The natural history of Parkinson’s disease
Parkinson’s disease is a neurodegenerative disorder characterised by the cardinal symptoms of stiffness, resting tremor,
slowness (bradykinesia) and reduction of movement (hypokinesia).1 Often the symptoms are asymmetric and insidious;
serious problems may not develop until several years after onset of symptoms.2
When patients with Parkinson’s disease are examined they generally display:
- Rigidity on passive movement at major joints, e.g. when the patient’s arm is moved by the clinician, sometimes with
a superimposed ratchet-like sensation known as the “cogwheel” phenomenon
- Resting tremor, most commonly 4 hertz (four cycles per second), typically affecting the upper limbs
- Impairment of dextrous upper limb movements and facial expression due to bradykinesia affecting the small muscle groups
of the face and hands, which is usually seen in the early phases of the condition
Bradykinesia in people with Parkinson’s disease often causes a deterioration of handwriting in which the script typically
slopes upwards and the writing is crabbed and becomes progressively smaller. Gait abnormalities typically manifest later
in the course of the disease. However, a lack of spontaneous arm swing when walking is an early sign. Turning en bloc,
where the whole body turns when changing direction, and a festinating gait, with small steps and tendency to shuffle as
if the patient is chasing their centre of gravity are seen in patients with more advanced disease. Falls, partly due to
slow activation of postural reflexes, occur in people with Parkinson’s disease.
Non-motor symptoms are very common in patients with Parkinson’s disease and may include hypotension, cognitive impairment,
disorders of excessive sweating, depression and a reduced sense of smell (hyposmia).3, 4 In some patients
with Parkinson’s disease non-motor symptoms can precede the classical motor symptoms by several years (see: “The
Braak theory of Parkinson’s disease progression”). However, non-motor symptoms are not useful for diagnosing Parkinson’s
disease as they have limited specificity. Early onset of prominent non-motor symptoms such as orthostatic hypotension
and cognitive impairment are also consistent with alternative diagnoses such as multi-system atrophy and Lewy body dementia.
Non-motor symptoms in patients with Parkinson’s disease can become more troublesome than motor symptoms and their management
becomes increasingly important as the condition progresses.
Parkinson’s disease pathophysiology
The pathological characteristic of Parkinson’s disease is a severe loss of pigmented dopaminergic neurons in the substantia
nigra of the midbrain (a brain area involved in movement). These neurons project to the corpus striatum and loss of these
projections leads to an overall decrease in cortical motor activity. This process also causes the positive symptoms of
Parkinson’s disease, such as tremor, by reducing the normal inhibitory neuronal control of movement; known as the release
Loss of dopaminergic neurons in patients with Parkinson’s disease is accompanied by the development of intracellular
protein aggregates within surviving pigmented neurons, known as Lewy bodies.4 Lewy bodies in patients with
Parkinson’s disease are pathologically indistinguishable from Lewy bodies in patients with Lewy body dementia.4 Long-term
studies have shown that nearly all patients with Parkinson’s disease eventually develop cognitive impairment and it seems
likely that Parkinson’s disease and Lewy body dementia represent a similar or overlapping neurodegenerative disorder.5 However,
early cognitive impairment in a patient suggests a diagnosis other than Parkinson’s disease.
As Parkinson’s disease advances, more widespread loss of neurons occurs, which is the likely cause of symptoms that
are not controlled by the dopaminergic treatments that are used in the earlier stages of the disease.3
Parkinson’s disease itself is not thought to be directly fatal, but falls, fractures and chest infections related to
swallowing disorders increase the mortality rate in people with Parkinson’s disease.
