Extrapyramidal Movement Disorders with Antipsychotic Medications (EPSE) – Assessment and Management

PARKINSONISM

The features of Parkinsonism associated with antipsychotic medication exposure are essentially the same as iatrogenic Parkinson’s disease.

The individual experiences a rigidity of the joints, with a characteristic ‘cog-wheeling’ evident throughout the range of passive movement: quite different from the ‘clasp-knife’ rigidity associated with, for example, contralateral cortical insults such as stroke.

The rigidity makes movements slow and shuffling gait and inability to negotiate a three-point turn are characteristic features.

Lack of arm swing while walking is an early sign, demonstrated by asking the individual to extend their arms laterally and drop them to their sides.

Normal tone allows a rapid fall with a characteristic ‘double slap’ that disappears early in the course of Parkinsonism.

There is a characteristic form of tremor associated with Parkinsonism: a slow (4-6Hz) movement of the thumb across the other fingers, a movement which has earned the descriptor ‘pill-rolling’ tremor (see video below).

Some people with Parkinsonism also experience other tremors, notably a fine resting tremor but this is a very non-specific type of movement disorder which is associated with numerous maladies, including anxiety, familial essential tremor, thyrotoxicosis, alcohol withdrawal and treatment with lithium. It can be brought out by placing a sheet of paper on the individual’s outstretched hands.

Another feature of Parkinsonism – and one that that requires differentiation from negative symptoms of schizophrenia – is a restriction of affect. Thus, the individual manifest little by way of facial expression even if the topic being discussed is emotionally charged.

Assessment:

The standard rating scale for the assessment of medication-induced Parkinsonism in The Simpson-Angus Scale, but in clinical settings, this can be cumbersome, and a short screening assessment can be reduced to:

• Ask the patient to walk to the door and then turn around and walk back: note in particular any reduction in the fluidity of gait, shuffling and difficulty performing a three-point turn; and reduced arm swing and a tendency for the arms to move in synchrony with the legs. In more severe cases festination might be apparent. Observe also for the classic ‘pill-rolling’ tremor.
• Ask the patient to hold their arms out to the side and let them fall with gravity to their sides: observe the rapidity to arm drop and the normal ‘double slap’ against the thighs.
• Explain to the patient that you want to feel the tone in their wrists and elbows and ask them to relax and neither to resist not assist you. The joints should be moved slowly, then ask the patient to move their head from side to side, as this can bring out latent cog-wheel rigidity. Ensure you perform this exercise on both left and right as rigidity can be asymmetrical.
• Observe the patient’s range of facial expression, notably whether there is variation. Try to put the patients at ease as affect can be restricted in the person is anxious or depressed. It can be useful to perform a glabellar tap, a positive sign being a failure to habituate (ie. stop blinking) to a light but firm taps to the forehead.

Treatment:

Any discussion of the treatment of Parkinsonism associated with antipsychotic medications needs to begin with the adage of not creating problems in the first place.

The advent of the newer so-called ‘atypical’ antipsychotics has meant that prescribers have a wide range of agents from which to choose; and generally, the newer medications have a lower propensity than the older ones, to cause EPSE.

Of course, this is vastly simplistic as a number of the older (‘first generation’) drugs have inherent anticholinergic properties, e.g. chlorpromazine) that make them less likely than the purer dopamine D2 blockers such as haloperidol, to result in Parkinsonism.

Also, some of the atypical agents such as risperidone, paliperidone and amisulpride tend, at higher doses, to emulate their historically older cousins in terms of EPSE induction.

But certainly, should a patient experience Parkinsonism on a certain medication, the first option would be to try to switch the drug to one with a lower risk thereof.

Learn more about the various receptor profiles of oral antipsychotics.

Should that manoeuvre fail or be otherwise contraindicated, the addition of regular anticholinergic treatment could be employed: 1-2mg of benztropine usually suffices, albeit some patients require higher doses.

DYSTONIA

Dystonia refers to an abnormality of tone, such that increased motor tone results in a sustained abnormal posture. Most striking is the acute variant, which can be frightening, painful and even fatal (e.g. laryngeal dystonia).

At its most extreme, the individual exhibits severe spasm of the muscles, with the strongest muscles prevailing: thus the back arches, the limbs extend, the head is pulled back, and the tongue protrudes; the eyes also roll back in the head.

There is no mistaking this emphatic clinical picture, which can occur shortly after exposure to a dopamine antagonist.

But less dramatic forms can be missed and tardive forms can be mistaken for other problems: for example, a limp might be interpreted as due to a leg problem when it is a manifestation of chronic paraspinal muscle spasm.

Treatment:

Acute dystonias are distressing, painful and potentially dangerous. Immediate treatment entails reassurance of the patient, ensuring they are breathing freely, and administering an anticholinergic agent such as benztropine (2mg) orally, intramuscularly or – in extreme cases – intravenously.

Relief is usually dramatic.

For chronic dystonias, consider changing the offending medication or at least reducing the dose: if these strategies are not clinically sensible, longer-term use of an anticholinergic agent can be employed, albeit there is some evidence to suggest this increases the risk of tardive dyskinesia.

Below is a video of tardive dystonia obtained from the article on tardive movement disorders.

Case:

A 42-year-old man with mood disorder treated with ziprasidone 60 mg daily developed mild facial grimacing and tapered off ziprasidone over 2 weeks followed by worsening and generalization of abnormal movements.

Video demonstrates cervical dystonia with retrocollis and torticollis to the left, jaw-opening dystonia, blepharospasm, truncal dystonia with opisthotonic trunk posturing, proximal arms dystonia with arm extension and internal rotation, and proximal legs dystonia.

