[Botulinum toxin type A (Incobotulinum toxin A) in spastic forms of cerebral palsy: a retrospective analysis of clinical experience]. / Botulinicheskii toksin tipa A (IncobotulinumtoxinA) pri spasticheskikh formakh detskogo tserebral'nogo paralicha: retrospektivnyi analiz klinicheskogo opyta.

OBJECTIVE: A retrospective analysis of the experience of using Incobotulinum toxin A injections for the treatment of spasticity in children with cerebral palsy (CP). MATERIAL AND METHODS: One hundred and eighty-five children with spastic forms of CP, including 114 boys (61,6%), were studied. The average age of the patients was 3,8±2,5 years; the average weight was 14,2±6,9. The patients received injections of Incobotulinum toxin A according to registered indications or recommendations of a consultation of specialists and voluntary informed consent of the patient's representative. At least 1 point decrease of muscle tone according to the modified Ashworth scale was used as a criterion of the antispastic effect of Incobotulinum toxin A. RESULTS: The total dose of Incobotulinum toxin A for the whole group of patients with CP was 154,5±67,7 U and 11,6±4,7 U per kg/body weight. The gracilis muscle (65,4% of cases, 95%CI 58,1-72,2) and the gastrocnemius muscle (49,4% of cases, 95%CI 41,8-56,6) were the most frequently injected targets in the lower extremities, and the pronator teres muscle (58,9% of cases, 95%CI 51,5-66,1) - in the upper extremities. Adverse events were observed in 13 patients (7,0%). They were mild in 9 patients and moderate in 4 patients. CONCLUSION: Our data confirmed the effectiveness and safety of Incobotulinum toxin A injections in spastic CP. The calculated average doses of Incobotulinum toxin A for target muscles and the frequency of different spasticity patterns could serve as a reference for the botulinum therapy planning.

[Changes of the spasticity patterns in children with cerebral palsy GMFCS III at the age of 2 to 12 years]. / Izmenenie patternov spastichnosti u detei s tserebral'nym paralichom s III urovnem dvigatel'nogo razvitiya po sisteme klassifikatsii bol'shikh motornykh funktsii (GMFCS III).

Spastic muscles in the pathological motor patterns may change at different ages that leads to the changes in anti-spastic treatment. OBJECTIVE: To study the specific patterns of spasticity in CP patients with level III according to the Gross Motor Function Classification System (GMFCS) in different age periods. MATERIAL AND METHODS: A retrospective analysis of injection protocols of Abobotulinum toxin A for 99 patients with bilateral spastic CP GMFCS III at the age of 2 to 12 years was performed. Spasticity patterns were evaluated according to the frequency of target muscle selection for the botulinum toxin A (Abobotulinum toxin A) injections. RESULTS: The equinus foot deformity (89.7%, 95%CI 72.8-97.2) and its combination with internal hip rotation (79.3%, 95% CI 61.3-90.5) and/or hip adduction (65.5%, 95% CI 47.3-80.2) were the main lower extremity spasticity pattern for the patients aged 2 to 4 years. Between 4 and 6 years, there was the decrease in injections to the gastrocnemius muscle (75%, 95% CI 52.8-89.2), and less to the m. gracilis (70%, 95% CI 47.9-85.7) and hip adductors (55% 95 CI 34.2-74.2). In the 6-12 year old patients, the predominant spasticity patterns were internal hip rotation (80%, 95% CI 66.8-88.9), adduction (54%, 95% CI 40.4-67.0) and knee flexion (66%, 95% CI 52.1-77.6). The leading upper extremity patterns at all observed ages were forearm pronation (70.7%, 95% CI 61.1-78.8) and elbow flexion (47.5%, 95% CI 37.9-57.2). The frequency of injections to these muscles slightly decreased in elder groups. CONCLUSIONS: CP GMFCS III patients demonstrate age-related changes of the spasticity patterns both in lower and upper extremities. These changes and typical spastic muscles should be taken into account during the rehabilitation and botulinum toxin treatment planning, as well as in the detection and prevention of the orthopaedic complications.

[Multilevel botulinum toxin treatment in severe spastic forms of cerebral palsy (GMFCS IV-V)]. / Mnogourovnevaya botulinoterapiya pri spasticheskikh formakh detskogo tserebral'nogo paralicha s tyazhelymi dvigatel'nymi narusheniyami (GMFCS IV­V).

