Treatments of Dystonia

The Godfather · 09-27-2006, 08:55 AM

A literature search has shown that treatment of Dystonia prior to the development of botulinum toxin was found to be very much hit and miss regarding a stable and useful treatment for Dystonia. With the exception of the use of levodopa in the treatment of Dystonia in the rare cases of Dopa-responsive Dystonia, the use of other drugs has proved extremely variable.

There have been a large number of different drugs used over the years with differing results, none of which have proved particularly effective. Until the pathogenesis of Dystonia is fully understood the treatment of the majority of Dystonias will unfortunately be non-specific, aimed at symptomatic treatment rather than the dystonic aetiology.

Systemic pharmacotherapy may provide an overall benefit in 30-40% of dystonic patients. Initial treatment is guided by the use of drugs with a low potential for side effects coupled with the anatomic distribution of the Dystonia. About 5% of patients with any form of idiopathic Dystonia may experience a spontaneous improvement or resolution of the movement disorder, this is most likely to occur within the first 5 years and relapses are often common.

ANTICHOLINERGIC/ANTIDYSKINETIC AGENTS (These agents work by blocking the effect of Ach at the neuromuscular junction, this inhibits the muscarinic receptors and therefore restores the balance between cholinergic and Dopaminergic activity; which in turn reduces the tonic contraction which is a characteristic feature of dystonia.

Anticholinergic drugs tend to block the transmission across the cholinergic synapse and Artane is in fact an Acetylcholine antagonist. Within a healthy individual muscarinic acetylcholine receptors exert an excitatory effect, which is in fact opposite to that of dopamine upon striatal neurones (which is an inhibitory effect), and also exerts a presynaptic inhibitory effect upon Dopaminergic terminals which would act to inhibit dopamine release, an effect that would be very much undesirable within dystonia (inhibition of dopamine release results in a decrease of excitatory effects). As such, drugs that target these receptors aid and help dystonic symptoms because it is the M1 receptor that the drugs inhibit which in turn reduce any excessive striatal cholinergic activity. Such receptors are found within the CNS and peripheral neurones. They are predominantly responsible for excitatory effects, for example the slow muscarinic excitation that is mediated by acetylcholine. Such excitation is achieved by a decrease in potassium conduction which is responsible for depolarisation. This means that if there is presynaptic inhibition at this point the slow excitation of the neural cells would be prevented.

Artane/Trihexyphenidyl/benzhexol is an oral synthetic tertiary antagonist of acetylcholine at muscarinic receptors. Its actions are similar to those of atropine (which also acts on M1 receptors too), and because it is a tertiary compound it is able to penetrate the CNS making it particularly useful in treating both Parkinson’s’ and Dystonia. It affects the receptor rather than the acetylcholine and as such blocks the muscarinic receptor which inhibits parasympathetic transmission by the above mechanisms. It is for this reason that muscarinic antagonists are often termed parasympatholytic as they have been found to selectively block the effects of the parasympathetic nerve activity (Rang et el 1999). The most important action of these drugs in respect to dystonia is that they affect the Extrapyramidal system (collection of nerve tracts within the pyramid of the medulla oblongata en route from the cerebral cortex to the spinal cord) of the CNS, which reduces the involuntary movements present within a dystonic person.

Drugs such as Benzhexol (Artane) an anticholinergic may help approximately 50% of children and 40% of adults but very large doses are needed (60-100mg) as opposed to people with Parkinson’s who may be given just 6mg to help tremor. Improvement is independent of age at onset, age at starting therapy, the severity of Dystonia at the start of therapy and aetiological diagnosis. However, it should be noted that improvement is very much dependent on dosage and sometimes the dosage side effects may in fact be intolerable to the patient. Neuroleptic induced dyskinesia (tardive) respond especially to anticholinergics and benzodiazepines.

