Download Neurology Management of Parkinson`s disease Module 177

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Neurology
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Management of Parkinson’s disease Module 177: May 2012
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ved
Management has improved considerably over the past two decades with the introduction of new
therapies and better utilisation of older ones offering more options for dealing with symptoms
(This module was facilitated by Drs Sarah Moran and Christina Donnellan)
Parkinson’s disease (PD) is a chronic, progressive,
neurodegenerative disorder of unknown cause. It is characterised by a resting tremor, rigidity, bradykinesia (slowness
of movement), and postural instability. The mean age of
onset of PD is 57 years1� and it affects 1-2% of the population over 60 years of age.
Quality of life is most affected by mental problems, gait
disorders and complications of dopaminergic medications.2
Dementia is diagnosed in 69.6% of patients3� and develops
after years of disease.4,5
The pathogenesis of Parkinson’s disease is likely to be
multifactorial. Some 10-15% of patients have a family
history, which suggests that PD may be inherited. Eleven
genetic forms of the disease have been described to date.
The motor impairments of Parkinson’s disease result from
selective loss of pigmented mid-brain neurons in the substantia nigra pars compacta.
Diagnosis
The most important investigation is clinical examination.
Patients must have bradykinesia in addition to one of two
other cardinal signs – tremor or rigidity. A response to acute
challenge testing with dopamine therapy is also supportive.
Routine bloods and imaging, ie. CT brain, are not routinely
required for diagnosis. However, it can be used if there are
atypical features to exclude a structural abnormality, ie.
normal pressure hydrocephalus.
Striatal dopamine transporter imaging using SPECT (DAT
scan) can help distinguish patients with PD and other Parkinson plus syndromes from patients with parkinsonism (ie
drug induced) or essential tremor.6,7
Clinical features that suggest a diagnosis other than
PD include a history of encephalitis, head injury, recurrent strokes, stepwise progression, rapid progression, use
of antipsychotic medication, abnormal CNS imaging, cerebellar signs, supranuclear gaze palsy, dementia preceding
or occurring concurrently with parkinsonism, apraxia, or
strictly unilateral signs after three years.
Features suggestive of an alternative cause for parkinsonism8 (ie. multisystem atrophy, progressive supranuclear
DL May/Parkinsons-NH 1
palsy, corticobasilar degeneration and dementia with Lewy
bodies) rather than PD include falls at presentation, a poor
response to dopamine, symmetrical motor signs, rapid progression, a lack of tremor and early dysautonomia.
There is increasing evidence that non-motor symptoms
such as loss of the sense of smell, sleep problems, sweating, fatigue, constipation, mood change and muscular
symptoms may be early signs and an index of suspicion is
required.
Pharmacological treatments
The main medications available for symptomatic therapy
include levodopa, MAO-B inhibitors, dopamine agonists
and COMT inhibitors (see Table 1).
Levodopa, MAO-B inhibitors or dopamine agonists (DA)
can be used as first-line treatment for PD in patients who
require symptomatic therapy. The choice depends on the
degree of functional impairment and comorbidities. In
younger patients a levodopa-sparing strategy can be a reasonable approach depending on circumstances.
Practitioners should always try to find the lowest effective dose of dopaminergic medication, either singly or in
combination, for patients with PD. It is essential that each
PD patient be evaluated and managed in a highly individualised manner.
Levodopa
Levodopa is established as the most effective drug for
the treatment of PD. Tremor and rigidity may also respond
to levodopa therapy, but postural instability is less likely
to do so.
Levodopa is combined with a peripheral decarboxylase
inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain
barrier) in order to prevent nausea, vomiting, and orthostatic hypotension.