OBJECTIVE: To evaluate the most typical target muscles and dosages for the first and repeated botulinum toxin A (BTA) injections in cerebral palsy (CP) patients with severe motor deficit - GMFCS IV-V. MATERIAL AND METHODS: A retrospective analysis of 677 protocols of the first and repeated Abobotulinumtoxin A (AboA) injections in 333 patients with CP GMFCS IV and V, aged 1 to 18 years, was carried out. RESULTS: Ninety-seven percent of patients received multilevel injections. In the lower extremities the most typical target muscles were: m.gracilis - 221 (66.4%) patients, hip adductors - 164 (49.2%), medial hamstring - 144 (43.2%). In the upper extremities the most typical muscles were: m.pronator teres - 237 (71.2%) patients, m.biceps brachii+m.brachialis - 197 (59.2%). The total dosages of AboA and dosages for every target muscle were calculated. Several patients required high dosages (more than 30 U/kg of AboA). Higher dosages per kg were used in younger children and for repeated injections. The age-related evolution of spastic patterns was described. Adverse events were observed in 36 cases (5.3% of all injections). CONCLUSION: The majority of patients with GMFCS IV-V required multilevel BTA injections in high dosages, especially in young age. Described selection of target muscles and dosages of AboA could be taken into account as a practical experience and reference for the BTA therapy in GMFCS IV-V patients.

[Priorities and Goals of Botulinum Toxin A Treatment in Cerebral Palsy]. / Vybor tselei i prioritetov botulinoterapii u patsientov s detskim tserebral'nym paralichom.

Botulinum toxin A (BTA) injections are an effective method of spasticity treatment in cerebral palsy (CP) but still there are a lot of questions about the selection of target muscles. The article summarizes currently accepted approaches to the goal setting and prioritizing in CP botulinum toxin therapy according to the form of CP, GMFCS level, age, spasticity level and other factors. The authors discuss the Goal Attainment Scale (GAS) and its possibilities in the BTA injections planning and evaluation of the results. Attention is also paid to the 'key muscle concept' in the multilevel spasticity treatment in CP and the additional factors that can influence the effectiveness of injections. The above approaches to the detection of patients' problems and setting of BTA treatment goals can help to prevent serious mistakes and disappointment in this effective method of treatment.

[Efficacy and safety of botulinum toxin type A (IncobotulinumtoxinA) in the treatment of patients with cerebral palsy]. / Éffektivnost' i bezopasnost' primeneniia botulinicheskogo toksina tipa A (IncobotulinumtoxinA) pri lechenii patsientov s detskim tserebral'nym paralichom.

AIM: To assess the safety and clinical and neurophysiological efficacy of xeomin in children with spastic equinus and equinovarus foot deformity in cerebral palsy. MATERIAL AND METHODS: Sixty-four patients with spastic forms of cerebral palsy (levels I-IV on the GMFCS) were enrolled into this multi-center open-label comparative randomized trial. The patients were administered xeomin or botox once, each drug being administered to 32 patients. Efficacy was evaluated based on clinical characteristics (the modified Ashworth scale, goniometry) and electromyography data. The subjects were observed for 3 months (90±7 days) after injections. The incidence, severity and intensity of adverse events (AE) was also determined. RESULTS: Treatment with xeomin according to the suggested protocol has proven its high clinical efficacy. The efficacy was demonstrated by significant, stable and long-term decrease in the gastrocnemius muscle tone: in the xeomin group, the score on the modified Ashworth scale decreased from 2.6±0.49 points at baseline to 1.8±0.54 points (р<0.000001, paired t-test; р<0.000004, Wilcoxon test). In the botox group, this score decreased from 2.4±0.56 points to 1.6±0.45 points (р<0.000001, paired t-test; р<0.000002, Wilcoxon test). The increased range of ankle joint movements at passive and voluntary feet extension. In the xeomin group, the significant proportion of patients (45.1%) moved to the group of lower spasticity defined as less than two score points on the modified Ashworth scale. The clinical data fully matched the changes in electromyography parameters, which were characterized by the lower amplitude and area of the target muscle (lateral and medial gastrocnemius heads) M-responses. AE developed in three patients (9.4%) administered xeomin and in two patients (6.3%) administered botox. The AE recorded in the study are described in the recommendations on the use of xeomin and botox. In three cases (50.0%), AE intensity was determined as mild, in the remaining three cases (50.0%) as moderate. CONCLUSION: The results have shown the safety and efficacy of xeomin in the treatment of gastrocnemius spasticity in pediatric patients with cerebral palsy. These data are confirmed by the lack of significant differences in any clinical or electromyography parameters with the results in the reference group administered botox.

