after injury to the upper motor neurons ( umn ) such as the brain or spinal cord , certain 
 clinical deficits present immediately or at delayed times . weakness and loss of dexterity 

spasticity or 
 spastic hypertonia elicited by passive stretch of a muscle at rest can interfere with active 
 or passive movement1 .
hyperexcitability of 
 spinal reflexes causes spasticity and spastic hypertonia , but it is not the only mechanism 
 that contributes to spasticity after brain injury .
recent studies indicate that abnormal 
 stretch reflex activity is insufficient to explain increased muscle tone2,3,4 .
increased stiffness of a muscle during 
 stretching due to changes in collagen tissue and tendons , enhancement of the intrinsic 
 stiffness of muscle fibers , and loss of sarcomeres can lead to subclinical contractures5 .
each of the therapeutic interventions to reduce spasticity including physical therapy , 
 occupational therapy , orthoses , pharmacological treatment , chemodenervation , orthopedic 
 surgery , and neurosurgery has different indications and advantages6 .
there is currently a lack of specific guidelines for the 
 stratification and individualization of therapeutic interventions .
extracorporeal shock wave therapy ( eswt ) was first applied to patients in 1980 to break up 
 kidney stones7 , and later it was 
 successfully employed for many orthopedic diseases such as nonunion of long bone 
 fracture8 , plantar fasciitis9 , 10 , 
 calcifying tendinitis of the shoulder11 , 12 , and several inflammatory tendon 
 diseases13 ; myofascial pain 
 syndrome14 , 15 ; and treatment of spasticity .
the mechanisms of how eswt induces 
 the healing process in human tissue remain uncertain , but recent studies suggest that eswt 
 appears to involve a cascade of interaction between physical shock wave energy and biologic 
 responses including the expression of angiogenesis - related growth factors such as enos 
 ( endothelial nitric oxide synthase ) , vegf ( vessel endothelial growth factor ) , and pcna 
 ( proliferating cell nuclear antigen ) and neovascularization16,17,18,19 . the indications for eswt 
 in orthopedic disorders continue to expand13 . recently
, clinical trials have been performed to evaluate the efficacy of eswt . however , 
 each study adopted different clinical scales that were insufficient to draw a definite 
 conclusion about the efficacy of eswt in reducing spasticity after brain injury .
to suggest 
 a firm conclusion , we searched for studies published up to june 2013 and meta - analyzed the 
 efficacy of eswt in reducing spasticity after brain injury .
we searched pubmed , tcl , embase , and scopus from their inception dates through june 2013 to 
 identify interventional studies using eswt to improve spasticity in patients with brain 
 lesion .
first , we searched pubmed and tcl records using the following criteria : ( ( muscle or 
 muscular ) and ( spastic * or hypertonia * or hypertonicit * ) ) or ( muscle tone increased or 
 spasticity ) and ( shock wave * or eswt ) .
second , we searched embase using the following 
 criteria : ( muscle hypertonia/exp or ( muscle or muscular and ( spastic * or hypertonia * or 
 rigidit * ) ) or ( muscle and tone and increased ) or spastic * ) and ( shock wave/exp or shock 
 wave * or 
third , we searched scopus using the following criteria : ( ( muscle or 
 muscular ) and ( spastic * or hypertonia * or rigidit * ) ) and ( shock wave * or  eswt  ) . 