When commencing levodopa, it is important to begin with
small doses, titrating slowly upwards (over weeks) to allow
for tolerance and to minimise side-effects with an aim to
use the lowest dose levodopa that produces symptomatic
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DISTANCE LEARNING Parkinson’s disease
Table 1
Common pharmacotherapy for Parkinson’s disease
Generic name
Trade name
Starting dose
Maximum dose
Carbidopa/levodopa
Sinemet
12.5/50mg
25/250mg 8/day
Levodopa/carbidopa/
entacapone
Stalevo
50/12.5/200mg
200/50/200mg 7/day
Levodopa/benserazide
Madopar
62.5mg
250mg
Mechanism of action
Dopamine precursor/dopa
decarboxylase inhibitor
Dopamine precursor/ dopa decarboxylase inhibitor/COMT inhibitor
Dopamine precursor/ dopa
decarboxylase inhibitor
Rasagiline
Azilect
1mg OD
1mg OD
Selegiline
Eldepryl
5mg
10mg OD
MAO-B inhibitor
Entacapone
Comtess
200mg
Max 10/day with
levodopa
COMT inhibitor
Pramipexole
Mirapexin
0.088mg
3.3mg
Rotigotine
Neupro
1mg patch
8mg patch/day
Dopamine agonist
Ropinirole
Requip
0.25mg
24mg/day
Dopamine agonist
relief. Absence of a response to escalating doses of levodopa
is suggestive of an alternative diagnosis to PD. An adequate
trial of dopamine therapy is defined as 1,000mg/day for at
least one month.9
Controlled or sustained-release levodopa preparations
are less completely absorbed and require a dose up to
30% higher to achieve an equivalent clinical effect. The
peak clinical effect of each tablet is typically less than for
immediate-release preparations, since controlled-release
formulations reach the brain more slowly over time. Therapy
should be started with an immediate-release preparation
with a subsequent switch to controlled-release if desired.
Controlled-release medications are usually used in circumstances such as an overnight medication.
Nausea can be treated with domperidone. Metoclopramide and prochlorperazine should be avoided as they are
dopamine receptor blockers and can therefore aggravate
parkinsonism.
MAO-B inhibitors
Rasagiline and selegiline are selective monoamine oxidase
(MAO) type B inhibitors. They are effective as first-line and
adjunctive treatments for PD for both motor complications
and motor fluctuations,10,11� and may have neuroprotective
properties.
Evidence suggests that early use can delay need for levodopa therapy and disability progression. The adverse effects
include nausea, headache, insomnia and confusion in the
elderly. MAO-B inhibitors are contraindicated with concomitant use of MAOIs.
Dopamine agonists
The dopamine agonists (DAs) are a group of synthetic
agents that directly stimulate dopamine receptors. They
include bromocriptine, pramipexole, ropinirole, rotigotine,
and injectable apomorphine.
DAs can be used as either first-line or adjunctive treatments for PD. As an adjunctive treatment they are useful
for treatment of:
Irreversible MAO-B inhibitor
Selective dopamine agonist
• Reduced levodopa response
• Motor fluctuations
• Dyskinesia
• Other adverse effects of levodopa.
The choice of DA depends on comorbidities and preferred
route of administration (ie. oral or topical). Adverse effects
include nausea, vomiting, somnolence, orthostatic hypotension, confusion, hallucinations, peripheral oedema and
constipation.
Somnolence can occur abruptly and without premonition,
particularly at a dose above 1.5mg/day. Patients with PD
who drive are at particular risk of developing these ‘sleep
attacks’.12 Patients should be warned of this potential sideeffect and asked about factors that may increase the risk
of drowsiness, such as concomitant sedating medications
and sleep disorders.
DAs may be associated with an increased risk of impulse
control disorders including pathological gambling, compulsive sexual behaviour or compulsive buying.13,14� Patients
with a history of cognitive impairment or psychiatric illness
may experience a deterioration in these comorbidities with
DA therapy, and they are therefore usually not used as firstline treatments in this setting.
Adverse effects of DAs can usually be avoided by initiating
treatment with very small doses and titrating to therapeutic
levels slowly over several weeks. In order to reduce sideeffects, patients can be prescribed domperidone to reduce
nausea at treatment commencement.
Patients intolerant to one DA may tolerate a different
DA. Some patients can experience a ‘dopamine agonist
withdrawal syndrome’ if they abruptly stop taking a DA.15
Symptoms of withdrawal include anxiety, panic attacks,
depression, sweating, nausea, pain, fatigue, dizziness, and
drug craving, and these symptoms are refractory to other
antiparkinsonian medications, including levodopa, only
responding to a resumption of the DA.
