parkinson disease is recognized as one of the most common neurologic disorders

7/29/2019 Parkinson Disease is Recognized as One of the Most Common Neurologic Disorders

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Parkinson disease is recognized as one of the most common neurologic disorders, affecting

approximately 1% of individuals older than 60 years. There are 2 major neuropathologicfindings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta

(SNpc) and the presence of Lewy bodies (see the following image). Most cases of Parkinson

disease (idiopathic Parkinson disease [IPD]) are hypothesized to be due to a combination of

genetic and environmental factors. However, no environmental cause of Parkinson disease hasyet been proven. A known genetic cause can be identified in approximately 10% of cases, and

these are more common in younger-onset patients.

Gross comparison of the appearance of the substantia nigra

between a normal brain and a brain affected by Parkinson disease. Note the well-pigmentedsubstantia nigra in the normal brain specimen on the left. In the brain of a Parkinson disease

patient on the right, loss of pigmented substantia nigra due to depopulation of pigmented neuronsis observed.

The classic motor features of Parkinson disease typically start insidiously and emerge slowly

over weeks or months, with tremor being the most common initial symptom. The 3 cardinal

signs of Parkinson disease are resting tremor, rigidity, and bradykinesia. Postural instability

(balance impairment) is sometimes listed as the fourth cardinal feature. However, balanceimpairment in Parkinson disease is a late phenomenon, and in fact, prominent balance

impairment in the first few years suggests that Parkinson disease is not the correct diagnosis.

(See Presentation.)

When a patient presents with tremor, the clinician evaluates the patient's history and physical

examination findings to differentiate Parkinson disease tremor from other types of tremor. Inpatients with parkinsonism, careful attention to the history is necessary to exclude causes such as

drugs, toxins, or trauma. (See Differential Diagnosis.) Other common causes of tremor include

essential tremor, physiologic tremor, and dystonic tremor.

No laboratory or imaging study is required in patients with a typical presentation of Parkinson

disease. Such patients are aged 55 years or older and have a slowly progressive and asymmetric

parkinsonism with resting tremor and bradykinesia or rigidity. There are no red flags such as

prominent autonomic dysfunction, balance impairment, dementia, or eye-movementabnormalities. In such cases, the diagnosis is ultimately considered confirmed once the patient

goes on dopaminergic therapy (levodopa or a dopamine agonist) as needed for motor symptomcontrol and exhibits a robust and sustained benefit. (See Workup.)

Imaging studies can be considered, depending on the differential diagnosis. Magnetic resonanceimaging (MRI) of the brain can be considered to evaluate possible cerebrovascular disease
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(including multi-infarct state), space-occupying lesions, normal-pressure hydrocephalus, and

other disorders.

Iodine-123labeled fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT

I123

) (Ioflupane, DaTscan) single-photon emission computed tomography (SPECT) can be

considered in cases of uncertain parkinsonism to help differentiate disorders associated with aloss of dopamine neurons (Parkinson disease and atypical parkinsonisms, including multiple

system atrophy [MSA] and progressive supranuclear palsy [PSP]) from those disorders notassociated with a loss of dopamine neurons (eg, essential tremor, dystonic tremor, vascular

parkinsonism, medication-induced parkinsonism or tremor, psychogenic conditions).[1]

Levodopa coupled with a peripheral decarboxylase inhibitor (PDI), such as carbidopa, remains

the gold standard of symptomatic treatment of motor features of Parkinson disease. It provides

the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However,

its long-term use is associated with the development of fluctuations and dyskinesias. Moreover,the disease continues to progress, and patients accumulate long-term disability. (See Treatment.)

Dopamine agonists such as pramipexole (Mirapex) and ropinirole (Requip) can be used as

monotherapy to improve symptoms in early Parkinson disease or as adjuncts to levodopa in

patients who are experiencing motor fluctuations. Monoamine oxidase (MAO)-B inhibitors, such

as selegiline (Eldepryl) and rasagiline (Azilect) provide mild benefit as monotherapy in earlydisease and as adjuncts to levodopa in patients with motor fluctuations. (See Medication.)

