Botulinum Toxin’s using in Treatment of Cerebral Palsy

Haitao Tian

, Zehao Wu

and Chen Yang

Macleans college, Auckland, 2010, New Zealand

University of Washington, Seattle, WA, 98109, U.S.A.

Biological Science, University of California Davis, Davis, CA, 95618, U.S.A.

†

These authors contributed equally

Keywords: Botulinum Toxin, Cerebral Palsy.

Abstract: Using botulinum toxin (BTX) to treat CP patients has become more mature and widely used recently. In this

article, the authors first briefly introduce the CP and BTX, then summarize the mechanisms of BTX on the

treatment of CP through a flow chart, following by opinions driven from recent clinical treatment results.

Most articles mentioned by the authors conclude that BTX therapy is one of the most important treatments

for CP patients, and the opposed research shows that it is rebuttable. Through careful analysis, the data

confirms the effectiveness of BTX therapy in the treatment of CP patients and concludes that BTX

treatment should be treated as a supportive treatment monitoring with the involvement of other therapies.

Further studies are needed to discover which 1. Impact of cerebral palsy on infant therapy is the best for a

company with BTX therapy in different situations.

1 INTRODUCTION

Cerebral palsy (CP), which is a group of disorders

that could affect one’s ability to move and maintain

balance and posture, is the most common motor

disability in childhood, about 1 in 345 children has

been identified with CP according to CDC’s data.

Such disorders have symptoms of muscle spasms,

stiff feeling, poor muscle control, feeding difficulties

and so on, forcing patients to live with assistance

equipment like wheelchairs and walking sticks,

reducing life quality dramatically. Although CP

could not be cured, physical therapy (PT), as the

main part of rehabilitation treatment, could improve

the situation of patients dramatically. However, the

symptom of CP makes the patients under hypertonia

situation, making their unable to control the body,

including undergoing PT treatment.

Since the hypertonia situation prevent CP

patients from PT treatment, which is one of the most

direct treatment towards CP, the way of eliminating

such negative impact become the hot topic of

treating CP patients. Botulinum toxins (BTX), the

most poisonous neurotoxic protein know produced

https://orcid.org/0000-0003-1773-8047

https://orcid.org/0000-0002-5449-8516

https://orcid.org/0000-0001-8498-1456

by the bacteria “Clostridium botulinum”, are

discovered by the scientists and seems to become a

promising drug for such situation with its two

special characters. Firstly, BTX could block the

release of acetylcholine neurotransmitter, prevent

the transmission of action potential through the

neuron system, reduce the muscle stimulation. With

lower muscle stimulation, the symptom of

hypertonia reduced dramatically. Without

hypertonia, patients regain the ability to move

normally and undergo the physical therapy. More

importantly, scientists discovered that even though

BTX is the most poisonous neurotoxic protein, the

damage it brings to the neuron system is totally

reversible, granting the drug ability to undergo

clinical trials. In this review, we highlight the

mechanism of BTX under the treatment of CP,

examine the research have done so far on the

effectiveness of BTX for CP treatment, compare

pros and cons of such treatment, and provide our

own insight of future treatment directions.

2 IMPACT OF CEREBRAL PALSY

ON INFANT

As introduced before, Cerebral Palsy (CP) is defined

as motor impairment, including a broad range of

Tian, H., Wu, Z. and Yang, C.

Botulinum Toxin’s using in Treatment of Cerebral Palsy.

DOI: 10.5220/0011252400003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 661-665

ISBN: 978-989-758-595-1

661

muscle and movement disorders. The aetiology is

mainly attributed to non-progressive disturbances

during brain development in foetuses or infants, for

example, the lack of oxygen to the brain, gene

mutation or head trauma. These injuries can all lead

to abnormal development. The injuries can also

cause other illnesses. CP is frequently accompanied

by impaired cognition, communication and sensory

perception, behavioural abnormalities, seizure

disorders, or a combination of these features.

According to the main type of movement

disorder involved, CP is classified into four main

types, depending on which brain areas are affected:

spastic, dyskinetic, ataxic, and mixed. Spastic

cerebral palsy is the most common type of CP,

which affects about 80% of the patients. People with

this type of CP have increased muscle tone, which

means their muscles are stiff, and their movements

can be awkward as a result.

The spastic CP is also described with the body

parts that are affected. For example, Spastic diplegia

is when the stiffness is mainly in the legs, the arms

are less affected or not affected at all. Dyskinetic

cerebral palsy means problems are controlling the

movements of hands, arms, feet, and legs. Patients

would be more difficult to sit and walk due to the

involuntary movements, which can either be slow

and writhing or rapid and jerky. The ataxic CP

stands for problems with balance and coordination.

Patients would have a hard time with quick

movements. They would be unsteady when walking,

actions which require lots of control, such as

writing, can also be difficult for them.

Some patients would get mixed CP, which means

they would have symptoms of more than one type of

CP, a very common type of mixed CP is spastic-

dyskinetic CP. The method we introduce in the later

text of injecting botulinum toxin (BTX) would only

work for the spastic, dyskinetic, and a few mixed

CP, as it works by blocking the patient’s muscle

stimulation.

