Neurochirurgie, 1998 Sep, 44(3), 192 - 6 {Treatment of spasticity with injections of botulinum toxin . Review of the literature}; Feve A et al.; Botulinum toxin injections are a new treatment for limb spasticity . Intramuscular injections can be performed in spastic muscles; efficacy occurs one or two weeks later, with a mean duration of three months . Clinical action is related to chemical denervation of presynaptic motor end nerves by the botulinum toxin . Double blind studies versus placebo have demonstrated the improvement of limb spasticity after injections of botulinum toxin . Ashworth scales, articular angulations, pain and spasms improve both in upper and lower limb spasticity . Functional scores are not changed in the upper limb, but quality of life improves . Kinematic parameters of gait are improved in lower limb spasticity, especially in children with cerebral palsy disorders . There were no reports of serious side effects . Botulinum toxin is a safe and effective treatment of localized spasticity in adults and children. Muscle Nerve Suppl, 1997, 6, S221 - 31 Physical and occupational therapy considerations in adult patients receiving botulinum toxin injections for spasticity; Albany K; Physical and occupational therapists play important roles in the evaluation and management of patients receiving botulinum toxin injections for spasticity . Baseline evaluation includes areas beyond the muscles being injected, since local spasticity reduction may lead to more widespread functional changes . Because the evaluation itself influences tone, a consistent order of muscle evaluation is recommended . The range of preinjection assessments includes evaluation of tone, mobility, strength, balance, endurance, assistive devices, and others . After injection, therapeutic interventions have multiple aims, including strengthening and facilitation, increasing range of motion, retraining of ambulation and gait, improving the fit and tolerance of orthoses, and improved functioning in ADLs. Muscle Nerve Suppl, 1997, 6, S208 - 20 Dosing, administration, and a treatment algorithm for use of botulinum toxin A for adult-onset spasticity . Spasticity Study Group; Brin MF; Botulinum toxin type A (BTX-A) has been shown to be a safe and effective treatment for focal or segmental muscle overactivity, including spasticity . Local injections of BTX-A are particularly valuable in relieving focal spasticity around a joint or a series of joints . When integrated into an overall spasticity treatment plan with clearly outlined functional goals, BTX-A may offer significant benefits to the appropriately selected adult or pediatric patient . A range of clinical outcome measures are used to evaluate the patient prior to injection . Initial dosing guidelines are offered, though each patient may have a unique drug response profile and set of modifying factors that will be used as a basis for dose adjustments . Clinical benefit usually lasts for approximately 12 weeks, though in some patients the duration of effect may be longer . Assessment of the patient's clinical and functional status is performed at each follow-up appointment, and the contribution of BTX therapy to the goals of the patient and caregiver are evaluated . Other therapeutic options should be considered where appropriate, and the treatment plan revised when necessary . Guidelines for dilution, handling, and office procedure are offered. Muscle Nerve Suppl, 1997, 6, S194 - 207 Children undergoing treatment with botulinum toxin: the role of the physical therapist; Leach J; For the cerebral palsy patient undergoing botulinum toxin (BTX) therapy, the physical therapist is involved in each step of treatment, from patient selection to outcome assessment . Prior to treatment, the therapist collects detailed baseline information, including assessment of motor ability, functional activities, current therapies and assistive devices, and the concerns of the caregiver and family . After BTX injection, the therapy program may include exercise, neurodevelopmental training, functional training, modalities, splinting, casting, orthoses, and positioning . The weakness brought on by BTX treatment provides important opportunities for functional retraining . It may also necessitate new assistive devices or modifications in the old ones. Muscle Nerve Suppl, 1997, 6, S176 - 80 Injection techniques for botulinum toxin using electromyography and electrical stimulation; O'Brien CF; Increasing data supports the use of botulinum toxin injection as a therapeutic intervention in the management of spasticity . The avid binding of botulinum toxin (BTX) to presynaptic neuron terminals and the diffusion characteristics of the medication allow relative ease of administration . For many clinical applications, efficacy may be improved, and adverse effects reduced, by more precise targeting of the muscles to be injected . Electromyographic guidance (EMG) is commonly used to confirm appropriate localization of the injection needle in specific muscles immediately before injection . Electrical stimulation (ES) may be more useful in patients who are unresponsive or sedated . Equipment options and technical aspects of EMG and ES are discussed, including some adjunctive imaging methods for injecting difficult-to-localize muscles. Muscle Nerve Suppl, 1997, 6, S169 - 75 Clinical trials of botulinum toxin in the treatment of spasticity; Simpson DM; Botulinum toxin has been tested as a treatment for spasticity resulting from cerebral palsy, multiple sclerosis, traumatic brain injury, spinal cord injury, and stroke . The results of 18 studies are reviewed in this article . In both open label and double-blind, placebo-controlled trials, botulinum toxin has proven to be an effective measure for reduction of focal spasticity . Improvements have been documented in tone reduction, range of motion, hygiene, autonomic dysreflexia, gait pattern, positioning, and other criteria, though not all criteria tested showed improvement in all studies . In none of the studies were there significant adverse effects . Future trials may be improved by refinement of several design parameters, including patient selection, treatment timing, and selection of dose and injection site. Muscle Nerve Suppl, 1997, 6, S61 - 91 Traditional pharmacological treatments for spasticity . Part I: Local treatments; Gracies JM et al.; Spasticity is a velocity-dependent increase in stretch reflex activity . It is one of the forms of muscle overactivity that may affect patients with damage to the central nervous system . Spasticity monitoring is relevant to function because the degree of spasticity may reflect the intensity of other disabling types of muscle overactivity, such as unwanted antagonistic co-contractions, permanent muscle activity in the absence of any stretch or volitional command (spastic dystonia), or inappropriate responses to cutaneous or vegetative inputs . In addition, spasticity, like other muscle overactivity, can cause muscle shortening, which is another significant source of disability . Finally, spasticity is the only form of muscle overactivity easily quantifiable at the bedside . Under the name pharmacological treatments of spasticity, we understand the use of agents designed to reduce all types of muscle overactivity, by reducing excitability of motor pathways, at the level of the central nervous system, the neuromuscular junctions, or the muscle . Pharmacologic treatment should be an adjunct to muscle lengthening and training of antagonists . Localized muscle overactivity of specific muscle groups is often seen in a number of common pathologies, including stroke and traumatic brain injury . In these cases, we favor the use of local treatments in those muscles where overactivity is most disabling, by injection into muscle (neuromuscular block) or close to the nerve supplying the muscle (perineural block) . Two types of local agents have been used in addition to the newly emerged botulinum toxin: local anesthetics (lidocaine and congeners), with a fully reversible action of short duration, and alcohols (ethanol and phenol), with a longer duration of action . Local anesthetics block both afferent and efferent messages . The onset of action is within minutes and duration of action varies between one and several hours according to the agent used . Their use requires resuscitation equipment available close by . When a long-lasting blocking agent is being considered, we favor the use of transient blocks with local anesthetics for therapeutic tests or diagnostic procedures to answer the following questions: Can function be improved by the block? What are the roles played by overactivity and contracture in the impairment of function? Which muscle is contributing to pathologic posturing? What is the true level of performance of antagonistic muscles? A short-acting anesthetic can also serve as preparation to casting or as an analgesic for intramuscular injections of other antispastic treatment . Alcohol and phenol provide long-term chemical neurolysis through destruction of peripheral nerve . Experience with ethanol is more developed in children using intramuscular injection, while experience with phenol is greater in adults with perineural injection . In both cases, there are anecdotal reports of efficacy but studies have rarely been controlled . Side effects are numerous and include pain during injection, chronic dysesthesia and chronic pain, and episodes of local or regional vascular complications by vessel toxicity . In the absence of controlled studies, a theoretical comparison of neurolytic agents with botulinum toxin is proposed . Neurolytic agents may be preferred to botulinum toxin on a number of grounds, including earlier onset, potentially longer duration of effect, lower cost, and easier storage . Conversely, pain during injection, tissue destruction with chronic sensory side effects, and lack of selectivity on motor function with neurolytic agents may favor the use of botulinum toxin . Neurolytic agents and botulinum toxin may be used in combination, the former for larger proximal muscles and the latter for selective injection into distal muscles . In the future, neurolytic agents may prove more appropriate in very severely affected patients for whom the purposes of the block are comfort and hygiene . (ABSTRACT TRUNCATED) Muscle Nerve Suppl, 1997, 6, S36 - 60 Outcome measures in spasticity management; Pierson SH; Development of validated and reliable outcome measures for spasticity rehabilitation has been hampered by the difficulty of quantifying functionally important parameters such as pain, ease of care, and mobility . Nonetheless, a combination of measures designed to assess technical and functional outcomes, patient satisfaction, and the cost effectiveness of treatment can be used together to evaluate status and track change in spasticity management, including treatment programs involving botulinum toxin . While double-blind, placebo-controlled studies remain the gold standard for clinical testing, the single-subject design is a useful alternative in many treatment protocols . Because no single tool can measure the many types of changes possible with treatment, the choice of assessment tools must be based on the functional changes expected from the treatment . A wide range of assessment tools are critically reviewed for their sensitivity, reliability, validity, and ease of administration. Eur J Morphol, 1998 Aug, 36 Suppl, 46 - 9 Snare proteins essential for cyclic AMP-regulated exocytosis in salivary glands; Fujita-Yoshigaki J et al.; Rat parotid acinar cells secrete amylase through the stimulation of beta-adrenoceptors followed by accumulation of intracellular cAMP . However, it remains unclear at the molecular level how secretory granules fuse with the apical membranes . We have examined whether SNARE proteins are involved in exocytosis in the salivary glands, and have found that one of the SNARE proteins, VAMP-2, is localized at the secretory granule membrane of rat parotid acinar cells . Moreover, botulinum neurotoxin B, which has endoprotease activity that cleaves VAMP-2, inhibited cAMP-dependent amylase release but did not inhibit basal secretion in the absence of cAMP . These results suggest that VAMP-2 is essential for cAMP-regulated exocytosis in rat parotid acinar cells . In contrast, both neurotoxins A and C1 (endoproteases that cleave SNAP-25 and syntaxin 1 respectively) failed to inhibit cAMP-dependent amylase release . Therefore, neither SNAP-25 nor syntaxin 1 are involved in amylase secretion in the parotid glands . Clarification of the mechanism of secretion will require the identification of proteins that interact and function cooperatively with VAMP-2 . This approach may also reveal details of the molecular mechanism by which the cAMP facilitates secretion in other systems, including neurotransmission. Med Hypotheses, 1998 Oct, 51(4), 305 - 7 A re-evaluation of the mechanism of action of botulinum toxin on facial movement disorders in man; Leon-S FE et al.; Despite a lot of research aimed at clarifying the mechanism of action of botulinum toxin, mostly at supraspinal levels, a complete understanding of it is still elusive . However, recent investigations, including our own, allow us to suggest that, in facial muscles, the effects of botulinum toxin are not only in the neuromuscular junctions affecting the acetylcholine release but also modify the sensory inflow with subsequent changes on the muscle spindle-gammamotoneuron system. Eur J Neurosci, 1998 Nov, 10(11), 3369 - 78 Dual effects of botulinum neurotoxin A on the secretory stages of chromaffin cells; Gil A et al.; Truncation of the C-terminal domain of the synaptosomal associated protein of 25 kDa (SNAP-25) by botulinum neurotoxin A (BoNT A) has been shown to block neuroendocrine cell secretion . It is unclear, however, if toxin mechanism involved the affection of a single or more events of the exocytotic cascade . BoNT A induced changes in both the degree of inhibition and the kinetics of catecholamine secretion from populations of cultured bovine chromaffin cells . Ca2+-dependent secretion from digitonin-permeabilized cells showed partial inhibition associated with the alteration of a slow secretory phase at different toxin concentrations . In contrast, in intact cells stimulated by depolarization, cell treatment with low concentrations (1 nM) of the