[Treatment of spasticity after traumatic brain injury in children: the role of botulinum toxin therapy]. / Korrektsiia spastichnosti posle cherepno-mozgovykh travm u detei: mesto botulinoterapii.

Traumatic brain injury (TBI) is one of the main reasons of death and disability in children and adolescents in Russia and abroad. Spasticity is a frequent outcome of the TBI that influences on the rehabilitation prognosis, degree of movement disorders and quality of life after trauma. Early spasticity correction and complex rehabilitation lead to the optimal recovery and prevent secondary complications. This review presents the current data about the prognostic role of the spasticity in children after TBI, methods of its correction and their scientific evidence. Limitations and challenges of per-oral antispastic agents are described especially for the patients with local spasticity. Attention is focused on the methods of treatment of local hypertonus, in particular botulinum toxin A (BTA) injections proved to be effective in adults with acquired brain injury. The article summarizes the results of international investigations, systematic reviews and consensus statements about the efficacy and safety of botulinum toxin treatment in children after the TBI. The authors describe an algorithm of the optimal patient selection and goal setting for BTA injections in children with acquired brain injury.

[The First Russian Consensus on the Multilevel Abobotulinumtoxin A Injections in Spastic Forms of Cerebral Palsy]. / Pervyi Rossiiskii konsensus po primeneniyu mnogourovnevykh in''ektsii abobotulinumtoxin A pri lechenii spasticheskikh form detskogo tserebral'nogo paralicha.

Spasticity treatment is one of the key aspects of the contemporary cerebral palsy (CP) rehabilitation that influences on the effectiveness of other methods. The paper presents the first Russian document that unites the recommendations for the BTA treatment of CP and could be used as the guideline for the multilevel injections. The Russian consensus on the multilevel botulinum toxin A (BTA) treatment of spastic CP is based on the international data and the results of national studies. The authors describe typical CP spasticity patterns in the upper and lower extremities, give recommended intervals for the BTA (Abobotulinum toxin A) dosages for the whole injection procedure and for the separate muscles. The method of dosage calculation for functional segments is also described. Attention is paid to the frequency, optimal intervals between the repeated injections and the whole duration of BTA treatment. The authors discuss effectiveness and safety of BTA, factors that potentially influence the results of the injections, including ultrasound and electromyography control, and indications for the continuation and termination of treatment.

[Selection of a dose of the botulinum toxin A in spastic forms of cerebral palsy]. / Vybor dozy preparata botulinicheskogo toksina tipa A pri lechenii spasticheskikh form detskogo tserebral'nogo paralicha.

AIM: To analyze the efficacy and safety of dose ranges of abobotulinum toxin A (BTA) for multilevel injections into upper and lower extremity muscles in children with spastic forms of cerebral palsy (CP). MATERIAL AND METHODS: We analyzed retrospectively multilevel BTA injections for 216 patients, aged from 2 to 17 years. Children received 1-6 repeated injections and complex physiotherapy. Patients were classified according to the GMFCS. Treatment results were evaluated with the modified Ashworth and Tardieu scales. RESULTS: Multilevel BTA injections were indicated for the most (89/8%) of the patients with spastic forms of CP, and in most of them the total dosage exceeded 30 U/kg. In the bilateral forms of CP, the total dosage (U and U/kg) was higher compared to the unilateral forms. Doses for each muscle in U/kg were similar in all CP forms. The total doses of BTA and the intervals between the repeated injections were stable for each patient. CONCLUSION: The dose ranges suggested for CP are effective and safe for the reduction of spasticity in several functional segments of upper and lower extremities in one treatment session.

[Clinical experience of the repeated multilevel injections of the botulinum toxin type A (abobotulinum toxin A) in the spastic forms of cerebral palsy].