The epidemiology and genetics of Parkinson’s disease
Parkinson’s disease affects an estimated 1% of people aged over 65 years.4 A General Practitioner in New
Zealand can expect to have approximately three patients with Parkinson’s disease per 1000 patients, although this will
vary depending on practice characteristics.6 The median age of onset is 60 years and life expectancy is on
average 15 years following diagnosis.4
The cause of Parkinson’s disease is unknown. Some rare autosomal dominant genes for Parkinson’s disease have been identified,
but account for only a few cases. In people diagnosed after age 60 years, there is a negligible increased risk of their
children developing the condition, if there is no other family history of Parkinson’s disease.4 However, in
people with Parkinson’s disease, who also have an affected parent or other affected first degree relative, the likelihood
of one of the rare genes for Parkinson’s disease being present may be as high as 5%.4
Environmental toxins, e.g. industrial waste and pesticides, may be a causative factor in the development of Parkinson’s
disease, however, mitochondrial dysfunction, oxidative damage and abnormal protein processing have also been implicated.7 Non-smokers
are twice as likely to develop Parkinson’s disease as people who smoke; it is not known why.4
An expert opinion is recommended for diagnosis
Diagnosing patients with Parkinson’s disease is challenging and it is important that all patients suspected of having
the condition are examined by an experienced Neurologist or Geriatrician before treatment is initiated.8 A
specialist second opinion will improve the likelihood of a good outcome and provide reassurance that an alternative diagnosis
does not better fit the patient’s presentation.
A response to levodopa is a key criterion for the diagnosis of Parkinson’s disease. Common alternative diagnoses include
medicine-induced parkinsonism, essential tremor and multiple cerebral infarctions.
Managing the motor symptoms of Parkinson’s disease
Although there is no cure for Parkinson’s disease, patients can achieve good symptom control during the first few years
of treatment, unlike in other neurodegenerative conditions. It is reasonable to expect treatment to provide functional
benefit for at least ten years.4
A multidisciplinary approach is usually recommended in the treatment of patients with Parkinson’s disease, although
there is a lack of robust evidence to support the usefulness of this approach. Physiotherapists, Occupational Therapists,
Speech Therapists and Nurse Specialists may all be involved in the care of a patient with Parkinson’s disease, in addition
to a Neurologist or a Geriatrician and a General Practitioner.
Exercise should be encouraged and formal exercise rehabilitation is likely to benefit patients with
Parkinson’s disease. Physiotherapists experienced in the treatment of people with Parkinson’s disease may be able to provide
specific interventions for overcoming disabilities such as start hesitancy, freezing of gait, festination and falls. The
results of clinical trials suggest three broad physical therapy strategies may be useful:9
- Strategy training, e.g. instruction with reinforcement to use longer stride length
- Management of musculoskeletal issues, e.g. weakness and loss of range of movement
- General promotion of physical activity with specific interventions for falls prevention
A systematic review of physiotherapy interventions in patients with Parkinson’s disease found a wide-range of techniques
introduced for a period of up to three months improved gait speed and balance as well as improving measures of the impact
of Parkinson’s disease, e.g. the Unified Parkinson’s Disease Rating Scale (UPRDS).10 There was no evidence
that one particular approach was better than any other, although the quality of the comparisons was poor. A more recent
review provides some inconsistent evidence that more intensive and longer duration interventions provide greater benefits.11
Occupational therapy may assist people with Parkinson’s disease to safely maintain activity and employment.
Continued activity and employment is likely to improve self-esteem as well as maintaining the patient’s role within their
family.12 Patients may also be referred to occupational therapists specially trained in assessing driving
performance to determine if they are medically fit to drive (see: “Driving a motor vehicle”).
Speech therapy may be appropriate; soft speech (hypophonia) is a particular problem for patients with
Parkinson’s disease. Voice training can improve voice quality and audibility.3 Some speech therapists run
intensive exercise programmes in which the patient focuses on increasing the volume of their speech. Speech therapists
are also able to assess dysphagia in patients with Parkinson’s disease which can affect speech and may also be a contributor
to poor dietary intake.
Weight loss may be an issue for some people with Parkinson’s disease, although it is not clear if this
is part of the process of Parkinson’s disease, i.e. extra energy expenditure due to tremor or rigidity, altered swallowing,
changes to satiety, or due to the appetite reducing affect of dopaminergic treatment. Patients who are underweight may
benefit from dietary supplements but there is little evidence of a strong effect. Some patients with Parkinson’s disease
experience constipation and dietary changes may alleviate this, although, pharmacological treatments are more likely to
be reliable for management. However, be aware that for some patients with Parkinson’s disease the timing and protein content
of meals can affect levodopa absorption.
The support and shared experiences of other people of a similar age with the same condition is important.
