Q12 How could you monitor and assess Mr. LN’s response to these changes?

- By charting his mobility regularly.

- Some neurology wards use mobility charts

on which an indication of a patient’s

mobility can be recorded at suitable

intervals.

- Such charts can be a valuable aid to the

manipulation of drug administration in

order to optimize therapy.

Mobility Chart

Q13 Can you suggest any non-drug management that might benefit Mr. LN?

Non-pharmacological Management

Exercise.

Nutritional counseling.

Psychological and social support.

Occupational therapy.

Speech therapy and swallow evaluations.

Surgical therapy: Deep brain stimulation (DBS):

DBS: battery-powered neurostimulation device that is

surgically implanted under the clavicle with electrical wires

projecting to brain area of interest.

Proposed action mechanisms of DBS include depolarization

blockade, synaptic inhibition, synaptic depression,

stimulation-induced disruption of pathological network, and

stimulation of afferent axons projecting to the subthalamic

nucleus.

Generally, DBS is considered adjunct to pharmacotherapy for

patients whose symptoms are not adequately controlled with

optimal medication therapy and requires routine monitoring and adjustments.

• Mr. LN’s drug therapy was changed to one Madopar dispersible 62.5 mg tablet (L-dopa 50 mg + benserazide 12.5 mg) on waking around 7 am,

• and one Sinemet Plus tablet (Carbidopa 25 mg+L-dopa 100 mg) at 10 am, 1 pm, 4 pm and 7 pm.

• In addition, he was prescribed

one Sinemet CR tablet at 10 pm.

• The nursing staff were asked to complete an hourly ‘on–off’ chart. Parts of the chart for days 1 and 5 are shown in the

Table here under.

Month 66, Day 6: Mr. LN’s mobility and dyskinesias were improved; however, he remained depressed about his condition.

Q14 Would Mr. LN benefit from an antidepressant?

- Probably. Depression is very common in Parkinson’s disease,

approximately 40–50% of patients suffer from depression at

least once during the course of their disease.

- Depression in Parkinson’s disease is characterized by feelings

of guilt, helplessness, remorse and sadness. It is independent of

age, disease duration, severity of symptoms or cognitive

impairment.

- Ensuring adequate treatment for Parkinson’s disease should be

the first step before considering more specific antidepressant

therapy.

- This has been achieved in Mr LN, so a trial of an

antidepressant would be reasonable.

Q15 If so, which would you choose?

- A tricyclic antidepressant (TCA) or

selective serotonin reuptake inhibitor

(SSRI) could be prescribed for Mr. LN.

- At present, there is insufficient evidence

to recommend one

antidepressant/antidepressant class over

another. This lack of data is also

highlighted in the NICE guidance.

- Clinical practice, as well as trial data, supports

the use of some TCAs (e.g. amitriptyline,

nortriptyline) in Parkinson’s disease; however,

they are often associated with anticholinergic

effects and orthostatic hypotension, which may

limit their usefulness.

- The SSRIs (e.g. fluoxetine, sertraline,

citalopram) have also been shown to be

effective in Parkinson’s disease. They are free

of the anticholinergic effects associated with

the tricyclics, and theoretical concerns that

they may worsen parkinsonian symptoms have

not been borne out by recent studies.

Month 66, Day 8

• Mr. LN had noticed a significant reduction in the shaking of his arms following his recent regimen change;

• however, he was still becoming considerably immobile about 1 hour before his dose of Sinemet.

• His sleep had improved so that he was getting at least 6 continuous hours’ sleep and no longer woke in pain from cramps.

• The consultant neurologist recommended commencing entacapone.

Q16 Why has the consultant neurologist recommended entacapone, and does this necessitate the adjustment of Mr. LN’s other PD therapy?

- Mr. LN is still displaying signs of end-of-

dose akinesia, despite appropriate

adjustment to his levodopa therapy.