Such drugs are given to dystonic patients because of the proposed lack of inhibitory neurotransmitters and the resulting imbalance between excitation inhibition. Although there is no definitive understanding as to why these agents work on some dystonic patients and not others. It must be due to the fact that within some people (especially children) there are varying degrees of chemical imbalance. That is to say that within children and some adults an inhibition within the cholinergic neurones is enough to tip the balance, whereas in others there is too much of an imbalance and even thought a cholinergic inhibition helps it is not enough to prevent the dystonic symptoms. It should be noted though that these drugs are seldom used in isolation but are predominantly administered as part of a combination therapy. Although perhaps it is important to note that there appears to be a class of dystonia that is aided by pharmacological intervention and there are those that have no positive response or only a rather limited response. This tends to incline my thoughts to peruse the notion that maybe some dystonia is merely a chemical imbalance correctable by pharmacological therapy and then that there is dystonia that encompasses this and something else such as definitive problem within reciprocal inhibition or within the Extrapyramidal tracts. >top

GABA ASSOCIATED DRUGS

BACLOFEN was introduced in 1972 and like GABA it acts upon many types of nerve terminal to inhibit the release of the neurotransmitter, however, unlike GABA, baclofen has little postsynaptic inhibitory effects. Baclofen is a GABA-B transmembrane receptor agonist which is predominantly responsible for presynaptic inhibition and acts via second messengers. Acting at this point actually increases the quantity of neurotransmitter released by the post synaptic terminal button acting as an agonist. Such an agonistic action aids to increase GABA-B neurotransmitter release which naturally acts as an inhibitor within the CNS and as such serves to counteract the excessive neuronal messages present within dystonic patients. A further step in the administration of baclofen was to administer it in an intrathecal manner. Such an administration meant that lower doses of the baclofen would be necessary which ultimately minimises the side effects. This is attributable to the fact that it is administered directly into the CSF so a lower dose is needed than if it were administered orally whilst also providing superior effects. A pump is implanted within the abdomen of the patient and a small tube then leads from this pump up the spinal column of the patient to an approximate level of T4. The drug is delivered directly to the CSF and as such is able to make its way to the brain very quickly, which has mainly GABA-A receptors. The dosage is then increased gradually until a satisfactory result is obtained, with most patients receiving a dose of one thousand micrograms. It should be noted though that the patient does still have some side effects, they are not as severe as they would be if the patient were to receive an equivalent oral dose

Another class of drugs recently used within Dystonia management are those that have a GABA derivative, such as GABAPENTIN, CARBAMAZEPINE, LAMOTRIGINE and VALPROATE. These drugs are anti-epileptics and were found to help dystonia by accident, when a person suffering with both epilepsy and dystonia was put on these drugs to help her epilepsy and had a subsequent improvement in her dystonic symptoms.
Gabapentin is slightly different to the latter drugs as it is a GABA-A-receptor agonist, although ironically it has little or no effect on GABA receptors/transporter and as such its mechanism of action remains elusive.

The aforementioned drugs are not as new as Gabapentin and as such their mechanism of action is better understood. These drugs affect the membrane excitability by acting upon the voltage dependent upon sodium channels which relay the inward membrane current necessary for the generation of an action potential (Rang et el 1999). They have been found to preferentially block the excitation of cells that repeatedly fire, and the level of blocking correlates directly with the rate of firing, i.e. the more they fire the more they are blocked (Ib Id 1999). This characteristic was then found to be favourable to the treatment of dystonia as the ability of a drug to block the abnormal high frequency hyperactive discharge seen within dystonia without disproportionately interfering with the low frequency firing of neurones within the normal state. Such a property arises from the adeptness of the blocking drugs to differentiate between the sodium channels in their resting, open and activated states. The depolarisation of the neurones serves to increase the disparity of the sodium channels in the quiescent state. The aforementioned anti-epileptic drugs bind in a biased action to channels in this state and therefore truncate the number of functional channels available to generate action potentials (op cit1999)

The drug valproate has been found to significantly burgeon the GABA content of the brain (a neuronal inhibitor, which may be lacking in dystonic people) whilst also serving to impede two enzyme systems that inactivate GABA, namely, GABA-transaminase, and succinic semialdehyde dehydrogenase, whilst also effecting the sodium channels (as detailed above) (op cit 1999)

GABA drugs are administered to aid an increase within the inhibitory neurotransmitter and its actions. Such a theory may be substantiated by the fact that a mutation within GAD genome which is responsible for the formation of GABA has been noted, but if this mutation some how had a knock on effect upon the production of GABA and its subsequent actions then a therapeutic dose of GABA associated drugs would ensure that there is a correctly operative dose of the inhibitory GABA neurotransmitter. >top