 

DYSKINESIA

‘Kinesis’ is the Greek word for ‘movement’ and in the context of EPSE, the term ‘dyskinesia’ usually refers to the ‘tardive’ or ‘later onset’ form.

Fortunately, this stigmatising and sometimes grotesque movement disorder seems somewhat less common with the newer antipsychotics, but it certainly can occur, and clinicians should be vigilant about early signs as the fully-fledged disorder is notoriously difficult to treat.

The main focus is on the mouth and lips, and it can begin with subtle lip movements such as repeated pursing of the lips; as it evolves the tongue can become involved, with licking movements and more noticeable lip smacking.

In its full form, it is quite unmissable, with repeated unsightly oro-facio-bucco-lingual movements that can make swallowing difficult. The trunk and limbs can also be involved, but usually to a lesser degree.

Video from this article.

Risk factors for tardive dyskinesia include long-term exposure to antipsychotic agents (especially at high dose): the first generation drugs seem to carry a higher risk than those from the second generation.

Older age, greater illness severity and being female have also been cited as risk factors for tardive dyskinesia, but these may be confounded and teasing all the factors apart is difficult.

Treatment:

Tardive dyskinesia is thought to be due to hypersensitivity (supersensitivity) of the dopamine system, hence merely adding anticholinergic drugs is usually of no benefit.

Indeed, stopping the offending antipsychotic is also no solution: the movement disorder can become even more pronounced.

Of the antipsychotics, clozapine is both least likely to cause tardive dyskinesia, as well as sometimes ameliorating the symptoms.

A vast array of other therapeutic strategies have been used – from vitamin E to ECT, galantamine to pallidal deep brain stimulation –  with almost all proving not to withstand clinical trial scrutiny.

Interventions that have a supportive evidence base include amantadine (300mg daily) and ginkgo biloba, but the benefits are modest.

Tetrabenazine, which essentially depletes dopamine stores in the nigrostriatal tract, has a long been used in Huntington’s Disease and for tardive dyskinesia. Its use has been limited in part by its side effect profile (insomnia, akathisia, pseudoparkinsonism; and depression and suicidality) and in part by its short half-life, requiring multiple daily dosing.

A recent development has been a deuterated form (deutertrabenazine) which slows the catabolism, making it better tolerated and allowing twice-daily dosing.

Another approach has been the development of valbenazine, a highly selective VMAT2 inhibitor.

Both deutertrabenazine and valbenazine have been approved by the FDA for tardive dyskinesia: their place in clinical practice will be determined in due course.

Read more on tardive dyskinesia where we cover the AIMS examination and include a video on examination.

AKATHISIA

Akathisia is an inner restlessness such that the individual feels ‘compelled’ to move but movement actually does little to alleviate it, leading to overt and relentless movement of the legs in particular.

What used to be referred to as the ‘stelazine stomp’ after a now-expunged first-generation antipsychotic notorious for evoking this very unpleasant sensation.

The experience most similar to akathisia is restless legs syndrome, but unlike the latter, which occurs mostly at night, akathisia is experienced right through the day: it can be particularly frustrating at night, as the compulsion to move is difficult to accommodate, and it can lead to insomnia.

Case:

The video below is of a 34-year-old man with paranoid schizophrenia treated with haloperidol 10 mg daily for 2.5 years and lurasidone 80 mg daily for 6 months developed restlessness, inability to stay still, and abnormal hand movements. The video demonstrates extreme restlessness and hand-rubbing stereotypies. (Source)

It is important to appreciate clinically that there are two components:  objective restlessness (which in itself can be mistaken for anxiety or psychotic agitation) and the subjective feeling described above: one patient described it as ‘an itch deep in my very bones’.

No antipsychotic – clozapine possibly again being the exception – is free from akathisic potential. Whilst the newer agents have a relatively lower propensity than the older ones, to induce severe akathisia, the dopamine partial agonists, due to their inherent dopamine agonism, are particular culprits, albeit brexpiprazole has a much lesser effect than aripiprazole, due to the former having lower dopamine agonism.

Akathisia can be assessed through the Barnes Akathisia Rating Scale. 

Treatment:

Akathisia can be enormously unpleasant and has even been associated with suicidality.

It needs to be recognised and treated in a targeted manner and not dismissed as psychotic agitation: indeed, the latter mislabelling often leads to increased doses of antipsychotics, whilst the amelioration of akathisia requires the dose to be lowered.

If lower dosing is not feasible or is ineffective, various agents might be useful in the shorter term to reduce akathisia.

These include beta-blockers (beware of asthma and lowing of blood pressure) benzodiazepines (beware of dependence) and the antidepressant mirtazapine, which has the added virtue of hypnotic effects (beware longer-term weight gain).

Usually, akathisia lessens with time but can become enduring, in which case a switch to a lower-propensity antipsychotic should be considered.

View a detailed video on the pathophysiology, diagnosis and management of akathisia. 

Examination of EPSEs (AIMS) -video from psychinterview.com

CONCLUSIONS

Despite the development of antipsychotics with an over lower propensity to those movement disorders that were so problematic with the first generation drugs, clinicians need to be aware that no antipsychotic is entirely free from the induction or worsening of EPSE.

Vigilance for early signs and symptoms of EPSEs, and prompt and effective management need still to be top of mind in the treatment of people with schizophrenia.

Also, given the broader use of antipsychotics in the mood and anxiety disorders, choice of agent should reflect the risk of EPSEs, and patients need to be fully informed in this regard.

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