1

Introduction

The spastic paretic muscle is subject to structural changes compared to healthy skeletal muscles. These changes are independent from the initial etiology of the neurological lesion. The literature describes an increased variability of the size and type of muscle fibers, decreased numbers of sarcomeres, proliferation of the extracellular matrix (ECM) with an increased collagen concentration . When the first motor neuron is affected, muscle retraction can get settled under the influence of two main factors. The disuse of the paretic muscle or “functional immobilization”, which initiates muscle atrophy and reduces the number of sarcomeres by a disequilibrium of the protein-proteolysis synthesis balance in favor of the proteolysis . Chronic muscle hyperactivity maintains the muscle in a short position, reducing the longitudinal tension . Thus, the shortening of the muscle fibers and accumulation of conjunctive tissue are responsible of these changes in biomechanical viscoelastic properties of the muscles, with a decreased passive extension capacity .

Muscle changes contribute to functional impairments. Gait speed and step length have been significantly correlated to passive mechanical properties of the plantar flexor muscles, determined by the measure of the passive torque/joint angle ratio of the talocrural joint . For Dietz and Sinkjaer, the spastic muscle at rest is submitted to an overexcitability of the alpha motor neuron (presynaptic inhibition and increased activity of type Ia ascending fibers) with little changes during voluntary contractions. Thus, hyperreflexia is hardly involved in pathologic spastic movements .

Injections of botulinum toxin type A (BoNtA) are a first-line therapeutic method to treat focal spasticity ). Their action is triggered by the fixation on the SNARE proteins and inhibited release of acetylcholine (ACh) from the presynaptic terminals. The therapeutic objective is to decrease reflex muscle overactivity and fight muscle hypertonia. The functional benefit will affect gait patterns and movement amplitude . However, the impact of BoNtA injections on muscle structure and the stretching capacity of muscle tissue have rarely been reported in the literature. The challenge is to differentiate the consequences related to spastic paresis from those linked to the injections of botulinum toxin. We propose a review of the literature with the following objectives:

• •
  

  analyze changes in the structure and stiffness of muscle tissue described after an injection of botulinum toxin in one muscle of the limbs;

  
  
• •
  

  discuss the evaluation methods used.

2

Methodology

A systematic review of the literature was conducted abiding by the PRISMA recommendations ( www.prisma-statement.org ). We searched the Pubmed and Cochrane Library databases, using the following keywords

“Botulinum toxin” AND (“muscle structure” OR “muscle atrophy”) and, “Botulinum toxin” AND “muscle elasticity”. Articles stemming from this research were independently put aside by 2 authors (LM and BP) and were then evaluated. Articles were kept if they met the following criteria:

• •
  

  the study focused on the analysis of a striated skeletal muscle of the limbs, paretic spastic or healthy (to differentiate changes related to spastic paresis), in men and humans;

  
  
• •
  

  the study analyzed the consequences of injections of botulinum toxin on muscle structure and/or muscle tissue stiffness;

  
  
• •
  

  evaluation methods in the fields of histological, mechanical and medical imaging analyses were described;

  
  
• •
  

  the full manuscripts were published in English between 1990 and October 2014. References of the articles included were used to eventually complete the selection. In case of disagreement, a decision was taken after further discussion.

The methodological quality of the articles was evaluated using a specific scale developed based on the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) principles . Each item was categorized, and the maximum global score is 28 ( Table 1 ).

2

Methodology

A systematic review of the literature was conducted abiding by the PRISMA recommendations ( www.prisma-statement.org ). We searched the Pubmed and Cochrane Library databases, using the following keywords

“Botulinum toxin” AND (“muscle structure” OR “muscle atrophy”) and, “Botulinum toxin” AND “muscle elasticity”. Articles stemming from this research were independently put aside by 2 authors (LM and BP) and were then evaluated. Articles were kept if they met the following criteria:

• •
  

  the study focused on the analysis of a striated skeletal muscle of the limbs, paretic spastic or healthy (to differentiate changes related to spastic paresis), in men and humans;

  
  
• •
  

  the study analyzed the consequences of injections of botulinum toxin on muscle structure and/or muscle tissue stiffness;

  
  
• •
  

  evaluation methods in the fields of histological, mechanical and medical imaging analyses were described;

  
  
• •
  

  the full manuscripts were published in English between 1990 and October 2014. References of the articles included were used to eventually complete the selection. In case of disagreement, a decision was taken after further discussion.

