The Canadian Movement Disorder Group
Tardive Stereotypy

Clinical

Stereotypies can be defined as an "involuntary, coordinated, patterned, repetitive, rhythmic, purposeless, but seemingly purposeful or ritualistic, movement or utterance". The diagnosis of stereotypies is based on the recognition of the typical type of movement. Stereotypies can be seen in a variety of medical conditions including autism, mental retardation, Rett's syndrome, restless leg syndrome and akathisia.

It is important to realize that up to 14% of non-medicated schizophrenic patients have involuntary movements. 1-8% of the elderly develop spontaneous oral facial dyskinesias. This is higher in the edentulous population. The overall prevalence of tardive dyskinesia among patients chronically treated with neuroleptics is about 25%. The incidence in young adults is about 5% per year. Aging, female gender, a positive family history, mood disorders, "organic" brain dysfunction, as well as early extrapyramidal  side effects all increase the risk of developing these movements. The risk directly correlates with the duration of the neuroleptic exposure. The longer the tardive movements are present the less likelihood they will resolve.

The most common and typical tardive stereotypies are the repetitive oral facial and lingual movements that resemble chewing, lip smacking, tongue protrusion (" fly-catching") or lateral tongue movements in the floor of the mouth (Bon-Bon sign). Often the patient is unaware of these early movements which are often predictive of future dyskinesias. Other examples of tardive stereotypies include repetitive and patterned hand waving, toe waving, body rocking, and head bobbing. More complex movements consist of repetitive leg crossing, standing and sitting, picking at clothes, rubbing the face and head, shifting weight, as well as marching. Abdominal and pelvic muscle involvement can produce pelvic rocking ("copulatory stereotypy"). In  younger patients the limbs are more frequently involved. Vocal stereotypies include humming, moaning, and altered breathing patterns ("respiratory stereotypies").

Unlike typical idiopathic dystonia, tardive dystonia improves with action, and is usually not helped by "sensory tricks". Facial stereotypies improve when protruding the tongue and tend not to involve the upper face distinguishing these movements from those seen in Huntington's Disease. Tardive stereotypies are accentuated by distraction such as writing or performing rapid alternating movements and like tics they are suppressible  but to a much lesser degree.

Pathophysiology of Tardive Stereotypies

The pathophysiology of tardive stereotypy is not understood but striatal dopamine (D2) receptor super-sensitivity has been the traditional explanation. Although there are several dopamine containing systems in the CNS,  it is believed that the nigro-striatal system is the most important in tardive stereotypy. There is significant evidence revealing up-regulation of striatal dopamine receptors in patients and animals in Dopamine receptor ligand binding studies. Rodent models treated with neuroleptics for two weeks show an increased activity and number of Dopamine D2 receptors. More recent human studies including P.E.T. scanning data have not confirmed this. There is PET scan data showing that the metabolic rates are increased in the motor cortex and the globus pallidus suggesting over activity of these regions.

There are several problems with an isolated Dopamine hypothesis:

1) The late appearance of the abnormal involuntary movements (AIMS), yet receptor super sensitivity is seen very early.

2. Dopamine receptor supersensitivity is likely present in all patients but only 25 % get tardive AIMS.

3. Tardive movements persist after drug withdrawal even though there is a resolution of supersensitivity.

4. Tardive stereotypy is not seen with dopamine depleting agents that can  also induce dopaminergic receptor supersensitivity. Other transmitter systems are likely involved including GABA and noradrenaline. A GABA-hypothesis has been suggested whereby neuroleptics induce the  destruction of a sub-population of the GABA neurons in the striatum. Supporting this is the finding of decreased levels of glutamate decarboxylase activity in the basal ganglia of patients with tardive stereotypy. Additionally recent drug trials with GABA agonists look promising.

A third hypothesis is related to an excess of free radicals producing cytotoxic damage. It is possible the neuroleptics may interact with transitional metals in  the basal ganglia and this may produce neural damage through the production of the excessive free radicals. There are some studies suggesting free radical scavengers including vitamin E. may be helpful in management. A recent  meta-analysis combining studies published since 1987 demonstrated that a significant subgroup (28.3%) show a modest improvement in tardive dyskinetic movements with vitamin E. This isn't considered generally accepted as proven. Recently abnormalities in mitochondrial complex I enzymes have been found in rat brain and human platelets with chronic neuroleptic exposure. This may therefore lead to further support for the free radical theory.

Some investigators hypothesize that neuroleptics enhance striatal glutamatergic neurotransmission by blocking presynaptic dopamine receptors, which causes neuronal damage as a consequence of oxidative stress. CSF studied in patients with schizophrenia and tardive dyskinesia had significantly higher concentrations of N-acetylaspartate, N-acetylaspartylglutamate, and aspartate in their CSF than patients without tardive dyskinesia. These findings suggest that there are elevated levels of oxidative stress and glutamatergic neurotransmission in tardive dyskinesia, both of which may be relevant to the pathophysiology of tardive dyskinesia.

Research has also demonstrated abnormalities in a variety of other peptide systems including cholecystokinin, neurotensin, and opiates. Further work is needed to delineate the significance of these neurochemical findings in human tardive dyskinetic patients.