Once the types of CP have been diagnosed, it is

then very important to evaluate the severity of the

disease. The Gross Motor Function Classification

System (GMFCS) is the most widely used clinical

foundational classification of CP. It is an ordinal

scale that categorizes a child’s mobility or lower

limb function in five levels, ranging from walking

without restrictions (level I) to inability to maintain

antigravity head and trunk postures (level V), below

is a summary of the criteria of GMFCS: (Table 1).

Table 1: Level of GMFCS’ Criteria.

Grade CLINICAL MANIFESTATIONS

Level 1 Walks without limitations

Level 2 Walks with limitations

Level 3 Walks using hand-held mobility device

Level 4 Self-mobility with limitations; may use

owered mobilit

Level 5 Transported in a wheelchair.

3 ILLUSTRATIONS OF BTX AS

AN EFFECTIVE TREATMENT

FOR CP

3.1 Basic Information about BTX

BTX is produced by Clostridium botulinum under

anaerobic conditions and consists of a complex

mixture of proteins containing botulinum neurotoxin

and various non-toxic proteins. As a neurotoxin,

BTX-Type-A(BTX-A) can target and control

unpredictable body movement. There are seven

different serotypes of BTX, and they could be

distinguished by the letters A to G. Different types

have a high degree of sequence homology, but their

toxicity and molecular action sites are different.

Different serotypes bind to different protein

receptors. These serotypes inhibit the release of

acetylcholine from nerve endings, intracellular

targets, action characteristics, and potency. The

indirect effects of BTX on the central nervous

system are reflex inhibition, reversal of reciprocal

inhibition changes, cortical inhibition and

somatosensory evoked potential, and formalin-

induced pain reduction, suggesting that TB has a

direct analgesic effect. In BTX-A, SV2 (isoforms A–

C) is the receptor for BTX-A. BTX -A has a

complex 3D structure. It is folded into three

domains: the heavy chain receptor-binding domain,

the heavy chain translocation, and the light chain

catalytic domain (Figure 1). It is the most widely

studied serotype for therapeutic purposes. BTX

interferes with the spinal stretch reflex by blocking

the fibres of the fusiform muscle, resulting in

reduced afferent signals carried by fibres IA and II

and decreased muscle tone. Treating CP with BTX-

A can influence the signals to transmit.

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3.2 Mechanisms of BTX on the

Treatment of CP

BTX injection can reduce muscle spasms. It works

as an inhibitor. BTX-A can bind to the presynaptic

membrane through gangliosides and protein

receptors and then is internalized into the endosome

through endocytosis. After this, the light chain is

transferred across the membrane to the cytosol,

where it acts as a specific endopeptidase against any

SNARE (Soluble N-ethylmaleimide-sensitive factor

attachment protein receptor) protein. BTX cleaves

its substrate before forming the SNARE complex.

After BTX-A is incorporated within the early

endosomes, the acidic environment of the

endocytosis vesicles is believed to induce a

conformational change in the neurotoxin structure.

The heavy chain is inserted into the synaptic vesicle

membrane to form a transmembrane protein-

conducting channel that translocates the light chain

into the cytosol. After BTX-A is internalized into the

cytosol of neurons, BTX-A exerts its toxic effect by

virtue of the metalloprotease activity of the light

chain. Light chains can specifically cleave three

kinds of soluble N-ethylmaleimide. One of the

imine-sensitive factor attachment protein receptor

SNARE proteins is an indispensable part of vesicle

transport and neurotransmitters. BTX-A specifically

cleaves SNAP-25 (Synaptosome-associated protein

of 25 kDa) at the unique peptide bond. By cutting

SNAP-25, BTX-A can block the transmission of

some nerve signals in the neurotransmitter and thus

act as an inhibitor. Using this specialty, BTX-A is

effective in the targeted treatment of CP's

uncontrollable muscle tremor, as shown in figure 1.

Figure 1: Mechanism of BTX. Mechanism of BTX light

chain cleave SNAP-25 then cause muscle membrane do

not fuse and the muscle will not be going to be fiber

paralyzed.

BTX type A has two different types under the

serotype classification, and they could be named by

A1LL and A2NTX. According to the article by

Norio Akaike et al., when the newly developed

BTX-A2 (A2NTX) was injected into the foreleg

muscle of a rat, it was transported to the

contralateral muscle. This finding is consistent with

the retrograde propagation of neurotoxins through

spinal cord neurons and then through motor neurons

across synapses to reach the contralateral motor

neurons in the spinal cord and reach the soleus

muscle. The muscle relaxation on the ipsilateral side

of the injected toxin was faster and stronger in

A2NTX-treated rats than A1LL. This is because

A1LL is transported to the contralateral muscle

almost equally through nerve pathways and blood

flow. A2NTX is mainly delivered to the

contralateral muscle through blood. A1LL is more

successfully transported to the contralateral spinal

neuron than A2NTX. From this, by comparing that

A1LL can be transported faster compared to

A2NTX. However, the actual use effect of A2NTX

may be better than that of A1LL. In an article,

people experimented with A1LL could cause a

decrease in the grip strength of rats’ foreleg, but the

A2NTX could not make that. Therefore, the actual

use effect of BTX-A1 will be better than BTX-A2.

