Download Parkinson`s disease clinical features and diagnosis

Vol 3
December 2011
Clinical Pharmacist
Parkinson’s disease
clinical features and diagnosis
By Annett Blochberger, DipClinPharm, MRPharmS,
and Shelley Jones, DipClinPharm, MRPharmS
P
arkinson’s disease (PD) is a progressive
neurodegenerative disorder, caused by the loss of
dopaminergic neurones in the substantia nigra. The
disease is characterised by tremor, rigidity, akinesia and
postural instability. Although PD is predominantly a
movement disorder, patients also experience non-motor
symptoms including psychiatric problems, sleep disorders,
dysfunction of the autonomic nervous system and sensory
disturbances.
James Parkinson, an English surgeon and apothecary,
published the first formal description of the symptoms of
PD in 1817 in “An essay on the shaking palsy”.1 Later, the
French neurologist Jean-Martin Charcot credited Dr
Parkinson’s findings by referring to the disease as “La
maladie de Parkinson”.
Quality of life for patients with PD is severely affected
by both motor effects (eg, disabling tremor, falls) and nonmotor symptoms (eg, anxiety, depression).2, 3 Input from a
multidisciplinary team can improve outcomes for patients
and carers.
SUMMARY
Parkinson’s disease (PD) is a progressive neurological disorder that results
from the loss of dopaminergic neurones in the substantia nigra. The cause
of this neuronal damage remains largely unknown, but it is believed to be
associated with both genetic and environmental factors.
PD is characterised by motor and non-motor symptoms. The main motor
features are rigidity, tremor, bradykinesia and hypokinesia. Non-motor
symptoms include: neuropsychiatric conditions (eg, dementia, depression
and hallucinations); autonomic disturbances (eg, constipation, postural
hypotension); sleep disorders; and sensory symptoms (such as pain).
Africa; this could reflect a difference in life expectancy
since PD is, mainly, a disease of older people.4
In the UK there are approximately 60,000–108,000
people affected by PD (based on a prevalence of 100–180
per 100,000).5 The annual incidence in the UK is between
four and 20 per 100,000 people,5 and a typical GP surgery
with 6,000 patients could expect to have between six and
11 patients with PD on its list.
The average age of onset is 65 years. Young-onset PD,
defined as appearance of the condition under the age of 40
years, accounts for about 5–10% of all cases.6
Epidemiology
Causes
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About 5.2 million people suffer from PD worldwide. It is
more common in Europe and North America than in
The cause of PD remains largely unknown. Although the
condition is more prevalent in older people, age is not the
only factor contributing to the development of PD. It has
been suggested that a combination of an inherited
susceptibility and exposure to environmental risk factors
could cause PD and this warrants further research.
Genetics There is little doubt that genetic factors
contribute to the development of PD, but their significance
has yet to be established clearly. Advances in genetic
research have enabled the identification of 12 genes
associated with PD (PARK1 to PARK11, and NR4A2).
Each gene mutation expresses different clinical features,
with some overlap. This contributes to a hypothesis that
Annett Blochberger is lead pharmacist for
neurosciences at St George’s Healthcare NHS Trust
and Shelley Jones is clinical pharmacy team leader
for neurosciences at King’s College Hospital NHS
Foundation Trust.
E: [email protected]
CLINICAL FOCUS
Tremor, bradykinesia, hypokinesia and rigidity are well known features of Parkinson’s disease, but
patients also experience troublesome non-motor symptoms, such as depression, pain and insomnia
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Clinical Pharmacist
December 2011
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PD is an umbrella term for several neurodegenerative
diseases.7
A person has a 2.5–3 times higher risk of developing PD
if a first-degree relative has the disease.8 However, familial
PD is rare (<5%).9 Twin studies have shown that age of
onset plays an important role — onset after the age of 50
years is less likely to be genetically influenced.10
Environment Several non-genetic risk factors for PD
have been suggested, based on presumed pathogenic
pathways. However, the evidence of an association
between environmental risk factors and development of
PD is weak and the literature should be interpreted with
caution. Suggested environmental factors include
exposure to pesticides (eg, MPTP), herbicides or heavy
metals (manganese, copper).
Conversely, cigarette smoking is negatively associated
with the development of PD. Other factors that are
proposed to reduce the risk of PD include coffee
consumption, drinking alcohol and physical activity.