The Parkinson’s New Zealand website provides information on local services and support for people diagnosed with Parkinson’s
disease, and their families. The fifth edition of “Parkinson’s: A guide for the newly diagnosed” was published in October,
For further information visit: www.parkinsons.org.nz
Counselling for the patient can assist in the development of self-management techniques for anxiety
and depression. Caring for a family member with Parkinson’s disease can place additional strain on relationships. Counselling
may help the carer and family with coping strategies. In the final stages of Parkinson’s disease palliative care and advanced
care planning may be beneficial for the patient and their family.
For further information see: “End-of-life
care for patients with chronic disease: the need for a paradigm shift”, BPJ 40 (Nov, 2011).
Driving a motor vehicle
People with Parkinson’s disease may have a reduced ability to drive before a functional disability becomes apparent,
due to cognitive impairment or as an adverse effect of dopaminergic treatment, e.g. daytime sleepiness. Limb strength,
accuracy of rapid foot movements and joint proprioception should be assessed.13 If a General Practitioner
is uncertain about a patient’s ability to drive then referral to an Occupational Therapist trained in driving assessment
will be helpful. A Parkinson’s disease Nurse Specialist, a Neurologist or Geriatrician may also be consulted before a
final decision is made.
Driving should always cease if there is doubt about a person’s ability to control a vehicle in an emergency situation.13 It
is reasonable to assume that if a person has trouble walking then they may not be fit to drive.13
Pharmacological treatment of motor symptoms
Motor symptoms in patients with Parkinson’s disease typically respond well to medicines that boost dopamine function
and this response is part of the diagnostic criteria for Parkinson’s disease. When motor symptoms are well controlled
this is referred to as the patient’s “on” state; conversely periods of poor motor symptom control are referred to as “off”
states. There is little evidence that treatment with either levodopa or long-acting dopamine agonists in the early phases
of Parkinson’s disease results in improved long-term outcomes for the patient. However, levodopa will eventually be used
in the treatment of all patients. If a patient does not respond to dopaminergic treatment then alternative diagnoses,
e.g. medicine-induced Parkinsonism, essential tremor or multiple cerebral infarctions, should be strongly considered.
Motor fluctuations, including dyskinesias, mainly associated with levodopa treatment develop in all patients with Parkinson’s
disease. These can vary in severity from a “wearing off” phenomenon, where a patient notices an increase in stiffness
and slowness after a dose of medication, to very severe fluctuations between rigid-akinetic states and severe episodes
of dyskinetic (involuntary) movements (see: “Motor fluctuations and levodopa”).
When to start pharmacological treatment?
Treatment for Parkinson’s disease should be considered once the patient reports troubling symptoms.14 In
most cases, a Neurologist or Geriatrician with experience in diagnosing Parkinson’s disease will be responsible for initiating
treatment. Diagnostic trials of levodopa, e.g. for a patient with functional disabilities and a strong clinical suspicion
of Parkinson’s disease, should generally not be considered without discussion with a Neurologist or Geriatrician. If there
will be a substantial delay in the patient’s referral, case-by-case management is required involving initial telephone
consultation with a Neurologist or Geriatrician, and consideration of the patient’s level of disability, circumstances,
e.g. living alone, co-morbidities and individual preference for treatment.
Levodopa with a dopa-decarboxylase inhibitor is usually first-line
Patients with motor symptoms of Parkinson’s disease will benefit from dopamine treatment. However, dopamine itself does
not cross the blood brain barrier easily and causes severe nausea and vomiting when given at doses high enough to have
a motor effect. Levodopa, a metabolic precursor to dopamine, is able to cross the blood brain barrier and is therefore
used instead. However, levodopa is rapidly metabolised to dopamine by the enzyme decarboxylase which is present in the
body’s periphery as well as in the brain. In order to allow sufficient levodopa to reach the brain it must be administered
with a peripheral decarboxylase inhibitor. In New Zealand carbidopa or benserazide are commonly used (Table
1) and given in fixed combination with levodopa.
In patients aged over 40 years with Parkinson’s disease, combination levodopa medicines are generally
the first-line treatment (see “Levodopa treatment should not be delayed in patients aged
over 40 years”).14 These are available in tablets, capsules, immediate release and modified release preparations,
and dispersible tablets. Preparations should be swallowed whole, and not halved or broken, unless specified. Dispersible
tablets shorten the onset of effect and may be useful for patients with difficulties swallowing or when rapid effect is
needed, e.g. in the early morning. Adherence to levodopa treatment may be a problem for some patients due to the frequent
dosing regimen, e.g. at least three times daily. A Pharmacist may be able to provide further information about which preparation
is most suitable.
