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Clinical applications of botulinum neurotoxin

in the treatment of spasticity

Petr Kaňovský

Department of Neurology

Palacky University Medical School

University Hospital

Olomouc, Czech Republic

Spasticity has firstly been characterised by William John Little (1810 - 1894) in the description of cerebral palsy:

“Pathology has gradually taught that the fetus in utero is the subject to similar diseases to those which afflict the economy at later periods of existence. This is especially true if we turn to the study of the special class of abnormal conditions, which are called deformities...“

On the influence of abnormal parturition, difficult labours, premature birth and asphyxia neonatorum, on the mental and physical condition of the child, especially in relation to deformities

by WJ Little, MD, Senior Physician to the London Hospital, founder of the Royal Orthopaedic Hospital, Visiting Physician to Asylum for Idiots, Earlswood

Transactions of the Obstetrical Society of London 1861, 3: 293

Spasticity is defined as an increase in the muscle tone, which depends

on the increase of the tonic stretch reflex and on the velocity of the

passive movement. The hyperexcitability of the stretch reflex has been

supposed as its origin (Lance 1980, Brown 1994, Sheean 2004)

Spastic muscle contraction is, in fact, a kind of pathological tonic muscle

response appearing as the consequence of phasic increase of muscle tone

The muscle response on the phasic increase of its tone can be tested in two

ways:

1) Passive movement in different velocities

2) Tapping on the muscle tendon (reflex examination)

Stretch reflex is managed by the very fast Ia afferent fibres originating in

the muscle spindles. Stretch reflex depends on the velocity of passive

movement and on the length of the muscle

The increased response of stretch reflex is caused by the central

hyperexcitability, which is one of the basic characteristics of the “spastic

movement disorder“

Spasticity is not caused by the isolated lesion of corticospinal pathway

itself. The selective lesion of corticospinal pathway causes a flaccid

paralysis.

Only the lesion of other descendent inhibition pathways (tectospinal,

olivospinal, nigrospinal, rubrospinal), together with the re-organisation

of spinal neuronal feed-back circuits, causes the increase of muscle tone

typical for spasticity.

Current model of the evolution of spastic hypertonus and spastic

muscle contraction:

The reduction of inhibitory inputs from the cortex and basal ganglia

leads to the disordered modulation of monosynaptic affarentation via primary

Ia afferent fibres and polysynaptic afferentation from the exteroreceptores.

This disorder of modulation causes the hyperexcitability of spinal alpha motor

neurons.

Spinal interneurons are the “key player“ in this “modulatory“ phase,

because of their ability of pre-synaptic and reciprocal inhibition (via Ia

fibers).

Ventromedial pontine reticular formation has an additive inhibitory input to

the spinal interneurons. Vestibular nuclei (via vestibulospinal tracts) have, on

the contrary, an additive inhibitory input to the spinal interneurons.

Brown 1994, Sheean 2004, Kanovsky 2005, Rosales & Kanovsky 2011

Spasticity treatment options and methods:

I. Non-surgical

A. Non-pharmacological

B. Pharmacological

II. Surgical

III. Chemodenervation with botulinum toxin A

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Study Year Invertion Outcome Measures Quality

(JADAD)

Brashear 2002 ONA or Placebo Functional disability, muscle tone, global assessment,

safety, neutralizing abs

3

Bakheit 2001 ABO or Placebo MAS, aes, ROM, pain, Functional ability, goal attainment,

global assessment

5

Hesse 1998 ABO or Placebo +- electrical

stimulation

MAS, ROM, functional ability, pain 3

Simpson 1996 ONA or Placebo BP, pulse rate, Asworth, Caregiver dependency, function

and pain, motor task/function, grip strength and global

assessment of spasticity; FIM, Rand 36-item health

survey and Fugl-Meyer

3

Bhakta 2000 ABO or Placebo Disability, care burden, muscle power, grip, MAS, ROM,

pain

5

O’Brien 1995 ONA or Placebo Ashworth, global assessment of spasticity, aes 2

Childers 1999 ONA or Placebo EAS, pulmonary function, physician global assessment,

aes

2

De Beyl 2000 ONA or Placebo EAS, ROM, aes 2

Kirazli and

On

1998 ONA or Phenol ROM, AS, global assessment of spasticity 2

Johnson 2002 ABO and FES and PT or PT Walking speed, physiological cost index of gait 3