Entacapone (Comtan), a catechol-o-methyltransferase (COMT) inhibitor, reduces the peripheral

metabolism of levodopa, thereby making more levodopa available to enter the brain over alonger period; this agent is used as an adjunct to levodopa in patients with motor fluctuations.

Anatomy

Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei

situated at the base of the forebrain. The striatum, composed of the caudate and putamen, is the

largest nuclear complex of the basal ganglia. The striatum receives excitatory input from severalareas of the cerebral cortex, as well as inhibitory and excitatory input from the dopaminergic

cells of the substantia nigra pars compacta (SNc). These cortical and nigral inputs are received

by the spiny projection neurons, which are of 2 types: those that project directly to the internalsegment of the globus pallidus (GPi), the major output site of the basal ganglia; and those that

project to the external segment of the globus pallidus (GPe), establishing an indirect pathway to

the GPi via the subthalamic nucleus (STN).

For an illustration of the subthalamic nucleus, see the image below.


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Sagittal section, 12 mm lateral of the midline, demonstrating thesubthalamic nucleus (STN) (lavender). The STN is one of the preferred surgical targets for deep

brain stimulation to treat symptoms of advanced Parkinson disease.

The actions of the direct and indirect pathways regulate the neuronal output from the GPi, which

provides tonic inhibitory input to the thalamic nuclei that project to the primary and

supplementary motor areas.

Pathophysiology

No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as thespecificity and sensitivity of its characteristic findings have not been clearly established.

However, the following are the 2 major neuropathologic findings in Parkinson disease:

Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta The presence of Lewy bodies and Lewy neurites

The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra.

Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson

disease emerge.

Some individuals who were thought to be normal neurologically at the time of their deaths are

found to have Lewy bodies on autopsy examination. These incidental Lewy bodies have beenhypothesized to represent the presymptomatic phase of Parkinson disease. The prevalence of

incidental Lewy bodies increases with age. Note that Lewy bodies are not specific to Parkinson

disease, as they are found in some cases of atypical parkinsonism,Hallervorden-Spatz disease,and other disorders. Nonetheless, they are a characteristic pathology finding of Parkinson

disease.

Motor circuit in Parkinson disease

The basal ganglia motor circuit modulates the cortical output necessary for normal movement

(see the following image).
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Schematic representation of the basal ganglia - thalamocortical motor

circuit and its neurotransmitters in the normal state. From Vitek J. Stereotaxic surgery and deep

brain stimulation for Parkinson disease and movement disorders. In: Watts RL, Koller WC, eds.Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240.

Copyright, McGraw-Hill Companies, Inc. Used with permission.

Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motorcircuit and return to the same area via a feedback pathway. Output from the motor circuit is

directed through the internal segment of the globus pallidus (GPi) and the substantia nigra pars

reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppressesmovement.

Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:

In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatalneurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr

The indirect pathway contains inhibitory connections between the striatum and theexternal segment of the globus pallidus (GPe) and between the GPe and the subthalamicnucleus (STN); striatal neurons with D2 receptors are part of the indirect pathway andproject to the GPe

The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory

output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from

nigrostriatal (substantia nigra pars compacta [SNpc]) neurons to activate the direct pathway and

inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increasedinhibitory output from the GPi/SNr via both the direct and indirect pathways (see the following

image).


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Schematic representation of the basal ganglia - thalamocortical motor

circuit and the relative change in neuronal activity in Parkinson disease. From Vitek J.

Stereotaxic surgery and deep brain stimulation for Parkinson disease and movement disorders.In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New

York: McGraw-Hill, 1997:241. Used with kind permission. Copyright, McGraw-Hill

Companies, Inc.

The increased inhibition of the thalamocortical pathway suppresses movement. Via the directpathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr.

Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe,resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output

to the thalamus.

Etiology

Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be dueto a combination of genetic and environmental factors. Currently known genetic causes of

Parkinson disease account for approximately 10% of cases.

Environmental causes

Environmental risk factors commonly associated with the development of Parkinson disease

include use of pesticides, living in a rural environment, consumption of well water, exposure toherbicides, and proximity to industrial plants or quarries.[2] The National Institutes of Health-

AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that

higher caffeine intake was associated with lower risk of Parkinson disease in both men and

women. A similar association was found for smoking and Parkinson disease risk.[3]

Thebiological mechanisms underlying the inverse relationship between caffeine or smoking and

Parkinson disease risk are not well elucidated.