two reviewers working independently screened all the 
 abstracts and the titles for the candidate studies and discarded the studies in which 
 extracorporeal shock waves were used for different purposes other than spasticity . after the 
 initial screening , they reviewed the full text publications for eligibility , and 
 disagreements between the two reviewers were resolved by consensus .
all of the studies using eswt for the purpose of ameliorating spasticity in patients with 
 any brain injury were included .
the studies involving other concomitant interventional 
 procedures , such as botulinum toxin injection , were excluded .
we included the studies that 
 provided both baseline and postprocedure modified ashworth scale ( mas ) grades for selected 
 muscles .
the mas grade was assessed immediately after application of eswt in all included 
 studies . among them
, four studies suggested mas grade which was assessed 4 weeks after 
 application of eswt .
the mas grade ranged from 0 to 4 , with 0 indicating no increase in 
 muscle tone and 4 indicating rigid in flexion and extension . from the selected studies , we abstracted data regarding follow - up durations , pre- and 
 postprocedure mas grades , and mas grades at four weeks after eswt , and compared them between 
 time intervals .
mean  standard deviation values for pre- and 
 postprocedure mas grades and for the mas grades at four weeks after eswt were provided in 
 all studies .
heterogeneity refers to the differences between studies in terms of 
 methodological factors , such as use of blinding and concealment of allocation .
significant 
 statistical heterogeneity arising from methodological diversity or differences in outcome 
 assessments suggests that the studies are not all estimating the same quantity but does not 
 necessarily suggest that the true intervention effect varies . a number of options are 
 available if statistical heterogeneity is identified among a group of studies that would 
 otherwise be considered suitable for a meta - analysis20 .
the i test describes the rate of 
 variation across studies due to heterogeneity rather than chance and ranges from 0 ( no 
 heterogeneity ) to 100 ( maximum heterogeneity ) .
all results are reported with 95% confidence 
 intervals ( 95% ci ) , and all p - values are two - tailed . when a significant 
 heterogeneity among the outcomes was found ( i>50 ) , the 
 random effects model according to dersimonian - laird was used22 .
this model assumes that the true treatment effects in individual 
 studies may be different from one another and that these treatment effects are normally 
 distributed .
those outcomes that did not present with heterogeneity 
 ( i<50 ) were analyzed with the fixed - effects model .
the 
 fixed - effects model uses the inverse variance approach , and it is assumed that all studies 
 come from a common population .
subgroup analysis was also used to detect heterogeneity 
 according to the muscle groups assessed in each study .
the mas grades assessed immediately 
 after eswt ( i= 0.0% ) and 4 weeks after eswt 
 ( i= 0.0% ) were analyzed by the fixed - effects model . because 
 of the small number of studies in each subgroup , we used a funnel plot , begg s test , and 
 egger s test simultaneously to detect publication bias .
the analysis was performed using comprehensive meta - analysis 
 version 2.0 ( biostat , englewood , nj , usa ) .
the primary search for the effect of eswt on spasticity in patients with brain injury 
 identified 73 relevant studies , and 32 duplicate studies were discarded .
two studies were additionally excluded : 
 one study used botulinum toxin injection before application of eswt , and the other study 
 presented insufficient data for meta - analysis .
four studies examined the spasticity of the ankle plantar flexor , and one 
 study examined wrist and finger flexors ( table 
 1table 1.studies that evaluated the effect of extracorporeal shock wave therapyyearpublishedauthorpopulationtestedmuscleno .
ofpatientsfollow - up(weeks)modified ashworth scalebaselineafter eswtp - value4 weeksafter eswtp - valuemeansdmeansdmeansd2013gonokova et al.cerebral palsyplantar flexor2542.700.092.000.080.0012.150.070.0012010amelio et al.cerebral palsyplantar flexor12123.300.491.800.380.0012.250.450.0012005manganotti et al.strokewrist flexor20123.400.702.000.900.0012.300.700.001finger flexor20123.200.600.800.400.0011.300.400.0012013moon et al.strokeplantar flexor3042.500.671.410.670.0021.750.620.0192011sohn et al.strokeplantar flexor10 - 2.671.151.221.030.035-eswt = extracorporeal shock wave therapy , fig .
