Botulism

Gastrointest Endosc, 2001 Dec, 54(6), 754 - 9
Treatment of symptomatic diffuse esophageal spasm by endoscopic injections of botulinum toxin: a prospective study with long-term follow-up; Storr M et al.; BACKGROUND: Diffuse esophageal spasm is a rare esophageal motility disorder for which there are no satisfactory pharmacologic alternatives for treatment . The aim of this study was to investigate whether botulinum toxin (BTX) injection is an effective short- and long-term treatment for patients with symptoms caused by diffuse esophageal spasm . Whether recurrence of clinical symptoms can be successfully retreated by BTX injection was also studied . METHODS: Nine symptomatic patients (6 women, 3 men; 57-86 years) with manometrically proven diffuse esophageal spasm underwent BTX injection . One hundred IU BTX were diluted in l0 mL of saline solution and injected endoscopically at multiple sites along the esophageal wall beginning in the region of the lower esophageal sphincter and moving proximally in 1- to 1.5-cm intervals, and into endoscopically visible contraction rings . Symptom scores based on an analogue scale for dysphagia, regurgitation, and noncardiac chest pain were assessed before and after therapy, 1 day thereafter, and at 1 and 6 months . RESULTS: Symptoms improved immediately in 7 (78%) patients after 1 injection session . After 4 weeks 8 (89%) patients were in remission with a decrease in total symptom score . The total symptom score decreased from a median 8.0 (interquartile range: 6.75; 9.0) before treatment to 2.0 (1.5; 3.75) after 1 day (p < 0.01) and to 2.0 (interquartile range: 0.75; 3.0) after 1 month (p < 0.01) . After 6 months all 8 patients with a response at 1 month still had a symptom score of 3 or less without further treatment . Subsequently 4 patients required reinjection 8, 12, 15, or 24 months after the initial treatment with similarly good results . No serious adverse effects were observed . CONCLUSIONS: BTX injection at several levels of the tubular esophagus is an effective treatment for patients with symptoms caused by diffuse esophageal spasm . Symptom relapse can be effectively treated by repeated BTX injection.

Invest Ophthalmol Vis Sci, 2001 Dec, 42(13), 3158 - 64
Long-term changes in myosin heavy chain composition after botulinum toxin a injection into rat medial rectus muscle; Kranjc BS et al.; PURPOSE: To study long-term changes of extraocular muscles after botulinum toxin (Botx) A-induced paralysis, with special emphasis on myosin heavy chain (MyHC) isoform pattern in muscle fibers . METHODS: Botx A (5 IU) was injected into the ocular medial rectus (MR) muscles of adult rats . After 1, 5, and 8 months muscle cross sections were examined immunohistochemically, histochemically, and morphometrically . MyHC content was analyzed by gel electrophoresis . RESULTS: Paralyzed MR muscles displayed mildly atrophic and hypertrophic muscle fibers and decreased oxidative metabolism, due to decreased succinate dehydrogenase activity . However, muscle morphology was not grossly disturbed . MyHC profile was shifted toward slower isoforms . Electrophoretic analysis showed that the share of MyHCI, and especially of MyHCIIa and MyHCIIx/d, increased several fold, whereas the share of MyHCIIb decreased heavily during the first 5 months . Immunohistochemical analysis generally mirrored the results obtained by electrophoresis . Moreover, specific extraocular MyHC isoform MyHCeom disappeared and could not be detected during the whole experimental period . The portion of MyHCIIb relatively increased 8 months after Botx A injection, although the MyHC profile was still far from normal . CONCLUSIONS: These long-lasting changes in Botx A-paralyzed ocular MR muscles most probably reflect their inability to regain their unique functional characteristics after new motor end plate formation and recovery of muscle contraction.

Phys Med Rehabil Clin N Am, 2001 Nov, 12(4), 833 - 74, vii-viii
Botulinum neurotoxin intramuscular chemodenervation . Role in the management of spastic hypertonia and related motor disorders; Yablon SA; There is a range of interventions available in the management of spastic hypertonia among patients with central nervous system injury . Many of these treatment options can be used concurrently with great effectiveness . Although manifestations of spastic hypertonia vary from patient to patient, they usually are not limited to one site . Nevertheless, problematic spastic muscle overactivity may be localized to one or more specific extremities, and these may be referred to as examples of focal dysfunctional spasticity . Botulinum neurotoxin (BTX) intramuscular chemodenervation procedures are an important therapeutic technique in focal spasticity management . Magnitude and duration of response varies with successful selection and localization of targeted muscles, spasticity severity, BTX dosage, and chosen functional goals . In focal dysfunctional spasticity and related motor disorders, BTX injections have demonstrated efficacy and safety when performed by clinicians familiar with the agent, regional anatomy, the specific condition, and patient being treated.

Curr Opin Neurol, 2001 Dec, 14(6), 771 - 6
Botulinum treatment of spasticity: why is it so difficult to show a functional benefit?
Sheean GL.
Clinical experience seems to indicate that botulinum toxin injections can, in selected patients with upper motor neurone syndrome, reduce spasticity and improve voluntary movement and active function . However, double-blind placebo-controlled trials have had difficulty showing active functional improvement, despite the clear ability of botulinum toxin to reduce spasticity . This prompts a re-analysis of the basic assumption that spasticity impairs voluntary movement and a review of the methodology of the clinical trials . Motor dysfunction is usually caused by weakness and the other "negative" features of upper motor neurone syndrome, rather than muscle overactivity . Recent research has explored the pathophysiological basis of the voluntary movement disorder, in particular the role of the various forms of motor overactivity, which might be amenable to botulinum toxin treatment . The failure of double-blind placebo-controlled clinical trials to show improvement in active function is, to a large extent, a result of their methodology, especially patient selection, injection protocols, and the choice of outcome measures . Clinical trials need to be re-designed and based upon expert experience and a better understanding of the pathophysiology of the motor disorder.

Gerontology, 2001 Nov-Dec, 47(6), 295 - 9
Spasticity: a rehabilitation challenge in the elderly; Barnes MP; There is no doubt that spasticity is a significant cause of disability in the elderly . Regrettably, it is a condition that is often poorly treated and can result in a range of unnecessary complications which can cause further problems for the disabled person and their family . There are now a number of effective treatment options . However, before such options are defined the specific goals of rehabilitation need to be clarified and an appropriate outcome measure chosen in order to determine when such goals are being met . The treatment should be multidisciplinary and input from both the physician and a physiotherapist is essential . Involvement of the elderly person with spasticity, and often their family, is also important in the education process . Simple physiotherapy interventions can be remarkably helpful, including attention to positioning and seating . The role of the physician initially focuses on oral medication . Although we still have older drugs including diazepam, baclofen and dantrolene there are now more modern drugs including tizanidine and, more recently, gabapentin . However, most spasticity is focal in origin and thus requires focal treatment . Although phenol nerve blocks are sometimes helpful the use of botulinum toxin is now to be highly recommended . There is now clear evidence of the efficacy of botulinum toxin, which has been a significant advance in our management of spasticity . More advanced and difficult to treat problems can be alleviated by intrathecal baclofen or sometimes intrathecal phenol or, as a last resort, surgical intervention . The advent of lycra garments for the overall management of more diffuse spasticity is now becoming both fashionable and effective . Conclusion: The management of spasticity in the elderly person is a significant challenge to the rehabilitation team and a combined approach can produce significant benefit for the disabled elderly person .

Dysphagia, 2001 Fall, 16(4), 244 - 8
Cricopharyngeal muscle hypertrophy associated with florid myositis; Bachmann G et al.; Hypertrophy of the cricopharyngeal muscle is a serious clinical condition that can cause severe dysphagic symptoms, including prolonged deglutition and postdeglutitive aspiration . Although the therapeutical concepts are well established, the pathogenic mechanism of cricopharyngeal hypertrophy remains unclear . We present a patient with a ten-year history of progressive dysphagia . The neurological and MRI findings were normal . However, videocineradiography showed severe hypertrophy of the cricopharyngeal muscle . This condition was first treated by injections of botulinum toxin, which did not alleviate the symptoms . Next, myotomy and muscle biopsy were performed . Histological evaluation disclosed lymphoplasmacellular florid myositis, single-fiber atrophy, and muscle fiber necrosis with phagocytosis . There were no signs of inclusion body myositis or oculopharyngeal muscular dystrophy . Our finding of severe cricopharyngeal muscle hypertrophy associated with myositis has been published previously (n = 34) . The study presented here shows cricopharyngeal dysphagia associated with various systemic diseases, including motor neuron disease, general granulomatous disease, dermatomyositis, or inclusion body myositis . Isolated changes of the cricopharyngeal muscle were described in 65% of the cases.

Zhonghua Er Bi Yan Hou Ke Za Zhi, 1998 Oct, 33(5), 291 - 3
{Blepharospasm and hemifacial spasm treated with botulinum A toxin injection}; Wang J et al.; OBJECTIVE: To study the efficacy of botulinum A toxin (BTA) injections for the treatment of blepharospasm and hemifacial spasm (HFS) . METHODS: Twelve patients with blepharospasm and thirty eight patients with HFS were treated with BTA local injections (2.5 U to 5 U for each injection) . RESULTS: Of the fifty patients, ten (86.7%) in blepharospasm and thirty two (84.2%) in HFS were completely relieved, two (13.3%) and five (13.2%) were remarkably relieved respectively, zero and one (2.6%) were partial relieved respectively . All patients experienced relief from spasm . The duration of the effect in blepharospasm were 10 to 24 weeks (mean, 18 weeks) and in HFS 14 to 32 weeks (mean, 22 weeks) . The local side effects were transient and mild, including minor facial paralysis in eight patients, ptosis in four patients and tearing in four patients . No systemic adverse and allergic reactions were noted . CONCLUSION: Botulinum A toxin local injection is a safe, effective and simple means for the treatment of blepharospasm and HFS.

Ann Otol Rhinol Laryngol, 2001 Nov, 110(11), 1045 - 50
Botulinum toxin type A induces apoptosis in nasal glands of guinea pigs; Rohrbach S et al.; Nasal hypersecretion is predominantly caused by overaction of nasal glands, which are mainly under cholinergic control . In this work, we investigated the influence of botulinum toxin A (BTA) on the nasal mucosal tissue of the maxillary sinus turbinates of guinea pigs (n = 10) that were painlessly sacrificed 10 days (short-term group) or 3 months (long-term group) after local treatment with 20 units of BTA (Botox) or 0.2 mL of 0.9% sodium chloride (control) . Histologic investigation of the nasal mucosal tissue of the BTA-treated animals (short-term group) showed degeneration of glands and ducts and apoptotic nuclei on TUNEL staining of these structures . The control animals revealed normal glandular tissue and no apoptosis . The animals of the long-term group showed almost normal glandular tissue and only a few apoptotic nuclei . In conclusion, BTA induces temporary apoptosis in the nasal glandular compartment of guinea pigs.

ORL J Otorhinolaryngol Relat Spec, 2001 Nov-Dec, 63(6), 382 - 4
Minimally invasive application of botulinum toxin type A in nasal hypersecretion; Rohrbach S et al.; We report on the effect of the local application of botulinum toxin A on nasal hypersecretion in a female patient with intrinsic rhinitis . 20 units of botulinum toxin A (Botox) was inserted into each nostril using a small sponge in close contact with the lower and middle turbinates . The effect was scored by the patient and by rhinomanometry . Nasal hypersecretion diminished clearly 5 days after the treatment . The rhinomanometric flow increased 2 weeks after the application . No side effects occurred . We conclude that this minimal invasive method of local botulinum toxin application might be a very effective and safe option for the treatment of nasal hypersecretion of different etiologies .

Arch Facial Plast Surg, 2001 Oct-Dec, 3(4), 268 - 9
Botulinum toxin A for mentalis muscle dysfunction; Papel ID et al.; OBJECTIVE: To describe the use of botulinum toxin A for treatment of mentalis muscle dysfunction secondary to failed augmentation mentoplasty . DESIGN: Clinical observations were made in the treatment of mentalis muscle dysfunction . Patients with the postmentoplasty signs of mental skin dimpling and soft tissue ptosis were injected with 20 U of botulinum toxin A and observed for visual and functional improvement . Photographs were taken for documentation . SETTING: Private facial plastic surgery practice . PATIENTS: Three patients with a history of failed augmentation mentoplasty were identified and signs/symptoms recorded . Each patient was treated with 20 U of botulinum toxin A and observed for clinical improvement . MAIN OUTCOME MEASURES: Pretreatment and posttreatment photographs of active and passive mentalis function together with patient satisfaction surveys . RESULTS: Of the 3 patients treated, all reported alleviation of the mentalis dysfunction and improved appearance . The symptoms began to return as the botulinum toxin A effects subsided . CONCLUSIONS: Botulinum toxin A is a safe and effective treatment of mentalis dysfunction secondary to failed augmentation mentoplasty . The effects are predictable, although temporary.

Biochem Soc Trans, 2001 Nov, 29(Pt 6), 742 - 5
Regulation of glycine transporters; Lopez-Corcuera B et al.; The regulation of neurotransmitter transporters is a central aspect of their physiology . Recent studies that focused on syntaxin-1 transporter interactions led to the postulation that syntaxin-1 is somehow implicated in protein trafficking . Because syntaxin-1 is involved in the exocytosis of neurotransmitters and it interacts with glycine transporter 2 (GLYT2), we stimulated exocytosis in synaptosomes and examined its effect on GLYT2 surface-expression and transport activity . We found that GLYT2 is rapidly trafficked first towards the plasma membrane and then internalized under conditions that stimulate vesicular glycine release . However, when syntaxin-1 was inactivated by pre-treatment of synaptosomes with the botulinum neurotoxin C, GLYT2 was unable to reach the plasma membrane but still was able to leave it . These results indicate the existence of a SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated regulatory mechanism that controls the surface expression of GLYT2 . Syntaxin-1 is involved in the transport of GLYT2 to, but not its retrieval from, the plasma membrane . Immunogold-labelling on purified vesicular preparations from synaptosomes showed that GLYT2 is present in small synaptic-like vesicles . This may represent neurotransmitter transporter that is being trafficked . The subcellular distribution of the glycine transporters was further examined in PC12 cells that were stably transfected with the fusions of GLYT1 and GLYT2 with green fluorescent protein . There was a clear difference in their intracellular distribution, GLYT1 being present mainly on the plasma membrane and GLYT2 being localized mainly on large, dense-core vesicles . We are trying to find signal sequences responsible for this differential localization.

Drugs, 2001, 61(13), 1921 - 43
Cervical dystonia pathophysiology and treatment options; Velickovic M et al.; Dystonia is a syndrome of sustained involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal posturing . Cervical dystonia (CD) is a form of dystonia that involves neck muscles . However, CD is not the only cause of neck rotation . Torticollis may be caused by orthopaedic, musculofibrotic, infectious and other neurological conditions that affect the anatomy of the neck, and structural causes . It is estimated that there are between 60,000 and 90,000 patients with CD in the US . The majority of the patients present with a combination of neck rotation (rotatory torticollis or rotatocollis), flexion (anterocollis), extension (retrocollis), head tilt (laterocollis) or a lateral or sagittal shift . Neck posturing may be either tonic, clonic or tremulous, and may result in permanent and fixed contractures . Sensory tricks ('geste antagonistique') often temporarily ameliorate dystonic movements and postures . Commonly used sensory tricks by patients with CD include touching the chin, back of the head or top of the head . Patients with CD are classified according to aetiology into two groups: primary CD (idiopathic--may be genetic or sporadic) or secondary CD (symptomatic) . Patients with primary CD have no evidence by history, physical examination or laboratory studies (except primary dystonia gene) of any secondary cause for the dystonic symptoms . CD is a part of either generalised or focal dystonic syndrome which may have a genetic basis, with an identifiable genetic association . Secondary or symptomatic CD may be caused by central or peripheral trauma, exposure to dopamine receptor antagonists (tardive), neurodegenerative disease, and other conditions associated with abnormal functioning of the basal ganglia . In the majority of patients with CD, the aetiology is not identifiable and the disorder is often classified as primary . Unless the aetiological investigation reveals a specific therapeutic intervention, therapy for CD is symptomatic . It includes supportive therapy and counselling, physical therapy, pharmacotherapy, chemodenervation {botulinum toxin (BTX), phenol, alcohol}, and central and peripheral surgical therapy . The most widely used and accepted therapy for CD is local intramuscular injections of BTX-type A . Currently, both BTX type A and type B are commercially available, and type F has undergone testing . Pharmacotherapy, including anticholinergics, dopaminergic depleting and blocking agents, and other muscle relaxants can be used alone or in combination with other therapeutic interventions . Surgery is usually reserved for patients with CD in whom other forms of treatment have failed.

Biochem Biophys Res Commun, 2001 Nov 16, 288(5), 1231 - 7
Site-directed mutagenesis identifies active-site residues of the light chain of botulinum neurotoxin type A; Rigoni M et al.; Botulinum neurotoxins (BoNTs) are metalloproteases which block neuroexocytosis via specific cleavage and inactivation of SNARE proteins . Such proteolysis accounts for the extreme toxicity of these neurotoxins and of their prolonged effect . The recently determined structures of BoNT/A and/B allows one to design active-site mutants to probe the role of specific residues in the proteolysis of SNARE proteins . Here we present the results of mutations of the second glutamyl residue involved in zinc coordination and of a tyrosine and a phenylalanine residues that occupy critical positions within the active site of BoNT/A . The spectroscopic properties of the purified mutants are closely similar to those of the wild-type molecule indicating the acquisition of a correct tertiary structure . Mutation of the Glu-262* nearly abolishes SNAP-25 hydrolysis as expected for a residue involved in zinc coordination . The Phe-266 and Tyr-366 mutants have reduced proteolytic activity indicating a direct participation in the proteolytic reaction, and their possible role in catalysis is discussed .

Dent Clin North Am, 2001 Oct, 45(4), 685 - 700
Headaches and their relationship to sleep; Biondi DM; Despite the complex influences of normal sleep physiology and sleep disorders on the development or presentation of headache, it is important to recognize and understand these relationships . Successful outcomes depend on the provision of treatment interventions specifically directed toward each condition . Nocturnal or early morning headaches that are associated with OSA are often eradicated after the sleep disorder is successfully managed with CPAP, oral appliances, or surgery . Substantial improvement in headache can also result from the successful management of other sleep disorders that may incite headaches such as heavy snoring, PLMS, or the various forms of insomnia . To improve headache patterns associated with bruxism and TMD, it is often necessary to formulate a multidisciplinary treatment approach that combines oral appliance therapy, stress management, biofeedback, oromandibular physical therapy, and, at times, pharmacologic treatment (i.e., tricyclic antidepressant, intramuscular botulinum toxin injections) . There are still many gaps in the understanding of the interrelationships of sleep physiology and headache pathophysiology . More well-designed clinical trials are needed so that enough data can be amassed for the formulation of evidence-based guidelines or consensus statements that can better delineate the identification, diagnostic evaluation, and treatment of sleep-related headache disorders and headaches that develop as a consequence of disordered sleep.

HNO, 2001 Oct, 49(10), 807 - 13
{Blocking secretion of exocrine glands in the head-neck area by administration of botulinum toxin A . Therapy of a rare disease picture}; Ellies M et al.; BACKGROUND: Hypersecretion disorders of the exocrine glands of the head and neck area are a therapeutic problem in the field of otorhinolaryngology . In the present study, we demonstrate the effectiveness of local injections of botulinum toxin A to block secretions of exocrine glands of the head and neck area . PATIENTS AND METHODS: Four patients suffering from hypersecretion disorders received local injections of botulinum toxin A . Two patients suffered from disorders of the salivary glands: one presented an idiopathic hypersialorrhea and another a salivary fistula after parotidectomy . A third patient suffered from epiphora and a further patient presented severe hyperhidrosis on the pilose head region . In a retrospective clinical study, the outcome of therapy was evaluated by clinical examination and chemical parameters . RESULTS: Clear blocking of secretion in the treated glands could be demonstrated in all four cases . Possible side effects of the treatment could not be observed . CONCLUSIONS: The present study was able to demonstrate a clear blocking of secretion of the exocrine glands of the head and neck region through botulinum toxin A, offering an improvement in therapy especially for the innovative indication of blocking the salivary glands of the head.

Pediatrics, 2001 Nov, 108(5), 1062 - 71
Botulinum toxin type a neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial; Koman LA et al.; BACKGROUND: Focal spasticity of the gastrocnemius-soleus muscles causes equinus gait in children with cerebral palsy (CP) . Botulinum toxin type A (BTX-A), a neuromuscular blocking agent, reduces muscle tone/overactivity in dystonia, stroke, and CP . OBJECTIVE: A prospective, open-label, multicenter clinical trial evaluated the long-term safety and efficacy of repeated intramuscular injections of BTX-A on equinus gait in CP children . METHODS: Nine centers enrolled 207 children . BTX-A injections (4 U/Kg) were given approximately every 3 months (maximum dose 200 U per treatment) . Outcome measures included a Physician Rating Scale of gait, ankle range of motion measurements, and the incidence and profile of adverse events . RESULTS: One hundred fifty-five (75%) of 207 children completed at least 1 year with a total of 302 patient years of BTX-A treatment . The mean duration of BTX-A exposure was 1.46 years per patient . Dynamic gait pattern on the Physician Rating Scale improved in 46% of patients (86/185) at first follow-up . The response was maintained in 41% to 58% of patients for 2 years . Both gait pattern and ankle position improved at every visit . The most common treatment-related adverse events included increased stumbling, leg cramps, leg weakness, and calf atrophy in 1% to 11% of patients . No treatment-related serious adverse events were reported . Only 6% (7/117) of patients with pre- and postantibody samples had both detectable antibodies and a subsequent treatment failure . CONCLUSION: BTX-A proved both safe and effective in the chronic management of focal muscle spasticity in children with equinus gait.

Gac Med Mex, 2001 Sep-Oct, 137(5), 403 - 11
{Botulin toxin as treatment for spasticity and dystonia in infantile cerebral paralysis}; Aguilar-Rebolledo F et al.; Treatment of spasticity and dystonia in PCI with Botulinum toxin A . BACKGROUND: Botulinum-A (NxTxBoA) toxin produce neuromuscular blockade, it has been effective with therapeutic purposes in strabismus, focal dystonias and spasticity . OBJECTIVE: Evaluate the therapeutically effects off NxTxBoA in cerebral palsy (CP) spastic and/or dystonic in children . Prospective study . MATERIAL AND METHODS: 12 CP patients (8 spastic and 4 spastic/dystonic) were treated with NxTxBoA in affected muscles at least for 2 doses by up 12 months . The indication was: improve limb function, to avoid surgical correction or improve hygienic or dressing . Ashworth Spasticity Scale (ASS), functional scale for Dystonic Sindou-Millet (SMS) and O'Brien Global Assessment Scale (OGAS) were used to evaluate improvement . STATISTICAL METHODS: No parametric tests, Wilcoxon's rang's test and sign test were used with p < 0.05 . RESULTS: Total doses session was 3-10 U/kg . AAS showed muscle spasticity improvement in two grades in 8 patients, and one grade in the rest (p = 0.004) . SMS showed the muscle dystonic improve up 60% in two patients improve 50% in others (p = 0.006) . OGAS demonstrated a good correlation . Mean treatment effect during 4.8 months (rank 4 to 10 m) . Two patients had side effects, general weakness, instability, and focal haematoma . CONCLUSIONS: Botulinum toxin type A proved a highly useful adjuvant therapy and conservative management in CP.

Nervenarzt, 2001 Oct, 72(10), 787 - 90
{Effectiveness of botulinum toxin A in the treatment of gustatory sweating}; Kuttner C et al.; Frey's syndrome is present in almost all patients after parotidectomy . Gustatory sweating reduces quality of life . Injections of botulinum toxin A have recently been described as effective . This study was designed to evaluate the efficacy of this new treatment . Nineteen patients with severe gustatory sweating following superficial parotidectomy were treated . One unit/cm2 botulinum toxin A was injected intracutaneously into the affected area once . Minor's starch iodine test was performed to prove the outcome of therapy 4 weeks later . Eight patients lost their sweating . However, another seven patients had some blue spots on their cheeks . In four patients whose sweating had extended beyond the hairline, remnants of gustatory sweating showed up . Overall, the affected area of gustatory sweating could be reduced by botulinum toxin A from an average of 31 cm2 before treatment to 4 cm2 after treatment . Although there were some remnants of sweating in a few patients, Frey's syndrome was gone in all cases . No side effects could be observed . Intracutaneous injections of botulinum toxin A are highly effective and safe in treatment of gustatory sweating.

Cochrane Database Syst Rev . 2001;(4):CD001332.
Anti-spasticity agents for multiple sclerosis; Shakespeare DT et al.; BACKGROUND: Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care . A variety of oral and parenteral medications are available . OBJECTIVES: To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients . SEARCH STRATEGY: Randomised controlled trials (RCTs) of anti-spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies . SELECTION CRITERIA: Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration . DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and the findings of the trials were summarised . Missing data were collected by correspondence with principal investigators . A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed . MAIN RESULTS: Twenty-three placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam and threonine) and thirteen comparative studies met the selection criteria . Only thirteen of these studies used the Ashworth scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs . Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive . REVIEWER'S CONCLUSIONS: The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing . The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.

J Eur Acad Dermatol Venereol, 2001 May, 15(3), 207 - 11
Subcutaneous curettage vs . injection of botulinum toxin A for treatment of axillary hyperhidrosis; Rompel R et al.; BACKGROUND: Axillary hyperhidrosis is a functional non-inflammatory abnormality of the eccrine sweat glands . The cause of genuine hyperhidrosis is unknown and, therefore, no specific corrective therapy is available and conservative treatment often fails . Subcutaneous sweat gland curettage of the axillae is one of the proven surgical modalities . Local injection of botulinum toxin A (BT-A) is a promising new conservative approach . OBJECTIVE: The purpose of this study was to compare the efficacy of subcutaneous curettage vs . injection of BT-A in axillary hyperhidrosis . METHODS: A total of 113 patients (36.3% males, 63.7% females) suffering from genuine axillary hyperhidrosis were treated by either subcutaneous curettage (n = 90) or local injection of BT-A (n = 23) . Median follow-up period was 23.5 months . Questionnaires were handed out to patients for a subjective assessment of symptoms before treatment, 6 months after the procedure, and at the time of last follow-up . The patients were asked to rate the amount of axillary sweating based on a score ranging from 1 (no axillary secretion) to 6 (maximum axillary secretion) . The subjective scores of sweating at rest, at high temperatures, under physical stress, under emotional stress and after spicy meals were assessed . RESULTS: The patients' subjective assessments of the overall outcome after subcutaneous curettage were 'very good' in 36.4%, 'good' in 29.9% and 'satisfactory' in 16.9% . The subjective score of axillary sweating at rest was reduced to 40.0% after 6 months, and finally to 45.7% at the end of follow-up (median: 28.2 months) . Patients treated by BT-A injection assessed outcome as 'very good' in 39.1%, 'good' in 21.7% and 'satisfactory' in 8.7% . Sweating at rest was reduced to 48.5% after 6 months, and finally to 68.8% at the end of follow-up (median: 16.1 months) . The mean duration of the antiperspiration effect of BT-A was 7.6 months (median: 7 months), but there were two cases of long durations, i.e . 14 and 18 months . CONCLUSIONS: Subcutaneous curettage and injection of BT-A both present major advantages compared with earlier methods . Subcutaneous curettage offers the same permanent efficacy but far fewer side-effects than sympathectomy, and less scarring than local excisional procedures, respectively . Of the conservative approaches BT-A is by far the most efficacious . Patients should be informed of the advantages and disadvantages of both methods.

Int J Clin Pharmacol Ther, 2001 Oct, 39(10), 460 - 3
Botulinophilia: contraindication for therapy with botulinum toxin; Harth W et al.; Botulinum toxin inhibits neuromuscular transmission and is one of the most potent toxins . It has proven to be effective in the treatment of hyperhidrosis and is being more frequently demanded for therapy . Patients with body dysmorphic disorder also seek costly treatment with botulinum toxin . This botulinophilia is a new venenophilia . Body dysmorphic disorder is defined as a preoccupation with an imagined defect in appearance . If a slight physical anomaly is present, the person's concern is markedly exessive . The patient's preoccupation causes clinically significant distress or impairment in socially, occupational, or other important areas of functioning . The sweat test according to Minor is negative . Patients with botulinophilia are among the most difficult patients managed by the dermatologist . They are demanding and time-consuming . In our clinic, 23.1% of a series of patients seeking treatment with botulinum toxin screened positive for body dysmorphic disorder . Botulinophilia is a contraindication for therapy with botulinum toxin but is an indication for psychotherapy.

Am J Physiol Heart Circ Physiol, 2001 Nov, 281(5), H2124 - 32
Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons; Morris JL et al.; The role of the soluble NSF attachment protein receptor (SNARE) protein complex in release of multiple cotransmitters from autonomic vasodilator neurons was examined in isolated segments of guinea pig uterine arteries treated with botulinum neurotoxin A (BoNTA; 50 nM) . Western blotting of protein extracts from uterine arteries demonstrated partial cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) to a NH2-terminal fragment of approximately 24 kDa by BoNTA . BoNTA reduced the amplitude (by 70-80%) of isometric contractions of arteries in response to repeated electrical stimulation of sympathetic axons at 1 or 10 Hz . The amplitude of neurogenic relaxations mediated by neuronal nitric oxide (NO) was not affected by BoNTA, whereas the duration of peptide-mediated neurogenic relaxations to stimulation at 10 Hz was reduced (67% reduction in integrated responses) . In contrast, presynaptic cholinergic inhibition of neurogenic relaxations was abolished by BoNTA . These results demonstrate that the SNARE complex has differential involvement in release of cotransmitters from the same autonomic neurons: NO release is not dependent on synaptic vesicle exocytosis, acetylcholine release from small vesicles is highly dependent on the SNARE complex, and neuropeptide release from large vesicles involves SNARE proteins that may interact differently with regulatory factors such as calcium.

Pediatr Surg Int, 2001 Sep, 17(7), 521 - 3
The treatment of internal anal sphincter achalasia with botulinum toxin; Messineo A et al.; Internal anal sphincter (IAS) achalasia is a disorder of defecation in which the IAS fails to relax . Botulinum toxin (BT), which has been successfully used to relax the anal and lower esophageal sphincters, was injected twice into the IAS of one adolescent and three infants with manometric, radiologic, and in 2 cases histochemical diagnosis of anal achalasia: in the adolescent a third injection was necessary . Spontaneous defecation was achieved in all patients following the second injection . In one case a diagnosis of short-segment Hirschsprung's disease was obtained after the second injection . Local infiltration of BT into the IAS proved effective in the treatment of IAS achalasia . Double-blind studies and longer follow-up periods are needed to better evaluate these preliminary results and define the limits of this promising therapy.

Ann Otol Rhinol Laryngol, 2001 Oct, 110(10), 941 - 5
Adductor spasmodic dysphonia and botulinum toxin treatment: the effect on well-being; Langeveld TP et al.; Adductor spasmodic dysphonia (AdSD) is a controversial and enigmatic voice disorder . It is generally accepted that it has a neurologic, although undetermined, cause, and it is accompanied by much psychological and physical distress . In this prospective study, standardized psychometric tests were used to assess the personality characteristics and psychological and somatic well-being of 46 patients with AdSD . Moreover, the effect of botulinum toxin (Botox) treatment on their well-being was evaluated . No significant differences could be detected between patients and a representative norm group concerning 7 personality characteristics . Nevertheless, before treatment, there were significantly more psychological and somatic complaints . After establishment of a normal to near-normal voice with Botox injections, these complaints were reduced to normal levels--a finding suggesting these phenomena to be secondary to the voice disorder . These findings, and the normal personality characteristics, do not support a psychogenic cause of AdSD.

J AAPOS, 2001 Oct, 5(5), 327 - 8
Traumatic rupture of the medial rectus muscle; Ling R et al.; Traumatic rupture of an extraocular muscle, in the absence of significant injury to the globe and adnexa, is uncommon . We report the case of a patient with an isolated mid-belly rupture of the medial rectus muscle following ocular trauma and describe the technique of repairing the ruptured muscle by suturing the distal segment to the Tenon sleeve of the proximal segment . This was combined with postoperative botulinum toxin injection to the ipsilateral lateral rectus muscle . Good primary position alignment was achieved 7 months after surgery . The patient regained a useful horizontal field of binocular single vision totaling 27 degrees.

Toxicon, 2001 Dec, 39(12), 1815 - 20
A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice; Aoki KR; This study compared the respective intramuscular (IM) safety margins of two preparations of botulinum toxin (BTX) serotype A and one preparation each of BTX serotypes B and F in mice . Mice received an IM injection (0-200 U kg(-1) body weight) of BTX-A (BOTOX or DYSPORT), an experimental preparation of BTX-B (WAKO Chemicals, Inc.), or an experimental preparation of BTX-F (WAKO) . An observer who was masked to treatment scored muscle weakness using the Digit Abduction Scoring (DAS) assay . Peak DAS responses were plotted and IM ED(50) values calculated . The safety margin for each BTX preparation was calculated as a ratio of the IM median lethal dose after hind limb injection to the median effective dose in the DAS assay (IM LD(50)/IM ED(50)) . Experiments were repeated 4-6-times for each preparation (10 mice/dose) . Mean safety margin values were highest for BTX-F (WAKO; 16.7+/-3.9) and one of the BTX-A preparations (BOTOX; 13.9+/-1.7) . Mean safety margins values for the other BTX-A preparation (DYSPORT) and BTX-B (WAKO) were significantly lower (7.6+/-0.9 and 4.8+/-1.1, respectively) . Thus, the BTX preparations exhibited different safety margins in mice . These results support the hypothesis that the preparations are unique therapeutics and are not interchangeable based on a simple dose ratio.

Spine, 2001 Oct 15, 26(20), 2283 - 8
Spinal lordosis with marked opisthotonus secondary to dystonia musculorum deformans: case report with surgical management; Fricka KB et al.; STUDY DESIGN: A case report of severe spinal lordosis with marked opisthotonus and retrocollis secondary to dystonia musculorum deformans is presented . OBJECTIVE: To describe a case of dystonia musculorum deformans with progressive spinal lordosis and its surgical treatment . SUMMARY OF BACKGROUND DATA: Four patients with correction of coronal spinal deformity associated with dystonia musculorum deformans have been reported in the literature . No reports of sagittal spinal deformity treated with surgical instrumentation and fusion were found . METHODS: A retrospective chart and radiographic review of a single case was conducted . RESULTS: Orthotic management and pharmacologic therapy with botulinum toxin injections were unsuccessful in controlling the deformity . Severe spinal lordosis (170 degrees ) from occiput to sacrum was corrected surgically, allowing an upright posture . CONCLUSION: Dystonia musculorum deformans is a rare condition resulting in coronal or sagittal plane deformities . When other treatment methods are unsuccessful, surgical instrumentation and arthrodesis may correct the deformity and improve function.

Neurophysiol Clin, 2001 Aug, 31(4), 239 - 46
Interventional neurophysiology of the sacral nervous system; Vodusek DB; Clinical neurophysiological tests have been introduced for the sacral neuromuscular system to aid with diagnosis of neurogenic conditions involving the lower urinary tract, anorectal and sexual dysfunction . The tests have, however, the potential to be of value in different interventions outside of the neurophysiological laboratory . EMG monitoring can be used for exact application of botulinum toxin by the relatively non-invasive transcutaneous approach in treatment of male detrusor sphincter dyssynergia . Checking for compound muscle action potentials of the external anal sphincter is proposed as the best method for exact placement of wire electrodes close to the 3rd sacral roots in treating lower urinary tract dysfunction by 'neuromodulation' . Presently the most established use of clinical neurophysiological techniques--outside the laboratory--as related to the sacral neuromuscular system is in the operating theatre . These tests have been introduced to identify relevant structures, for instance pudendal afferents within dorsal sacral roots, which should be spared during rhizotomy procedures for treatment of spasticity . Modified techniques are used intraoperatively to monitor the integrity of the lower sacral reflex arc (the bulbocavernosus reflex) or the lower sacral afferents throughout the spinal cord (pudendal SEP) . Clinical neurophysiological tests are expected to become established in several interventions involving the sacral neuromuscular system.

Neurophysiol Clin, 2001 Aug, 31(4), 220 - 9
Botulinum toxin in motor disorders: practical considerations with emphasis on interventional neurophysiology; Traba Lopez A et al.; After a brief review of the pharmacological properties of the botulinum toxin (BT), its mechanism of action on the nerve endings of the neuromuscular junctions, and the general therapeutic principles and adverse side effects, we discuss the advantages of interventional neurophysiology for the treatment of focal motor disorders by means of botulinum toxin A (BTA) muscle infiltration . Electromyography (EMG) provides a valuable objective information in the diagnosis of many motor disturbances and enables the precise identification of the muscles that contribute to the abnormal movement or posture . The use of EMG guidance for BTA injection seems advisable in every muscle but it become indispensable in those difficult to access, deeply located or partially atrophied by previous toxin infiltrations . The EMG study also serves to localise the areas with the highest abnormal activity and the motor point of the muscle, where the injection of toxin exerts its maximal effect . Consequently, lower doses of BTA can be employed without decreasing the efficacy of treatment but reducing the potential risk of side effects, antibody production and the cost of treatment . Electrophysiological diagnosis and BTA treatment may be performed during the same exploration . Considerations on the particular aspects and lines of action are given referring to the main focal muscular hyperactivity motor disorders such as cervical, oromandibular and laryngeal dystonias, blepharospasm, writer's cramp, hemifacial and hemimasticatory spasms, infantile and adult forms of spasticity and some other focal disturbances such as strabismus, detrusor-sphincter dyssynergia and anismus.

J Biol Chem, 2001 Dec 7, 276(49), 45979 - 87 Epub 2001 Oct 04.
Constitutive activation of NF-kappa B and secretion of interleukin-8 induced by the G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus involve G alpha(13) and RhoA; Shepard LW et al.; The Kaposi's sarcoma herpesvirus (KSHV) open reading frame 74 encodes a G protein-coupled receptor (GPCR) for chemokines . Exogenous expression of this constitutively active GPCR leads to cell transformation and vascular overgrowth characteristic of Kaposi's sarcoma . We show here that expression of KSHV-GPCR in transfected cells results in constitutive transactivation of nuclear factor kappa B (NF-kappa B) and secretion of interleukin-8, and this response involves activation of G alpha(13) and RhoA . The induced expression of a NF-kappa B luciferase reporter was partially reduced by pertussis toxin and the G beta gamma scavenger transducin, and enhanced by co-expression of G alpha(13) and to a lesser extent, G alpha(q) . These results indicate coupling of KSHV-GPCR to multiple G proteins for NF-kappa B activation . Expression of KSHV-GPCR led to stress fiber formation in NIH 3T3 cells . To examine the involvement of the G alpha(13)-RhoA pathway in KSHV-GPCR-mediated NF-kappa B activation, HeLa cells were transfected with KSHV-GPCR alone and in combination with the regulator of G protein signaling (RGS) from p115RhoGEF or a dominant negative RhoA(T19N) . Both constructs, as well as the C3 exoenzyme from Clostritium botulinum, partially reduced NF-kappa B activation by KSHV-GPCR, and by a constitutively active G alpha(13)(Q226L) . KSHV-GPCR-induced NF-kappa B activation is accompanied by increased secretion of IL-8, a function mimicked by the activated G alpha(13) but not by an activated G alpha(q)(Q209L) . These results suggest coupling of KSHV-GPCR to the G alpha(13)-RhoA pathway in addition to other G proteins.