OBJECTIVE: Our aim was to analyze the dosages of Abobotulinum toxin A used for each muscle in the clinically effective and safe repeated multilevel injections in CP children, and the intervals between injections. METHODS: Retrospective analysis of 229 injection sessions into 359 muscles of the upper and 361 muscles of the lower extremities in 133 children (2-18 years) with spastic CP. Analysis included only patients who were injected for the first time and demonstrated decrease of spasticity in injected muscles according to modified Ashworth and/or Tardieu scales without significant side effects 2-4 weeks after injections. Motor deficit according to GMFCS was: GMFCS I--16(12%) children, GMFCS II--26 (19.6%), GMFCS III--43 (32.3%), GMFCS IV--30 (22.6%), GMFCS V--18 (13.5%). Repeated injections (up to 5 sessions) were done in 59 children. Maximum follow-up perion was 22 months. 40 patients (30.1%) had one-sided injections, 93 (69.9%)--two-sided, 125 (94%)--multilevel injections. RESULTS: We presented minimal and maximal dosages, interquartile ranges for each injected muscle, also "off-label" and our proposition of per-segment calculation of dosages in multilevel injections in CR. We also demonstrated the stability of intervals between repeated injections and dosages per kg in a patient. These results are compared with the official Russian and international recommendations of BTX-A treatment for children. CONCLUSION: We presented our experience of BTX-A dosages calculation for the spastic CP treatment which could be used as a recommendation and guide for the multilevel injections treatment according to the aims of rehabilitation, spasticity level, muscle size and motor deficit of a concrete patient.

[Assessment of motor and sensory pathways of the brain using diffusion-tensor tractography in children with cerebral palsy].

BACKGROUND: Diffusion tensor tractography--a new method of magnetic resonance imaging, that allows to visualize the pathways of the brain and to study their structural-functional state. OBJECTIVE: The authors investigated the changes in motor and sensory pathways of brain in children with cerebral palsy using routine magnetic resonance imaging and diffusion-tensor tractography. METHODS: The main group consisted of 26 patients with various forms of cerebral palsy and the comparison group was 25 people with normal psychomotor development (aged 2 to 6 years) and MR-picture of the brain. Magnetic resonance imaging was performed on the scanner with the induction of a magnetic field of 1,5 Tesla. Coefficients of fractional anisotropy and average diffusion coefficient estimated in regions of the brain containing the motor and sensory pathways: precentral gyrus, posterior limb of the internal capsule, thalamus, posterior thalamic radiation and corpus callosum. RESULTS: Statistically significant differences (p < 0.05) values of fractional anisotropy and average diffusion coefficient in patients with cerebral palsy in relation to the comparison group. All investigated regions, the coefficients of fractional anisotropy in children with cerebral palsy were significantly lower, and the average diffusion coefficient, respectively, higher. CONCLUSION: These changes indicate a lower degree of ordering of the white matter tracts associated with damage and subsequent development of gliosis of varying severity in children with cerebral palsy. It is shown that microstructural damage localized in both motor and sensory tracts that plays a leading role in the development of the clinical picture of cerebral palsy.

[An electromyographic study on the development of optimal tactics of botulinum toxin type A injections in children with spastic forms of cerebral palsy].

We studied 67 children, aged 2-9 years, with cerebral palsy including 56 children with a spastic form. An electromyographic method was used for the development of optimal tactics of botulinum toxin type A injections in different clinical presentations of spasticity. The best clinical results were obtained in children with the following changes on EMG: 1) the tonic muscle activity in resting state was minimal (<10 microvolts) and had local or regional distribution; 2) the pathological synkinetic activity during voluntary movements was minimal (synergetic activity coefficient for shin muscles was less than 0.45); 3) the disturbance of interactions between synergistic and antagonistic muscles was moderate (reciprocity coefficient was not less than 0.4); 4) EMG amplitude in voluntary muscle contraction should not be less than 150 microvolts. This approach to the treatment allowed to reach higher levels on The Gross Motor Function Classification System in part of children.

[Development of motor functions and manual abilities in pediatric patients with spastic cerebral palsy after botulinum toxin treatment and complex rehabilitation].

AIM: To investigate the dynamic of general motor function and manual abilities in children with spastic forms of cerebral palsy (CP) after complex rehabilitation combined with single and repeated injections of botulinum toxin A (BTA). PATIENTS AND METHODS: The article presents 18 month followup of 52 patients with mono- and bilateral spastic forms of CP after single and multiple injections of botulinum toxin A and complex rehabilitation/ Patients received totally 74 injection sessions: 17 (32.7%) children--twice, 5 (9.6%) children--three times. Motor development assessment was done according to the GMFCS and GMFMS-88 scales and centile curves of normal motor development connected with these scales, hand function was classified according to the MACS scale. For the first time results of botulinum toxin therapy and rehabilitation were compared with the natural motor development of patients with different levels of motor disturbances according to centile tables. RESULTS: Patients with bilateral cerebral palsy improved slowly than hemiparetic and changes lasted for longer period. Level according to the MACS scale didn't depend on the gestational age of the patients, was higher in children with hemiparesis and changed for 1 level in 4 (7.7%) patients after the first botulinum toxin A injections.