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362
Pathophysiology
The discovery of dopamine as a neurotransmitter in the
1950s by Arvid Carlsson and colleagues led to the
identification of the role of dopamine in the
pathophysiology of PD. Professor Carlsson observed a
high level of dopamine in the basal ganglia, an area of the
brain important for movement. In his experiments, animals
that were given reserpine (a drug that depletes dopamine)
subsequently developed symptoms similar to PD.
There are three pathological hallmarks of PD: the
presence of Lewy bodies; neuronal death in the pars
compacta of the substantia nigra; and the loss of pigmented
neurons (neuromelanin) in pigmented brainstem nuclei.
Lewy bodies, named after the German pathologist Fritz
Heinrich Lewy, are protein aggregates of abnormal asynuclein and other neurofilaments within the neuronal
cytoplasm. The exact role of Lewy bodies in the
pathophysiology of PD has yet to be established but they
are believed to be pathogenic in PD, leading to neuronal
cell death. Nevertheless, the presence of Lewy bodies can
be asymptomatic and not associated with PD. Lewy bodies
are also found in other neurodegenerative diseases (eg,
Lewy body dementia, Alzheimer’s disease, multisystem
atrophy). The number of Lewy bodies increases with age,
which correlates with the increasing incidence of PD
among older people.
Degeneration of dopaminergic neurones in the
substantia nigra pars compacta leads to profound depletion
of dopamine within the brain. Compensatory mechanisms
are so effective that the clinical symptoms of PD only
develop when 80% of dopaminergic neurones have
degenerated.8
Symptoms
The clinical features of PD are classified into two
groups — motor symptoms and non-motor symptoms.
The classic motor features are:
● Resting tremor — fine rhythmic movement
(frequency 4–6Hz) and often one of the first signs of
PD; initially seen in one upper limb and typically
Around a third of patients with Parkinson’s disease suffer from depression
❝
SUDDEN STOPPING
OR THE INABILITY
TO INITIATE
MOVEMENTS IS
REFERRED TO AS
‘FREEZING’. THIS IS
DIFFERENT FROM
‘SWITCHING OFF’,
WHICH IS A MOTOR
COMPLICATION OF
PD DRUG THERAPY
❞
involving both upper limbs at later stages of the
disease; involvement of the thumb and the index
finger is known as “pill-rolling”
● Bradykinesia — slowness of movement, usually in
the upper body
● Hypokinesia — poverty of movement, including
impassive facial expression and loss of arm swing
when walking and progressing to general difficulty
with fine movements
● Rigidity — the feeling of resistance to passive
movement, which begins unilaterally and progresses
to bilateral rigidity in advanced disease; the term
“lead pipe” is used to describe continuous resistance,
whereas “cogwheel” rigidity refers to more jerky
rigidity caused by superimposed tremor
Other motor symptoms that develop in later stages of
PD include motor freezing and postural and gait
instability. Postural disturbances can include stooped
posture, poor balance and stumbling, which frequently
lead to falls. Gait becomes slow with shuffling and
festination (involuntary quickening).
Sudden stopping or the inability to initiate movements
is referred to as “freezing”. This is different from
“switching off ”, which is a motor complication of PD drug
therapy where the treatment effect wears off before the
next dose is due (see accompanying article, p368).
A greater awareness of non-motor features of PD is
developing. Widespread use of the PD “non-motor
symptoms scale” questionnaire has provided evidence
that non-motor symptoms often have an equal or greater
impact on quality of life than motor complications of
PD.11 Patients may not be aware that non-motor
symptoms are related to PD. Although non-motor
symptoms are often difficult to control, it is important
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● Neuropsychiatric symptoms — dementia (24–
31%), depression (30%), anxiety, visual
hallucinations12, 13
● Autonomic — constipation, urinary incontinence,
hyperhidrosis, sialorrhoea, postural hypotension
(another cause of falls)
● Sleep disorders — rapid eye movement sleep
behaviour disorder, restless leg syndrome, vivid
dreams, narcolepsy
● Sensory symptoms — pain (dystonic and nondystonic), paraesthesia
Diagnosis
Accurate diagnosis of PD relies on clinical examination
and a thorough review of a patient’s history. No definitive
laboratory or imaging tests are available to confirm the
diagnosis until post-mortem.
There is a high error rate in the diagnosis of PD
(24–35% of diagnosed cases are false positives) because of
the lack of definitive laboratory or imaging tests to confirm
diagnosis. Evidence suggests that the error rate is 47% in
primary care compared with 6–8% in tertiary care and,
therefore, if PD is suspected patients should be referred
(preferably untreated) to a movement disorder clinic for
diagnosis.5 The UK Parkinson’s Disease Society’s “brain
bank criteria” (see Box 1, p366) can be used to aid
diagnosis and ongoing patient review.
