocol for nonestablished dosage and indication for  treatment was initiated to monitor safety and effect.

Treatment was intended to  supplement, not replace, other desirable treatment modalities. The effect was to be  measured by the return of efficacy of conservative treatment in halting curve progression.  Short-term results show that none of the children had worsened scoliosis; all had some  reduction in curve measurement (up to >50 degrees). 

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67.)Has botulinum toxin type A a place in the treatment of spasticity in spinal cord injury  patients? 

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Spinal Cord 1998 Dec;36(12):854-8 

Al-Khodairy AT, Gobelet C, Rossier AB 

Department of Physical Medicine and Rehabilitation, Hopital de Gravelone, CH-1950  Sion, Switzerland. 

OBJECTIVE: To present and discuss treatment of severe spasms related to spinal cord  injury with botulinum toxin type A.

DESIGN: A 2-year follow-up study of an incomplete  T12 paraplegic patient, who was reluctant to undergo intrathecal baclofen therapy,  presenting severe painful spasms in his lower limbs treated with intramuscular injections of  botulinum toxin type A.

SETTING: Department of Physical Medicine and Rehabilitation,  Hopital de Gravelone, Sion, Switzerland.

SUBJECT: Single patient case report. MAIN  OUTCOME MEASURE: Spasticity, spasms and pain measured with the modified  Ashworth scale, spasm frequency score and visual analogue scale.

RESULTS: Treatment  of spasticity with selective intramuscular injections of botulinum toxin type A resulted in  subjective and objective improvement.

CONCLUSION: Botulinum toxin type A has its  place in the treatment of spasticity in spinal cord injury patients. This treatment is  expensive and its effect is reversible. It can complement intrathecal baclofen in treating  upper limb spasticity in tetraplegic patients. Tolerance does occur to the toxin. Although  high doses of the product are well tolerated, the quantity should be tailored to the patient's  need. The minimal amount necessary to reach clinical effects should be adhered to and  booster doses at short period intervals should be avoided. 

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68.) Use of botulinum A toxin in patients at risk of wound complications following eyelid  reconstruction. 

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Ophthal Plast Reconstr Surg 1997 Dec;13(4):259-64 

Choi JC, Lucarelli MJ, Shore JW 

Ophthalmic Consultants of Boston, Massachusetts, USA. 

Our purpose was to determine the efficacy of botulinum A toxin (BOTOX) in promoting  wound immobilization and preventing wound dehiscence in patients at risk of  wound-healing complications following eyelid reconstruction. In 11 patients at risk of  postoperative wound complications, we injected BOTOX into the periocular musculature  in addition to standard suture tarsorrhaphy.

Each patient experienced excellent wound  immobilization and wound healing. There were no complications. Adjuvant use of  BOTOX, in conjunction with suture tarsorrhaphy, immobilizes the eyelids and promotes  wound healing in patients at risk of wound complications following eyelid reconstruction. 

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69.) Botox for the treatment of dynamic and hyperkinetic facial lines and furrows:  adjunctive use in facial aesthetic surgery. 

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Plast Reconstr Surg 1999 Feb;103(2):701-13 

Fagien S 

Boca Raton Center for Ophthalmic Plastic Surgery, Fla, USA. 

Our improved understanding of the pathophysiology of facial lines, wrinkles, and furrows  has broadened the treatment options for a variety of facial cosmetic blemishes.

The  persistence or recurrence of certain facial rhytids after surgery has confirmed the lack of  full comprehension of their origin. Glabellar forehead furrows (frown lines) and lateral  canthal rhytids (crow's feet) have been the most popular facial lines that have been shown  to be mostly the result of regional hyperkinetic muscles, and their eradication may be  more suitable, at times, to chemodenervation than to soft-tissue fillers, skin resurfacing, or  surgical resection.

Aesthetic surgical procedures that have yielded suboptimal results may  also occur from failure to recognize other causative factors including hyperkinetic or  dynamic musculature, which may contribute to etiology of the visible soft-tissue changes  and lack of persistent effect after surgery. Chemodenervation with botulinum toxin A  (Botox) has proven to be useful both as a primary treatment for certain facial rhytids and  as an adjunctive agent for a variety of facial aesthetic procedures to obtain optimal 

results. 