toxin affected the late phase of secretion, whereas 100 nM BoNT A-poisoned cells showed an alteration even of fast components . The high degree of inhibition associated with fast secretory component alteration was dependent on Ca2+ entry through the Ca2+ channels, as it was absent from cells permeated with the A23187 Ca2+ ionophore . Vesicle pools implicated in the effect of BoNT A on the secretory response from single cells were identified using amperometry . These studies supported the macroscopic view by showing that secretion from BoNT A-treated permeabilized cells presented specific inhibition of late vesicle fusions . Intact cells showed alterations in the late vesicle pool (t1/2 = 39 s) recruited during prolonged or repetitive KCI depolarizations using 1 nM BoNT A-treated cells as well as in an intermediate kinetic pool (t1/2 = 18 s) at higher toxin concentrations (100 nM) . The faster resolved component (t1/2 = 8 s) or the membrane fusion event itself were not affected . Our results demonstrate that removal of the last nine C-terminal amino acids of SNAP-25 by BoNT A has a specific effect on two different and distal secretory stages in chromaffin cells. Neurology, 1998 Nov, 51(5), 1494 - 6 Botulinum toxin type F for treatment of dystonia: long-term experience; Chen R et al.; The authors analyzed retrospectively the results of open-labeled botulinum toxin type F (BTXF) treatment for 1 year or longer in 18 BTXA-resistant patients . All patients except one primary nonresponder to BTXA improved initially with BTXF . Most patients continued to respond to BTXF for 1 year or longer, but four patients became resistant to BTXF . BTXF-resistant patients received a higher dose per treatment and a higher cumulative dose than BTXF-responsive patients . BTXF can be used for long-term treatment of dystonia . It seems prudent to limit BTX doses of all serotypes to the lowest necessary for clinical efficacy. Semin Neurol, 1998, 18(3), 389 - 95 Multiple sclerosis: symptomatic therapies; Metz L; Although new disease-altering treatments offer hope for those with multiple sclerosis, they are not appropriate for most . Management of symptoms, however, can help everyone with the disease . Several new therapies, including tizanidine, intrathecal baclofen, botulinum toxin injections, gabapentin, ondansitron, thalamic stimulation, and lamotrigine, increase our treatment options . Better understanding of the sleep disorders that commonly occur in those with multiple sclerosis will help us treat another disabling symptom . This chapter reviews the medical and surgical management of multiple sclerosis symptoms, including these new options. HNO, 1998 Sep, 46(9), 786 - 98 {Idiopathic facial paralysis}; Wolf SR; Although acute idiopathic facial paresis is often labelled "Bell's palsy", historical studies show that Nicolaus Anton Friedreich (1761-1836) from Wurzburg was the first physician to describe the typical symptoms of the disorder in 1797, approximately 24 years prior to the paper published by Sir Charles Bell . Diagnostics has now improved to the extent that acute idiopathic facial palsy can more frequently be assigned to etiologies caused by inflammatory disorders . Herpes simplex virus type I and Borrelia burgdorferi are particularly relevant . Underestimation of the degree of paresis is, particularly in children, a drawback of the clinical examination . "Incomplete eyelid closure" is not a reliable indicator of remaining nerve function . For this reason complete electromyography (EMG) is recommended in all cases of severe facial paresis . Since electroneurography does not reliably reflect the degree of denervation present, needle EMG is preferred . The therapy of the facial palsy of unclear etiology is still not well defined . Nevertheless, we recommend that a combined treatment should be used early, at least in patients with disfiguring pareses . Combinations may consist of cortisone, virostatic agents and hemorrheologic substances and possibly antibiotics . Surgical decompression of the facial nerve remains controversial, since positive surgical results lack statistical support . Individual instructions for facial exercises, massage and muscle relaxation can support rehabilitation and possibly reduce the production of pathological synkinesia . Electrical stimulation should not be used . There are a number of possibilities available to reduce the effects of misdirected reinnervation, especially the use of botulinum-A-toxin . However, intensive diagnosis and therapy in the early phase of paresis are decisive in obtaining a favorable outcome . Further refinements in rehabilitation and comparative multicenter controlled studies are still required for future improvements in affected patients. J Neurol Neurosurg Psychiatry, 1998 Nov, 65(5), 722 - 8 Peripherally induced oromandibular dystonia; Sankhla C et al.; OBJECTIVES: Oromandibular dystonia (OMD) is a focal dystonia manifested by involuntary muscle contractions producing repetitive, patterned mouth, jaw, and tongue movements . Dystonia is usually idiopathic (primary), but in some cases it follows peripheral injury . Peripherally induced cervical and limb dystonia is well recognised, and the aim of this study was to characterise peripherally induced OMD . METHODS: The following inclusion criteria were used for peripherally induced OMD: (1) the onset of the dystonia was within a few days or months (up to 1 year) after the injury; (2) the trauma was well documented by the patient's history or a review of their medical and dental records; and (3) the onset of dystonia was anatomically related to the site of injury (facial and oral) . RESULTS: Twenty seven patients were identified in the database with OMD, temporally and anatomically related to prior injury or surgery . No additional precipitant other than trauma could be detected . None of the patients had any litigation pending . The mean age at onset was 50.11 (SD 14.15) (range 23-74) years and there was a 2:1 female preponderance . Mean latency between the initial trauma and the onset of OMD was 65 days (range 1 day-1 year) . Ten (37%) patients had some evidence of predisposing factors such as family history of movement disorders, prior exposure to neuroleptic drugs, and associated dystonia affecting other regions or essential tremor . When compared with 21 patients with primary OMD, there was no difference for age at onset, female preponderance, and phenomenology . The frequency of dystonic writer's cramp, spasmodic dysphonia, bruxism, essential tremor, and family history of movement disorder, however, was lower in the post-traumatic group (p<0.05) . In both groups the response to botulinum toxin treatment was superior to medical therapy (p<0.005) . Surgical intervention for temporomandibular disorders was more frequent in the post-traumatic group and was associated with worsening of dystonia . CONCLUSION: The study indicates that oromandibular-facial trauma, including dental procedures, may precipitate the onset of OMD, especially in predisposed people . Prompt recognition and treatment may prevent further complications. J Fr Ophtalmol, 1998 Aug-Sep, 21(7), 508 - 14 {Value of delayed botulinum toxin injection in esotropia in the child as first line treatment}; Robert PY et al.; PURPOSE: Evaluation of botulinum toxin to treat esotropia in children over 3 years old . MATERIAL AND METHODS: Eight children (6 boys and 2 girls), aged from 3 to 6 years (mean 4), underwent bilateral injection of 1.25 UI botulinum toxin Botox in medial rectus muscles, under general anesthesia . Preoperative diagnosis was infantile esotropia in 7 cases, and decompensated esophoria in 1 case . Six children had alternating isoacuity before injection, and two had amblyopia . Mean follow-up was 1.8 months (6 to 24 months) . RESULTS: One transient exotropia, and one transient ptosis were reported . Lasting orthotropia was achieved in four children (including one who presented again spasms in near vision), and lasting angle reduction in another child . Another child had late recurrence at 18 months . The injection was a failure for the two amblyopic children . DISCUSSION: Botulinum therapy allowed to avoid surgery in three cases, and to perform a more limited operation in one case . CONCLUSION: Botulinum toxin injection in extraocular muscles is of interest in infantile esotropia as a first treatment, even in children over 3 years . The success relies principally on the absence of deep amblyopia, and muscular elongation troubles . However, the use of botulinum is limited, because it requires general anesthesia, and because of its price. Clin Rehabil, 1998 Oct, 12(5), 381 - 8 Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trial; Hesse S et al.; OBJECTIVE: To investigate whether the combined approach of botulinum toxin type A (BtxA) and electrical stimulation was more effective than the toxin alone in the treatment of chronic upper limb spasticity after stroke . DESIGN: Randomized, placebo-controlled study with four treatment groups: 1000 units BtxA (Dysport) + electrical stimulation (A), 1000 units BtxA (B), placebo + electrical stimulation (C) and placebo (D) . SETTING: A neurological rehabilitation clinic . SUBJECTS: Twenty-four stroke patients with chronic upper limb spasticity after stroke, six patients in each treatment group . INTERVENTIONS: Intramuscular injection of either toxin or placebo into six upper imb flexor muscles . In group A and C additional electrical stimulation of the injected muscles with surface electrodes, three times half an hour each day for three days . MAIN OUTCOME MEASURES: Muscle tone rated with the modified Ashworth score, limb position at rest and difficulties encountered during three upper limb motor tasks assessed before and 2, 6 and 12 weeks after injection . RESULTS: Most improvements were observed in patients of group A . Cleaning the palm (p = 0.004) differed across groups . Pairwise comparison for this target variable showed that group A differed from group B and D (p <0.01), but not from C . Indicative across-group differences were obtained for elbow spasticity reduction (p = 0.011), and improvement of putting the arm through a sleeve (p = 0.020) . CONCLUSIONS: The placebo-controlled trial favours the concept that electrical stimulation enhances the effectiveness of BtxA in the treatment of chronic upper limb flexor spasticity after stroke. Histochem Cell Biol, 1998 Oct, 110(4), 395 - 406 Intracellular dynamics of alkaline phosphatase-containing granules in electropermeabilized human neutrophils; Kobayashi T et al.; Human neutrophils possess alkaline phosphatase-containing intracellular granules which are upregulated to the cell surface upon stimulation . The mechanism that governs the intracellular dynamics of these granules is, however, poorly understood . The aim of the present study was to investigate the possible participation of GTP-binding proteins in the reorganization and exocytosis of the alkaline phosphatase-containing granules using electropermeabilized cells . Biochemical assays using intact neutrophils showed that the alkaline phosphatase activity was upregulated and exocytosed into the extracellular space upon stimulation with AIF4 and N-formyl peptide . This upregulation was inhibited by treatment of cells with pertussis toxin and botulinum toxin . Alkaline phosphatase activity was also upregulated in electropermeabilized cells stimulated with guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), but not with guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS) . Cytochemically, alkaline phosphatase-containing granules were dispersed throughout the cytoplasm in unstimulated electropermeabilized neutrophils . Upon stimulation with GTPgammaS, but not with GDPbetaS, these granules fused to form elongated tubular structures which eventually became associated with the plasma membrane . Nocodazole disturbed the reorganization of the alkaline phosphatase-containing granules in cells stimulated with GTPgammaS . The results from this study indicate that GTP-binding proteins participate in the reorganization and exocytosis of alkaline phosphatase-containing granules associated with the microtubules in electropermeabilized human neutrophils. Toxicon, 1998 Nov, 36(11), 1539 - 48 Development of recombinant vaccines for botulinum neurotoxin; Smith LA; Synthetic genes encoding non-toxic, carboxyl-terminal regions (approximately 50 kDa) of botulinum neurotoxin (BoNT) serotypes A and B (referred to as fragment C or HC) were constructed and cloned into the methylotropic yeast, Pichia pastoris . Genes specifying BoNTA(HC) and BoNTB(HC) were expressed as both intracellular and secreted products . Recombinants, expressed intracellularly, yielded products with the expected molecular weight as judged by SDS PAGE and Western blot (immunoblot) analysis, while secreted products were larger due to glycosylation . Gene products were used to vaccinate mice and evaluated for their ability to elicit protective antibody titers in vivo . Mice given three intramuscular vaccinations with yeast supernatant containing glycosylated BoNTA(HC) were protected against an intraperitoneal challenge of 10(6) 50% mouse lethal doses (MLD50) of serotype A neurotoxin, a result not duplicated by its BoNTB(HC) counterpart . Vaccinating mice with cytoplasmically produced BoNTA(HC) and BoNTB(HC) protected animals from a challenge of 10(6) MLD50 of serotype A and B toxins, respectively . Because of the glycosylation encountered with secreted BoNT(HC), our efforts focused on the production and purification of products from intracellular expression. Clin Neuropharmacol, 1998 Sep-Oct, 21(5), 307 - 11 Blink reflex recovery cycle in patients with blepharospasm unilaterally treated with botulinum toxin; Grandas F et al.; To determine whether Botulinum Toxin Type A (BTXA) has an effect on the Central Nervous System, the authors studied the excitability of the blink reflex recovery cycle in 12 patients with blepharospasm before and 3 weeks after unilateral BTXA injections . To avoid recording from severely denervated muscles, the R2 response of the blink reflex was obtained from the untreated orbicularis oculi with both ipsilateral and contralateral supraorbital nerve stimulation . Baseline recovery curves were compared with a control group (n = 11) and showed an enhanced recovery of the R2 component . There were no significant differences between the recovery curves of the R2 component of the blink reflex taken before BTXA treatment and those taken after treatment . This finding confirms that BTXA does not modify the excitability of brainstem interneurons that mediate the bilateral R2 response of the blink reflex in patients with blepharospasm. Schweiz Rundsch Med Prax, 1998 Sep 16, 87(38), 1213 - 21 {Achalasia: botulinus toxin, interventional balloon dilatation, myotomy?