Additional investigations (outlined below) are not
usually necessary, but may be useful if diagnosis is unclear.
❝
ALTHOUGH NONMOTOR SYMPTOMS
ARE OFTEN
DIFFICULT TO
CONTROL, IT IS
IMPORTANT THAT
THEY ARE
ADDRESSED AND
TREATED TO
MINIMISE THEIR
IMPACT ON QUALITY
OF LIFE
❞
Clinical Pharmacist
recommended. Testing may be of value for patients with
young-onset disease and with a strong family history of
PD.
Olfactory testing Impairment of sense of smell is one of
the early symptoms of PD and is seen in 85% of patients.5
Testing for this is not recommended for diagnosis because
of the lack of specificity of the symptom (other conditions
such as Alzheimer’s disease also feature diminished sense
of smell).
Differential diagnosis
Some neurodegenerative and Parkinsonian conditions (eg,
multisystem atrophy, progressive supranuclear palsy,
Wilson’s disease and cortico-basal degeneration) can
present with symptoms similar to PD and this can
complicate diagnostic accuracy. Evaluation of age of onset,
family history, symmetry, eye movements, tremor,
presence of dementia, onset and nature of falls, levodopa
response, cardiovascular autonomic failure and bladder
disturbance are helpful in differentiating these diseases.
Essential tremor is a symmetrical, task-related tremor
of 8–10 Hz that occurs mainly in the arm and upper limbs.
To differentiate between PD and essential tremor patients
are often asked to complete a writing test. This usually
reveals progressively bigger text written by a patient with
essential tremor compared with patients with PD for
whom the writing becomes smaller.
Drug-induced Parkinsonism is the second most
common cause of Parkinsonian symptoms in older people
(idiopathic is the most common).14 Drugs commonly
A writing test can be used to distinguish essential tremor from Parkinson’s disease
Levodopa challenge Improved symptoms in response to
levodopa is one of the characteristics of PD; therefore
administration of single doses has been suggested as a
diagnostic test. However, the test is not recommended as a
diagnostic tool because it carries a risk of: assessor bias;
placebo effect from dose administration; and false negative
results from patients who require higher doses for a longer
period to elicit a response. The test is also not sufficiently
specific (other conditions, such as multisystem atrophy
and progressive supranuclear palsy, can respond to
levodopa initially).
(SPECT) measures the uptake of radiolabelled tracers that
bind to the dopamine transporter protein (DAT) in
nigrostriatal nerve endings. A DAT scan will be abnormal
for patients with PD, multisystem atrophy or progressive
supranuclear palsy, but can be used to differentiate these
conditions from essential tremor and drug-induced
Parkinsonism (in which a DAT scan would be normal).
Other imaging techniques (eg, transcranial ultrasound
of the substantia nigra) are currently not recommended
because of high cost and lack of evidence. They are
sometimes used in clinical trials.
Genetic testing Specific genes that are associated with
PD have been identified, but monogenic forms of the
disease are rare and routine testing is therefore not
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Imaging Single photon emission computed tomography
365
CLINICAL FOCUS
that they are addressed and treated to minimise their
impact on quality of life. Non-motor clinical features
include:
December 2011
Clinical Pharmacist
December 2011
Vol 3
Box 1: Diagnosis of Parkinson’s disease
CLINICAL FOCUS
366
There are three main steps in the diagnosis
of Parkinson’s disease, recommended by
the UK Parkinson’s Disease Society:5
● Sustained remission
● Negative response to large doses of
Step 1 Diagnosis of a Parkinsonian
syndrome, characterised by bradykinesia
and at least one of the following:
●
● Muscular rigidity
● Resting tremor (4–6Hz)
● Postural instability unrelated to
primary visual, cerebellar, vestibular
or proprioceptive dysfunction
●
●
●
levodopa (if malabsorption is
excluded)
Strictly unilateral features after three
years
Other neurological features — eg,
supranuclear gaze palsy, cerebellar
signs, early severe autonomic
involvement, early severe dementia
Exposure to a known neurotoxin
Presence of cerebral tumour or
communicating hydrocephalus on
neuroimaging
Step 3 Identifying whether the patient
meets the supportive criteria for PD. Three
or more of the following are required for a
definite diagnosis:
●
●
●
●
●
●
●
●
Unilateral onset
Resting tremor present
Progressive disorder
Persistent asymmetry affecting the
side of onset most
Excellent response to levodopa
Severe levodopa-induced chorea
Levodopa response for over five years
Clinical course of over 10 years
Step 2 Ascertaining whether the patient
meets any of the exclusion criteria for PD,
namely:
● Repeated strokes with stepwise
progression of Parkinsonian features
Diagnose Parkinsonian
syndrome
● Repeated head injury
● Antipsychotic or other dopamine-
Does the patient meet
the exclusion criteria?