1.flow diagram of the study selection process ) . for quality assessment of the studies included in this meta - analysis ,
the 
 newcastle - ottawa scale was used ( table 
 2table 2.quality assessments using the newcastle - ottawa scaleyear publishedauthornewcastle - ottawa scaleselectioncomparabilityexposure2013gonokova et al.*******2010amelio et al.*******2005manganotti et al.*******2013moon et al.******2011sohn et al.* * * * )
. the characteristics of the intervention and relevant outcome measurements 
 for each study are described in table 
 3table 3.characteristics of intervention , outcome , and results of the individual studies 
 in our reviewstudyenergy / pressuredosage and treated musclesrelevant outcomegonokova et al .
( 2005)0.030 mj/ mm1,500 shots for the flexor muscles of the forearm and 3,200 shots 
 for the interosseus muscles of the hand ( 800 shots for each muscle)prommascmap latency and amplitudef - wave latency and 
 amplitudemoon et al .
( 2011)0.2 mj / mm1,500 shots in the gastrocnemius mascmap latency , amplitude , conduction velocityf - wave latency 
 h - reflex latencyh - m ratioprom = passive range of motion ; mas = modified ashworth scale ; cmap = compound muscle 
 action potential .
eswt = extracorporeal shock wave therapy flow diagram of the study selection process prom = passive range of motion ; mas = modified ashworth scale ; cmap = compound muscle 
 action potential five studies assessed the effects of eswt on improvement of the mas grade immediately after 
 application of eswt .
the mas grade was 
 significantly improved after eswt compared with the baseline values ( standardized mean 
 difference [ smd ] , 0.792 ; 95% ci , 1.001 to 0.583 ; p<0.001 ) ( fig .
std diff = standard difference ; ci = confidence interval ; pf = plantar 
 flexor ; wf = wrist flexor ; ff = finger flexor ) .
significant inter - study heterogeneity was not found (  = 2.53 , p= 0.77 , 
 i = 0.0% ) .
begg s test ( p=0.09 ) and egger s test ( p=0.06 ) 
 suggested that some bias source might be included in this sample of studies , but the classic 
 fail - safe n was 83 .
3.funnel plots to assess for publication bias at the time immediately ( a ) and 4 weeks 
 ( b ) after extracorporeal shock wave therapy .
mas = modified ashworth scale ; eswt = 
 extracorporeal shock wave therapy ; std diff = standard difference ) .
we also performed a subgroup analysis based on the tested muscles , and it did not 
 show any different results ( fig .
4.forest plot of the subgroup analysis to assess for heterogeneity depending on muscle 
 groups assessed immediately ( a ) and 4 weeks ( b ) after extracorporeal shock wave 
 therapy . eswt = extracorporeatl shock wave therapy ; std diff = standard difference ; ff 
 = finger flexor ; pf = plantar flexor ; wf = wrist flexor ) .
std diff = standard difference ; ci = confidence interval ; pf = plantar 
 flexor ; wf = wrist flexor ; ff = finger flexor funnel plots to assess for publication bias at the time immediately ( a ) and 4 weeks 
 ( b ) after extracorporeal shock wave therapy .
mas = modified ashworth scale ; eswt = 
 extracorporeal shock wave therapy ; std diff = standard difference forest plot of the subgroup analysis to assess for heterogeneity depending on muscle 
 groups assessed immediately ( a ) and 4 weeks ( b ) after extracorporeal shock wave 
 therapy .
eswt = extracorporeatl shock wave therapy ; std diff = standard difference ; ff 
 = finger flexor ; pf = plantar flexor ; wf = wrist flexor the mas grade was also assessed four weeks after application of eswt .
the mas grade was significantly improved after eswt compared with 
 the baseline values ( standardized mean difference [ smd ] , 0.735 ; 95% ci , 0.951 to 0.519 ; 
 p<0.001 ) ( fig . 5fig .
eswt = extracorporeal shock wave therapy ; std diff = standard difference ; pf = plantar 
 flexor ; ff = finger flexor ; wf = wrist flexor ) .
significant inter - study heterogeneity was not found (  = 4.706 , p= 
 0.319 , i = 14.994% ) .
begg s test ( p=0.05 ) and egger s test 
 ( p=0.009 ) suggested that some bias source might be included in this sample of studies . 