MPTP interference with mitochondrial function

Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-

4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity,

and tremor, which progressed over several weeks and improved with dopamine replacement


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therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium

(MPP+) by monoamine oxidase (MAO)-B.[4]

MPP+ accumulates in mitochondria and interferes with the function of complex I of the

respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides

suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but nospecific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in

Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.

Oxidation hypothesis

The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative

metabolism, plays a role in the development or progression of Parkinson disease. The oxidative

metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally,

hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not clearedadequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with

cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels ofreduced glutathione are decreased, suggesting a loss of protection against formation of free

radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons,thereby promoting the formation of free radicals.

Parkinson disease is associated with increased dopamine turnover, decreased protective

mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased

lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due tolevodopa administration could increase oxidative damage and accelerate loss of dopamine

neurons. However, there is no clear evidence that levodopa accelerates disease progression.

Genetic factors

If genetic factors are important in a particular disease, concordance in genetically identical

monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50%of genes. Early Parkinson disease twin studies generally found low and similar concordance ratesfor MZ and DZ pairs.

However, genetic factors in Parkinson disease appear to be very important when the disease

begins at or before age 50 years. In a study of 193 twins, overall concordance for MZ and DZ

pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before

age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.[5]

The identification of a few families with familial Parkinson disease sparked further interest in the

genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinsondisease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-

for-G substitution at base 209 of the alpha-synuclein gene.[6]

Termed PD-1, this mutation codes

for a substitution of threonine for alanine at amino acid 53. These individuals were characterizedby early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1


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years), lack of tremor, and good response to levodopa therapy.[6]

Five small Greek kindreds were

also found to have the PD-1 mutation.

In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C

for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that

mutations in the alpha-synuclein gene can cause Parkinson disease.

[7]

A few additional familialmutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It

is now clear that these mutations are an exceedingly rare cause of Parkinson disease.

A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations

within 6 of these loci (SNCA,LRRK2, PRKN,DJ1, PINK1, andATP 13A2) are well-validatedcauses of familial parkinsonism.[8] Inheritance is autosomal dominant for SNCA andLRRK2

(althoughLRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for

PRKN,DJ1, PINK1, andATP13A2. In addition, polymorphisms within SNCA andLRRK2, as

well as variations inMAPTand GBA, are risk factors for Parkinson disease.[8]

(For more information on genes/loci underlying monogenic parkinsonism and susceptibilitygenes/loci for Parkinson disease, see Tables 1 and 2, respectively, in The Genetics of Parkinson

Disease.[8] )

In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64

patients (6.7%) had a PRKNmutation, 1 patient (0.2%) had aDJ1 mutation, 35 patients (3.6%)had anLRRK2 mutation, and 64 patients (6.7%) had a GBA mutation.

[9]. Mutations were more

common in patients with age at onset of 30 years or younger (40.6%) than in those with age atonset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%)

than in non-Jewish patients (13.7%); and more common in patients reporting a first-degree

family history of Parkinson disease (23.9%) than in those without such a family history

(15.1%).

[9]

Although the mechanisms by which genetic mutations cause Parkinson disease is not known,evidence to date converges on mechanisms related to abnormal protein aggregation, defective

ubiquitin-mediated protein degradation, mitochondrial dysfunction, and oxidative damage.

Alpha-synuclein conformational changes and aggregation

Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewyneurites, which are characteristic pathologic findings in Parkinson disease. Missense mutations

and multiplications in the SNCA gene that encodes alpha-synuclein, although rare, cause

autosomal dominant Parkinson disease. However, genome-wide association studies have alsodemonstrated a link between SNCA and sporadic Parkinson disease.

Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson

disease, and understanding its relationship to the disease process holds major promise for thedevelopment of a cure.


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Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when

bound to membranes or vesicles containing acidic phospholipids, it takes on an alpha-helicalstructure. Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals and may

play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor

activating protein receptor) proteins that are involved in neurotransmitter release.

Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted

to the betasheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinsondisease. Most evidence currently suggests that it is the intermediate soluble oligomers that are

toxic to neurons.

Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein

could exert neurotoxicity.[10]

One hypothesis suggests that oligomeric alpha-synuclein can

promote formation of ion-permeable pores on neuronal membranes, leading to increased calcium

influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesiclesinto the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair

mitochondrial complex I activity, and oligomeric alpha-synuclein may have a direct effect onmitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-

stabilizing protein, tau.[11]

Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated

by a balance between synthesis and degradation. SNCA multiplications lead to increased

synthesis of alpha-synuclein and can cause Parkinson disease. Alpha-synuclein appears to bedegraded by the ubiquitin proteasome system and the autophagy-lysosome pathway. Several

genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein

degradation. For example, increased risk of Parkinson disease in carriers ofGBA (beta-

glucocerebrosidase gene) mutations, which encode for the lysosomal enzymeglucocerebrosidase, may be due to lysosomal dysfunction and consequent alpha-synuclein

accumulation and oligomerization.

How the Parkinson disease process begins is not known. Once it is initiated, however, it may

propagate by a prionlike process in which misconformed proteins induce the templated

misfolding of other protein molecules. In Parkinson disease, synuclein pathology begins in thelower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the

neocortex. One set of observations in support of a prionlike process comes from experience with

fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease, because

these grafts develop Lewy bodies, suggesting host-graft transmission of disease.[12]

Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowingor stopping Parkinson disease progression.

Epidemiology

Parkinson disease is recognized as one of the most common neurologic disorders, affecting

approximately 1% of individuals older than 60 years. The incidence of Parkinson disease has


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been estimated to be 4.5-21 cases per 100,000 population per year, and estimates of prevalence

range from 18 to 328 cases per 100,000 population, with most studies yielding a prevalence ofapproximately 120 cases per 100,000 population. The wide variation in reported global incidence

and prevalence estimates may be the result of a number of factors, including the way data are

collected, differences in population structures and patient survival, case ascertainment, and the

methodology used to define cases.

[13]

The incidence and prevalence of Parkinson disease increase with age, and the average age ofonset is approximately 60 years. Onset in persons younger than 40 years is relatively uncommon.

Parkinson disease is about 1.5 times more common in men than in women.

Prognosis

Before the introduction of levodopa, Parkinson disease caused severe disability or death in 25%

of patients within 5 years of onset, 65% within 10 years, and 89% within 15 years. The mortalityrate from Parkinson disease was 3 times that of the general population matched for age, sex, and

racial origin. With the introduction of levodopa, the mortality rate dropped approximately 50%,and longevity was extended by many years. This is thought to be due to the symptomatic effects

of levodopa, as no clear evidence suggests that levodopa stems the progressive nature of thedisease.[14, 15]

The American Academy of Neurology notes that the following clinical features may help predict

the rate of progression of Parkinson disease[16] :

Older age at onset and initial rigidity/hypokinesia can be used to predict (1) a more rapidrate of motor progression in those with newly diagnosed Parkinson disease and (2) earlier

development of cognitive decline and dementia; however, initially presenting with tremor

may predict a more benign disease course and longer therapeutic benefit from levodopa A faster rate of motor progression may also be predicted if the patient is male, has

associated comorbidities, and has postural instability/gait difficulty (PIGD)

Older age at onset, dementia, and decreased responsiveness to dopaminergic therapy maypredict earlier nursing home placement and decreased survival

Patient Education

Patients with Parkinson disease should be encouraged to participate in decision making regarding

their condition.[17]

In addition, individuals and their caregivers should be provided with

information that is appropriate for their disease state and expected or ongoing challenges

[15]

.Psychosocial support and concerns should be addressed and/or referred to a social worker or

psychologist as needed.

Prevention of falls should be discussed. The UK National Institute for Health and Clinical

Excellence has severalguidance documentsincluding those for patients and caregivers.
http://guidance.nice.org.uk/CG21http://guidance.nice.org.uk/CG21http://guidance.nice.org.uk/CG21http://guidance.nice.org.uk/CG21


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Other issues that commonly need to be addressed at appropriate times in the disease course

include cognitive decline, personality changes, depression, dysphagia, sleepiness and fatigue,and impulse control disorders. Additional information is also often needed for financial planning,

insurance issues, disability application, and placement (assisted living facility, nursing home).

