Tardive Dyskinesia Case File

Tardive Dyskinesia Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 6

A 65-year-old woman was referred to the neurologist for a recent onset of abnormal, involuntary movements of the mouth and face. She has been in good health until 3 years ago, when she developed problems with nausea and constipation. She was placed on metoclopramide and omeprazole with some relief of symptoms. A complete gastrointestinal (GI) workup was negative, although it was hypothesized that she had decreased gastric motility. The patient was also started on methimazole for hyperthyroidism. The abnormal movements began approximately 6 months ago, and they have been getting progressively worse. The movements do not interfere with speech but do interfere with eating. She also occasionally has arching spasms of the back and neck. Her examination is remarkable for stereotypical repetitive movements of the tongue and jaw and sustained neck extension.

▶ What is the most likely diagnosis?

▶ What is the next step in therapy?

ANSWERS TO CASE 6:

Tardive Dyskinesia                                        

Summary: A 65-year-old woman was referred to a neurologist for recent-onset abnormal involuntary movements of the mouth and face. She was placed on metoclopramide and developed these movements nearly 1 year later. The movements are getting progressively worse. They do not interfere with speech but do interfere with eating. She also occasionally has arching spasms of the back and neck. Her examination is remarkable for stereotypical repetitive movements of the tongue and jaw and intermittent neck and back extension.

• Most likely diagnosis: Tardive dyskinesia (TD).
• Next step in therapy: Discontinuation of metoclopramide. Consider treatment with benzodiazepines, baclofen, or tetrabenazine if the movements persist.

ANALYSIS

Objectives

1. Recognize the differential diagnosis of involuntary oral movements.
2. Describe the potential motor complications of dopamine receptor antagonist use.
3. Distinguish the treatment options available for the treatment of TD.

Considerations

This is an older woman who has developed abnormal involuntary movements involving primarily the oral–buccal–lingual muscles. Her symptoms started rather insidiously and progressed gradually. Her examination is remarkable for stereotypical hyperkinetic movements, which include tongue protrusion and lip smacking. She has been treated with a medication to help her with GI symptoms, but it is also a very potent blocker of dopamine receptors. Differential diagnosis could include TD, Huntington disease (HD), Wilson disease, neuroacanthocytosis, Sydenham chorea, antiphospholipid antibody syndrome, and anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis. TD is mostly likely in light of her medication history. TD is a disorder that develops relatively late after the initiation of medications that block dopamine receptors, such as the metoclopramide. The proton pump inhibitor omeprazole is associated with GI side effects or headaches; methimazole can cause bone marrow suppression or rarely arthralgias. Various movement disorders can be caused by these medications (Table 6–1).

APPROACH TO:

Tardive Dyskinesia                                        

TD is caused by long-term treatment with dopamine-blocking agents, such as antipsychotics (neuroleptics) or certain antiemetics (eg, metoclopramide). The actual mechanism for TD is unknown. It is thought that prolonged dopamine receptor blockade by dopamine antagonists leads to upregulation of striatal dopamine receptors. In addition, it is possible that structural changes in the neurons or receptors may have taken place. These could lead to increased sensitivity of the dopaminergic neurons to dopamine, resulting in a hyperkinetic state, dyskinesia (compare this to Parkinson disease [PD] where the loss of dopaminergic neurons results in a hypokinetic state manifesting as hypokinetic movements).

The diagnosis of TD is based on the presence of involuntary dyskinetic movements, a history of at least 1 month of dopamine receptor antagonist treatment, and the exclusion of other causes of dyskinesias. TD or tardive syndrome (TS) is characterized by repetitive, involuntary, purposeless movements. Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk may also occur. Involuntary movements of the fingers may also be present. Though these abnormal movements are often more distressing to the family than patients, they can be quite debilitating and result in significant damage to dentition and interference with oral intake of nutrition.

Differentiating TD from idiopathic dystonia syndromes is sometimes difficult. Dystonia can occur as a focal manifestation around the mouth, as well as in a so-called segmental form involving the muscles of the face and neck. However, arching spasms of the back and neck are characteristic of the tardive condition.

TD is sometimes associated with more appendicular involuntary movements. As such, it can be confused with HD. However, the chorea of HD drifts in a random fashion around the musculature, whereas TD tends to be more stereotypic.

Because patients with HD can have chorea and behavioral problems that are treated with neuroleptics, the two conditions can coexist.