[Determinants of resistance to chlortetracycline and other antibiotics in chlortetracycline-producing strain of Streptomyces aureofaciens]. / Determinanty ustoichivosti k khlortetratsiklinu i drugim antibiotikam u shtamma Streptomyces aureofaciens--produtsenta khlortetratsiklina.

Data are presented on resistance of Streptomyces aureofaciens strain TB-633 FU--the producer of chlortetracycline (CTC) to autogenous antibiotics and a number of other antibiotics. It is demonstrated that resistance to CTC is specified by ctr genes of constitutive expression as well as by inducible genes. CTC and ethidium bromide may serve as efficient inductors of inducible ctr genes. The induction process is accompanied by increase in antibiotic biosynthesis level. Genes responsible for strain resistance to a number of macrolide antibiotics and thiostrepton are inducible and only function in the presence of appropriate antibiotics in the medium. The action of inducible mtr gene(s) is described in detail. The gene(s) simultaneously ensure increase in resistance to CTC and a number of macrolide antibiotics in the presence of exogenous inductors in media, such as both CTC and macrolide antibiotics. Mutants have been isolated which provide constitutive level of resistance to these antibiotics. A series of ctr and mtr mutants have increased CTC biosynthesis as compared to the initial level. Data on comparative analysis of the results obtained from hybridization of fragments of S. aureofaciens and S. rimosus DNAs to actI and actIII genes, responsible for polyketide synthases' synthesis, demonstrate that genes for CTC and OTC biosynthesis are situated on DNA fragments of similar size. This determines the strategy for cloning ctr and mtr genes as well as genes for CTC biosynthesis from S. aureofaciens.

[Physical mapping of Streptomyces coelicolor A3(2) actinophages. VII. Formation of deletions in the region of phi C43 insertion sequence]. / Fizicheskoe kartirovanie akinofagov Streptomyces coelicolor A3(2). VII. Obrazovanie deletsii v oblasti vstavochnoi posledovatel'nosti faga phi C43.

The correlation between the plaque morphology and the presence of the insertion sequence at the phage genomes have been found for different variants of phi C43, obtained by spontaneous induction of strain S. lividans 803. Phages carrying complete insertion have Tum phenotype and they are represented in 4% of induced lysate. Phages carrying the part of insertion have Tu phenotype, their portion in induced lysate is about 26%. Phages without insertion have Stu phenotype and they are the majority of the lysate (70%). All variants phi C43, except wild-type phage, have lost the fragment of phage genome. Phage phi C43ins1, carrying the complete insertion give rise spontaneously at the frequency 10(-2) to deletion derivatives. Heteroduplex experiments show that in the deletion derivatives phi C43ins1 also in the Stu and Tu variants phi C43 one of the termini of the deletions is located within the insertion or at its end. Considerable portion of deletion variants in induced lysate phi C43 also the formation of deletion derivatives phi C43ins1 with high frequency strongly suggest that insertion sequence generates deletions similar to IS of Tn elements.

[Physical mapping of actinophage Streptomyces coelicolor A3(2). VI. The use of deletion mutants of actinophage phi C31 for construction of phage vectors]. / Fizicheskoe kartirovanie aktinofagov Streptomyces coelicolor A3(2). VI. Ispol'zovanie deletsionnykh mutantov aktinofaga phi C31 dlia konstruirovaniia fagovogo vektora.

Nonessential region responsible for G function has been identified in theta C31 phage genome by means of deletion mutants. The mutant phenotype is expressed upon theta C31 phage propagation in Streptomyces albus G strains differing in functioning of restriction and modification systems. Based on their increased resistance to EDTA, deletions were located in theta C31 delta 10 and theta C31 delta 65 phage mutants. Data are presented on physical mapping of nonessention region of theta C31 phage. The total length of this region is 24.1% of the overall length of DNA molecules. The DNA segment of 19.1% of the whole genome contains overlapped deletions. Theta C31 actinophage is proposed to be used as a cloning vector for Streptomyces. Various deletion mutants obtained, with the capacity of about 3 thousands base pairs may serve as "insertion vectors". The presence of the stretched nonessential genome region allows to use theta C31 phage as a "replacement vector". Then, insertion of foreign DNA to replace the EcoRI--C fragment of theta C31 DNA of 6.4 x 10(3) base pairs is possible. The phages comprising hybrid molecules may be selected for G and Lyg phenotypes.