}; Schneider JH et al.; 67 patients with achalasia were treated either medically, endoscopically or surgically from 1987 to 1997 in the Department of Surgery of the University of Tubingen . 27/67 (40%) of the patients, who were pneumatically dilatated, had a very successful therapy within the first year after dilatations . 12/67 (17%) of the patients had good results with a dysphagia score less than 1 after dilatations within the first year . The perforation rate of interventionally treated patients was 1.4% without any surgical procedure . Open myotomy according to Heller was performed in 28 of 67 patients (41%); after 1993 a laparoscopic procedure was performed in all patients . The average hospitalization for MIC was 5.4 days . The manometric control investigations showed a decrease of the basal LES pressure from preoperative values . When evaluated manometrically 87% showed good results in the follow up time of at least 24 months . 14% of those who underwent surgery had to be endoscopically dilatated after surgery. Semin Ophthalmol, 1998 Sep, 13(3), 142 - 8 Cosmetic indications for botulinum A toxin; Foster JA et al.; This article describes the use of botulinum toxin type A in the cosmetic treatment of facial wrinkles . Injection techniques, volumes, and concentration of the botulinum A toxin are described for various types of facial wrinkles. Int J Biochem Cell Biol, 1998 Oct, 30(10), 1069 - 73 SNAP-25; Hodel A; SNAP-25 belongs to a family of evolutionarily conserved proteins whose members are essential for exocytosis . Neurons and neuroendocrine cells differentially express two SNAP-25 isoforms in a developmentally regulated manner, and related homologues have been detected in most eukaryotic cells . SNAP-25 is localised on the cytoplasmic face of the plasma membrane and on secretory vesicles . It forms a stable ternary complex with two other exocytotic proteins: syntaxin and the synaptic vesicle protein synaptobrevin . A cytosolic ATPase dissociates this complex during priming of the exocytotic apparatus . Subsequent reassembly is promoted by SNAP-25 and may drive Ca(2+)-triggered vesicle-plasma membrane fusion . A mutant mouse that lacks the SNAP-25 gene is defective in neuronal dopamine signalling and exhibits similar behaviour as sufferers from hyperactivity disorders . Use of this animal model thus provides a promising avenue for the development of therapeutic treatments . Additionally, SNAP-25-based peptides that mimic the effect of botulinum neurotoxin A may be used for the treatment of involuntary muscle spasms. Ophthal Plast Reconstr Surg, 1998 Sep, 14(5), 305 - 17 Blepharospasm: past, present, and future; Anderson RL et al.; To investigate causes, associations, and results of treatment with blepharospasm, 1,653 patients were evaluated by extensive questionnaires to study blepharospasm and long-term results of treatment with the full myectomy operation, botulinum-A toxin, drug therapy, and help from the Benign Essential Blepharospasm Research Foundation (BEBRF) . The percent of patients improved by the BEBRF was 90%, full myectomy 88%, botulinum-A toxin 86%, and drug therapy 43% . The patient acceptance rate for the BEBRF was 96%, full myectomy 82%, botulinum-A toxin 95%, and drug therapy 57% . Blepharospasm is multifactorial in origin and manifestation . A vicious cycle and defective circuit theory to explain in origin and direct treatment rather than a defective specific locus is presented . All four forms of therapy evaluated are useful and must be tailored to the patient's needs . Mattie Lou Koster and the BEBRF have helped blepharospasm sufferers more than any other modality, and all patients should be informed of this support group . The full myectomy is reserved for botulinum-A toxin failures, and the limited myectomy is an excellent adjunct to botulinum-A toxin. J Nat Toxins, 1998 Oct, 7(3), 227 - 38 Predictions of secondary structure and solvent accessibility of the light chain of the clostridial neurotoxins; Lebeda FJ et al.; Predictions were made of the secondary, two-dimensional (2-D) structures and side-chain solvent accessibilities of the light (L) chains of the clostridial neurotoxins (botulinum neurotoxin serotypes A-G and tetanus neurotoxin) . An artificial neural network was used to make these predictions from a multiple alignment of their primary structures and was the approach used in making successful predictions for the C-fragments of these neurotoxins (Lebeda et al., J . Prot . Chem., 17:311, 1998) . We also exploited the fact that the L-chains are Zn-dependent proteases . Although no other metalloproteases were found to be sequentially homologous to these neurotoxin L-chains, a sequence clustering algorithm showed that several bacterially derived Zn-dependent proteases, including thermolysin, were the most similar . A 2-D structure topology map for the type A L-chain was constructed by using thermolysin as a design template . As in thermolysin, the region containing the Zn-binding sequence motif, which is part of the active site in these neurotoxins, was predicted to be minimally solvent accessible . On the other hand, the locations of residues with highly exposed side chains were predicted to occur in non-periodic structure elements . Together, these 2-D structure and solvent accessibility predictions can be used to identify important solvent-exposed regions of the L-chain . These regions may include sites that interact with residues of the neurotoxin heavy chain, sites that bind to vesicle-docking substrates or sites that form antibody epitopes. J Physiol Paris, 1998 Apr, 92(2), 135 - 9 On the action of botulinum neurotoxins A and E at cholinergic terminals; Washbourne P et al.; Botulinum neurotoxins type A and E (BoNT/A and /E) are metalloproteases with a unique specificity for SNAP-25 (synaptosomal-associated protein of 25 kDa), an essential protein component of the neuroexocytotic machinery . It was proposed that this specificity is based on the recognition of a nine-residue sequence, termed SNARE motif, which is common to the other two SNARE proteins: VAMP (vesicle-associated membrane protein) and syntaxin, the only known substrates of the other six clostridial neurotoxins . Here we report on recent studies which provide evidence for the involvement of the SNARE motif present in SNAP-25 in its interaction with BoNT/A and /E by following the kinetics of proteolysis of SNAP-25 mutants deleted of SNARE motifs . We show that a single copy of the motif is sufficient for BoNT/A and /E to recognise SNAP-25 . While the copy of the motif proximal to the cleavage site is clearly involved in recognition, in its absence, other more distant copies of the motif are able to support proteolysis . We also report on studies of poisoning human neuromuscular junctions with either BoNT/A or BoNT/E and describe the unexpected finding that the time of recovery of function after poisoning is much shorter in the case of type E with respect to type A intoxication . These data are discussed in terms of the different sites of action of the two toxins within SNAP-25. Arch Phys Med Rehabil, 1998 Oct, 79(10), 1303 - 5 Management of focal dystonia of the extensor hallucis longus muscle with botulinum toxin injection: a case report; Sherman AL et al.; Recently botulinum toxin has been used with increasing frequency as a safe and effective treatment for many previously refractory conditions associated with excessive muscle activity . The indications for use of botulinum toxin injection continue to expand . This report describes the case of an 83-year-old woman with a history of diabetes mellitus and lumbar spinal stenosis who developed a severe focal dystonia of the left great toe, such that the toe maintained the extended position . Functionally, the resultant deformity prevented the patient from wearing shoes . In addition, the patient had significant pain in the left great toe . Under needle electromyographic localization, 50 units of botulinum toxin were injected into the left extensor hallucis longus muscle . Two weeks after the injection the patient was symptom free and could place her left foot into a shoe . Seven months later, she remained symptom free . This case illustrates that localized injection of botulinum toxin to a specific lower limb muscle can effectively result in decreased muscle activity and functional improvement. Laryngoscope, 1998 Oct, 108(10), 1435 - 41 Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients; Blitzer A et al.; OBJECTIVES: This paper reviews a 12-year experience in more than 900 patients with spasmodic dysphonia who have been treated with botulinum toxin . STUDY DESIGN: This is a retrospective analysis of patients with adductor spasmodic dysphonia (strain-strangled voice), abductor spasmodic dysphonia (whispering voice), and adductor breathing dystonia (paradoxical vocal fold motion), all of whom have been treated with botulinum toxin injections for relief of symptom . METHODS: All of the patients were studied with a complete head and neck and neurologic examination; fiberoptic laryngostroboscopy; acoustic and aerodynamic measures; and a speech evaluation including the Universal spasmodic dysphonia rating scale . Some were given electromyography . All patients received botulinum toxin injections into the affected muscles under electromyographic guidance . RESULTS: The adductor patients had an average benefit of 90% of normal function lasting an average of 15.1 weeks . The abductor patients had an average benefit of 66.7% of normal function lasting an average of 10.5 weeks . Adverse effects included mild breathiness and coughing on fluids in the adductor patients, and mild stridor in a few of the abductor patients . CONCLUSION: Botulinum toxin A injection of the laryngeal hyperfunctional muscles has been found over the past 12 years to be the treatment of choice to control the dystonic symptoms in most patients with spasmodic dysphonia. J Biol Chem, 1998 Oct 23, 273(43), 28322 - 31 Actin filaments facilitate insulin activation of the src and collagen homologous/mitogen-activated protein kinase pathway leading to DNA synthesis and c-fos expression; Tsakiridis T et al.; The exact mechanism of the spatial organization of the insulin signaling pathway leading to nuclear events remains unknown . Here, we investigated the involvement of the actin cytoskeleton in propagation of insulin signaling events leading to DNA synthesis and expression of the immediate early genes c-fos and c-jun in L6 muscle cells . Insulin reorganized the cellular actin network and increased the rate of DNA synthesis and the levels of c-fos mRNA, but not those of c-jun mRNA, in undifferentiated L6 myoblasts . Similarly, insulin markedly elevated the levels of c-fos mRNA but not of c-jun mRNA in differentiated L6 myotubes . Disassembly of the actin filaments by cytochalasin D, latrunculin B, or botulinum C2 toxin significantly inhibited insulin-mediated DNA synthesis in myoblasts and abolished stimulation of c-fos expression by the hormone in myoblasts and myotubes . Actin disassembly abolished insulin-induced phosphorylation and activation of extracellulor signal-regulated kinases, activation of a 65-kda member of the p21-activated kinases, and phosphorylation of p38 mitogen-activated protein kinases but did not prevent activation of phosphatidylinositol 3-kinase and p70(S6k) . Under these conditions, insulin-induced Ras activation was also abolished, and Grb2 association with the Src and collogen homologous (Shc) molecule was inhibited without inhibition of the tyrosine phosphorylation of Shc . We conclude that the actin filament network plays an essential role in insulin regulation of Shc-dependent signaling events governing gene expression by facilitating the interaction of Shc with Grb2. Muscle Nerve, 1998 Nov, 21(11), 1540 - 2 Intrasphincteric injection of botulinum toxin is effective in long-term treatment of esophageal achalasia; Annese V et al.; We investigated the long-term efficacy and safety of intrasphincteric injections of botulinum toxin (100 U) in 57 patients with esophageal achalasia . One month after treatment, 50 patients had improved (88%); both symptom score and LES pressure were significantly reduced (P < 0.001) . After a mean follow-up of 24+/-15 months (range 6-48), 43 patients (75%) are still in remission, although repeat injections of toxin were needed to achieve a stable effect on symptoms. J Neurol Neurosurg Psychiatry, 1998 Oct, 65(4), 472 - 8 Outcome of selective ramisectomy for botulinum toxin resistant torticollis; Ford B et al.; OBJECTIVE: To investigate the long term outcome of selective ramisectomy denervation in patients with botulinum toxin resistant spasmodic torticollis . BACKGROUND: The published surgical series of ramisectomy treatment for torticollis do not provide systematic information on patients who develop resistance to the current standard of treatment-botulium toxin injections . Moreover, there is little information on surgical outcome using rating scale measurements of torticollis, or assessments of functional and occupational capacity . METHODS: Using a structured interview format and videotape assessments of severity of dystonia in a retrospective fashion, detailed follow up information was obtained on 16 patients who underwent open label selective denervation for severe, disabling torticollis, refractory to injections of botulinum toxin . RESULTS: Of 16 patients with disabling torticollis followed up postoperatively for a mean of 5 years, six (37.5%) had a moderate or complete return of normal neck function, as determined using functional capacity scales, whereas 10 had only minimal relief of dystonia or gain in function . Six of the 16 patients (37.5%) underwent a second peripheral denervation operation, and one required a third . Of 11 patients working outside the home before surgery, nine were disabled by dystonia, and only one continued to work after surgery . Dystonia rating scale scores of videotaped