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Impact of early intervention with onabotulinumtoxinA treatment in adult patients with post-stroke lower limb spasticity
14
Abstracts / Basal Ganglia 8 (2017) 1–22
skin surface by the injected fluid volume was measured every 30 s with the optical 3D sensor. The temperature change of the same region could be recorded as a continuous film with thermal information. The influence of the volume on the subdermal distribution could be estimated by different dilution ratios and thus, alternating injection volumes (0.02 ml and 0.04 ml) with a constant dose of active substance: only individual subjects were compared to exclude interindividual differences in the skin. The injections of 0.04 ml of aqueous solution (n = 11) cooled the skin 5 s after injection by an average of 5.78 ◦ C and the diameter of this cooled area was an average of 5.89 mm. On injection of 0.02 ml of aqueous solution, the skin temperature dropped 5 seconds after the injection only by 3.5 ◦ C (p < 0.00) and the diameter of this cooled area was significantly smaller with 4.71 mm in average (p = 0.03). Results/discussion: The combination of these optical methods makes it possible for the first time to directly observe the subdermal spread of botulinum toxin solution in real time and thus, to check the influence of injection techniques and dilutions on the distribution and hence, on the area of pharmacological effect. Further clinical trials are necessary to systematically examine these factors. http://dx.doi.org/10.1016/j.baga.2017.02.040 Entropion senile – 25 years of experience with botulinum toxin (BoNT) therapy, including a very dramatic case Andrea Stenner ∗ , Gerhard Reichel Paracelsusklinik KZB, Zwickau, Germany Introduction: Entropion is a malposition of the eyelid, most commonly the lower one. The lid is turned inwards, with eyelashes touching the cornea. This will cause pain, the sensation of a foreign body in the eye, and inflammation, resulting in permanent reflexive closing of the eye, i.e. functional blindness. Treatment of Entropion with BoNT has already been recommended since the nineteen eighties. Methods: We started treating Entropion with BoNT in 1992, and have treated 24 patients with single or multiple BoNT dosages so far (62–90 years). Effects could be noticed after 2–6 days. 12 patients needed another injection after 3 to 6 months, 25 percent of them after about one year, and in 6 patients no relapse occurred. Repetitive injections were more effective than just the first injection. Before her first treatment with BoNT, one patient had had 4 surgeries at her lower eyelid; the scar from these operations was causing pressure at her cornea, resulting in problems which finally lead to reflexive eye closing. Results/discussion: In one case (a 90-year old woman), an undetected Entropion senile in both eyes resulted in persistent eye closing for more than 3 years, causing functional blindness. She was forced to use a wheelchair to reduce the risk of falling. Entropion senile was first diagnosed when the patient, who had no signs of brain dysfunction, was referred to us for the treatment of an additional hemifacial spasm. Treatment with BoNT at 4 orbital points around her left eye and one on both her lower eyelids had the following results in only 4 days: Her hemifacial spasm was interrupted, she was able to open and close both her eyes without problems, so she did not need her wheelchair any longer. She still receives BoNT treatment for her hemifacial spasm every 4 months. Conclusion: In summary, we are suggesting BoNT treatment of Entropion senile as gold standard technique. http://dx.doi.org/10.1016/j.baga.2017.02.041
Justinus Kerner and the “sausage poison” Steffen Häfner CELENUS DEKIMED, Bad Elster, Germany Introduction: The 19th century German romantic poet and medical officer Justinus Kerner (1786–1862) provided the first detailed clinical description of botulism and its associations with faulty sausage production. Method: A literature research was done on the terms “Justinus Kerner” and “botulism”. Results: Kerner collected data on 230 cases of botulism and published two important monographs in 1820 and 1822. He gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and physical findings – 70 years before this was identified being caused by anaerobic microbes. He drank an extract of the faulty sausage poison to study the symptoms in a very