J Neurosci, 2001 Oct 15, 21(20), 8270 - 7
Coincident spiking activity induces long-term changes in inhibition of neocortical pyramidal cells; Holmgren CD et al.; In pyramidal cells, induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission by coincidence of presynaptic and postsynaptic activity is considered relevant to learning processes in vivo . Here we show that temporally correlated spiking activity of a pyramidal cell and an inhibiting interneuron may cause LTD or LTP of unitary IPSPs . Polarity of change in synaptic efficacy depends on timing between Ca(2+) influx induced by a backpropagating train of action potentials (APs) in pyramidal cell dendrites (10 APs, 50 Hz) and subsequent activation of inhibitory synapses . LTD of IPSPs was induced by synaptic activation in the vicinity of the AP train (<300 msec relative to the beginning of the train), whereas LTP of IPSPs was initiated with more remote synaptic activation (>400 msec relative to the beginning of the AP train) . Solely AP trains induced neither LTP nor LTD . Both LTP and LTD were prevented by 5 mm BAPTA loaded into pyramidal cells . LTD was prevented by 5 mm EGTA, whereas EGTA failed to affect LTP . Synaptic plasticity was not dependent on activation of GABA(B) receptors . It was also not affected by the antagonists of vesicular exocytosis, botulinum toxin D, and GDP-beta-S.

Br J Pharmacol, 2001 Oct, 134(3), 507 - 20
Determination of effects of antiepileptic drugs on SNAREs-mediated hippocampal monoamine release using in vivo microdialysis; Murakami T et al.; 1 . To elucidate possible mechanisms underlying the effects of carbamazepine (CBZ), valproate (VPA) and zonisamide (ZNS) on neurotransmitter exocytosis, the interaction between these three antiepileptic drugs (AEDs) and botulinum toxins (BoNTs) on basal, Ca(2+)- and K(+)-evoked release of dopamine (DA) and serotonin (5-HT) were determined by microdialysis in the hippocampus of freely moving rats . 2 . Basal release of monoamine was decreased by pre-microinjection of the syntaxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhibitor, BoNT/B . Ca(2+)-evoked release was inhibited by BoNT/C selectively . K(+)-evoked release was reduced by BoNT/B predominantly and BoNT/C weakly . 3 . Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively . Perfusion with VPA increased basal 5-HT release concentration-dependently, whereas basal DA release was affected by VPA biphasic concentration-dependently, similar to CBZ and ZNS . This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly . 4 . Ca(2+)-evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations . These effects of the AEDs on Ca(2+)-evoked release were inhibited by BoNT/C, but not by BoNT/B . 5 . K(+)-evoked monoamine release was reduced by AEDs concentration-dependently . The inhibitory effect of these three AEDs on K(+)-evoked release was inhibited by BoNT/B, but not by BoNT/C . 6 . These findings suggest that the therapeutic-relevant concentration of CBZ, VPA and ZNS affects exocytosis of DA and 5-HT, the enhancement of syntaxin-mediated monoamine release during resting stage, and the inhibition of synaptobrevin-mediated release during depolarizing stage.

Eye, 2000 Dec, 14(Pt 6), 873 - 8
Efficacy and complications of dose increments of botulinum toxin-A in the treatment of horizontal comitant strabismus; Sener EC et al.; PURPOSE: To investigate the efficacy and complications associated with dose increments of botulinum toxin-A (BTA) for comitant horizontal strabismus patients . METHODS: Twenty-five esotropic (ET) and 45 exotropic (XT) patients received 2.5-20 U of BTA injection . Parameters for achieving less than 10 prism dioptres (pd) of horizontal deviation and percentage correction of the pretreatment deviation were assessed for injections of less than 10 U and more than 10 U of BTA . Induced ptosis and vertical deviation were examined within and after 6 months of follow-up . RESULTS: The mean pretreatment deviations were 38.6 +/- 2.5 pd and 37.6 +/- 1.9 pd for the ET and XT groups, respectively . After receiving 1.6 and 1.5 injections on average, improvement to less than 10 pd at the primary position occurred in 32% of ET and 22% of XT patients; the difference was not statistically significant . The percentage corrections of the ET patients were 41.4 +/- 9.3% and 36.9 +/- 5.6% in those treated with less than 10 U and more than 10 U of BTA respectively; the difference between the two groups was insignificant . For the XT patients the values were 42.1 +/- 7.4% and 28.9 +/- 3.5% respectively, which also were not statistically significantly different . Frequency of induced ptosis was more common in ET than XT patients (p = 0.01) and this difference was more pronounced with increased doses of BTA (7.7% in ET and 5.3% in XT patients with less than 10 U of BTA, and 24.0% in ET and 4.3% in XT patients with more than 10 U of BTA) . Ptosis resolved completely within 6 weeks in all cases . Induced vertical deviation with less than 10 U of BTA was encountered in one case of ET (11.1%, 9 pd) and in another case of XT (8.3%, 4 pd), increasing to 60.0% (2-20 pd) and 38.8% (4-16 pd) respectively with more than 10 U of BTA injection . In about a year, induced vertical deviation resolved in approximately 40%, and decreased in 30% of the cases . CONCLUSION: Increasing the dose of BTA is clinically effective in larger deviations, although statistically indifferent, especially in ET compared with XT . However, an increased dose is accompanied by increased incidence of induced ptosis and vertical deviation . Ptosis is temporary, but vertical deviation may persist for a long time and may present a cosmetic problem for some patients when more than 10 U of BTA is used.

Invest Ophthalmol Vis Sci, 2001 Oct, 42(11), 2542 - 6
Long-term outcome and predictor variables in the treatment of acquired esotropia with botulinum toxin; Tejedor J et al.; PURPOSE: To determine the long-term results of botulinum therapy in acquired esotropia and to identify predictors of a satisfactory outcome . METHODS: Sixty-eight children (age range, 8-64 months) with acquired esotropia were enrolled in a prospective study . Botulinum toxin A was injected in the two medial recti . Motor and sensory statuses were evaluated at 1 and 2 weeks; 3, 6, and 12 months; and every year after the last injection . Univariate and multivariate logistic regression analyses were performed to relate motor and sensory outcome to variables recorded as potential predictors . RESULTS: After an average follow-up of 4.8 years since the last injection, motor success was obtained in 36 children with one injection (52.9%), increasing to 48 (70.6%) and 60 (88.2%) children after two and three injections, respectively . Forty-eight (70.6%) patients had at least peripheral fusion (category 1 binocularity) and 32 (47.1%) had stereoacuity of at least 400 seconds of arc (category 2 binocularity) . Higher hypermetropia, less severe amblyopia, and a smaller angle of esotropia were the best predictors of motor success . Minimal amblyopia and favorable motor alignment were associated with better binocularity outcome . CONCLUSIONS: Botulinum is an effective long-term treatment of acquired esotropia . It is especially useful in children with high hypermetropia, minimal amblyopia, and small esotropic deviation.

Clin Lab Med, 2001 Sep, 21(3), 593 - 605
Toxins as weapons of mass destruction . A comparison and contrast with biological-warfare and chemical-warfare agents; Madsen JM; Toxins are toxic chemical compounds synthesized in nature by living organisms . Classifiable by molecular weight, source, preferred targets in the body, and mechanism of action, they include the most potent poisons on the planet, although considerations of production, weaponization, delivery, environmental stability, and host factors place practical limits on their use as WMD . The two most important toxin threats on the battlefield or in bioterrorism are probably botulinum toxin (a series of seven serotypes, of which botulinum toxin A is the most toxic for humans) and SEB, an incapacitating toxin . Ricin and the trichothecene mycotoxins, including T-2 mycotoxin, are of lesser concern but are still potential threats . Botulinum toxin is a neurotoxin, ricin and trichothecene mycotoxins are membrane-damaging proteins, and SEB is a superantigen capable of massive nonspecific activation of the immune system . The clinical intoxications resulting from exposure to and absorption (usually by inhalation) of these agents reflect their underlying pathophysiology . Because of the hybrid nature of toxins, they have sometimes been considered CW agents and sometimes BW agents . The current trend seems to be to emphasize their similarities to living organisms and their differences from CW agents, but examination of all three groups relative to a number of factors reveals both similarities and differences between toxins and each of the other two categories of non-nuclear unconventional WMD . The perspective that groups toxins with BW agents is logical and very useful for research and development and for administrative and treaty applications, but for medical education and casualty assessment, there are real advantages in clinician use of assessment techniques that emphasize the physicochemical behavior of these nonliving, nonreplicating, intransmissible chemical poisons.

Traffic, 2001 Oct, 2(10), 717 - 26
Actin microfilaments facilitate the retrograde transport from the Golgi complex to the endoplasmic reticulum in mammalian cells; Valderrama F et al.; The morphology and subcellular positioning of the Golgi complex depend on both microtubule and actin cytoskeletons . In contrast to microtubules, the role of actin cytoskeleton in the secretory pathway in mammalian cells has not been clearly established . Using cytochalasin D, we have previously shown that microfilaments are not involved in the endoplasmic reticulum-Golgi membrane dynamics . However, it has been reported that, unlike botulinum C2 toxin and latrunculins, cytochalasin D does not produce net depolymerization of actin filaments . Therefore, we have reassessed the functional role of actin microfilaments in the early steps of the biosynthetic pathway using C2 toxin and latrunculin B . The anterograde endoplasmic reticulum-to-Golgi transport monitored with the vesicular stomatitis virus-G protein remained unaltered in cells treated with cytochalasin D, latrunculin B or C2 toxin . Conversely, the brefeldin A-induced Golgi membrane fusion into the endoplasmic reticulum, the Golgi-to-endoplasmic reticulum transport of a Shiga toxin mutant form, and the subcellular distribution of the KDEL receptor were all impaired when actin microfilaments were depolymerized by latrunculin B or C2 toxin . These findings, together with the fact that COPI-coated and uncoated vesicles contain beta/gamma-actin isoforms, indicate that actin microfilaments are involved in the endoplasmic reticulum/Golgi interface, facilitating the retrograde Golgi-to-endoplasmic reticulum membrane transport, which could be mediated by the orchestrated movement of transport intermediates along microtubule and microfilament tracks.

J Neurol Sci, 2001 Sep 15, 190(1-2), 95 - 7
Recurrent jaw dislocation after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis; Tan EK et al.; Botulinum toxin (BTX) has been used successfully to treat various movement disorders, and is increasingly used for many other medical conditions . Sialorrhoea is a disabling symptom in many neurological patients including those with Parkinson's disease, stroke and amyotrophic lateral sclerosis (ALS) . BTX has recently been shown to be effective for treating sialorrhoea.We report an ALS patient who developed recurrent jaw dislocation following BTX treatment for sialorrhoea to highlight the observation that intraparotid BTX may be complicated by jaw dislocations in some at-risk ALS patients . Clinicians using BTX to treat sialorrhoea in ALS need to be aware of this potentially serious complication.

J Am Acad Dermatol, 2001 Oct, 45(4), 508 - 14
Quantification of the efficacy of botulinum toxin type A by digital image analysis; Heckmann M et al.; BACKGROUND: Botulinum toxin type A (BT-A) is increasingly being used by dermatologists for correction of frown lines . Because objective measurements of clinical results appear to be difficult, several different treatment protocols have been issued purely empirically or on the basis of subjective ratings . OBJECTIVE: Our purpose was to establish objective parameters to measure the efficacy of BT-A for correction of hyperkinetic facial lines . METHODS: Thirty consecutive patients received BT-A injections for correction of facial expression lines . For each patient a full range of facial expressions was recorded by means of a digital imaging system that allowed identical positioning and illumination before and after treatment . Computer-assisted measurements of brow mobility were used to measure muscular paralysis . RESULTS: Reproducibility of serial photographs by means of a digital overlay technique was confirmed by 4 independent observers . Upward mobility of brows was decreased to 35% at 2 weeks and 71% at 12 weeks after treatment . In contrast, inward mobility (frowning) was decreased to 7% at 2 weeks and 57% at 12 weeks . Brow-to-brow distance in repose increased with treatment by 13% and displayed a negative correlation with age . CONCLUSION: The effects of BT-A on upper face muscular activity can reproducibly be measured by digital image analysis; this is a valuable tool for clinical documentation and evaluation of treatment efficacy . Onset and offset of the effects of BT-A display a longer time course than previously assumed . Tissue qualities such as elasticity contribute measurably to smoothing facial expression lines after BT-A treatment and correlate inversely with age.

J Protein Chem, 2001 Apr, 20(3), 221 - 31
Enzymatic autocatalysis of botulinum A neurotoxin light chain; Ahmed SA et al.; Highly purified recombinant zinc-endopeptidase light chain of the botulinum neurotoxin serotype A underwent autocatalytic proteolytic processing and fragmentation . In the absence of added zinc, initially 10-28 residues were cleaved from the C-terminal end of the 448-residue protein followed by the appearance of an SDS-stable dimer and finally fragmentation near the middle of the molecule . In the presence of added zinc, the rate of fragmentation was accelerated but the specificity of the cleavable bond changed, suggesting a structural role for zinc in the light chain . The C-terminal proteolytic processing was reduced, and fragmentation near the middle of the molecule was prevented by adding the metal chelator TPEN to the light chain . Similarly, adding a competitive peptide inhibitor (CRATKML) of the light-chain catalytic activity also greatly reduced the proteolysis . With these results, for the first time, we provide clear evidence that the loss of C-terminal peptides and fragmentation of the light chain are enzymatic and autocatalytic . By isolating both the large and small peptides, we sequenced them by Edman degradation and ESIMS-MS, and mapped the sites of proteolysis . We also found that proteolysis occurred at F266-G267, F419-T420, F423-E424, R432-G433, and C430-V431 bonds in addition to the previously reported Y250-Y251 and K438-T439 bonds.

Neurosurgery, 2001 Oct, 49(4), 847 - 54; discussion 854-6
Delayed resolution of residual hemifacial spasm after microvascular decompression operations; Ishikawa M et al.; OBJECTIVE: After microvascular decompression to treat hemifacial spasm (HFS), resolution of the HFS is often gradual . We carefully investigated the course of the gradual resolution of HFS and examined the differences between patients with and without postoperative HFS . METHODS: One hundred seventy-five patients with HFS were monitored, for observation of 1) whether postoperative HFS occurred, 2) when it occurred, and 3) when it disappeared after microvascular decompression . For two groups of patients, with (Group I) and without (Group II) postoperative HFS, we investigated age, sex, spasm side, preoperative facial nerve block (botulinum toxin treatment), decompression material, preoperative HFS period, offender (compressing vessel), temporary and permanent postoperative complications, and electromyographic findings . RESULTS: In Group I (88 patients), postoperative HFS began within 4 days after surgery, a period that we have termed the silent period of postoperative HFS; the median value for the time to resolution was 28 days . The other 87 patients exhibited no postoperative HFS (Group II) . There was a significantly higher incidence of postoperative facial weakness in Group II (Group II, 41.3%; Group I, 25.5%; P = 0.02 by logistic regression analysis) . In Group I, there was no statistically significant relationship between the investigated parameters and the silent period or the postoperative HFS period, as determined by Cox proportional-hazards regression analysis, except for the number of preoperative facial nerve blocks . Electromyographic investigation of F waves revealed facial paresis during the silent period in a patient . CONCLUSION: Approximately 50% of patients with HFS exhibited residual spasm postoperatively . An immediate postoperative silent period of 4 days without spasm was characteristic . One-quarter, one-half, and 90% of the residual spasm resolved by 1 week, 1 month, and 8 months after surgery, respectively.

J Neurol Neurosurg Psychiatry, 2001 Oct, 71(4), 499 - 504
Social phobia in spasmodic torticollis; Gundel H et al.; OBJECTIVES: To study the prevalence of psychiatric comorbidity assessed by the use of a structured clinical interview in a large, representative sample of patients with spasmodic torticollis (ST) and to test the hypothesis that social phobia would be highly prevalent . METHODS: In a consecutive cohort of 116 patients with ST treated with botulinum toxin overall psychiatric comorbidity was studied prospectively with the structured clinical interview (SCID) for DSM-IV axis I disorders . Physical disability and psychosocial variables were also assessed with standardised self rating questionnaires . RESULTS: 41.3% of the subjects met DSM-IV clinical criteria A-G for current social phobia as the primary psychiatric diagnosis . This figure rose to 56% including secondary and tertiary psychiatric diagnosis . There was no correlation between severity of disease (Tsui score, severity of pain, body image dissatisfaction score) and psychiatric comorbidity . The only significant predictor of psychiatric comorbidity was depressive coping behaviour (logistic regression analysis, p < 0.01; OR=10.8) . Compared with a representative sample of the general adult population, in the patients with ST the prevalence of clinically relevant social phobia is 10-fold, of mood disorders 2.4-fold, and of lifetime psychiatric comorbidity 2.6-fold increased . CONCLUSIONS: A particularly high prevalence of social phobia was found in the cohort of patients with ST . The finding of a high prevalence of social phobia and depressive coping behaviour as the main predictor of psychiatric comorbidity may make a subgroup of patients with ST particularly amenable to specific psychotherapeutic interventions.

Curr Pain Headache Rep, 2001 Oct, 5(5), 407 - 11
Interventional approaches to the management of myofascial pain syndrome; Criscuolo CM; Interventional therapies are a valuable addition to our armamentarium when treating myofascial pain syndromes . When combined with other therapies, interventional techniques can be an effective adjunct in the multidisciplinary management of pain . This article describes current interventional therapies that are employed in treating myofascial pain syndromes . The mainstay of injection therapies, the myofascial trigger point injection, is emphasized . More recent advances, such as the use of botulinum toxin, are also discussed . In addition, other techniques such as acupuncture and the use of laser therapy are mentioned.

BMJ, 2001 Sep 15, 323(7313), 596 - 9
Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial; Naumann M et al.; OBJECTIVES: To evaluate the safety and efficacy of botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis . DESIGN: Multicentre, randomised, parallel group, placebo controlled trial . SETTING: 17 dermatology and neurology clinics in Belgium, Germany, Switzerland, and the United Kingdom . PARTICIPANTS: Patients aged 18-75 years with bilateral primary axillary hyperhidrosis sufficient to interfere with daily living . 465 were screened, 320 randomised, and 307 completed the study . INTERVENTIONS: Patients received either botulinum toxin type A (Botox) 50 U per axilla or placebo by 10-15 intradermal injections evenly distributed within the hyperhydrotic area of each axilla, defined by Minor's iodine starch test . MAIN OUTCOME MEASURES: Percentage of responders (patients with >/=50% reduction from baseline of spontaneous axillary sweat production) at four weeks, patients' global assessment of treatment satisfaction score, and adverse events . RESULTS: At four weeks, 94% (227) of the botulinum toxin type A group had responded compared with 36% (28) of the placebo group . By week 16, response rates were 82% (198) and 21% (16), respectively . The results for all other measures of efficacy were significantly better in the botulinum toxin group than the placebo group . Significantly higher patient satisfaction was reported in the botulinum toxin type A group than the placebo group (3.3 v 0.8, P<0.001 at 4 weeks) . Adverse events were reported by only 27 patients (11%) in the botulinum toxin group and four (5%) in the placebo group (P>0.05) . CONCLUSION: Botulinum toxin type A is a safe and effective treatment for primary axillary hyperhidrosis and produces high levels of patient satisfaction.

Arch Otolaryngol Head Neck Surg, 2001 Sep, 127(9), 1083 - 5
Outcomes of botulinum toxin treatment for patients with spasmodic dysphonia; Benninger MS et al.; BACKGROUND: Spasmodic dysphonia (SD) is a focal dystonia of the larynx . Although individuals with SD have variable degrees of difficulty in everyday communication and speaking, many report significant impairments . The impact of SD on the quality of life of people with the disorder has not been well measured . OBJECTIVES: To assess the impact of SD using a voice-specific, validated outcomes instrument, the Voice Handicap Index (VHI), and to evaluate the effect of botulinum toxin treatment on quality of life . METHODS: The VHI measures 3 subscales (physical, functional, and emotional) of impact of a voice disorder as well as a total impact score . The VHI was completed by 30 consecutive patients with SD before receiving botulinum toxin injection and 2 to 4 weeks after injection . Pretreatment scores on the VHI were compared with posttreatment scores . RESULTS: Pretreatment scores on the VHI showed significant impairment in all 3 subscales (physical, 25.5; functional, 21.4; and emotional, 20.4) and the total score (67.6) . Statistically significant improvements occurred in all 3 subscale scores and the total score (P =.001) for the 22 patients who completed the posttreatment survey . CONCLUSIONS: Spasmodic dysphonia has a significant impact on patients' perception of quality of life as measured by the VHI . Significant improvements in all 3 subscale scores and the total score on the VHI occur after treatment with botulinum toxin.

Headache, 2001 Jul-Aug, 41(7), 658 - 64
Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial; Schmitt WJ et al.; In addition to vascular and supraspinal influences, contraction of craniofacial muscles or central sensitization processes following continuous nociceptive input of craniofacial muscles may play an important role in the pathogenesis of tension-type headache . Chemodenervation induced by botulinum toxin injection is successfully used to decrease muscle tension . If muscle tension is important in this type of headache, then botulinum toxin could be helpful in its treatment . We conducted a randomized, placebo-controlled study to examine the effect of 20 U botulinum toxin injected into frontal and temporal muscles in patients with chronic tension-type headache . During a baseline of 4 weeks and a posttreatment period of 8 weeks, the effect was evaluated with daily records and the West Haven-Yale Multidimensional Pain Inventory . Some improvement in affective variables were demonstrated in the botulinum group, but important outcome variables, such as pain intensity, the number of pain-free days, and consumption of analgesics, were not statistically different between the groups . Reasons for these moderate effects may include the injection sites, dose of botulinum toxin, and duration of treatment.

Eur J Neurol, 2001 Sep, 8(5), 451 - 6
Side-effects of intradermal injections of botulinum A toxin in the treatment of palmar hyperhidrosis: a neurophysiological study; Swartling C et al.; Focal palmar hyperhidrosis can be effectively abolished by intradermal injections with botulinum toxin . Muscle weakness of finger grip has been reported as a reversible side-effect of this new treatment . The objective of this work was to measure muscular side-effects after treatment of palmar hyperhidrosis with botulinum toxin . As botulinum toxin has been used in the treatment of pain, we studied whether the toxin might influence afferent thin-fibre function by measuring temperature perception thresholds . Thirty-seven patients treated with botulinum toxin (Botox, Allergan Pharmaceuticals, Irvine, CA, USA) showed a decrease in compound muscle action potential (CMAP) for both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) compared with pre-injection values on average by 64 and 36%, respectively, at 3 weeks which returned nearly to normal at 37 weeks . Muscle power for both finger abduction and finger opposition decreased to a lesser extent . Repetitive nerve stimulation and single fibre electromyography (EMG) showed a disturbed neuromuscular transmission . Thus, despite careful technique with small doses of botulinum toxin injected intradermally, the toxin diffuses to underlying muscles . With regard to the present results, one should be careful in using higher doses of Botox than 0.8 mU/cm(2) in the palmar skin above intrinsic muscles . No influence on thin-fibre function was seen.

Infect Immun, 2001 Oct, 69(10), 6511 - 4
Epitope mapping of neutralizing botulinum neurotoxin A antibodies by phage display; Mullaney BP et al.; Single-chain antibodies neutralize activity and bind nonoverlapping epitopes of botulinum A neurotoxin . Two phage display epitope libraries were constructed from the 1.3 kb of binding domain cDNA . The minimal epitopes selected against the single-chain Fv-Fc antibodies correspond to conformational epitopes with amino acid residues 1115 to 1223 (S25), 1131 to 1264 (3D12), and 889 to 1294 (C25).

Aliment Pharmacol Ther, 2001 Sep, 15(9), 1389 - 96
Randomized controlled trial comparing botulinum toxin injection to pneumatic dilatation for the treatment of achalasia; Mikaeli J et al.; BACKGROUND: Therapeutic options for achalasia include pharmacological therapy, surgical myotomy, pneumatic dilatation and intrasphincteric botulinum toxin injection . AIM: To compare botulinum toxin injection with pneumatic dilatation in a randomized trial . PATIENTS/METHODS: Forty adults with newly diagnosed achalasia were randomized to receive botulinum toxin (n=20) or pneumatic dilatation (n=20) . Symptom scores were evaluated at 1, 6 and 12 months . Clinical relapse was defined as a symptom score greater than 50% of baseline . Relapsers received a second botulinum toxin injection or pneumatic dilatation . RESULTS: The cumulative 12-month remission rate was significantly higher after a single pneumatic dilatation (53%) compared to a single botulinum toxin injection (15%)(P < 0.01) . The 12-month estimated adjusted hazard for relapse and need for retreatment for the botulinum toxin group was 2.69 times that of the pneumatic dilatation group (95% confidence interval; 1.18-6.14) . When a second treatment was administered to the relapsers in each group, the cumulative remission rate 1 year after initial treatment was significantly higher in the pneumatic dilatation group (100%) compared to the botulinum toxin group (60%) (P < 0.01) . There were no major complications in either group . CONCLUSIONS: Pneumatic dilatation is more efficacious than botulinum toxin in providing sustained symptomatic relief in patients with achalasia . The efficacy of a single pneumatic dilatation is similar to that of two botulinum toxin injections.

Allergy Asthma Proc, 2001 Jul-Aug, 22(4), 199 - 202
Treatment update: nonallergic rhinitis; Lieberman P; Chronic nonallergic rhinitis is a diagnosis of exclusion . The pathophysiology underlying this disorder is unknown . There probably are several mechanisms involved and several different variations of this condition . Therapies which have been approved for use in the treatment of chronic nonallergic rhinitis include topical corticosteroids and azelastine . Topical corticosteroid preparations that have received approval are fluticasone, budesonide, and beclomethasone . Topical nasal saline also has been established as a beneficial adjunct to therapy in some instances . Other therapies have included capsaicin, silver nitrate, botulin toxin, and various surgical procedures . These procedures include turbinate reduction, which has been performed by a number of techniques including submucosal diathermy, cryosurgery, laser cautery, and classic resection . Ethmoidal and vidian neurectomies have been performed by excision, diathermy, and cryotherapy . These procedures have met with varying degrees of success.

Schweiz Rundsch Med Prax, 2001 Aug 23, 90(34), 1408 - 12
{Treatment of hyperfunctional facial lines with botulinum toxin}; Boni R et al.; Lines and wrinkles in the face are not only due to intrinsic and photoaging, but are also caused by lines of facial expression due to muscular action . Botulinum toxin A, which blocks the cholinergic transmission resulting in flaccid paralysis, is a powerful therapeutic tool in the treatment of frown lines, glabellar lines, crow-feet and platysma-bands . It has to be kept in mind, however, that the benefits of this treatment are transient and repeated injections are necessary . A treatment guide with injection sides and concentration of the toxin is presented in the context of the current literature.

Pediatr Neurosurg, 2001 Aug, 35(2), 57 - 65
Selective posterior rhizotomy and intrathecal baclofen for the treatment of spasticity; von Koch CS et al.; Spasticity occurs in children and adults due to a wide range of conditions, including cerebral palsy, head and spinal cord trauma, cerebrovascular accidents and multiple sclerosis . Multiple treatment options have been described, including medical and surgical treatments . Medical treatments include intramuscular botulinum A toxin, oral baclofen and supportive bracing . Surgical approaches include selective posterior rhizotomy, intrathecal baclofen and orthopedic procedures to address deformities . Many reports have been published on these different treatment options, but rarely has a comparison been made between them . Therefore, this review is aimed at comparing selective posterior rhizotomy and intrathecal baclofen injection for spasticity due to cerebral palsy, especially in children .

Eur J Pediatr, 2001 Aug, 160(8), 509 - 12
Botulinum toxin A: a new option for treatment of drooling in children with cerebral palsy . Presentation of a case series; Jongerius PH et al.; Drooling beyond the age of 4 years is pathological, particularly if it occurs in children with neurological and developmental impairment and disability . Considering the therapeutic spectrum of botulinum toxin A and in view of the innervation of the salivary glands, we postulated that intraglandular injections into the submandibular glands with botulinum toxin A could reduce the secretion of saliva and consequently decrease drooling . Three patients with cerebral palsy and severe drooling were selected and evaluated over a 4-month period . Under ultrasound guidance, one dose of botulinum toxin A was injected bilaterally into the submandibular glands . Saliva secretion was measured at baseline and repeated four times during the following 4 months . In the three patients, maximal salivary flow rate of the sublingual and submandibular glands was reduced by 51% to 63% . The time of the maximal effect differed among the three children . The parents reported a satisfactory reduction of drooling throughout the whole study period . No objectionable disturbances of oral functions were observed . There was mild transient thickening of saliva in one of the patients . CONCLUSION: The application of botulinum toxin A to the submandibular gland is a promising technique to reduce salivary flow rate and probably an alternative in the treatment of drooling in children with cerebral palsy.

Curr Opin Neurol Neurosurg, 1992 Jun, 5(3), 301 - 7
The dystonias; Markham CH; The various dystonias have been found in at least five different hereditary backgrounds . The gene responsible for one of the dystonias, idiopathic torsion dystonia (ITD), lies on chromosome 9q32-34, with flanking markers now 1-2 cM apart . Magnetic resonance imaging and computerized tomography (CT) abnormalities in the basal ganglia, especially in the putamen, are found in many secondary dystonias . Botulinum toxin therapy is proving very useful in the treatment of focal dystonias.

Clin Geriatr Med, 2001 Nov, 17(4), 769 - 94, vii
Lasers and cosmetic dermatologic surgery for aging skin; Rohrer TE; Many topical agents and physical modalities have been used throughout the years to give the face a more youthful appearance . The goal has always been to effectively and consistently rejuvenate the face while minimizing the time of recovery and risk for complications . Because each person is unique, there is no one modality that is best for everyone . This article reviews some of the options available for treating photoaged skin in 2001 . Various lasers (e.g., vascular lesion, pigmented lesion, hair removal, and resurfacing), botulinum A toxin, chemical peels, and various dermal and subcutaneous filler substances all are discussed.

Cutis, 2001 Aug, 68(2), 99 - 101
Dermatologic surgery into the next millennium, part II; Warmuth IP et al.; This is the second article in a 4-part series on dermatologic surgery . This section provides detailed information about filling agents and botulinus toxin A . The filling agents discussed here are frequently used in our office . It is emphasized that meticulous technique and patient selection predict a good cosmetic result . To select the right agent, patient safety must be a priority.

Neurol Clin, 2001 Aug, 19(3), 681 - 705, vii
Dystonia and its disorders; Friedman J et al.; Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures . The term dystonia does not signify a single disease, but instead describes a symptom and sign that may be part of many disorders with a variety of causes . Dystonia may be classified by age of onset, distribution of symptoms, or by etiology . An increasing number of genetic forms of dystonia have been recognized and the findings have advanced knowledge of underlying neural mechanisms of pathogenesis . Options for treatment of dystonia include pharmacological therapy, botulinum toxin injection, or neurosurgical procedures.

J Electromyogr Kinesiol, 2001 Aug, 11(4), 231 - 46
EMG-interference pattern analysis; Finsterer J; The EMG interference pattern, built up of single motor unit action potentials, may be analyzed subjectively, or objectively by computer aided, quantitative methods, like counting of zero-crossings, counting of spikes, amplitude measurements, integration of the area under the curve, decomposition techniques, power spectrum analysis and turn/amplitude analysis . Since the shape of the interference pattern of healthy muscles is dependent on age, sex, force, muscle, temperature, fatigue, fitness level, recording site and surrounding tissue, electrode type, sensitivity, filters, sampling frequency and threshold level, all methods of analyzing the IP have to be standardized . Quantitative methods of analyzing the EMG interference pattern may be used for monitoring botulinum toxin therapy of dystonia and spasticity, quantifying spontaneous activity, assessment of chronic muscle pain, neuro-urological and proctological function, and diagnosing neuromuscular disorders . For diagnostic purposes, the methods favored are those that use needle electrodes and do not require measurement or monitoring of muscle force . The most well-evaluated methods are those using turn/amplitude analysis, like the cloud methods and the peak-ratio analysis . Peak-ratio analysis has the advantage that reference limits are easy to obtain and that its utility is well established and confirmed by several investigations . Overall, automatic methods of EMG interference pattern analysis are powerful tools for diagnostic and non-diagnostic purposes.

Br J Dermatol, 2001 Aug, 145(2), 289 - 93
Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients; Schnider P et al.; BACKGROUND: The blocking action of botulinum toxin type A (BTX-A) on cholinergically innervated sweat glands has been used successfully to treat patients with focal hyperhidrosis . OBJECTIVES: To investigate the long-term efficacy and safety of intradermal injections of BTX-A . METHODS: We performed an open-label study in 61 patients treated over a period of 3 years for axillary or palmar hyperhidrosis . A total dose of 400 mU BTX-A (Dysport) was injected into both axillae or 460 mU BTX-A (Dysport) into both palms . The injections were repeated after relapse . Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets . RESULTS: Four weeks after BTX-A treatment the median reduction in sweat production was 71% compared with baseline (P < 0.001) in the axillary group and 42% (P = 0.005) in the palmar group . Subjective assessment of sweat production by the patients using a visual analogue scale (0, no sweating; 100, the most severe sweating) showed a significant reduction in both the axillary (P < 0.001) and palmar groups (P < 0.001) . Secondary disturbances due to focal hyperhidrosis interfering with daily activities were markedly improved in both groups . The median time interval between the sets of injections was 34 weeks for axillary hyperhidrosis and 25 weeks for palmar hyperhidrosis . The treatment of palmar hyperhidrosis was complicated by transient but not disabling weakness of the small hand muscles in nine of 21 patients . CONCLUSIONS: Repeated intradermal injections of BTX-A in patients with axillary and palmar hyperhidrosis are as effective as first treatments.

Hosp Med, 2001 Aug, 62(8), 477 - 9
The use of botulinum toxin in ophthalmology; Denniston A et al.; As the diversity of clinical applications for the botulinum neurotoxin continues to grow, exciting developments are occurring in its use around the eye, where indeed its benefits were first recognized . These include use to treat strabismus, eyelid disorders and a number of other ocular conditions.

ORL J Otorhinolaryngol Relat Spec, 2001 Sep-Oct, 63(5), 294 - 7
Treatment of gustatory sweating with botulinum toxin: special aspects; Laskawi R et al.; Botulinum toxin treatment is an efficient, well-tolerated technique for patients suffering from gustatory sweating, first described by our group . With the experience gained in recent years we were able to improve on some of our skills in the diagnosis and treatment of gustatory sweating and here we wish to focus on some interesting aspects: (1) the necessity for an exact anamnesis before treatment with botulinum toxin to ensure correct treatment; (2) the advantages of Minor's test in special situations, for example, when sweating occurs in regions of hairy skin, retroauricular, at the back of the auricle and in areas distant from the site of salivary gland surgery; (3) the reduction of pain during treatment using an anesthetic ointment containing lidocaine and prilocaine as active substances; (4) intracutaneous injections in areas anterior to the fascia-protected skin of the lateral face-covering mimetic muscles, and (5) the occasional necessity for short-time reinjection in small areas of persistent sweating .

Neurorehabil Neural Repair, 2001, 15(1), 57 - 68
The estimated cost of managing focal spasticity: a physician practice patterns survey; Radensky PW et al.; The purpose of this study was to estimate the overall cost of managing focal spasticity after stroke (CVA) and traumatic brain injury (TBI) and the cost impact of individual treatments . Sixty physicians described management strategies over six treatment visits for four focal spasticity case studies (one upper and one lower extremity case for CVA and TBI) . Mean and median per-case costs were determined across physicians; median per-case costs of physicians who did or did not report use of specific treatments were compared . Mean per-case costs of managing spasticity are as follows: CVA upper, $5,131; CVA lower, $5,384; TBI upper, $14,615; and TBI lower, $13,966 . Median per-case costs for strategies including botulinum toxin type A (BTX-A) were less than those without BTX-A in CVA upper; median costs for strategies including oral baclofen were more than those without baclofen in CVA lower . Fewer total treatments were reported with BTX-A than without; more total treatments were reported with baclofen than without . No individual treatment had a significant impact on median treatment costs in TBI . Physician-reported spasticity management costs are substantial . Despite higher drug costs for BTX-A compared with oral therapies like baclofen, strategies for managing spasticity in CVA that include BTX-A may cost less than those without BTX-A.

Anal Biochem, 2001 Sep 1, 296(1), 130 - 7
High-throughput assays for botulinum neurotoxin proteolytic activity: serotypes A, B, D, and F; Schmidt JJ et al.; Botulinum neurotoxins (BoNT) are zinc metalloproteases that cleave and inactivate cellular proteins essential for neurotransmitter release . Because the paralytic effect of BoNT is a consequence of its enzymatic activity, selective inhibitors may be useful as drugs or as tools for further research . To expedite inhibitor discovery, we developed high-throughput, solid-phase protease activity assays for four of the seven BoNT serotypes: A, B, D, and F . Each assay consisted of a cleavable oligopeptide, based on the natural substrate sequence, labeled with fluorescein and covalently attached to maleimide-activated multiwell plates . Solutions of holotoxin or nontoxic catalytic domain of BoNT were incubated in substrate-coated wells, with or without test compounds, followed by transfer and assay of solubilized product in a multiwell fluorometer . Routine toxin concentrations ranged from 10 to 100 ng/ml, but concentrations as low as 2 ng/ml gave reproducible signals . The fluorescence assays were selective, gave very low background readings, and were stable upon prolonged storage . Using the nontoxic catalytic domain of BoNT A, we determined the relative inhibitory potencies of a family of structurally related pseudotripeptide compounds . Unlike previous methods, our assays did not employ antibodies or reverse-phase extraction steps, only well-to-well transfers, and were easily adapted to a high-throughput automated environment .

J Neurol, 2001 Jul, 248(7), 572 - 6
The effect of botulinum toxin injections to the calf muscles on freezing of gait in parkinsonism: a pilot study; Giladi N et al.; 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.