For patient education information, see theBrain & Nervous System Center,as well asParkinson's Disease Dementia.
http://www.emedicinehealth.com/brain-and-nervous-system/center.htmhttp://www.emedicinehealth.com/brain-and-nervous-system/center.htmhttp://www.emedicinehealth.com/brain-and-nervous-system/center.htmhttp://www.emedicinehealth.com/parkinson_disease_dementia/article_em.htmhttp://www.emedicinehealth.com/parkinson_disease_dementia/article_em.htmhttp://www.emedicinehealth.com/parkinson_disease_dementia/article_em.htmhttp://www.emedicinehealth.com/brain-and-nervous-system/center.htm


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Parkinson's Disease

Neil Archibald, MA BMBCh MRCP; David Burn, FRCP MD MA MBBS


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Definition

Defining Parkinsons disease (PD) is a little difficult because of the variability of signs and

symptoms present. Broadly speaking, patients exhibit signs of parkinsonismbradykinesia,

tremor and rigidityalthough these clinical features are not unique to PD. Another common

term used to describe such symptoms is extrapyramidalseparating the clinical features from

disorders of the motor cortex and pyramidal tracts. The most common form of PD is often

referred to as idiopathic to help distinguish it from the rarer genetic forms of PD and the more

atypical extrapyramidal disorders.

Epidemiology

PD is the second most common neurodegenerative disorder in the UK after Alzheimers disease

(AD) and, given our ageing population, will become increasingly important in future years.Epidemiological studies are difficult to interpret, in part due to methodological problems, and

also because of diagnostic uncertainty within cohorts. These problems are even more marked in

developing countries, and the worldwide prevalence of PD is effectively unknown. In the UK,prevalence in the general population is 0.3%, with an estimated incidence of 818 per 100,000

person years.1 Both these figures increase with age, and prevalence is estimated at 1% in the over

60s and 4% in the over 80s.2,3

In other words, an average GP practice will see between two and

four new cases per year, and an average Premiership football crowd will contain 1215 sufferers.

Pathology and Pathogenesis

Pathological examination of the brains of PD patients reveals abnormal protein aggregations ofa-synuclein, often collected into intracellular inclusions (Lewy bodies). In addition, there is

marked loss of dopaminergic cells in an area of the brainstem known as the substantia nigra,leading to degeneration of projections to other regions of the brain. Most of these projections

terminate in the putamen and globus pallidus, although there are also projections to the cerebral


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cortex, thalamus and other areas of the brainstem. Dopamine deficiency is the hallmark of PDbut many other neurotransmitters are also affected in the condition. This degeneration ultimately

leads to dysfunction of a complex network of excitatory and inhibitory feedback loops, resulting

in the symptoms seen in PD. We need not concern ourselves too much with the bewildering

array of connections in this update. (Figure 1)

Genetic factors play a role in the development of PD, although true Mendelian inheritance is

rare. It is thought that susceptibility genes in combination with a range of environmental factorsplay a role in the development of PD, and around 90% of cases are sporadic, with no family

history. Potential causative environmental factors are elusive although pesticide exposure has

been consistently isolated as an independent risk factor. It seems likely that smoking isassociated with a decreased risk of developing PD, although how much of this reduction is due to

selective mortality in smokers is uncertain. Higher caffeine intake has also been reported to have

an inverse correlation with risk of developing PD.4

Patients and relatives are often interested or concerned about these issues, and it is important to

counsel them appropriately. Whilst there is a small (two-fold) increase in relative risk ofdeveloping PD for first-degree relatives, this is not a condition that is passed on in the truestsense of the phrase. We still have an incomplete understanding of the role that environmental

factors play in the development of PD.