dangerous self-experiment. Thereby he could describe that it was sour and could produce early stages of the “sausage poisoning”. For the treatment of this disease he described the use of a gastric tube, 50 years before such experiments were recorded officially. Beyond of that he applied an extracorporal “pacemaker” – 100 years before this was introduced into clinical medicine. Finally, Kerner suggested the potential therapeutic use of botulinum toxin to block abnormal motor movements, such as chorea, and speculated on its use in other disorders with hypersecretion, for example. Discussion: Kerner’s first description of “botulismus” is a highlight of pure natural science, of exact diagnosis and innovative therapy, already anticipating the modern indications for botulinum toxin in an excellent way. http://dx.doi.org/10.1016/j.baga.2017.02.042 Impact of early intervention with onabotulinumtoxinA treatment in adult patients with post-stroke lower limb spasticity Wolfgang H. Jost ∗ , Atul T. Patel, Anthony B. Ward, Carolyn Geis, Liu Chengcheng, Rozalina Dimitrova Parkinson-Klinik Ortenau, Wolfach, Germany Introduction: This analysis aims to evaluate the impact of timing of treatment initiation since stroke on the efficacy of onabotulinumtoxinA in post-stroke lower limb spasticity (PSLLS). Methods: This multicenter, phase 3, placebo-controlled study was undertaken across 60 global centers, enrolling patients with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors. During the 12-week double-blind phase, patients were randomized to receive onabotulinumtoxinA (300U, mandatory muscles [gastrocnemius, soleus, tibialis posterior]; and ≤100U, optional lower limb muscles [flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, extensor hallucis, rectus femoris]) or placebo. The primary endpoint was a change from baseline in MAS average score of weeks 4 and 6. Secondary endpoints included physician-assessed CGI Change average score of weeks 4 and 6 and physician-assessed Goal Attainment Scale (GAS; active and passive at weeks 8 and 12). Results/discussion: In the intent-to-treat population, (onabotulinumtoxinA, n = 233; placebo, n = 235), significant improvements vs. placebo were observed in MAS (−0.81 vs. −0.61; P = 0.01), CGI (0.86 vs. 0.65; P = 0.01), and passive GAS scores (week 12, −0.6 vs. −0.9; P = 0.044). When stratified by time of treatment initiation post-stroke (<24 months, n = 153; >24 months, n = 315, posthoc), patients who were treated ≤24 months since stroke experienced greater improvements (mean difference) in MAS (−0.31 vs. −0.17), CGI (0.49 vs. 0.12), and passive GAS scores (week 12, 0.37 vs. 0.26).
Abstracts / Basal Ganglia 8 (2017) 1–22
Among patients ≤24 months since stroke, a greater proportion achieved ≥1 point improvement in active (week 12; P = 0.039) and passive (week 8; P = 0.023) GAS scores vs. placebo. OnabotulinumtoxinA 300–400 U was well tolerated with no new safety findings. Conclusions: OnabotulinumtoxinA 300-400U is effective in improving MAS, CGI, and GAS scores in patients with PSLLS with greater benefits among those initiating treatment ≤24 months post-stroke.
Duration of effect of abobotulinumtoxinA ® (Dysport ) in adult patients with upper limb spasticity (ULS) post-stroke or traumatic brain injury
http://dx.doi.org/10.1016/j.baga.2017.02.043
Ipsen, Les Ulis, France
The Adult Spasticity International Registry (ASPIRE) study: 1 year results Wolfgang H. Jost ∗ , Gerard E. Francisco, Daniel S. Bandari, Ganesh Bavikatte, Aubrey Manack Adams, Joan Largent, Alberto Esquenazi Parkinson-Klinik Ortenau, Wolfach, Germany Objective: To examine the 1-year interim onabotulinumtoxinA safety, effectiveness, and exploratory treatment utilization data from the ASPIRE study. Background: OnabotulinumtoxinA treatment for patients with spasticity is individualized, variable, and dependent on numerous factors. Findings from ASPIRE will help guide onabotulinumtoxinA treatment strategies in patients with spasticity and optimize outcomes. Methods: This is a multicenter, prospective, observational study across 54 international sites (NCT01930786) examining adult patients with spasticity treated with onabotulinumtoxinA at the discretion of the treating physician. Follow-up assessments include utilization patterns, patient and physician satisfaction, taken at each treatment visit, 6 weeks post-treatment, and approximately 12 weeks after the final visit. Results/discussion: At