BENZODIAZEPINES

These drugs (Diazepam etc) act upon three unambiguous binding sites, which are closely related to the aforementioned GABA-A receptor. When the benzodiazepine obligates its receptor GABA-A , it induces a conformational change which augments the actions of the inhibitory neurotransmitter GABA on the ÿ-subunit. When GABA binds to its receptor, the influx of calcium ions into the cell increases which ultimately results in membrane hyperpolarisation and as such diminished cell excitability. It is important to note that Benzodiazepines act only in the presence of GABA to enhance GABA mediated opening of the ion channel, they have no direct action upon the channel. Such actions naturally result in an increase within inhibitory neurotransmission, a desirable effect within dystonic people. >top

BOTULINUM TOXIN

Despite an incomplete understanding of the neurological mechanisms underlying Dystonia, relief of dystonic posturing and associated pain and discomfort has improved markedly with the introduction of botulinum toxin (BTX therapy) in the late 1980s

BTX is one of the most potent biological substances known to man, but in very small doses it has proven itself to be an effective acetylcholine antagonist which prevents neurotransmitter release by the terminal buttons and thereby paralyses the muscles it is injected into. It acts by binding presynaptically to high affinity recognition sites within cholinergic nerve terminals and thereby decreases the release of acetylcholine, resulting in a neuromuscular blocking effect by preventing exocytosis. It is important to note that this treatment is not permanent and needs repeating every 2-4 months, this is due the fact that recovery from the neuromuscular block occurs through proximal axonal sprouting and muscle reinnervation by formation of a new neuromuscular junction. This is supported by a recent study from De Paiva and colleagues (www.emedicine.com 2002) who suggest that eventually regeneration of the original neuromuscular junction will occur.

There are 7 distinct serotypes these being A, B, C, D, E, F and G they are all of similar sizes and structures. Although it is important to note that each serotypes specifically differ in their potency, duration of action and cellular target sites. However, each of the seven serotypes of BTX are composed of three domains, namely, the translocation domain, the enzymatic domain and the binding domain. The actual toxin itself is synthesised as a single chain peptide with a molecular mass of approximately 150 Kd. This form has relatively little significance as a neuromuscular blocking agent and its activation to become significant requires a two step modification of the tertiary structure of the protein. Such a process then converts what is a single chain neurotoxin into a di-chain neurotoxin consisting of a 100 Kd Heavy chain (HC) linked by a disulphide bond to a 50 Kd Light chain (LC) . Once in this formation the BTX as previously noted acts at the neuromuscular junction where it exerts its effect by inhibiting the release of ACH from the presynaptic nerve terminal.
The ACH is contained within vesicles and several proteins such as VAMP, SNAP-25 and syntaxin are required to mediate the fusion of these vesicles with the axon terminal membrane (Chapman Nature 1993). It should be noted that the BTX binds to the presynaptic terminal via the HC. The toxin is then internalised and the HC and LC are then separated. The LC from BTX-A has been found to cleave SNAP-25, and the LCs from serotypes B and F cleave VAMP, and those from serotype C cleave SYNTAXIN. Ultimately this disrupts ACH release and subsequent neuromuscular transmission, resulting in weakness of the injected muscle and hence a weakness within the previously dystonic muscle (Brin et el Neurology 2000) and (F Molley Dept Neurology 2002). Should BTX be injected into a non-dystonic person, then they too would experience weakness within the injected muscle but as that muscle was not hypertonic then there would be no increased tone to overcome and as such the person would get weakness and a resultant drooping of the muscle. For this reason it is used for cosmetic surgery to inject into wrinkles which are the result of a slightly overactive facial muscle. The doses as such are adjusted accordingly and are necessarily smaller than those administered to a dystonic patient (D. Kedlaya, www.emedicine.com).

