Infiltration with botulinum toxin A (Xeomin®) in flexible intervals to reach appropriate modulation of spasticity

Giancarlo Ianieri, E. Romanelli, L. Mastromauro, R. Marvulli, G.B. Marzo

Introduction and Objectives: The technical definition of spasticity is: Type of increase in muscle tone at rest characterized by, increased resistance to passive stretch, velocity dependent and asymmetric about joints [1,2]. Spasticity management is complex and requires therapy tailored to the patient because the contributing factors to resistance to movement in the context of limb spasticity following damage to the brain or spinal cord ( neurogenic component: overactive muscle contraction and biomechanical component: stiffening and shortening of the muscle and other soft tissues) depending on the size, location and age of the lesion, and may have several harmful effects such as pain, deformity or contracture (continuous tightening of muscle, tendons, ligaments, or skin to restrict normal movement) [2] , loss of range of motion, and impaired function. In addition, much of the increase in muscle tone arises from changes in muscle and motor units, independent of reflex mechanisms[1,2]. The primary aim of the treatment of spastic muscles is to maintain length and allow normal positioning of the limbs to prevent secondary soft tissue shortening. Current standard treatment for patients with focal spasticity includes botulinum neurotoxin type A (BTX-A) infiltrations but it is important to remember that BTX-A itself is only effective in reducing the neurogenic component of spasticity, and for successful use there must be a significant component of muscle overactivity and an appropriate rehabilitation programme.The chronic nature of spasticity requires repeated injections of botulinum toxin (injection intervals ≥3 months). In some patients, the multiple injections can lead to secondary failure of treatment, due to the production of antibodies, directed specifically against the complexing proteins, which surround the neurotoxin. In this study we used incobotulinumtoxin A NT 201 (Xeomin®), because it is free from complexing proteins and can minimize the risk of immune-resistance in patients being treated for chronic clinical conditions, which require high doses of BTX-A and short intervals.The aim of this study was to demonstrate high dosage and appropriate flexible intervals between infiltrations cause a significant clinical efficacy over time or a rise in adverse reactions.

Methods: In this study, we analyzed 3 parameters: patient satisfaction (outcome), Modified Ashworth Scale (MAS) and myotonometry tone with MyotonPRO®. This device has a testing end (probe) that is applied under constant pre-load (0.18 Newton=N) on superficial muscle. The probe then exerts a brief, 15 ms tap, at a pre-determined force (0.4N) followed by quick release, inducing dampened natural oscillations of the muscle. The device records these oscillations in the form of an acceleration graph performing 3 muscle parameters: Frequency (Hz; F=fmax; higher frequency=higher muscle tone), Stiffness (N/m; muscle’s ability to resist an external force that modifies its shape; higher value=greater stiffness) and Elasticity (logarithmic decrement; indicating ability of the tissue to recover its shape after being deformed; higher value=lower amount of mechanical energy lost during a single oscillation cycle) [8,9]. This device has a triaxial accelerometer and a system which allows multidirectional measurements in relation to the gravity vector. The probe is held perpendicular to the skin surface to ensure that the energy from a mechanical impulse goes to the muscle maximally and constantly. However, due to the fact that muscle tissue is affected by gravity, it is recommended that recordings are made with the device held between 0-90 degrees to the gravity vector[16]. Myometric measure is non invasive, safe and objective because no operator dependent (such as other clinical scales of spasticity) [3].

Results: 28 patients were infiltrated for a total of 4 times. Table 1: Number of patients treated at 6, 12 and 16 weeks for each botulinum toxin treatment cycle. Table 2: Analysis of variance between groups and within groups demonstrated that therapeutic effect of Xeomin, assessed by Myoton, were constant in time regardless of timing of reinfiltration (F<Fcrit) Table 3: The outcome improvement was invariable during the study (adiusted H>d.f.)Table 4: The 12 populations studied have no significant differences in median, then infiltrations performed on a flexible intervals do not vary significantly over time the improvement of muscle MAS between infiltration and control (adiusted H<d.f.)