the 1-year assessment, 731 patients received ≥1 onabotulinumtoxinA treatment; 1345 and 1429 treatment sessions for upper and lower limb spasticity, respectively, and 265 patients received treatment for both upper and lower limbs. Most commonly treated presentations were clenched fist (2121 treatment sessions) and equinovarus foot (2938 treatment sessions) for upper and lower limbs respectively. Electromyography was the most frequently used localization technique (39.5–61.5% of treatment sessions). Across all treatments, 91.1% of physicians and 82.3% of patients reported being satisfied or extremely satisfied that treatment helped manage spasticity; 84.6% of physicians and 74.8% of patients reported that the treatment benefit was sustained, and 97.4% of physicians and 89.8% of patients would definitely or probably continue treatment with onabotulinumtoxinA. A total of 211 patients (28.9%) reported 560 adverse events (AEs); 23 events in 17 patients (2.3%) were considered treatment-related. Serious AEs (136 events) were reported by 75 patients (10.3%); 5 serious AEs in 2 patients (0.3%) were considered treatment-related. No new safety signals were identified. Conclusions: One-year results demonstrate the safety and effectiveness of onabotulinumtoxinA for the treatment of spasticity. Further analyses will examine clinical and burden outcomes and the differences across etiology and presentation. http://dx.doi.org/10.1016/j.baga.2017.02.044
15
Claire Vilain ∗ , Allison Brashear, Christina Marciniak, Robert Jech, Marta Banach, Philippe Marque, Anne-Sophie Grandoulier, Philippe Picaut, Jean-Michel Gracies
Introduction: Current botulinum toxin labeling indicates injections once every 12 weeks but few studies have assessed the treatment interval after repeated injections. In a recent doubleblind (DB) study followed by an open-label (OL) extension abobotulinumtoxinA (aboBoNT-A, Dysport) was efficacious and demonstrated a favorable safety profile in adult patients with upper limb spasticity (ULS) after single and repeated injections (Gracies, et al. Lancet Neurology, 2015; Brashear et al. American Academy of Neurology, 2016). This additional analysis focuses on the retreatment intervals after repeated injections of aboBoNT-A. Methods: Phase III, international, multicentre, DB, singletreatment study of aboBoNT-A in adults with ULS, followed by a long-term OL extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator’s clinical judgement and possible at Weeks 12, 16, 20, and 24. Results: Among the subjects who received aboBoNT-A in the DB study and were treated in Cycle 1 of the OL extension, 37% were re-injected at Week 16 or later (17% at Week 16, 10% at Week 20, 10% at Week 24 or later). For those who received a second cycle of treatment in the OL phase, 35% of subjects were re-injected at Week 16 or later (20% at Week 16, 7.0% at Week 20, 8% at Week 24 or later). For those who received a third cycle of treatment in the OL phase, 24% of subjects were re-injected at Week 16 or later (19% were retreated at Week 16, 3% at Week 20, 2% at Week 24 or later). Conclusions: These data show that 24–37% of subjects did not require re-injection before Week 16 across multiple cycles. This long duration of clinical effect leads to longer intervals between injections, and thus may reduce the burden associated with frequency of injections for patients and their caregivers/families. This also highlights the needs for a tailored approach in the treatment of patients with ULS. http://dx.doi.org/10.1016/j.baga.2017.02.045 Time to retreatment after abobotulinumtoxinA ® (Dysport ) injections in children with dynamic equinus foot deformity Claire Vilain ∗ , Nigar Dursun, Jorge Carranza, Ann Tilto, Resa Aydin, Ece Unlu, Belgin Erhan, Maria Luisa Rodriguez, Philippe Picaut, Anne-Sophie Grandoulier, Mauricio R. Delgado Ipsen Pharma, Les Ulis, France Introduction: It is always difficult to know when a child-being treated with botulinum toxin for spasticity secondary to cerebral palsy (CP) will require retreatment. The minimum interval between injections is 12 weeks, however a longer duration of therapeutic benefit is of potential interest in this population. Delgado et al. (2016) reported the results of a Phase III study demonstrating superiority of a single injection of abobotulinumtoxinA (AboBoNT-A) vs. placebo in improving hypertonia (Modified Ashworth Scale, MAS) of the gastroc/soleus complex and in the Physicians Global Assessment (PGA) of treatment response. Here we describe the different