Over time there is often a need to increase the doses of levodopa or to add dopamine agonists or other medicines that
inhibit the metabolism of dopamine. The patient’s treatment should be adjusted according to the level of disability experienced
in the performance of everyday activities.14 The severity of a patient’s dyskinesias will often determine
the maximum dose and length of time that levodopa treatment can be tolerated.14 Modified release levodopa
does not reduce motor fluctuations related to the absorption of levodopa but may be useful for patients whose symptom
control is insufficient between doses.3
In patients aged under 40 years with Parkinson’s disease a dopamine agonist is generally
the first-line treatment, rather than levodopa. This is because in these patients the likelihood of developing
motor fluctuations within five years of beginning levodopa treatment is effectively 100%.14 Levodopa monotherapy
is also associated with earlier and more severe motor fluctuations compared with using dopamine agonists for
Dopamine agonists are an alternative first-line treatment
Dopamine agonists, e.g. ropinirole or pramipexole (Table 1), may be considered as an alternative
first-line treatment for motor symptoms in patients with Parkinson’s disease, particularly in those aged under 40 years.14 Dopamine
agonists are also frequently used in combination with levodopa for patients who have not achieved adequate symptom control
and may “smooth-out” motor fluctuations (see: “Motor fluctuations and levodopa”).3 Patients
taking dopamine agonists may experience fewer motor complications than patients taking levodopa treatment.3 However,
compared to levodopa, dopamine agonists cause more sleepiness, oedema and hallucinations, and are reported to be associated
with higher “dropout” rates in clinical trials.16 The development of impulse control disorders, e.g. binge-eating,
compulsive shopping, gambling or hypersexuality is associated with dopamine agonists, and levodopa, and these possible
adverse effects should be discussed with the patient and their family. Modified release preparations of dopamine agonists
are not available in New Zealand.
Ergot-derived dopamine agonists, e.g. bromocriptine and pergolide, are generally no longer prescribed for patients with
Parkinson’s disease due to the possibility of cardiac valvular fibrosis, pulmonary fibrosis or retroperitoneal fibrosis
developing.3 Patients who are still being treated with these medicines should be monitored for dyspnoea, persistent
cough, chest pain, cardiac failure, and abdominal pain or tenderness.17 If long-term treatment is expected
lung-function tests may be helpful, or consider switching to a non-ergot derived dopamine agonist, i.e. ropinirole or
Motor fluctuations and levodopa
The cause of motor fluctuations in patients with Parkinson’s disease is unknown. In normal physiology, dopamine is
stored in pre-synaptic terminals. As people with Parkinson’s disease lose dopaminergic neurons the dopamine storage capacity
of the brain is reduced. The length of time that levodopa doses are able to provide benefit then decreases because dopamine
in the blood is metabolised more quickly than it is in synaptic terminals.14
In patients with more advanced Parkinson’s disease, symptomatic “off” periods can begin when levodopa blood levels
drop below therapeutic levels. When this occurs dosing of levodopa needs to be more frequent.14 However,
the adverse effect of more frequent levodopa dosing is the occurrence of peaks of dopamine concentration which cause
dyskinesias. Altered dopamine receptor function in the corpus striatum may also cause “supersensitivity” to blood dopamine.
Disabling dyskinesias may require a reduction in levodopa dosing and other dopaminergic medicines, e.g. dopamine agonists,
may become more useful.3
A monoamine oxidase type B inhibitor may be appropriate for mild symptoms
Selegiline (Table 1) may be appropriate for patients with Parkinson’s disease who have mild
motor symptoms and early treatment with selegiline can delay the need for levodopa treatment.17 Selegiline
can be prescribed alone or in combination with a levodopa-dopa-carboxylase inhibitor combination. Selegiline inhibits
the catabolism of dopamine and may also be combined with levodopa treatment to reduce symptoms in patients with advanced
Parkinson’s disease. However, in patients who have postural hypotension selegiline together with levodopa should be avoided
or used with extreme caution.17 Currently there are issues surrounding the supply of selegiline and therefore
this medicine is unapproved by Medsafe in New Zealand, although this is likely to change in the near future.