Arch Surg, 2001 Aug, 136(8), 870 - 7
Laparoscopic Heller myotomy and Dor fundoplication for achalasia: analysis of successes and failures; Patti MG et al.; BACKGROUND: In the treatment of achalasia, surgery has been traditionally reserved for patients with residual dysphagia after pneumatic dilatation . The results of laparoscopic Heller myotomy have proven to be so good, however, that most experts now consider surgery the primary treatment . HYPOTHESIS: The outcome of laparoscopic myotomy and fundoplication for achalasia is dictated by technical factors . SETTING: University hospital tertiary care center . DESIGN: Retrospective study . PATIENTS AND METHODS: One hundred two patients with esophageal achalasia underwent laparoscopic Heller myotomy and Dor fundoplication . Fifty-seven patients had been previously treated by pneumatic dilatation or botulinum toxin . The design of the operation involved a 7-cm myotomy, which extended 1.5 cm onto the gastric wall, and a Dor fundoplication . Esophagrams, esophageal manometric findings, and video records of the procedure were analyzed to determine the technical factors that contributed to the clinical success or failure of the operation . MAIN OUTCOME MEASURE: Swallowing status . RESULTS: In 91 (89%) of the 102 patients, good or excellent results were obtained after the first operation . A second operation was performed in 5 patients to either lengthen the myotomy (3 patients) or take down the fundoplication (2 patients) . Dysphagia resolved in 4 of these patients . The remaining 6 patients were treated by pneumatic dilatation, but dysphagia improved in only 1 . At the conclusion of treatment, excellent or good results had been obtained in 96 (94%) of the 102 patients . CONCLUSIONS: These data show that a Heller myotomy was unsuccessful in patients with an esophageal stricture; a short myotomy and a constricting Dor fundoplication were the avoidable causes of residual dysphagia; a second operation, but not pneumatic dilatation, was able to correct most failures; and that the identified technical flaws were eliminated from the last half of the patients in the series.

J Biol Chem, 2001 Oct 19, 276(42), 39469 - 75 Epub 2001 Aug 14.
Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia; Kawakami M et al.; Erythropoietin (EPO) reduced Ca(2+)-induced glutamate (Glu) release from cultured cerebellar granule neurons . Inhibition was also produced by EPO mimetic peptide 1 (EMP1), a small synthetic peptide agonist of EPO receptor (EPO-R), but not by iEMP1, an inactive analogue of EMP1 . EPO and EMP1 induced autophosphorylation of Janus kinase 2 (JAK2), a tyrosine kinase that associates with EPO-R . Furthermore, genistein, but not genistin, antagonized both the phosphorylation of JAK2 and the suppression of Glu release induced by EPO and EMP1 . During chemical ischemia, substantial amounts of Glu were released from cultured cerebellar and hippocampal neurons by at least two distinct mechanisms . In the early phase, Glu release occurred by exocytosis of synaptic vesicle contents, because it was abolished by botulinum type B neurotoxin (BoNT/B) . In contrast, the later phase of Glu release mainly involved a BoNT/B-insensitive non-exocytotic pathway . EMP1 inhibited Glu release only during the early exocytotic phase . A 20-min exposure of hippocampal slices to chemical ischemia induced neuronal cell death, especially in the CA1 region and the dentate gyrus, which was suppressed by EMP1 but not iEMP1 . However, EMP1 did not attenuate neuronal cell death induced by exogenously applied Glu . These results suggest that activation of EPO-R suppresses ischemic cell death by inhibiting the exocytosis of Glu.

Prescrire Int, 2001 Feb, 10(51), 12 - 4
Botulinum toxin type A and dynamic equinus in children with cerebral palsy: new indication . Better than repeat casts; Ca(2+) influx and cAMP elevation overcame botulinum toxin A but not tetanus toxin inhibition of insulin exocytosis; Department of Medicine, University of Toronto, Toronto M5S 1A8, Ontario, Canada M5G 1X8Previous reports showed that cleavage of vesicle-associated membrane protein-2 (VAMP-2) and synaptosomal-associated protein of 25 kDa (SNAP-25) by clostridial neurotoxins in permeabilized insulin-secreting beta-cells inhibited Ca(2+)-evoked insulin secretion . In these reports, the soluble N-ethylmaleimide-sensitive factor attachment protein target receptor proteins might have formed complexes, which preclude full accessibility of the putative sites for neurotoxin cleavage . In this work, VAMP-2 and SNAP-25 were effectively cleaved before they formed toxin-insensitive complexes by transient transfection of insulinoma HIT or INS-1 cells with tetanus toxin (TeTx) or botulinum neurotoxin A (BoNT/A), as shown by immunoblotting and immunofluorescence microscopy . This resulted in an inhibition of Ca(2+) (glucose or KCl)-evoked insulin release proportionate to the transfection efficiency (40-50%) and an accumulation of insulin granules . With the use of patch-clamp capacitance measurements, Ca(2+)-evoked exocytosis by membrane depolarization to -10 mV was abolished by TeTx (6% of control) but only moderately inhibited by BoNT/A (30% of control) . Depolarization to 0 mV to maximize Ca(2+) influx partially overcame BoNT/A (50% of control) but not TeTx inhibition . Of note, cAMP activation potentiated Ca(2+)-evoked secretion by 129% in control cells but only 55% in BoNT/A-transfected cells and had negligible effects in TeTx-transfected cells . These results indicate that, whereas VAMP-2 is absolutely necessary for insulin exocytosis, the effects of SNAP-25 depletion on exocytosis, perhaps on insulin granule pool priming or mobilization steps, could be partially reversed by higher levels of Ca(2+) or cAMP potentiation.

Infect Immun, 2001 Sep, 69(9), 5709 - 15
Candidate vaccine against botulinum neurotoxin serotype A derived from a Venezuelan equine encephalitis virus vector system; Lee JS et al.; A candidate vaccine against botulinum neurotoxin serotype A (BoNT/A) was developed by using a Venezuelan equine encephalitis (VEE) virus replicon vector . This vaccine vector is composed of a self-replicating RNA containing all of the VEE nonstructural genes and cis-acting elements and also a heterologous immunogen gene placed downstream of the subgenomic 26S promoter in place of the viral structural genes . In this study, the nontoxic 50-kDa carboxy-terminal fragment (H(C)) of the BoNT/A heavy chain was cloned into the replicon vector (H(C)-replicon) . Cotransfection of BHK cells in vitro with the H(C)-replicon and two helper RNA molecules, the latter encoding all of the VEE structural proteins, resulted in the assembly and release of propagation-deficient, H(C) VEE replicon particles (H(C)-VRP) . Cells infected with H(C)-VRP efficiently expressed this protein when analyzed by either immunofluorescence or by Western blot . To evaluate the immunogenicity of H(C)-VRP, mice were vaccinated with various doses of H(C)-VRP at different intervals . Mice inoculated subcutaneously with H(C)-VRP were protected from an intraperitoneal challenge of up to 100,000 50% lethal dose units of BoNT/A . Protection correlated directly with serum enzyme-linked immunosorbent assay titers to BoNT/A . The duration of the immunity achieved was tested at 6 months and at 1 year postvaccination, and mice challenged at these times remained refractory to challenge with BoNT/A.

J Neurol, 2001 Jun, 248(6), 478 - 82
Clinical characteristics of the geste antagoniste in cervical dystonia; Muller J et al.; The geste antagoniste (moving an arm to the face or head) is a well-known clinical feature in cervical dystonia (CD) to alleviate the abnormal posture . The clinical phenomenology of these manoeuvres has not so far been assessed systematically . Fifty patients with idiopathic CD aware of at least one geste antagoniste (60% women, mean age at onset 44.1 years, mean disease duration 7.5 years) were subjected to a standardized investigation including a semiquantitative clinical rating scale and polymyographic recordings of six cervical muscles . Twenty-seven patients (54%) demonstrated more than one geste antagoniste (range 2-5) . A clinically significant (> or = 30%) reduction of head deviation was observed in 41 patients (82 %) . Dystonic head posture improved by a mean of 60 % along all planes by the geste manoeuvre with a complete cessation of head oscillations in nine of 33 patients (27 %) with phasic CD . No significant laterality of the "geste-arm" or the facial target area was found . The duration of geste-effects depended significantly on disease duration and determined the patient's self-rating of the benefit of the manoeuvre . EMG-polygraphy revealed two types of geste-induced polymyographic changes: a decrease in recruitment density and amplitude in at least one dystonic muscle (66%), and an increased tonic muscle activation in the remaining patients . The remarkable efficacy of the geste antagoniste and the considerable variety in performance, duration, and EMG-pattern of these manoeuvres warrant further investigation of the therapeutic use of sensorimotor stimulation, in particular for those CD patients who experience limited or no effect from botulinum toxin therapy.

Arch Facial Plast Surg, 2001 Jul-Sep, 3(3), 165 - 9
Effect of botulinum toxin pretreatment on laser resurfacing results: a prospective, randomized, blinded trial; Zimbler MS et al.; BACKGROUND: Facial laser resurfacing and chemodenervation with botulinum toxin type A are used independently as means of nonsurgical facial rejuvenation . Recent reports in the literature have described combining these 2 therapies, claiming improved and longer-lasting laser resurfacing results . To date, no scientific investigation has been undertaken to prove or disprove this theory . DESIGN: Institutional review board-approved, prospective, randomized, blinded study at university-affiliated outpatient cosmetic surgery offices . INTERVENTION: Patients had one side of their face injected, at specific anatomic subsites (crow's feet, horizontal forehead furrows, and glabellar frown lines), with botulinum toxin 1 week before laser resurfacing . After receiving an injection, patients underwent cutaneous laser exfoliation on both sides of the face with either a carbon dioxide or an erbium dual-mode laser . MAIN OUTCOME MEASURES: Patients' injected (experimental) and noninjected (control) sides were compared after laser resurfacing . Follow-up was documented at 6 weeks, 3 months, and 6 months after laser resurfacing . Subjective evaluation, based on a visual analog scale, was performed in person by a blinded observer . Furthermore, a blinded panel of 3 expert judges (1 facial plastic surgeon, 1 oculoplastic surgeon, and 1 cosmetic dermatologist) graded 35-mm photographs taken during postoperative follow-up visits . RESULTS: Ten female patients were enrolled in the study . A 2-tailed t test showed that all sites that were pretreated with botulinum toxin showed statistically significant improvement (P< or =.05) over the nontreated side, with the crow's feet region showing the greatest improvement . Comparing results between the carbon dioxide and erbium lasers did not result in any statistically significant differences . CONCLUSIONS: Hyperdynamic facial lines, pretreated with botulinum toxin before laser resurfacing, heal in a smoother rhytid-diminished fashion . These results were clinically most significant in the crow's feet region . We recommend pretreatment of movement-associated rhytides with botulinum toxin before laser resurfacing . For optimum results, we further recommend continued maintenance therapy with botulinum toxin postoperatively.

Funct Neurol, 2001 Apr-Jun, 16(2), 135 - 41
The position of the head in space: a kinematic analysis in patients with cervical dystonia treated with botulinum toxin; Albani G et al.; Many instruments have been employed in recent years in order to quantify the posture and motion of the head in normal and pathological subjects . Evaluations of this type present many difficulties related to the influence of individual and external factors and to the accuracy of the system used . In patients with cervical dystonia (CD) the only rating scales currently used are semi-quantitative and subjective . More precise information on disease severity and response to the treatment is needed . Posture and motion of the head were evaluated by means of ELITE motion analyser (BTS, Milan, Italy) in 6 patients with the left laterocollis form of CD undergoing treatment with botulinum toxin (BTX) . The method emerged as very useful for the quantification of the therapeutic response (which was more marked in motion than in posture) . We found an inverse relationship between the degree of motion improvement and the restriction of motion before treatment.

Dermatol Surg, 2001 Aug, 27(8), 703 - 8
Botulinum-A toxin treatment of the lower eyelid improves infraorbital rhytides and widens the eye; Flynn TC et al.; Botulinum-A exotoxin (BTX-A) can be used cosmetically to improve rhytides, particularly of the upper one-third of the face . In this study, fifteen women had BTX-A (BOTOX, Allergan, Inc.) injected into the orbicularis oculi muscle . One lower eyelid received two units just subdermally in the midpupillary line three millimeters below the ciliary margin . The opposite periocular area received two units BTX-A in the lower eyelid with 12 units BTX-A injected into the lateral orbital ("crow's foot") area . Three injections of four units each were placed 1.5 cm from the lateral canthus, each 1 cm apart . Patients and physicians independently evaluated the degree of improvement (grade 0 = no improvement, grade 1 = mild improvement, grade 2 = moderate improvement, and grade 3 = dramatic improvement) . An independent photographic analysis was performed . Patients reported a grade of 0.73 when two units were injected alone into the lower lid, and a grade of 1.9 when the lower eyelid and the lateral orbital areas were injected . Physician assessment was grade 0.7 with injection of the eyelid alone and grade 1.8 with injection of the lower eyelid and lateral orbital area . Single investigator photographic analysis demonstrated that 40% of the subjects who had injection of the lower eyelid alone had an increased palpebral aperture (IPA), while 86% of the subjects who had injection of the lower eyelid and lateral orbital area had an IPA . Subjects receiving two units alone had an average 0.5 mm IPA and a mean 1.3 mm IPA at full smile . Concomitant treatment of the lateral orbital area produced a mean 1.8 mm IPA at rest and a mean 2.9 mm IPA at full smile . The results were more notable in the Asian eye . Two units of BTX-A injected into the lower eyelid orbicularis oculi muscle improves infraorbital wrinkles, particularly when used in combination with BTX-A treatment of the lateral orbital area.

Acta Neurol Scand, 2001 Aug, 104(2), 110 - 2
Gabapentin in the treatment of hemifacial spasm; Daniele O et al.; OBJECTIVES: To evaluate the efficacy of gabapentin in the treatment of hemifacial spasm . MATERIAL AND METHODS: Twenty-three patients with hemifacial spasm not suitable for surgery or therapy with botulinum toxin were treated with gabapentin . The main efficacy parameter was the percentage of spasm reduction . RESULTS: A clinically significant reduction of spasms was obtained by 16 patients . CONCLUSION: Gabapentin was effective and safe in reducing hemifacial spasm in 16 out 23 (69.6%) patients.

Rev Med Suisse Romande, 2001 Jun, 121(6), 471 - 4
{Current indications for the treatment with botulin toxin}; Kohler A et al.; Botulinum toxin is more and more frequently used as a therapeutic agent . The toxin blocks selectively and reversibly the neuromuscular junction, causing a muscle relaxation . Indications are mainly muscular hypercontraction, such as dystonia, blepharospasm, focal spasticity, strabismus or tics . The range of action extend to focal hyperhydrosis, palmar, axillary or plantar . It seems now that some painful syndrome such as migraine or tension headache may benefit from toxin injections . Esthetic indications constitute an extension to the pure medical indications.

Hepatogastroenterology, 2001 Jul-Aug, 48(40), 977 - 9
Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure; Madalinski MH et al.; BACKGROUND/AIMS: Combined BT-A (botulinum toxin A) therapy and local application of nitrates can be more effective than BT-A alone for chronic anal fissure treatment, but so far the optimal dose of BT-A is not known . The aim of our study was to learn if BT-A doses higher than those used so far could change the outcome of fissure treatment . METHODOLOGY: We enrolled 14 consecutive patients suffering from idiopathic chronic anal fissure who did not respond to previous local treatment of nitric oxide donor and subsequent BT-A therapy (25 U of Botox) . They were offered a local nitroglycerin treatment . In failure cases patients received the greater doses of BT-A (50 U of Botox) . RESULTS: In all 11 patients with chronic anal fissure who applied nitroglycerin after BT-A injection, an effect on the internal anal sphincter relaxation was observed but fissure healing after topical nitroglycerin occurred only in 1 case . Of 13 patients with chronic anal fissure who received 50 U of BT-A no healing was reported in 6 cases . One male from this group received a greater dose (100 U of Botox) and then the fissure healed . CONCLUSIONS: The effect of topical nitrates on internal anal sphincter relaxation after botulinum toxin injection is not the last line for nonsurgical treatment of chronic anal fissure . Always we ought to consider using the next greater dose of BT-A before surgical treatment.

Restor Neurol Neurosci, 2000, 17(1), 1 - 8
Lower limb muscle activity in ambulatory children with cerebral palsy before and after the treatment with Botulinum toxin A; Hesse S et al.; Purpose: The study investigated the effect of Botulinum toxin A on the gait and lower limb muscle activity of ambulatory CP children . Methods: 19 spastic diplegic and 4 left hemiparetic CP children were injected with a mean dose of 23.5 units of Botulinum toxin A/kg body weight into the gastrocnemius and hamstring muscles . Muscle tone and gait analysis including the kinesiological electromyogram of the shank and thigh muscles were assessed before and four weeks after injection and compared with the help of a multivariate analysis (p < 0.05) . Results: Botulinum toxin A caused a definite reduction of plantarflexor, knee and hip hypertonia in 21 children, resulting in a more plantar grade and erect gait in 17 children four weeks after injection . Gait analysis showed a statistically significant improvement in peak ankle dorsi-flexion and knee extension during stance, and the length of the force point of action under both feet increased . Electromyography revealed sig-nificantly less co-contraction of the lower leg muscles, due to a more phasic instead of a tonic activity of the tibialis anterior muscle, and an improved activation pattern of the left rectus and biceps femoris muscles . Conclusions: The present study demonstrated that the injection of Botulinum toxin A resulted in a more mature muscle activation pattern of CP children . Most of the children walked more plantigrade and erect, the functional gait parameters, however, did not change.

Parkinsonism Relat Disord, 2001 Oct, 8(2), 109 - 21
Dystonia and parkinsonism; Jankovic J et al.; Parkinsonism and dystonia may coexist in a number of neurodegenerative, genetic, toxic, and metabolic disorders and as a result of structural lesions in the basal ganglia . Parkinson's disease (PD) and the 'Parkinson-plus' syndromes (PPS) account for the majority of patients with the parkinsonism-dystonia combination . Dystonia, particularly when it involves the foot, may be the presenting sign of PD or PPS and these disorders should be suspected when adults present with isolated foot dystonia . Young age, female gender, and long disease duration are risk factors for PD-related dystonia, but dystonia in patients with PD is usually related to levodopa therapy . The mechanism of dystonia in PD is not well understood and the management is often challenging because levodopa and other dopaminergic agents may either improve or worsen dystonia . Other therapeutic strategies include oral medications (baclofen, anticholinergics and benzodiazepines), local injections of botulinum toxin, intrathecal baclofen, and surgical lesions or high frequency stimulation of the thalamus, globus pallidus, or subthalamus.

J Neurosci, 2001 Aug 15, 21(16), 6058 - 68
Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking; Lan JY et al.; Regulation of neuronal NMDA receptors (NMDARs) by group I metabotropic glutamate receptors (mGluRs) is known to play a critical role in synaptic transmission . The molecular mechanisms underlying mGluR1-mediated potentiation of NMDARs are as yet unclear . The present study shows that in Xenopus oocytes expressing recombinant receptors, activation of mGluR1 potentiates NMDA channel activity by recruitment of new channels to the plasma membrane via regulated exocytosis . Activation of mGluR1alpha induced (1) an increase in channel number times channel open probability, with no change in mean open time, unitary conductance, or reversal potential; (2) an increase in charge transfer in the presence of NMDA and the open channel blocker MK-801, indicating an increased number of functional NMDARs in the cell membrane; and (3) increased NR1 surface expression, as indicated by cell surface Western blots and immunofluorescence . Botulinum neurotoxin A or expression of a dominant negative mutant of synaptosomal associated protein of 25 kDa molelcular mass (SNAP-25) greatly reduced mGluR1alpha-mediated potentiation, indicating that receptor trafficking occurs via a SNAP-25-mediated form of soluble N-ethylmaleimide sensitive fusion protein attachment protein receptor-dependent exocytosis . Because group I mGluRs are localized to the perisynaptic region in juxtaposition to synaptic NMDARs at glutamatergic synapses in the hippocampus, mGluR-mediated insertion of NMDARs may play a role in synaptic transmission and plasticity, including long-term potentiation.

HNO, 2001 Jul, 49(7), 548 - 52
{Botulinum toxin type A-induced "rebalancing" in bilateral vocal cord paralysis?}; Ptok M et al.; BACKGROUND: Upper airway obstruction due to bilateral vocal cord paralysis in an 80-year-old female patient was successfully relieved by injection of botulinum toxin A (BTA) into the laryngeal adductor muscles . The patient achieved satisfactory airway ventilation . Spirograms obtained preoperatively and postoperatively documented improved peak flow rates and 1-s forced expiratory volume values . Voice quality was breathy after the injection; however, neither aspiration nor dysphagia developed . Surprisingly, the maximum phonation time increased . PATIENTS AND METHODS: During a follow-up check 4 months later, the patient still reported less dyspnea although the vocal cords were closer together than initially after the injection . The decrease in dyspnea as reported by the patient lasted approximately 2 years . RESULTS: The improvement in breathing following injection of BTA can be interpreted as a paralysis or weakening of the laryngeal adductors . However, it remains unclear why the maximum phonation time increased . Comparable findings, i.e., improvement in overall laryngeal function, are described in the literature as BTA-mediated laryngeal rebalancing.

Acta Neurol Belg, 2001 Jun, 101(2), 121 - 3
Axillary injection of botulinum A toxin in a patient with muscle cramps associated with severe axillary hyperhidrosis; Filosto M et al.; Muscle cramps may be caused by fluid and salt loss induced by diffuse or focal hyperhidrosis . Recent reports have described the efficacy of botulinum, toxin in the treatment of primary focal hyperhidrosis . Botulinum toxin inhibits sweating by blocking exocytosis of acetylcholine from presynaptic cholinergic nerve terminals . We report the case of a patient who complained of frequent muscle cramps associated with unusually severe axillary hyperhidrosis . We used botulinum toxin to treat the excessive focal sweating presuming that it would also reduce the muscle cramps . A total dose of 200 MU of botulinum A toxin (Dysport) per axilla markedly reduced sweating and cramps . The beneficial effect started four days after the injection and it was still present five months later . Treatment was repeated in the sixth month with analogous results . No side-effects were observed and no compensatory sweating occurred.

Pancreas, 2001 Aug, 23(2), 125 - 33
Cholecystokinin-regulated exocytosis in rat pancreatic acinar cells is inhibited by a C-terminus truncated mutant of SNAP-23; Huang X et al.; INTRODUCTION: Exocytosis is thought to result from the fusion of vesicle and plasma membranes caused by the formation of a trans-complex between proteins of the vesicle-associated membrane protein (VAMP) family on the vesicle with members of the syntaxin and synaptosomal-associated protein of 25 kd (SNAP-25) families on the plasma membrane . In the pancreatic acinar cell, synaptosomal-associated protein of 23 kd (SNAP-23) is the major SNAP-25 isoform expressed in pancreatic acinar cells, but its role in acinar cell exocytosis has not been determined . AIMS: To examine the role of SNAP-23 in regulated exocytosis in acinar cells, we subcloned into adenoviral vectors SNAP-23, SNAP-25, and dominant negative mutants in which the C-terminal domains corresponding to the botulinum neurotoxin A cleavage sites are deleted . METHODOLOGY AND RESULTS: High-efficiency infection of rat pancreatic acini in culture with these adenoviruses by subcellular fractionation showed that the overexpressed SNAP-23, SNAP-25, and their truncated mutant proteins were uniformly targeted to the zymogen granules and plasma membrane . To maximally stimulate apical exocytosis from these infected acini, we used the cholecystokinin-phenylethyl ester analog (CCK-OPE), which does not show inhibition of secretion from maximal levels at high doses . CCK-OPE-stimulated amylase release from adenovirus-cytomegalovirus (AdCMV)-SNAP-23 or AdCMV-SNAP-25-infected acini to the same extent as from acini infected with the empty vector . In contrast, CCK-OPE-evoked enzyme secretion from AdCMV-SNAP-23deltaC8- and AdCMV-SNAP-25(1-197)-infected acini were inhibited by 60% and 40%, respectively . The identical targeting of the mutant SNAP-23 and SNAP-25 proteins to the same membrane compartments as SNAP-23 suggests that the inhibition of secretion was a result of their competition against endogenous SNAP-23 . This is supported by the fact that this inhibition by the mutant proteins was partially reversed or rescued when the AdCMV-SNAP-25AC8- or AdCMV-SNAP-25(1-197)-infected acini were co-infected with wild-type SNAP-23 or SNAP-25 . CONCLUSION: From these results, we conclude that SNAP-23 plays a role in CCK-evoked regulated exocytosis in the acinar cells.

Mov Disord, 2001 Jul, 16(4), 779 - 82
Case of essential palatal tremor: atypical features and remarkable benefit from botulinum toxin injection; Cho JW et al.; We describe a 21-year-old man with essential palatal tremor . The patient had rhythmic contractions not only of tensor veli palatini but also of facial, lingual, temporalis, pharyngeal, and neck muscles . He had some voluntary control of palatal tremor and ear clicks . He was treated with 5 units of botulinum toxin-A (BOTOX) injected into each tensor veli palatini, and had complete resolution of all the symptoms.

Mov Disord, 2001 Jul, 16(4), 764 - 5
Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy; Thobois S et al.; A 71-year-old woman was treated by botulinum toxin (BTX) type A injections for cervical dystonia related to a multiple system atrophy (MSA) . A few days later and persisting for the next 4 months, she developed a severe dysphagia, requiring nasogastric feeding . This implicates cautious use of BTX in a case of MSA.

J Pediatr Surg, 2001 Aug, 36(8), 1248 - 51
Laparoscopic Heller myotomy and Dor fundoplication for esophageal achalasia in children; Patti MG et al.; BACKGROUND/PURPOSE: In the past, surgical treatment in achalasia usually has been reserved for patients whose dysphagia does not respond to pneumatic dilatation . The success of minimally invasive myotomy, however, has resulted in a shift in practice in adult patients, whereby laparoscopic surgery is becoming preferred as primary treatment by most gastroenterologists and surgeons . The aim of this study was to assess the efficacy of laparoscopic Heller myotomy and Dor fundoplication for esophageal achalasia in children . METHODS: Thirteen patients with esophageal achalasia (median age, 15 years; 6 boys and 7 girls; median duration of symptoms, 24 months) underwent laparoscopic Heller myotomy and Dor fundoplication between 1996 and 1999 . Two patients had been treated previously by pneumatic dilatation, and 1 patient had received intrasphincteric Botulinum toxin injections . RESULTS: Median duration of the operation was 130 minutes . The patients were fed after an average of 33 hours, and they all left the hospital within 2 days . At a median follow-up of 19 months, there was no residual dysphagia in any patient . CONCLUSIONS: Laparoscopic Heller myotomy and Dor fundoplication were effective and safe for children with esophageal achalasia . Hospital stay and recovery time was short, and the functional results were excellent . These data support the notion that laparoscopic Heller myotomy should become the primary treatment of esophageal achalasia in children .

Biochemistry, 2001 Aug 7, 40(31), 9374 - 8
Differential roles of developmentally distinct SNAP-25 isoforms in the neurotransmitter release process; Puffer EB et al.; The role of SNAP-25 (synaptosomal associated protein of 25 kDa) isotypes in the neurotransmitter release process was examined by varying their relative abundance during PC12 cell differentiation induced by nerve growth factor (NGF) . Norepinephrine release by NGF-differentiated PC12 cells is more sensitive to type A botulinum toxin (BoNT/A) than by nondifferentiated cells, while both differentiated and nondifferentiated PC12 cells are equally sensitive to type E botulinum toxin (BoNT/E) . The differential sensitivity to BoNT/A corresponds to an altered susceptibility of SNAP-25 isotypes to BoNT/A cleavage in vitro, whereas both isotypes are equally vulnerable to cleavage by BoNT/E . Using recombinant SNAP-25 preparations, we show that BoNT/A cleaves SNAP-25b (present in differentiated cells) 2-fold more readily than SNAP-25a (present in both differentiated and nondifferentiated cells) . Structural studies using far-ultraviolet circular dichroism (UV--CD) and thermal denaturation suggest a difference in the polypeptide folding as the underlying molecular basis for the differential sensitivity of SNAP-25b and SNAP-25a to BoNT/A cleavage . We propose differential roles for SNAP-25b and SNAP-25a in the neurotransmitter release process since our results suggest that BoNT/A inhibits neurotransmitter release by primarily cleaving SNAP-25b.

Ophthal Plast Reconstr Surg, 2001 Jul, 17(4), 276 - 80
Differential section of the seventh nerve as a tertiary procedure for the treatment of benign essential blepharospasm; Fante RG et al.; PURPOSE: To examine the efficacy of differential section of the seventh nerve in treatment of patients with blepharospasm refractory to botulinum toxin and eyelid protractor myectomy . METHODS: A retrospective noncomparative interventional case series consisting of a cohort of 228 patients with benign essential blepharospasm followed from 1987 to 1997 in a university ophthalmic plastic surgery referral practice . Patients were treated with botulinum toxin injections, eyelid protractor myectomy, and differential section of the seventh nerve in stepwise fashion as needed for symptomatic control . RESULTS: Thirty-four patients (15% of total) underwent eyelid protractor myectomy during this period . Eyelid protractor myectomy failed to control blepharospasm in 7 (21%) of these 34 patients, who then underwent differential section of the seventh nerve an average of 2 years after myectomy . Patients were followed up for an average of 36 months, with a success rate of 42% (3 of 7) . The remaining 4 patients had repeat differential section of the seventh nerve with a 50% success rate, which brought the overall success rate from differential section of the seventh nerve to 71% . Lower eyelid ectropion requiring surgical repair complicated 27% of differential section of the seventh nerve procedures . CONCLUSIONS: Differential section of the seventh nerve is a reasonable alternative in the treatment of patients who have persistent disability despite treatment with botulinum toxin injections and eyelid protractor myectomy.

Semin Cutan Med Surg, 2001 Jun, 20(2), 93 - 100
Botulinum toxin type A (BOTOX) for treatment of migraine; Binder WJ et al.; An open-label study and 2 double-blind, placebo-controlled studies have provided supporting evidence of botulinum toxin type A (BTX-A) as an effective, well-tolerated treatment for migraine . Observed durations of benefit were consistent with known properties of BTX-A . Findings suggest that response may vary by features of preinjection headaches, such as migraine frequency . The precise mechanism by which BTX-A provides pain relief is hypothesized to be related not only to acetylcholine inhibition but also to a blocking action on the parasympathetic nervous system . Additional studies that control factors likely to be related to response may lead to better understanding of the BTX-A effect on migraine and an optimal treatment protocol.

Semin Cutan Med Surg, 2001 Jun, 20(2), 71 - 84
Botulinum toxin type A: history and current cosmetic use in the upper face; Carruthers A et al.; This article reviews the cosmetic use of botulinum toxin in upper face from both the historic and clinical viewpoints . The published literature and our current experience are outlined . Botulinum toxin type A in the upper face has become an extremely poplular cosmetic procedure and is outstandingly safe.

Semin Cutan Med Surg, 2001 Jun, 20(2), 121 - 6
Other noncosmetic uses of BOTOX; Verheyden J et al.; Botulinum toxin A has a wide variety of clinical applications, which are related by blockade of acetylcholine and often are related to abnormal muscle contractures . These applications include ocular disorders, disorders of the upper aerodigestive tract, dystonia and hemifacial spasm, cosmetic, gastrointestinal disorders, genitourinary disorders, management of pain, and use in autonomic nervous system disorders . Many of these diseases will be discussed with regard to their treatment with botulinum toxin compared to conventional treatments . Advantages and disadvantages of botulinum toxin use are delineated . General guidelines for adult and pediatric dosing will also be discussed.

Semin Cutan Med Surg, 2001 Jun, 20(2), 101 - 8
Treatment of palmar hyperhidrosis with botulinum toxin; Glogau RG; Excessive sweating of the palms, axillae, and soles can be managed with intradermal injections of botulinum toxin as an alternative to more aggressive surgical therapies such as sympathectomy and less effective techniques including topical antiperspirants . The dosage and injection techniques can be optimized to provide several months of freedom from this troubling disorder.

Neurol Clin, 2001 Feb, 19(1), 129 - 44, vi-vii
Treatment of tremor and dystonia; Goetz CG et al.; Treatment of movement disorders has expanded beyond traditional therapies with oral medications to include injection of drugs like botulinum toxin and the use of surgical interventions in cases that do not respond to medical therapy . This article provides an overview to the diagnosis and treatment of tremor and dystonia . The distinguishing features of rest, postural, and kinectic tremor are detailed with medical and surgical modalities for treatment . A discussion of idiopathic and secondary dystonia with focus on diagnosis and medical and surgical treatments encompasses the second part of the article.

Ophthalmology, 2001 Aug, 108(8), 1457 - 60
Predictors of nonrecovery in acute traumatic sixth nerve palsy and paresis; Holmes JM et al.; PURPOSE: To evaluate whether nonrecovery from acute traumatic sixth nerve palsy could be predicted from demographic factors or palsy characteristics . DESIGN: Prospective, observational case series SETTING: Multicenter (academic and private practices) . OUTCOME MEASURE: Nonrecovery, defined as the presence of diplopia in primary position or more than 10 prism diopters of distance esotropia in primary position at 6 months after onset . METHODS: Using data from a previously described cohort of 84 eligible patients with acute traumatic sixth nerve palsy, we performed multivariate analyses of demographic factors and palsy characteristics . RESULTS: Nonrecovery at 6 months after onset was associated with a complete palsy (adjusted risk ratio, 9.11; 95% confidence interval {CI}, 2.77-14.84) and with a bilateral palsy or paresis (adjusted risk ratio, 2.53; 95% CI, 0.98-4.29) . The choice of conservative management (observation, prism, or patch) versus acute injection of Botulinum toxin (within 3 months of injury) did not influence final recovery . CONCLUSIONS: In acute traumatic sixth nerve palsy or paresis, failure to recover by 6 months after onset was associated independently with inability to abduct past midline at presentation and bilaterality . Although the overall recovery rate is high in acute traumatic sixth nerve palsy or paresis, a complete or bilateral case has a poor prognosis and is more likely to need strabismus surgery.

Curr Treat Options Gastroenterol, 2001 Aug, 4(4), 293 - 297
Outlet Dysfunction Constipation; Wald A; The diagnosis of outlet dysfunction constipation in patients with idiopathic constipation that responds poorly or not at all to conservative measures, such as fiber supplements, fluids, and stimulant laxatives, is based upon diagnostic testing . These tests include colonic transit of radio-opaque markers, anorectal manometry or electromyography, barium defecography, and expulsion of a water-filled balloon . The literature suggests that conditions such as pelvic floor dyssynergia exist but may be over-diagnosed as a laboratory artifact . In our laboratory, we screen patients with balloon expulsion studies, and then test for dyssynergia only if the result of the balloon expulsion test is abnormal . In my opinion, anal sphincter electromyogram and manometry are equivalent in establishing the diagnosis . Barium defecography is helpful in making a diagnosis of a rectocele, but I prefer to document that vaginal pressure on the rectocele significantly improves rectal evacuation . Manometry also helps to establish the presence of megarectum, hypotonia, and weak expulsion efforts . Conceptually, biofeedback training, which incorporates simulated defecation, is the most logical approach to pelvic floor dyssynergia . It incurs no risk and benefits 60% to 80% of patients . The drawbacks are the time-intensive nature of the therapy and the short-term costs, which are offset if there is sustained benefit . There is no evidence that biofeedback is helpful in children with constipation . Habit training has established benefits, but recurrences are frequent and long-term reinforcement is helpful to maintain success . Laxatives and enemas are adjunctive therapies in both habit training and biofeedback . Surgery is effective in those uncommon patients with physiologically significant rectoceles, but surgical division of the puborectalis muscle is risky and unproven . Likewise, botulinum toxin injection into the puborectalis is unproven, but the effects are rarely permanent should incontinence occur . Diagnostic measures and therapeutic success are enhanced when patients are seen in centers experienced with the evaluation of these disorders.

Curr Treat Options Gastroenterol, 2001 Apr, 4(2), 123 - 131
Chronic Visceral Right Upper Quadrant Pain Without Gallstones; Shrestha S et al.; Patients with chronic visceral right upper quadrant pain without gallstones can be broadly categorized into two groups: patients with gallbladder dyskinesia, and patients with sphincter of Oddi dysfunction (SOD) . Treating patients with these disorders is often challenging to clinicians due to the difficulty at arriving at a definite diagnosis, and the lack of efficacy of various treatment modalities . The only real treatment option for patients with gallbladder dyskinesia is cholecystectomy; however, the results are difficult to predict in an individual patient . Patients with SOD can be approached according to a classification that at least partially reflects the underlying pathophysiology . Patients with type I SOD have underlying papillary stenosis, and benefit from empiric sphincterotomy . Patients with type II SOD may have muscle spasm as predominant pathophysiology; this group of patients benefit from sphincterotomy only if increased sphincter pressure is demonstrated by sphincter of Oddi manometry . Patients with type III SOD may have visceral hyperalgesia; a trial of antidepressants or a therapeutic trial with botulinum toxin injection into the ampulla should be considered prior to more invasive endoscopic therapy.

Br J Ophthalmol, 2001 Aug, 85(8), 912 - 5
A comparison of different depth ablations in the treatment of painful bullous keratopathy with phototherapeutic keratectomy; Maini R et al.; AIM: To study the efficacy of phototherapeutic keratectomy (PTK) for pain relief for patients with painful bullous keratopathy and poor visual potential . METHODS: Patients with painful bullous keratopathy and poor visual potential were treated with superficial PTK (8-25 microm), intermediate (50-100 microm) or deep PTK (25% stromal thickness) using the Nidek EC5000 excimer laser after manual epithelial debridement . Follow up ranged from 1 to 24 months (mean 6.5 months) . Outcome measures included symptomatic relief and need for further treatment . RESULTS: In the superficial PTK group five of eight (62%) patients improved symptomatically after treatment . The three (38%) who did not improve went on to have penetrating keratoplasty for pain relief . In the intermediate depth group only two of five (40%) patients had symptom alleviation . The three others (60%) required further procedures . 20 of 24 (83%) patients treated with deep PTK had significant or total alleviation of symptoms . Of these, one developed acute anterior uveitis 9 months after PTK and two required botulinum ptosis for persistent corneal epithelial defects, one of whom had three consecutive episodes of microbial keratitis . Three of 24 suffered occasional discomfort and one patient required a penetrating keratoplasty for continued pain . CONCLUSION: PTK can be a useful therapeutic measure in painful bullous keratopathy with poor visual potential . Deep PTK appears to be more successful in pain management than superficial treatment.

Ann Otol Rhinol Laryngol, 2001 Jul, 110(7 Pt 1), 627 - 34
Evaluation of voice quality in adductor spasmodic dysphonia before and after botulinum toxin treatment; Langeveld TP et al.; In this prospective study, the efficacy of botulinum toxin (Botox) injections in patients with adductor spasmodic dysphonia (AdSD) was assessed by 3 different modalities: perceptual and acoustic analyses and subjective self-assessment . This was done by comparing AdSD patients' pretreatment and posttreatment values and comparing these values with those of normal control speakers . In contrast to most other studies, the posttreatment status was defined as the optimal voice quality as judged by the patient . The aim of the study was to assess to what extent Botox injections actually improve voice quality and function . The AdSD subjects rated a significantly improved voice quality and function after Botox treatment . However, the results were never within normal limits . Perceptually, the characteristic and severely impaired AdSD voice improved, but another "type" of pathological voice was detected after Botox treatment . Acoustic analyses demonstrated a significant improvement, as well . Nevertheless, the "optimally" treated AdSD voice still remained significantly deviant as compared to normal voice production . Currently, Botox injection is the therapy of first choice for AdSD . Although significant improvement could be measured in our study perceptually, acoustically, and subjectively, the optimal voice that was achieved never fully matched normal voice quality or function.