examinations using a modification of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) improved in 12 of 14 patients (85.7%) who underwent selective ramisectomy . When patients with primary botulinum toxin resistance were excluded, the magnitude of benefit for this subgroup was 31.9% of the baseline dystonia score (p<0.0002), comparable with the degree of improvement in a group of control patients receiving botulinum toxin treatment for torticollis . CONCLUSION: About one third of patients with torticollis resistant to injections of botulinum toxin may derive modest long term functional improvement from selective denervation, with a reduction in dystonia by about 30%, but remain unable to work. Aesthetic Plast Surg, 1998 Sep-Oct, 22(5), 366 - 71 Eyebrow asymmetry: ways of correction; Muhlbauer W et al.; Ocassionally a patient asks for correction of his asymmetric eyelids . In many instances, however, a careful analysis reveals that the actual cause is an asymmetry of the eyebrows . Generally, asymmetric eyebrows are due to excessive muscle dynamics (i.e., a hyperkinesia of the frontalis or the depressor supercilii muscles) . Therefore, the asymmetry will not be corrected by an asymmetric blepharoplasty, which will instead disclose the preexisting asymmetry, much to the concern of the patient . Management of the asymmetric brow is demanding and requires a preoperative problem-oriented and detailed analysis of the individual patient to achieve satisfactory results . We present 10-years' experience using a problem-specific approach . This included intramuscular botulinum toxin A injection, superselective neurotomy, endoscopic browlift and traditional procedures such as the coronal and direct browlift . Indication, patient selection, results, and complications are discussed. J Paediatr Child Health, 1998 Oct, 34(5), 480 - 2 A Chinese girl with Leigh syndrome: effect of botulinum toxin on dystonia; Leung TF et al.; Leigh syndrome is a form of neurodegenerative disease which is associated with intracranial infarcts . The diagnosis is made by finding hyperlactacidaemia together with cerebral infarcts on neuroimaging . We report a 4-year-old Chinese girl with Leigh syndrome who had several atypical features . She presented with generalized dystonia and developmental regression . In addition, she suffered from an unusual feature of bladder dystonia . This patient appeared to be suffering from respiratory chain complex I deficiency from studies on cultured skin fibroblasts . Assays for respiratory chain enzymes as well as mitochondrial DNA point mutations and major deletions in muscle were normal . Dystonia persisted despite treatments with muscle relaxants and a ketogenic diet . Intramuscular botulinum toxin resulted in significant relief of dystonia. Eur J Neurosci, 1998 Aug, 10(8), 2617 - 28 Presynaptic protein interactions in vivo: evidence from botulinum A, C, D and E action at frog neuromuscular junction; Raciborska DA et al.; The present study examines the paralytic action of botulinum neurotoxins at their natural target, the neuromuscular junction . We asked whether syntaxin, synaptosome-associated protein of 25 kDa (SNAP-25) and vesicle-associated membrane protein (VAMP/synaptobrevin), the proteins proteolysed by botulinum, are susceptible to cleavage in frog nerve terminals, and whether they form complexes in vivo . In control terminals, the three SNAREs were distributed in broad bands at 1 micrometer intervals, at sites consistent with presynaptic Ca2+ channels . Within 3 h, botulinum A, C, D and E (BoNT/A/C/D/E) blocked nerve-evoked muscle contractions but their effects on substrate immunoreactivity varied . The effect of BoNT/A on either C-terminus or N-terminus immunoreactivity of SNAP-25 was undetectable after 3-h incubation, although C-terminus immunoreactivity was reduced after 24 h; N-terminus immunoreactivity was not affected even after 36 h . BoNT/E reduced C-terminus immunoreactivity of SNAP-25 1.5 h after toxin application when transmitter release was blocked, but required 24 h to reduce N-terminus immunoreactivity . BoNT/C reduced syntaxin immunoreactivity after 24-h incubation but did not affect SNAP-25 . BoNT/D reduced VAMP immunoreactivity at 3 h while it increased SNAP-25 C-terminal staining fourfold . BoNT/A and BoNT/C applied together for 24 h reduced syntaxin immunoreactivity and that of both C- and N-terminus of SNAP-25, indicating that retention of SNAP-25 N-terminus after cleavage by BoNT/A depended on intact syntaxin . Therefore, we infer that SNAP-25 interacts with VAMP and with syntaxin in vivo . Neurotoxin action abolished only 40-60% of SNAP-25, VAMP or syntaxin immunoreactivity suggesting that distinct pools of these proteins, not immediately involved in triggered exocytosis, are resistant to proteolysis. Dev Med Child Neurol, 1998 Sep, 40(9), 622 - 5 Musculoskeletal modelling in determining the effect of botulinum toxin on the hamstrings of patients with crouch gait; Thompson NS et al.; This study aimed to determine the effect of hamstring botulinum toxin A (Btx-A) injection in 10 children with crouch gait in terms of changes in muscle length and lower-limb kinematics . Before Btx-A injection limb kinematics were recorded . Maximum hamstring lengths and excursions were calculated by computer modelling of the lower limb . Data were compared with the averaged hamstring lengths of 10 control children . Hamstrings were defined as short if their length was shorter than the average maximum length minus one standard deviation . Gait analysis was repeated 2 weeks after isolated hamstring Btx-A injection . Pre- and postinjection kinematic data and muscle lengths were then compared . Four of 18 injected limbs in three subjects had short medial hamstring before injection, none of the subjects had short lateral hamstrings . Muscle excursion was significantly reduced in the short and adequate maximum muscle length groups . A significant increase in the semimembranosus and semitendinosus length in all of the injected limbs was noted . Only in the short muscle group was a significant increase in muscle excursion observed . Knee extension improved by 13 degrees in the adequate muscle length group and by 15.6 degrees in the short muscle length group . Pelvic tilt and hip flexion increased in both groups non-significantly . Average walking speed postinjection increased from 0.60 ms(-1) to 0.71 ms(-1) . Short hamstrings are over-diagnosed in crouch gait . Hamstring Btx-A injection in patients with crouch gait produces significant, repeatable muscle lengthening and improved ambulatory function. J Biol Chem, 1998 Oct 16, 273(42), 27620 - 4 Brain-derived neurotrophic factor induces rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons; Takei N et al.; There is increasing interest in the involvement of neurotrophins in neural transmission and plasticity . Thus, we investigated the effects of brain-derived neurotrophic factor (BDNF) on glutamate release from cortical neurons . Treatment of cultured cortical neurons with BDNF induced rapid and transient release of glutamate . This effect was suggested to be mediated by TrkB activation because K252a inhibited the release of glutamate and BDNF phosphorylated TrkB within 30 s . BDNF-induced glutamate release was observed even when using Ca2+-free assay buffer but was inhibited by BAPTA-AM, a cell-permeable Ca2+ chelator . Therefore, BDNF-induced glutamate release was independent of extracelluar Ca2+ but dependent on intracellular Ca2+ . Because normal neurotransmitter release is exocytotic, the involvement of the exocytotic pathway in BDNF-induced glutamate release was examined . As botulinum toxin is known to cleave exocytosis-associated proteins, thereby inhibiting exocytosis, it was applied to neurons prior to the release assay . Although botulinum toxin B cleaved VAMP2 and inhibited Ca2+-triggered glutamate release, it did not inhibit the BDNF-induced release of glutamate . These results strongly suggested that BDNF induces rapid and transient release of glutamate from cortical neurons through a non-exocytotic pathway. Rev Invest Clin, 1998 May-Jun, 50(3), 263 - 76 {New concepts on the physiopathology, diagnosis, and treatment of achalasia}; Carmona-Sanchez R et al.; OBJECTIVES: To review the most relevant publications on the pathophysiology, clinical manifestations, diagnosis and treatment of esophageal achalasia, and the clinical experience achieved at our institution in order to propose a practical strategy to facilitate the management of these patients . DATA SOURCES: Manual and MEDLINE search of key articles published between January 1986 and July 1997 in addition to publications of our institute of thirty years . STUDY SELECTION: All kinds of publications with substantial clinical experience, new information or research protocols . DATA SYNTHESIS: Achalasia is an uncommon disorder of the myenteric plexus of the esophagus . Main symptoms are dysphagia, regurgitations and chest pain . The diagnosis is established by manometric criteria . Esophagogram, endoscopy and radionuclide esophageal emptying test help to differentiate other conditions and evaluate the response to treatment . Pharmacotherapy may provide relief to patients with mild symptoms and is useful for patients with high risk of complications . Dilations and myotomy are safe, effective and long lasting procedures . Botulinum toxin may be effective in selected cases . Predictive factors of response have been described for each therapy . CONCLUSION: A systematic approach to the management of patients with achalasia is necessary . Introduction of new therapies as botulinum toxin and minimal invasion surgery are changing the therapeutic decisions in this field . Drugs and BoTox are considered the first line of treatment for high risk patients and dilation and surgery for patients with no risk. J Comp Neurol, 1998 Oct 12, 400(1), 1 - 17 Effects of botulinum neurotoxin type A on the expression of gephyrin in cat abducens motoneurons; Moreno-Lopez B et al.; In this study, we investigated the effects of long-term synaptic blockade on postsynaptic receptor clustering at central inhibitory glycinergic synapses . High doses of botulinum neurotoxin type A injected in the lateral rectus muscle completely abolishes inhibitory postsynaptic potentials onto abducens motoneurons within 2 days postinjection, and transmission remains blocked for at least 2 months . Using this model, we analyzed the expression of gephyrin, a glycine receptor clustering protein, on the membrane of motoneuron somata after botulinum neurotoxin type A injection in their target muscle . Immunofluorescence or electron microscopy immunohistochemistry revealed gephyrin-immunoreactive clusters (most < 0.5 microm in diameter) densely covering the surface of control abducens motoneurons . Ultrastructurally, presynaptic terminals containing flattened synaptic vesicles (F terminals) were found associated with multiple gephyrin-immunoreactive postsynaptic densities (average 1.24 gephyrin clusters/F+ profile) . No significant changes in gephyrin-immunoreactive clusters were observed at 5 days postinjection, but we found significant reductions (25-40%) in the density of gephyrin clusters 19 and 35 days postinjection . Hence, the physiological alterations reported in this model precede structural changes on postsynaptic receptor cluster density . The decrease in gephyrin-immunoreactive clusters was paralleled by reductions in synaptic covering (F+ terminals per 100 microm of membrane) . Presumed inactive F+ terminals that remained attached to the motoneuron surface displayed normal gephyrin-immunoreactive clusters; however, the pre- and postsynaptic membranes in between synaptic active zones frequently appeared separated by enlarged extracellular spaces . We concluded that postsynaptic receptor cluster dissolution seemed more directly related to terminal retraction than to inactivity alone. J Voice, 1998 Sep, 12(3), 389 - 98 Does botulinum toxin alter laryngeal secretions and mucociliary transport? Fisher KV, Giddens CL, Gray SD. Localized botulinum toxin injection disrupts cholinergic transmission and has potential to cause focal dysautonomia . Mucociliary transport and laryngeal secretions are thought to be mediated in part by autonomic, cholinergic transmission . We questioned whether patients who receive Botox injection for adductor spasmodic dysphonia (ADSD) report postinjection symptoms possibly related to altered mucociliary clearance or laryngeal secretions . Medical histories, audiotaped interviews, and symptom ratings were retrospectively examined for 29 patients with ADSD who were followed after one or more Botox injections . Patients had received bilateral, percutaneous Botox injections of 2.5 units using an EMG-guided approach . One or more weeks after injection, four patients reported either burning, tickling, or irritation of the larynx/throat, excessive thick secretions, or dryness . Symptoms recurred with subsequent injections in two patients and were not associated with swallowing difficulty . These symptoms are consistent with, but not diagnostic of, the known effects of botulinum toxin on cholinergic, autonomic transmission. J Voice, 1998 Sep, 12(3), 383 - 8 Laryngeal rebalancing for the treatment of arytenoid dislocation; Rontal E et al.; In almost every type of functional laryngeal operation a successful result hinges on the surgeon's ability to control the muscular and ligamentous forces that act upon the vocal folds . Most of the time these forces are small in relation to the manipulations and resections performed . Occasionally, the forces are significant relative to the problem encountered, resulting in a failed surgery . Of all the many conditions that fit in to this latter description, perhaps the best example in arytenoid dislocation . Dislocation of the arytenoid is usually secondary to trauma with the majority of reported cases resulting from some type of anesthetic misadventure . Two types of dislocation have been described, anteromedial and posterolateral, each with a different mechanism of causation . This paper concerns itself with the more common anteromedial variety and its treatment using botulinum toxin. Neurol Neurochir Pol, 1998 Mar-Apr, 32(2), 277 - 84 {Facial hemispasm: modern views on the etiology, pathogenesis and treatment . Personal experience with botulinum A toxin treatment}; Slawek J et al.; The authors present current opinions on the etiology and strategies of treatment of hemifacial spasm . In the vast majority of patients it is caused by compression of facial nerve by redundant loops of vertebral and basilar arteries and their branches . It was confirmed by neuroradiology imaging techniques and during surgical interventions . In recent years a new, non-invasive method of treatment has gained a wide approval--the local injections of botulinum toxin A into contracting muscles is a highly effective (90%) and safe method of treatment . Our own material (10 patients, 22 sessions) confirms it as well. J Biol Chem, 1998 Oct 9, 273(41), 26772 - 8 Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes . Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression; Tanaka T et al.; The role of the mevalonate cascade in the control of cell cycle progression in astrocytes has been investigated . Serum stimulation of rat astrocytes in primary culture induces the expression of cyclin E followed by the activation of cyclin-dependent kinase 2 (Cdk2) during G1/S transition . The expression of p27, cyclin D1, and the activities of Cdk4 and Cdk-activating kinase (CAK), composed of Cdk7 and cyclin H, were not affected . Serum did, however, stimulate the expression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA at mid-G1 phase . Moreover, an inhibitor of HMG-CoA reductase, pravastatin, reduced cyclin E expression and Cdk2 activation and caused G1 arrest in the astrocytes . In contrast, mevalonate and its metabolite, geranylgeranylpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP), reversed the inhibitory effects of pravastatin on cyclin E expression and Cdk2 activation and allowed G1/S transition . Rho small GTPase(s) were geranylgeranylated and translocated to membranes in the presence of GGPP during G1/S transition . The effect of GGPP on cyclin E expression was abolished by botulinum C3 exoenzyme, which specifically inactivates Rho . These data indicate that geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E expression, Cdk2 activation, and G1/S transition in rat astrocytes. J Laparoendosc Adv Surg Tech A, 1998 Aug, 8(4), 201 - 7 Laparoscopic resection of esophageal epiphrenic diverticulum; Myers BS et al.; Symptomatic esophageal epiphrenic diverticula are usually repaired with a diverticulectomy and esophagomyotomy via a left thoracotomy with substantial postoperative pain and morbidity . If a laparoscopic approach could be shown to be safe and effective, the decrease in postoperative pain and potentially shorter hospital stay would make this technique beneficial . We report three cases repaired via a transabdominal approach . The first two cases were done laparoscopically . The third case was attempted laparoscopically and completed via a midline laparotomy, demonstrating that thoracotomy is not necessary even if laparoscopy is not possible . All three patients had long-standing debilitating symptoms refractory to standard nonsurgical therapies (botulinum toxin injection, pneumatic dilation, antispasmodic medication) with abnormal esophageal motility . There was one intraoperative complication of a left pneumothorax that required neither laparotomy nor thoracostomy . An esophagram on the first postoperative day demonstrated no extravasation and good flow into the stomach . The postoperative course was uneventful for all three patients, with the laparoscopic patients discharged on the second postoperative day and the laparotomy patient discharged on the seventh postoperative day . In conclusion, laparoscopic repair of symptomatic esophageal epiphrenic diverticula is a safe and effective technique with minimal postoperative pain and morbidity . It should be considered as an alternative to the traditional transthoracic approach, and may become the standard technique. FEBS Lett, 1998 Sep 11, 435(1), 84 - 8 The 26-mer peptide released from SNAP-25 cleavage by botulinum neurotoxin E inhibits vesicle docking; Ferrer-Montiel AV et al.; Botulinum neurotoxin E (BoNT E) cleaves SNAP-25 at the C-terminal domain releasing a 26-mer peptide . This peptide product may act as an excitation-secretion uncoupling peptide (ESUP) to inhibit vesicle fusion and thus contribute to the efficacy of BoNT E in disabling neurosecretion . We have addressed this question using a synthetic 26-mer peptide which mimics the amino acid sequence of the naturally released peptide, and is hereafter denoted as ESUP E . This synthetic peptide is a potent inhibitor of Ca2+-evoked exocytosis in permeabilized chromaffin cells and reduces neurotransmitter release from identified cholinergic synapses in in vitro buccal ganglia of Aplysia californica . In chromaffin cells, both ESUP E and BoNT E abrogate the slow component of secretion without affecting the fast, Ca2+-mediated fusion event . Analysis of immunoprecipitates of the synaptic ternary complex involving SNAP-25, VAMP and syntaxin demonstrates that ESUP E interferes with the assembly of the docking complex . Thus, the efficacy of BoNTs as inhibitors of neurosecretion may arise from the synergistic action of cleaving the substrate and releasing peptide products that disable the fusion process by blocking specific steps of the exocytotic cascade. FEBS Lett, 1998 Sep 11, 435(1), 61 - 4 Type A botulinum neurotoxin proteolytic activity: development of competitive inhibitors and implications for substrate specificity at the S1' binding subsite; Schmidt JJ et al.; Type A botulinum neurotoxin (botox A) is a zinc metalloprotease that cleaves only one peptide bond in the synaptosomal protein, SNAP-25 . Single-residue changes in a 17-residue substrate peptide were used to develop the first specific, competitive inhibitors of its proteolytic activity . Substrate analog peptides with P4, P3, P2' or P3' cysteine were readily hydrolyzed by the toxin, but those with P1 or P2 cysteine were not cleaved and were inhibitors . Peptides with either D- or L-cysteine as the N-terminus, followed by the last six residues of the substrate, were the most effective inhibitors, each with a Ki value of 2 microM . Elimination of the cysteine sulfhydryl group yielded much less effective inhibitors, suggesting that inhibition was primarily due to binding of the active-site zinc by the sulfhydryl group . Botox A displayed an unusual requirement for arginine as the P1' inhibitor residue, demonstrating that the S1' binding subsite of botox A is dissimilar to those of most other zinc metalloproteases . This characteristic is an important element in shaping the substrate specificity of botox A. J Clin Gastroenterol, 1998 Sep, 27(2), 166 - 8 Symptomatic gastroparesis in a patient with achalasia; Gutierrez-Galiana E et al.; We present a case of a patient with achalasia who developed symptomatic gastroparesis after botulinum toxin injection therapy . Symptoms responded to prokinetics . Pathophysiology of gastric motility disturbances in patients with achalasia is discussed. Neurology, 1998 Sep, 51(3), 815 - 9 Electromyography in cervical dystonia: changes after botulinum and trihexyphenidyl; Brans JW et al.; BACKGROUND: The value of physical examination in detecting involved neck muscles in cervical dystonia (CD) is uncertain and little is known about changes in electromyographic (EMG) features after botulinum toxin type A (BTA) treatment . METHODS: In a double-blind, randomized study we recorded the EMG activities of 420 neck muscles in 42 patients with CD before and after treatment with BTA or trihexyphenidyl . We regarded any needle EMG activity higher than 100 microV as the gold standard for involuntary involvement of a muscle in the dystonic posture and compared this with the results of physical examination . We calculated EMG total scores by adding the scores of the individual muscles . RESULTS: Physical examination had a low predictive value in the detection of involved muscles . There was a significant correlation between changes in EMG total scores and changes in clinical measurements . We observed increased EMG activity in 20% of noninjected muscles after BTA treatment and in 27% of noninjected muscles after trihexyphenidyl treatment . A switch from one most active muscle to another was seen equally in both groups and had no influence on clinical response . CONCLUSION: Physical examination alone is not sufficient to detect involved muscles, and repeated, simultaneous EMG-guided application of BTA may be helpful . In addition to clinical measurements, changes in EMG activity due to treatment can be used as a physiologic measure in evaluating treatment response . Increased activity of noninjected muscles and a switch from one most active muscle to another are not related to BTA treatment, but are probably pathophysiologic phenomena of CD itself. Infect Immun, 1998 Oct, 66(10), 4817 - 22 Purification, potency, and efficacy of the botulinum neurotoxin type A binding domain from Pichia pastoris as a recombinant vaccine candidate; Byrne MP et al.; Recombinant botulinum neurotoxin serotype A binding domain {BoNT/A(Hc)}, expressed in Pichia pastoris, was developed as a vaccine candidate for preventing botulinum neurotoxin type A (BoNT/A) intoxication . After fermentation and cell disruption, BoNT/A(Hc) was purified by using a three-step chromatographic process consisting of expanded-bed chromatography, Mono S cation-exchange chromatography, and hydrophobic interaction chromatography . Two pools of immunogenic product were separated on the Mono S column and processed individually . Both products were more than 95% pure and indistinguishable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA) . Each protein was assayed for potency in mice at immunogen doses ranging from 2.4 ng to 10 microg, followed by challenge with 1,000 mouse intraperitoneal 50% lethal doses (i.p . LD50) of BoNT/A . The calculated 50% effective dose for both peaks was approximately 0.1 microg/mouse . Peak 1 was evaluated further in a mouse efficacy assay . Mice were injected either once, twice, or three times at five different doses and subsequently challenged with 100,000 mouse i.p . LD50 of BoNT/A . In general, multiple injections protected better than one, with complete or nearly complete protection realized at doses of >/=0.5 microg/mouse . Serum neutralization and ELISA titers were also determined . Tellingly, 82 of 83 mice with antibody titers of >/=1, 600, as measured by ELISA, survived, but only 6 of 42 mice with titers of </=100 survived . This work shows that the purified BoNT/A(Hc) produced was a highly effective immunogen, able to protect against a high challenge dose of neurotoxin. Klin Monatsbl Augenheilkd, 1998 Jul, 213(1), 15 - 22 {Protective ptosis by botulinum A toxin injection in corneal affectations}; Gusek-Schneider GC et al.; BACKGROUND: Botulinum toxin A has been introduced as a local injection therapy of different conditions with focal muscular hypercontractions . In the ophthalmologic field the toxin has proven its efficacy in the therapy of blepharospasm and hemifacial spasm . There are only few reports on the use of a botulinum toxin A to induce a protective ptosis in patients with persistent corneal ulcers . PATIENTS AND METHODS: 21 patients who failed to respond to conservative therapy of corneal erosions or ulcers of different origin received a botulinum toxin A injection into the levator palpebrae superioris muscle . RESULTS: The ptosis began after a mean of 1.5 days (1-3 days) and was complete after a mean of 5.1 days (3-12 days) after injection . Complete recovery of the levator function could be observed after a mean of 12.4 weeks (4-24 weeks) . In 13 patients (61.8%) the botulinum toxin A induced protective ptosis lead to a complete healing of indolent ulcers or erosions, in 4 patients (19%) an additional tarsorrhaphy was necessary . In 3 patients no healing could be observed during follow up, in one patient (with neuroparalytic ulcer) the injection was given prophylactically . The period of healing on average was 3.8 weeks . There was no relationship between the healing rate and the duration of the corneal disease prior to the botulinum toxin injection . The mean healing rate of younger patients was higher (75%) than that of older patients (53.8%) and higher in erosions (70%) than in ulcers (30%) . No side effects were observed besides in one patient the undesirable duration of the ptosis of a half year . CONCLUSION: The induction of a protective ptosis with botulinum toxin A injection is an efficacious treatment alternative in persistent corneal erosions and ulcers before performing a tarsorrhaphy . This method is preferrable especially in patients with lagophthalmos due to facial nerve paresis with potential recovery. Arch Neurol, 1998 Sep, 55(9), 1233 - 7 Sensory modulation of the blink reflex in patients with blepharospasm; Gomez-Wong E et al.; OBJECTIVE: To measure the effects of a prepulse stimulus on the blink reflex responses elicited by an electrical stimulation of the supraorbital nerve in patients with blepharospasm with and without an effective sensory trick . DESIGN: Blink reflexes to supraorbital nerve stimulation were preceded in test trials by a prepulse electrical stimulus to the third finger at various leading intervals . SETTING: Ambulatory patients were treated regularly with botulinum toxin in the Neurology Department of the Hospital Clinic in Barcelona, Spain . SUBJECTS: Seventeen patients with dystonic blepharospasm and 11 age-matched control subjects . Eight of the patients with dystonic blepharospasm used a sensory trick to alleviate spasms and 9 did not . MAIN OUTCOME MEASURES: We measured amplitude of R1 and area of R2 responses elicited by the supraorbital electrical stimulus and determined the percentage of facilitation or inhibition induced by the prepulse . RESULTS: Prepulse facilitation occurred in the R1 response at intervals of 60 to 100 milliseconds and was normal in all patients . Prepulse inhibition occurred in the R2 response at intervals between 50 and 200 milliseconds and was abnormally reduced in 11 patients (64.7%), including all 9 patients who did not use a sensory trick and 2 of the 8 patients who did use a sensory trick . There was a positive correlation between absence of sensory trick and abnormality of the prepulse effects (chi(2)= 23.8; P < .001) . CONCLUSIONS: Prepulse inhibition of the trigeminofacial reflex is abnormal in a percentage of patients with