Types A and B are now commonly used for dystonic symptoms and have been found to be safe and effective during double blind clinical trials for the treatment of Dystonia. (R. Hauser, www.emedicine.com, 2002). One formulation of BTX-A is marketed worldwide under the trade name BOTOX or DYSPORT and was approved by the FDA for “the treatment of strabismus, Blepharospasm and focal spasms including Hemifacial spasm and Torticollis) (Ib Id pg2). A formulation of BTX-B was approved in December 2000 for the treatment of cervical/Torticollis Dystonia only and is marketed under the name Neurobloc. >top

DOPAMINERGIC DRUGS

Dopamine produces, both excitatory and inhibitory post synaptic potentials, depending upon the post synaptic receptor be they D1, D2, D3, D4, or D5. It is termed a catecholamine and the8 precursor molecule bears little resemblance to the final dopamine product because the pre-cursor molecule is slightly modified step by step until it reaches its final shape. Each of these steps detailed below are controlled by a different enzyme which causes a small part to be either added or subtracted. The precursor molecule is an essential amino acid (meaning it can only be obtained from our diet as we are unable to produce it ourselves) termed TYROSINE.

Within a non-dystonic patient DA is synthesised within the presynaptic terminal from tyrosine which converts the DA into L-DOPA (by the addition of an OH group (hydroxyl group) coupled with Tyrosine Hydroxylase (TH) which is the compound that adds the OH group. The L-DOPA molecule than loses a carboxyl group (COOH) through the activity of an enzyme named DOPA decarboxylase an aromatic amino acid and becomes dopamine. (Widmer et el 2000; Carlson 2001). The DA is then taken up and stored within the synaptic vesicles at the presynaptic terminal. Following the release of DA from the vesicles into the synaptic cleft, reuptake by the dopamine transporters (DAT) into the presynaptic membrane occurs after which the DA is transported back into the vesicles or alternatively is degraded to DOPAC (dihydroxyphenylacetic acid) by type B monoamine oxidase (Oliver et el 2000; Shin et el 1999).

The brain contains numerous systems consisting of Dopaminergic neurones. The three most important of them originate within the midbrain, the substantia nigra and the ventral tegmental area. The most important of these in respect to Parkinson’s’/dystonia is the NIGROSTRIATAL SYSTEM, whose neuronal cell bodies are located within the substantia nigra whilst their axons project into the neostriatum, caudate nucleus and the putamen. THE NEOSTRIATUM IS AN IMPORTANT AREA WITHIN THE BASAL GANGLIA WHICH IS ESSENTIAL FOR MOVEMENT CONTROL. People with Parkinson’s and dystonia are often given Levodopa (brand name madopar or sinemet) a dopamine precursor. By supplying the brain with dopamine pre-cursor, the brain can convert it into dopamine, since dopamine production may be depleted. Levodopa must be administered with a chemical named decarboxylase inhibitor (DCI). DCI prevents the break down of the levodopa within the brain before it may be converted to dopamine. Brand names such a sinemet/madopar contain both levodopa and DCI. Such Dopaminergic drugs are agonistic in their actions and act to stimulate D2 receptors. This is important because D2 receptors inhibit adenylyl cyclase via a “Gia-subunit or are linked to phosphatidylinositol turnover or to potassium and calcium channels” (vallar et el 1988 cited by www.unifr.ch/biochem 2002). As such D2 receptors are inhibitory and therefore inhibit excess neuronal activity within the brain.

It is believed that dystonic patients like Parkinson’s’ patients may have a deficit of dopamine. As Parkinson patients often develop dystonic symptoms it was initially believed that perhaps the two disorders were interrelated and as such dystonic patients began to receive Parkinson’s’ drugs and in many people therapeutic benefit was observed. The exact mechanism of why they work is still not fully understood. There is a specific sub-class of dystonia called Dopa responsive dystonia (DRD). First described by Segawa, Japan, (Adv Neurol, 14: 215-33, 1976). Responds very well to L-dopa. Often requires doses higher than usual anti-PD doses. Usually childhood onset, affects the legs, may be confused with spastic cerebral palsy. Upto 10% of childhood onset dystonia may be DRD (Dipanker Nandi Cons Neurosurgeon and Neurophysiologist 2002). Within Dopa-responsive dystonia there is evidence of inferior dopamine synthesis coupled with a marked decrease in striatal dopamine content in the presence of a normal number of substantia nigra neurones coupled with a regular striatal L-dopa uptake (Sawle et el, 1991). As such the dramatic and rather exceptional response to L-dopa is most probably directly related to the structural integrity of dopamine neurones in this disorder (Munson 1996).

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