Apomorphine is used in specialist centres as a treatment for disabling motor fluctuations that persist despite
adequate levodopa and dopamine agonist treatment. It
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Figure 1
Management of Parkinson’s disease: pharmacological approach
DIAGNOSIS
Provide education upon diagnosis and
monitor for functional impairment or
failure to cope. Consider referral to consultant neurologist or geriatrician with an
interest in PD on suspicion of diagnosis
Consider:
Dopamine agonist (non-ergot/ergot*)
Consider:
MAOB-I
(rasagiline/selegiline)
Monitor for two or more cardinal signs affecting
daily function or psychological impact: rest
tremor, rigidity, bradykinesia, poor balance,
freezing of gait, stooped posture and gait
disturbance. When commencing medication,
consideration of patient’s age, lifestyle, personal
preference and circumstances are essential
Consider:
Amantadine#
Consider:
**Levodopa +/- entacapone
(QDS recommended)
Monitor for symptom relief in both motor
and non-motor symptoms using UPDRS~,
‘wearing off’ questionnaire and non-motor
questionnaire. Observe for motor fluctuations, wearing-off and dyskinesia
Consider:
**Levodopa +/- entacapone
(QDS recommended)
Medications may be adjusted,
added or removed from an
individual’s regime throughout
the course of the disease
Tolcapone protocol must be
followed. Prescription indicated if patient is unresponsive
to entacapone. Liver function
tests every two weeks
Consider:
Surgical option
(deep brain stimulation)
Consider (if not already prescribed):
MAO-B inhibitors
(rasagiline/selegiline)
Consider (if not already prescribed):
Dopamine agonist
(non-ergot/ergot*)
Consider:
Tolcapone
(COMT inhibitor)
Consider:
Apomorphine
(subcutaneous pen injection or pump infusion)
The following options can be
added in during treatment:
• Amantadine (dyskinesia, tremor, rigidity)
• Diazepam (anxiety, aggravated tremor)
• Akineton/kemadrin*** (predominant tremor)
• Laxatives/high-fibre diet (constipation)
• Modafinil (daytime sleepiness)
• Antidepressants SSRIs/SNRIs (depression)
• Quetiapine/clozapine (hallucinations)
• Acetylcholinesterase inhibitor/memantine
(cognitive impairment/dementia)
• Clonazepam (REM sleep behaviour disorder)
Consider:
Levodopa/carbidopa gel
(via PEG infusion pump)
*Caution: monitor for cardiac valve fibrosis (cabergolide and pergolide)
** Take half an hour before food if tolerated
*** Caution in elderly or cognitively impaired
#
Watch for ankle and leg swelling, leg rash, hallucinations and postural hypotension
~Unified Parkinson’s Disease Rating Scale
Adapted from the Management in Parkinson’s disease: Pharmacological approach 2nd edition 2010 by Prof Timothy Lynch and Mr Brian Magennis
is usually commenced under nursing supervision with a
challenge test and blood pressure monitoring. It must be
commenced under antiemetic cover with domperidone.
Concomitant use of ondansetron is contraindicated as it
may lead to hypotension.
COMT inhibitors
The catechol-O-methyl transferase (COMT) inhibitor entacapone (Comtess) is useful as a levodopa adjunct therapy.
These medications are mainly used to treat patients with
motor fluctuations who are experiencing end-of-dose ‘wearing off’ periods. They should be given at the same time
as levodopa therapy and in order to facilitate compliance
and reduce pill burden they are usually prescribed as a
combination medication (levodopa/carbidopa/entacapone,
Stalevo).
Inhibition of catechol-O-methyl transferase reduces the
peripheral methylation of levodopa and dopamine, which
in turn increases the plasma half-life of levodopa, produces
more stable plasma levodopa concentrations, and prolongs
the therapeutic effect of each dose. Use of COMT inhibitors
may allow a reduction in the total daily levodopa dose by
as much as 30%. The net result is an increased levodopa
effect.
Adverse effects include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension and diarrhoea.
Amantadine
Amantadine is an antiviral agent that has mild antiparkinsonian activity.16 Its mechanism of action is uncertain.
It is known to increase dopamine release, inhibit dopamine
reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects.
The dose of amantadine is 200-300mg daily. The main
advantage of this agent is a low incidence of side-effects. It
is excreted unchanged in the urine. Peripheral side-effects
include livedo reticularis and ankle oedema, which are
rarely severe enough to limit treatment.
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DISTANCE LEARNING Parkinson’s disease
Pharmacological summary
Initial treatment of early PD and motor symptoms includes
some therapies first line. Levodopa may be prescribed in
combination with a dopa decarboxylase inhibitor, monoamine oxidase inhibitors or topical levodopa.17
Suggested treatment regimens include those as outlined
in Figure 1, while typical starting doses of medications are
outlined in Table 1.