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Course of the Disease

PD follows a progressive course with a highly variable tempo. There is no cure nor do we havetreatments to reverse or retard the neurodegeneration. Treatment is therefore symptomatic and itis important that patients are aware of this. There is a reduction in life expectancy associated

with the diagnosis, with mortality hazard ratios of between 1.5 and 2.7. Most of the increased

mortality is associated with the development of dementia in PD, accompanied by the myriad

medical problems seen in this situation. Dementia is increasingly recognized as a complication ofPD, with cross-sectional prevalence of between 25% and 40% in PD populations and a six-fold

increase in the risk of developing dementia compared with that in the general population.5,6

We are beginning to recognize clinical features in patients with PD that might predict a stormier

course. In general terms, the later one develops the disease, the longer one has PD, and the more

severe the disease is, the greater the likelihood of developing complications. Essentially,developing PD late in life is often associated with other co-morbid conditions and less


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physiological reserve than younger patients. In addition, the longer you have PD, the more likelyyou are to develop complications such as dementia, falls, etc. Hence, both are poor prognostic

indicators. In addition, the presence of neuropsychiatric features early on (depression and hal-

lucinations) predicts worse outcome. Two main clinical phenotypes are now emerging:

tremor-dominant PD patients those with more marked postural instability and gait disorders (PIGD group).

The latter have a markedly increased risk of cognitive decline and dementia in later years.7

Diagnosis

Despite advances in structural and functional brain imaging, the diagnosis of PD remains

clinical. There is great potential for misdiagnosis and even in patients with advanced disease at

tertiary referral centres neuropathological studies suggest an incorrect diagnosis in around 10%of cases.8 In the real world, this diagnostic inaccuracy is likely to be higher. The cardinal clinical

features are:

bradykinesia (essential) plus at least one of the following: rest tremor rigidity.

UK Brain Bank criteria (Table 1) are often used to aid diagnosis and, although not infallible, are

at least applicable in a clinical environment. It is beyond the scope of this article to coverexhaustively all the clinical features of PD and the numerous potential differential diagnoses. We

hope to provide a few clinical insights, however, to help you avoid the common pitfalls.

Rules of thumb are:

Tremor is not needed for a diagnosis of PD nor does the presence of tremor necessarily suggestPD

Parkinsonism describes the clinical features seen in PD. It does not necessarily imply that thediagnosis is PD

Atypical features (Table 1) should make you question the diagnosis as should a poor response totreatment

Neurologists get it wrong too, and it is often better to leave the diagnosis open if you are notsure.

History

Motor Features

Patients often complain of a tremor, present when sitting quietly, which improves on movement.

This is usually asymmetrical in distribution. In addition, most patients notice difficulty walking,

finding themselves more stooped, slower or shuffling. Manual dexterity is affected, and writing

becomes less legible and smaller across the page (micrographia). Patients may notice difficulty


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getting out of chairs and turning over in bed. Their balance may be affected and they frequentlycomplain of feeling unsteady. Early backward falls should be considered an atypical feature and

suggest an alternative diagnosis. (Table 2).

Non-motor Features

Apathy and low mood are frequent, although not often reported by patients. We have alreadymentioned dementia as a potential complication, and psychosis, either in association with

cognitive impairment or as a result of medication, is also a common problem. Depression is a

frequent feature in PD and can be considered one of the most common neuropsychiatric featuresof the disease. Sleep disorders are frequent, with patients often reporting sleep fragmentation

rather than initial insomnia (ie, difficulty staying asleep rather than falling asleep). They may

also describe unpleasantly vivid dreams characteristic of REM-sleep behaviour disorder (RBD).

In RBD, patients physically act out their dreams, and it is not unheard of for patients to punchtheir spouse or even throw themselves out of bed whilst asleep. Hyposmia is a notable feature in

PD (most studies suggest between 7090% of PD patients have some degree of hyposmia),

although not frequently volunteered, and both sleep disturbance and loss of sense of smell canpredate motor symptoms by decades. Visual symptoms are also a common feature of PD,

ranging from dry eyes and reading difficulties through to a feeling of presence in the room andfrank visual hallucinations. The early development of visual hallucinations should alert the

physician to an alternative diagnosis, such as dementia with Lewy bodies (DLB). Constipation,urinary frequency, nocturia and postural dizziness may reflect underlying autonomic

involvement in PD.