The methodological quality of the articles was evaluated using a specific scale developed based on the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) principles . Each item was categorized, and the maximum global score is 28 ( Table 1 ).

3

Results

3.1

Selection of the studies

In all, 228 articles were initially identified ( Fig. 1 ). Thirty-two articles were deemed relevant after reading the titles and abstracts. Twenty-one were included in the review (11 were excluded because they did not meet the selection criteria). Fourteen studies focused on the structural analysis, 3 studies on muscle stiffness analysis and 4 studies on both structure and stiffness analysis. Overall, there were very few studies, with often a restricted population sample (from 1 to 56 patients in men) and various exploration methods.

Selection diagram of the reviewed articles. ^* A common study in humans and animals. Some articles are referring to multiple methods and fields of investigation.

3.3

Literature analysis ( Table 3 )

The methodological variability among the small number of studies, made it mandatory to conduct an evaluation based on changes in muscle structure and passive mechanical properties and according to the exploration techniques used .

Table 3

Summary table of the results.

Author Year	Human/Animal	Control group	Age	Population (number)	Neurological Condition	Muscle system	BoNtA Number of injections and dose	Measurement tool	Study criteria	Changes	First–Last evaluation	First changes	Recovery
Alhusaini et al., 2011	Human	No	4 to 10 years	16	CP	TS + TA + TCJ unit	Botox, 1, ?	Dynamometer–Potentiometer	TS + TA + TCJ unit stiffness	None	6 weeks–6 weeks	None	?
Boyaci et al., 2014	Human	Yes	Avg: 49 ± 16 months	16	CP	GM, GL, So	Botox, 1, 1,5U/kg in GM	B-mode US	Muscle thickness	None in injected GM Increase in GL, Soleus	1week pre-BoNtA–4 weeks post-BoNtA	4 weeks	?
								Sonoelastography	Strain ratio	Decrease in injected GM and in GL
									Red Pixel intensity	Decrease in injected GM and in GL
Choi et al., 2007	Rat	Yes	Mature, 4 year	80	Healthy	RF	? 4 groups 0, 1, 3, 9 ng/kg/day, daily for 4 weeks	Balance	Body weight	Dose-dependent weight loss	D1–4 weeks	Dose-dependent	No
								Histology	Muscle structure	Decrease of muscle fiber diameter Increase of nuclei number Increase of collagen Increase of adipocytes
Dodd et al., 2005	Rat	Yes + contralateral limb	Mature, 4 months	?	Healthy	TS	Dysport, 1 4 groups: 3 U, 6 U, 12 U, 18 U	Balance	Muscle mass	Decrease	D1–D67	D67	No
								Histochemistry	MHC isoforms	Decrease MCH IIx → IIa et I
Fortuna et al., 2011	Rat	Yes	Mature, 1 year	20	Healthy	RF, VL, VM	Botox, monthly, 3,5 U/kg	Balance	Muscle mass	Decrease	1 months–6 months	1 month	?
								Histology	Contractile proteins %	Decrease		3 months
Frick et al., 2007	Rat	Yes + contralateral limb	Mature	30	Healthy	TA	Botox, 1 3 groups: 0,625 U, 2,5 U, 10 U	Balance	Muscle mass	Dose-dependent decrease	128 days–128 days	128 days	?
Haubruck et al., 2012	Rat	Yes	Mature	36	Healthy	GCM + TA + calcaneus unit	?, 1, 6 U/kg	Dynamometer + lenght measure	GCM + TA + calcaneus unit stiffness	Decrease	8 days–8 days	8 days	?
Kwon et al., 2012	Human	Yes	28 years	1	CP	GCM, So	Botox, 1, 20 U	B-mode US	Muscle thickness	Increase	4 weeks–4 weeks	4 weeks	?