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70.) Botulinum toxin A, adjunctive therapy for refractory headaches associated with  pericranial muscle tension. 

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Headache 1998 Jun;38(6):468-71 

Wheeler AH 

Charlotte Spine Center, NC 28207, USA. 

Pericranial muscle tension may contribute to the development of facial discomfort, chronic  daily headache, and migraine-type headache. Elimination of pericranial muscle tension  may reduce associated myalgia and counteract influences that can trigger secondary  headaches which fall within the migraine continuum. Four patients with chronic,  predominantly tension-type headaches and associated pericranial muscle tension failed  prolonged conventional treatment and, therefore, symptomatic areas were treated with  botulinum toxin A.

This alleviated myalgia and reduced the severity and frequency of  migraine-type headaches with a concomitant reduction in subsequent medical and physical  therapy interventions. Judicious use of botulinum toxin A into defined areas of pericranial  muscle tension may be useful for reducing primary myalgia and secondary headache. 

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71.) The role of botulinus toxin type A in treatment--with special reference to children. 

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Brain Dev 1999 Apr;21(3):147-51 

Gordon N 

Although botulinum toxin A was first introduced to treat strabismus and blepherospasm it  is now used in an increasing number of conditions, many in the field of pediatrics. Its  action results from a prevention of the release of acetylcholine from nerve terminals. A  number of studies recording the effects of the toxin in the treatment of spastic cerebral  palsy are reviewed, and although these can be criticized, there seems to be no doubt that  it can be of benefit.

It is few side effects, but it may reveal an underlying weakness. Other  disadvantages are its cost and the need for repeated injections. It can be used for the  relief of rigidity, although the effects in the extrapyramidal form of cerebral palsy are not  so dramatic.

Also it can be beneficial in some forms of dystonia, rarely if this is  generalized, but certainly if it is focal, and especially if there is accompanying pain. There  are several conditions seen in children, such as strabismus, blepherospasm and tremors, in  which this form of treatment will rarely be indicated; but they will be mentioned. An  exception may be spasmodic torticollis during adolescence if it does not respond to other  therapy, as it is so disabling. Botulinum toxin can be used to block the discharges from  cholinergic sympathetic and parasympathetic terminals.

Focal hyperhidrosis can be very  distressing among older children, and the use of the toxin should sometimes be considered  in this and other autonomic disorders. 

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72.) Botulinum toxin type A injection for the treatment of frown lines. 

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Ann Pharmacother 1998 Dec;32(12):1365-7 

Song KH 

Professional Product Information, Roche Laboratories, Inc., Nutley, NJ 07110, USA. 

Patients who have exaggerated frown lines frequently ask for treatment because others  mistake them to be constantly angry or annoyed. Current treatment options (surgery or  implants) do not address the underlying cause of these lines, namely the excessive nerve  stimulation.

The mechanism of action of BTX makes it an ideal agent to target the major  cause of these lines. BTX inhibits calcium metabolism in the presynaptic neuron, thereby  inhibiting neuromuscular transmission and producing muscle paralysis. The current medical  literature indicates that BTX can be used safely and effectively for the cosmetic treatment  of frown lines.

The procedure can be performed in an ambulatory setting and the use of  an EMG instrument may provide better direction for the placement of the drug. However,  the benefits are transient and repeated injections are necessary. The adverse effects  associated with BTX injections were mild and transient. Currently, there are no safety  data on the long-term effects of continuous BTX injections for the treatment of frown  lines. However, studies on the long-term use of BTX at doses to treat blepharospasm and  Meige's disease have shown no serious adverse effects or production of antibodies to  BTX.

Muscle biopsies taken from patients who have received numerous doses of BTX  for more than 7 years have not shown any signs of atrophy or permanent muscle  degeneration. The medical literature supports BTX therapy as an option for the treatment  of cosmetic facial frown lines.