we also performed a subgroup analysis based on tested muscles , and it 
 did not show any different results ( fig .
eswt = extracorporeal shock wave therapy ; std diff = standard difference ; pf = plantar 
 flexor ; ff = finger flexor ; wf = wrist flexor
spasticity , as defined by lance in 1980 , is a motor disorder characterized by a 
 velocity - dependent increase in tonic stretch reflexes (  muscle tone  ) with exaggerated 
 tendon jerks , resulting from hyperexcitability of the stretch reflex , as one component of 
 upper motor neuron syndrome24 .
the 
 pathophysiology of spasticity and hypertonus is complex and not clearly understood yet . 

different spinal and supraspinal pathways contribute to it , and multiple neuronal mechanisms 
 lead to increased reflex excitability .
even though spasticity and hypertonus provide some 
 benefits to patients25 , most of the 
 result of the spasticity may be detrimental .
spasticity can cause discomfort and stiffness 
 and limitations in physical activities such as walking , transferring , picking up objects , 
 washing , dressing , or sexual activity26 . 

four of the studies included in this meta - analysis evaluated the reduction of spasticity in 
 ankle plantar flexors because it has a major functional implication in gait in patients with 
 cerebral palsy or stroke27,28,29,30 .
poorly managed spasticity of the plantar flexors is 
 responsible for muscle shortening and the development of tendon and soft tissue 
 contractures , leading to an impaired swing phase of gait .
one of the studies evaluated 
 spasticity of wrist and finger flexors in patients affected by stroke because it may 
 seriously impair hand functions and activities of daily living31 .
a number of pharmacological agents and non - pharmacological treatments such as physical 
 therapy , orthoses , and transcutaneous electrical nerve stimulation ( tens ) have been tried 
 for the treatment of spasticity and hypertonus32 .
chemodenervation also called neurolysis or neuromuscular blockade 
 are used to prevent nerve - muscle transmission with perineural injection of phenol33 , 34 
 or ethyl alcohol35 and intramuscular 
 injection of botulinum toxin36,37,38,39,40,41 . more invasive treatment options such as rhizotomy42,43,44 and intrathecal baclofen45,46,47,48 

could be another choice for patients who are resistant to conventional treatments or have 
 intractable spasticity .
treatment of spasticity needs to be performed with a stepped care 
 approach that begins with simple and reversible treatments that have few side effects and 
 proceeds to irreversible treatments that have more side effects .
botulinum toxin injection has been tried in many studies and proven to be effective on 
 improving muscle spasticity36,37,38,39,40,41 .
however , the efficacy of botulinum toxin injection has 
 been challenged by several reasons .
the formation of neutralizing antibodies after botulinum 
 toxin injection happens in more than one - third of dystonic patients who are labeled as 
  nonresponders49 .
other reasons for 
 the lack of response to botulinum toxin injections are inappropriate dosing , changes in the 
 pattern of muscle involved , incorrect injection sites , reconstitution , and/or storage 
 failure50 .
the indications for eswt , which was first applied for lithotripsy7 , have expanded to a variety of orthopedic diseases over the 
 last decades .
two different mechanisms of the effect of eswt are noted ; one mechanism of 
 effect is the high positive pressure and short rise time , which are responsible for the 
 direct shock wave effect , and the other is the tensile wave for the cavitations , which is 
 called the indirect shock wave effect51 . 

nitric oxide 
 has a very important physiological function in the central nervous system and in the 
 transmission of the nerve impulse in the neuromuscular junction52 .
a number of studies have investigated the effect of eswt 
 by inducing enzymatic and nonenzymatic nitric oxide synthesis17 , 53 . although , it has been 
 suggested that nitric oxide plays an important role in regulating inflammatory events , 
 biomechanical mechanisms underlying these effects have yet to be elucidated19 .
although the etiology of spasticity is central , secondary changes in peripheral nerves and 
 muscles are critical factors in producing spasticity .
most published micrographs of muscle from spastic 
 patients showed abnormalities such as increased fiber size variability , increased number of 
 rounded fibers , moth - eaten fibers , and increased extracellular space .
in addition , spastic 
 muscles present increased joint stiffness , and this is presumably due to fibrosis within the 
 muscle tissue or an increase in the number of crossbridges attached during contraction . 