Rev Gastroenterol Mex, 2000 Jan-Mar, 65(1), 18 - 21
{Utility of botulinum toxin in stasis esophagitis secondary to achalasia . Report of a case}; Carmona-Sanchez R et al.; Upper gastrointestinal bleeding is an infrequent complication of achalasia . Stasis esophagitis is a rare cause of esophageal bleeding in which conventional forms of treatment may be associated with a high risk of complications . Botulinum toxin has emerged as a therapeutic alternative with few secondary effects . We present a case report of achalasia complicated by upper gastrointestinal bleeding secondary to stasis esophagitis which was successfully treated with botulinum toxin . Interesting aspects related to stasis esophagitis and the potential role of botulinum toxin in achalasia are discussed.

Hypertension, 2001 Jul, 38(1), 100 - 4
Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells; Funakoshi Y et al.; Recently, it was shown that Rho-kinase plays an important role in blood pressure regulation . However, it is not known whether Rho-kinase is involved in atherogenesis . Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine that regulates monocyte recruitment and atherogenesis . Therefore, we examined the role of Rho and Rho-kinase in the angiotensin (Ang) II-induced expression of MCP-1 . Ang II dose- and time-dependently enhanced the expression of MCP-1 mRNA and the protein production in vascular smooth muscle cells . CV11974, an Ang II type 1 receptor (AT(1)-R) specific antagonist inhibited the enhancement of MCP-1 expression by Ang II, suggesting that the effect of Ang II is mediated by the AT(1)-R . Botulinum C3 exotoxin, a specific inhibitor of Rho, suppressed Ang II-induced MCP-1 production . To examine the role of Rho-kinase in Ang II-induced MCP-1 expression, we used adenovirus-mediated overexpression of the dominant negative mutant of Rho-kinase (AdDNRhoK) or Y-27632, a specific inhibitor of Rho-kinase . Both AdDNRhoK and Y-27632 strongly inhibited Ang II-induced MCP-1 expression . Although inhibition of extracellular signal-regulated protein kinase (ERK) by PD 098,059 also inhibited Ang II-induced MCP-1 expression, Y-27632 did not affect Ang II-induced activation of ERK . These results indicate that Rho-kinase plays a critical role in Ang II-induced MCP-1 production independent of ERK . The Rho-Rho-kinase pathway may be a novel target for the inhibition of Ang II signaling and the treatment of atherosclerosis.

J Neurol Neurosurg Psychiatry, 2001 Aug, 71(2), 193 - 9
Health related quality of life is improved by botulinum neurotoxin type A in long term treated patients with focal dystonia; Hilker R et al.; OBJECTIVES: The advent of botulinum neurotoxin type A (BoNT/A) gave rise to substantial progress in the treatment of focal dystonias . In the light of the high costs of the toxin and the necessity to establish valid outcome indices for this treatment apart from sheer reduction of dystonic muscle tone and posture, the impact of focal dystonia and its treatment with BoNT/A on patients' health related quality of life (HRQL) was determined . METHODS: Fifty patients with cranial and cervical dystonia treated long term with BoNT/A were enrolled in a prospective, open labelled cohort study . The HRQL was assessed using the EuroQol (EQ-5D) and the short form 36 health survey questionnaire (SF-36) at baseline before BoNT/A injections and at two follow up visits after 6 and 12 weeks covering one BoNT/A treatment period with maximum effect size at the first follow up . RESULTS: Compared with a general population sample, a considerable negative impact of focal dystonia on HRQL was found in patients under investigation . In both disease types, BoNT/A treatment led to a significant improvement in several HRQL dimensions, in particular providing moderate to marked effect sizes in the fields of mental health and pain . The impairment of HRQL due to pain as well as the BoNT/A induced improvement within this SF-36 subscore were significantly higher in patients with cervical dystonia . Under BoNT/A therapy, no correlation was found between changes of clinical outcome scores and HRQL measures . CONCLUSIONS: The data confirm that BoNT/A is able to induce a significant, but temporary amelioration of several aspects of HRQL in both types of focal dystonia . This may substantially contribute to the patients' subjective benefit from the therapy . Moreover, the data provide further arguments to accept high costs of the BoNT/A treatment in these severely handicapped patients, as a consequence of its considerable benefit on quality of life.

Strabismus, 2001 Jun, 9(2), 79 - 82
Botulinum toxin to the lateral rectus for the treatment of esotropia with paradoxical diplopia; Harris G et al.; A retrospective review of six patients with paradoxical diplopia in the presence of esotropia was carried out . All patients were treated with botulinum toxin to the lateral rectus of the affected side . Five patients had no diplopia post toxin and the remaining patient had diplopia which could be ignored . The number of injections per patient ranged between 3 and 34 . Three patients went on to have surgery to increase the angle of esotropia, with relief of diplopia . We conclude that botulinum toxin has a role in the treatment of esotropic patients with paradoxical diplopia.

Facial Plast Surg Clin North Am, 2001 May, 9(2), 197 - 204, vii
Botulinum toxin (botox) chemodenervation for facial rejuvenation; Carruthers J et al.; A positive attitude toward life at any age is now seen to be consistent with inclusion in all societal activities . A mere increase in years is no longer enough reason for "ageism." Botulinum Toxin (Botox) aesthetic treatments, because of their outstanding effectiveness and safety, can continue to play a positive role in the rebuttal of "ageism."

J Physiol, 2001 Jul 15, 534(Pt . 2), 501 - 10
Serotonin facilitates AMPA-type responses in isolated siphon motor neurons of Aplysia in culture; Chitwood RA et al.; 1 . Serotonin (5-HT) facilitates the connections between sensory and motor neurons in Aplysia during behavioural sensitization . The effect of 5-HT on sensorimotor synapses is believed to be primarily presynaptic . Here we tested whether 5-HT can have an exclusively postsynaptic facilitatory effect . 2 . Siphon motor neurons were individually dissociated from the abdominal ganglion of Aplysia and placed into cell culture . Brief pulses of glutamate, the putative sensory neuron transmitter, were focally applied (0.1 Hz) to solitary motor neurons in culture, and the glutamate-evoked postsynaptic potentials (Glu-PSPs) were recorded . 3 . When 5-HT was perfused over the motor neuron for 10 min, the amplitude of the Glu-PSPs was significantly increased . The 5-HT-induced enhancement of the Glu-PSPs persisted for at least 40 min after washout . 4 . Prior injection into the motor neuron of the calcium chelator BAPTA, GDP-beta-S or GTP-gamma-S blocked the 5-HT-induced facilitation of the Glu-PSPs . However, the facilitation was not blocked when APV, an NMDA receptor antagonist, was applied together with the 5-HT . 5 . The enhancement of the Glu-PSPs by 5-HT was reversed by the AMPA receptor antagonist DNQX, indicating that 5-HT increased the functional expression of AMPA-type receptors in the motor neuron . 6 . The presence of botulinum toxin in the motor neuron blocked the 5-HT-induced enhancement of the Glu-PSPs . As botulinum toxin prevents exocytosis we hypothesize that during sensitization 5-HT causes the insertion of additional AMPA-type receptors into the postsynaptic membrane of sensorimotor synapses via exocytosis . This postsynaptic mechanism may contribute to facilitation of the synapses.

Dysphagia, 2001 Summer, 16(3), 171 - 5
Botulinum toxin in the treatment of cricopharyngeal dysphagia; Haapaniemi JJ et al.; Dysphagia is a common symptom in various neurological disorders affecting pharyngeal functions . Cricopharyngeal dysfunction is one of the major findings in these patients . The most effective treatment for restoring normal swallowing function in persistent cricopharyngeal dysfunction is cricopharyngeal myotomy, especially when mechanical obstruction or a well-localized neuromuscular dysfunction, such as a cricopharyngeal muscle spasm, is present . However, when there is a more diffuse neurological disorder present the results of surgery are more disappointing . In unclear cases, or in patients with temporary problems, no good method other than swallowing training, bougienage, and tube feeding are available . During the past decade, botulinum toxin has been found to be of therapeutic value in the treatment of a variety of neurological disorders associated with inappropriate muscular contractions such as torticollis and spasmodic dysphonia . Recently, injections of botulinum toxin in patients with cricopharyngeal muscle dysfunction have been reported to result in marked relief of dysphagia . In this article we describe our experiences with botulinum toxin injections to treat four patients suffering from deglutition problems and cricopharyngeal dysphagia of different origins . Botulinum toxin was injected into the cricopharyngeus muscle that was identified by endoscopy under general anesthesia . In this study, no major side effects were observed . Three patients obtained a significant improvement of esophageal symptoms after the first injection . The treatment had limited effect in one patient who had reflux disease and only slight cricopharyngeus dysfunction.

Dysphagia, 2001 Summer, 16(3), 161 - 7
Botulinum toxin treatment for cricopharyngeal dysfunction; Shaw GY et al.; Hypertonicity and spasticity of the cricopharyngeal muscle (CPM) often result in dysphagia characterized by difficulty passing a bolus through the upper esophageal sphincter . Past treatments for this problem have included mechanical dilation and endoscopic and transcervical cricopharyngeal myotomy . More recently, botulinum toxin injections into the CPM have been successful, but only in isolated case studies and small series . This study reports pre- and post-botulinum toxin A injection results for 12 subjects, including patient ratings of symptom severity, changes noted during modified barium swallow studies, and, in some cases, manometry of the upper esophageal sphincter . Results indicate that botulinum toxin A treatment provided significant improvement in swallowing as indicated by patient symptom ratings and investigator ratings of function from modified barium swallow studies . Greater improvement was seen in those with more isolated CPM or Xth nerve dysfunction rather than those with more global dysphagia abnormalities.

Disabil Rehabil, 2001 Sep 10, 23(13), 549 - 58
Contractures in orthopaedic and neurological conditions: a review of causes and treatment; Farmer SE et al.; PURPOSE: To examine the techniques used for the treatment of contracture in the context of current scientific knowledge of muscle . METHOD: Synthesis of data available from MEDLINE, RECAL, EMBASE, the Cochrane Library and relevant texts . RESULTS: The development of contractures through immobilisation, muscle weakness and spasticity is described . The effects of passive stretching, continuous passive movement, serial plastering, splinting, electrical stimulation, botulinum injections and surgical tenotomies in the treatment of contractures in persons with neurological and orthopaedic conditions are identified . The strengths and weaknesses of these modalities are discussed . CONCLUSION: Predisposing factors persist after treatment of contractures thus for treatment to be effective long-term management programmes need to be developed . New treatment techniques, used in series or combined, offer the prospect of improved management of contracture . Scientific and clinical research is needed to investigate the effect of contracture treatment.

Neurol Sci, 2000 Dec, 21(6), 349 - 53
Botulinum toxin treatment for functional disability induced by essential tremor; Pacchetti C et al.; This study aimed to improve botulinum toxin's (BTX) efficacy and to reduce its unwanted effects in the treatment of functional disability due to essential tremor (ET) of the hand . Twenty patients with disabling ET, not responding to conventional pharmacological therapy, were enrolled in this open-label study . Activities of daily living self-questionnaire (ADLS) and severity tremor scale (STS) were used to establish patients' functional disability and tremor severity . Accelerometry and surface electromyography were used to identify the arm muscles with tremorogenic activity during impaired positions . Global rating was used to measure treatment efficacy and unwanted effects . BTX type A was injected into the muscles principally responsible for impaired positions . After BTX treatment, there was a significant reduction in both severity and functional rating scales scores (ADLS and STS) and of tremor amplitude as measured with accelerometry and EMG . Adverse effects were limited to a slight third finger extension weakness in 15% of patients . BTX injections are effective and safe in reducing disability due to ET, if based on the criterion of functional selection.

Arch Soc Esp Oftalmol, 2001 Jul, 76(7), 437 - 40
{Percutaneous topical anaesthesia applications in ocular surgery}; Grande Baos C; PURPOSE/METHODS: The results of our experience with EMLA cream used as a topical anaesthetic is analysed in a series of forty patients having bilateral and simultaneous oculoplastic procedures, such as the injection of different substances (botulinum toxin, triamcinolone), the removal of superficial skin lesions, or previous to subcutaneous infiltration of local anaesthetics . Patient's reaction to pain and its degree were assessed by the use of topical placebo on the other than EMLA site and compare both subjective and <<objective>> scales . RESULTS/CONCLUSIONS: Patient's discomfort and pain were found to be milder with a statistically significant difference (p<0.0001) compared to placebo when EMLA cream was previously used over the surgical site . Therefore, in our experience, the use of EMLA cream as percutaneous anaesthetic is effective in diminishing pain associated with minor oculoplastic procedures.

No To Shinkei, 2001 Jun, 53(6), 547 - 50
{Therapeutic outcome of spasmodic torticollis}; Hasegawa O et al.; We investigated 117 patients with spasmodic torticollis who had visited us to seek for appropriate treatment in these 14 years . They were 71 men and 46 women, aged 44 +/- 14 (mean +/- SD) years, and suffered from this disorder during 4 +/- 5 years, maximum 26 years . Involuntary abnormal head positions, not only torticollis but also laterocollis and antero- or retrocollis, were contained in this study . Most of them were torticollis due to idiopathic focal dystonia . One or more courses of alcoholization therapy was accomplished in 82 patients who wished to be done . This therapy course consisted of about ten times totally of 99% ethanol injection to the motor point of two most hypertonic neck muscles, either side of the sternocleidomastoideus and the opposite side of the splenius in most cases, repeated every 2 or 3 weeks . One patient received as many as 98 times of this injection and resolved completely . Training to reinforce antagonistic muscles was also instructed . Twenty-one patients (26%) were resolved completely after this treatment . Fifty-four patients (66%) were ameliorated and satisfied partially, but 18 of them relapsed in 1 to 4 years after the treatment and were obliged to repeat one more course of this treatment . On the other hand, in five patients their torticollis improved under certain drug therapy alone . Sixteen patients (14%) gave up to continue the treatment within two months, and 14 patients (12%) dropped out before starting the therapy . This alcoholization therapy resulted in amelioration of torticollis in about 90% of the patients with a long effective period . Nevertheless, this alcohol injection is painful, and requires 5 to 6 months to be completed . In 2 patients who had already received many times of this injection, sudden hoarseness occurred one day immediately after the alcohol injection to the sternocleidomastoideus . This complication was presumably brought about by the unexpected infiltration of alcohol to the laryngeal area, located posterior to that muscle . They recovered in two months, but careful attention should be paid to the adverse effects . If botulinum toxin be available also in our country, we will be able to have another choice of therapy and the treatment of this disorder will become easier.

Emerg Med J, 2001 Jul, 18(4), 310 - 1
Mild head injury with isolated third nerve palsy; Muthu P et al.; Traumatic isolated cranial nerve palsies are uncommon and when they do occur, they are usually associated with severe head trauma . Cranial nerve palsy associated with mild head injury is rare . A case is reported of complete left third nerve palsy associated with mild head injury . The rate of recovery for complete third nerve palsy is slow and prolonged . The ptosis recovered in 10 months; the divergent squint required botulinum toxin to the lateral rectus muscle followed by surgery.

Ann Pharm Fr, 2001 May, 59(3), 176 - 90
{Mechanism of action and therapeutic uses of botulinum and tetanus neurotoxins}; Popoff MR et al.; Botulinum neurotoxins are produced by anaerobic spore forming bacteria, Clostridiumbotulinum . They are synthesized as a single chain protein (150kDa) which is not or weakly active . The active form results from proteolysis that cleaves the precursor into a light chain (about 50kDa) and a heavy chain (about 100kDa) which are linked by a disulfide bridge . The heavy chain is involved in the recognition of a specific neurone surface receptor and mediates the internalization of the light chain into the cytosol . The light chain is responsible for the intracellular activity . It catalyzes the proteolysis of SNARE proteins which are involved in the exocytosis of synaptic vesicles containing acetylcholine . Hence, the release of acetylcholine at the neuromuscular junction is blocked leading to a flaccid paralysis . The tetanus neurotoxin shares with botulinum neurotoxins a common structure and mechanism of action . Tetanus neurotoxin blocks the release of neurotransmitters in the inhibitory interneurons leading to spastic paralysis . The paralytic properties of the botulinum neurotoxins are used to treat certain myoclonies such as blepharospasm, torticolis, hemifacial paralysis . Botulinum neurotoxins are thus efficient therapeutic agents helpful in avoiding surgery.

Plast Reconstr Surg, 2001 Jul, 108(1), 208 - 14; discussion 215-7
Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytids; Matarasso SL et al.; Inactivation of the orbicularis oculi muscle by chemodenervation with botulinum toxin type A (Botox, Allergan, Inc., Irvine, Calif.) as a sole procedure or in conjunction with blepharoplasty has proved to be a reliable method to improve the appearance of the periocular area . Botox has the unique and ideal characteristic in that, with repeated use, there is potential for a prolonged clinical effect with smaller dosages . In addition, if a complication does arise--while not aesthetically acceptable and potentially untoward--it is time-limited, and the anatomical area will eventually return to its pretreatment baseline status . In this study, in three cases {in more than 1000 crow's feet treatment sessions (2000 sides)} over the course of 1 year, partial lip ptosis resulting from weakening of the zygomaticus major muscle after the injection of Botox into the periocular region are reported . This article reviews suggested treatment guidelines and anatomic considerations for the periocular region to maintain injection standardization and improve the safety profile of Botox as the aesthetic indications for its use expand and the number of individuals who inject it increases.

J Neurol Neurosurg Psychiatry, 2001 Jul, 71(1), 67 - 72
Prospective study of swallowing function in patients with cervical dystonia undergoing selective peripheral denervation; Munchau A et al.; OBJECTIVE: To characterise swallowing function in patients with cervical dystonia with botulinum toxin treatment failure, before and after selective peripheral denervation surgery . METHODS: Twelve patients with cervical dystonia had a thorough examination including standardised assessment for cervical dystonia, scoring of subjective dysphagia, and videofluoroscopic swallow . Videofluoroscopy was scored by consensus opinion between a speech and language therapist and an independent blinded radiologist using a validated scoring system . RESULTS: Seven patients with cervical dystonia experienced no subjective dysphagia either before or after surgery, although in all these patients there was objective videofluoroscopic evidence of underlying mild to moderate oropharyngeal dysphagia preoperatively and postoperatively . The most common finding was delayed initiation of swallow . Three other patients, also without subjective dysphagia before surgery, developed postoperative dysphagia . In these patients, videofluoroscopy showed a delayed swallow reflex before surgery, which was worse postoperatively in two . The remaining two patients had mild subjective dysphagia before surgery that improved postoperatively in one and deteriorated in the other . In the first, videofluoroscopy was normal preoperatively and postoperatively, and in the second, oral bolus preparation was moderately abnormal preoperatively and swallow initiation was delayed postoperatively . Mean subjective dysphagia scores did not change significantly . Apart from a significant improvement of tongue base retraction, videofluoroscopic scores were not significantly different after surgery . Postoperatively there was significant improvement of overall cervical dystonia severity and abnormal head rotation in the group as a whole . There was no correlation between age, duration of symptoms of cervical dystonia, preoperative or postoperative cervical dystonia severity, subjective dysphagia scores, or videofluoroscopic scores . However, in the five patients with persisting anterior sagittal head shift as part of the torticollis, tongue base retraction was less likely to improve after surgery compared with those without head shift . CONCLUSION: Surgical denervation of dystonic neck muscles, leading to improved neck posture, can also improve tongue base retraction, which is a key component of normal bolus propagation . However, delayed swallow initiation, a common feature in patients with cervical dystonia, can be further compromised by surgery, leading to subjective dysphagia . In general, selective peripheral denervation seems to be a safe procedure with no major compromise of swallowing function.

Am J Physiol Heart Circ Physiol, 2001 Jul, 281(1), H266 - 74
Regulation of tyrosine phosphorylation of PYK2 in vascular endothelial cells by lysophosphatidylcholine; Rikitake Y et al.; Lysophosphatidylcholine (LPC), a component of oxidized low-density lipoprotein, exerts various biological effects on vascular endothelial cells . However, the intracellular signaling of LPC is poorly understood . In this study, we investigated the involvement of proline-rich tyrosine kinase (PYK2) in LPC signaling in cultured bovine aortic endothelial cells by immunoprecipitation and Western blotting assays . Treatment of cells with LPC promoted a rapid increase in tyrosine phosphorylation of PYK2 . LPC-stimulated PYK2 phosphorylation was inhibited by calcium chelators, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, EGTA, protein kinase C (PKC) inhibitor, GF-109203X, or PKC depletion by phorbol esters . PYK2 phosphorylation was inhibited by treatment with cytochalasin D but with neither botulinum C3 transferase nor overexpression of a dominant negative mutant of Rho A . LPC stimulated the association of Shc with PYK2, Shc tyrosine phosphorylation, and Grb2 binding to Shc and induced Ras activation . These results provide evidence that 1) LPC tyrosine phosphorylates PYK2 by calcium- and PKC-dependent mechanisms, 2) the intact cytoskeleton is required for LPC-stimulated PYK2 phosphorylation, and 3) LPC-activated Ras via the PYK2/Shc/Grb2 signaling.

Arch Otolaryngol Head Neck Surg, 2001 Jun, 127(6), 691 - 3
Endoscopic laser cricopharyngeal myotomy to salvage tracheoesophageal voice after total laryngectomy; Bastian RW et al.; Development of voice after tracheoesophageal puncture, following laryngectomy, is sometimes hampered by spasm of the cricopharyngeal muscle . This problem has been addressed by various means, including bougienage, botulinum toxin injection, and open surgical division of the muscle . We believe that endoscopic carbon dioxide laser cricopharyngeal myotomy represents a direct, simple, and effective solution.

Proc Natl Acad Sci U S A, 2001 Jun 19, 98(13), 7582 - 7 Epub 2001 Jun 12.
Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice; Millecamps S et al.; Using adenoviruses encoding reporter genes as retrograde tracers, we assessed the capacity of motoneurons to take up and retrogradely transport adenoviral particles injected into the muscles of transgenic mice expressing the G93A human superoxide dismutase mutation, a model of amyotrophic lateral sclerosis . Surprisingly, transgene expression in the motoneurons was significantly higher in symptomatic mice than in control or presymptomatic mice . Using botulinum toxin to induce nerve sprouting at neuromuscular junctions, we showed that the unexpectedly high level of motoneurons retrograde transduction results, at least in part, from newly acquired uptake properties of the sprouts . These findings demonstrate the remarkable uptake properties of amyotrophic lateral sclerosis motoneurons in response to denervation and the rationale of using intramuscular injections of adenoviruses to overexpress therapeutic proteins in motor neuron diseases.

Dig Liver Dis, 2001 Apr, 33(3), 266 - 77
Current trends in the management of achalasia; Bruley des Varannes S et al.; Despite the recent advances in the understanding of the pathophysiology of achalasia, aetiology remains obscure and this primary oesophageal motor disorder is still considered "idiopathic" in nature . As a consequence, the therapeutic approach remains palliative . Since there is little or no chance of improving the motor abnormalities of the oesophageal body, treatment of achalasia is aimed at symptomatic relief of functional lower oesophageal sphincter obstruction . Pharmacologic treatment induces only a limited and brief improvement . It may be used to treat early cases of achalasia without significant oesophageal dilatation and to manage patients exhibiting some but not all the characteristics of achalasia (e.g . transitional forms) . In any event, drug therapy should be seen as a short-term measure and be considered as an alternative only in patients unfit to undergo pneumatic dilatation or surgery . Pneumatic dilatation and surgical myotomy (now increasingly carried out through a minimally invasive approach) remain, therefore, the two main approaches which guarantee long-lasting symptomatic relief . Unfortunately, both pneumatic dilatation and Heller cardiomyotomy are only palliative as neither reliably reverses oesophageal aperistalsis not corrects the incomplete postdeglutition relaxation of the lower oesophageal sphincter . They do, however, improve symptoms by lowering lower oesophageal sphincter pressure thus enhancing oesophageal emptying by gravity . Recently a third approach, consisting in perendoscopic injection of botulinum toxin into the lower oesophageal sphincter is gaining acceptance . Indeed, more endoscopists are finding this kind of treatment attractive because it does not carry the risk of perforation that can occur with pneumatic dilatation . However, since symptomatic improvement with botulinum toxin only lasts a few months, either repeated injections are required or the patient must be switched to other therapy . There may be, however, subsets of patients for whom BoTox injection is the preferred approach . They probably include elderly patients or patients with multiple medical problems who are poor candidates for more invasive procedures as well as those unwilling to have either surgery or pneumatic dilatation . Future approaches to achalasia may markedly change from the suggested algorithm depending on the long-term efficacy and safety as well as cost analysis of BoTox injection and of minimally invasive surgery.

Neurology, 2001 Jun 12, 56(11), 1523 - 8
A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor; Brin MF et al.; OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand . BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor . METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment . Injections were made into the wrist flexors and extensors . Patients were followed for 16 weeks . The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment . Hand strength was evaluated by clinical rating and by a dynamometer . RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks . However, kinetic tremor was significantly reduced only at the 6-week examination . Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment . Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group . Adverse reactions consisted mainly of dose-dependent hand weakness . CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy . Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Biochem Biophys Res Commun, 2001 Mar 30, 282(2), 621 - 8
Protein kinase C-dependent supply of secretory granules to the plasma membrane; Tsuboi T et al.; To elucidate the mechanism for supplying secretory granules to the cell membrane, chromaffin cells isolated from the bovine adrenal medulla were observed by the evanescent wave microscopy after staining their granules with acridine orange . The secretory granules showed only a very small fluctuation, indicating their docking to the plasma membrane . The rate and range of movement increased greatly by application of botulinum toxin A or C . The number of secretory granules docked to the plasma membrane significantly decreased by botulinum toxin C . Conversely, the number increased greatly by activation of protein kinase C with phorbol 12,13-dibutyrate (PDBu) . In the presence of an anti-actin reagent cytochalasin D, no increasing effect of PDBu on the number of docked granules was observed . While in the presence of an anti-mitotic reagent, colchicine, a clear increasing effect of PDBu was observed . The final step for supplying granules to the plasma membrane in endocrine cells is concluded to be mediated by a phosphorylation-dependent and actin-based transport system .

Mol Membr Biol, 2001 Jan-Mar, 18(1), 39 - 44
Syntaxin 1A up-regulates GABA transporter expression by subcellular redistribution; Horton N et al.; Neurotransmitter transporters are regulated through a variety of signal transduction mechanisms which appear to operate in order to maintain appropriate levels of transmitter in the synaptic cleft . One such mechanism is the trafficking of the transporter in association with synaptic vesicle release machinery . This report examines the specifics of trafficking regulation of the rat brain GABA transporter GAT1 by syntaxin 1A, a plasma membrane component of the SNARE complex which is involved in vesicle membrane fusion . In hippocampal neurons, botulinum neurotoxin 1C, which specifically cleaves syntaxin 1A, down-regulates plasma membrane GAT1 levels as assessed by surface biotinylation, suggesting that syntaxin 1A is a positive regulator of GAT1 surface expression . The up-regulation correlates with a decrease in intracellular GAT1 levels and is complete within several minutes . These data suggest that syntaxin 1A mediates the redistribution of GAT1 on a time scale important for the rapid regulation of extracellular GABA levels . Expression of different syntaxin 1A constructs in Xenopus oocytes suggests that several portions of the syntaxin 1A molecule are required for the trafficking of GAT1 . These data suggest that the trafficking of GAT1 will be subject to regulatory control by the many molecules known to interact with various domains of syntaxin 1A.

Eur J Gastroenterol Hepatol, 2001 May, 13(5), 603 - 9
Indications and efficacy of botulinum toxin in disorders of the gastrointestinal tract; Mandal A et al.; In recent years, botulinum toxin type A (BT) has been found to be effective in the treatment of various spastic disorders of smooth muscle in the upper and lower gastrointestinal tract . The short-term efficacy of intrasphincteric injection of BT in achalasia is now well established, however, because of the chronic nature of the disease, patients will require repeated injections at regular intervals . In contrast, after a single injection into the anal sphincter, BT has impressively high healing rate with minimal side effects . BT remains a novel therapeutic approach in a range of other gastrointestinal motility disorders including diffuse oesophageal spasm, sphincter of Oddi dysfunction and anismus, and the list of its indications is increasing . BT seems to be safe but as its long-term effects remain unestablished, it should be used with caution in younger patients . In this review we discuss the mechanism of action, indications, efficacy and side-effects of BT with its use in various areas of gastrointestinal tract.

Gastroenterol Clin North Am, 2001 Mar, 30(1), 167 - 81
Anal Fissure; Jonas M et al.; Anal fissure is a common condition, and although most are short-lived and heal spontaneously, those that persist and require intervention cause considerable morbidity in an otherwise healthy young population . Traditionally, lateral internal sphincterotomy was the gold standard treatment for chronic fissures, but this procedure is associated with a risk of incontinence to some degree in 30% of patients . The discovery of pharmacologic agents that effectively cause a chemical sphincterotomy and heal most fissures has led to approximately two thirds of patients avoiding surgery . Topical 0.2% GTN ointment probably is the most widely used first-line treatment . Other drugs currently under investigation may offer effective treatment with fewer side effects . Another advantage of these novel treatments is that by acting through different pathways, they may be effective in the 30% of cases in which GTN fails, the risks associated with surgery may be avoided . Studies of botulinum toxin injection into the anal sphincter have reported excellent healing rates, although the procedure is more invasive, and patients may find it uncomfortable and less tolerable . Chemical sphincterotomy is particularly suitable in patients with associated inflammatory bowel disease, in whom sphincterotomy for anal fissure generally is contraindicated . When pharmacologic therapy fails or fissures recur frequently and patients have raised resting anal pressure, lateral internal sphincterotomy is the surgical treatment of choice . The results are satisfactory when patients are selected carefully and the incision is limited to the length of the fissure . When chemical sphincterotomy fails and resting anal pressures are not elevated, as is commonly the case with patients developing fissures postpartum, an advancement flap should be considered.

Paediatr Drugs, 2001, 3(5), 355 - 63
Tourette syndrome: clinical characteristics and current management strategies; Kossoff EH et al.; Tourette Syndrome (TS) is a disorder comprised of involuntary motor and phonic tics often associated with psychiatric conditions . The etiology for TS is unclear, with both genetic and immunological theories being studied to date . When pharmacotherapy is considered by the patient and physician to be required, owing to either functional impairment from tics or comorbid psychiatric illness, dopamine receptor antagonists are commonly used . Our first-line agents for tic suppression include clonidine, guanfacine, clonazepam and baclofen . Should these agents be ineffective, we would recommend pimozide, fluphenazine, risperidone or haloperidol . The potential benefit of other agents, such as olanzapine, ziprasidone, pergolide and botulinum toxin, is encouraging . Despite many years of concern, we have found little exacerbation of tics with stimulant medications for attention deficit hyperactivity disorder, but clearly clonidine and guanfacine can ameliorate both comorbid conditions . Obsessive compulsive disorder, when associated with TS, may be treated with either a selective serotonin reuptake inhibitor in association with a dopamine receptor antagonist or risperidone alone . New therapies for all aspects of TS and its comorbid conditions are in active clinical trials.

J Pediatr Ophthalmol Strabismus, 2000 Nov-Dec, 37(6), 328 - 32; quiz 354-5
Critical age of botulinum toxin treatment in essential infantile esotropia; Campos EC et al.; PURPOSE: To assess the results of botulinum toxin treatment in 60 consecutive children with essential infantile esotropia . METHODS: Bilateral simultaneous injection of botulinum toxin into the medial rectus muscle was performed in 60 patients under direct visualization with an "open sky" technique . Fluothane/sevoflurane insufflation anesthesia was used . Each patient underwent a single bilateral botulinum toxin injection . Patient age at the time of injection ranged from 5-8 months . RESULTS: Mean patient age at the time of treatment for the 88% of patients who gained a good alignment (within +10 prism diopters {delta} of residual esotropia) was 6.5 months, while mean patient age at time of injection for the 12% of patients who were undercorrected or the deviation relapsed was 7.8 months . Follow-up averaged 5.2 years (range: 2-9 years, SD 2) . No variation of the angle of strabismus was observed after 6 months from injection . In some patients with hyperopic refraction, plus lens corrections were prescribed during follow-up to stabilize the alignment . CONCLUSION: Botulinum toxin can be effective in essential infantile esotropia when children are treated by age 7 months.

Curr Atheroscler Rep, 2001 Jul, 3(4), 295 - 8
Botulinum toxin for the management of muscle overactivity and spasticity after stroke; Esquenazi A et al.; Stroke is a major cause of disability involving the arm and leg . This disability results from the upper motoneuron syndrome (UMN) evident after stroke . It is commonly associated with spasticity and muscle overactivity, which can lead to abnormal limb posturing that interferes with active and passive function . The origin of limb deformity in patients with UMN is based on the concept of unbalanced agonist and antagonist muscle forces acting across joints . In the past decade, botulinum toxin A (BTX-A) a new medication that modifies muscle force and, hence, can treat muscle imbalance, has become available and has renewed interest in the management of muscle overactivity and spasticity after stroke . A reduction in muscle tone, painful spasms, and improved functionality can be obtained . Research and clinical reports support the concept that chemodenervation with BTX-A is an excellent intervention for treating focal muscle overactivity and spasticity secondary to stroke . Many muscles differing in size, shape, and location have been injected, and clinical effectiveness is particularly notable in elbow flexors, ankle plantar flexors, and smaller limb muscles, such as intrinsics of the hand and wrist . Smaller muscles are readily accessible for injection and require smaller amounts of toxin.

Eur Neurol, 2001, 45(4), 257 - 60
Botulinum toxin antibody testing: comparison between the immunoprecipitation assay and the mouse diaphragm assay; Dressler D et al.; Antibodies against botulinum toxin (BT) are currently best detected by the mouse diaphragm assay (MDA) . Nevertheless, the MDA still has disadvantages, so that an immunoprecipitation assay (IPA) was introduced recently . We sought to compare the results of both tests . 33 samples from patients with cervical dystonia and complete or partial BT therapy failure underwent blinded simultaneous IPA and MDA testing . 27 (82%) samples showed concordant results, 17 (52%) being positive and 10 (30%) negative for both IPA and MDA resulting in a significant association of the dichotomous test results (Fisher's exact test, p < 0.01) . The other six samples (18%) showed discordant results, all being IPA-negative and MDA-positive . This excess of MDA-positive results was also significant (Sign rank test, p = 0.03) . IPA and MDA results showed a very strong and significant qualitative and quantitative association . The IPA seems to be less sensitive than the MDA for detection of low BT-AB titres, but the clinical relevance of this still needs to be established . Since the IPA is simpler, faster and cheaper than the MDA and avoids sacrifice of animals, it could become the preferred BT-AB test .

Eur Neurol, 2001, 45(4), 222 - 8
Polymyography combined with time-locked video recording (video EMG) for presurgical assessment of patients with cervical dystonia; Munchau A et al.; We assessed 26 patients with cervical dystonia, in whom botulinum toxin (BT) injections had failed, before selective peripheral denervation . We decided to base the decision which muscle should be denervated on both clinical information and EMG data and focussed on the following features: activity at onset or during 'dystonic spasms' (according to the concept of the 'leading' dystonic muscle), paradoxical activity during voluntary head movements causing restriction of head movements opposite the side of head turn or tilt and activity when symptoms deteriorated during walking . To identify these muscles we developed a new recording system that integrates simultaneous video-taping and polymyography (video EMG) by means of a digital counter, driven by the recording software (resolution 0.1 s), that was fixed in view of the video camera . This system time-locked clinical signs with relevant EMG activity thus allowing demonstration of the above features . These were found in 68% of dystonic muscles with each of them being present in approximately 40% . Video EMG allows an integrated approach to identify overactive neck muscles in patients with cervical dystonia taking into account both relevant clinical findings and EMG data .

Toxicon, 2001 Sep, 39(9), 1309 - 15
Correlation of cleavage of SNAP-25 with muscle function in a rat model of Botulinum neurotoxin type A induced paralysis; Jurasinski CV et al.; Injection of botulinum neurotoxin serotype A (BoNT/A) into muscle results in cleavage of the synaptosomal associated protein of 25 kDa (SNAP-25) and relatively long-term paralysis . However, nerve-terminal sprouting, which appears to require intact SNAP-25, has been reported to occur much earlier . The difference between the long-term paralysis induced by injection of BoNT/A and the short time needed for sprouting led us to investigate the relationship between BoNT/A catalyzed cleavage of SNAP-25 and muscle function . The effect of BoNT/A on SNAP-25 present in nerve endings innervating gastrocnemius muscles of rats was monitored over time . Cleaved SNAP-25 was found in nerve terminals innervating the muscles within 24h of inoculation with BoNT/A and was present more than 2 months later . Comparison of the ratios of cleaved to intact SNAP-25 from the onset of BoNT/A-induced paralysis until function was regained indicated that paralysis was probable when the ratio of cleaved to intact SNAP-25 was greater than 0.35.

Hautarzt, 2001 Apr, 52(4), 312 - 5
{Botulinophilia . The new life style venenophilia}; Harth W et al.; BACKGROUND AND OBJECTIVE: Botulinum toxin is effective in the treatment of hyperhidrosis and the demand for therapy is increasing . Simultaneously we have observed an increase in patients with body dysmorphic disorders who also want botulinum toxin therapy . This botulinophilie is a new variant of venenophilie . We investigated the prevalence of this new diagnosis in our patient population . PATIENTS/METHODS: In the first quarter of 2000 we studied the biopsychosocial features of 13 patients with hyperhidrosis . RESULTS: In 23.1% of our cases we were able to confirm a botulinophilie with body dysmorphic disorder and a normal Minor sweat test . CONCLUSIONS: Botulinophilie is not an indication for botulinum toxin therapy but for psychotherapy.

Acta Neurol Belg, 2001 Mar, 101(1), 39 - 41
Type A botulinum toxin in the treatment of chronic facial pain associated with temporo-mandibular dysfunction; von Lindern JJ; In an open-label study 41 patients suffering from the muscular form of temporo-mandibular dysfunction were treated with botulinum toxin type A injections into masticatory muscles (average of 200 U on each side) and followed for an average of 6.7 months . Eighty percent of patients improved by a mean reduction of 45% on a visual analogue pain scale . During the observation period, 17% of patients had to receive a second injection because of recurrent pain . Reversible speech and swallowing difficulties occurred in only 1 patient . These encouraging results need to be confirmed by a randomized controlled trial.