However, there is not enough information on what patient  characteristics are ideal in a candidate to achieve optimal response with BTX. Also, no  data are available on the safety and efficacy of continuous injections in the long-term use  of BTX for facial frown lines. Therefore, the use of BTX to treat frown lines should be  examined carefully against other therapeutic options. 

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73.) Dilution and storage of botulinum toxin. 

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Dermatol Surg 1998 Nov;24(11):1179-80 

Klein AW 

Department of Dermatology, UCLA School of Medicine, USA. 

BACKGROUND: There has been an ongoing controversy as to the best dilution for  botulinum toxin for use in cosmetic applications. Recommended dilutions have ranged  from 1 ml per vial to 10 ml per vial. There has also been much discussion on the diluent,  i.e., preserved versus unpreserved saline, to be used and on storage time of the material  after dilution.

OBJECTIVES: The objective of this paper is to examine the literature and  experience of practitioners in the field to try to resolve some of the questions concerning  dilution and storage of botulinum toxin.

CONCLUSIONS: Although there is great  variation in the dilutions adopted by various physicians, much of this is a matter of  personal preference. It does seem to appear that most clinicians use a dilution near 2.5 to  3.0 ml per vial and three-quarters of them limit the storage of the diluted product to 1  week or less. 

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74.) Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome. 

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Mov Disord 1997 Nov;12(6):1060-3 

Liguori R, Cordivari C, Lugaresi E, Montagna P 

Institute of Neurology, University of Bologna, Italy. 

We studied the effect of botulinum toxin A (BTA) on painful muscular spasms and rigidity  in two bedridden patients with clinical, electrophysiologic, and immunologic evidence of  stiff-person syndrome.

We injected BTA or saline solution into several limb muscles with  both the rater and patient blinded to the order of the injections. A physician, unaware of  the treatment order, used an objective rating scale for rigidity and spasm frequency scale  and independently assessed the treatment results.

BTA administration significantly  reduced rigidity and stopped the spasms in all limbs. Following BTA injection on one  side, the spasm frequency decreased bilaterally possibly because of the spread of  hematogenous toxin. 

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75.) [Oromandibular dystonia and botulinum toxins]. 

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Acta Stomatol Belg 1996 Mar;93(1):37-41 

[Article in French] 

Van Durme B, Loeb I, Van Reck J 

Service de Stomatologie et Chirurgie Maxillo-Faciale, C.H.U. St. Pierre, Bruxelles. 

The authors describe the Meige's Syndrome also known as blepharospasm or  mandibulo-oral dystonia. This Syndrome rather known by Neurologists and  Ophthalmologists than by Stomatologists actually benefits by a specific treatment based  on botulin toxins. 

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76.) Treatment of gustatory sweating with botulinum toxin. 

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Ann Neurol 1997 Dec;42(6):973-5 

Naumann M, Zellner M, Toyka KV, Reiners K 

Department of Neurology, Bayerische Julius-Maximilians-Universitat, Wurzburg,  Germany. 

Gustatory sweating is an autonomic disorder that frequently occurs after parotid gland  surgery. We investigated the action of intracutaneous injections of botulinum toxin (BTX)  (1.0-2.0 mouse units/2.25-cm2 skin area) in 45 patients (mean age, 52 years) with  gustatory sweating.

The area of hyperhidrosis was determined by Minor's iodine test  before and up to 24 weeks after the injection. The effect of BTX was assessed by  measuring the hyperhidrotic area. The maximum BTX-induced reduction of gustatory  sweating was seen at 7.4 +/- 4.5 days after injection.

The area of sweating decreased  from 17.6 +/- 8.6 cm2 before BTX to 1.3 +/- 1.6 cm2 after BTX (p < 0.0001). Half the  patients rated gustatory sweating subjectively as completely abolished, and the remainder  felt pronounced improvement.

No toxic effects were observed. In none of the patients did  hyperhidrosis recur over a 6-month follow-up. We conclude that BTX is a safe and  effective treatment that can be recommended as the therapy of choice in gustatory  sweating. 

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77.) Diplopia following subcutaneous injections of botulinum A toxin for facial spasms. 