blepharospasm, and this abnormality occurs more frequently in patients who do not use a sensory trick . This sensory derangement may contribute to the maintenance of the dystonic spasms by reducing the amount of physiological gating from peripheral nerve inputs on trigeminofacial reflexes. Australas J Dermatol, 1998 Aug, 39(3), 158 - 63 Botulinum toxin for the correction of hyperkinetic facial lines; Goodman G; The present article illustrates the effects of low dose botulinum toxin (BTx) injections for the improvement of hyperkinetic facial lines and presents a grading treatment chart designed to standardize the reporting of the improvement seen . A questionnaire of patient acceptance, the patients' impression of therapy and short-term results and complications are reported . Twelve patients with 26 injected-paired regions were charted and the response to injection was graded . Patients had hyperkinetic facial lines in glabella, periorbital regions or horizontal forehead lines . Diluted BTx type A (1 IU/0.1 mL) was injected and patients were assessed at 10 days . A second follow up injection was offered to patients at this stage if required . Objectively, all patients' hyperkinetic actions and lines improved or diminished . The degree of improvement was similar in all areas injected and a symmetry of results was always observed . In a minority of cases, all movement was lost (7/26) and in others it was weakened but present (19/26) . In some injected areas the actual expression line that was visible at rest disappeared entirely (11/26): in the others it was diminished (15/26) . Complications were few . Two patients had temporary brow ptosis that spontaneously recovered within the first week . No eyelid ptosis was noted . Bruising and headaches were the most common reported complications . Low dose BTx is an effective and well-tolerated treatment for hyperkinetic facial lines with few significant complications in this small pilot study . The grading chart may allow easier comparisons of results between studies on the effects of BTx therapy. Rev Neurol, 1998 Aug, 27(156), 258 - 63 {Clinical presentations, differential diagnosis and management of obstetric brachial palsy}; Alfonso I et al.; INTRODUCTION: The brachial plexus originates from C5 to T1 spinal segments . The brachial plexus includes the ventral ramus, trunks, divisions, cords and branches . DEVELOPMENT AND CONCLUSIONS: Brachial plexus injuries produce clinical syndromes . The Duchenne-Erb syndrome is the most frequent presentation of obstetric brachial plexus injury . The differential diagnosis of brachial plexus palsy include decreased arm movements due to pain, or weakness caused by a lesion of the nervous system outside in the brachial plexus, or by a lesion in the brachial plexus due to non-obstetrical causes . Management of these patients initially includes considering the possibility of clavicular and humeral fractures and posterior subluxation of the shoulder; and subsequently considering the possibilities of subscapularis muscle contraction or posterior shoulder subluxation in patients that develop internal rotation contracture of the shoulder; or flexion, pronation or supination contracture in patients with forearm deformation . Treatment consist of physical therapy, administration of botulinum toxin, electrical stimulation, neurolysis, nervatization, removal of neuromas and nerve grafting, treatment of fractures and subluxation, release of muscle contracture and tendon transplantation. Dermatol Surg, 1998 Aug, 24(8), 817 - 9 Botulinum A neurotoxin for axillary hyperhidrosis . No sweat Botox; Glogau RG; BACKGROUND: Axillary hyperhidrosis causes considerable emotional stress and is associated with extraordinary costs and limitations in clothing . Existing topical and surgical therapies are either ineffective or associated with unacceptable morbidity and sequelae . Botulinum A neurotoxin (Botox) has been shown to decrease sweating in normal skin and in palmar hyperhidrosis . OBJECTIVE: The current study was undertaken to demonstrate the utility of using Botox in the treatment of axillary hyperhidrosis . METHODS: Twelve patient with axillary hyperhidrosis underwent intradermal injection with 50 units of Botox in the axillary skin bilaterally . RESULTS: All patients enjoyed relatively complete anhidrosis of the axillary skin in periods ranging from 4 to 7 months . Repeat injections produced similar results . CONCLUSION: Botulinum A neurotoxin (Botox) is an elegant and simple treatment for axillary hyperhidrosis. Cesk Slov Oftalmol, 1998 May, 54(3), 174 - 8 {Use of botulinum toxin in the treatment of strabismus}; Gerinec A et al.; The authors present their two years experience with the administration of botulotoxin, the first observations in this country in connection with treatment of strabismus . Botulotoxin was injected by the i.m . route to 26 children mostly with residual deviations above 20 PD in concomitant strabismus . After a single injection the deviation declined to less than 20 PD in all patients . However persistence of deviations under 10 PD was not permanent and after reappearance of the deviation the administration of botulotoxin had to be repeated . The authors consider the therapeutic results satisfactory and draw attention to advantages and disadvantages of this method . They discuss in particular problems of the long-term effect of treatment. Prostate, 1998 Sep 15, 37(1), 44 - 50 Botox-induced prostatic involution; Doggweiler R et al.; BACKGROUND: A simple approach to induced prostatic atrophy was explored . Surgical denervation is known to produce profound atrophy of the rat prostate . Because Botulinum toxin type A (Botox) produces a long-term chemical denervation, the potential to induce atrophy of the rat prostate was explored . METHODS: Thirty rat prostates were injected with varying doses of Botox . Single and serial injections were used, and rats were subsequently sacrificed after either 1 or 4 weeks, respectively . The prostate glands were harvested, weighed, and histologically studied for morphologic and apoptotic changes . RESULTS: The total prostate volume and weight were found to be reduced in all Botox-injected animals . Histologically, a generalized atrophy of the glands was observed with the H&E stain . There was also diffuse glandular apoptosis evident with the Tunel stain . There were no significant complications (e.g., urinary retention, weight loss, or hind/limb weakness) . CONCLUSIONS: Botulinum toxin type A injection into the prostate gland induces selective denervation and subsequent atrophy of the prostate . Apoptosis was seen diffusely throughout the gland . It may be possible that in the future, this long-acting neurotoxin could be used for the treatment of common pathologies of the human prostate. Gen Hosp Psychiatry, 1998 Jul, 20(4), 255 - 9 Emotional symptoms are secondary to the voice disorder in patients with spasmodic dysphonia; Liu CY et al.; The aims of this study were to evaluate the emotional status and life quality of the patients with spasmodic dysphonia (SD) before and after botulinum toxin treatment, and to ascertain whether SD is a somatoform disorder . Ten patients with spasmodic dysphonia were injected unilaterally into the vocal cord with botulinum toxin . Before botulinum toxin treatment, two clinician's rating scales--Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS), and three self-rating psychometrics--Zung's Self-Rating Depression Scale (SDS), Life Quality Scale (GHQ/QL-12), and Symptom Distress Checklist (SCL-90) were applied . Self-rating scales were also administered in 20 matched normal controls . The patients were reevaluated 1 month after botulinum toxin treatment . The Clinical Global Impression Scale (CGI) was also rated by the patients themselves and a speech pathologist . The mean scores of SD patients were significantly higher than that of controls in SDS, and subscales of somatization, obsessive-compulsive symptoms, depression, anxiety, and psychoticism in SCL-90 . The mean score of GHQ/QL-12 was significantly higher in the control group . The scores of HDRS, SDS, GHQ/QL-12 and subscales of somatization, depression, and anxiety in SCL-90 showed significant improvement after botulinum treatment . In CGI, seven patients were rated as improved by patients themselves and the speech pathologist . The patients with SD had more anxiety, depression and somatization symptoms, and poor life quality than normal controls . Their emotional status and life quality improved after botulinum toxin treatment . The results suggest that the emotional symptoms of patients with SD are mainly secondary to voice disorder. Am J Phys Med Rehabil, 1998 Jul-Aug, 77(4), 348 - 50 Botulinum toxin treatment of lumbrical spasticity: a brief report; Palmer DT et al.; Botulinum toxin A has been used to treat wrist and finger spasticity mainly through injection of the forearm flexor muscles . This case study describes its first reported use in managing spastic lumbricals of the hand . A 19-year-old male had significant flexion deformity and hypertonicity of the left wrist and hand, particularly the second through fifth metacarpophalangeal joints, after traumatic brain injury . By using the 0-4 Ashworth scale, spasticity of the lumbricals across the second to fourth metacarpophalangeal joints was rated 2, with persistent clonus of the finger flexors as confirmed by electromyography to the middle and ring fingers, even after botulinum toxin A injection of the flexor digitorum sublimis and profundus muscles . By using the electromyography-guided technique, botulinum toxin A was injected into the first lumbrical of the index finger (12 units), second and third lumbricals of the middle and ring fingers, respectively (15 units each), and fourth lumbrical of the little finger (10 units) . At follow-up, clinical and electromyographic examination revealed a significant reduction in tone and clonus of the injected lumbricals . Ashworth scores of the lumbricals from the index to little finger improved to 1 . Botulinum toxin A injection of the lumbricals can be beneficial in managing spasticity of these muscles . It is well tolerated and effective at doses of 10 to 15 units . Lumbrical injection of botulinum toxin A is a useful adjunct in our percutaneous armamentarium for managing the spastic hand. Yale J Biol Med, 1998 Jan-Feb, 71(1), 23 - 30 Achalasia in a sixty-four-year-old man; Komisaruk EA et al.; Achalasia is an esophageal motility disorder characterized by increased lower esophageal sphincter pressure and absence of peristalsis in the lower esophagus . Patients typically present with complaints of progressive difficulty swallowing over a period of several years . Diagnosis is confirmed by esophageal manometry . Complications of achalasia include esophagitis, aspiration and possibly an increased risk of esophageal carcinoma . Medical treatment options include pneumatic dilatation, esophageal bougienage, nitrates, calcium channel blockers and botulinum toxin injections . The primary method of surgical treatment is the Heller myotomy, in which longitudinal incisions are made in the muscle fibers of the lower esophageal sphincter to reduce sphincter pressure . Frequently, a fundoplication is performed in addition to the myotomy to decrease the likelihood of development of gastroesophageal reflux . In recent years, the Heller myotomy has been performed both thoracoscopically and laparoscopically . An additional development has been the placement of an endoscope in the esophagus to provide transillumination during surgery; intraoperative endoscopy allows improved assessment of the depth of myotomy incisions and reduces the risk of esophageal perforation . The case report below describes a 64-year-old-man with achalasia who presented with persistent dysphagia despite multiple attempts at medical treatment . A laparoscopic Heller myotomy with Toupet fundoplication was performed with subsequent eradication of symptoms . A discussion of the epidemiology, etiology, clinical presentation, diagnosis and treatment of achalasia follows the case report. Br J Ophthalmol, 1998 May, 82(5), 528 - 33 Botulinum toxin A treatment of overactive corrugator supercilii in thyroid eye disease; Olver JM; BACKGROUND/AIM: Patients with thyroid eye disease with upper eyelid retraction often develop overaction of the accessory muscles of eyelid closure, the glabellar muscles corrugator supercilii and procerus . The resultant glabellar furrowing (frown lines) contributes to the typical thyroid facies . The aim of this study was to evaluate the use of botulinum toxin A reversible chemodenervation of the glabellar muscles as adjunctive treatment in the rehabilitation of patients with thyroid eye disease . METHODS: 14 patients (13 females) ages 39-76 years (mean 52) with inactive thyroid eye disease and associated medial eyebrow ptosis and prominent glabellar frown lines were recruited . All patients had a history of upper eyelid retraction . Each patient was treated with a single botulinum toxin injection (Dysport 0.2 ml, 40 units) into each corrugator supercilii and sometimes procerus muscles as an outpatient procedure . The effectiveness and acceptability of the treatment was assessed clinically and from a patient questionnaire . RESULTS: The injections were tolerated by 13/14 (93%) patients . There was resultant flattening of the glabellar region and improvement of medial eyebrow contour in all patients, with onset of paralysis within 1 week . All patients reported a subjective improvement in appearance . Side effects included one patient (7%) with reversible partial ptosis . The beneficial effect lasted 4-6 months, with a gradual return of function . Repeat treatment was indicated where there was persistent upper eyelid retraction and protractor overaction . CONCLUSION: Botulinum toxin A chemodenervation of the glabellar muscles in these patients was effective and acceptable . Chemodenervation should be considered in the rehabilitation of patients with thyroid eye disease where there is upper eyelid retraction and overacting protractors resulting in a thyroid frown . Once the eyelid retraction has been successfully treated by surgery, the need for further glabella muscle chemodenervation is considerably reduced. J Otolaryngol, 1998 Aug, 27(4), 213 - 6 Botulinum toxin treatment of essential palatal myoclonus tinnitus; Bryce GE et al.; OBJECTIVE: The purpose of this study was to review the use of botulinum toxin in the treatment of essential palatal myoclonus tinnitus . DESIGN: Two case series . METHOD: Four to 10 units of botulium toxin are injected into the tensor veli palatini muscle . The dose and interval between doses is titrated according to patient symptoms . With bilateral symptoms, injection is alternated between sides at sequential visits . OUTCOME MEASURES: Relief of tinnitus with cessation of palatal contractions . RESULTS: Both patients had relief of tinnitus . One patient required ventilation tube placement to relieve aural fullness . CONCLUSIONS: Tensor veli palatini botulinium toxin injection is an effective treatment for essential palatal myoclonus tinnitus. J Clin Gastroenterol, 1998 Jul, 27(1), 21 - 35 Current therapies for achalasia: comparison and efficacy; Vaezi MF et al.; Achalasia is a primary esophageal motor disorder of unknown etiology producing complaints of dysphagia, regurgitation, and chest pain . The current treatments for achalasia involve the reduction of lower esophageal sphincter (LES) pressure resulting in improved esophageal emptying . Calcium channel blockers and nitrates, once used as initial treatment strategy for early achalasia, are now only used in patients who are not candidates for pneumatic dilation or surgery and those not responding to botulinum toxin injections . By virtue of the more rigid balloons, the current pneumatic dilators are more effective and have better efficacy than the older more compliant balloons . The graded approach to pneumatic dilation using the Rigiflex balloons (3.0, 3.5, and 4.0 cm) are now the most commonly used nonsurgical means of treating patients with achalasia, resulting in symptom improvement in up to 90% of patients . Surgical myotomy, once with high morbidity and long hospital stay, can now be performed laparoscopically with similar efficacy to the open surgical approach (94% vs . 