Neuroscience, 2001, 104(2), 599 - 607
The transmembrane domain of syntaxin 1A negatively regulates voltage-sensitive Ca(2+) channels; Trus M et al.; Syntaxin 1A has a pronounced inhibitory effect on the activation kinetics and current amplitude of voltage-gated Ca(2+) channels . This study explores the molecular basis of syntaxin interaction with N- and Lc-type Ca(2+) channels by way of functional assays of channel gating in a Xenopus oocytes expression system . A chimera of syntaxin 1A and syntaxin 2 in which the transmembrane domain of syntaxin 2 replaced the transmembrane of syntaxin 1A (Sx1-2), significantly reduced the rate of activation of N- and Lc-channels . This shows a similar effect to that demonstrated by syntaxin 1A, though the current was not inhibited . The major sequence differences at the transmembrane of the syntaxin isoforms are that the two highly conserved cysteines Cys 271 and Cys 272 in syntaxin 1A correspond to the valines Val 272 and Val 273 in syntaxin 2 transmembrane . Mutating either cysteines in Sx1-1 (syntaxin 1A) to valines, did not affect modulation of the channel while a double mutant C271/272V was unable to regulate inward current . Transfer of these two cysteines to the transmembrane of syntaxin 2 by mutating Val 272 and Val 273 to Cys 272 and Cys 273 led to channel inhibition . When cleaved by botulinum toxin, the syntaxin 1A fragments, amino acids 1-253 and 254-288, which includes the transmembrane domain, were both unable to inhibit current amplitude but retained the ability to modify the activation kinetics of the channel . A full-length syntaxin 1A and the integrity of the two cysteines within the transmembrane are crucial for coordinating Ca(2+) entry through the N- and Lc-channels.These results suggest that upon membrane depolarization, the voltage-gated N- and Lc-type Ca(2+)-channels signal the exocytotic machinery by interacting with syntaxin 1A at the transmembrane and the cytosolic domains . Cleavage with botulinum toxin disrupts the coupling of the N- and Lc-type channels with syntaxin 1A and abolishes exocytosis, supporting the hypothesis that these channels actively participate in Ca(2+) regulated secretion.

Neurology, 2001 May 22, 56(10), 1290 - 3
Botulinum toxin A and chronic low back pain: a randomized, double-blind study; Foster L et al.; OBJECTIVES: To investigate the efficacy of botulinum toxin A in chronic low back pain and associated disabilities . METHODS: Thirty-one consecutive patients with chronic low back pain who met the inclusion criteria were studied: 15 received 200 units of botulinum toxin type A, 40 units/site at five lumbar paravertebral levels on the side of maximum discomfort, and 16 received normal saline . Each patient's baseline level of pain and degree of disability was documented using the visual analogue scale (VAS) and the Oswestry Low Back Pain Questionnaire (OLBPQ) . The authors reevaluated the patients at 3 and 8 weeks (visual analogue scale) and at 8 weeks (OLBPQ) . RESULTS: At 3 weeks, 11 of 15 patients who received botulinum toxin (73.3%) had >50% pain relief vs four of 16 (25%) in the saline group (p = 0.012) . At 8 weeks, nine of 15 (60%) in the botulinum toxin group and two of 16 (12.5%) in the saline group had relief (p = 0.009) . Repeat OLBPQ at 8 weeks showed improvement in 10 of 15 (66.7%) in the botulinum toxin group vs three of 16 (18.8%) in the saline group (p = 0.011) . No patient experienced side effects . CONCLUSION: Paravertebral administration of botulinum toxin A in patients with chronic low back pain relieved pain and improved function at 3 and 8 weeks after treatment.

J Biol Chem, 2001 Jul 27, 276(30), 28503 - 8 Epub 2001 May 23.
A discontinuous SNAP-25 C-terminal coil supports exocytosis; Chen YA et al.; Membrane fusion requires the formation of four-helical bundles comprised of the SNARE proteins syntaxin, vesicle-associated membrane protein (VAMP), and the synaptosomal-associated protein of 25 kDa (SNAP-25) . Botulinum neurotoxin E cleaves the C-terminal coil of SNAP-25, inhibiting exocytosis of norepinephrine from permeabilized PC12 cells . Addition of a 26-mer peptide comprising the C terminus of SNAP-25 that is cleaved by the toxin restores exocytosis, demonstrating that continuity of the SNAP-25 C-terminal helix is not critical for its function . By contrast, vesicle-associated membrane protein peptides could not rescue botulinum neurotoxin D-treated cells, suggesting that helix continuity is critical for VAMP function . Much higher concentrations of the SNAP-25 C-terminal peptide are required for rescuing exocytosis (K(assembly) = approximately 460 microm) than for binding to other SNAREs in vitro (Kd < 5 microm) . Each residue of the peptide was mutated to alanine to assess its functional importance . Whereas most mutants rescue exocytosis with lower efficiency than the wild type peptide, D186A rescues with higher efficiency, and kinetic analysis suggests this is because of higher affinity for the cellular binding site . This is consistent with Asp-186 contributing to negative regulation of the fusion process.

Ann Otol Rhinol Laryngol, 2001 May, 110(5 Pt 1), 406 - 12
Assessment of posterior cricoarytenoid botulinum toxin injections in patients with abductor spasmodic dysphonia; Bielamowicz S et al.; In this study, we compared 2 techniques for injection of botulinum toxin type A (Botox) into the posterior cricoarytenoid (PCA) muscle for the treatment of abductor spasmodic dysphonia (ABSD) . Fifteen patients with ABSD were enrolled in a prospective randomized crossover treatment trial comparing the 2 injection techniques . The PCA muscle was injected with 5 units on each side, with the injections staged 2 weeks apart, via either a percutaneous posterior-lateral approach or a transnasal fiberoptic approach . Eleven patients reported some benefit with the injections; however, the patient-perceived benefits were not related to changes in symptoms on blinded counts by speech pathologists . No significant reductions in the numbers of breathy breaks occurred with either technique, and no differences were found between techniques . Although patients perceived a benefit, blinded symptom counts did not substantiate these benefits . Thus, PCA muscle injections of Botox provided limited benefits to patients with ABSD, demonstrating the need for a more effective therapy for these patients.

Mund Kiefer Gesichtschir, 2001 Mar, 5(2), 144 - 9
{Frey syndrome after lateral parotidectomy . Follow-up and therapeutic outlook}; Kuttner C et al.; BACKGROUND: Gustatory sweating is a common complication of parotid surgery . PATIENTS AND METHODS: In order to evaluate the incidence of Frey's syndrome following superficial parotidectomy, 69 patients who underwent surgery due to adenoma were studied . Forty-three patients (62%) suffered from gustatory sweating following superficial parotidectomy, and 33 of them requested treatment . Nineteen patients felt that their quality of life had been decreased by the symptoms . RESULTS: Minor's starch iodine test proved that 85% of the patients who did not notice Frey's syndrome after surgery actually had a subclinical manifestation . Eight patients were successfully treated with intracutaneous injections of botulinum toxin A . Within 1 week gustatory sweating disappeared . CONCLUSION: Frey's syndrome is present in almost all patients following superficial parotidectomy and there is a strong need for treatment . Intracutaneous injection of botulinum toxin A is an effective treatment in severe cases of the syndrome.

Neuroscience, 1976 Aug, 1(4), 345 - 7
Motor end-plates in regenerating rat skeletal muscle exposed to botulinum toxin; Jirmanova I et al.; Botulinum toxin type A, when applied to the extensor digitorum longus muscle of rats, reduces spontaneous and evoked transmitter release to a few per cent of the normal level . The toxin, however, fails to affect the morphological redifferentiation of the postsynaptic part of the neuromuscular junction following muscle degeneration-regeneration induced by a selective myotoxic agent, bupivacaine . This indicates that neither transmitter release nor resulting muscle activity are necessary for the differentiation of the sole plate.

Drugs, 2001, 61(5), 579 - 91
Current concepts on pathophysiology, diagnosis and treatment of diffuse oesophageal spasm; Storr M et al.; Diffuse oesophageal spasm is a functional oesophageal motility disorder of unknown aetiology, which appears to be due to a disturbance of the normal pharmacological timing of propulsive contraction occurring in the oesophageal body after swallowing . The lack of pathophysiological understanding may be due to the fact that there is more than one pathophysiological pathway causing symptoms of diffuse oesophageal spasm . Barium studies, oesophageal scintigraphy and fiberoptic examination can be helpful in finding the correct diagnosis, but manometry is still the gold standard of diagnostic procedures . Similar to other spastic oesophageal motility disorders, pharmacological treatment of diffuse oesophageal spasm includes nitrates, calcium antagonists, anticholinergics and antidepressants with varying beneficial effects . Botulinum toxin, which provides sufficient treatment as measured by symptom score and manometric patterns in patients with achalasia, was recently evaluated for the treatment of diffuse oesophageal spasm in small patient selections with promising results.

J Biol Chem, 2001 Jul 13, 276(28), 26680 - 7 Epub 2001 May 18.
Calcium regulation of exocytosis in PC12 cells; Chen YA et al.; The calcium (Ca(2+)) regulation of neurotransmitter release is poorly understood . Here we investigated several aspects of this process in PC12 cells . We first showed that osmotic shock by 1 m sucrose stimulated rapid release of neurotransmitters from intact PC12 cells, indicating that most of the vesicles were docked at the plasma membrane . Second, we further investigated the mechanism of rescue of botulinum neurotoxin E inhibition of release by recombinant SNAP-25 COOH-terminal coil, which is known to be required in the triggering stage . We confirmed here that Ca(2+) was required simultaneously with the SNAP-25 peptide, with no significant increase in release if either the peptide or Ca(2+) was present during the priming stage as well as the triggering, suggesting that SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex assembly was involved in the final Ca(2+)-triggered event . Using this rescue system, we also identified a series of acidic surface SNAP-25 residues that rescued better than wild-type when mutated, due to broadened Ca(2+) sensitivity, suggesting that this charged patch may interact electrostatically with a negative regulator of membrane fusion . Finally, we showed that the previously demonstrated stimulation of exocytosis in this system by calmodulin required calcium binding, since calmodulin mutants defective in Ca(2+)-binding were not able to enhance release.

Laryngoscope, 2001 May, 111(5), 844 - 50
Functional study of four neurotoxins as inhibitors of post-traumatic nerve regeneration; Paydarfar JA et al.; OBJECTIVES/HYPOTHESIS: Chemical inhibition of nerve regeneration was studied as a potential adjunct in the treatment of injuries to the facial or recurrent laryngeal nerve . We propose that by treating selected muscles with an inhibitor of nerve regeneration shortly after injury, synkinesis may be controlled . STUDY DESIGN: Nerve regeneration after crush injury was studied in the rat posterior tibial and sciatic nerves, well-established models for the study of peripheral nerve injuries . METHODS: Four days after controlled crush injury to the posterior tibial nerve, the gastrocnemius muscle was injected with saline (control, n = 8), phenol (n = 6), doxorubicin (n = 6), or vincristine (n = 11) . Injection without crush injury was performed using vincristine (n = 4) or botulinum toxin (n = 4) . Four rats underwent crush injury to the sciatic nerve followed 4 days later by botulinum toxin injection to the gastrocnemius muscle . The percent of functional recovery (%FR) of the nerve was assessed using walking track analysis . RESULTS: Vincristine significantly retarded nerve regeneration . Five weeks after injury, %FR returned to normal in controls, as well as in the phenol, doxorubicin, and botulinum toxin groups, while in the vincristine group %FR was less than 60% of baseline (P <.0001) . Vincristine injections without crush injury showed no significant reduction in print length factor . Functional recovery in the botulinum/crush group was more rapid than the botulinum without crush group . CONCLUSIONS: Application of vincristine to the gastrocnemius muscle significantly inhibits regeneration of the posterior tibial nerve after crush injury . Botulinum toxin does not prolong functional recovery after nerve injury; rather, crush injury protects against the prolonged chemodenervation seen with botulinum toxin . Doxorubicin and phenol injection did not prolong functional recovery at the doses tested.

J Biol Chem, 2001 Jul 20, 276(29), 27034 - 41 Epub 2001 May 17.
The role of zinc binding in the biological activity of botulinum toxin; Simpson LL et al.; Botulinum toxin is a zinc-dependent endoprotease that acts on vulnerable cells to cleave polypeptides that are essential for exocytosis . To exert this poisoning effect, the toxin must proceed through a complex sequence of events that involves binding, productive internalization, and intracellular expression of catalytic activity . Results presented in this study show that soluble chelators rapidly strip Zn(2+) from its binding site in botulinum toxin, and this stripping of cation results in the loss of catalytic activity in cell-free or broken cell preparations . Stripped toxin is still active against intact neuromuscular junctions, presumably because internalized toxin binds cytosolic Zn(2+) . In contrast to soluble chelators, immobilized chelators have no effect on bound Zn(2+), nor do they alter toxin activity . The latter finding is because of the fact that the spontaneous loss of Zn(2+) from its coordination site in botulinum toxin is relatively slow . When exogenous Zn(2+) is added to toxin that has been stripped by soluble chelators, the molecule rebinds cation and regains catalytic and neuromuscular blocking activity . Exogenous Zn(2+) can restore toxin activity either when the toxin is free in solution on the cell exterior or when it has been internalized and is in the cytosol . The fact that stripped toxin can reach the cytosol means that the loss of bound Zn(2+) does not produce conformational changes that block internalization . Similarly, the fact that stripped toxin in the cytosol can be reactivated by ambient Zn(2+) or exogenous Zn(2+) means that productive internalization does not produce conformational changes that block rebinding of cation.

J Neurol, 2001 Apr, 248 Suppl 1, 39 - 44
Botulinum toxin: evidence-based medicine criteria in rare indications; Jost WH et al.; Presently, there are more than 50 possible indications for the application of botulinum toxin . In some indications the use of botulinum toxin has already been approved; others are about to be approved . For most of these indications a sufficient number of studies have been published . For rare indications, an insufficient number of studies are available . In part there are only published case reports . Classification according to the criteria of evidence-based medicine is thus difficult . Here we try to describe the range of possible indications for botulinum toxin A and assess its therapeutic value for rare indications . The number of studies available on botulinum toxin B is still limited.

J Neurol, 2001 Apr, 248 Suppl 1, 34 - 8
Evidence-based medicine: botulinum toxin A in migraine and tension-type headache; Gobel H et al.; The therapeutic effect of botulinum toxin in headache was observed coincidentally . The rationale for this new indication initially met with a great deal of scepticism, because the toxin's mechanism of action, cholinergic chemodenervation, does not fit the pathophysiological concept of migraine and other forms of headache . Meanwhile a fair number of studies have been published which indicate efficacy for botulinum toxin and recommend its use for the treatment of tension headache and migraine . According to the evidence-based medicine criteria, grade I evidence has been demonstrated . In addition the use of botulinum toxin for cluster-headache and secondary headache is discussed . Further large scale studies will be regarded to demonstrate the long-term efficacy.

J Neurol, 2001 Apr, 248 Suppl 1, 31 - 3
Evidence-based medicine: botulinum toxin in focal hyperhidrosis; Naumann M; All studies performed so far indicate that BTX-A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis . Based on two large well-designed, double-blind, placebo-controlled study there is class 1 evidence for the efficacy of BTX-A in axillary hyperhidrosis, and class 2 evidence for BTX-A in gustatory and palmar sweating (classification according to the Quality Standards Subcommittee of the American Academy of Neurology, 1994) . Other indications (forehead sweating, plantar hyperhidrosis, truncal sweating) are only anecdotally reported.

J Neurol, 2001 Apr, 248 Suppl 1, 3 - 10
Pharmacology and immunology of botulinum toxin serotypes; Aoki KR; Botulinum toxin preparations can provide patients with a therapeutic modality that may improve both their medical condition and quality of life . The mechanism of action of the various botulinum toxin preparations and serotypes is similar: they all block neurotransmitter release . The majority of clinical conditions treated are based upon the targeted temporary chemodenervation of the selected organ . The antinociceptive effects of botulinum toxin type A (BTX-A), based on preclinical studies and clinical experiences in treating movement disorders and other painful conditions, will also be reviewed to illustrate how this compound may act as it alleviates the discomfort associated with various conditions . Chronic therapies with preparations with the lowest amount of neurotoxin protein provide the best chance for long-term therapy by minimizing the potential of the patient to form neutralizing antibodies . Differences in formulations or serotypes impart unique efficacy and safety profiles and thus does not support a simple dose ratio conversion between products.

J Neurol, 2001 Apr, 248 Suppl 1, 28 - 30
Botulinum toxin treatment in cerebral palsy: evidence for a new treatment option; Kirschner J et al.; Intramuscular injections of botulinum toxin type A (BTX-A) have increasingly been used to reduce spasticity in specific muscle groups in children with cerebral palsy . Targets of therapeutic efforts are improvement of gross motor function, alleviation of pain or facilitation of hygienic care . Placebo-controlled studies have shown the local and functional effectiveness of BTX-A for the treatment of dynamic pes equinus . Whether long-term treatment with BTX-A improves motor development and delays contractures is still under investigation.

J Neurol, 2001 Apr, 248 Suppl 1, 25 - 7
Botulinum toxin for treatment of spasticity in adults; Reichel G; Although a few hundred papers have been published on the treatment of adult spasticity with botulinum toxin, the number of randomized placebo-controlled double-blind studies, by comparison, is relatively small . Criteria of highest evidence classes are met by the following observations: 1) Botulinum toxin improves motor functions (ability to walk and stand in the presence of spastic equinus deformity and knee flexor spasticity, upper-extremity movements) . 2) Botulinum toxin makes attendance of spastic adults easier (personal hygiene in patients presenting with severe adductor spasticity; self-care and dressing in the presence of arm spasticity) . 3) Early initiation of treatment with botulinum toxin yields better results than delayed institution (hemispasticity).

J Neurol, 2001 Apr, 248 Suppl 1, 21 - 4
Botulinum toxin: evidence-based medicine criteria in blepharospasm and hemifacial spasm; Jost WH et al.; Botulinum A toxin is recognized and approved for symptomatic treatment of hemifacial spasm and blepharospasm . The state of trials is good, although double-blind placebo-controlled studies have been carried out involving only a small number of cases . Open case control studies have been done with large patient collectives . In both indications, treatment with botulinum toxin reaches the highest EBM degree in a critical evaluation.

J Neurol, 2001 Apr, 248 Suppl 1, 14 - 20
Evidence-based medicine in botulinum toxin therapy for cervical dystonia; Ceballos-Baumann AO; Early controlled studies of botulinum toxin (BTX) in cervical dystonia were unblinded and indicated that BTX injections are more successful than medication . In this article, the use of botulinum toxin (BTX) in cervical dystonia is reviewed according to evidence-based medicine . To document the efficacy of BTX, there have been a number of prospective, placebo-controlled studies of the use of BTX in cervical dystonia . Most were double-blind, some included videotapes to provide blinded objective assessments . The more recent studies of BTX in cervical dystonia focused on particular issues such as utility of EMG guidance, comparison to anti-cholinergic treatment, BTX serotype B in BTX type A resistant and non-resistant patients and different dosages . Despite the wealth of data generated with prospective placebo-controlled studies on the effectiveness of BTX in cervical dystonia, there is uncertainty on which outcome measures to use to express the efficacy of treatments for cervical dystonia . Disease specific instruments to measure quality of life in cervical dystonia have not been used so far . Data on the use of BTX for cervical dystonia have long been restricted to small series of patients reflecting exclusively the experience of individual specialized centers.

J Neurol, 2001 Apr, 248 Suppl 1, 11 - 3
Some unresolved issues with botulinum toxin; Guyer BM; Issues concerning botulinum toxin still need resolution in the laboratory and clinic . Assay nomenclature is unsatisfactory and attempts to establish common units and/or equivalents are misguided and dangerous . Optimum toxin concentrations for most indications are unknown . Loss of response is too readily ascribed to antibody formation . New therapeutic indications for toxin raise the possibility of additional mechanisms of action.

Dis Colon Rectum, 2001 May, 44(5), 661 - 5
Chronic idiopathic anal pain: analysis of ultrasonography, pathology, and treatment; Christiansen J et al.; PURPOSE: This study was undertaken to analyze whether intra-anal ultrasound examination, anorectal physiologic evaluation, and histopathologic examination in patients with chronic idiopathic anal pain presented any common features and whether the results of different treatment modalities correlated with these findings . METHODS: Eighteen patients who met the criteria for chronic idiopathic anal pain were studied . All had an intra-anal ultrasound examination and a complete anorectal physiologic evaluation . In a selected group of patients, ultrasound-guided biopsy samples were taken from pathological areas in the internal and external sphincter . Treatment consisted of analgesics only in four patients, 0.2 percent nitroglycerin ointment in four, and ultrasound injection of botulin (botulinum toxin, Botox) into the intersphincteric space in nine . Two patients, including one who was previously treated with botulin, ultimately had a colostomy . RESULTS: Four patients were managed satisfactorily on analgesic treatment under the guidance of the hospital's pain clinic . Nitroglycerin ointment resulted in temporary pain relief in one of four patients . Injection of botulin resulted in a permanent improvement in four patients, a temporary improvement in one patient, and no effect in four patients . Two patients had a colostomy, resulting in complete pain relief . The effect or lack of effect of nitroglycerin ointment and botulin was not related to changes in anal pressure . CONCLUSION: Chronic idiopathic anal pain is a condition of unknown origin for which no proven therapy exists . As in other syndromes based on muscular dystonia, some patients may benefit from injection of botulin.

Am J Physiol Lung Cell Mol Physiol, 2001 Jun, 280(6), L1094 - 103
IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways; Schraufstatter IU et al.; Stimulation of microvascular endothelial cells with interleukin (IL)-8 leads to cytoskeletal reorganization, which is mediated by combined activation of the CXCR1 and the CXCR2 . In the early phase actin stress fibers appear, followed by cortical actin accumulation and cell retraction leading to gap formation between cells . The early response (between 1 and 5 min) is inhibited by an antibody that blocks the CXCR1 . The later phase (from about 5 to 60 min), which is associated with cell retraction, is prevented by anti-CXCR2 antibody . Furthermore, anti-CXCR2, but not anti-CXCR1, antibody blocked IL-8-mediated haptotaxis of endothelial cells on collagen . The later phase of the IL-8-mediated actin response is inhibited by pertussis toxin, indicating that the CXCR2 couples to G(i) . In contrast, the early phase is blocked by C3 botulinum toxin, which inactivates Rho, and by Y-27632, which inhibits Rho kinase, but not by pertussis toxin . Furthermore, the early CXCR1-mediated formation of stress fibers was prevented by dominant negative Rho . Dominant negative Rac on the other hand initially translocated to actin-rich filopodia after stimulation with IL-8 and later prevented cell retraction by blocking the CXCR2-mediated cytoskeletal response . These results indicate that IL-8 activates both the CXCR1 and the CXCR2 on microvascular endothelial cells, using different signal transduction cascades . The retraction of endothelial cells due to activation of the CXCR2 may contribute to the increased vascular permeability observed in acute inflammation and during the angiogenic response.

Aesthetic Plast Surg, 2001 Mar-Apr, 25(2), 73 - 84
Botulinum toxin A and facial lines: the variable concentration; Le Louarn C; Our improved understanding of the functional anatomy of the face and of the action of the botulinum toxin A leads us to determine a new injection procedure which consequently decreases the risk of eyebrow and eyelid ptosis, and increases the toxin injection's possibilities and efficiencies . Variable toxin injection concentrations adapted to each injected area are used . Thanks to the new procedure in the upper face, toxin A action is quite close to an endoscopic surgical action . In addition, interesting results are achievable on the nose, upper part of the nasolabial fold, jawline and neck regions . Lastly, a smoothing effect on the skin is obtained by the anticholinergic action of the toxin A on the dermal receptors.

Semin Neurol, 2001, 21(1), 85 - 90
The botulinum toxins in the treatment of cervical dystonia; Brashear A; The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease . Two forms of toxins, botulinum toxin type A (BTX-A) and botulinum toxin type B (BTX-B), have each been studied in large multicenter trials in subjects with CD . A study of BTX-A demonstrated improvement of 5.15 to 10.65 degrees in head position using the Cervical Dystonia Severity Scale (CDSS) in those treated with BTX-A (trade name BOTOX) compared with placebo . A study in patients who continued to respond to BTX-A and a similarly designed study in patients who were resistant to BTX-A demonstrated statistical improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in those treated with BTX-B (evaluated as NeuroBloc) compared with placebo . The potential availability of both forms of toxin will allow physicians to offer further treatment options to patients with CD.

Parkinsonism Relat Disord, 2001 Oct, 7(4), 329 - 332
Quantitative assessment of parkinsonian sialorrhea and results of treatment with botulinum toxin; Friedman A et al.; Aim: To assess quantitatively sialorrhea in Parkinson's disease (PD) and the efficacy of botulinum toxin (BOTOX) in its treatment.Material: 11 patients with a clinical diagnosis of idiopathic PD and drooling were assessed at least two points on the UPDRS Part II and 14 control subjects.Methods: Salivation was measured by weighing dental rolls before, and 2min after, insertion at six points of highest secretion of saliva in the mouth (buccal vestibule, and sublingual area) . PD patients were assessed before and 1 week after injections of five units of BOTOX into each parotid salivary gland and the results were compared to the salivation production of controls.Results: Average secretion of saliva in PD patients was significantly higher than in controls-0.39+/-0.4g/2min . (range: 0.02-1.82) vs 0.19+/-0.16g/2min . (range: 0.02-0.98) (P=0.03) . After treatment, the average secretion of saliva in PD patients decreased to 0.25+/-0.26g/2min . (range: 0.004-0.99) and did not differ significantly from controls . Nine patients improved also according to UPDRS . No side effects were observed in any of the patients injected.Conclusion: Botulinum toxin may be an effective and safe treatment of parkinsonian sialorrhea.

Drugs Aging, 2001, 18(4), 255 - 62
Botulinum toxin A treatment of adult upper and lower limb spasticity; Hesse S et al.; This article discusses the treatment of spasticity with botulinum toxin A as a new approach in the neurological rehabilitation of patients after stroke . Clinical studies have been reviewed to provide information about target groups, technical aspects and the advantages and disadvantages of treating spasticity with botulinum toxin A . Open and controlled studies showed that the intramuscular injection of Dysport 500 to 1,500U or Botox 100 to 300U could reversibly relieve upper limb flexor and lower limb extensor spasticity . A reduced muscle tone, pain relief, better hand hygiene and improved walking function were the main benefits . Patients tolerated the treatment well . Activity or, if not possible, electrical stimulation of the injected muscles may enhance the effectiveness of the costly toxin . Serial casting is another option . With respect to the action of botulinum toxin A, it is suggested that the effect of the toxin could be mediated by paresis of both the extrafusal and intrafusal muscle fibres, thereby altering the afferent discharge in the muscle.

Int J Lang Commun Disord, 2001, 36 Suppl, 282 - 7
Drooling in Parkinson's disease: a novel speech and language therapy intervention; Marks L et al.; Drooling and difficulty swallowing saliva are commonly reported in people with Parkinson's disease (PD) . Drooling in PD is the result of swallowing difficulties rather than excessive saliva production . Currently, there is little research into the effectiveness of treatments to reduce drooling . The aims of the study were to develop objective measures of saliva volume and drooling for PD and to assess the efficacy of two therapeutic strategies to control drooling, i.e . specific speech and language therapy (SLT) including a portable metronome brooch to cue swallowing and injections of botulinum toxin into both parotid glands to reduce the amount of saliva produced . This paper will describe the assessments used, including the measurement of saliva, swallowing and drooling . The main focus will be the strategies used in the SLT intervention . The preliminary results are presented.

Hosp Med, 2001 Apr, 62(4), 228 - 30
The use of botulinum toxin in otorhinolaryngology; Walshe P et al.; In recent years, the use of botulinum toxin has become more popular for the treatment of a wide variety of diseases in the head and neck . It offers the possibility of non-invasive treatment of conditions whose aetiology lies in neuromuscular dyskinesis.

J Med Assoc Thai, 2001 Feb, 84(2), 171 - 6
Botulinum toxin treatment of the sixth nerve palsy: an experience of 5-year duration in Thailand; Chuenkongkaew W et al.; Forty-five patients (48 eyes) with sixth nerve palsy were treated with botulinum toxin injection to antagonist medial rectus muscle at Siriraj Hospital from October 1995 to September 2000 . The common causes of palsy were ischemia, trauma and inflammation . Thirty-eight patients (group I) had an interval to treatment of less than 24 weeks (average, 8.7 weeks) and seven patients (group II), longer than 24 weeks . The mean pre-injection esodeviation and extent of abduction in group I were 28.1 prism diopters (PD) and 28.4 per cent, and in group II were 38 PD and 8.1 per cent respectively . After a mean follow-up of 12.2 months, twenty-seven (71.1%) patients in group I recovered completely after the first injection and three (7.9%), after the second injection with a mean interval to recovery of 8.1 weeks . One (14.3%) of 7 patients of group II obtained complete recovery without fusion . Twenty-six (83.9%) of 31 patients with complete resolution achieved binocular function . We conclude that botulinum toxin treatment is a safe and effective alternative to traditional surgery of acute onset sixth nerve palsy.

Arch Otolaryngol Head Neck Surg, 2001 Apr, 127(4), 393 - 9
Long-term therapy for spasmodic dysphonia: acoustic and aerodynamic outcomes; Mehta RP et al.; OBJECTIVE: To evaluate the long-term aerodynamic, acoustic, and electromyographic effects of serial botulinum toxin (BT) injections in patients with adductor spasmodic dysphonia . DESIGN: Two-year, nonrandomized, controlled, before-after study . SETTING: Ambulatory care clinic at a single academic medical center . PATIENTS: A convenience sample of 91 patients with adductor spasmodic dysphonia evaluated and treated during 2 years and 64 age- and sex-matched controls . INTERVENTIONS: Injections of BT into the thyroarytenoid muscles in conjunction with electromyographic evaluation and acoustic and aerodynamic evaluation before and after serial BT injections . MAIN OUTCOME MEASURES: Translaryngeal airflow, jitter, shimmer, signal-to-noise ratio, fundamental frequency, standard deviation of fundamental frequency, maximum phonation time, and inappropriate muscle activity by electromyography . RESULTS: Translaryngeal airflow, jitter, and shimmer improved significantly after serial BT treatments and showed sustained improvement over time . Fundamental frequency, standard deviation of fundamental frequency, and signal-to-noise ratio did not change significantly after BT treatment . Electromyographic data suggested decreased inappropriate muscle activity with repeated BT injections . CONCLUSION: Treatment with BT provides ongoing relief of voice perturbations in patients with adductor spasmodic dysphonia who undergo long-term cumulative therapy.

Arch Otolaryngol Head Neck Surg, 2001 Apr, 127(4), 389 - 92
Impact on quality of life of botulinum toxin treatments for spasmodic dysphonia and oromandibular dystonia; Bhattacharyya N et al.; OBJECTIVE: To determine the impact on quality of life of botulinum toxin treatments for common dystonias of the head and neck . DESIGN: Cross-sectional survey study of a patient cohort treated with botulinum toxin injections for spasmodic dysphonia (SD) or oromandibular dystonia (OMD) . INTERVENTIONS AND OUTCOME MEASURES: The Glasgow Benefit Inventory was used to quantify the health benefit of treatment . Data were collected for demographics, time intervals relative to diagnosis, treatment duration, and frequency of injections . The groups were compared to determine whether differences existed in benefit from treatment . Correlation analysis was conducted for inventory scores and time intervals . RESULTS: A total of 23 patients (5 with OMD and 18 with SD) completed the questionnaire . The mean total benefit score was +38.04 (possible range, -100 to +100) for the whole group (P<.001) . The OMD group derived a nonsignificantly smaller benefit (+21.67 vs +42.59) (P =.07) . The mean subscores for the combined group were +39.67, +26.81, and +42.75 for the general, social support, and physical health subscores, respectively (P< or =.001) . The difference in mean subscores between the 2 groups was not statistically significant, although patients with OMD had a lower social support subscore (+6.67 vs . +32.41) . No correlation was found between duration of therapy or frequency of injections and the Glasgow Benefit Inventory score . CONCLUSIONS: Patients with OMD or SD derive considerable benefit when treated with botulinum toxin . The magnitude of benefit is largely independent of the time course of therapy . Treatment with botulinum toxin for these conditions is effective on the basis of quality-of-life criteria.

Diabetes, 2001 May, 50(5), 1039 - 46
Increased intracellular calcium is required for spreading of rat islet beta-cells on extracellular matrix; Bosco D et al.; Rat islet beta-cells spread in response to glucose when attached on the matrix produced by a rat bladder carcinoma cell line (804G) . Furthermore, in a mixed population of cells, it has been observed previously that spread cells secrete more insulin acutely in response to glucose, compared with cells that remain rounded . These results suggest bi-directional signaling between the islet beta-cell and the extracellular matrix . In the present study, the role of increased intracellular free Ca2+ concentration {Ca2+}i as an intracellular step linking glucose stimulation and beta-cell spreading (inside-out signaling) was investigated . Purified rat beta-cells were attached to this matrix and incubated under various conditions known to affect {Ca2+}i . The effect of glucose on beta-cell spreading was mimicked by 25 mmol/l KCl (which induces calcium influx) and inhibited by diazoxide (which impairs depolarization and calcium entry) and by the L-type Ca2+ channel blocker SR-7037 . When a 24-h incubation at 16.7 glucose was followed by 24 h at 2.8 mmol/l, beta-cells that had first spread regained a round phenotype . In the presence of thapsigargin, spreading progressed throughout the experiment, suggesting that capture of calcium by the endoplasmic reticulum is involved in the reversibility of spreading previously induced by glucose . Spreading was still observed in degranulated beta-cells and in botulinum neurotoxin E-expressing beta-cells when exocytosis was prevented . In summary, the results indicate that increased {Ca2+}i is required for the glucose-induced spreading of beta-cells on 804G matrix and that it is not a consequence of exocytotic processes that follow elevation of {Ca2+}i.

Diabetes, 2001 May, 50(5), 1012 - 20
Ca2+-dependent exocytosis of L-glutamate by alphaTC6, clonal mouse pancreatic alpha-cells; Yamada H et al.; Pancreatic islet cells express receptors and transporters for L-glutamate and are thus believed to use L-glutamate as an intercellular signaling molecule . However, the mechanism by which L-glutamate appears in the islets is unknown . In the present study, we investigated whether L-glutamate is secreted through exocytosis by alphaTC6 cells (clonal mouse pancreatic alpha-cells) . An appreciable amount of L-glutamate was released from cultured cells after the addition of KCl or A23187 in the presence of Ca2+ and 10 mmol/l glucose in the medium . The KCl-induced glutamate release was significantly reduced when assayed in the absence of Ca2+ or when the cells were pretreated with EGTA-AM . The KCl-induced Ca2+-dependent glutamate release was inhibited approximately 40% by voltage-gated Ca2+ channel blockers, such as nifedipine at 20 micromol/l . The degree of KCl-induced Ca2+-dependent glutamate release was correlated with an increase in intracellular {Ca2+}, as monitored by fura-2 fluorescence . Botulinum neurotoxin type E inhibited 55% of the KCl-induced Ca2+-dependent glutamate release, followed by specific cleavage of 25 kDa synaptosomal-associated protein . Furthermore, bafilomycin A1, a specific inhibitor of vacuolar H+-ATPase, inhibited 40% of the KCl-induced Ca2+-dependent glutamate release . Immunoelectronmicroscopy with antibodies against synaptophysin, a marker for neuronal synaptic vesicles and endocrine synaptic-like microvesicles, revealed a large number of synaptophysin-positive clear vesicles in cells . Digitonin-permeabilized cells took up L-glutamate only in the presence of MgATP, which is sensitive to bafilomycin A1 or 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile (a proton conductor) but insensitive to either oligomycin or vanadate . From these results, it was concluded that alphaTC6 cells accumulate L-glutamate in the synaptophysin-containing vesicles in an ATP-dependent manner and secrete it through a Ca2+-dependent exocytic mechanism . The Ca2+-dependent glutamate release was also triggered when cells were transferred in the medium containing 1 mmol/l glucose, suggesting that low glucose treatment stimulates the release of glutamate . Our results are consistent with the idea that L-glutamate is secreted by alpha-cells through Ca2+-dependent regulated exocytosis.

J Biol Chem, 2001 Jul 13, 276(28), 26589 - 96 Epub 2001 May 01.
D-Aspartate is stored in secretory granules and released through a Ca(2+)-dependent pathway in a subset of rat pheochromocytoma PC12 cells; Nakatsuka S et al.; D-Aspartate in mammalian neuronal and neuroendocrine cells is suggested to play a regulatory role(s) in the neuroendocrine function . Although D-aspartate is known to be released from neuroendocrine cells, the mechanism underlying the release is less understood . Rat pheochromocytoma PC12 cells contain an appreciable amount of D-aspartate (257 +/- 31 pmol/10(7) cells) . Indirect immunofluorescence microscopy with specific antibodies against d-aspartate indicated that the amino acid is present within a particulate structure, which is co-localized with dopamine and chromogranin A, markers for secretory granules, but not with synaptophysin, a marker for synaptic-like microvesicles . After sucrose density gradient centrifugation of the postnuclear particulate fraction, about 80% of the d-aspartate was recovered in the secretory granule fraction . Upon the addition of KCl, an appreciable amount of D-aspartate (about 40 pmol/10(7) cells at 10 min) was released from cultured cells on incubation in the presence of Ca(2+) in the medium . The addition of also triggered d-aspartate release . Botulinum neurotoxin type E inhibited about 40% of KCl- and Ca(2+)-dependent d-aspartate release followed by specific cleavage of 25-kDa synaptosomal-associated protein . alpha-Latrotoxin increased the intracellular {Ca(2+)} and caused the Ca(2+)-dependent d-aspartate release . Bafilomycin A1 dissipated the intracellular acidic regions and inhibited 40% of the Ca(2+)-dependent D-aspartate release . These properties are similar to those of the exocytosis of dopamine . Furthermore, digitonin-permeabilized cells took up radiolabeled d-aspartate depending on MgATP, which is sensitive to bafilomycin A1 or 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile . Taken together, these results strongly suggest that d-aspartate is stored in secretory granules and then secreted through a Ca(2+)-dependent exocytotic mechanism . Exocytosis of D-aspartate further supports the role(s) of D-aspartate as a chemical transmitter in neuroendocrine cells.