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J Pediatr Ophthalmol Strabismus 1997 Jul-Aug;34(4):229-34 

Wutthiphan S, Kowal L, O'Day J, Jones S, Price J 

Ocular Motility Clinic, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. 

PURPOSE: To study the incidence, cause, recovery time, and prevention of diplopia  following subcutaneous injection of botulinum A toxin for the treatment of facial spasms.  METHODS: Patients who experienced diplopia after botulinum A toxin injections had  their deviations examined in detail.

When the muscle that caused diplopia was identifiable,  the injection closest to that muscle was omitted in the next treatment in an attempt to  prevent diplopia. RESULTS: Of 250 patients receiving about 1500 sets of injections, 25  (1.7%) incidents of diplopia occurred in 10 patients. Excluding two patients who declined  further treatment after having diplopia on their first botulinum A toxin treatment, seven of  the remaining eight patients had multiple incidents of diplopia.

The most common pattern  of diplopia was "uncertain diagnosis." The most common identifiable cause of diplopia  was paresis of the inferior oblique muscle. Omission of the injection into the central  portion of the lower eyelids in the next treatment prevented recurrence of diplopia in only  one of the four patients. No significant correlation between botulinum A toxin doses  injected and times to recovery was noted. CONCLUSIONS: Diplopia following  botulinum A toxin treatment is uncommon. Seven patients (3% of patients studied) had 22  episodes of diplopia (88% of episodes).

When diplopia occurs, it tends to recur on  reinjection, sometimes with a prolonged recovery time. This response may not be dose  dependent. The extraocular muscles of some patients may be more susceptible to  chemodenervation than others, or botulinum A toxin may diffuse to extraocular muscles  more easily in some patients than in others. 

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78.) Prevalence of periocular depigmentation after repeated botulinum toxin A injections  in African American patients. 

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J Neuroophthalmol 1999 Mar;19(1):7-9 

Roehm PC, Perry JD, Girkin CA, Miller NR 

Neuro-Ophthalmology Unit, The Johns Hopkins Medical Institutions, Baltimore,  Maryland, USA. 

Botulinum toxin A (Botox), administered by subcutaneous or intramuscular injection, is  the most commonly used and most successful medication for many craniocervical  dystonias. Although some patients experience side effects related to the neuroparalytic  action of the medication, these side effects are temporary.

In 1996, permanent periocular  cutaneous depigmentation was reported in three white patients after repeated Botox  injections, suggesting that loss or alteration of melanin pigment might be a permanent side  effect of long-term Botox injections.

The authors examined and photographed 26 African  American patients who were receiving periocular Botox injections for hemifacial spasm  and essential blepharospasm. The authors found no evidence of periocular cutaneous  depigmentation in any of these patients. 

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79.) Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical  dystonia. 

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Neurology 1997 May;48(5):1440-2 

Ansved T, Odergren T, Borg K 

Department of Neurology, Karolinska Institute, Karolinska Hospital, Stockholm,  Sweden. 

Previous electrophysiologic studies on the effects of local injections of botulinum toxin  type A (BTX-A) have indicated impaired neuromuscular transmission in distant muscles.  To further study possible distant effects of repeated BTX-A injections, we obtained  percutaneous muscle biopsies of the vastus lateralis muscle from 11 patients with cervical  dystonia. We examined the biopsies with histopathology and morphometry, and  compared them with age-matched healthy controls. There was an increased frequency of  angular atrophic type IIB fibers in the patient group, and the mean size of IIB fibers was  significantly smaller (p < 0.05).

In addition, there was a negative correlation between  accumulated dose of botulinum toxin and relative size of type IIA fibers (p < 0.05). We  postulate that the observed atrophy is due to distant effects of botulinum toxin causing  progressive denervation-like changes in non-treated muscle. This observation calls for  further, prospective studies of the long-term effects of the treatment. 

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80.) Acute anxiety and depression induced by loss of sensation and muscle control after  botulinum toxin A injection. 

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South Med J 1999 Jul;92(7):738 

Brenner R, Madhusoodanan S, Korn Z, Spitzer M 

Publication Types: 

Letter