- Entacapone therapy may improve these

symptoms, but his other IPD therapies will

need to be adjusted as the drug is

introduced.

Clinical Pearls Entacapone is licensed for use as an adjunct to

levodopa in Parkinson’s disease.

Studies have shown that its use can significantly reduce

‘off’ time and increase ‘on’ time in patients with

‘wearing-off’ episodes.

It should be given at a dose of 200 mg with each dose of

levodopa, up to 10 times daily.

The introduction of entacapone to a regimen can cause

a new-onset or worsening of existing dyskinesias.

In order to minimize this, the daily dose of levodopa

should be reduced by about 10–30% by extending the

dosing intervals and/or by reducing the amount of

levodopa per dose.

In practice, the choice varies from

patient to patient.

Tolcapone, the only other commercially

available COMT inhibitor, differs from

entacapone in that it also blocks

central COMT.

Tolcapone was withdrawn in 1998 after

a number of cases of hepatitis, but has

since been relaunched with strict

monitoring parameters and guidance

on use.

Q17 What counselling points would you highlight to a patient commencing entacapone?

- Entacapone can discolor the urine reddish

brown.

- Patients should also be advised that nausea

and vomiting can occur due to

augmentation of levodopa, and that

diarrhea is a common adverse effect.

- The large size of the tablets may cause

problems for patients with swallowing

difficulties.

Month 66, Day 11:

• During the ward round, you noted that Mr. LN’s morning medication was still on his bedside table.

• His medication now comprised one Madopar dispersible 62.5 mg tablet on waking around 7 am, one Sinemet Plus tablet at 10 am, 1 pm, 4 pm and 7 pm, and a Sinemet CR tablet at 10 pm. In addition, he was taking one entacapone tablet alongside each dose of Sinemet Plus and 3 mg ropinirole three times a day (made up of a 1 mg and a 2 mg tablet for each dose).

• His regimen thus comprised a total of 16 tablets per day. On questioning, Mr. LN informed you that although he was feeling better, he was concerned at the number of tablets he was taking and feared that he would have problems remembering to take them all when he returned home.

• He also found the new tablet quite hard to swallow because of its size.

Q18 In view of MR. LN’s concerns, what options are there for rationalizing his medications?

- The use of combination products and

alternative formulations could be considered.

- In the literature it has been noted that

approximately 20% of patients with IPD are

non-adherent with their medication.

• The transdermal patch rotigotine and the oral formulation ropinirole XL are both designed for once-daily administration.

- Stalevo is a combined preparation of levodopa, carbidopa and entacapone formulated into one tablet.

- A Stalevo tablet is smaller than a tablet of entacapone alone and is thus also helpful in patients with swallowing difficulties who require therapy.

- Stalevo is available in a number of strengths, although dose titration is more limited than with the individual components.

- Mr LN could be started on Stalevo in place of Sinemet and entacapone.

Month 75:

• Mr. LN was admitted as an emergency by his GP, having developed visual and auditory hallucinations over the previous week.

• He was hearing voices talking about him, threatening to kill him.

• He was also seeing insects crawling up the walls and burrowing into his skin.

• On examination he was clearly distressed and very frightened.

• His medication on admission was one Madopar dispersible tablet on waking, one Stalevo 100/25/200 tablet four times daily, one Sinemet CR tablet at night and one ropinirole XL tablet 8 mg daily

Q19 Which drugs might have contributed to Mr. LN’s symptoms?

- All the drugs prescribed for Mr. LN can cause the

psychiatric complications described.

- Levodopa causes a variety of psychiatric

symptoms, including hallucinations.

- Dopamine agonists such as ropinirole can cause

central nervous system effects such as

hallucinations and confusion. These psychiatric

complications are especially common in elderly

patients. In addition, progression of the disease

itself may contribute to these symptoms.

Q20 What adjustments would you recommend be made to Mr. LN’s medication?