Does the patient meet
the supportive criteria?
depleting drugs
● Definite encephalitis or oculogyric
crisis without drug treatment
● More than one affected relative
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implicated are antipsychotics (typical antipsychotics
more often than atypical) and antiemetics, due to
their dopamine-blocking properties. Drug-induced
Parkinsonism is also associated with amiodarone, calcium
channel blockers, lithium and antiepileptics (eg, valproate
and phenytoin). Drug-induced Parkinsonism is underdiagnosed and can lead to permanent symptoms in 15% of
cases, even after withdrawal of the causative medicine; it is
not clear whether these cases reflect an unmasking of
underlying idiopathic PD.15
Prognosis
Rates of disease progression vary considerably among PD
patients. PD in itself is not fatal — the cause of death for
most people with PD is a secondary comorbid disorder (eg,
pneumonia). This is believed to have led to discrepancies
in the mortality rates reported in epidemiological studies.
Overall, most studies conclude that PD does reduce life
expectancy, with reported mortality hazard ratios varying
from 1.5 to 2.16.
Some 25–40% of patients with PD will develop
dementia, which is thought to contribute heavily to the
reduced life expectancy.16 Mortality rates associated with
PD have remained largely stable. A decrease in mortality
was noted in the late 1970s and early 1980s and this was
followed by an increase back to previous levels (explained
by the introduction of levodopa, which is believed to delay
death by about five years).17
2
Quelhas R, Costa RD. Anxiety, depression and quality of life in
Parkinson’s disease. Journal of Neuropsychiatry and Clinical
Neurosciences 2009;21:413–9.
3
Global Parkinson’s Disease Survey Steering Committee. Factors impacting
on quality of life in Parkinson’s disease: results from an international
survey. Movement Disorders 2002;17:60–7.
4
World Health Organization. Global burden of disease: 2004 update.
www.who.int/healthinfo/global_burden_disease/2004_report_update
(accessed 05 April 2011).
5
National Institute for Health and Clinical Excellence. Parkinson’s disease:
diagnosis and management in primary and secondary care. June 2006.
www.nice.org.uk/cg035 (accessed 5 April 2011).
6
Zhang ZX, Román GC. Worldwide occurrence of Parkinson’s disease: an
updated review. Neuroepidemiology 1993;12:195–208.
7
van Rooden SM, Heiser WJ, Kok JN, et al. The identification of
Parkinson’s disease subtypes using cluster analysis a systematic review.
Movement Disorders 2010;25:969–78.
8
Edwards M, Quinn N, Bhatia K. Parkinson’s disease and other movement
disorders. Oxford: Oxford University Press; 2008.
9
Clarke C. Parkinson’s disease in practice. 2nd edition. London: Royal
Society of Medicine Press; 2007.
10 Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an
etiologic study. JAMA 1999;281:341–6.
11 Martinez-Martin P, Rodriguez-Blazquez C, Kurtis M, et al. The impact of
non-motor symptoms on health-related quality of life of patients with
Parkinson’s disease. Movement Disorders 2011;26:399–406.
12 Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies
of dementia in Parkinson's disease. Movement Disorders
2005;20:1255–63.
13 Slaughter JR, Slaughter KA, Nichols D, et al. Prevalence, clinical
manifestations, etiology and treatment of depression in Parkinson’s
disease. Journal of Neuropsychiatry and Clinical Neurosciences
2001;13:187–96.
14 Thanvi B, Treadwell S. Drug-induced parkinsonism: a common cause of
parkinsonism in older people. Postgraduate Medical Journal
2009;85:322–6.
15 Nguyen N, Pradel V, Micallef J, et al. Drug-induced Parkinson syndromes.
Therapie 2004;59:105–12.
16 de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet
Neurology 2006;5:525–35.
References
1
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and Clinical Neurosciences 2002;14:223–36.
17 Clarke CE. Mortality from Parkinson’s disease in England and Wales
1921–89. Journal of Neurology, Neurosurgery and Psychiatry
1993;56:690–3.