Botuinum toxin - Detailed explanation


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Botulinum Toxin - Detail

For a simple explanation of botulinum toxin and leaflet click here.

Botulinum toxin injections are the treatment most commonly used in treating focal dystonias in adults. This article explains what botulinum toxin is, why it is used and how the treatment works. It also discusses possible side effects, the different types of toxin and the history of the treatment.

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How a muscle contraction starts

To understand the role of botulinum toxin, it is necessary first to understand how the brain initiates a muscle contraction as it is in this process that botulinum toxin is used to intervene.

The muscle is connected to the brain by the nervous system which is a complex network of neurons – these are long cells that can pass information using either electrical or chemical signals. Chemical signals pass between neurons and muscles through synapses which are specialised connections linking cells. The chemicals that are used to pass these messages are called neurotransmitters.

In the case of a muscle contraction, the chemical signal is passed using a neurotransmitter called acetylcholine. This sits in the neuron in a vesicle, a small bubble surrounded by a membrane, until it is required. When the neuron receives a message from the nervous system to initiate a muscle contraction, the acetylcholine is released from the vesicle and passes through the synapse into the muscle fibre.

btxa-1To achieve this, the vesicles need to be transported to, and fuse with, the neuron membrane that adjoins the synapse between the nerve and the muscle. This process is controlled by a group of proteins called the SNARE complex. The three main proteins involved are Syntaxin (which connects to the nerve membrane), Synaptobrevin (which connects to the vesicle) and SNAP-25 (which helps the other SNARE proteins link up). These proteins join together to cause the vesicle to move to the nerve membrane and fuse with it. The acetylcholine can then be released across the synapse and pass into the muscle. This then triggers a chain of events that causes the muscle contraction.

The role and structure of botulinum toxin

Dystonia is caused by the brain requesting an excess of muscle activity so one method of treatment involves breaking the causal chain that passes the request from the brain to the muscle. Botulinum toxin does this by preventing the release of acetylcholine through the synapse. By stopping this happening, the toxin prevents the muscle activity. The brain is still trying to cause the muscle contraction but because the toxin has created a missing link in the chain the muscle doesn’t realise it and so doesn’t contract.

Botulinum toxin is produced by a bacterium called Clostridium botulinum. This bacterium is associated with causing botulism, a rare form of food poisoning. Botulinum toxin is exceptionally toxic but, when purified and used in tiny, controlled doses, it can be used effectively to relax excessive muscle contraction.

Botulinum toxin is a complex molecule that, when hugely magnified, looks like this:

Btxa-molecule

The parts of the molecule are called the light chain (the bulge on the right) and the heavy chain (the rest of the molecule). The light chain is the active part of the toxin and without it the heavy chain has no effect.

There are seven types of botulinum toxin produced by different types of Clostridium botulinum (types A through G). Of these, only 2 types are used to treat dystonia - A and B. Type A is most commonly used and the mechanisms described below explain how type A works.

How is botulinum toxin introduced to the muscle?

The toxin is introduced into the body by an injection into the muscles where the unwanted activity is taking place. Some people find this hurts a little but others are not concerned about it at all. If it is a problem, doctors sometimes offer a local anaesthetic cream or medicine to help the pain.

Depending on the location of the muscle spasm doctors will either select the muscles by observing the abnormal postures or movements and feeling for the muscle spasm or will use an electromyography (EMG) machine which measures muscle activity.

The effect of introducing type A botulinum toxin into the muscle

When botulinum toxin is injected into the muscle, it binds rapidly with the neuron membrane. The bound toxin is taken up into the neuron and at this point it splits into the heavy chain and an active light chain:

btxa-2

The light chain has a specific affinity to cleave certain proteins involved in the movement of acetylcholine. Botulinum toxin type A cleaves SNAP-25. This prevents the SNARE proteins from binding so acetylcholine cannot reach or pass through the neuron membrane. As a result, it does not reach the muscle and so the muscle contraction does not start:

btxa-3

Because each muscle affected by dystonia has to be injected separately, and also because there is a limit to the total amount of toxin that can be injected into the body at one time, botulinum toxin is more suitable for treating dystonias which are focal to one or two areas of the body rather than generalised dystonia – although sometimes the toxin is used to treat a specific part of the body in generalised dystonia as part of a wider treatment regime.

Where it is a suitable treatment, botulinum toxin provides significant relief for the majority of people but it is not perfect. In our 2008 survey of members, 74% of those who had received botulinum toxin treatment reported that they got relief more than half the time.

Why is the effect of botulinum only temporary?