J Gastrointest Surg, 2001 Mar-Apr, 5(2), 192 - 205
A decision analysis of the optimal initial approach to achalasia: laparoscopic Heller myotomy with partial fundoplication, thoracoscopic Heller myotomy, pneumatic dilatation, or botulinum toxin injection; Urbach DR et al.; In the absence of randomized controlled trials that directly compare all of the modern methods of managing achalasia, decision analysis may help determine the optimal treatment strategy . Four strategies for the initial management of achalasia were compared using the following decision model: (1) laparoscopic Heller myotomy and partial fundoplication; (2) pneumatic dilatation; (3) botulinum toxin injection; and (4) thoracoscopic Heller myotomy . Probabilities of clinical events and utilities of health states were estimated using review of the medical literature and patient interviews . A recursive decision tree (Markov model) was used to simulate all the important outcomes of each initial treatment option, allowing for complications, relapses over time, and transitions between strategies when appropriate . After 10 years, laparoscopic Heller myotomy with partial fundoplication was associated with the longest quality-adjusted survival (quality-adjusted life years {QALY} = 7.41) . The difference between this strategy and either pneumatic dilatation or botulinum toxin injection was small . Thoracoscopic Heller myotomy was associated with the poorest quality-adjusted survival (QALY = 7.15) . Pneumatic dilatation was the favored strategy when the effectiveness of laparoscopic surgery at relieving dysphagia was less than 89.7%, the operative mortality risk was greater than 0.7%, or the probability of reflux after pneumatic dilatation was less than 19% . In a decision model, laparoscopic Heller myotomy with partial fundoplication is at least as effective as endoscopic approaches for managing achalasia symptoms . However, the differences are small enough that patient preferences and local expertise should be taken into consideration when tailoring a treatment plan for an individual patient.

Pediatr Rehabil, 2001 Jan-Mar, 4(1), 29 - 36
The role of botulinum toxin in the neuro-rehabilitation of young patients with brachial plexus birth palsy; Desiato MT et al.; PURPOSE: To favour the active movements of the shoulder abductor/external rotator, elbow extensor and supinator muscles, through the partial inhibition of the uninvolved antagonistic muscles, in the Brachial Plexus birth Palsy (BPP) . METHODS: The type A Botulinum Neuro Toxin (BNT-Dysport, Ipsen) was injected in 50 outpatients (mean age: 4.7 +/- 3.4 years) with BPP according to the criteria: early and current neuro-rehabilitation (Reflex Locomotion-RL), age <14 years, no cognitive impairment . Repeat injections (1.9 +/- 0.8) were performed in 30 patients . RESULTS: The range of active movements increased at the maximal benefit phase, compared to the baseline values (p < 0.05-0.01) . The gain of shoulder's abduction was directly related to the youngest age (r = 0.6) . An expanded compliance of the injected muscles and a faster response to the RL, in respect to that experienced in the pre-BNT sessions, was detected . The Global Clinical Rating Scale disclosed the temporal profile of the clinical outcome, with step-like increases of the function in 70% of the patients, and a 'plateau' trait in the remaining ones (+29.8 +/- 10.5%) . The video-taped recordings showed an improvement in the global movements . CONCLUSIONS: The employment of BNT in the management of young patients with BPP has beneficial effects in the integration of the bodily scheme.

J Protein Chem, 2001 Jan, 20(1), 73 - 80
Peptide phage display library as source for inhibitors of clostridial neurotoxins; Zdanovsky AG et al.; Clostridial neurotoxins are the most powerful toxins known . There are no available antidotes to neutralize neurotoxins after they have been internalized by neuronal cells . Enzymatic domains of clostridial neurotoxins are zinc-endopeptidases specific for protein components of the neuroexocytosis apparatus . Thus, attempts were made to find such antidotes among molecules possessing chelating properties . Subsequently, it was proposed that the process of interaction between clostridial neurotoxins and their substrates might be more complex than viewed previously and may include several separate regions of interaction . Phage display technology is free from bias toward any particular model . This technology in combination with recombinantly produced light chains of botulinum neurotoxins serotypes A, B, and C was used to identify potential inhibitors of clostridial neurotoxins . Identified sequences did not show substantial similarity with substrate proteins of clostridial neurotoxins . Nevertheless, three peptides chosen for further analysis were able to inhibit enzymatic activity of all clostridial neurotoxins tested . This work demonstrates that at least one of these peptides could not be cleaved by clostridial neurotoxin . Attempts to delete amino acid residues from this peptide resulted in dramatic loss of its inhibitory activity . Finally, this work presents a novel approach to searching for inhibitors of clostridial neurotoxins.

Nippon Ganka Gakkai Zasshi, 2001 Apr, 105(4), 218 - 22
{Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles}; Ishikawa H et al.; PURPOSE: To investigate the effects of botulinum toxin type A(botulinum A toxin) on the autonomic and other non-adrenergic, non-cholinergic nerve terminals . METHODS: The effects of neurotoxin on twitch contractions evoked by electrical field stimulation (EFS) were studied in isolated rabbit iris sphincter and dilator muscles using isometric tension recording . RESULTS: Botulinum A toxin(150 nM) inhibited the fast cholinergic and slow substance P-ergic component of contraction evoked by EFS in the rabbit iris sphincter muscle without affecting the response to carbachol and substance P . Botulinum A toxin(150 nM) did not affect the twitch contraction evoked by EFS in the rabbit iris dilator muscle . CONCLUSION: These data indicated that botulinum A toxin may inhibit not only the acetylcholine release in the cholinergic nerve terminals, but also substance P release from the trigeminal nerve terminals of the rabbit iris sphincter muscle . However, neurotoxin has little effect on the adrenergic nerve terminals of the rabbit iris dilator muscle.

Biochemistry, 2001 Feb 20, 40(7), 2234 - 42
Thermal stabilization of the catalytic domain of botulinum neurotoxin E by phosphorylation of a single tyrosine residue; Blanes-Mira C et al.; The catalytic domain of clostridial neurotoxins is a substrate of tyrosine-specific protein kinases . The functional role of tyrosine phosphorylation and also the number and location of its (their) phosphorylation site(s) are yet elusive . We have used the recombinant catalytic domain of botulinum neurotoxin E (BoNT E) to examine these issues . Bacterially expressed and purified BoNT E catalytic domain was fully active, and was phosphorylated in vitro by the tyrosine-specific kinase Src . Tyrosine phosphorylation of the catalytic domain increased the protein thermal stability without affecting its proteolytic activity . Covalent modification of the endopeptidase promoted a disorder-to-order transition, as evidenced by the 35% increment of the alpha-helical content, which resulted in a 4 degrees C increase of its denaturation temperature . Site-directed replacement of tyrosine at position 67 completely abolished phosphate incorporation by Src . Constitutively unphosphorylated endopeptidase mutants exhibited functional properties virtually identical to those displayed by the nonphosphorylated wild-type catalytic domain . These findings indicate the presence of a single phosphorylation site in the catalytic domain of clostridial neurotoxins, and that its covalent modification primarily modulates the protein thermostability.

Eur J Neurol, 2001 May, 8(3), 247 - 52
Botulinum A toxin improves life quality in severe primary focal hyperhidrosis; Swartling C et al.; Focal hyperhidrosis is a condition that may disturb emotional, social and professional life . Treatment options for severe cases are surgical sympathectomy and local chemical sweat gland denervation by intradermal injections of botulinum toxin A (Btx A) . The Dermatology Life Quality Index (DLQI) is a simple validated questionnaire designed to measure and compare disability in different skin diseases . The aim of this study was to assess quality of life with the DLQI before and after treatment with botulinum toxin injections in a group of patients with severe hyperhidrosis . DLQI was administered to 58 randomly chosen patients before and after treatment . All patients answered the DLQI questionnaire prior to treatment and 53/58 at mean 5.2 months after treatment . The mean DLQI score in the 58 patients before treatment was 10.3 (2-23) . In the group of 16/53 patients who had a relapse of sweating when answering the DLQI a second time, no significant improvement was seen {score 10.6 before and 8.8 after treatment (P = 0.21)} . In patients without relapse, a 76% improvement was obtained (DLQI was reduced from 9.9 to 2.4; P < 0.0001) . The study showed that focal hyperhidrosis may considerably reduce life quality and the disability experienced by the patients can be largely reversed by botulinum toxin injections.

J Ir Dent Assoc, 2000, 46(3), 84 - 6
The medical management of masseteric hypertrophy with botulinum toxin; Finn S et al.; The authors present a series of cases of masseteric hypertrophy with associated muscular facial pain treated with botulinum toxin.

J Commun Disord, 2001 Jan-Apr, 34(1-2), 21 - 37
Identification of symptoms for spasmodic dysphonia and vocal tremor: a comparison of expert and nonexpert judges; Barkmeier JM et al.; Spasmodic dysphonia is a rare voice disorder that is most successfully treated by injection of botulinum toxin (i.e., BOTOX) into the affected laryngeal muscles . BOTOX is currently available for use by professionals outside of metropolitan voice centers who may be unfamiliar with this rare disorder . Patients may seek assessment and treatment locally from clinicians who are unfamiliar with the speech symptoms for adductor-type (ADSD) or abductor-type (ABSD) spasmodic dysphonia . Although these disorders have been described in the literature, the symptoms have not been well defined and may appear similar to those of vocal tremor or muscle tension dysphonia (MTD) . Thus, patients with spasmodic dysphonia might not be easily identified by local clinicians for treatment . The purpose of the current study was to determine whether voice clinicians with infrequent exposure to patients with spasmodic dysphonia could learn to identify speech symptoms for ADSD and ABSD comparable to voice clinicians with extensive experience with these disorders . The ratings of five nonexpert judges were compared to the ratings obtained from three expert judges . The results of this study demonstrated that nonexpert judges could be trained to identify the speech symptoms associated with ADSD, ABSD, and vocal tremor . While the nonexpert judges tended towards false positive judgements for the speech symptoms of interest, the overall speech symptom profiles for each type of voice disorder appeared comparable to those obtained from the expert judges . The symptom identificationscales used, therefore, have potential for use by clinicians unfamiliar with these disorders for correctly identifying persons with symptoms of ADSD and ABSD . Educational objectives: Readers will be able to (1) define the predominant speech symptoms reflective of the voice disorder categories of ABSD, ADSD, and vocal tremor; and (2) describe the methods utilized in a new perceptual training protocol for teaching clinicians how to identify predominant speech symptoms associated with the voice disorder categories of ABSD, ADSD, and vocal tremor.

Nervenarzt, 2001 Apr, 72(4), 302 - 6
{Reduction of pain and muscle spasms by botulinum toxin A}; Kelm S et al.; Botulinum toxin A (BoNT-A) develops its muscle-relaxing effect by the inhibition of acetylcholine (ACh) release . This toxin is also known to relieve muscular pain in different disorders . Conspicuously, pain in some patients responds earlier and sometimes even better than muscle tension, indicating that the effect of BoNT-A on pain is not only due to inhibition of ACh release . A questionnaire was distributed to 88 patients suffering from cervical dystonia (CD) . Thirty-five completed questionnaires could be used for data analysis . After intramuscular injections of BoNT-A, patients with CD experience significant reductions in pain which sometimes occur significantly earlier than the improvements in head posture . In the iris sphincter muscle of the rabbit and in dorsal root ganglion cells (DRG) of the rat, inhibition of the release of substance P by BoNT-A has been shown experimentally, and BoNT-C has been proven to develop endopeptidase activity toward substance P (SP) in vitro . Findings in the current literature and our observations allow the conclusion that alleviation of muscle pain by BoNT-A may also be due to an effect on the release of nociceptive neuropeptides, among which SP seems to have a key function.

Nervenarzt, 2001 Apr, 72(4), 261 - 74
{Botulinum toxin A for the treatment of headache disorders and pericranial pain syndromes}; Gobel H et al.; For 20 years botulinum toxin A has been used for the treatment of a variety of disorders characterised by pathologically increased muscle contraction . Recently, treatment of tension headache, migraine, cluster headache, and myofascial pain syndromes of neck, shoulder girdle, and back with botulinum toxin A has become a rapidly expanding new field of research . Several modes of action are discussed for these indications . The blockade of cholinergic innervation reduces muscular hyperactivity for 3 to 6 months . Degenerative changes in the musculoskeletal system of the head and neck are prevented . Nociceptive afferences and blood vessels of the pericranial muscles are decompressed and muscular trigger points and tender points are resolved . The normalisation of muscle spindle activity leads to a normalisation of muscle tone and central control mechanisms of muscle activity . Oromandibular dysfunction is eliminated and muscular stress removed . However, the effect of botulinum toxin A cannot be explained by muscular actions only . Its retrograde uptake into the central nervous system modulates the expression of substance P and enkephalins in the spinal cord and nucleus raphe . Recent findings suggest an inhibition of sterile inflammation which may lead to a blockade of the neurogenic inflammation believed to be the pathophysiological substrate of primary headache disorders . The efficacy of botulinum toxin A in the treatment of pain disorders is being investigated in several studies at the moment . The results and experiences obtained so far present new alternatives in the treatment of chronic pain disorders . The practical use of botulinum toxin A is demonstrated.

Gastrointest Endosc Clin N Am, 2001 Apr, 11(2), 387 - 408, viii
Etiology and treatment of achalasia in the pediatric age group; Pineiro-Carrero VM et al.; Achalasia in children bears many similarities to the disorder in adults, both in terms of clinical features and in terms of the approach to therapy . Pharmacologic management is of limited temporary benefit until more definitive therapy is undertaken . Intrasphincteric injections of botulinum toxin provides safe but short-term relief from symptoms . Based on our review of the safety and effectiveness of pneumatic dilation, we advocate this procedure as the primary form of definitive therapy for achalasia in children . In patients who do not achieve satisfactory results from a series of graduated pneumatic dilations, Heller myotomy provides safe and effective surgical treatment.

Gastrointest Endosc Clin N Am, 2001 Apr, 11(2), 359 - 70, viii
Comparison and cost analysis of different treatment strategies in achalasia; Richter JE; Currently there are three acceptable long-term treatments of achalasia: pneumatic dilatation, laparoscopic Heller myotomy, and botulinum toxin injection . Primarily retrospective studies suggest equal efficacy of pneumatic dilatation and surgical myotomy, especially in centers with expertise in both treatments . Randomized prospective studies find pneumatic dilatation superior to botulinum toxin because of the need for serial frequent treatments with the latter therapy . All cost analysis studies support the superiority of pneumatic dilatation over the two other treatments.

Gastrointest Endosc Clin N Am, 2001 Apr, 11(2), 325 - 46, vii
Pneumatic balloon dilation for esophageal achalasia; Kadakia SC et al.; Pneumatic balloon dilation remains the medical treatment of choice for patients with achalasia . It is superior to other medical therapies including intrasphincteric botulinum toxin injection . The overall efficacy rate for long-term excellent or good result is 80 to 85% . It is extremely important that the endoscopist be quite experienced in the technique of pneumatic dilation and develop a standard protocol to minimize the complications . The technique of graded balloon dilation starting with 3.0-cm Rigiflex balloon as the initial dilator and progressing to 3.5-cm and 4.0-cm balloon in absence of response to previous balloon size offers the safest approach . Patients not responding to three serial dilations should be offered surgery, although some patients may prefer repeat dilations to surgery . The overall complication rate for Rigiflex dilation is about 3% and for Witzel dilation is about 6% . Some patients will develop GER when measured by 24-hour esophageal pH monitoring, but most patients remain asymptomatic.

Gastrointest Endosc Clin N Am, 2001 Apr, 11(2), 311 - 24, vii
Pharmacologic therapy in treating achalasia; Hoogerwerf WA et al.; This article focuses on the different pharmacologic treatments for achalasia . Most smooth muscle relaxants such as nitrates and calcium antagonists are temporizing at best . Botulinum toxin, acting at the neuronal level, is effective in two thirds of the patients and has a duration of action of several months . It may be particularly suitable for the elderly or high-risk patient . The mechanism of action and efficacy of the different drugs are discussed in detail.

Eye, 2001 Feb, 15(Pt 1), 18 - 22
Active management in patients with ocular manifestations of myasthenia gravis; Bentley CR et al.; PURPOSE: Myasthenia gravis can cause variable strabismus with disabling diplopia and/or poor cosmesis . A retrospective study of a group of patients with myasthenia gravis or 'myasthenia gravis like' syndromes was made . METHODS: The study group consisted of patients who had undergone botulinum toxin treatment and/or surgery for disabling diplopia, poor cosmesis or both . Surgical treatment was by conventional techniques including recess/resect, posterior fixation, superior oblique tenotomy and adjustable sutures . RESULTS: There were 9 patients in the study group (8 female, 1 male) . Age at surgery ranged from 21 to 59 years (mean 46 years) . Six were symptom-free following treatment . Two, although symptomatically improved, had occasional diplopia . One patient failed treatment and required an occlusive contact lens . CONCLUSIONS: The ocular manifestations of myasthenia gravis or 'myasthenia gravis like' syndromes may respond to surgery and/or botulinum toxin injection . Active intervention should be considered when deviations become stable . To our knowledge this is the first report of the use of botulinum toxin in such patients.

J Physiol, 2001 May 1, 532(Pt 3), 759 - 69
Involvement of Rho-kinase and tyrosine kinase in hypotonic stress-induced ATP release in bovine aortic endothelial cells; Koyama T et al.; Hypotonic stress induces ATP release followed by Ca2+ oscillations in bovine aortic endothelial cells (BAECs) . We have investigated the cellular mechanism of the hypotonic stress-induced ATP release . Hypotonic stress induced tyrosine phosphorylation of at least two proteins, of 110 and 150 kDa . Inhibition of tyrosine kinase by the tyrosine kinase inhibitors herbimycin A and tyrphostin 46 prevented ATP release and ATP-mediated Ca2+ oscillations induced by hypotonic stress . ATP release was also inhibited by the pretreatment of the cells with botulinum toxin C3, and augmented by lysophosphatidic acid . Furthermore, pre-treating the cells with Y-27632, a selective inhibitor of Rho-kinase, also suppressed the hypotonic stress-induced ATP release and Ca2+ oscillations, indicating that Rho-mediated activation of Rho-kinase may be involved in the hypotonic ATP release . Hypotonic stress also induced a transient rearrangement of the actin cytoskeleton, which was suppressed by the tyrosine kinase inhibitors Y-27632 and cytochalasin B . However, pretreatment of the cell with cytochalasin B inhibited neither the hypotonic stress-induced ATP release nor the Ca2+ oscillations . These results indicate that tyrosine kinase and the Rho-Rho-kinase pathways are involved in hypotonic stress-induced ATP release and actin rearrangement, but actin polymerization is not required for ATP release in BAECs.

J Pediatr Ophthalmol Strabismus, 2001 Mar-Apr, 38(2), 68 - 71
Effect of botulinum toxin A chemodenervation in sensory strabismus; Han SH et al.; PURPOSE: To study the effect of botulinum toxin type A chemodenervation in sensory strabismus . METHODS: Twelve patients with sensory strabismus were treated with an injection of botulinum toxin type A (Botox; Allergan, Irvine, Calif) . Botulinum toxin type A was diluted with 0.9% sodium chloride without preservative at a dose that ranged from 1.25-5 U . A Teflon-coated needle electrode was inserted into the medial rectus muscle in cases of esotropia and into the lateral rectus muscle in cases of exotropia . Four patients were treated with > or =2 injections of botulinum toxin type A . Changes in the angle of strabismus and related complications were followed for >6 months postinjection . RESULTS: The mean deviation before injection was 33.8 prism diopters (delta) and the mean corrective effect on the deviation was 72.8% after injection in patients with sensory strabismus . The final deviation in 9 patients was <10 delta . Complications were hypertropia in 3 (25%) patients and conjunctival hemorrhage in 1 (8.3%) patient . CONCLUSION: Botulinum toxin type A is likely to prevent muscle contracture and affect muscle and neuronal tissues . This study on the effects of sensory strabismus with botulinum toxin type A injection suggests it has the potential to replace surgery or be used as an adjuvant therapy.

Toxicon, 2001 Aug, 39(8), 1151 - 9
Active-site mutagenesis of tetanus neurotoxin implicates TYR-375 and GLU-271 in metalloproteolytic activity; Rossetto O et al.; Tetanus neurotoxin (TeNT) blocks neurotransmitter release by cleaving VAMP/synaptobrevin, a membrane associated protein involved in synaptic vesicle fusion . Such activity is exerted by the N-terminal 50kDa domain of TeNT which is a zinc-dependent endopeptidase (TeNT-L-chain) . Based on the three-dimensional structure of botulinum neurotoxin serotype A (BoNT/A) and serotype B (BoNT/B), two proteins closely related to TeNT, and on X-ray scattering studies of TeNT, we have designed mutations at two active site residues to probe their involvement in activity . The active site of metalloproteases is composed of a primary sphere of residues co-ordinating the zinc atom, and a secondary sphere of residues that determines proteolytic specificity and activity . Glu-261 and Glu-267 directly co-ordinates the zinc atom in BoNT/A and BoNT/B respectively and the corresponding residue of TeNT was replaced by Asp or by the non conservative residue Ala . Tyr-365 is 4.3A away from zinc in BoNT/A, and the corresponding residue of TeNT was replaced by Phe or by Ala . The purified mutants had CD, fluorescence and UV spectra closely similar to those of the wild-type molecule . The proteolytic activity of TeNT-Asp-271 (E271D) is similar to that of the native molecule, whereas that of TeNT-Phe-375 (Y375F) is lower than the control . Interestingly, the two Ala mutants are completely devoid of enzymatic activity . These results demonstrate that both Glu-271 and Tyr-375 are essential for the proteolytic activity of TeNT.

Dev Med Child Neurol, 2001 Apr, 43(4), 234 - 8
Safety profile and efficacy of botulinum toxin A (Dysport) in children with muscle spasticity; Bakheit AM et al.; Botulinum toxin A (BTX-A) is widely used in the management of muscle spasticity in children . However, at present the dose of BTX-A for a given patient is selected empirically . The aim of this study is to provide dosage guidelines that are based on risk/benefit assessment . This was a multicentre retrospective study of the safety profile and efficacy of BTX-A in children with chronic muscle spasticity . Data in 758 patients who received a total of 1594 treatments were analysed (mean age 7.2 years; 429 males, 329 females) . Spastic cerebral palsy (CP) was the most common diagnosis (94% of the study sample) . Of all treatments 7% resulted in adverse events; incidence was related to the total dose rather than the dose calculated on the basis of body weight . The highest incidence of adverse events was observed in patients who received >1000 IU of BTX-A per treatment session . The odds of an adverse event was 5.1 times greater for this group of patients than for those who had 250 IU or less (p<0.001) . A good overall response to treatment was reported in 82% and treatment goals were fully or partially achieved in 3% and 94% of participants respectively . More patients in the highest dose group reported functional deterioration . Interestingly, multilevel treatments resulted in a better response than single-level treatments (odds ratio 1.7, 95% CI 1.3 to 2.2,p=0.001).

Ther Umsch, 2001 Mar, 58(3), 128 - 33
{Diagnosis and treatment of esophageal motility disorders}; Katschinski M; Apart from gastroesophageal reflux disease, achalasia, non-cardiac chest pain and functional dysphagia are the most important manifestations of disturbed esophageal motility . Achalasia is characterized by esophageal aperistalsis and impaired deglutitive relaxation of the lower esophageal sphincter . The morphological correlate is a degeneration of nitrergic neurons in the myenteric plexus . Diagnosis is based on barium esophagram or esophageal manometry with the latter setting the gold standard . Endoscopic exclusion of a tumor at the gastroesophageal junction is mandatory . Appropriate therapeutic interventions are pneumatic dilatation or (laparoscopic myotomy) of lower esophageal sphincter . In patients unfit for these procedures endoscopic injection of botulinum toxin into the lower esophageal sphincter is appropriate . Non-cardiac chest pain may be of esophageal origin . Gastroesophageal reflux, spastic motility disorders and visceral hypersensitivity are arguable underlying mechanisms . The most important diagnostic procedure is 24 h esophageal pH metry correlating symptoms and reflux episodes . Proton pump inhibitors and tricyclic antidepressants serving as visceral analgesics are appropriate therapeutic approaches . Functional dysphagia defines the sensation of impaired passage without mechanical obstruction or a neuromuscular disease with known pathology, e.g . scleroderma . Impaired transit is proven by esophageal scintigraphy or radiogram both using solid boluses . Manometry assesses the underlying mechanisms.

JSLS, 2001 Jan-Mar, 5(1), 57 - 62
Pseudoachalasia as a result of metastatic cervical cancer; Bholat OS et al.; BACKGROUND: Distinguishing achalasia from pseudoachalasia can be difficult, as the clinical, radiological, and manometric findings can be similar to those seen in achalasia . The features that may differentiate achalasia from pseudoachalasia are reviewed and the pathogenesis of pseudoachalasia is discussed . METHODS: A patient presented with a clinical scenario of achalasia that was documented by radiographic, endoscopic, and manometric studies . Her past medical history was significant for cervical cancer . Although brief improvement in symptoms was achieved with botulinum toxin injections and esophageal dilation, she had continued progression of symptoms . This direct involvement of the esophagus by a tumor was not demonstrated by any of the routine preoperative studies . RESULTS: At the time of surgery, extensive involvement of the diaphragm, esophagus, and pericardium by a tumor was noted . Pathologic analysis of the tumor was consistent with metastatic cervical cancer CONCLUSION: Pseudoachalasia has been known to occur in response to both benign and malignant causes . Differentiating between pseudoachalasia and achalasia is often difficult because of the similarities . As in this case, the diagnosis of pseudoachalasia may be made by surgical exploration.

Rev Neurol, 2001 Jan 16-31, 32(2), 148 - 56
{Diagnostic and therapeutic approaches in oculomotor paralyses}; Rodriguez Sanchez JM et al.; OBJECTIVES . We wish to unify current criteria regarding oculomotor paralysis (POM) . Based on our experience, we have designed a diagnostic-therapeutic protocol which permits an early approach, especially since botulinum toxin has been used for treatment . DEVELOPMENT . To make things easier to understand, we start with the concept of POM, including the physiopathogenic description of phenomena secondary to eye movements . Then we consider the aetiological-topographical incidence and assess the overall causes of POM and the relative frequency of the involvement of the different cranial oculomotor nerves . Finally, we consider each cranial nerve more fully from two different angles: the aetiologic-topographic diagnosis and therapeutic attitudes . CONCLUSIONS . The current approach to POM should include a systematic study to classify the disorder as isolated, associated with other neurological causes or of some other type (metabolic, auto-immune, etc) . Satisfactory early treatment should include consideration of infilbration with botulinum toxin in all paresis or paralysis presenting with contractures . In cases of total paralysis the contractures may occur within a week of onset of the condition . In partial paralyses close follow-up of three parameters evolution of the degree of ocular deviation, limitation of movement and exploration of passive movements makes it possible to determine the best moment to treat the contracture by injection of botulinum toxin: This treatment resolves or improves the diplopia, with recovery of oculomotor equilibrium, when it is given during the acute phase.

Arq Neuropsiquiatr, 2001 Mar, 59(1), 97 - 100
{Use of botulinum toxin in the treatment of laryngeal dystonia (spasmodic dysphonia): preliminary study of twelve patients}; Teive HA et al.; Laryngeal dystonia (spasmodic dysphonia) is a movement disorder characterized by involuntary contractions of laryngeal muscles involved with vocalization . The introduction of botulinum toxin in the treatment of laryngeal dystonia had a major clinical impact due to the striking improvement of symptoms . We report the preliminary results of therapeutical use of botulinum toxin in the treatment of twelve patients with laryngeal dystonia . After an extensive clinical evaluation, the patients underwent a videostroboscopic exam for diagnostic confirmation . Botulinum toxin was injected in the cricothyreoid membrane, directed towards the thyreoaritenoid muscle, with the aid of eletromyography needles . Most of patients who underwent botulinum toxin injection had a significant improvement of their symptoms (83%), with effects lasting for four months in average and without important side effects.

Mov Disord, 2001 Mar, 16(2), 286 - 9
To test or not? The value of diagnostic tests in cervical dystonia; Risvoll H et al.; It has long been suspected that idiopathic cervical dystonia is result of a dysfunction of the brain, but the cause of the disease has been elusive . The purpose of this study was to determine the diagnostical value of different radiological and laboratory tests in cases of cervical dystonia . Cerebral computer tomography and/or cerebral magnetic imaging were carried out in all of the 149 patients who were included in this study . A total of 25 scans revealed some minor findings that did not alter patients' management . Of the 128 cervical plain x-ray examinations, 63.1% showed degenerative changes . Cerebrospinal fluid (CSF) was examined in 125 patients, and was normal in 103 . Some degree of pathology was found in the remaining 22 CSF samples . All patients under the age of 50 years were tested for serum ceruloplasmin and no decreased level was found . Seven patients had elevated ANA titre; four of them also developed Botulinum toxin antibodies . We can conclude that the detection rate of pathologic findings in patients with idiopathic cervical dystonia is similar to what we can expect in the general population, provided the neurological findings are normal apart from the involuntary movements . In the adult form of typical cervical dystonia we do not recommend any standard laboratory or imaging tests if the neurological examination is normal aside from the abnormal head movements .

Mov Disord, 2001 Mar, 16(2), 252 - 7
Dystonia in corticobasal degeneration; Vanek Z et al.; OBJECTIVE: To characterize the clinical features, particularly dystonia, in patients with clinically diagnosed or pathologically proven corticobasal degeneration (CBD) . BACKGROUND: Although dystonia has been reported in many neurodegenerative disorders, it has not been studied in CBD . Dystonia, often accompanied by painful rigidity and fixed contractures, is one of the most disabling features of CBD . METHODS: The medical records, imaging studies, and videotapes of 66 patients who satisfied the clinical criteria of CBD, evaluated between 1988 and 1998, were reviewed . The occurrence, nature, and distribution of dystonic features were analyzed and correlated with other features of CBD . RESULTS: Of the 66 patients with CBD, 39 (59.0%) had dystonia . The mean age at onset of initial symptoms was 63.9 years (range 44--75) . In 20 (51.0%) patients, dystonic symptoms began in one arm, while 13 (33.0%) patients had initial leg involvement . At least one arm was affected in 36 (92.0%) dystonic patients . Although 11 (28.0%) patients had leg dystonia, the leg was the predominant site of involvement in only 1 patient . Only 12 (31.0%) patients had dystonia involving the head, neck, or trunk in the course of the disease . The diagnosis of CBD was confirmed in all 4 patients who had autopsies . CONCLUSION: In this large series of CBD patients we found that asymmetric limb dystonia, particularly affecting one arm, is a common manifestation of CBD; dystonia may be the initial manifestation of this neurodegenerative disorder . Axial or leg dystonia, without significant involvement of an arm, is rare . There is no effective treatment for this relentless disorder, except for temporary relief of dystonia and pain, with local botulinum toxin injections .

Arch Phys Med Rehabil, 2001 Apr, 82(4), 480 - 4
Botulinum toxin for people with dystonia treated by an outreach nurse practitioner: a comparative study between a home and a clinic treatment service; Whitaker J et al.; OBJECTIVE: To study whether a trained outreach nurse practitioner could provide a service that is as good as, or better than, that provided at a hospital outpatient clinic for people who had been diagnosed with dystonia and required treatment with botulinum toxin . DESIGN: Randomized trial . SETTING: An outpatient department of a regional neurorehabilitation center and patients' homes in northern England . PATIENTS: Eighty-nine patients with a clinical diagnosis of spasmodic torticollis, blepharospasm, or hemifacial spasm who had ongoing treatment of dystonia with botulinum injections . INTERVENTIONS: Individuals were randomly allocated either to receive ongoing botulinum injections at home by the nurse practitioner or to continue attending the hospital outpatient clinic and be injected by medical staff . MAIN OUTCOME MEASURES: The following measures were recorded at each visit: demographic descriptors, dosage of botulinum toxin, treatment interval, side-effect profile, external referrals, and a questionnaire to determine qualitative opinion . RESULTS: Efficacy and duration of the botulinum was similar in both groups . Botulinum dosage and side-effect profiles were similar in both groups except for significantly less dysphagia (p < .018) in the home group (7 vs 24 occasions) . Subjective opinion by the patients indicated statistically significant preference for home injections . Economic analysis indicated that the overall cost of the treatment was less in the home injection group (total cost per visit $36.90 { pound 23.36} vs $79.00 { pound 50.01}), but this difference was not statistically significant . CONCLUSION: A trained outreach nurse practitioner provided a service that was as good as, and in certain aspects better than, that provided by a hospital outpatient clinic . The nurse practitioner provided a more flexible, much appreciated, safe, and cost-effective service for this client group . Wider use of outreach nurse practitioners for dystonia should be encouraged.

Biochemistry, 2001 Apr 17, 40(15), 4693 - 702
A correlation between differential structural features and the degree of endopeptidase activity of type A botulinum neurotoxin in aqueous solution; Cai S et al.; Botulinum neurotoxin type A is one of the most toxic substances known to man (LD(50) for mouse 0.1 ng/kg) . It is also an effective therapeutic drug against involuntary muscle disorders and for pain management . BoNT/A is a Zn(2+) endopeptidase which selectively cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), a critical component of the exocytotic machinery . Based on nucleotide sequence, BoNT/A is a 145 kDa protein, which appears as a 145 kDa protein band on sodium dodecyl sulfate--polyacrylamide gel electrophoresis . We have examined the structure of BoNT/A in aqueous solution, and found the structure in aqueous solution differs dramatically from that resolved by X-ray crystallography, both at secondary and at quaternary levels . In terms of secondary structure, BoNT/A in aqueous solution has about 47% beta-sheet structure as revealed by infrared spectroscopy, while X-ray crystallography revealed only 17% beta-sheet structure . In terms of quaternary structure, the estimated molecular mass of the native BoNT/A in aqueous solution ranged between 230 and 314 kDa, based on results from different chemical and biophysical techniques (native gel electrophoresis, chemical cross-linking, size exclusion chromatography, and fluorescence anisotropy) . These results indicate that BoNT/A exists as a dimer in aqueous solution, which contrasts with the reported monomeric structure of BoNT/A based on X-ray crystallography . The dimeric form of BoNT/A can self-dissociate into the monomeric form at a concentration lower than 50 nM . This concentration-dependent structural change has a significant impact on the endopeptidase activity of BoNT/A: the catalytic efficiency of the monomeric BoNT/A is about 4-fold higher than that of its dimeric form . This difference implies a sterically restricted catalytic site of BoNT/A in the dimeric form of BoNT/A.

J Child Neurol, 2001 Feb, 16(2), 113 - 8
Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review; Gormley ME et al.; Over the last several years, botulinum toxin type A has gained widespread use for the management of focal spasticity in children with cerebral palsy . To assess the current patterns of botulinum toxin type A use in the clinical setting, the dose, muscles injected, age at injection, and interval between injections of botulinum toxin type A treatments were examined in a retrospective chart review of children with cerebral palsy (N = 270) over a 2-year period at three major treatment centers . The average dose of botulinum toxin type A across the three centers ranged from 7.7 to 10.8 U/kg body weight, and the average total amount of botulinum toxin type A injected at a single visit ranged from 154 to 205 U . The majority of botulinum toxin type A injections were to the muscles to the lower limbs . The average age at first injection was 6.2 years, and the average interval between injections ranged from 134 to 199 days.

J Nat Toxins, 2001 Feb, 10(1), 27 - 32
Production of polyclonal antibodies in mice against cobratoxin, botulinum toxin and ricin without altering their toxicity or use of adjuvant; Lipps BV; Purified venom components, botulinum toxin and ricin have been successfully used as immunogenes, after converting to toxoids and using adjuvant for production of polyclonal antibodies in animals . This communication reports that polyclonal antibodies specific to cobratoxin, botulinum toxin and ricin were generated in Balb/C mice . The toxins were used for immunization without adjuvant and without altering their toxicity or converting them to toxoids . Initially, lethal dose for botulinum toxin, cobratoxin and ricin were determined in mice and found to be 1 microg, 4 microg and 2 microg, respectively . For the production of antibodies mice were injected with half lethal dose of the toxins in natural form four times, two weeks apart . The potency of antitoxins was assayed by enzyme-linked immunosorbent assay . High titer antibodies were generated by botulinum toxin, cobratoxin and ricin after three injections consisting of half mouse lethal dose . Such minute amounts of botulinum toxin, cobratoxin and ricin in their natural form were able to produce high titer antibodies, perhaps because these toxins may fall in the category of super-antigens.

Brain, 2001 Apr, 124(Pt 4), 769 - 83
Prospective study of selective peripheral denervation for botulinum-toxin resistant patients with cervical dystonia; Munchau A et al.; We have carried out a prospective study of selective peripheral denervation (SPD) in cervical dystonia (CD) patients with primary or secondary botulinum toxin (BT) treatment failure using independent standardized assessment . Patients referred for surgery had a standardized clinical examination, neck muscle EMG, videofluoroscopic swallow and CT of the cervical spine, and were selected for surgery on the basis of the results of these investigations . CD severity, disability and pain were assessed preoperatively and at 3, 6, 9, 12 and 18 months postoperatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) . Severity of head tremor and dysphagia were scored using established rating scales . Additionally, psychosocial function was assessed in a representative subsample of patients (n = 12) using several established questionnaires . Of the 62 patients who were assessed, 22 (35.5%) were not offered surgery, most commonly because of widespread dystonia . Of the remaining 40 patients, 37 have so far had surgery, 31 of whom have been followed up for at least 1 year, and 15 for 18 months after surgery (mean follow-up duration 16.7 months) . Using the TWSTRS global outcome score, 68% of patients derived functionally relevant improvement at 12 months after surgery . In the entire operated group, total TWSTRS scores were reduced by 30% at 6 and 12 months after surgery (P < 0.0001) . The subscores for severity, disability and pain were reduced by 20, 30 and 40%, respectively, at 6 months (P < or = 0.01) and 20, 40 and 30%, respectively, at 12 months (P < 0.01) . Pain increased over time, which appeared to result from muscle reinnervation . TWSTRS scores were not significantly improved in the six patients with primary BT treatment failure . Head tremor did not change . There was a significant improvement of body concept, perceived disfigurement, stigma, and quality of life in the 12 patients whose psychosocial function was assessed . Preoperative disability and restriction of head movement were negatively correlated and the initial response to BT treatment positively correlated with global outcome score . Spread or deterioration of dystonia elsewhere in the body occurred in three patients, with unpleasant sensory symptoms in denervated posterior cervical segments occurring in 14 . Ten patients developed mild to moderate dysphagia, and two developed severe dysphagia . We conclude that SPD is an effective treatment for patients with secondary, but probably not for those with primary, BT treatment failure . Reinnervation is not infrequent and can compromise outcome . Postoperative morbidity is low, but there is a risk of dysphagia.

Neurol Sci, 2000 Oct, 21(5), 329 - 31
Therapeutic considerations in cerebellopontine angle lipomas inducing hemifacial spasm; Ruggieri RM et al.; Lipoma is a very rare tumour at the cerebellopontine angle . We report a case of incomplete hemifacial spasm, associated with a lipoma involving and compressing both facial and acoustic nerves at their origin in the brainstem . The patient was treated with medical therapy (botulinum toxin A) and surgery . We present a review of the last ten years of the literature, with particular regard to management.