- Gradually reduce his dose of

ropinirole XL and stop if

necessary.

Q21 What course of action would you suggest to improve Mr. LN’s symptoms?

- Add a low dose of an ‘atypical’

antipsychotic drug, or consider

acholinesterase inhibitor.

• Mr. LN was started on rivastigmine 1.5 mg twice daily.

• The dose was increased over the next 10 days to 4.5 mg twice daily.

• His dopaminergic therapy was adjusted to one Stalevo 100/25/200 tablet five times daily,

• one Sinemet CR tablet at night and one Madopar 62.5 mg dispersible tablet upon waking.

• His ropinirole XL therapy was discontinued.

• His hallucinations resolved and acceptable control of his Parkinson’s symptoms was achieved. He was discharged on this regimen.

Q22 What is the long-term outlook for Mr. LN?

- It is likely that Mr. LN’s condition will

continue to deteriorate with time, and

that he will experience more ‘off’ time

and increasing dyskinesias. His

cognitive function may also decline

further.

Clinical Pearl

Amantadine has been used for the management of

dyskinesias based on its antiglutamate activity;

however, its side-effects (confusion, hallucinations)

would preclude its use in Mr. LN. Other side-

effects of amantadine include ankle swelling and

livedo reticularis.

A small number of other therapies can be used at

this stage in patients with Parkinson’s disease, but

their risks and financial implications are

considerable.

The use of apomorphine, a potent dopamine agonist licensed for the treatment of refractory motor fluctuations (‘off’ periods) in IPD, is a possibility in patients who deteriorate despite maximum tolerated oral therapy. The drug cannot be given orally and must be administered subcutaneously. It may be given as a continuous subcutaneous infusion or as single injections. It causes severe nausea and vomiting, so 3 days’ pretreatment with domperidone (20 mg three times daily) is used to minimize this. Domperidone therapy may be continued until tolerance to this side-effect develops.

Apomorphine is effective within 5–10 minutes, and

patients may remain in the ‘on’ state for up to 60

minutes. During this time an oral dose of medication

should have taken effect. Many patients are helped by up

to five injections a day, although up to 10 may be needed

in some patients. If the number of injections needed is

high, then continuous infusions of apomorphine should

be considered. If the nausea and vomiting can be

overcome, apomorphine therapy is generally well

tolerated. Bruising, nodules or abscesses may form at the

site of an infusion, so the site should be changed daily. As

Mr. LN has had psychotic features in the past that

resolved following discontinuation of his dopamine

agonist, the use of apomorphine may not be appropriate

and may further exacerbate this symptom.

The use of surgical techniques such as subthalamic deep brain stimulation (STN-DBS) may also be precluded in Mr. LN by his previous psychotic symptomatology. The relatively high morbidity and mortality rate associated with lesioning operations such as thalamotomy and pallidotomy has recently made STN-DBS more favorable. STN-DBS involves the placement of tiny wires into the subthalamic nucleus (STN). These emit continuous electrical impulses from a neurostimulator, which is similar to a heart pacemaker. This stimulation can have a positive effect on the brain activity involved in controlling movement, and can improve tremor, stiffness, slowness and dyskinesia. In addition, with improvement in these symptoms medication can be reduced, thereby further reducing dyskinesias.

Mr. LN may, however, be an appropriate candidate for Duodopa, a gel formulation of levodopa/carbidopa that is infused directly into the duodenum. Duodopa is designed to mimic the pharmacokinetic profile of endogenous dopamine release. The technique, albeit initiated using a nasogastric tube, requires a percutaneous gastrostomy tube for long-term administration. Such a procedure in patients with advanced Parkinson’s disease can be hazardous.

Although there have been many recent advances in the management of IPD, there is still no cure. Ongoing research is targeted at neuroprotection strategies: interventions to protect or rescue vulnerable dopaminergic neurons, and to slow down or stop disease progression. Gene therapy trials are also currently under way.