84%, respectively), reduced morbidity, and hospitalization time . Given the advances in both balloon dilation and laparoscopic myotomy, most patients with achalasia can now choose between these two equally efficacious treatment options . Botulinum toxin injection of the LES should be reserved for patients who cannot undergo balloon dilation and are not surgical candidates. Digestion, 1998 Aug, 59(5), 509 - 29 Endoscopic ultrasonography; Caletti G et al.; Endoscopic ultrasonography (EUS) is nowadays a clinically relevant technology and its findings can have a major impact on patient management . This technique is currently indicated for staging digestive cancers, assessment of submucosal tumors, diagnosis of intestinal wall infiltrative diseases, common bile-duct stones and gut neuroendocrine tumors . As far as neoplasms are concerned, EUS appears to be a reliable and safe technique, thus making the physician able to plan either an aggressive surgical treatment, or a conservative palliative therapy . This is of the utmost importance in order to optimize medical-related costs, and to make the best therapeutic decision for each individual patient . EUS is also helpful in monitoring the course of a disease, as it is simple and virtually without complications . When EUS findings are not sufficient for a complete diagnosis, it is now possible to perform an EUS-guided fine-needle biopsy, which can allow a cytological diagnosis . Finally, some therapeutic endosonography-guided procedures are being increasingly adopted, such as cystoenterostomy, celiac plexus neurolysis, cholangio-pancreatography and selective injection of botulinum toxin in the muscle layer of the lower esophageal sphincter. Spine, 1998 Aug 1, 23(15), 1662 - 6; discussion 1667 A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome; Wheeler AH et al.; STUDY DESIGN: In a randomized, double-blind study, two dosage strengths of botulinum toxin type A were compared with normal saline injected into symptomatic trigger points in the cervicothoracic paraspinal muscles . OBJECTIVES: To compare the effect of botulinum toxin type A injections with that of normal saline to determine the former's usefulness in the management of neck pain and disability . SUMMARY OF BACKGROUND DATA: The results of several studies have suggested that botulinum toxin type A may reduce pain associated with myofascial pain syndromes . METHODS: Thirty-three participants were divided randomly to receive either 50 or 100 units of botulinum toxin type A, or normal saline . Patients were re-evaluated over a 4-month period by assessment of their pain and disability and pressure algometer readings, and then offered a second injection of 100 units of botulinum toxin type A . RESULTS: All three groups showed significant treatment effects as measured by a decline in the scores on the Neck Pain and Disability Visual Analogue Scale and an increase in the pressure algometer scores . Group differences were apparent only when the authors considered the number of patients who were asymptomatic as a result of the injections . CONCLUSIONS: Although no statistically significant benefit of botulinum toxin type A over placebo was demonstrated in this study, the high incidence of patients who were asymptomatic after a second injection suggests that further research is needed to determine whether higher dosages and sequential injections in a larger cohort might show a botulinum toxin type A effect. J Neurosci, 1998 Aug 15, 18(16), 6103 - 12 Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A; Beckman ML et al.; Syntaxin 1A inhibits GABA uptake of an endogenous GABA transporter in neuronal cultures from rat hippocampus and in reconstitution systems expressing the cloned rat brain GABA transporter GAT1 . Evidence of interactions between syntaxin 1A and GAT1 comes from three experimental approaches: botulinum toxin cleavage of syntaxin 1A, syntaxin 1A antisense treatments, and coimmunoprecipitation of a complex containing GAT1 and syntaxin 1A . Protein kinase C (PKC), shown previously to modulate GABA transporter function, exerts its modulatory effects by regulating the availability of syntaxin 1A to interact with the transporter, and a transporter mutant that fails to interact with syntaxin 1A is not regulated by PKC . These results suggest a new target for regulation by syntaxin 1A and a novel mechanism for controlling the machinery involved in both neurotransmitter release and reuptake. Protein Expr Purif, 1998 Aug, 13(3), 357 - 65 Production and purification of the heavy-chain fragment C of botulinum neurotoxin, serotype B, expressed in the methylotrophic yeast Pichia pastoris; Potter KJ et al.; A recombinant Hc fragment of botulinum neurotoxin, serotype B (rBoNTB(Hc)), has been successfully expressed in a Mut+ strain of the methylotrophic yeast Pichia pastoris for use as an antigen in a proposed human vaccine . The fermentation process consisted of batch phase on glycerol, followed by glycerol and methanol fed-batch phases yielding a final cell mass of 60 g/L (dcw) and was easily scaled-up to 60 L . A multistep ion-exchange chromatographic purification process was employed to produce 99% pure Hc fragment . The final yield of the purified antigen was 390 mg per kilogram of wet cell mass . The purified Hc fragment of serotype B was stable, elicited an immune response in mice, and protected upon challenge with native botulin . J Nat Toxins, 1998 Feb, 7(1), 95 - 9 Comparative evaluation of mechanism of neuromuscular (n-m) blockade due to enhydrotoxin-A (EsNTx-a) and D-tubocurarine (d-TC); Gawade SP; Effects of major E . schistosa neurotoxin (NTx) EsNTx-a are compared with plant alkaloid d-TC for its onset (LP) and duration of action as the time required for 50% n-m blockade (DT1/2) in normal Ca2+ and modified Ca2+ Krebs Heinsleit (K-H) at two different (low and high) concentrations (conc.) . Toxin-EsNTx-a in low Ca2+ K-H and d-TC in both normal and modified Ca2+ K-H did not show LP, whereas LP is increased significantly in 2 Ca2+ K-H in high conc . of EsNTx-a . DT1/2 is increased significantly in high conc . of EsNTx-a and in low conc . of d-TC in 2 Ca2+ K-H . N-m blocking actions are further compared with alpha-bungarotoxin (alpha-BuTx), beta-bungarotoxin (beta-BuTx), and botulinum toxin (B-Tx) for their effects on tetanus, Wednesky inhibition (W.I.), and post tetanic potentiation (PTP). Pediatr Rehabil, 1997 Oct-Dec, 1(4), 235 - 7 Treatment of cerebral palsy with botulinum toxin A: functional benefit and reduction of disability . Three case reports; Mall V et al.; Three patients with cerebral palsy are described suffering, respectively, of pes equinus, spasm of the m . teres major and flexion spasm of the hand, who were treated with botulinum toxin A . These patients demonstrate not only the local reduction of the muscular hyperactivity following treatment with botulinum toxin A but also the potential functional benefit resulting from such a treatment . Thus, local intramuscular injection of botulinum toxin A in children with cerebral palsy should be considered as part of a multidisciplinary treatment concept, since reduction of the disability and the functional improvements could have high impact on daily living activities. Mov Disord, 1998 Jul, 13(4), 706 - 12 Treatment of cervical dystonia: a comparison of measures for outcome assessment; Lindeboom R et al.; There is little agreement on which outcome measures to use to express the efficacy of treatments for cervical dystonia . We analyzed change scores on various scales of 64 new patients with cervical dystonia before and after repeated injections with botulinum toxin . METHOD: The association between change in impairment (Tsui), and change in pain (TWSTRS-Pain) and functional health (TWSTRS-D, MOS-20) was expressed in percentages of variance explained . Effect sizes of the outcome measures from patients who continued botulinum treatment and dropouts were compared . Performance of outcome measures to distinguish patients who continued treatment and dropouts was analyzed with ROC curves and areas under the curve (AUC) . Results: Impairments explained < or =7% of the score variance in functional health . There were no differences between the effect sizes of impairment and pain of patients who continued treatment and dropouts (p > 0.60) . This suggests a poor reflection of the treatment efficacy by these outcome measures . Conversely, there were significant differences between the effect sizes of the functional status scales of the patients who continued treatment and the dropouts (p < or = 0.01) . ROC curve analysis showed that the disability, handicap, and global disease burden scale accurately distinguished between the two groups (AUCs > 0.80) . Impairments showed no discriminative accuracy (AUC = 0.46) . CONCLUSION: Neurologic impairments have a small impact on the functional health of cervical dystonia patients . Disability, handicap, and a global measure of disease burden were the most suitable outcome parameters to express the clinical efficacy of botulinum therapy. Eye, 1998, 12 ( Pt 2), 219 - 23 A clinical algorithm for the management of facial nerve palsy from an oculoplastic perspective; Sadiq SA et al.; BACKGROUND/AIMS: Facial nerve palsy can be a sight-threatening complication . We have developed a flow diagram to aid in the management of these patients so that corneal complications may be avoided . This involves the recognition of a facial palsy and institution of treatment as guided by the flow chart . METHOD: Fifty-six patients suffered a facial nerve palsy following acoustic neuroma surgery . All received regular topical ocular lubrication, followed by either botulinum toxin A (BTXA)-induced ptosis (if corneal exposure developed despite conservative treatment) or definitive eyelid surgery . RESULTS: Twenty-one patients required regular lubrication only . Of these patients treated for corneal exposure, 20 received BTXA with good resulting corneal cover . Unfortunately, 9 of these suffered diplopia, although in 4 this resolved quickly . Twenty-four patients underwent a total of 64 eyelid procedures including levator recession, lateral tarsorraphy, lateral canthal sling, medical canthoplasty and gold weight insertion . All patients had good corneal cover post-operatively and were cosmetically improved . Of the 56 patients with a facial nerve palsy, 7 presented with a corneal epithelial defect or an infected corneal ulcer . These all responded to treatment with BTXA, topical antibiotics and/or lubrication, and eyelid surgery . CONCLUSIONS: Post-operative facial palsy may result in a significant ophthalmic workload . Although a proportion of patients with a facial nerve palsy manage well with regular lubrication, additional help with eyelid closure, either in the way of BTXA-induced ptosis in the short term or definitive eyelid surgery in the long term, is often required . Eyelid surgery seems to be the mainstay of treatment, for both function and cosmesis, with many patients requiring a combination of procedures. J Med Assoc Thai, 1998 Jun, 81(6), 413 - 22 Botulinum treatment for post-stroke spasticity: low dose regime; Viriyavejakul A et al.; The purpose of this study was to investigate the effects of botulinum A toxin for the treatment of post-stroke spasticity patients . Twenty two post-stroke spasticity patients were recruited in the study . All patients had moderate to severe spasticity of upper and lower extremities . Botulinum toxin was injected intramuscularly according to the spasticity pattern . Injections were performed at either 2, 3, or 6 month intervals as determined by the neurologist . The total dose of each session of injection varied between 50-100 IU . Subjective and objective examinations were conducted by the physiotherapist prior to the first injection and subsequently at 1st week, 2nd week and every month after each injection . All patients were asked subjectively about their satisfaction with the treatment . The objective examinations used in this study were Ashworth scale and Fugl-Meyer Sensorimotor Assessment Form . All patients were satisfied with the treatment . Marked reduction of the spasticity was found after one to two weeks of injection . The duration of effectiveness of botulinum toxin for spasticity is from 3-6 months . The average improvement in Ashworth score was between 1 and 1.5 points . The Fugl-Meyer scores showed significant improvement in most patients for the motor