J Cell Biol, 2001 Apr 2, 153(1), 177 - 90
Restriction of secretory granule motion near the plasma membrane of chromaffin cells; Johns LM et al.; We used total internal reflection fluorescence microscopy to study quantitatively the motion and distribution of secretory granules near the plasma membrane (PM) of living bovine chromaffin cells . Within the approximately 300-nm region measurably illuminated by the evanescent field resulting from total internal reflection, granules are preferentially concentrated close to the PM . Granule motion normal to the substrate (the z direction) is much slower than would be expected from free Brownian motion, is strongly restricted over tens of nanometer distances, and tends to reverse directions within 0.5 s . The z-direction diffusion coefficients of granules decrease continuously by two orders of magnitude within less than a granule diameter of the PM as granules approach the PM . These analyses suggest that a system of tethers or a heterogeneous matrix severely limits granule motion in the immediate vicinity of the PM . Transient expression of the light chains of tetanus toxin and botulinum toxin A did not disrupt the restricted motion of granules near the PM, indicating that SNARE proteins SNAP-25 and VAMP are not necessary for the decreased mobility . However, the lack of functional SNAREs on the plasma or granule membranes in such cells reduces the time that some granules spend immediately adjacent to the PM.

Res Microbiol, 2001 Jan-Feb, 152(1), 27 - 35
Sup35p yeast prion-like protein as an adapter for production of the Gag-p55 antigen of HIV-1 and the L-chain of botulinum neurotoxin in Saccharomyces cerevisiae; Ivanov PA et al.; Effective expression of the HIV-1 core protein Gag-p55 was obtained in Saccharomyces cerevisiae under control of the inducible UASgal/CYC1 promoter as a translational fusion with the prion-forming NM domain of the translation terminator Sup35p (eRF3) of S . cerevisiae . where only poor expression of the original-type Gag-p55 was observed . A deletion within the Sup35NM prion-forming domain altering Sup35-associated {PSI} inheritance did not compromise expression of the Sup35NM Gag-p55 fusion protein . Therefore, either the mechanism of this phenomenon is not directly related to the effect of Sup35p prion-formation or the modified protein maintains residual prion-forming abilities . The recombinant Sup35p-Gag-p55 protein was quite stable under boiling in an alkali/sodium dodecyl sulfate (SDS) solution and completely retained its antigenic properties . Moreover, 10-min boiling of the native yeast cells in this solution allowed immediate inhibition of lysosomal and other yeast proteases, responsible for autolysis of many natural and recombinant proteins . The use of this method of preliminary enrichment for the recombinant fusion protein Sup35p-Gag-p55 with the SDS-alkaline extraction could be useful for yeast heterologous expression and purification of other of insoluble and unstable proteins . A translational fusion with the NM domain of Sup35p was also used to produce another poorly soluble protein, the L-chain of botulinum exotoxin A, in S . cerevisiae . When the Sup35p fragment was removed from the recombinant construct encoding a fused Sup35/BoNT protein, a dramatic drop in both transformation efficiency and growth rate of transformants was shown.

Headache, 1999 Oct, 39(9), 662 - 5
Improvement of tension-type headache when treating wrinkles with botulinum toxin A injections; Carruthers A et al.; Botulinum toxin A has been used to treat a spectrum of neuromuscular diseases . In recent years, it has become an accepted treatment for dynamic facial wrinkles . Following treatment of glabella and forehead wrinkles with botulinum toxin A, 9 of 134 patients coincidentally reported improvement of tension-type headache . We have retrospectively studied this group of patients in whom improvement of facial wrinkles closely paralleled improvement of tension-type headache . This observation suggests a role for muscle action in tension-type headache and a novel treatment.

J Biol Chem, 2001 Apr 20, 276(16), 13476 - 82 Epub 2001 Jan 23.
The role of the synaptic protein snap-25 in the potency of botulinum neurotoxin type A; Keller JE et al.; Botulinum neurotoxin serotype A (BoNT/A) is distinguished from BoNT/E by longer duration of paralysis and greater potency . The proteolytic activity of BoNT/A in cultures of dissociated spinal cord neurons persists beyond 80 days, whereas BoNT/E activity persists for less than 1 day (Keller, J . E., Neale, E . A . Oyler, G., and Adler, M . (1999) FEBS Lett . 456, 137-142) . This single quality of toxin activity can account for the differences observed in the duration of muscle block . In the present work we sought to understand the basis for the apparent greater potency of BoNT/A . BoNT/E cleaves a 26-amino acid fragment from the C terminus of the synaptic protein SNAP-25 whereas BoNT/A removes only nine residues creating a 197-amino acid fragment (P197) that is 95% the length of SNAP-25 . We show that inhibition of neurotransmitter release by BoNT/E is equivalent to the damage caused to SNAP-25 . However, synaptic blockade by BoNT/A is greater than the extent of SNAP-25 proteolysis . These findings can be explained if P197 produces an inhibitory effect on neurotransmitter release . A mathematical model of the experimentally determined relationship between SNAP-25 damage and blockade of neurotransmission supports this interpretation . Furthermore, neurotransmitter release following complete cleavage of SNAP-25 can be achieved by P197, but with about 5-fold less sensitivity to external Ca(2+) . In this case, vesicular release is restored by increasing intracellular Ca(2+) . These data demonstrate that P197 competes with intact SNAP-25, but is unable to initiate normal synaptic vesicle fusion in physiological concentrations of Ca(2+).

Nat Neurosci, 2001 Apr, 4(4), 382 - 90
Protein kinase C modulates NMDA receptor trafficking and gating; Lan JY et al.; Regulation of neuronal N-methyl-D-aspartate receptors (NMDARs) by protein kinases is critical in synaptic transmission . However, the molecular mechanisms underlying protein kinase C (PKC) potentiation of NMDARs are uncertain . Here we demonstrate that PKC increases NMDA channel opening rate and delivers new NMDA channels to the plasma membrane through regulated exocytosis . PKC induced a rapid delivery of functional NMDARs to the cell surface and increased surface NR1 immunofluorescence in Xenopus oocytes expressing NMDARs . PKC potentiation was inhibited by botulinum neurotoxin A and a dominant negative mutant of soluble NSF-associated protein (SNAP-25), suggesting that receptor trafficking occurs via SNARE-dependent exocytosis . In neurons, PKC induced a rapid delivery of functional NMDARs, assessed by electrophysiology, and an increase in NMDAR clusters on the surface of dendrites and dendritic spines, as indicated by immunofluorescence . Thus, PKC regulates NMDAR channel gating and trafficking in recombinant systems and in neurons, mechanisms that may be relevant to synaptic plasticity.

Clin Neurophysiol, 2001 Apr, 112(4), 636 - 40
Remote F-wave changes after local botulinum toxin application; Wohlfarth K et al.; OBJECTIVE: Although the therapeutic effects of botulinum toxin A can be explained by its action at the neuromuscular junction, central or more proximal effects have also been discussed . METHODS: Eleven patients with torticollis spasmodicus and 3 patients with writer's cramp were studied before and 1 and 5 weeks after the first treatment with botulinum toxin . We measured compound muscle action potentials (CMAPs), motor conduction velocities (MCVs), the shortest (SFL) and the mean F-wave latencies (MFL) and F-wave persistence (30 trials) of untreated muscles for each side (ulnar nerve-abductor digiti minimi muscle, peroneal nerve-tibialis anterior muscle) . RESULTS: CMAPs and MCVs showed no significant changes . For both nerves, however, SFL and MFL were prolonged slightly 1 week after treatment and returned to about baseline after 5 weeks (t test) . The F-wave persistence was reduced 1 week after treatment for the right ulnar and both peroneal nerves (t test) . CONCLUSIONS: These results are not likely due to an impairment of neuromuscular transmission . Instead, we propose a decreased excitability of alpha-motoneurons supplying non-treated muscles . A reduction of muscle spindle activity or changes of the recurrent inhibition are discussed as possible causes.

J Assoc Physicians India, 2000 Jun, 48(6), 622 - 30
A spectrum of dystonias-clinical features and update on management; Das SK et al.; Dystonia is an interesting disorder characterized by involuntary movement of the body part or parts leading to abnormal deformed postures . The usual signs and symptoms are local pain, spasm and abnormal movements . Sensory trick is an important clinical phenomenon and is characteristic of dystonia . It is usually separated from other movement disorders such as chorea, athetosis, tics and myoclonus clinically . Various non-dystonic conditions simulate dystonia and need to be separated in view of different line of management . Improved understanding in molecular biology has helped in understanding of the disease . Confusing neuropathology and neurochemistry have deterred the finding of an effective drug, however empirical use of few drugs have improved the gloomy situation . Few conditions such as dopa-responsive dystonia have definite treatment . Recently use of botulinum toxin has provided beneficial response in hyper muscular contraction states such as dystonia and spasticity, Surgery and other non-medical therapies are effective in few situations.

Can J Gastroenterol, 2001 Mar, 15(3), 195 - 9
Pneumatic dilation in achalasia; Bittinger M et al.; Pneumatic dilation is the most common first-line therapy for the treatment of achalasia . The aim of dilation is a controlled disruption of circular muscle fibres of the lower esophageal sphincter to reduce the functional obstruction . Several types of dilators and different dilation techniques are used, but the achieved results are similar . The mean success rate is about 80% in the short term, but some patients need redilation in the further course (particularly young patients) . Best long term results are obtained if the lower esophageal sphincter pressure can be reduced below 10 mmHg . Major complications are rare after pneumatic dilation; the most serious complication is esophageal perforation, which occurs at a mean rate of about 2.5% . Considering the pros and cons of other effective forms of treatment of achalasia (esophagomyotomy and intrasphincteric injection of botulinum toxin), pneumatic dilation is still the treatment of choice in the majority of patients with achalasia.

J La State Med Soc, 2001 Feb, 153(2), 92 - 7
Clinical application of botulinum toxin in otolaryngology, head and neck practice (brief review); Yin S et al.; Botulinum toxin (Botox) is useful in controlling the symptoms of patients with movement disorders . Application of Botox serves to (1) inhibit hypertonicity, (2) enhance the action of the antagonistic muscles, and (3) avoid an impingement in order to reestablish "the balance of forces" . In accordance with the principles mentioned above, Botox can be used to treat dystonias of the larynx (adductor laryngeal spasmodic dysphonia, abductor laryngeal spasmodic dysphonia), laryngeal granulomas, laryngeal joint dislocation, cricopharyngeal spasm, and posterior glottic synechiae . In addition, extra-laryngeal disorders such as blepharospasm, hemifacial spasm, oromandibular dystonia, and spasmodic torticollis respond well to Botox . The effects of Botox are reversible and have specific localized activity . Hence, Botox has served as a powerful diagnostic method in exploring the underlying mechanism of various types of dystonias and provides some therapeutic benefits before pursuing surgical options . Here we review the literature and describe our experiences with Botox, including such topics as preparing and storing Botox, identifying the target muscles under EMG-guidance, choosing an appropriate dose, and outlining the applications of Botox in Otolaryngology, Head and Neck Surgery practice.

J Urol, 2001 Apr, 165(4), 1107 - 10
Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction; Phelan MW et al.; PURPOSE: Botulinum toxin injection into the external urinary sphincter in spinal cord injured men with detrusor-sphincter dyssynergia has been reported . We expand the clinical use of botulinum toxin for a variety of bladder outlet obstructions and to decrease outlet resistance in patients with acontractile detrusor but who wish to void by the Valsalva maneuver . MATERIALS AND METHODS: Prospective treatment was performed for voiding dysfunction in 8 men and 13 women 34 to 74 years old . The reasons for voiding dysfunction included neurogenic detrusor-sphincter dyssynergia in 12 cases, pelvic floor spasticity in 8 and acontractile detrusor in 1 patient with multiple sclerosis who wished to void by the Valsalva maneuver . Using a rigid cystoscope and a collagen injection needle, a total of 80 to 100 units of botulinum A toxin (Botox) were injected into the external sphincter at the 3, 6, 9 and 12 o'clock positions . RESULTS: Preoperatively 19 of 21 patients were on indwelling or intermittent catheterization . After botulinum A injection all but 1 patient were able to void without catheterization . No acute complications, such as general paralysis or respiratory depression, occurred and none of the patients had dribbling or stress urinary incontinence . Postoperative post-void residual decreased by 71% and voiding pressures decreased on average 38% . Of the 21 patients 14 (67%) reported significant subjective improvement in voiding . Followup ranges from 3 to 16 months, with a maximum of 3 botulinum A injections in some patients . CONCLUSIONS: Urethral sphincter botulinum injection should be considered for complex voiding dysfunction . Encouraging improvement without complications were seen in most of our patients . We have expanded the use of botulinum toxin to treat pelvic floor spasticity and also women.

J Neurol Neurosurg Psychiatry, 2001 Apr, 70(4), 538 - 40
Treatment of sialorrhoea with ultrasound guided botulinum toxin type A injection in patients with neurological disorders; Porta M et al.; OBJECTIVES: To investigate the safety and efficacy of ultrasound guided botulinum toxin type A (BTX-A) injections into salivary glands for the treatment of sialorrhoea in patients with neurological disorders . METHODS: The parotid and submandibular glands of 10 patients were injected with BTX-A using ultrasound guidance . Before injection, the baseline rate of salivation was assessed using a visual analogue scale . Postinjection, assessments were repeated at regular intervals for up to 1 year . RESULTS: Of the 10 patients treated, nine (90%) reported a subjective reduction in salivation post-treatment and one patient (10%) found no improvement . Visual analogue scale scores showed a reduction of 55% in the mean rate of salivation for all patients and a reduction of 60.8% for the group of responders . No serious adverse events occurred and no procedure related complications were reported . CONCLUSIONS: This is the first study to report (1) the injection of BTX-A (BOTOX) into both parotid and submandibular glands, and (2) the use of ultrasound guidance during the administration of BTX-A into salivary glands . The results suggest that the technique is safe and that BTX-A injections are effective for the treatment of sialorrhoea in patients with neurological disorders.

Br J Plast Surg, 2001 Apr, 54(3), 197 - 200
A prospective study of the effect of botulinum toxin A on masseteric muscle hypertrophy with ultrasonographic and electromyographic measurement; To EW et al.; We evaluated the effect of botulinum toxin A on masseteric muscle hypertrophy by using ultrasound and electromyography . Five patients (four with bilateral and one with unilateral masseteric muscle hypertrophy) were studied prospectively . In each patient, ultrasound-guided percutaneous intramuscular injection of botulinum toxin A was carried out . The change in muscle bulk was evaluated using serial ultrasonography and the electrical activity was assessed with electromyography . All five patients (nine hypertrophic muscles) showed a good response, with the maximal effect of a 31% reduction in muscle bulk seen 3 months after treatment . The effect remained stable one year after injection for six of the hypertrophic muscles, whereas three muscles needed a second injection to maintain the atrophy . This preliminary prospective study suggests that botulinum toxin A is a safe alternative method of treating masseteric muscle hypertrophy . However, the effect may be temporary and further intramuscular injection may be required to maintain atrophy .

Clin Plast Surg, 2001 Jan, 28(1), 127 - 48
Primary and adjunctive use of botulinum toxin type A (Botox) in facial aesthetic surgery: beyond the glabella; Fagien S et al.; The use of Botox for the treatment of hyperkinetic facial lines and furrows is another effective primary, adjunctive, or prophylactic therapy to offer cosmetic patients in the spectrum of treatment options for full facial rejuvenation . Unwanted side effects can be minimized, and beneficial effects can be maximized with a thorough understanding of the facial soft-tissue anatomy, proper patient selection, and administration of the lowest effective doses with minimal volume of delivery . Most often, Botox injection does not replace surgery, skin resurfacing, soft-tissue augmentation, or skin care; however, it is useful when used alone or with the various treatment options to give selected patients the most effective and comprehensive solutions for a more youthful appearance.

Am J Surg, 2001 Jan, 181(1), 60 - 4
A comparison of common bile duct pressures after botulinum toxin injection into the sphincter of Oddi versus biliary stenting in a canine model; Marks JM et al.; BACKGROUND: Botulinum toxin A (Botox) functionally paralyzes the sphincter of Oddi in both animals and humans, resulting in reduced pressures . No study, however, has specifically addressed common bile duct (CBD) pressures after Botox injection into the sphincter of Oddi with regard to treating biliary leaks and fistulae . The goals of this present study are to compare, versus biliary stenting, the change in CBD pressures after Botox injection into the sphincter of Oddi, as well as to evaluate the timing of onset and duration of these effects on sphincteric relaxation . METHODS: After midline laparotomy in 20 mongrel dogs, a pediatric umbilical catheter was inserted into the CBD via a small cholecystotomy and attached to a water-perfused pressure transducer . After baseline CBD pressure readings, a lateral duodenotomy was performed . A total of 100 units of Botox was injected with an endoscopic sclerotherapy needle into all four quadrants of the ampulla . The dogs were randomly divided into four groups to undergo repeat laparotomy at either postoperative day 1 (group I), postoperative day 3 (group II), postoperative day 7 (group III), or postoperative day 14 (group IV) . At the time of second laparotomy, a pressure-sensing catheter was reinserted into the CBD and pressures recorded . Each dog then underwent transpapillary biliary stenting with a 7 Fr . x 5 cm Cotton-Leung biliary stent and CBD pressures were again recorded . RESULTS: CBD pressures were significantly lower as compared with baseline for all groups after Botox injection and after biliary stenting (P <0.001) In addition, no significant differences in the degree of CBD pressure reduction were identified between groups I through IV after Botox injection . The measured decrease in CBD pressure from baseline after Botox injection as compared with biliary stenting was significantly different for groups I and II (P <0.05) but not for groups III and IV . CONCLUSION: Botox injection into the sphincter of Oddi results in significant CBD pressure reduction within 24 hours and continues for 14 days . Also, after postoperative day 3, there is no significant difference in the reduction of CBD pressure from baseline between Botox injection and biliary stenting . Based on these findings, Botox injection into the sphincter of Oddi may be a beneficial alternative to biliary stenting for the treatment of biliary leaks and fistulae.

Proc Natl Acad Sci U S A, 2001 Mar 13, 98(6), 3561 - 6
Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis; Skeberdis VA et al.; Insulin potentiates N-methyl-d-aspartate receptors (NMDARs) in neurons and Xenopus oocytes expressing recombinant NMDARs . The present study shows that insulin induced (i) an increase in channel number times open probability (nP(o)) in outside-out patches excised from Xenopus oocytes, with no change in mean open time, unitary conductance, or reversal potential, indicating an increase in n and/or P(o); (ii) an increase in charge transfer during block of NMDA-elicited currents by the open channel blocker MK-801, indicating increased number of functional NMDARs in the cell membrane with no change in P(o); and (iii) increased NR1 surface expression, as indicated by Western blot analysis of surface proteins . Botulinum neurotoxin A greatly reduced insulin potentiation, indicating that insertion of new receptors occurs via SNARE-dependent exocytosis . Thus, insulin potentiation occurs via delivery of new channels to the plasma membrane . NMDARs assembled from mutant subunits lacking all known sites of tyrosine and serine/threonine phosphorylation in their carboxyl-terminal tails exhibited robust insulin potentiation, suggesting that insulin potentiation does not require direct phosphorylation of NMDAR subunits . Because insulin and insulin receptors are localized to glutamatergic synapses in the hippocampus, insulin-regulated trafficking of NMDARs may play a role in synaptic transmission and plasticity, including long-term potentiation.

Neurology, 2001 Mar 13, 56(5), 605 - 10
Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial; Marras C et al.; OBJECTIVE: To determine the effect of injections of botulinum toxin on simple motor tics . BACKGROUND: Case series with unblinded assessments have reported improvement in tic frequency and associated urge with botulinum toxin . METHODS: Patients with suitable simple motor tics were randomized to receive botulinum toxin and placebo in a double blind, crossover design . All outcomes compared week 2 to baseline measurements . The primary outcome measure was the number of treated tics per minute on a videotape segment . Secondary outcome measures were number of untreated tics per minute, the Shapiro Tourette Syndrome Severity Scale score, a numerical assessment of the urge to perform the treated tic (0 to 4), the premonitory sensation associated with the treated tic (0 to 4), and the patient's global impression of change . RESULTS: Eighteen patients completed the study . The median relative change in treated tics per minute with botulinum toxin was -0.39 (or a 39% reduction) versus 0.058 (or a 5.8% increase) with placebo (net effect -0.37, p = 0.0007) . The average change in urge scores (score range 0 to 4) was -0.46 in the treatment phase and +0.49 in the placebo phase (net effect 0.94, p = 0.02) . Other secondary outcome measures were not significantly different between the two groups . CONCLUSION: Botulinum toxin reduced treated tic frequency and the urge associated with the treated tic . Despite these changes, patients did not report an overall benefit from the treatment . Careful consideration of the contribution of the target tic to the patient's disability is needed before making treatment decisions.

Am J Physiol Cell Physiol, 2001 Apr, 280(4), C775 - 81
Role of SNAP-23 in trafficking of H+-ATPase in cultured inner medullary collecting duct cells; Banerjee A et al.; The trafficking of H+-ATPase vesicles to the apical membrane of inner medullary collecting duct (IMCD) cells utilizes a mechanism similar to that described in neurosecretory cells involving soluble N-ethylmaleimide-sensitive factor attachment protein target receptor (SNARE) proteins . Regulated exocytosis of these vesicles is associated with the formation of SNARE complexes . Clostridial neurotoxins that specifically cleave the target (t-) SNARE, syntaxin-1, or the vesicle SNARE, vesicle-associated membrane protein-2, reduce SNARE complex formation, H+-ATPase translocation to the apical membrane, and inhibit H+ secretion . The purpose of these experiments was to characterize the physiological role of a second t-SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)-23, a homologue of the neuronal SNAP-25, in regulated exocytosis of H+-ATPase vesicles . Our experiments document that 25-50 nM botulinum toxin (Bot) A or E cleaves rat SNAP-23 and thereby reduces immunodetectable and (35)S-labeled SNAP-23 by >60% within 60 min . Addition of 25 nM BotE to IMCD homogenates reduces the amount of the 20 S-like SNARE complex that can be immunoprecipitated from the homogenate . Treatment of intact IMCD monolayers with BotE reduces the amount of H+-ATPase translocated to the apical membrane by 52 +/- 2% of control and reduces the rate of H+ secretion by 77 +/- 3% after acute cell acidification . We conclude that SNAP-23 is a substrate for botulinum toxin proteolysis and has a critical role in the regulation of H+-ATPase exocytosis and H+ secretion in these renal epithelial cells.

Plast Reconstr Surg, 2000 May, 104(6), 2219 - 2225
Intraoperative Injection of Botulinum Toxin A into Orbicularis Oculi Muscle for the Treatment of Crow's Feet; Guerrissi JO; The purpose of this investigation was to evaluate the degree of efficacy of eliminating crow's feet by means of direct injection of botulinum toxin A into orbicularis oculi muscles under direct surgical vision during either blepharoplasty or face lift operations . Eighteen patients were injected with Botox A-14 in each orbicularis oculi muscle . Dilution was obtained by adding 4 ml of preservative-free saline to 100 IU of Botox A . Doses ranged from 15 to 50 IU in each muscle, varying according to the severity of wrinkles and intensity of muscle contraction . In 10 patients (56 percent), the Botox was injected throughout the outer surface of both orbicularis oculi dissected during a face-lift operation . In eight other patients (44 percent), the toxin was injected into the inner surface of both orbicularis oculi exposed during classic blepharoplasty procedures . Most authors have demonstrated that the effect produced by transcutaneous Botox lasts between 4 and 6 months; the paralysis obtained by direct muscular injection was effective for 9 months in 14 patients (78 percent) and 10 months in the other 4 patients (22 percent) . Results were documented by means of preinjection and postinjection photographs, videotapes, and electromyographs . Neither local nor general adverse effects were noted . The improvement obtained in crow's feet was satisfactory to the patient and to us . The use of Botox intraoperatively permitted at the same time not only the treatment of crow's feet by paralysis of orbicularis oculi muscles but also the correction of senile changes in the lids and face by means of either blepharoplasty or face-lift operations.

Ment Retard Dev Disabil Res Rev, 2001, 7(1), 30 - 7
Advances in prevention and treatment of cerebral palsy; Petersen MC et al.; In recent years there have been a number of advances in understanding of predisposing and protective factors in the development of cerebral palsy in infants . Multiple gestation births, maternal infection, and maternal and fetal thrombophilic conditions all predispose to the development of CP in the infant . Opportunities for prevention of CP may develop from an improved understanding of these factors and their mechanisms of operation . Similar progress has been made in the evaluation of treatments for CP and the effects of these treatments on the individual's impairment, function, and disability . Selective posterior rhizotomy and Botulinum toxin A are now widely used in the treatment of spasticity . The challenge remains to determine how effectively these promising interventions can alter long-term function and quality of life outcomes in children and adults with CP.

J AOAC Int, 2001 Jan-Feb, 84(1), 85 - 8
Comparison of amplified ELISA and mouse bioassay procedures for determination of botulinal toxins A, B, E, and F; Ferreira JL; The amplified enzyme-linked immunosorbent assay (amp-ELISA) was compared to the mouse bioassay for determination of botulinal neurotoxin types A, B, E, and F . Twelve different toxin-producing type A, 13 proteolytic type B, 9 nonproteolytic type B, 16 type E, 8 proteolytic type F, 5 nonproteolytic type F, and 6 nontoxigenic clostridial strains were tested . The cultures were inoculated into cooked meat medium (CMM) and tryptone-peptone-glucose-yeast extract (TPGY) medium, incubated for 5 days, and then examined for biological toxicity in mice and amp-ELISA endpoints . The amp-ELISA was less sensitive in detecting toxins produced by nonproteolytic than proteolytic strains of type B and F organisms . All of the toxin-producing strains tested were positive by the AOAC method and the amp-ELISA in either undiluted TPGY or CMM culture fluids regardless of mouse toxicity level, source, or strain . Cross-reactivity was observed between some but not all of the botulinal strains tested . None of the nontoxigenic strains were positive by the amp-ELISA . Purified botulinal toxins were also assayed using these 2 methods . The sensitivity of the amp-ELISA using purified neurotoxins was about 0.1 ng/mL for types A, B, and E and about 1.0 ng/mL for type F.

Dermatol Surg, 2001 Jan, 27(1), 34 - 6
Improving botulinum toxin therapy for palmar hyperhidrosis: wrist block and technical considerations; de Almeida AR et al.; Botulinum A exotoxin has become an excellent therapeutic option to treat focal hyperhidrosis, but when the problem affects the palmar region the technique has some drawbacks . Pain with injection is difficult to tolerate and the large dose needed to treat both hands are two concerns, as well as muscle weakness secondary to botulinum toxin diffusion and the possibility of antibody production . All these problems limit the number of patients treated . The author's suggestion is to treat only the dominant hand, after performing a wrist block . The use of a device adapted from a cartridge rubber may help to control the injection depth and the risk of muscular weakness.

Can J Ophthalmol, 2001 Feb, 36(1), 18 - 25
Vertical rectus muscle transposition and botulinum toxin for complete sixth nerve palsy; Flanders M et al.; BACKGROUND: Effective surgical treatment of complete unrecovered sixth nerve palsy must include the transfer of abducting power to the temporal aspect of the globe with release of medial rectus contracture nasally . We describe our experience in the treatment of five such patients who underwent full vertical rectus transposition combined with botulinum toxin chemodenervation of the ipsilateral medial rectus muscle . METHODS: The five patients all had primarily unilateral complete unrecovered sixth nerve palsy . They all underwent a complete preoperative and postoperative eye examination and an orthoptic assessment . Excursion into abduction was graded from -8 (globe immobilized in extreme adduction) to -4 (abduction as far as primary position) to 0 (full abduction) . Abduction saccades and a forced muscle generation test confirmed the presence of complete unrecovered sixth nerve palsy, and forced duction testing measured the degree of medial rectus contracture . All patients received ipsilateral medial rectus injection of botulinum toxin in the preoperative (8 to 2 months before surgery) and perioperative periods, and underwent complete superior rectus-inferior rectus transposition temporally . RESULTS: The average length of follow-up was 21 (range 6 to 48) months . The average preoperative distance alignment was 52 (range 25 to 80) prism dioptres (PD) . Vertical rectus transposition combined with botulinum toxin injection resulted in an average distance alignment change of 66 PD (range 50 PD to 82 PD) of exoshift . The average final deviation was 1 PD of esotropia (range 4 PD of esotropia to 6 PD of exotropia) . Average abduction improved from -6 (range -3 to -8) preoperatively to -1.7 (range -1 to -2) postoperatively . Saccades averaged -4 preoperatively and improved to -2 postoperatively . Normal vertical eye movements were preserved in all patients . A total field of single binocular vision was created in all patients, which averaged 55 degrees (range 30 degrees to 75 degrees) in the horizontal meridian . The field of single binocular vision from primary position into abduction averaged 23 degrees (range 18 degrees to 28 degrees) . INTERPRETATION: Temporal transposition of the vertical rectus muscles combined with perioperative botulinum toxin injection of the ipsilateral medial rectus muscle is a reliable and effective way of restoring functional binocular vision in patients with complete unrecovered sixth nerve palsy.

J Child Neurol, 2001 Jan, 16(1), 37 - 46
Clinical utility of botulinum toxin in the treatment of cerebral palsy: comprehensive review; Edgar TS; The physical properties, mechanism of action, and clinical evidence supporting the use of botulinum toxin in the management of spasticity in cerebral palsy are discussed . Assessment methods, patient selection criteria, and methodology for preparation and administration of botulinum toxin are discussed in detail and a treatment algorithm based on the cumulative experience of the author is provided . Botulinum toxin type A is well tolerated, safe, and effective in the treatment of patients with spastic cerebral palsy . Appropriate patient selection is imperative . Treatment goals need to be well defined and tailored to the individual patient's needs . Growth and development is a continuous and evolving process, necessitating the constant reassessment of the patient and modification of future treatment goals . The ultimate success of management in cerebral palsy is dependent on the development of a comprehensive spasticity team with complementing skills who, together, can significantly improve the quality of life of these patients.

Childs Nerv Syst, 2001 Jan, 17(1-2), 1 - 18
Outcomes after selective dorsal rhizotomy for spastic cerebral palsy; Steinbok P; OBJECT: The purpose of this article was to review the published outcomes after selective dorsal rhizotomy (SDR) for treatment of spastic cerebral palsy . METHODS: A literature search identified all articles related to outcomes after SDR . The outcomes were reviewed according to a paradigm developed by the National Center for Medical Rehabilitation Research (NCMRR) . The quality of the evidence for each outcome was assessed using Sackett's criteria and the classification system developed by the Brain Trauma Foundation and the American Association of Neurological Surgeons . RESULTS: There is very strong evidence for benefits of SDR in the impairment domain of the NCMRR classification . SDR has been shown conclusively to decrease lower limb spasticity and increase lower limb range of motion . There is strong, but not as conclusive evidence that SDR has a positive impact in the functional limitation dimension, with improvements in motor function, and in particular the Gross Motor Function Assessment (GMFM) . There is a moderate degree of certainty that SDR results in improvements in the disability dimension, as evidenced particularly by improvements in the Functional Independence Measure for Children (WeeFIM) and Pediatric Evaluation of Disability Inventory (PEDI) . There is a moderate degree of certainty that SDR results in positive suprasegmental effects, especially related to upper limb function and cognition . There is weak evidence that SDR may reduce the need for orthopedic procedures in patients with spastic cerebral palsy, and the impact on hip subluxation relative to the natural history of this problem is unclear . CONCLUSIONS: This information could help to define the role of SDR in the management of the child with spastic cerebral palsy, in the light of alternative therapies, such as intrathecal baclofen and botulinum toxin, which have been introduced more recently . It also reveals the need for further studies, particularly dealing with quality of life and economic impact.

Mov Disord, 2001 Jan, 16(1), 100 - 5
Muscle paralysis produced by botulinum toxin type A injection in treated torticollis patients compared with toxin naive individuals; Sloop RR et al.; We sought to determine whether the response to varying doses of botulinum toxin type A (BTX-A) injected in BTX-A-treated torticollis patients differed from the same injections given in toxin-naive individuals . We have developed a technique to objectively measure muscle weakness resulting from BTX injections in humans and have validated the technique in those not previously treated with BTX . We now examine BTX-A-treated torticollis patients to see if their response to BTX-A injection is similar to that of toxin-naive individuals . We injected 11 torticollis patients who had been receiving BTX-A injections with a standard 5-mouse unit (mu) dose into one extensor digitorum brevis (EDB) muscle and a varying dose into the other EDB, measuring muscle paralysis 2 weeks after the injection . Nine of the 11 patients were clinical and electrophysiologic responders . Two patients were non-responders . In the 9 responding patients the dose response curve to increasing doses of BTX-A was very similar to that seen in toxin-naive individuals . The mean muscle paralysis from the standard 5 mu dose was also similar to that previously reported in toxin-naive individuals . Torticollis patients who continue to respond clinically to BTX-A injections demonstrate essentially the same degree of muscle paralysis from the EDB injections as do subjects who have never been exposed to BTX-A.

Plast Reconstr Surg, 2001 Feb, 107(2), 327 - 32
Type A botulinum toxin for the treatment of hypertrophy of the masseter and temporal muscles: an alternative treatment; von Lindern JJ et al.; The treatment of hypertrophy of the masseter and temporal muscles has to date been dominated by conservative and surgical measures . Local therapy with type A botulinum toxin permits an alternative method of treatment . After targeted, sometimes electromyographically controlled, intramuscular injection of the affected muscles, marked inactivity atrophy occurred in the muscles of seven patients over the course of 3 to 8 weeks . This atrophy remained constant over a follow-up period of up to 25 months, and no side effects were observed . Because of its minimal invasiveness, this technique seems to have an advantage over conventional surgical therapy . Consequently, treatment with type A botulinum toxin can be regarded as a sensible alternative to surgery in cases of hypertrophy of the masseter and/or temporal muscles.

Laryngoscope, 2001 Feb, 111(2), 218 - 26
Botulinum toxin: basic science and clinical uses in otolaryngology; Blitzer A et al.; The role of botulinum toxin as a therapeutic agent is expanding rapidly in otolaryngology . Botulinum toxin is a protease that blocks the release of acetylcholine from nerve terminals . Its effects are transient and nondestructive, and largely limited to the area in which it is administered . These effects are also graded according to dose, allowing for individualized treatment of patients and disorders . Botulinum toxin has been used primarily to treat disorders of excessive or inappropriate muscle contraction . In the field of otolaryngology, these include spasmodic dysphonia, oromandibular dystonia, and blepharospasm; vocal tics and stuttering; cricopharyngeal achalasia; various tremors and tics; hemifacial spasm; temporomandibular joint disorders; and a number of cosmetic applications . Botulinum toxin treatment has recently begun to show some benefit in the control of pain from migraine and tension headache . It may also prove useful in the control of autonomic dysfunction, as in Frey syndrome, sialorrhea, and rhinorrhea . In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy.

Med J Malaysia, 2000 Sep, 55(3), 379 - 81
Two cases of severe non-specific oesophageal dysmotility showing different response to botulinum injection therapy; Suresh RL et al.; We report 2 cases where treatment of achalasia type symptoms due to severe non-specific oesophageal dysmotility have shown symptom resolution and manometric improvement to intrasphincteric botulinum injections either by itself or in combination with oesophageal dilatation.

J Protein Chem, 2000 Aug, 19(6), 475 - 87
Light chain of botulinum A neurotoxin expressed as an inclusion body from a synthetic gene is catalytically and functionally active; Ahmed SA et al.; Botulinum neurotoxins, the most potent of all toxins, induce lethal neuromuscular paralysis by inhibiting exocytosis at the neuromuscular junction . The light chains (LC) of these dichain neurotoxins are a new class of zinc-endopeptidases that specifically cleave the synaptosomal proteins, SNAP-25, VAMP, or syntaxin at discrete sites . To facilitate the structural and functional characterization of these unique endopeptidases, we constructed a synthetic gene for the LC of the botulinum neurotoxin serotype A (BoNT/A), overexpressed it in Escherichia coli, and purified the gene product from inclusion bodies . Our procedure can provide 1.1 g of the LC from 1 L of culture . The LC product was stable in solution at 4 degrees C for at least 6 months . This rBoNT/A LC was proteolytically active, specifically cleaving the Glu-Arg bond in a 17-residue synthetic peptide of SNAP-25, the reported cleavage site of BoNT/A . Its calculated catalytic efficiency kcat/Km was higher than that reported for the native BoNT/A dichain . Treating the rBoNT/A LC with mercuric compounds completely abolished its activity, most probably by modifying the cysteine-164 residue located in the vicinity of the active site . About 70% activity of the LC was restored by adding Zn2+ to a Zn2+-free, apo-LC preparation . The LC was nontoxic to mice and failed to elicit neutralizing epitope(s) when the animals were vaccinated with this protein . In addition, injecting rBoNT/A LC into sea urchin eggs inhibited exocytosis-dependent plasma membrane resealing . For the first time, results of our study make available a large amount of the biologically active toxin fragment in a soluble and stable form.

Zh Nevrol Psikhiatr Im S S Korsakova, 2000, 100(12), 60 - 3
{Botox in combined treatment of cerebral palsy in children}; Kalinina LV et al.; Ten patients with cerebral palsy (CP) were treated with botox (botulinum toxin, type A) . The next forms of the disease were observed in the patients: a spastic dysplegia, a spastic hemiplegia, a spastic-hyperkinetic form of CP . Botox was injected into the damaged muscles in a dose of 100-300 Units . Therapeutical effect was found in 90% of the patients, an average duration of the medical effect was 6-12 months . Because of the small cohort of the patients treated with botox there was made a preliminary conclusion about the high efficiency and safety of botox for CP treatment . The need of further clinical observations was emphasized.

Clin Ther, 2000 Dec, 22(12), 1516 - 24
Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review; Brashear A et al.; BACKGROUND: Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in patients with cervical dystonia . To maintain the clinical benefits of BTX-A, injections need to be repeated whenever patients' symptoms begin to recur . OBJECTIVE: The purpose of this study was to determine, in clinical practice settings, the mean duration of effect of BTX-A in the treatment of adult patients with cervical dystonia . METHODS: A retrospective chart review was undertaken at an academic center and a private neurology practice . At each site, > or =50 patients being treated for cervical dystonia were identified and randomized for chart review . Patients had to have received the first assessable injection of BTX-A between January 1, 1998, and March 31, 1998, to coincide with the clinical availability of the most current formulation of the neurotoxin . A chart was eligible for review if the patient was aged > or =18 years, had a documented diagnosis of idiopathic cervical dystonia, was being treated with BTX-A, and had been under the continuous care of investigators from January 1, 1998, to August 31, 1999 . Of the 102 patients initially identified, the first 30 from each site who met the study inclusion criteria were assessed for (1) age and sex; (2) severity of dystonia; (3) years of BTX-A use; (4) dates of first, second, third, and fourth BTX-A injections; (5) drug dose; (6) use of electromyography; (7) use of other prescribed therapies; (8) laboratory tests; and (9) adverse events . The mean interval between each visit and mean per-patient duration of effect were calculated and stratified by patient characteristics . RESULTS: The mean age of the patients was 56.4 years . Two thirds of the patients were women . Forty-one of the 60 patients (68.3%) had either moderate or severe disease, and 48 (80.0%) had experienced cervical dystonia for >5 years . The mean per-patient duration of effect across the 4 visits was 15.5 weeks (range, 12.2-24.3 weeks) . The duration of effect did not differ significantly between study sites despite the differences in disease severity, drug dose, and use of adjunctive therapy . CONCLUSION: BTX-A the controls symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

Neurology, 2000, 55(12 Suppl 5), S9 - 14
Pharmacological and surgical options for the treatment of cervical dystonia; Adler CH et al.; Cervical dystonia (CD) is a condition in which patients experience involuntary and abnormal head movements, such as tilting, twisting, or extension, often accompanied by pain . Although the exact pathologic mechanisms underlying idiopathic CD have not yet been identified, a number of therapeutic strategies have been developed to alleviate the symptoms of this disorder . Oral medications include anticholinergic agents, dopamine receptor antagonists, and GABAmimetic agents . These drugs are employed in a trial-and-error manner and have a low rate of efficacy . Localized therapy using botulinum toxin injections has revolutionized the treatment of CD, providing a high rate of response with a low incidence of side effects . However, as with oral medications, neurotoxin therapy is palliative, not curative, and repeated injections are required . In patients who develop resistance to botulinum toxin therapy and who do not achieve an adequate response to, or are intolerant of, oral medications, surgical approaches are appropriate . Among the options for peripheral surgery, the greatest experience and most consistent results have been achieved with selective dorsal ramisectomy . Recent developments in stereotactic surgery suggest that, for more complex forms of CD or when more widespread dystonia is present, bilateral pallidotomy or globus pallidus deep brain stimulation may be the treatment of choice.