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Examination

PD patients will usually have a rather expressionless face with reduced blink frequency

(hypomimia). Assessing gait will reveal reduction in arm swing and, perhaps, a slight stoop and

shuffle. Standing behind the patient and, with appropriate warning and safeguards, pulling themback may reveal retropulsion or even a tendency to fall stiffly like a felled tree. Tremor is at a 46 Hz frequency and will usually diminish when the limb is used. For this reason patients should

not have marked difficulty performing tests of cerebellar function. Parkinsonian patients

demonstrate a reduction in amplitude of alternating movements (rapidly pronating/supinating the

wrist, opening and closing the hand, and tapping thumb and forefinger together) and themovements may be very slow (bradykinesia). Unlike spasticity, increase in muscle tone (rigidity)

is not velocity dependent, but rather more constant throughout the range of movement. It can be

accentuated by asking the patient to move the opposite limb whilst you manipulate the other.

With superimposed tremor, the rigidity becomes cog-wheeled with a stop-start, ratchetingfeel when moving the joint. Such abnormal tone is best examined using a combination of flexion,

extension and rotation at the wrist joint.


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Investigations

As mentioned previously, the diagnosis of PD remains largely clinical. Tests are therefore

employed to avoid an incorrect diagnosis being made rather than to confirm a clinical suspicion.You will note from Table 2 that there is a broad range of neurodegenerative disorders that feature

parkinsonism as part of their clinical phenotype. We will not discuss the investigation of thesemore atypical disorders here.

A fine resting tremor can be a feature of anxiety disorders although all movement disorders

worsen at times of stress, and this feature should not put you off an organic diagnosis. It isworth considering thyrotoxicosis briefly in any tremor disorder and, if necessary, looking for

further historical clues. There are few blood tests that would be considered first line in the

investigation of movement disorders outside the specialist setting. Structural brain imaging

(computed tomography or magnetic resonance imaging) is indicated for atypical features and themost common findings are the hallmark changes of cerebrovascular disease.

When it proves difficult to differentiate clinically between movement disorders, or when there isa poor response to treatment, functional imaging of the dopaminergic system can be undertaken.

By labelling the dopamine transporters in the basal ganglia with radioisotopes, we can now

assess the integrity of the projections from the brainstem to the rest of the basal ganglia. Theseprojections degenerate in PD (and other disorders such as multiple system atrophy, progressive

supranuclear palsy, etc.) but are preserved in vascular parkinsonism, drug-induced parkinsonism

and essential tremor (ET). An abnormal dopamine transporter (DaT) scan can therefore

distinguish between conditions such as ET and PD but is unhelpful in differentiating betweenmore closely linked conditions such as PD and Multiple System Atrophy (MSA). (Figure 2)

Unhelpfully, it is possible to have a normal DaT scan and still have PD, but such cases are

fortunately rare.

Management

It is our belief that all patients with presumed PD should be seen, at least initially, by a physician

skilled in the diagnosis and management of movement disorders. Ideally, given the multisystem

nature of the condition and its complications, they should have access to a multidisciplinary teamincluding specialist nurses, physiotherapists, occupational therapists, social workers, speech and

language therapists, and dieticians. Successful management relies on:

patient and caregiver education pharmacological therapy for PD treatment of PD complications input from the multidisciplinary team appropriate palliative care in advanced disease.

Patient and Caregiver Education

In part, this can be achieved through the specialist clinics, with support from PD specialist nurses

and community support workers. In addition, GPs provide invaluable support for their patients


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during the long wait between outpatient appointments.

Numerous support groups exist for patients and caregivers, and information on these as well as

downloadable information sheets can be obtained from the Parkinsons Disease Society(http://www.parkinsons.org.uk).

Pharmacological Therapy for PD

Any discussion of PD treatment should begin with the statement that not all patients need tocommence treatment at diagnosis. It is only when symptoms begin to interfere with daily life thatpharmacotherapy is necessary. The mainstay of treatment for PD is dopaminergic replacement

therapy. The two most common classes of drugs are the dopamine agonists, which stimulate

dopamine receptors in the brain, and levodopa (L-DOPA)-containing drugs where the L-DOPA

is taken up by dopaminergic neurons in the brain, converted to dopamine and released. Becauseof the risk of developing L-DOPA-induced additional movements (dyskinesias) after prolonged

or high-dose therapy, initial treatment often consists of dopamine agonist therapy unless there are

contraindications. Unfortunately, the use of these agonists is limited by side effects such assomnolence, confusion and hallucinations, particularly in the elderly, making them less than

ideal for many patients with later-onset disease. Recently, the dopamine agonists have also been

associated with impulse control disorders (for example, pathological gambling andhypersexuality). Treatments for PD are comprehensively discussed in the National Institute for

Health and Clinical Excellence guidelines for management of PD9 and summarized in Table 3.