Discussion: Xeomin® shows low immunogenicity even using doses four to five times higher than the equivalent clinically recommended highest doses for humans in therapeutic indications. In a recent study of up to 89 weeks in patients with upper limb spasticity who received one injection of Xeomin® or placebo followed by up to five injections of Xeomin®, no patient developed neutralizing antibodies throughout the study[4, 5, 6]. Treatment with Xeomin® may result in a reduced incidence of antibody-induced therapy failure after long-term treatment compared with other BoNT/A [7]. Studies demonstrated that no patient developed neutralizing antibodies during the treatment in chronic therapy (up to 6 injection sessions with an interval of 12 weeks between each sessions) [7,8].Moreover, treatment with high doses of Xeomin® is safe and well tolerated [9]. The overall incidence of adverse events (AEs) was low considering the long-term observation period and patient population. Only 11% of patients experienced AEs considered by the investigator to be related to NT 201 treatment, which is comparable to similar BoNT/A studies in post-stroke spasticity [10,11,12]. None of these AEs were rated severe or serious. The most frequent NT 201-related AEs were injection site pain, muscular weakness and dysphagia. In this study, there were no AEs.In this study, we demonstrated that infiltrations administered at high doses and flexible intervals (6, 12 and 16 weeks) modulate spasticity satisfactorily, allowing personalized treatment. In fact, therapeutic effect of infiltration at different time intervals is maintained constant in time (P<0.05, see graph 1). Myometric outcome and MAS measurement demonstrated that therapeutic effects were regardless by timing of reinfiltration during the study. The opportunity to reduce the time between infiltrations is due to the pharmacologic properties of incobotulinumtoxinA, which is free from complexing proteins. BoNT/A, blocking the release of acetylcholine by cleaving nine aminoacids from a SNARE protein called synaptosomal-associated protein 25[12], lasts approximately 12 weeks.

Time Patients

reinfiltration 6 weeks 7

Cycle 1 reinfiltration 12 weeks 13

reinfiltration 16 weeks 8

reinfiltration 6 weeks 11

Cycle 2 reinfiltration 12 weeks 9

reinfiltration 16 weeks 8

reinfiltration 6 weeks 5

Cycle 3 reinfiltration 12 weeks 12

reinfiltration 16 weeks 11

reinfiltration 6 weeks 9

Cycle 4 reinfiltration 12 weeks 11

reinfiltration 16 weeks 8

Table1: number of patients treated at 6, 12 and 16 weeks for each cycle

Variance SS DF MS F Significance F crit

Between groups 1,512877733 11 0,137534339 0,388139387 0,957947408 1,885687

Within groups 35,43426512 100 0,354342651

Total 36,94714286 111

adjusted H: 13,317

d.f.: 11

P value: 0,273

Table1: number of patients treated at 6, 12 and 16 weeks for each cycle

Table2: variance analysis between and within groups. SS = Variance (sum of squares) DF = Degrees of freedom, MS = Mean squares (deviation)

Table 3: Outcome dataduring the study

Table 4: MAS difference during the study

adjusted H: 2,667968365

d.f.: 11

P value: 0,994426679

References1. Sheean G., The pathophysiology of spasticity.Eur J Neurol. 2002 May;9 Suppl 1:3-9; dicussion 53-61. 2. Burke D, Wissel J, Donnan GA. Pathophysiology of spasticity in stroke. Neurology. 2013 Jan 15;80(3 Suppl 2):S20-6.3. Ianieri G., Saggini R, Marvulli R, Tondi G, Aprile A, Ranieri M, Benedetto G, Altini S, Lancioni GE, Goffredo L, Bellomo RG, Megna M, Megna G. New approach in the assessment of the tone, elasticity and the muscular resistance: nominal scales vs MYOTON. Int J