Abstracts / Basal Ganglia 8 (2017) 1–22
skin surface by the injected fluid volume was measured every 30 s with the optical 3D sensor. The temperature change of the same region could be recorded as a continuous film with thermal information. The influence of the volume on the subdermal distribution could be estimated by different dilution ratios and thus, alternating injection volumes (0.02 ml and 0.04 ml) with a constant dose of active substance: only individual subjects were compared to exclude interindividual differences in the skin. The injections of 0.04 ml of aqueous solution (n = 11) cooled the skin 5 s after injection by an average of 5.78 ◦ C and the diameter of this cooled area was an average of 5.89 mm. On injection of 0.02 ml of aqueous solution, the skin temperature dropped 5 seconds after the injection only by 3.5 ◦ C (p < 0.00) and the diameter of this cooled area was significantly smaller with 4.71 mm in average (p = 0.03). Results/discussion: The combination of these optical methods makes it possible for the first time to directly observe the subdermal spread of botulinum toxin solution in real time and thus, to check the influence of injection techniques and dilutions on the distribution and hence, on the area of pharmacological effect. Further clinical trials are necessary to systematically examine these factors. http://dx.doi.org/10.1016/j.baga.2017.02.040 Entropion senile – 25 years of experience with botulinum toxin (BoNT) therapy, including a very dramatic case Andrea Stenner ∗ , Gerhard Reichel Paracelsusklinik KZB, Zwickau, Germany Introduction: Entropion is a malposition of the eyelid, most commonly the lower one. The lid is turned inwards, with eyelashes touching the cornea. This will cause pain, the sensation of a foreign body in the eye, and inflammation, resulting in permanent reflexive closing of the eye, i.e. functional blindness. Treatment of Entropion with BoNT has already been recommended since the nineteen eighties. Methods: We started treating Entropion with BoNT in 1992, and have treated 24 patients with single or multiple BoNT dosages so far (62–90 years). Effects could be noticed after 2–6 days. 12 patients needed another injection after 3 to 6 months, 25 percent of them after about one year, and in 6 patients no relapse occurred. Repetitive injections were more effective than just the first injection. Before her first treatment with BoNT, one patient had had 4 surgeries at her lower eyelid; the scar from these operations was causing pressure at her cornea, resulting in problems which finally lead to reflexive eye closing. Results/discussion: In one case (a 90-year old woman), an undetected Entropion senile in both eyes resulted in persistent eye closing for more than 3 years, causing functional blindness. She was forced to use a wheelchair to reduce the risk of falling. Entropion senile was first diagnosed when the patient, who had no signs of brain dysfunction, was referred to us for the treatment of an additional hemifacial spasm. Treatment with BoNT at 4 orbital points around her left eye and one on both her lower eyelids had the following results in only 4 days: Her hemifacial spasm was interrupted, she was able to open and close both her eyes without problems, so she did not need her wheelchair any longer. She still receives BoNT treatment for her hemifacial spasm every 4 months. Conclusion: In summary, we are suggesting BoNT treatment of Entropion senile as gold standard technique. http://dx.doi.org/10.1016/j.baga.2017.02.041
Justinus Kerner and the “sausage poison” Steffen Häfner CELENUS DEKIMED, Bad Elster, Germany Introduction: The 19th century German romantic poet and medical officer Justinus Kerner (1786–1862) provided the first detailed clinical description of botulism and its associations with faulty sausage production. Method: A literature research was done on the terms “Justinus Kerner” and “botulism”. Results: Kerner collected data on 230 cases of botulism and published two important monographs in 1820 and 1822. He gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and physical findings – 70 years before this was identified being caused by anaerobic microbes. He drank an extract of the faulty sausage poison to study the symptoms in a very dangerous self-experiment. Thereby he could describe that it was sour and could produce early