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Initial treatment of PD is usuallyeffective and well tolerated but, as time and the disease progress, patients begin to developproblems. Tremor can be difficult to treat, and pushing the doses ever higher in an attempt to

control this feature of PD is often counterproductive. Motor fluctuations include wearing-off ofthe drug effect before the next dose, unexpected freezing, particularly in narrow spaces such as

doorways, and a prolonged time to onset of action. To some extent, these problems can be

overcome with judicious increments in medication dose, or with additional agents to prolong theeffect of L-DOPA, such as Catechol-O-methyltransferase (COMT) inhibitors. If motor

fluctuations become intolerable despite optimizing oral therapies, then consideration can begiven to parenteral routes (jejunal infusions of L-DOPA gel or subcutaneous apomorphine) or

even deep brain stimulation procedures (particularly of the subthalamic nucleus).

Most PD patients dread in-patient hospital admissions, even on specialist neurology wards. This

is because patients evolve a complex routine of medication dosage and timing to suit their daily


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existence. They may also choose odd meal times to avoid interactions with their drugs. Needlessto say, the busy general medical ward is not the place to accommodate these regimens. In

addition, hospital staff often poorly understand the need for accurate, patient-administered

dosing if PD patients are to keep control of their motor symptoms. The ward diet may also differ

considerably from what the patient is used to, and in advanced cases this may be sufficient to

disrupt the precarious motor control. Discussing the individual needs of the patient with seniorward staff as well as patients and caregivers can help to minimize these problems.

Treatment of PD Complications

Complications are universal in PD and one can sometimes feel overwhelmed by the daunting

array of complaints. Even in very advanced PD there is always something the team can offer and

this should not be forgotten. We have already touched upon treatment of motor problems in the

previous section, and we shall focus on the non-motor aspects here.

Dementia in PD (PDD) has recently been characterized in consensus diagnostic criteria,10

the key

features being a progressive cognitive decline impacting on daily life with associated fluctuatingdrowsiness, somnolence and visual hallucinations. In many ways, the clinical features are

identical to those seen in DLB. It would appear that PDD patients respond well to cholinesterase

inhibitors (eg, rivastigmine, donepezil), particularly if they have prominent visual hallucinations,and a therapeutic trial in such circumstances is vital. It should be borne in mind that PD patients

can suffer adverse reactions to typical neuroleptic medications, and dopamine D2 receptor

blocking drugs such as haloperidol should be avoided. REM Sleep behaviour disorders (RBD)

can be effectively treated with clonazepam or melatonin, sometimes with resulting improvementsin daytime somnolence.

Depression responds to standard therapies, highlighting the importance of asking about mood

disturbance in PD. Autonomic involvement can be challenging, particularly when it involvessymptomatic orthostatic hypotension (OH). It can be difficult to work out how much of the OH

has resulted from the PD, the PD medications, the patients age or comorbidities and othermedications. Closely linked with this is the risk of falls, which require a careful assessment

owing to their multifactorial nature. Bladder and bowel function are often overlooked by

specialist and non-specialist alike, but both are amenable to treatment with appropriate consid-eration and investigation.


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Declaration of Interests

None


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3. de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinsons disease in the elderly:the Rotterdam Study. Neurology 1995;45:21432146

4. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S. A meta-analysis of Parkinsons disease andexposure to pesticides . Neurotoxicology 2000;21:435440

5. Cummings JL. Intellectual impairment in Parkinsons disease: clinical, pathologic, andbiochemical correlates . J Geriatr Psychiatry Neurol 1988;1:2436 .

6. Aarsland D, Zaccai J, Brayne C. Systematic review of prevalence studies of dementia inParkinsons disease . Mov Disord 2005;20:12551263

parkinson disease is recognized as one of the most common neurologic disorders

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