Immunopathol Pharmacol. 2009 Jul-Sep;22(3 Suppl):21-4.4. Rossetto O, Montecucco C. How botulinum toxins work. In: Handbook of Botulinum Toxin Treatment (Second Edition). Moore P, Naumann M (Eds). Blackwell Science Ltd, Oxford, UK (2003).5. Blümel J, Frevert J, Schwaier A. Comparative antigenicity of three preparations on botulinum neurotoxin A in the rabbit. Neurotox Res. 2006;9:238. 6. Lisa Shaw, Helen Rodgers Botulinum Toxin Type A for Upper Limb Spasticity after Stroke. DisclosuresExpert Rev Neurother. 2009;9(12):1713-1725.7. Greensboro, NC. Xeomin®: Summary of Product Characteristics. Merz Pharmaceuticals; 2010.8. Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins;NT 201) in post-stroke upper limb spasticity. Petr Kaňovský, MD, PhD1, Jaroslaw Slawek, MD, PhD2, Zoltan Denes, MD, PhD3,Thomas Platz, MD,

PhD4, Georg Comes5, Susanne Grafe, MD5 and Irena Pulte, MD5 J Rehabil Med 2011; 43: 486–492.9. J Neural Transm. 2014 Jul 17. Safety aspects of incobotulinumtoxinA high-dose therapy. Dressler D1, Adib Saberi F, Kollewe K, Schrader C. 10.Elovic EP, Brashear A, Kaelin D, Liu J, Millis SR, Barron R, et al. Repeated treatments with botulinum toxin type A produce sustained decreases in the limitations associated with focal upperlimb poststroke spasticity for caregivers and patients. Arch Phys Med Rehabil

2008; 89: 799–806. 11. Gordon MF, Brashear A, Elovic E, Kassicieh D, Marciniak C, Liu J, et al. Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 2004; 63: 1971–1973. 12.Bakheit AMO, Fedorova NV, Skoromets AA, Timerbaeva SL, Bhakta BB, Coxon L. The beneficial antispasticity effect of botulinum toxin type A is maintained after repeated treatment cycles. J Neurol Neurosurg Psychiatry 2004; 75: 1558–1561.

Conclusions: Due to the pharmacological properties of incobotulinumtoxin type A (no adverse reactions and no development of neutralizing antibodies) we can properly modulate muscle spasticity independently interval between infiltrations. In this way, it is possible to obtain a specific and personalized treatment for each patient, so as to facilitate also the effect of physiotherapy to slow the modification that lead to the formation of muscle fibrosis (and therefore retractions tendon and joint locks). It is also fundamental the comprehensive assessment of spasticity, with measurements not only subjective (such as clinical scales) but also objective, as the myometry that allows us to evaluate small changes of rheological properties of muscle tissue, providing a complete pathophysiological vision of spastic muscle modifications.

We evaluated the effects of flexible intervals of incobotulinumtoxin A infiltrations (6, 12, 16 weeks) in 28 patients (mean age 60,03±9,14) with left spasticity treated for 16 months with Xeomin®, total average dose=736,78±105,12. We treated for the upper limb Biceps Brachii (AD=116,42±25,99), Flexor Digitorum Superficialis (AD=104,64±17,31), Palmaris Longus (AD=90,14±9,75), Pronator Teres (AD=85,35±6,7), Palmar Interossei (AD=40,132±10,76) and for the lower limb Soleus (AD=102,33±18,5), Medial (AD=99,42±7,8) and Lateral Gastrocnemius (AD=98,35±15,2). Biceps Brachii, Flexor Digitorum Superficialis, Palmaris Longus, Medial and Lateral Gastrocnemius, at rest, are assessed by myometry because most superficial. We used different statistical analysis for each measurement depending on the characteristic values of the measurements (rating scale and myometric data). MyotonPRO® data (reported as difference between muscle tone at infiltration vs muscle tone at control on 20 days) were analyzed with one-way Anova. Outcome data and difference of MAS (measured as difference between infiltration vs control on 20 days) were analyzed with Kruskal-Wallis

O.U. of Physical Medicine and Rehabilitation and Spinal Unit-Policlinico of Bari-Italy

Graphic 1: MYO and Outcome data trend