The body responds to the blockage of the junction between the nerve and muscle by growing new neurons. These try and bypass the blockage and re-connect the nervous system to the muscle. Once the botulinum toxin has all been absorbed by the nerves, any new connections will not get blocked and pathway between the brain and the muscle will start to be effective again.

This process takes some time which is why the effect of botulinum toxin lasts for 3-4 months but eventually the toxin ceases to be effective. This is also why regular injections are required.

Side-effects of botulinum toxin

The advantage of botulinum toxin over oral medication is that the toxin can be targeted only at the muscles causing the problem. In contrast, oral medication spreads round the body and so may affect areas other than those which need the treatment.

However, botulinum toxin can cause a number of different side effects depending on the location of the injection. For instance, in neck dystonia some people notice a new pain which arises from shrinkage of the affected muscle or the other neck muscles trying to compensate. Also injections in the neck area can result in some difficulties swallowing or speaking called dysphagia. For eye dystonia, the injection can result in droopy eyelids, blurred vision or over-production of tears.    

Usually these effects are mild and wear off relatively quickly. If the side-effects are a problem, then they need to be discussed with a doctor.

Why does botulinum sometimes stop working?

Botulinum toxin is an effective treatment that provides relief for the majority. However a minority of patients report limited relief. There are a number of reasons why this may happen and there are some steps that can be taken to address the problem - click here to learn more.

A very small percentage of patients develop immunity to botulinum toxin. It is thought that this is because the body develops antibodies that prevent the effectiveness of botulinum toxin by interfering with the process of the toxin binding with the neuron membrane. For some patients, the effectiveness can be restored by stopping using the toxin for a period of time (generally 2-3 years) and allowing the antibodies to disappear but for others the immunity is permanent.  

Types of Botulinum Toxin

There are 3 brands of type A botulinum toxin available in the UK: Botox, Dysport and Xeomin. They are all licensed by the government to treat neck (cervical) dystonia and eye dystonia (blepharospasm) in adults. In addition, one type B botulinum brand, Neurobloc, is also licensed to treat neck dystonia in adults. If patients develop immunity to one type of botulinum (either type A or type B) then sometimes the other type can be effective.  

In addition, botulinum toxin is also used to treat other dystonias such as some hand and voice dystonias. Although these uses are not licensed by the government, these treatments can be provided at the consultant’s discretion and are recommended as part of the guidelines of the European Federation of Neurological Societies (EFNS).   

Once dosage and injection siting are sorted out, the effectiveness of the different brands of botulinum in mitigating symptoms is similar. The strength of a unit differs between the brands and, once an individual’s treatment regime has been stabilised, conversion to a different brand is theoretically governed by dose conversion rules. However, there is some disagreement about the exact dose conversion ratios between brands as different research studies contradict each other. In addition, the correct dose conversion ratios can differ between patients as well. This can mean that when switching brands, it can take a while to establish the right dosage of the new brand and this can result in some short-term disruption in the effectiveness of the treatment.  

History of botulinum toxin treatment

Botulinum was first named by a German poet and medical writer, Justinus Kerner who died in 1862. In 1897, Emile van Ermengem found the producer of the botulinum toxin was a bacterium, which he named Clostridium botulinum.

Botulinum toxin was first used to treat muscle conditions in humans by an American opthalmologist, Dr Alan Scott. The first condition treated was crossed-eyes. As early as 1973, Dr Scott predicted that botulinum toxin might be used to treat eye dystonia (blepharospasm) and it was used to treat dystonia in UK for the first time in the early 80s using toxin imported from the US.

During the early 80s, doctors approached CAMR at Porton Down, part of the Public Health Laboratory Service, to manufacture the toxin locally. As toxin usage increased, production from Porton Down needed to be put on a commercial footing. As a result, in the early 90s, Dysport was launched. The name is short for Dystonia Porton Down.   

Botulinum toxin has a number of other medical applications other than treating dystonia – including treating spasticity, bladder problems and headache disorders. Most famously, it is used for cosmetic purposes – a use most closely associated with the brand name Botox.
 

Note: The diagrams above are used with permission of Ipsen UK.

Last reviewed May 2012

Disclaimer
The Dystonia Society provides the information on this page as general information only. It is not intended to provide instruction and you should not rely on this information to determine diagnosis, prognosis or a course of treatment. It should not be used in place of a professional consultation with a doctor.
The Dystonia Society is not responsible for the consequences of your decisions resulting from the use of this information, including, but not limited to, your choosing to seek or not to seek professional medical care, or from choosing or not choosing specific treatment based on the information. You should not disregard the advice of your physician or other qualified health care provider because of any information you receive from us. If you have any health care questions, please consult the relevant medical practitioner.

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