Withdrawal of the offending medication can ultimately result in cessation of the involuntary movements, with an average reversibility of about 50%; however, the data supporting this estimate is not very strong. It has been estimated that up to 50% of patients who are treated with dopamine receptor antagonists develop TD eventually.

The strongest risk factors for TD include advanced age, female gender, and coexistent brain damage. Treatment with typical antipsychotic agents can be associated with permanent TD in these individuals. The incidence of TD appears to have decreased with the use of atypical antipsychotics that do not cause such complete dopamine receptor blockade. Metoclopramide is used in the treatment of nausea and gastroparesis. There are other agents for nausea that have much less risk for the development of TD, though the currently approved agents for gastroparesis are limited in the United States. Domperidone is an excellent alternative for metoclopramide but must be obtained from outside the United States. It is a potent dopamine receptor blocking agent but does not cross the blood–brain barrier.

Treatment

The best treatment is prevention, and care should be instituted to avoid using dopamine receptor-blocking agents unless absolutely necessary. Treatment options include benzodiazepines, baclofen, and vitamin E, which are usually only effective in mild cases. Treatment with increased doses of dopamine receptor blocking agents may improve TD temporarily, but most clinicians believe that this results in worsening of the condition. Medications that deplete dopamine do not seem to cause this disorder but can be very beneficial in its treatment. Alpha methyl-p-tyrosine inhibits catecholamine formation by blocking the enzyme tyrosine hydroxylase, and reserpine irreversibly blocks the vesicular monoamine transporter (VMAT). Although useful, these agents have high incidences of side effects including orthostatic hypotension, depression, and parkinsonism. Tetrabenazine is another medication that selectively depletes monoamines at the nerve terminals and appears to be more effective with fewer side effects. Botulinum toxin injections into the relevant muscles may also be useful.

COMPREHENSION QUESTIONS

6.1 A 65-year-old woman is on multiple medications. Her son who is studying pharmacology is concerned about a movement disorder as a side effect of the medications. Which of the following drugs has the highest risk of causing TD?

A. Haloperidol

B. Trihexyphenidyl

C. Levodopa

D. Diazepam

6.2 The patient in Question 6.1 is examined and found to have mainly involuntary movements of the mouth. Which one of the following agents results in decreased severity of oral dyskinesias caused by TD?

A. Fluphenazine

B. Trihexyphenidyl

C. Levodopa

D. Dexedrine

6.3 A 25-year-old man who began treatment for schizophrenia 1 week ago presents to the emergency room (ER) for forceful sustained twisting movements of the neck. Which of the following medications is the best treatment?

A. Diphenhydramine

B. Corticosteroids

C. Haloperidol

D. Metoclopramide

ANSWERS

6.1 A. Haloperidol is a dopamine receptor blocker. Although levodopa can be associated with dyskinesia in patients with PD, this does not occur in association with other disorders.

6.2 A. Further and more complete dopamine receptor blockade will often decrease the manifestations of TD but is felt by many to represent increased risk for long-term continuation.

6.3 A. An anticholinergic medication such as diphenhydramine given intravenously (IV) usually will arrest the dystonic reaction. The acute onset of sustained involuntary twisting (cervical dystonia) soon after the initiation of antipsychotic medications is typical of an acute dystonic reaction.

    CLINICAL PEARLS    

▶ The cause of tardive dyskinesia (TD) is chronic use of dopamine-blocking agents, such as typical antipsychotic agents. ▶ TD may develop months after beginning dopamine receptor-blocking agents and most frequently causes stereotypical movements of the mouth and surrounding regions. ▶ Successful treatment or elimination of tardive dyskinesia is challenging; therefore, the best course is to avoid initiating offending agents. ▶ Backward arching movements of the neck (sustained neck extension), termed retrocollis, is strongly suggestive of an acute dystonic reaction.

REFERENCES

Bhidayasiri R, Boonyawairoj S. Spectrum of tardive syndromes: clinical recognition and management. Postgrad Med J. 2011;87:132-141. 

Chou KL, Friedman JH. Tardive syndromes in the elderly. Clin Geriatr Med. 2006;22:915-933. 

Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes. Neurologist. 2003;9:16-27. 

Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother. 2006;6:7-17. 

NINDS Tardive Dyskinesia Information Page. http://www.ninds.nih.gov/disorders/tardive/tardive .htm. Last accessed Nov 30, 2016. 

Soares-Weiser K, Rathbone J. Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev. 200625;(1):CD000459. 

Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk declining with modern anti-psychotics? Mov Disord. 2006;21(5):589-598.

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