stages of the “sausage poisoning”. For the treatment of this disease he described the use of a gastric tube, 50 years before such experiments were recorded officially. Beyond of that he applied an extracorporal “pacemaker” – 100 years before this was introduced into clinical medicine. Finally, Kerner suggested the potential therapeutic use of botulinum toxin to block abnormal motor movements, such as chorea, and speculated on its use in other disorders with hypersecretion, for example. Discussion: Kerner’s first description of “botulismus” is a highlight of pure natural science, of exact diagnosis and innovative therapy, already anticipating the modern indications for botulinum toxin in an excellent way. http://dx.doi.org/10.1016/j.baga.2017.02.042 Impact of early intervention with onabotulinumtoxinA treatment in adult patients with post-stroke lower limb spasticity Wolfgang H. Jost ∗ , Atul T. Patel, Anthony B. Ward, Carolyn Geis, Liu Chengcheng, Rozalina Dimitrova Parkinson-Klinik Ortenau, Wolfach, Germany Introduction: This analysis aims to evaluate the impact of timing of treatment initiation since stroke on the efficacy of onabotulinumtoxinA in post-stroke lower limb spasticity (PSLLS). Methods: This multicenter, phase 3, placebo-controlled study was undertaken across 60 global centers, enrolling patients with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors. During the 12-week double-blind phase, patients were randomized to receive onabotulinumtoxinA (300U, mandatory muscles [gastrocnemius, soleus, tibialis posterior]; and ≤100U, optional lower limb muscles [flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, extensor hallucis, rectus femoris]) or placebo. The primary endpoint was a change from baseline in MAS average score of weeks 4 and 6. Secondary endpoints included physician-assessed CGI Change average score of weeks 4 and 6 and physician-assessed Goal Attainment Scale (GAS; active and passive at weeks 8 and 12). Results/discussion: In the intent-to-treat population, (onabotulinumtoxinA, n = 233; placebo, n = 235), significant improvements vs. placebo were observed in MAS (−0.81 vs. −0.61; P = 0.01), CGI (0.86 vs. 0.65; P = 0.01), and passive GAS scores (week 12, −0.6 vs. −0.9; P = 0.044). When stratified by time of treatment initiation post-stroke (<24 months, n = 153; >24 months, n = 315, posthoc), patients who were treated ≤24 months since stroke experienced greater improvements (mean difference) in MAS (−0.31 vs. −0.17), CGI (0.49 vs. 0.12), and passive GAS scores (week 12, 0.37 vs. 0.26).
Abstracts / Basal Ganglia 8 (2017) 1–22
Among patients ≤24 months since stroke, a greater proportion achieved ≥1 point improvement in active (week 12; P = 0.039) and passive (week 8; P = 0.023) GAS scores vs. placebo. OnabotulinumtoxinA 300–400 U was well tolerated with no new safety findings. Conclusions: OnabotulinumtoxinA 300-400U is effective in improving MAS, CGI, and GAS scores in patients with PSLLS with greater benefits among those initiating treatment ≤24 months post-stroke.
Duration of effect of abobotulinumtoxinA ® (Dysport ) in adult patients with upper limb spasticity (ULS) post-stroke or traumatic brain injury
http://dx.doi.org/10.1016/j.baga.2017.02.043
Ipsen, Les Ulis, France
The Adult Spasticity International Registry (ASPIRE) study: 1 year results Wolfgang H. Jost ∗ , Gerard E. Francisco, Daniel S. Bandari, Ganesh Bavikatte, Aubrey Manack Adams, Joan Largent, Alberto Esquenazi Parkinson-Klinik Ortenau, Wolfach, Germany Objective: To examine the 1-year interim onabotulinumtoxinA safety, effectiveness, and exploratory treatment utilization data from the ASPIRE study. Background: OnabotulinumtoxinA treatment for patients with spasticity is individualized, variable, and dependent on numerous factors. Findings from ASPIRE will help guide onabotulinumtoxinA treatment strategies in patients with spasticity and optimize outcomes. Methods: This is a multicenter, prospective, observational study across 54 international sites (NCT01930786) examining adult patients with spasticity treated with onabotulinumtoxinA at the discretion of the treating physician. Follow-up assessments include utilization patterns, patient and physician satisfaction, taken at each treatment visit, 6 weeks post-treatment, and approximately 12 weeks after the final visit. Results/discussion: At the 1-year assessment, 731 patients received ≥1 onabotulinumtoxinA treatment; 1345 and 