Metabolism of most drugs influences their pharmacological and toxicological effects. Scattered information about genetic vulnerability leading to an  increase risk of NIMDS has been emerging over the years. It seems that human polymorphic variation of drug metabolism leading to adverse reactions is an unavoidable phenomenon (e.g. Tolcapone). Evidence for a familial co-occurrence of medication induced movement disorders has been increasing. Familial cases of drug induced parkinsonism, akathisia, tardive dyskinesia, neuroleptic malignant syndrome, and dystonia-parkinsonism have been described. Varying phenotypes of movement disorders have been identified among members of the same family. Genetic predisposition may relate to a defect in drug metabolism via an enzymatic defect, or to a familial co-factor or  heavy metal deficiency.

Iron deficiency has been associated with both restless leg syndrome and the akathisia, while ferritin levels have shown a correlation with the risk of tardive dyskinesia. In one study diabetes doubled the risk of tardive dyskinesia.

The strongest evidence for correlation of genetic factors and drug induced movement disorders occurs in patients with already known genetic  predisposition for movement disorders. For example neuroleptic malignant syndrome has been shown to be more frequent in association with Wilson's disease, Huntington's chorea, and variety of other familial neurodegenerative  diseases. It is quite likely that there is a pathophysiological link between the major psychiatric disorders and the neuro-motor dysfunction that occurs following exposure to some medications.

 Genetic polymorphisms have been described for many drug-metabolizing enzymes. The most characterized are cytochrome P450 2D6, cytochrome P450 2C19, glutathione S-transferases, and N-acetyl transferase 2. Two of the  most important enzymes for metabolism of neuroleptics and other psychoactive drugs are CYP2D6 and CYP2C19.

The CYP2D6 gene encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Tardive dyskinesia was found with a higher incidence in patients that were heterozygous carriers of 2D6 mutated alleles than in patients without CYP2D6 mutations. This further supports the free radical theory.

Recent genetic studies have also identified a higher frequency of tardive dyskinesia associated with homozygosity for the Ser9Gly variant of the gene for the D3 receptor subtype of the dopamine receptors.

Treatment:

As this condition can be refractory to all treatments the emphasis needs to be placed on prevention rather than treatment. Patients on chronic therapy need to be advised of the risks and reviewed periodically to screen for early manifestations of these movements.

In general neuroleptics should be used only when an psychosis is present and should not be used for anxiety, depression, or insomnia. Chronic use of drugs such as metoclopramide (maxeran) or Stemetil should be avoided. There are alternative medications  with a far lower risk of tardive movement disorders. If neuroleptics are to be used chronically, the lowest effective dose should be used and the need for these medications should be a reassessed every four to six months. Drug holidays from neuroleptics are now believed to increase the risk of persistent tardive movements and are not recommended. Chronic concomitant use of anticholinergics also appears to increase the risk of tardive stereotypy.

The first step in medical treatment of tardive stereotypy is to attempt to withdraw the neuroleptic if possible. This can be expected to increase the severity of the dyskinesia transiently. If discontinuation of the neuroleptic is not possible switching to a less potent neuroleptic would be the next option. The risk of AIMS with the novel antipsychotics is less than with the older conventional drugs, as agents that produce a lower likelihood of acute extrapyramidal syndromes produce less tardive dyskinesia.

If tardive stereotypy persists despite the above interventions there are a variety of other medications that have been used to try to control these movements. The previous first drug of choice, clonazepam is reported to help approximately 40% of the time (probably through GABA mechanisms). The newer drug of choice would be tetrabenazine, which is effective in suppressing these movements in up to 50%of cases. This drug comes in 25 mg tabs and is used in a tid regime up to 150 mgs /day. Side effects of concern include hypotension, depression, and parkinsonism. Propranolol more recently seems to have a high potential for success.

Other medications with some potential include Baclophen, Valproic Acid, cholinergic agonists, clonidine, and buspironel. Bromocriptine and diltiazem have also been useful in severe tardive  stereotypy.

Alpha-tocopherol (Vit E) as mentioned above may have potential therapeutic effect in a subgroup of patients.

Combinations of the above drugs may be required. For example the combination of clozapine and clonazepam is reported to be an effective treatment for tardive stereotypy (Shapleske et al 1996).

One option in the case of the elderly patient, or in a patient who would not tolerate some of the medications listed above, would be to simply return to the prior neuroleptic at a somewhat higher dose. In this approach the physician and patient accept the potential (but not inevitable) risk of developing more severe movements in the future.

ECT (electric shock therapy) may be considered for patients with severe disabling tardive stereotypy who have failed to respond to medications.

Dental prosthetic therapy has been recently reviewed (Sutcher et al 1998) and is of marked importance in the treatment of the orofacial manifestations of tardive stereotypy. Any team approach to the treatment of Tardive stereotypy should include an interested general dentist or prosthodonist.

Thankfully initial advances in atypical neuroleptics (clozapine and risperidone) are now being superseded by newer options such as olanzapine and seroquel. These new agents may prove it is possible to have effective antipsychotic agents with a low risk of tardive dyskinesia. They do need to be used carefully and AIMS should be watched for.

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