Motor fluctuations and dyskinesias (diagnosis and management).

Motor complications appear in approximately 50% of patients on levodopa (LD) therapy for more than 5 years. Chase et al[1] reported that 28--84% of LD-treated patients develop motor fluctuations after an average of 4.1 years after starting LD therapy. These occur as a result of progression of the disease process (increased neuronal degeneration) and the cumulative effect of prolonged treatment with dopaminergic drugs, especially LD.

The Motor Complications include

Motor fluctuations

Wearing off effects (end-of-dose deterioration): This is the most common initial manifestation of motor fluctuation. The patient starts to feel the reappearance of motor symptoms before the next dose. It is predictable and occurs 2--4 h after a dose of LD.[2] In the initial stages, the symptoms great promptly alleviated after the same dose of dopaminergic medications. However, later the dose needs to be increased or another medicine for PD needs to be added.

“ON” and “OFF” phenomena which can be predictable or unpredictable: Gradually, the patient starts having “OFF” periods when not on medications or after the effect of medicine goes away, and a predictably good “ON” response about 45 min to an hour after intake of LD (or other dopaminomimetics).

However, as the disease progress, the “ON” response may be suboptimal or erratic, and patient can develop unpredictable “ON”--“OFF” motor fluctuations. These “motor shifts” occur as a result of loss of presynaptic dopamine terminals and from fluctuating neurotransmitter level.[1]

Nighttime deterioration: In moderate to advanced disease, patients wake up in the night with motor symptoms, difficulty in rolling over in bed, muscular discomfort, and frequent urination.

Early morning deterioration: This can often be associated with painful foot dystonia.[3]

Dyskinesias/ dystonias.

These can be of the following types:[34]

At peak-dose, more often dyskinesias

During “OFF” periods, more often dystonias

A combination of peak-dose and “OFF” period (biphasic), patients often cycling in these two phases

Diagnosis

Diagnosis is based on meticulous history from the patient and caregivers. Patients need prolonged observation before and after a dose of medications for PD. Patients are often not concerned about the minor dyskinesias and therefore may deny this symptom. However, the caregivers are in a better position to confirm the presence of dyskinesias.

When in doubt about the presence or degree of motor complications, patients should be given 24 h diaries to be completed at home, marking the OFF, ON stages, time and severity of dyskinesias, and temporal relationship with the medications. If necessary, patients and caregivers should be shown video clippings of patients with dyskinesias.

Finally, patients may need a short admission in the hospital and evaluated in OFF and ON stages with UPDRS scales and scales for dyskinesias.

Principles of Management

Suboptimal clinical response, wearing-off phenomenon, delayed “ON” or no “ON” without dyskinesias or minimal dyskinesias

Optimize the current dosage of anti-PD medications (increase the strength of each dose or give more frequently) without causing side effects.

If already on optimal dosage of levodopa-carbidopa (LD) preparation only, try

adding COMT-inhibitor-entacapone (200 mg with each dose of LD, up to 1600 mg/day,[56]

changing over to controlled-release (CR) preparation of LD or add CR preparation to the standard LD preparation (especially a bedtime dosage of 200/50 mg CR preparation of LD for nighttime wearing-off),[78]

adding MAO-B inhibitor, e.g. selegiline (5 mg at morning and afternoon) or rasagiline (0.5 mg at morning, later can be increased to 1.0 mg at morning),[9]

adding amantadine, 100 mg once daily, increased to twice a day,[10]

adding a dopamine agonist (e.g. ropinirole or pramipexole),[3]

If already on an optimal dosage of dopamine agonist only, try

switching over to another agonist (e.g. from pramipexole to ropinirole and vice versa)

adding LD preparation (immediate or CR preparation)

adding MAO-B inhibitor or amantadine

redistribute dietary protein

consider surgery for PD

Nighttime deterioration: The following strategies may be tried:

A CR preparation of LD at bedtime

An extra dose of standard LD around midnight when patients wakes up

Addition of dopamine agonist or entacapone if patient is not on these drugs.

Early morning deterioration: Often patients are relieved by a standard preparation of LD, which can be given crushed and with carbonated drink or on empty stomach, if patient can tolerate.

Patients with disabling dyskinesias

Choreiform dyskinesias

Peak dose dyskinesias: The following strategies can be tried:

If patient is on CR preparation of LD, switch over to immediate release one[11]

Reduce individual dose of LD and give more frequent

If patient is on a COMT inhibitor, stop the drug

Reduce the total daily dose of LD and add a dopamine agonist (ropinirole or pramipexole) or increase the dose of dopamine agonist if patient is already taking one

Reduce dosage of LD and add amantadine. The dose of amantadine need to be 300-400 mg/day and the benefits tend to be short lived[12]

Reduce LD and add anticholinergic drugs (e.g. trihexyphenidyl)

Remove selegiline or rasagiline

Continuous drug delivery such as subcutaneous apomorphine or duodenal LD may be considered[13]

Atypical neuroleptics such as clozapine may be of help[14]

Consider surgery for PD (deep brain stimulation of bilateral subthalamic nucleus is most preferred target)[3]

Biphasic dyskinesias: It is difficult to treat this condition, but the following strategies may be tried.[11]

If patient is on a CR preparation of LD, change over to immediate release one

Increase the total dose of LD

Restrict use of LD to several early and/or mid-day doses

Add or increase the dose of dopamine agonist

ubcutaneous apomorphine injections can be tried at selected times

Try continuous drug delivery (as mentioned above)

Assess for psychiatric problems and treat when present

Try behavioural management

Consider surgery for PD

Dystonias

Peak-dose dystonia

Reduce dose of LD

Add or increase dose of dopamine agonists

Consider surgery for PD

Early-morning / OFF-period dystonia

Add CR preparation of LD at bedtime

Add dopamine agonist at bedtime

Add COMT inhibitor

Early morning immediate release LD may be tried 1--2 h before getting up from bed

Other drugs such as baclofen, diazepam, or anticholinergic drugs can be tried

In focal dystonia, injection of botulinum toxin type A in the dystonic muscles can be tried

Unpredictable “ON-OFF” periods: The following options may be considered.

Adjust time and dose of LD

Add dopamine agonist

Add COMT inhibitor

Add rasagiline

Change to liquid preparation of LD:[15]

Daily liquid preparation of LD needs to be prepared by crushing ten tablets of standard (immediate release) 100/25 levodopa/carbidopa, 2 g of ascorbic acid and dissolving in 1 L of water. This solution need to be administered every 60-90 min intervals, the dose being adjusted according to the response and side effects.

Redistribute dietary protein

Subcutaneous apomorphine

Freezing (motor blocks)

Only in “OFF” state

Management strategies as like in patients with wearing-off

Manage anxiety, if present, by appropriate drugs or behavioural therapy and nonpharmacologic techniques that involve the use of sensory or mental imagery, cues, or devices.[1116]

Both in “OFF” and “ON” stages

Increase LD to make optimal “ON”

Sensory cues

Assistive devices

Manage anxiety, if present, by appropriate drugs or behavioural therapy

Only “ON” freezing

It is very difficult to manage and patients sometimes benefit by reducing the dose of LD.

In summary, medical management of motor fluctuations in PD is challenging. Surgical treatment of PD may be a better option for carefully selected patients.