1429 treatment sessions for upper and lower limb spasticity, respectively, and 265 patients received treatment for both upper and lower limbs. Most commonly treated presentations were clenched fist (2121 treatment sessions) and equinovarus foot (2938 treatment sessions) for upper and lower limbs respectively. Electromyography was the most frequently used localization technique (39.5–61.5% of treatment sessions). Across all treatments, 91.1% of physicians and 82.3% of patients reported being satisfied or extremely satisfied that treatment helped manage spasticity; 84.6% of physicians and 74.8% of patients reported that the treatment benefit was sustained, and 97.4% of physicians and 89.8% of patients would definitely or probably continue treatment with onabotulinumtoxinA. A total of 211 patients (28.9%) reported 560 adverse events (AEs); 23 events in 17 patients (2.3%) were considered treatment-related. Serious AEs (136 events) were reported by 75 patients (10.3%); 5 serious AEs in 2 patients (0.3%) were considered treatment-related. No new safety signals were identified. Conclusions: One-year results demonstrate the safety and effectiveness of onabotulinumtoxinA for the treatment of spasticity. Further analyses will examine clinical and burden outcomes and the differences across etiology and presentation. http://dx.doi.org/10.1016/j.baga.2017.02.044
15
Claire Vilain ∗ , Allison Brashear, Christina Marciniak, Robert Jech, Marta Banach, Philippe Marque, Anne-Sophie Grandoulier, Philippe Picaut, Jean-Michel Gracies
Introduction: Current botulinum toxin labeling indicates injections once every 12 weeks but few studies have assessed the treatment interval after repeated injections. In a recent doubleblind (DB) study followed by an open-label (OL) extension abobotulinumtoxinA (aboBoNT-A, Dysport) was efficacious and demonstrated a favorable safety profile in adult patients with upper limb spasticity (ULS) after single and repeated injections (Gracies, et al. Lancet Neurology, 2015; Brashear et al. American Academy of Neurology, 2016). This additional analysis focuses on the retreatment intervals after repeated injections of aboBoNT-A. Methods: Phase III, international, multicentre, DB, singletreatment study of aboBoNT-A in adults with ULS, followed by a long-term OL extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator’s clinical judgement and possible at Weeks 12, 16, 20, and 24. Results: Among the subjects who received aboBoNT-A in the DB study and were treated in Cycle 1 of the OL extension, 37% were re-injected at Week 16 or later (17% at Week 16, 10% at Week 20, 10% at Week 24 or later). For those who received a second cycle of treatment in the OL phase, 35% of subjects were re-injected at Week 16 or later (20% at Week 16, 7.0% at Week 20, 8% at Week 24 or later). For those who received a third cycle of treatment in the OL phase, 24% of subjects were re-injected at Week 16 or later (19% were retreated at Week 16, 3% at Week 20, 2% at Week 24 or later). Conclusions: These data show that 24–37% of subjects did not require re-injection before Week 16 across multiple cycles. This long duration of clinical effect leads to longer intervals between injections, and thus may reduce the burden associated with frequency of injections for patients and their caregivers/families. This also highlights the needs for a tailored approach in the treatment of patients with ULS. http://dx.doi.org/10.1016/j.baga.2017.02.045 Time to retreatment after abobotulinumtoxinA ® (Dysport ) injections in children with dynamic equinus foot deformity Claire Vilain ∗ , Nigar Dursun, Jorge Carranza, Ann Tilto, Resa Aydin, Ece Unlu, Belgin Erhan, Maria Luisa Rodriguez, Philippe Picaut, Anne-Sophie Grandoulier, Mauricio R. Delgado Ipsen Pharma, Les Ulis, France Introduction: It is always difficult to know when a child-being treated with botulinum toxin for spasticity secondary to cerebral palsy (CP) will require retreatment. The minimum interval between injections is 12 weeks, however a longer duration of therapeutic benefit is of potential interest in this population. Delgado et al. (2016) reported the results of a Phase III study demonstrating superiority of a single injection of abobotulinumtoxinA (AboBoNT-A) vs. placebo in improving hypertonia (Modified Ashworth Scale, MAS) of the gastroc/soleus complex and in the Physicians Global Assessment (PGA) of treatment response. Here we describe the different