Neurology, 2000, 55(12 Suppl 5), S29 - 35
The safety and efficacy of botulinum toxin type B in the treatment of patients with cervical dystonia: summary of three controlled clinical trials; Lew MF et al.; Cervical dystonia (CD) is characterized by abnormal, involuntary contractions of the cervical and/or shoulder muscles . Direct injection of Botulinum toxin type A (BTX-A) into the affected muscles has been used successfully to treat this condition . However, clinical resistance to BTX-A therapy develops in a limited number of patients . Moreover, an unknown proportion of treated patients have a suboptimal response to their present therapy . BTX-B is antigenically distinct from BTX-A and possesses a different mechanism of action . Three randomized, double-blind, placebo-controlled clinical trials evaluated the safety and efficacy of BTX-B (Elan's BTX-B evaluated as NeuroBloc) as a treatment for patients with CD . Patients received a single dose of BTX-B ranging from 2,500 to 10,000 U . The primary efficacy evaluation for each of these studies used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score . Additional efficacy measures included the TWSTRS severity, disability, and pain subscale scores, as well as the Patient Analog Pain Assessment and Patient's and Physician's Global Assessments of Change . In all three studies, groups receiving BTX-B displayed statistically significant improvements in TWSTRS total score and other efficacy end points compared with those who received placebo treatment . The clinical benefits after BTX-B treatment lasted 12 to 16 weeks and were observed in both BTX-A-responsive and BTX-A-resistant patients . In general, treatment with BTX-B was well tolerated and most of the reported adverse events were of short duration, mild to moderate in severity, and anticipated . The results from the three controlled clinical trials demonstrate the safety and efficacy of BTX-B in the treatment of patients with CD, including those who are resistant to BTX-A treatment.

Neurology, 2000, 55(12 Suppl 5), S15 - 21
Use of botulinum toxin type A in the treatment of cervical dystonia; Comella CL et al.; Botulinum toxin is the most neurotoxic substance known, with a specific action at cholinergic synapses . Acting as a zinc endopeptidase, botulinum toxin cleaves specific proteins involved in vesicle fusion, thereby preventing release of acetylcholine . The therapeutic effect of the toxin taken up presynaptically at the neuromuscular junction is to weaken muscle . Botulinum toxin type A (BTX-A) has been shown to be safe and effective in the treatment of cervical dystonia (CD; also known as spasmodic torticollis) . In patients with CD, injections of botulinum toxin dampen or eliminate involuntary muscle activity and improve control of neck movement, pain, and range of motion . To successfully use botulinum toxin as a therapeutic modality, targeting the dystonic muscles, injecting a sufficient quantity of toxin and minimizing diffusion into uninvolved muscle collectively provide the best outcome with the fewest adverse reactions . EMG guidance may allow more precise injections . To maintain responsiveness to the toxin over repeated injections, using the lowest dose at the longest dosing interval has been suggested.

Ugeskr Laeger, 2000 Nov 27, 162(48), 6567 - 71
{Botulinum toxin treatment of patients with oromandibular dystonia}; Erdal J et al.; INTRODUCTION: Oromandibular dystonia (OMD) is a frequently disabling focal dystonia, which may be treated with injections of botulinum toxin in the affected muscles . The aim of the present study was to evaluate the population, effect and side-effects of patients treated in Denmark during a nine year period . METHODS: We evaluated all 45 consecutive patients treated with quantitative EMG guided injections of botulinum toxin for OMD . RESULTS: The OMD symptoms varied but were most often mixed symptoms (n = 13), jaw closing (n = 11) and jaw opening (n = 7) . Thirty-two patients (71%) had other focal or generalised dystonia, and in 24 the additional dystonia were also treated with botulinum toxin . The 45 patients had a total of 277 treatments (mean 6.2 treatments pr . patient), each including one to six muscles . Marked effect was observed or experienced after 193 (70%) treatments, and 33 patients (73%) experienced at least one effective treatment . Side-effects occurred after 35 treatments (13%) experienced by a total of 16 patients (35.6%), most frequently as transient mild dysphagia . DISCUSSION: The study shows that botulinum toxin treatment of OMD, guided by quantitative EMG, is safe and effective.

Ugeskr Laeger, 2000 Nov 27, 162(48), 6557 - 61
{Botulinum toxin . Use in the treatment of spasticity in children}; Rasmussen LN; The medical treatment of spasticity has improved since the introduction of botulinum toxin type A (BTA) for intramuscular injection into spastic muscles . Two not directly comparable preparations are on the market: Botox and Dysport . Botox is four times as potent as Dysport . BTA is especially used for spasticity in legs, arms, and the paravertebral musculature . Surface analgesic cream is applied and an oral or rectal sedative is given after which BTA is injected locally according to strict instructions . In the motor end plate, BTA blocks the release into the synaptic cleft of acetylcholine from vesicles in the terminal nerve fibres, thereby bringing about paralysis of muscle fibre . Blockade lasts for about four months . The treatment must therefore be repeated . Because the treatment is local, side effects are few, mild, and acceptable.

Rinsho Shinkeigaku, 2000 Jul, 40(7), 689 - 93
{Cervical echomyography in cervical dystonia and its application to the monitoring for muscle afferent block (MAB)}; Mezaki T et al.; Muscle afferent block (MAB) is an intramuscular injection of 0.5% lidocaine and pure ethanol with a volume ratio of 10:1, introduced as an alternative to botulinum toxin injection for focal dystonia and spasticity . As in the case of botulinum toxin injection, the precise localization of target muscles is crucial to obtain the maximal effect from MAB . For this purpose, we performed ultrasonography of cervical muscles (echomyography) in 20 patients with cervical dystonia (11 men, 9 women; mean age 46.1), with ultrasonograph SSD-5500 (Aloca Co . Ltd., Japan) and a 7.5 MHz linear probe . In untreated subjects, the boundaries of muscles could be easily identified, while they tended to become ambiguous after repeated MAB sessions . At rest, there were involuntary worm-like movements of a specific muscle group observed in all patients . Contrary to our expectation, in all but one patient abnormal contraction was limited only in a part of synergists responsible for the abnormal posture . In normal subjects there was no abnormal contraction at rest, and all the synergists were simultaneously activated by the voluntary neck deviation . Normal subjects could not mimick the pattern of muscle activity in dystonic patients . The echo-guided MAB was performed in 16 patients . We could easily observe the diffusion of lidocaine and ethanol into the targeted muscle, and injected portions of the muscle stopped their activities just after MAB . The effect persisted for 3-4 days in at least 5 out of 10 patients who had follow-up examination . On the other hand, the movement stopped only temporarily after the injection of saline or lidocaine only . In 3 out of 16 patients, some of the uninjected synergists were activated as if to substitute for the treated muscle just after the injection . We conclude that cervical echomyography is useful to investigate the pattern of muscle activity in cervical dystonia and to accurately localize the contracting muscles during MAB.

J AAPOS, 2001 Feb, 5(1), 21 - 5
Botulinum toxin for sixth nerve palsies in children with brain tumors; Kerr NC et al.; PURPOSE: Sixth nerve palsies in children with brain tumors have a low rate of spontaneous recovery . Botulinum toxin has been used to treat sixth nerve palsies . In this study, we review outcomes for children with brain tumors and sixth nerve palsies, some of whom were treated with botulinum toxin . METHODS: To determine whether botulinum toxin effected the outcome of children with sixth nerve palsies and brain tumors, a retrospective review of charts was conducted for patients identified as having brain tumors and sixth nerve palsies after evaluation at the St Jude Children's Research Hospital Eye Clinic between 1992 and 1999 . Of 48 charts identified, 19 met our inclusion criteria, having a record of brain tumor associated with sixth nerve palsy and 2 or more eye clinic visits at least 6 months apart . Children were considered recovered if they had an esotropia of less than 10 PD in primary gaze at the last follow-up visit and did not require surgical correction . RESULTS: Of the 19 children included in the study, 10 were managed conservatively (no botulinum toxin or surgery for at least 6 months after diagnosis) . Nine children received one or more botulinum toxin injections . Two (20%) of the 10 children in the conservatively managed group recovered without surgical intervention . Two (22%) of the 9 children in the botulinum toxin treatment group recovered without surgical intervention . CONCLUSIONS: Treatment with botulinum toxin did not improve the rate of recovery in our series of children with brain tumors and sixth nerve palsies.

J Pharmacol Exp Ther, 2001 Mar, 296(3), 980 - 6
Cleavage of SNAP-25 by botulinum toxin type A requires receptor-mediated endocytosis, pH-dependent translocation, and zinc; Kalandakanond S et al.; Previously we reported that SNAP-25, synaptobrevin II, and syntaxin I, the intracellular substrates of botulinum toxin originally identified in nontarget tissues, were present in a recognized mammalian target tissue, the mouse hemidiaphragm . Furthermore, we reported that SNAP-25, syntaxin I, and synaptobrevin II were cleaved by incubation of the intact hemidiaphragm in botulinum serotypes A, C, and D, respectively . The objective of the current study was to use the mouse phrenic nerve-hemidiaphragm preparation and botulinum serotype A to investigate 1) the relationship of substrate cleavage to toxin-induced paralysis, and 2) the relevance of substrate cleavage to the mechanism of toxin action . Immunoblot examination of tissues paralyzed by botulinum toxin type A (10(-8) M) revealed < or =10% loss of SNAP-25 immunoreactivity at 1 h postparalysis, and > or =75% loss at 5 h postparalysis . Triticum vulgaris lectin, an agent that competitively antagonizes toxin binding, antagonized toxin-induced paralysis as well as SNAP-25 cleavage . Methylamine hydrochloride, an agent that prevents pH-dependent translocation, also antagonized toxin-induced paralysis and SNAP-25 cleavage . Furthermore, zinc chelation antagonized toxin-induced paralysis and SNAP-25 cleavage . These results demonstrate that cleavage of SNAP-25 by botulinum serotype A fulfills the requirements of the multistep model of botulinum toxin action that includes receptor-mediated endocytosis, pH-dependent translocation, and zinc-dependent proteolysis . Furthermore, the minimal amount of SNAP-25 cleavage at 1 h postparalysis suggests that inactivation of only a small but functionally important pool of SNAP-25 is necessary for paralysis.

J Pharmacol Exp Ther, 2001 Mar, 296(3), 749 - 55
Cleavage of intracellular substrates of botulinum toxins A, C, and D in a mammalian target tissue; Kalandakanond S et al.; The objective of the current study was to determine whether the intracellular targets that mediate the mechanism of action of botulinum toxin at the mammalian neuromuscular junction are the same as those identified in nontarget tissues . Previous studies of this nature have been limited to nontarget tissues because of the perceived low abundance of neural proteins in a neuromuscular preparation . In the current study we have used differential centrifugation to concentrate neural proteins in a synaptosomal-enriched fraction from the mouse phrenic nerve-hemidiaphragm preparation . Immunoblot detection revealed the presence of discrete immunoreactive bands corresponding to SNAP-25, synaptobrevin II, and syntaxin I in the innervated region of the neuromuscular preparation . The ability of these proteins to serve as botulinum toxin substrates in neuromuscular tissue was determined by measuring toxin-induced proteolysis . Exposure of the intact hemidiaphragm preparation to botulinum serotypes A, C, and D (10(-8) M, 5-6-h exposure) resulted in significant reductions in SNAP-25 (67%), syntaxin I (56%), and synaptobrevin II (72%) immunoreactivity, respectively . The toxin-induced proteolysis was specific for each serotype examined . Collectively, these findings provide direct confirmation that botulinum toxin targets integral components of the molecular machinery mediating neurotransmitter release at the neuromuscular junction . To the best of our knowledge this is the first time that studies of this nature on the intracellular action of botulinum toxin have been extended to a recognized mammalian target tissue preparation.

Br J Pharmacol, 2001 Feb, 132(4), 797 - 8
Black tea extract, thearubigin fraction, counteract the effects of botulinum neurotoxins in mice; Satoh E et al.; Botulinum neurotoxin type A (BoNT/A, 1.5 nM) completely inhibited indirectly evoked twitches in in vitro mouse phrenic nerve-diaphragm preparations within 40 - 45 min . Black tea extract, thearubigin fraction (TRB), mixed with BoNT/A blocked the inhibitory effect of the toxin . The protective effect of TRB extended to botulinum neurotoxins types B and E (BoNT/B and BoNT/E) and tetanus toxin, but not to tetrodotoxin . TRB was also effective against oral toxicity of BoNT/A, B and E . Thus, TRB may be of potential benefit in protecting the paralytic actions of botulinum neurotoxins (BoNTs), but its use is limited by mixing with the toxin.

Curr Treat Options Gastroenterol, 2001 Feb, 4(1), 89 - 100
Achalasia; Dunaway PM et al.; The optimal treatment of achalasia includes several options and presents a challenge for most gastroenterologists . There are numerous patient variables that must be assessed including age, degree of symptoms, duration of disease, desires of each patient, and related comorbidities . Treatment includes both medical and surgical options, with medical therapy further subclassified into pharmacologic and pneumatic dilation . Pneumatic dilations with a polyethylene dilator (sizes of 3.0, 3.5, and 4.0 cm) and laparoscopic myotomy represent the most common forms of therapy . A graduated increase in dilator size, based on symptomatic response, minimizes complications and is successful in more than 90% of patients . Further dilations or adjustment of pharmacologic therapy should be based on symptoms, weight gain, and a timed barium meal . Referral for myotomy should be considered for patients who do not respond to medical therapy or individuals that do not desire pneumatic dilations . Most patients responding to botulinum toxin (Botox; Allergan, Irvine, CA) injections will require repeat treatment at 3- to 6-month intervals . Due to cost constraints, Botox therapy should be reserved for patients who are at an increased risk from possible complications of a dilation or surgery, or those with less than 2 years of life expectancy . The most cost-effective course of therapy per patient cured over a 5-year period is pneumatic dilation, then Botox, and finally laparoscopic myotomy.

J Pediatr Gastroenterol Nutr, 2001 Jan, 32(1), 103 - 6
Gastric adenocarcinoma mimicking achalasia in a 15-year-old patient: a case report and review of the literature; Aichbichler BW et al.; Although adenocarcinoma of the cardia is extremely rare in adolescent patients, the endoscopist should be alert to this disease in patients of any age with dysphagia, even if symptoms, and results of a barium study, upper endoscopy, and esophageal manometry are suggestive of primary achalasia, especially if family history is negative for achalasia . In addition, secondary achalasia should be suspected in patients who do not respond to therapy with botulinum toxin within 2 months . Because none of the mentioned tests can distinguish between primary achalasia and secondary forms due to carcinoma of the cardia, biopsy specimens should be obtained . It appears that, although there is a minimal risk for complications, a diagnostic procedure such as biopsy would be appropriate when the information obtained could be essential . In some cases EUS can be an additional diagnostic tool, because lesions of the submucosa and the surrounding area can be identified by EUS.

N Engl J Med, 2001 Feb 15, 344(7), 488 - 93
Botulinum toxin A for axillary hyperhidrosis (excessive sweating); Heckmann M et al.; BACKGROUND: Treatment of primary focal hyperhidrosis is often unsatisfactory . Botulinum toxin A can stop excessive sweating by blocking the release of acetylcholine, which mediates sympathetic neurotransmission in the sweat glands . METHODS: We conducted a multicenter trial of botulinum toxin A in 145 patients with axillary hyperhidrosis . The patients had rates of sweat production greater than 50 mg per minute and had had primary axillary hyperhidrosis that was unresponsive to topical therapy with aluminum chloride for more than one year . In each patient, botulinum toxin A (200 U) was injected into one axilla, and placebo was injected into the other in a randomized, double-blind manner . (The units of the botulinum toxin A preparation used in this study are not identical to those of other preparations.) Two weeks later, after the treatments were revealed, the axilla that had received placebo was injected with 100 U of botulinum toxin A . Changes in the rates of sweat production were measured by gravimetry . RESULTS: At base line, the mean (+/-SD) rate of sweat production was 192+/-136 mg per minute . Two weeks after the first injections the mean rate of sweat production in the axilla that received botulinum toxin A was 24+/-27 mg per minute, as compared with 144+/-113 mg per minute in the axilla that received placebo (P< 0.001) . Injection of 100 U into the axilla that had been treated with placebo reduced the mean rate of sweat production in that axilla to 32+/-39 mg per minute (P<0.001) . Twenty-four weeks after the injection of 100 U, the rates of sweat production (in the 136 patients in whom the rates were measured at that time) were still lower than base-line values, at 67+/-66 mg per minute in the axilla that received 200 U and 65+/-64 mg per minute in the axilla that received placebo and 100 U of the toxin . Treatment was well tolerated; 98 percent of the patients said they would recommend this therapy to others . CONCLUSIONS: Intradermal injection of botulinum toxin A is an effective and safe therapy for severe axillary hyperhidrosis.

J Cell Sci, 2001 Feb, 114(Pt 4), 775 - 84
Localization of a mammalian homolog of diaphanous, mDia1, to the mitotic spindle in HeLa cells; Kato T et al.; mDia1 is a mammalian homolog of Drosophila diaphanous and works as an effector of the small GTPase Rho . It is a member of the formin homology (FH) proteins and contains the Rho-binding domain and an FH3 region in its N terminus, an FH1 region containing polyproline stretches in the middle and an FH2 region in the C terminus . Several lines of evidence indicate that mDia1 and diaphanous are essential in cytokinesis . mDia1 is present in a large amount in the cytoplasm of both interphase and mitotic cells . Using the instantaneous fixation method that preferentially extracts soluble components, we have analyzed localization of mDia1 in mitotic HeLa cells . Immunocytochemistry using polyclonal anti-mDia1 antibody revealed specific immunofluorescence localized to the mitotic spindle . This localization was seen from prophase to telophase . Western blot analysis also detected anti-mDia1 immunoreactivity in the mitotic spindle fraction isolated from mitotic HeLa cells . Consistently, expression of full-length mDia1 as a fusion protein with green fluorescence protein (GFP) revealed the GFP fluorescence again in the mitotic spindle in HeLa cells . Expression of GFP fusions of various truncated mutants of mDia1 identified that this localization is determined by a 173 amino acid-long sequence between the Rho-binding domain and the FH1 region, which contains the C-terminal part of the FH3 region . Point mutation analysis revealed that Leu(434) and Leu(455) in the FH3 region are essential in localization to the mitotic spindle . Neither electroporation of botulinum C3 exoenzyme nor microinjection of Val14RhoA into mitotic cells affected the localization of endogenous mDia1 to the mitotic spindle, suggesting that mDia1 localizes to the mitotic spindle independent of Rho activity . The present study has thus established the mDia1 localization in the mitotic spindle . This localization suggests a role of mDia1 in the spindle-cleavage furrow interaction during cell division.

Exp Neurol, 2001 Mar, 168(1), 162 - 70
Botulinum A toxin: Dysport improvement of biological availability; Bigalke H et al.; We investigated the efficacy and potency of Dysport, a botulinum neurotoxin type A complex approved for therapy, under various conditions . Conditions for maximal expression of biological activity were explored in vitro in the phrenic nerve-hemidiaphragm preparation, while conditions for optimal distribution of the toxin were tested in vivo in a double blind trial involving volunteers, using the foot Muscles extensor digitorum brevis . In contrast to the recommendations of the manufacturer, the biological availability of Dysport could be enhanced by (1) lowering its concentration, (2) supplementing with albumin, and (3) increasing the injection volume . On the basis of these experimental findings Dysport was diluted to a final concentration of 50 U/ml for therapeutic purposes . In a blind, single crossover study patients suffering from various forms of dystonia were treated with Dysport, first diluted and dosed as suggested by the manufacturer and then with doses cut by approximately 70% in accordance with the experimental findings . The low-dose treatment was as effective as the treatment with the recommended higher doses, but side effects were considerably less apparent . The benefits to be derived from these adjustments include a low risk of antibody formation, which could preclude continued or future treatment and substantial cost savings .

Br J Dermatol, 2001 Jan, 144(1), 111 - 7
Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: measured by sudometry; Braune C et al.; BACKGROUND: Local injections of botulinum toxin type A (BTX-A) have been used successfully to treat focal hyperhidrosis, but because experimental data were lacking, doses have been chosen arbitrarily or empirically . OBJECTIVES: To analyse dose dependency and duration of BTX-A-derived suppression of sweat gland activity . METHODS: Employing a standardized scheme (four injections, square 2 x 2 cm), different doses of BTX-A {Dysport(R); 2.5-120 mouse units (MU)} were injected subcutaneously at the lateral aspects of both of the lower legs in 15 healthy volunteers . Sweat tests were performed before, and 3 weeks and 6 months after, BTX-A injections . Sweating was visualized by staining with iodine starch, and quantified by capacitance hygrometry after carbachol iontophoresis, the quantitative sudomotor axon reflex test (QSART) . RESULTS: Iodine starch staining indicated a threshold dose of 10 MU (2.5 MU cm-2) leading to visible anhidrotic skin spots after 3 weeks in all subjects . This was maintained for 6 months with doses of 50 MU (12.5 MU cm-2) or higher, but the size of the anhidrotic skin area decreased over time (P < 0.001) indicating partial recovery at the edges . After 3 weeks QSART was significantly reduced (P < 0.02) and completely suppressed by doses of 80 MU (20 MU cm-2) or more, although after 6 months QSART increased again to pre-BTX-A levels (P < 0.001) . Both methods indicated that the suppression of sweating is dose dependent (QSART: r = -0.70, P < 0.001; iodine starch staining: r = 0.74, P < 0.001) . CONCLUSIONS: Our findings suggest that BTX-A effectiveness can be quantified by testing sudomotor function . For the first time threshold doses for the suppression of sweating have been defined.

Biochem Biophys Res Commun, 2001 Feb 2, 280(4), 970 - 5
Small GTPase Rho regulates thrombin-induced platelet aggregation; Nishioka H et al.; Platelets play essential roles in hemostasis and thrombosis by aggregating with each other . However, the molecular mechanism governing platelet aggregation is not yet fully understood . Here, we established an assay system using platelets permeabilized with streptolysin-O to analyze mechanism of the thrombin-induced aggregation, focusing upon a controversial issue in the field whether small GTPase Rho regulates the aggregation . Incubation of the permeabilized platelets with Rho GDP-dissociation inhibitor, an inhibitory regulator for Rho family GTPases, extracted Rho family proteins extensively from the plasma and intracellular membranes, and inhibited the thrombin-induced aggregation . Incubation of the permeabilized platelets with botulinum exoenzyme C3, which specifically inhibits Rho function by ADP-ribosylating it, abolished the thrombin-induced aggregation . Thus, Rho is involved in thrombin-induced aggregation of platelets .

Surg Today, 2000, 30(3), 211 - 8
The treatment of primary palmar hyperhidrosis: a review; Hashmonai M et al.; Primary palmar hyperhidrosis (HH) is a pathological condition of overperspiration caused by excessive secretion of the eccrine sweat glands, the etiology of which is unknown . This disorder affects a small but significant proportion of the young population all over the world . Neither systemic nor topical drugs have been found to satisfactorily alleviate the symptoms . Although the topical injection of botulinum has recently been reported to reduce the amount of local perspiration, long-term results are required before a definitive evaluation of this method can be made . Hypnosis, psychotherapy, and biofeedback have been beneficial in a limited-number of cases . While radiation achieves atrophy of the sweat glands, its detrimental effects prohibit its use . Iontophoresis has attained some satisfactory results but it has not been assessed long term . Percutaneous computed tomography-guided phenol sympathicolysis achieves excellent immediate results, but its long-term failure rate is prohibitive . Furthermore, percutaneous radiofrequency sympathicolysis may be an effective procedure, but its long-term results are not superior to surgical sympathectomy . On the other hand, surgical upper dorsal (T2-T3) sympathectomy achieves excellent long-term results and the thoracoscopic approach has supplanted the open procedures . Despite some sequelae, mainly in the form of neuralgia and compensatory sweating which cannot be predicted and may be distressing, surgical sympathectomy remains the best treatment for palmar hyperhidrosis.

Skin Therapy Lett, 1999, 4(5), 1 - 2
Update on Botulinum Toxin; Carruthers A; Botulinum toxin type-A (BTX-A) is a neurotoxin which blocks presynaptic release of acetylcholine . It interferes with neuromuscular transmission, temporarily paralyzing the affected muscle . Of special interest for dermatologists is the unlabelled cosmetic applications, for conditions such as wrinkles and hyperhidrosis . Labelled indications in Europe are for cervical dystonia and cerebral palsy . In the US, it is approved for treatment of strabismus, blepharospasm and hemifacial spasm in adults . After repeated use of high doses, antibodies can develop in some individuals, making further treatment ineffective indefinitely . Even when used in high does for neurological conditions, the development of antibodies occurs in < 5&percnt of patients . In 1997, the US FDA approved a new bulk toxin source for use in the manufacture of BTX-A . It has a higher specific potency than original BTX-A formulations, reducing the amount of utilized neurotoxin protein, and thereby reducing antibody production . Another form of this neurotoxin (type B) also appears to be effective in patients who have developed antibodies to BTX-A . It is awaiting US FDA approval for treatment of cervical dystonia.

Biochem Pharmacol, 2000 Jun 1, 59(11), 1403 - 6
Capsaicin-stimulated release of substance P from cultured dorsal root ganglion neurons: involvement of two distinct mechanisms; Purkiss J et al.; Capsaicin, the pungent component of "hot" chili peppers, selectively activates a distinct population of primary sensory neurons responsive to noxious stimuli . Many of these fibres express neuropeptides including the tachykinin, substance P . Using cultured dorsal root ganglion neurons, we found that capsaicin (10 microM) stimulated a 2-fold increase in release of substance P in the absence of extracellular Ca(2+) . Elevated potassium (75 mM) was unable to induce release under these conditions . The introduction of Ca(2+) enhanced capsaicin-induced release and brought about a robust response to potassium . Preincubation of cells with botulinum neurotoxin A (100 nM) completely blocked potassium-induced release but the capsaicin response, in the absence of Ca(2+), was unaffected . However, toxin treatment dramatically reduced capsaicin-stimulated release in the presence of Ca(2+) . It is concluded that capsaicin induces release of substance P from dorsal root ganglion neurons via two mechanisms, one requiring extracellular Ca(2+) and the intact synaptosomal-associated protein 25 kDa (SNAP-25), and the other independent of extracellular Ca(2+) and not involving SNAP-25.

Gut, 2001 Feb, 48(2), 221 - 4
Topical nitrates potentiate the effect of botulinum toxin in the treatment of patients with refractory anal fissure; Lysy J et al.; BACKGROUND: Anal fissure is perpetuated by high sphincter pressures and secondary local ischaemia . Pharmacological approaches include topical nitrates and botulinum toxin (BT) which act to reduce anal pressure . BT lowers anal pressure by preventing acetylcholine release from nerve terminals while topical nitrates act by donating nitric oxide (NO) . The aims of the present study were to compare the therapeutic effect and lowering action on internal anal sphincter pressure of BT injection and local application of isosorbide dinitrate (ID) compared with BT given alone, in patients with chronic anal fissure (CAF) refractory to treatment with ID . METHODS: Thirty consecutive patients with CAF who did not respond to previous topical ID treatments were randomly assigned to receive one of the following treatments: group A, injection of BT (20 U into the internal anal sphincter) and subsequent daily applications of ID (2.5 mg three times daily for three months); and group B, BT injection only (20 U) . If at the end of six weeks following BT injection no improvement was seen in group B, ID was added . A series of anal pressure measurements, including resting basal pressure and resting pressure following topical ID (1.25, 2.5, and 3.75 mg), was carried out both before and two weeks after 20 U of BT injection into the internal anal sphincter . At the end of the trial, patients were followed up for an average period of 10 months . FINDINGS: At six weeks the fissure healing rate was significantly higher in group A patients (10/15 (66%)) compared with group B (3/15 (20%)) (p=0.025) . At eight and 12 weeks, no significant differences were seen: 11/15 (73%) v 11/15 (73%) and 9/15 (60%) v 10/15 (66%), group A v group B, respectively . Maximum anal resting pressure (MARP) was significantly lower two weeks after BT injection than baseline MARP (90 (4) v 110 (5) mm Hg; p<0.001) . A significantly greater reduction in MARP following local application of ID was achieved after BT injection compared with that achieved before BT injection (p=0.037) INTERPRETATION: (1) Combined BT injection and local application of ID in patients with CAF who failed previous treatment with ID was more effective than BT alone . This treatment modality appears to be safe and promising . (2) ID application induced a greater reduction in MARP following BT injection compared with ID application before BT injection . The improved potency of ID on MARP after BT injection suggests a primary cholinergic tonus dominance in some patients and not, as previously claimed, anal sphincter insensitivity to nitrates.

Clin Neuropharmacol, 2000 Sep-Oct, 23(5), 239 - 51
Dystonia update; Bressman SB; Dystonia is a syndrome of sustained muscle spasms of presumed central nervous system origin . Recent advances in molecular biology have permitted clearer understanding of the genetics of various forms of dystonia and suggest pathophysiological deficits at the origin of the clinical signs . Treatment has involved centrally-acting drugs, specifically the anticholinergic medications, as well as peripherally acting agents that block neuromuscular transmission (botulinum toxin) . Some forms of dystonia are particularly responsive to levodopa . A systematic approach to the diagnostic and treatment evaluation of dystonic patients permits optimal care for long-term management.

Acta Neurol Scand, 2001 Jan, 103(1), 49 - 52
Quality of life in patients with blepharospasm; Tucha O et al.; OBJECTIVES: Administration of botulinum neurotoxin A (BONT/A) is a common and effective treatment of blepharospasm . There is, however, no information regarding the emotional and social well-being of patients with blepharospasm and patient acceptance of BONT/A therapy . The purpose of this study was to investigate aspects of quality of life of patients with blepharospasm and level of patient satisfaction with treatment . MATERIAL AND METHODS: Fifty-one patients with blepharospasm who had been treated with BONT/A for years completed a questionnaire providing information about quality of life . RESULTS: Results revealed reductions in social and emotional well-being of patients but, nonetheless, good acceptance of BONT/A therapy . The positive effects of BONT/A therapy were, however, accompanied by fear of a decreasing effect of BONT/A injections . CONCLUSION: Although the objective findings following BONT/A injections in the treatment of blepharospasm are appreciated by the patients, their well-being is affected by fears and depression.

Bratisl Lek Listy, 2000, 101(8), 433 - 7
{Is complex therapy of achalasia using botulinum toxin combined with balloon dilatation an effective approach?}; Hep A et al.; BACKGROUND: Achalasia (ACHL) is not a very frequent disease and its etiology is still unclear . In addition to the oldest therapeutical approach represented by myotomy, two conservative methods are commonly used--balloon dilatation and application of botulotoxin . So far, both methods have been used only separately, and their effects have been compared . Literature provides no evidence of the renewal of oesophageal propulsive peristalsis in result of conservative treatment . OBJECTIVES: The aim is to use both approaches subsequently within a short period of time, in order to potentiate their effects and at the same time to reduce the risk of possible complications . METHODS: The group was formed by 9 patients . Achalasia was diagnosed by flow manometry . Pseudoachalasia was excluded endoscopically and endosonographically . The treatment included application of 250 J of botulotoxin (Dysport) into the region of the lower oesophageal sphincter, and balloon dilatation which was applied 7 days later . Following this treatment, patients were observed for 24 hours . The clinical and manometric examinations were performed in 3-month intervals . RESULTS: All patients felt significantly better after treatment . The clinical state in two patients required the performance of Heller's myotomy . After 1 year, evident clinical and manometric improvement was observed in 7 patients . The longest improvement so far lasted for 36 months . The treatment has renewed the propulsive oesophageal peristalsis in two women . CONCLUSION: The treatment of primary achalasia by means of combining the application of botulotoxin (Dysport) and balloon dilatation is effective, and it is possible to assume that the clinical remission will last longer than that in result of separate use of just one of the methods . The synchronous treatment of functional blocks in the cervical and thoracic regions of the spine and continuous rehabilitation can participate in the favourable clinical effect . The renewal of primary peristalsis of the oesophagus was achieved in two out of 9 patients . No such change has been either manometrically verified or described in literature . (Fig . 5, Tab . 1, Ref . 39.)

Eur J Cell Biol, 2000 Dec, 79(12), 883 - 91
Differential contribution of syntaxin 1 and SNAP-25 to secretion in noradrenergic and adrenergic chromaffin cells; Baltazar G et al.; We used botulinum neurotoxins (BoNT) to examine whether differences in the secretory activity of noradrenergic and adrenergic chromaffin cells are related to differences in the exocytotic machinery of these two types of bovine adrenal medulla cells . Cleavage of syntaxin and SNAP-25 by BoNT/C1 decreased in a dose-dependent way the release of both noradrenaline and adrenaline, but noradrenaline release was more sensitive to BoNT/C1 . Cleavage of SNAP-25 by BoNT/A also had a larger inhibitory effect on noradrenaline release than on adrenaline release . Neither BoNT/C1 nor BoNT/A affected the intracellular Ca2+ responses induced by K+-depolarisation, and the extent of the inhibition of K+-evoked catecholamine release by selective blockers of voltage-gated Ca2+ channels was not affected by BoNT/C1 . Therefore, our data do not support the hypothesis of a regulatory effect of syntaxin or SNAP-25 on the activity of Ca2+ channels . The lower sensitivity of adrenaline release to BoNT was not due to a reduced ability of the toxins to enter or to cleave their protein targets in adrenergic cells, since immunoblot analysis showed the cleavage of a larger fraction of syntaxin 1A in adrenergic cells, as compared to the cleavage in noradrenergic cells . The immunoblot analysis also showed larger amounts of syntaxin 1A in noradrenergic chromaffin cells than in adrenergic cells . Thus, in spite of a greater cleavage of syntaxin 1A in adrenergic cells by BoNT/C1, adrenaline release was less sensitive to BoNT/C1, suggesting that the release process in noradrenergic cells might be more dependent on syntaxin 1A and SNAP-25, as compared to adrenergic cells.

J Neurol, 2000 Nov, 247(11), 857 - 61
Botulinum toxin for treatment of craniofacial hyperhidrosis; Boger A et al.; The effect of botulinum toxin A (BTX) was studied on 12 patients with idiopathic craniofacial hyperhidrosis . After confirming the diagnosis by Minor's iodine starch test we first treated one-half of the forehead with an injection of 2.5-4 ng BTX (Dysport) equidistantly intracutaneously . After 4 weeks we assessed the efficacy by another Minor's iodine starch test and then treated the other half . Another 4 weeks later a standardized telephone interview was carried out . After 1-7 days the craniofacial sweating in the area injected had completely ceased in 11 patients and was mildly reduced in the remaining one . The efficacy was confirmed by repeated Minor's iodine starch tests . Mild weakness of frowning was the only side effect, lasting 1-12 weeks and completely resolving in all patients . Although sweating has not yet recurred in most patients at follow-up periods up to 27 months, one patient had a relapse 9 months after treatment . Following reports on palmar and axillary hyperhidrosis and gustatory sweating (Frey's syndrome) this is apparently the first report on the use of BTX in the treatment of idiopathic craniofacial hyperhidrosis . BTX seems a promising new treatment for localized hyperhidrosis.

Arch Soc Esp Oftalmol, 2000 Sep, 75(9), 581 - 7
{Post-cataract surgery diplopia: etiology and treatment}; Domingo Gordo B et al.; PURPOSE: To know the causes and treatment of diplopia observed after cataract surgery . METHODS: We make a descriptive retrospective study on 19 cases with persistent binocular diplopia following cataract surgery . RESULTS: They were classified by aetiology in four groups: myotoxic effects in surgery act (47.4%), alteration in binocular vision (amblyopia, previous strabismus or long sensory deprivation) (47.4%), refractive alterations (5.2%) and previous disease . Initially, treatment with prisms, was tolerated on 47.4%; surgery was required on 36.8%, botulinicum toxin on 5.3% and penalty on 10.5% to avoid diplopia . Eventually, 36.8% of patients went on with diplopia, just only one lay equal, disappearing on 63.2% because binocular vision was recovered or suppressed by themselves or by penalty . CONCLUSIONS: Diplopia after cataracts surgery, is a serious complication that surgeons must take into account . In spite of the different treatments used, it is not easy to get its disappearance.

Arch Soc Esp Oftalmol, 2000 Jul, 75(7), 471 - 6
{Treatment of sixth nerve palsy of traumatic or tumor etiology using botulinum toxin}; Gomez De Liano Sanchez P et al.; PURPOSE: To study the treatment of sixth nerve palsies of traumatic or tumoral etiologies using botulinum toxin . The factors and possible influences are analysed . METHODS: 35 patients with unilateral sixth nerve palsy are studied, 21 presenting traumatic (group I) and 14 with tumoral etiology (group II) . They have been treated with botulinum toxin into the medial rectus muscle, using topical anesthesia . In group I the mean preoperative deviation was 59 diopters, in group II it was 37 diopters . The follow-up time, the initial deviation, the dose, the number of injections, the colateral effects and the final results are analyzed . RESULTS: In group I, the mean number of injections was 1.7, and the dose 10.23 international units, success was achieved in 38% of the patients, better results are obtained when treatment is injected within six months after traumatism, when less initial deviation and better initial lateral muscle function are present . In group II, the mean number of injections was 1.5 and the dose 8.21 international units, success was achieved in 57%, no influence among these factors was found . CONCLUSIONS: We consider useful to treat the traumatic palsy with botulinum toxin within six months after traumatism . The results depend on the initial deviation and the previous lateral muscle function . It is also useful as a chronic treatment and as a diagnosis procedure.

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