function of upper and lower extremities, and balance . All patients demonstrated increase in passive range of joint motion and decrease in joint pain . This study demonstrates that botulinum toxin therapy is safe and effective in treating chronic upper and lower extremities' spasticity following stroke . The dosage used in this study is about one-half of the recommended dosage in the literature . The only drawback of this therapy is its high cost (300 US dollars for 100 I.U.). Drug Saf, 1998 Jul, 19(1), 57 - 72 Managing antipsychotic-induced acute and tardive dystonia; Raja M; Antipsychotic-induced extrapyramidal adverse effects continue to be a serious problem in the treatment of psychotic disorders . While the pathophysiology of these adverse effects is not well understood, much recent research has focused on improving our ability to use available pharmacotherapy in the most effective and least toxic manner . Acute dystonic reactions only occur within the first days of antipsychotic treatment . They are often distressing and frightening for the patient and may even be dangerous . However, they can be effectively prevented or reversed with anticholinergics . Furthermore, the growing use of the new atypical antipsychotics will lead to a significant decrease in the rate of acute dystonic reactions . In contrast, tardive dystonia is a long-lasting menace in the course of antipsychotic treatment, for which there is no established therapy . Tardive dystonia is sometimes disabling or disfiguring and, like other tardive disorders, is potentially irreversible . Because, in most cases, patients need to continue taking the antipsychotic that has caused the adverse effect to prevent relapse of the mental illness, preventive measures are crucial . Antipsychotics should be prescribed only for patients affected by psychotic disorders, when definitely indicated and at the lowest effective dosage . The use of clozapine and other novel antipsychotic agents is also likely to represent an important step in the prevention and treatment of tardive dystonia . Compared with traditional antipsychotics, most of the new antipsychotics are characterised by a low acute extrapyramidal adverse effects liability and they also bring the hope of reducing the risk of tardive disorders . If tardive dystonia has occurred, switching to clozapine or another atypical antipsychotic and treatment with tetrabenazine, reserpine and botulinum toxin are possible options. EMBO J, 1998 Jul 15, 17(14), 3909 - 20 Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+; Davletov BA et al.; alpha-Latrotoxin (LTX) stimulates massive neurotransmitter release by two mechanisms: Ca2+-dependent and -independent . Our studies on norepinephrine secretion from nerve terminals now reveal the different molecular basis of these two actions . The Ca2+-dependent LTX-evoked vesicle exocytosis (abolished by botulinum neurotoxins) is 10-fold more sensitive to external Ca2+ than secretion triggered by depolarization or A23187; it does not, however, depend on the cation entry into terminals but requires intracellular Ca2+ and is blocked by drugs depleting Ca2+ stores and by inhibitors of phospholipase C (PLC) . These data, together with binding studies, prove that latrophilin, which is linked to G proteins and inositol polyphosphate production, is the major functional LTX receptor . The Ca2+-independent LTX-stimulated release is not inhibited by botulinum neurotoxins or drugs interfering with Ca2+ metabolism and occurs via pores in the presynaptic membrane, large enough to allow efflux of neurotransmitters and other small molecules from the cytoplasm . Our results unite previously contradictory data about the toxin's effects and suggest that LTX-stimulated exocytosis depends upon the co-operative action of external and intracellular Ca2+ involving G proteins and PLC, whereas the Ca2+-independent release is largely non-vesicular. J Neurol Neurosurg Psychiatry, 1998 Jul, 65(1), 111 - 4 Botulinum toxin treatment of synkinesia and hyperlacrimation after facial palsy; Boroojerdi B et al.; OBJECTIVES: To investigate the effects of injection of botulinum toxin type A (BTX A) into the orbicularis oculi muscle and lacrimal gland in patients with aberrant regeneration after facial palsy (facial synkinesias and hyperlacrimation) . METHODS: The effect of the toxin injection (on average 75 mouse units of BTX A) into the orbicularis oculi muscle on facial synkinesias was assessed on a five point (0 to 4) scale in 10 patients with aberrant regeneration of facial nerve fibres after a peripheral facial nerve palsy . Six patients underwent a videographic control, which was assessed by a blinded independent investigator . In two patients with hyperlacrimation an extra dose of botulinum toxin (on average 20 mouse units BTX A) was injected into the lacrimal gland and the effect was assessed using the Schirmer test and on a three point scale . RESULTS: Botulinum toxin type A had a good to excellent (grades 3 and 4) effect over an average of six months after 91% of injections . In 9% the injections had a moderate (grade 2) effect . Patients with hyperlacrimation showed a nearly complete recovery . There were no systemic side effects but focal side effects due to a temporary weakness of the orbicularis oculi muscle were not uncommon . CONCLUSIONS: Botulinum toxin type A is the treatment of choice in motor and autonomic effects of aberrant regeneration of facial nerve after a peripheral palsy . The required dose is similar to or slightly lower than the dose usually recommended for hemifacial spasm. Brain Res, 1998 Jun 29, 797(2), 357 - 60 Incorporation of synaptotagmin II to the axolemma of botulinum type-A poisoned mouse motor endings during enhanced quantal acetylcholine release; Angaut-Petit D et al.; The involvement of terminal sprouts in neurotransmitter release by in vivo botulinum type-A toxin poisoned motor endings was investigated 15 to 40 days after a single injection of the toxin onto the levator auris longus muscle of the mouse . Enhanced quantal acetylcholine release was induced by alpha-latrotoxin or La3+ in conditions that prevent endocytosis, and an antibody directed against the lumenal domain of synaptotagmin II (Syt II) was used in the presence or absence of Triton X-100 . We showed that, under resting conditions, the intravesicular domain of Syt II requires Triton X-100 to be labelled, whereas it becomes exposed to the outside of the axolemma of both the original terminal arborization and the newly formed sprouts during enhanced exocytosis . These data were taken to indicate that, when sprouting is prominent, the whole modified terminal arborization, including the original branches and the sprouts, possesses the machinery for Ca2+-independent exocytosis . Laryngoscope, 1998 Jul, 108(7), 1055 - 61 Increased acute and chronic mitotic activity in rat laryngeal muscles after botulinum toxin injection; Inagi K et al.; OBJECTIVES: To characterize the acute and chronic cellular effects of botulinum toxin (BT) injection into rat laryngeal muscles . A complete characterization of these effects is important because patients with focal dystonias of the head and neck are commonly treated with BT injection . Further, potential muscular changes in the larynx must be carefully delineated owing to the critical phonatory and airway protective functions of these muscles . STUDY DESIGN: The acute and chronic cellular effects of BT injection were studied using 5'-bromo 2'-deoxyuridine (BrdU) following single and repeated BT injection into rat laryngeal muscles . BrdU is incorporated into mitotically active nuclei such that changes in cell proliferative behavior following BT injection can be monitored . RESULTS: Increased mitotic activity was detected in the tissue samples studied following BT injection . Differences in the times of the peak distribution of BrdU-labeled cells in each laryngeal muscle were observed . This may be related to the diffusion effects of BT . Prolonged muscle fiber changes, including splitting, were also observed as the result of repeated BT injection . CONCLUSIONS: The results of this study suggest that BT may induce a proliferative response in muscle tissue. Laryngoscope, 1998 Jul, 108(7), 1048 - 54 Physiologic assessment of botulinum toxin effects in the rat larynx; Inagi K et al.; OBJECTIVE: Botulinum toxin (BT) is a currently used treatment for spasmodic dysphonia (SD) and other related focal dystonias . The goal of this study is to provide a basis for using the rat larynx to objectively assess physiological and histological effects of BT . STUDY DESIGN: Dosages and volumes of BT injection were varied and three physiological parameters were measured . These measures included: optical density of PAS-stained laryngeal muscle after electrical stimulation, which is an indirect measure of denervation, spontaneous laryngeal muscle activity, and laryngeal movement . METHODS: A new microlaryngoscopic technique was developed, which made it possible to observe and manipulate the rat larynx endoscopically . Laryngeal movement and electromyographic (EMG) measures were made prior to injection and 3 days following BT injections of various dosages and volumes . Optical density measures were made 3 days after injection . RESULTS: Significant reductions in vocal fold motion and spontaneous laryngeal muscle activity as a function of increased BT dosage were observed . In addition, the optical density of PAS-stained laryngeal muscle after electrical stimulation was increased following BT injection . Significant volume effects in optical density were observed in the lateral thyroarytenoid and lateral cricoarytenoid muscles on the contralateral side . CONCLUSIONS: The rat laryngeal model is suitable for assessing BT effects . In addition, the three physiological variables provided useful and reliable measures of laryngeal function . It is the authors' intention to use the rat laryngeal model to further examine the physiological and histological effects of BT with the goal of developing new methods for the treatment of patients with SD and other focal dystonias. Headache, 1998 Jun, 38(6), 468 - 71 Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension; Wheeler AH; Pericranial muscle tension may contribute to the development of facial discomfort, chronic daily headache, and migraine-type headache . Elimination of pericranial muscle tension may reduce associated myalgia and counteract influences that can trigger secondary headaches which fall within the migraine continuum . Four patients with chronic, predominantly tension-type headaches and associated pericranial muscle tension failed prolonged conventional treatment and, therefore, symptomatic areas were treated with botulinum toxin A . This alleviated myalgia and reduced the severity and frequency of migraine-type headaches with a concomitant reduction in subsequent medical and physical therapy interventions . Judicious use of botulinum toxin A into defined areas of pericranial muscle tension may be useful for reducing primary myalgia and secondary headache. Zh Mikrobiol Epidemiol Immunobiol, 1998 Mar-Apr, (2), 22 - 6 {Coagglutination test . Its improvement and use in the production of anatoxins}; Speranskaia VN et al.; The reactor technology for obtaining suspensions of Staphylococcus aureus (strain Cowan 1) with active protein A was developed . On the basis of the sensitization of bacterial suspensions with antitoxic rabbit sera staphylococcal reagents to diphtherial, gas gangrene (perfringens, oedematiens), botulinic toxins-toxoids were obtained and for the first time the coagglutination test with toxoids was carried out . More sensitive "specifically directed" reagents for the coagglutination test were obtained; for this purpose bacterial suspensions were sensitized with pure antibodies isolated from rabbit immune sera by immunosorption . The possibility of using the coagglutination test with specifically directed staphylococcal reagents for the rapid evaluation of the dynamics of toxin formation in reactors for the titration of purified toxoids, for the control of the purification of toxoids by ultrafiltration, as well as for the evaluation of the sorption-desorption of toxoids in the production of the corresponding preparations, was shown. FEBS Lett, 1998 Jun 16, 429(3), 234 - 8 Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity; Adler M et al.; The novel inhibitor 7-N-phenylcarbamoylamino-4-chloro-3-propyloxyisocoumarin (ICD 1578) was tested for its ability to antagonize the zinc metalloprotease activity of botulinum toxin B (BoNT/B) . The efficacy of this compound was tested in a cell-free system using a 50-mer synaptobrevin peptide as substrate . The peptide, designated as {Pya88} S 39-88, had a fluorescent amino acid analog, L-pyrenylalanine (Pya), substituted for the normal Phe88 of synaptobrevin-2 . Cleavage by BoNT light chain yielded fragments of 38 and 11 amino acids, respectively . The smaller fragment, containing the Pya fluorophore, was readily separated and quantified by fluorescence spectroscopy at 377 nm . In the presence of 7-200 microM ICD 1578, cleavage of {Pya88} S 39-88 was progressively reduced (IC50 = 27.6 microM), and 100 microM ICD 1578 produced >95% inhibition . For comparison, captopril, a well-known zinc metalloprotease inhibitor, generated less than 10% inhibition at a concentration of 5 mM . ICD 1578 is the most potent antagonist of BoNT/B light chain thus far described. Mund Kiefer Gesichtschir, 1998 May, 2 Suppl 1, S125 - 9 {Botulinum toxin treatment of neurogenic dislocation of the temporomandibular joint}; Daelen B et al.; Botulinum toxin leads to paresis of the skeletal muscle lasting 2-4 months via an inhibition of acetylcholine release at the neuromuscular junction . Since 1995, botulinum toxin injections have been used in the treatment of recurrent dislocation of the temporomandibular joint (TMJ) . The chemical denervation of the external pterygoid muscle restricts the angle of mouth opening, thus helping to prevent dislocation . TMJ dislocations that occur as a result of increased tone in the protracted masticatory muscles were recently defined as neurogenic dislocations of the TMJ . We conducted a clinical study to investigate the efficacy of botulinum toxin injections into the external pterygoid muscle in five patients with recurrent neurogenic dislocations of the TMJ . In the 3 months prio