An individualised approach should be taken, particularly
in relation to the introduction of levodopa.
Some agents have shown promise as neuroprotective
treatment strategies but more research is needed.
Non-pharmacological treatments
These include regular exercise, physiotherapy, dietetics, patient education and support. There are also surgical
options including deep brain stimulation.
Non-motor features of Parkinson’s disease
Hallucinations and psychosis
Parkinson’s disease psychosis (PDP) is a common complication of PD. It is usually manifest by visual hallucination
and delusions. Sixty per cent of PD patients develop hallucinations or delusions, with an incidence rate of 79.7 per
1,000 person years.18
Risk factors for PDP include older age at onset, higher
baseline levodopa requirements and REM sleep disorder at
baseline (abnormal behaviour during REM sleep, including
physically acting out vivid dreams). In the setting of new
onset of hallucinations or psychosis in a patient with PD,
an assessment for delirium should be made and underlying cause addressed. Hallucinations may also be a feature
of PD dementia. All medications should be reviewed and
stopped as appropriate (ie. anticholinergics, opioids).
Cessation of PD medications is usually not a viable
option, but dose reductions can help.19 Atypical neuroleptics such as quetiapine and clozapine are useful if dose
reductions provide insufficient benefit, or symptoms are
debilitating.20,21
Quetiapine and clozapine cause less deterioration in
parkinsonism than risperidone, olanzapine and typical
neuroleptics (ie. haloperidol). Clozapine use in practice is
limited by the need for frequent haematological monitoring
(risk of agranulocytosis).
A recent study showed that 50% of patients diagnosed
with PD were prescribed an antipsychotic, with quetiapine
the most frequently prescribed (66%) and clozapine the
least frequently prescribed (2%).22
Depression
Depression is the most common psychiatric disturbance
seen in PD.23 It is generally mild to moderate in severity.
Major depression occurs in less than 10% of patients with
PD.24 However, despite its high prevalence, depression in
PD remains undertreated.25
It can be difficult to recognise depressive features in PD
as blunted affect and psychomotor slowing can mimic the
bradykinesia and mask like facies of PD. Somatic features
of depression, including reduced appetite and concentration, can occur in PD patients without depression.26 Clinical
features that can be helpful are low mood and anhedonia.
Guilt and feeling of worthlessness occur with less frequency
in the PD population. Suicide occurs at the same rate as
the general population.27
To date, there appears to be no clear consensus with
regard to the antidepressant of choice in the treatment of
PD-associated depression. Amitriptyline was recommended
by the American Academy of Neurology in their 2006 report
based on evidence available at that time. Caution was recommended when prescribing due to a possible increase in
postural instability.
Other reviews suggest commencing SSRIs as first-line
therapy. The first randomised trial of antidepressants in PD
was published in April 2012. It found that both paroxetine
and venlafaxine significantly improved depression, were
safe, well tolerated and did not worsen motor function.28
There are, however, theoretical concerns with the prescription of SSRIs in the setting of PD. The manufacturers
of selegiline have issued warnings about the possibility of
developing a serotonin syndrome in event of co-prescription
of selegiline and SSRIs.
Daytime somnolence
Excessive daytime sleepiness is common, affecting
74-98% of patients.29 Pharmacological treatments have not
been shown to be effective to date. Measures used include
nocturnal sleep hygiene.
Autonomic dysfunction
Autonomic dysfunction occurs with less frequency in
PD than it does in multisystem atrophy. Features include
orthostatic hypotension, urinary frequency and urgency,
dysphagia, diaphoresis and sexual dysfunction.
Constipation
Constipation is a common clinical problem which is
managed with laxatives. It can cause deterioration in motor
symptoms from reduced levodopa absorption.
Conclusion
PD is a progressive neurodegenerative condition resulting from the death of the dopamine-containing cells of the
substantia nigra.
The diagnosis is primarily clinical, based on a history and
examination. Management is individualised.
Sarah Moran is a specialist registrar in general internal
medicine/nephrology and Christina Donnellan is a consultant
geriatrician at South Tipperary General Hospital, Clonmel
Co Tipperary
Acknowledgements: The authors would like to thank Prof
Timothy Lynch and Mr Brian Magennis for allowing us to
reproduce their diagram The management of Parkinsons
Disease, Pharmacological approach.
References on request
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