								Sonoelastography	Elastic modulus with color maps	Softer muscles
Legerlotz et al., 2009	Rat	Yes	Juvenile, 4 weeks	30	Healthy	GCM	Botox, 1, 13 U/kg	Balance	Muscle mass	Decrease	3 weeks–3 weeks	3 weeks	?
								Histochemistry	MHC isoforms	MHCIIb → MHCIIx or IIa
								Gel Electrophoresis	Titin content	Decrease
Ma et al., 2004	Rat	Yes	Juvenile, 1 month	34	Healthy	GM, GL	?, 1 6 U/kg	Balance	Muscle mass	Decrease	1 week–1 year	1 week	6 months
								Histology: ME	NMJ morphometry: width	Increase		2 months	1 year
Park et Kwon, 2012	Human	No	Avg: 57 ± 22 months	17	CP	GM, GL	Botox, 1, 20 U/muscle	Sonoelastography	RTS score	Decrease	4 weeks	4 weeks	?
									Red pixel intensity	Decrease
Picelli et al., 2012	Human	No	Avg: 59 ± 14 ans	56	Stroke	GM, GL	?, 1, 250 U/GCM	B-mode US	Muscle echogenicity, Heckmatt Scale	No echogenicity changes Injections less effective depending on echogenicity	4 weeks–4 weeks	4 weeks	?
Schroeder et al., 2009	Human	Contralateral limb	31 and 47 years	2	Healthy	GL	Xeomin, 1, 75 U	MRI	Muscle signal	High signal intensity in STIR sequence	3 months–12 months	3 months	No
									Muscle cross-sectional area	Decrease
								OM	Muscle structure	Neurogenic atrophy Reinnervation
								EM	Muscle ultrastucture
Shaikh et al., 2014	Human	Yes	Avg: 47 years (min: 26–max: 63)	12	Piriformis syndrome	Piriformis	Botox, inconstant injections number, 100 U	MRI	Maximal muscle thickness	Decrease	Inconstant Avg: 7,3 ± 5,2 months post-injection	?	No
									Muscle volume	Decrease
									Fatty infiltration	Increase
Stone et al., 2011	Mouse	No	?	140	Healthy	GM, GL	Botox, 1, inconstant doses and volumes	Balance	Muscle mass	Dose- and volume-dependant decrease	4 weeks–12 weeks	4 weeks	12 weeks
Thacker et al., 2012	Rat	Contralateral limb	Mature	24	Healthy	TA	Botox, 1, 6 U/kg	Dynamometer + Length measure (muscle fibers)	Elastic modulus	Increase	1 month–1 month	1 month	?
								Histology	Collagen content	Increase
Tok et al., 2011	Human	Contralateral limb	Avg: 55 ± 14 years	26	Stroke	GM, GL	?, 1, ?	B-mode US	Pennation angle	Decrease	10 days–2 months	2 months	?
									Fascicular lenght	Increase
									Muscle thickness	Decrease
									Muscle compressibility	None
Tsai et al., 2010	Human	No	?	5	Calf asymetry	TS	Botox, 1, 20 ng calf	Meter	Maximal calf circumference	Decrease	4 weeks–26 weeks	4 weeks	26 weeks
	Rat	Yes	?	5	Healthy	GCM	3 groups: 1,5 ng/kg 6 months repeated 1,5 ng/kg 6 months repeated 1 ng/kg	EM	Muscle ultrastucture	Sarcomere distorsion	1 week–52 weeks	1 week	26 weeks
								Balance	Muscle mass	Decrease
Van Campenhout et al., 2012	Human	No	Avg: 12 years	7	CP	Proximal psoas Distal psoas	Botox, 1, 2 U/kg/psoas	MRI	Muscle volume	Decerase (proximal injected psoas) None (distal injected psoas)	2 months–6 months	2 months	No
Vasilescu et al., 2010	Human	Contralateral limb	3–10 years	7	CP	Inconstant	?	B-mode US	Muscle echogenicity Aponevrosis echogenicity, Diamètre musculaire	No description	?	?	?
								Sonoelastography	Elasticity pattern with color map	Softer muscles
William et al., 2013	Human	No	5–11 years	15	CP	GCM, So	Botox, 1, inconstant doses	MRI	Muscle volume	Decrease in injected muscles Increase in soleus muscle	5 weeks	5 weeks	?

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