Amantadine can be used to treat dyskinesia
Amantadine (Table 1) is a weak dopamine agonist and is a possible treatment option for people
with early onset Parkinson’s disease, but should not be considered as a first-line treatment.8 Amantadine
may be used in conjunction with other treatment, usually levodopa, to control dyskinesias once patients have begun to
display motor fluctuations.8 The effect of amantadine is thought to be modest and to last less than eight
months.16 However, a recent trial suggests that amantadine may help control dyskinesias for several years.18
Catechol-O-methyltransferase inhibitors may be added later in treatment
When patients with advanced Parkinson’s disease begin to experience “end-of-dose” deterioration that cannot be stabilised
by adjusting the regimen of current medicines, catechol-O-methyltransferase (COMT) inhibitors, i.e. entacapone and tolcapone
(Table 1), may be used as adjunctive treatment with levodopa and dopa-decarboxylase inhibitors.
COMT inhibitors, like dopa-decarboxylase inhibitors, prevent the peripheral conversion of levodopa to dopamine.
Antimuscarinic medicines are less effective than dopaminergic treatments
Antimuscarinic medicines, e.g. benztropine, procyclidine and orphenadrine hydrochloride, reduce medicine-induced Parkinsonian
symptoms in patients being treated with antipsychotics, but are generally not used in patients with Parkinson’s disease.17 However,
benztropine may be considered for the treatment of levodopa-resistant tremor in younger patients.3 Antimuscarinic
medicines are poorly tolerated by older patients and are associated with cognitive impairment and sedation.3 Tardive
(slow onset) dyskinesia is not improved by this treatment and may be worsened.17
Alternative treatments are not supported by evidence
There is no robust evidence that any herbal medicine or supplement is effective in the treatment of patients with Parkinson’s
disease.16 In particular, vitamin E should not be used as a neuroprotective agent as there is good evidence
that it does not slow the progression of Parkinson’s disease.16
Levodopa treatment should not be delayed in patients aged over 40 years
Patients aged over 40 years should be considered for levodopa treatment as soon as they display significant symptoms.14 Historically
there was a concern that early treatment with levodopa resulted in patients developing premature dyskinesias.14 This
idea was supported by two observations. Firstly, as many as 90% of patients treated with levodopa for ten years develop
dyskinesias.14 Secondly, the younger the age of onset of Parkinson’s disease, the more likely it is that
dyskinesia will occur.14 However, the benefit of levodopa treatment is greatest earlier in the course of
Parkinson’s disease.14 An Australian study of 149 people with Parkinson’s disease found that at fifteen-year
follow-up there was no difference in outcomes for motor complications and mortality for patients whose treatment was
initiated with either dopamine agonists or levodopa.15
Conversely, in patients aged under 40 years, treatment with levodopa is delayed and initiated when symptoms become
Managing the non-motor symptoms of Parkinson’s disease
Patients with Parkinson’s disease may display autonomic dysfunction, psychiatric symptoms and cognitive impairment (Table
2). These non-motor symptoms are a substantial component of Parkinson’s disease morbidity. Some non-motor symptoms
can be associated with the patient’s “off” state and optimisation of dopaminergic treatment may provide symptom relief.
Therefore attempting to increase “on” time should be considered first in the management of non-motor symptoms. For example,
musculoskeletal and visceral pain, is experienced by over 80% of patients with Parkinson’s disease and can be associated
with “off” states.3
Treatment of non-motor symptoms may involve additional medicines
Parkinson’s disease involves pathology beyond the nigrostriatal connections of the brain, therefore many of the non-motor
symptoms of Parkinson’s disease do not respond to dopaminergic medicines and other treatment options may be necessary.
Autonomic dysfunction resulting in orthostatic hypotension, erectile dysfunction, urinary incontinence and constipation
is present in most patients with advanced Parkinson’s disease (Table 2). Discussion with other
members of the multidisciplinary team is recommended to provide individualised treatment plans.
Patients with Parkinson’s disease usually experience a gradual worsening of motor and non-motor symptoms. If a patient’s
condition suddenly deteriorates then adherence to treatment and other potential causes, e.g. urinary tract infection,
should be investigated. If a patient displays unstable non-motor symptoms despite regular treatment then referral to a
Neurologist or Geriatrician is recommended.