3.3 Clinical Treatment Result

Pl After it was found that BTX could be a promising

medicine for CP patients, researchers almost head to

clinical trial directly. That is because BTX has been

used to treat different diseases regarding to

hypertonia for decades, beginning with the treatment

of strabismus in the 1970s. The long history of

utilizing BTX to treat hypertonia situations gives

physicians rich experiences to handle similar

situations. Also, the paralysis caused by BTX could

be long-lasting but reversible via the administration

of small amounts locally, making such therapy

relatively safe to be conducted.

Through years of application in the treatment of

CP patients, many clinical data have proven the

effectiveness of BTX injection therapy. In 2009, an

article conducted by Lukban and colleagues revied

cases of class I and class II CP patients, involving

115 children with spasticity of upper limb and 360

children with spasticity of lower limbs. After

reviewing the database of such, it concludes that

these data provide growing evidence for the

effectiveness of BTX treatment in reducing

spasticity degrees and could provide a time-limited

improvement of function in the upper and lower

limbs for children with CP. Another study conducted

in 2020 also concludes that BTX therapy has

significant improvement in both clinical and

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663

functional outcomes by utilizing different systems to

measure functional gains. Through the utilizing of

manual ability classification system (MACS) and

Canadian occupational performance measure

(COPM), such study provides clear and convincing

evidence that BTX therapy is one of the most

important treatments for CP patients.

Even though some research concluded that BTX

treatment is not effective, this research may

overlook certain key points. In 2020, an article

published by Farag and colleagues denied the

effectiveness of BTX in the field of CP; it reports

that although there is a positive effect for spasticity

degrees after BTX injection treatment for upper

limbs spasticity in children, the effect with respect to

the function gains or improvement of quality of life

remained insignificant or conflicting. Such

conclusion seems to be convincing, but researchers

actually overvalued what BTX really supposed to

do. What BTX treatment could do is to reduce the

spasticity degrees for the patients, which does not

necessarily mean that could improve the life quality

or function situations of patients. Rehabilitation

training like walking and running should really take

charge of improving patients’ quality of life. For CP,

it is not that a single therapy or medicine could cure

the diseases on its own, it has to be the way that

many therapies are used together alone the way. For

these patients who could not walk or run because of

hypertonia, BTX therapy could eliminate the

hypertonia situation as much as possible; however,

for these who have never walk or run for their entire

life, it is fair to assume that they could not gain the

function even without hypertonia situation, which

means that there should be someone here teaching

them how to do that, and rehabilitation treatment

would be “the person” to do that. In conclusion,

BTX therapy grants patients the possibility to walk

or run, but it does not teach them how to walk or

run. In this article, the result has already proved the

effectiveness of BTX therapy, and the analysis on

functional gains and quality of life seems to be too

far ahead.

As mentioned previously, for treatment of CP, it

is not that a single therapy or medicine could cure on

its own; most of the time, a combination of therapies

is so important that it could directly affect the result

from experiments. In 2019, a trail performed by

Cahlin and colleagues led to the conclusion that the

effect of BTX-A compared with placebo on outcome

variables was unsignificant at the group level and

the evidence could not prove the used of BTX-A as

a therapy of affected masticatory muscle in CP.

While in 2017, a study conducted by Dursun and

colleagues regarding to the treatment of spastic

equinus foot due to CP leads to the conclusion that

BTX-A injection treatment with physical therapy

provided additional benefit for the patients. One

significant difference between these two

experiments is that the latter experiment conducts

more than BTX treatments but also physical therapy

along the way. More importantly, even though the

former experiment leads to the conclusion that there

is no objective improvement, researchers reported

that most patients request for continuing BTX

injection treatment, implying that there is a subject

effect on patients. One plausible explanation would

be that patients feel better while undergoing other

treatments after BTX eliminates the hypertonia

situation. Through the comparison, the importance

of the combination of different therapies has been

revealed.

Above all, many clinical research have proven

the effectiveness of BTX therapy as a treatment for

CP patients. Although some research may provide

contradictory evidence, there are certain points that

we should be aware of, and further research are

needed. One example here would be the

combination of different treatments with BTX

therapy, and such a topic should be something

researchers want to focus on in future studies.

4 CONCLUSIONS

In conclusion, here provides information for how CP

affects infant and a flowchart for how BTX therapy

could be a treatment to eliminate such effect. There

are convincing evidences used from other articles

that BTX therapy could be one of the most important

treatments for CP patients. Evidence shows that

there are some opposed conclusions could be driven

by overlooking certain key points and combining

BTX therapy with other therapy like physical

therapy or hydrotherapy is the best way to monitor.

For future research, the study design for BTX

therapy should treat it as supportive therapy and

involve it with other therapy in order to produce the

maximum positive effect for the patients because it

is too demanding to test whether a supportive

therapy could play an important role alone. Also,

more research should be done to discover which

therapy is the best for the BTX therapy company.

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