Pittock 2003 ABO or Placebo Gait, PROM, AROM, MAS, pain, aes, global assessment

of benefit made by patient & investigator

5

Kanovsky 2009

2011

INCO or placebo MAS, aes, ROM, pain, functional ability, goal attainment,

global assessment

5

Evidence-based data

Study Year Invertion Outcome Measures Quality

(JADAD)

Koman 1994 ONA or Placebo Gait analysis, PT evaluation, Biodex evaluation, PRS and a parent

and guardian questionnaire

4

Uhbi 2000 ABO or Placebo VGA, GMFM, passive ankle dorsiflexion and PCI 4

Koman 2000 ONA or Placebo Dynamic gait pattern, active and passive ankle dorsiflexion ROM,

aes, EMG

3

Baker 2000 ABO or Placebo Muscle length, PROM, parent and investigator subjective

assessment of benefit, gastrocnemius muscle length, aes

4

Love 2001 ONA or placebo PROM, dynamic muscle range, dynamic ROM, passive resistance

to motion, MAS, GMFM, parantal satisfaction

1

Corry 1998 ONA or ABO Clinical exam, video and Vicon gait analysis, PRS 1

Flett 1999 ONA or fixed část Degree of ankle dorsiflexion, MAS, GMFM, PRS, global scoring

scales, gait parental satisfaction

2

Barwood 2000 ONA or Placebo Pain, nausea, vomiting, sedation, vital signs, analgesia,

complications, length of admission, remission rate

2

Boyd 2001 ONA or ONA and orthosis GMFM, radiological measures, clinical exam, MAS, questionnaires 3

Rickman 1996 ONA and PT and abduction position

wedges or PT and position wedges

Hip abduction, ROM, pain, carer burden of care, spasticity 1

Sutherland 1999 ONA or Placebo Passive ROM, neurological screening, muscle strength, gait

analysis

4

Reddihough 2002 ONA and PT or PT GMFM, Vulpe assessment battery, MAS, ROM, parent reported

pain, aes and perception

1

Kanovsky 2009 ABO or Placebo VGA of initial foot contact, GMFM, parental and investigator

subjective functional assessments

4

Evidence-based data

Methods of assessment of patient suffering from spasticity:

Clinical:

Clinical examination

Particular tests for presence of spastic signs

Goniometry

Scales:

Disability Assessment Scale (DAS)

Medical Research Council (MRC) scale on affected upper limb

Modified Ashworth scale

Neurophysiological:

EMG pattern

Polymyography

Motor evoked potentials

Clinical examination

Clinical examination should be done in the specialist centre.

During clinical examination, the specialist should assess the neurological

status of patient, and should remark the signs of upper motor neuron

syndrome.

Apart from that, the functional ability of patient and the possible treatment

outcomes and benefits should be also assessed.

It is important to achieve the co-operation of patient, and to properly show

to the patient the possible treatment goal (i.e. using midazolam i.v. test).

Particular tests for presence of spastic signs

Increased muscle tone

Typical (usually fast) response to passive muscle stretch

Brisk and increased tendon reflexes

Any of abnormal spastic skin responses (Babinski, Roch, Gordon,

Chaddock, Oppenheim)

Clonus

Disability Assessment Scale (DAS)

Hygiene: maceration, ulceration, and/or palmar infection, palm and hand

cleanliness, ease of cleanliness, ease of nail trimming, and the degree of

interference caused by hygiene-related disability in the patient´s daily life.

Dressing: difficulty of easewith which patient can put on clothing (e.g.

Shirts, jackets, gloves) and the degree of interference caused by dressing-

related disability in the patient´s daily life.

Limb position: abnormal position of the upper limb.

Pain: Intensity of pain or discomfort related to upper limb spasticity.

0 – no disability

1 – mild disability (noticeable but does not interfere significantly with

normal activities)

2 – moderate disability (normal activities require increased effort and/or

assistance

3 – severe disability (normal activities limited)

Medical Research Council (MRC) scale on affected upper limb

Elbow - Wrist - Thumb – Fingers (second to fifth finger)

flexors extensors

No contraction 0 0

Flicker or trace of contraction 1 1

Active movement, with gravity eliminated 2 2

Active movement against gravity 3 3

Active movement against gravity and resistance 4 4

Normal power 5 5

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Modified Ashworth Scale

(Bohannon and Smith 1986)

0= no increase in tone

1= slight increase in tone giving a “catch“ when the limb was moved in

flexion or extension

1+=slight increase in tone giving a “catch“ when the limb was moved in

flexion or extension (less than one half of ROM)

2=more marked increase in tone, but limb was easily flexed

3=considerable increase in tone – passive movements difficult

4=limb rigid in flexion or extension

Assessment of adductor tone

(Snow 1990)

0=no increase in tone

1=increase in tone, abduction of hips is possible to 45º with one person

2= abduction of hips is possible to 45º with one person and medium effort

3=abduction of hips is possible to 45º with one person and strong effort

4=two persons are needed for hip abduction to 45º

Spasm frequency scale

(Snow 1990)

How many spasm were present in the region af affected muscle or limb in the

last 24 hours?

Spasm frequency

0=no spasm present

1= < 1 spasm

2= 1-5 spasms

3= 5-9 spasms

4= >10 spasms

EMG pattern

Polymyography Motor evoked potentials

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Practical Issues

27-30G needles, 1-3 cm length

1-2 ml syringes 0.1 ml scale

EMG hollow needles in indicated cases

Preparation of BTX solution

2-4 ml normal saline/vial of XEOMIN®

resulting in

50/25 U/ml in XEOMIN®

Practical Issues

BTX-A should be injected directly into the muscle belly

Muscle belly should be localized by palpation

In indicated cases (upper limb, forearm) it should be localized by EMG

using recording and direct muscle stimulation

No need to target injections into the motor points

Usually one point per one muscle belly

Very slow (1ml/30s) injection to prevent muscle fibres rupture and pain

Short pressure on the injection point is useful

Target muscles of the upper limb

Upper arm girdle Flexed elbow pattern Flexed wrist and fingers

Flexed elbow: biceps, brachioradialis, brachialis

Flexed wrist: FCR, FCU (FDS, FDP)

Clenched fist: FDS, FDP plus

Thumb-in-palm: FPL, AP, 1st Dl plus

Common Muscle Patterns and Targets in the Upper Extremity

Biceps

Brachialis

Brachioradialis

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m. deltoideus 100/100/400

m. pectoralis maior 100/100/400

m. pectoralis minor 80/80/300

m. biceps brachii, long head 100/100/400

m. biceps brachii, short head 100/100/400

m. triceps brachii 80/80/300

m. brachioradialis 100/400/400

m. flexor carpi radialis 80/80/300

m. flexor carpi ulnaris 80/80/300

m. extensor dig. communis 80/80/300

m. flexor dig. superficialis 80/80/300

m. flexor dig. profundus 80/80/300

Practical Issues

ONA/INCO/ABO - BTX doses for muscles of upper limb (U):

Target muscles of the lower limb

Flexed knee and equinovarus Adductor group and equiniovarus

G-S, TA

G-S, TP

G-S, TA, TP

G-S, TA, TP, EHL

G-S, TP, EHL

G-S, EHL

G-S, FHL, TA

G-S, FHL, TP

G-S, FHL, EHL

G-S, FHL, TA, TP

G-S, FHL, TA, TP, EHL

G-S, FHL, FDL, TA

G-S, FHL, FDL, TP

G-S, FHL, FDL, TA, TP

G-S, FHL, FDL, TA, EHL

G-S, FHL, FDL, TA, TP, EHL

Possible Combinations Causing Equinovarus…..

Gastrocnemius

Tibialis posterior

m. gastrocnemius, medial head 100/100/400

m. gastrocnemius, lateral head 100/100/400

m. soleus 100/100/400

m. tibialis posterior 150/150/600

m. tibialis anterior 150/150/600

m. flexor hallucis longus 50/50/200

m. biceps femoris, long head 100/100/400

m. biceps femoris, short head 100/100/400

m. semitendinosus 100/100/400

m. semimembranosus 100/100/400

m. adductor femoris (group) 200/200/800

m. psoas 100/100/400

Practical Issues

ONA/INCO/ABO - BTX doses for muscles of lower limb (U):

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Conclusions

Botulinum toxin is a safe and effective treatment of spasticity caused by

different disorders of the brain structures.

It causes substantial reduction of spastic muscle tone, and in younger

cases it also allows the normal growth of treated muscles.

It even can prime the changes of the activation of motor structures, which

are involved in the control of movement and muscle tone.

Intensive physiotherapy is needed for the whole time of BTX-A induced

effect to achieve the best results in improving motor function.

Kanovsky and Bares 2004, Rosales and Kanovsky 2011

Treatment-induced change of

cortical activation: fMRI evidence

of the central effect of botulinum

toxin A in post-stroke spasticity

Brain cortex plasticity in the spastic movement disorder

Brain hemisphere affected by the stroke or MS lesion can

improve the motricity of hemiparetic limb and reduce

spasticity; both by the mechanism of cortical plasticity.

The botulinum toxin A treatment can relieve focal spasticity

(due to stroke or MS) not only by the local effect, but

predominantly due to dynamic changes at several levels of

central nervous system, including the brain cortex.

The processes primed by the cortical plasticity and changes

due to the BoNT-A treatment should be reflected in the

patterns of cortical activation during the motor or mental tasks

examined by the functional MRI.

Patients (3 groups)

9 patients (6 males/3 females) suffering from the distal upper

limb spasticity due to stroke, without the direct involvement of the

elocquent cortex

14 patients (9males/5females) suffering from the upper limb spasticity due

to stroke

14 patients (8males/6females) suffering from the upper limb spasticity due

to stroke, 7 with paretic upper limb, 7 with plegic upper limb

Functional MRI was done in three paradigms:

1) active movement of the fingers of the paretic hand in the Roland´s

paradigm (9 stroke patients)

2) active and resting phase, in the active phase patients performed knee

flexion and extension ; 34 flexions per minute in average (4 MS patients)

3) mental movement simulation, i.e. imagination of the sequential

movement in the Roland´s paradigm by the paretic hand (14 stroke

patients); block paradigm, 15 s mental movement simulation in turns with

15 sec resting state

Brain cortex plasticity in the spastic movement disorder

fMRI examination has been done 1 week prior to and 4 and 12 weeks

following to injection ob BoNT-A injections into the spastic muscles

detected by the palpation, EMG and electrical stimulation; the injection

has always been done with the EMG guidance.

Spasticity itself has been scored using the Modified Ashworth Scale

(MAS) and Rankin scale.

fMRI processing and analysis:

1. Side swapping of MRI data of right-lesioned brains

2. MRI data registration into common anatomical space (MNI template)

3. Two-stage statistical analysis using general linear model (FSL

software), treatment effect was tested using linear contrasts

Brain cortex plasticity in the spastic movement disorder

Study 1

9 patients (6 males/3 females) suffering from the

distal upper limb spasticity due to stroke, without the

direct involvement of the elocquent cortex, who

performed the sequential finger movement of the

paretic hand in the Roland´s paradigm

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Fig. 1. Lesion localization in individual patients displayed

on an axial Talairach template (z=+12mm).

Fig. 2. Functional MRI activation of the motor system

during finger movement before BoNT treatment (A) after

BoNT treatment of arm spasticity and (B) and during off-

BoNT examination (C).

Fig. 3. BoNT treatment effect location (ROI): dorsolateral

prefrontal cortex (DLPFC) showed the most significant

decrease in non- motor system activation after BoNT

treatment

Fig. 5

In the group data, the pre- >

post-BTX contrast showed a

significant decrease of

activation of posterior cingulum

/ precuneus regions following

the BoNT-A treatment

Fig. 4

Activation of extensive

network of motor areas by

the paretic hand

movement (green

markers´ crossing =

ipsilateral M1)

►►►

Study 2

14 patients (9males/5females) suffering from the

upper limb spasticity due to stroke and performing

the mental simulation of the movement with the

paretic hand interchanged with the resting state

Functional MRI activation during movement mental simulation:

1: before BoNT-A treatment

2: 4 weeks after BoNT-A

3: 12 weeks after BoNT-A application.

BoNT-A treatment effect when

compared 1 to 2 (significant

decrease in activation of the ipsilesional lateral occipital, supra-

marginal gyrus and precuneus cortex

BoNT-A treatment effect when

compared 1 to 3 (significant decrease

in activation of ipsilesional lateral

occipital cortex, frontal pole ,

contralesional superior frontal gyrus and

bilateral postcentral gyrus.

BoNT-A treatment effect when

compared 2 to 3 (significant

decrease in activation ofipsilesional insular cortex, caudatum,

contralesional superior frontal gyrus

and bilateral frontal pole.

Study 3

14 patients, suffering from spasticity of upper limb due to

stroke:

7 patients with paretic upper limb, performing the

sequential finger movements in the Roland´s paradigm

7 patients with plegic upper limb, performing mental

movement simulation (MMS) of sequential finger

movements in the Roland´s paradigm

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Functional MRI activation during imagery of finger movement in

group A (plegic): before BoNT treatment (a), 4 (b) and 11 weeks

after BoNT application (c). The Z-statistical images were

thresholded using a corrected cluster significance threshold of

P=0.05 and overlaid on top of averaged high resolution T1-

weighted images.

Functional MRI activation during sequential finger movement in

group B (paretic): before BoNT treatment (a), 4 (b) and 11 weeks

after BoNT application (c). The Z-statistical images were

thresholded using a corrected cluster significance threshold of

P=0.05 and overlaid on top of averaged high resolution T1-weighted

images.

The reduction of spasticity (either following stroke or due to multiple

sclerosis) by the botulinum toxin A treatment is - to the important extent -

caused by the change of central modulation of sensorimotor structures.

Undoubtedly; there is an important involvement of the structures outside the

classical motor system.

The areas posterior cingulum/precuneus, frontopolar cortex, DLPFC and

mesial occipital cortex were linked with the functions as global attention,

complex motor learning, motor memory or visual cognition rather than

active movement control.

In the condition of existing spasticity following stroke are these structures –

thanks to the brain cortex plasticity – used for the controlling of the volitional

movement.

Senkarova Z et al. J Neuroimaging 2010

Tomasova et al. J Neuroimaging, 2011

Veverka et al. J Neurol Sci 2012

Veverka et al. J Neurol Sci 2014©http://fmri.upol.cz

Department of Neurology, Palacky University Medical School,

Olomouc

fMRI laboratory team:

Petr Hlustik, Pavel Hok, Tomas Veverka, Robert Opavsky, Zuzana

Senkarova-Tomasova, Jana Klosova

EMG & BoNT-A team:

Pavel Otruba, Martin Nevrly, Katerina Mensikova, Miro Vastik, Igor

Nestrasil