moreover , muscle contractures occur secondary to spasticity due to a reduction in muscle 
 fiber length and a decrease in the number of serial sarcomeres within muscle fibers54 .
one possible effect of eswt is the 
 improvement in connective tissue stiffness acting on fibrosis of chronic hypertonic muscles . 

these considerations are consistent with recent studies assessing the advantages of eswt for 
 several orthopedic and traumatic indications including problematic soft tissue wound55,56,57 . when analyzing the results of eswt for treatment of spasticity and hypertonus , adopting a 
 reliable method for assessing spasticity is challenging .
the ashworth scale , first developed 
 in 196458 , is the best known scale for 
 measuring the degree of spasticity26 . 
 among the clinical evaluation tools ,
the mas which has a good interrater reliability , was 
 adopted for comparing pre- and posttreatment changes in severity of spasticity in this 
 meta - analysis .
the meta - analysis indicated that eswt improved the mas grade significantly 
 compared with the baseline values . in all studies ,
the mas grade decreased in a 
 statistically significant manner at the time immediately after eswt and at four weeks after 
 eswt , and the smds and 95% cis were 0.792 and 1.001 to 0.583 ( p<0.001 ) and 0.735 and 
 0.951 to 0.519 ( p<0.001 ) , respectively .
the mas , even though it is the most frequently 
 cited rating scale for measurement of spasticity , does not evaluate the velocity of passive 
 joint movement and the angle of contraction outbreak or potential tendon retraction59 , 60 .
also , even if this scale seems to measure the resistance adequately , 
 the reduced range of joint motion due to contracture might limit its reliability61 .
therefore , the mas does not substantially reflect spasticity according to lance s 
 definition , that is , a motor disorder characterized by a velocity - dependent increase in 
 muscle tone24 . on the other hand
, the 
 modified tardieu scale does take into account the velocity of passive joint movement and 
 assess the angle of catch and the speed at which the catch was obtained forms the basis of 
 the measure of spasticity .
in addition , the modified tardieu scale is more sensitive in the 
 detection of posttreatment changes because it measures muscle resistance as well as the 
 velocity of the movement that induces muscular contraction62 .
another limitation of the present study was that the mas does not include clinical features 
 including pain , spasm , and impact of function that could be associated with spasticity .
the 
 clinical impacts of spasticity that discourage patients include spasm or pain accompanied by 
 hypertonicity ; functional deterioration of activities of daily living such as walking , 
 transferring , dressing and washing ; and burden placed on caregivers .
therefore , other 
 clinical assessment scales such as the visual analogue scale ( vas ) for pain assessment , 
 spasm frequency scale ( sfs ) or clonus score , daily functional assessment scales , and 
 patient / caregiver goal assessment scale should be included in future studies .
the average 
 follow - up duration was only 4 weeks in two studies and was 12 weeks in two other studies ; 
 the final study evaluated immediate effects of eswt only .
therefore , it is difficult to 
 suggest the optimal treatment interval from this meta - analysis .
 [ purpose ] the purpose of this meta - analysis was to assess the effects 
 of extracorporeal shock wave therapy ( eswt ) on reducing spasticity immediately and 4 weeks 
 after application of eswt . 
 [ subjects and methods ] we searched pubmed , tcl , embase , and 
 scopus from their inception dates through june 2013 . the key words  muscle hypertonia or 
 spasticity  were used for spasticity , and the key words  shock wave or eswt  
 were used for 
 eswt . 
 five studies were ultimately included in the meta - analysis . 
 [ results ] the modified 
 ashworth scale ( mas ) grade was significantly improved immediately after eswt compared with 
 the baseline values ( standardized mean difference [ smd ] , 0.792 ; 95% confidence interval 
 [ ci ] , 1.001 to 0.583 ) . 
 the mas grade at four weeks after eswt was also significantly 
 improved compared with the baseline values ( smd , 0.735 ; 95% ci , 0.951 to 0.519 ) . 
 
 [ conclusion ] eswt has a significant effect on improving spasticity 
 . further 
 standardization of treatment protocols including treatment intervals and intensities needs 
 to be established and long - term follow up studies are needed . 
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION