MOVEMENT DISORDERSParkinsons diseaseNeil Archibald

David Burn

AbstractParkinsons disease (PD) is the second most common neurodegenera-

tive condition affecting patients in the UK after Alzheimers disease. It

is broadly classified as a movement disorder with a variety of clinical

features, including bradykinesia, rigidity and tremor. Traditional focus has

fallen on the treatment of motor complications such as tremor and mobil-

ity problems although these features are only a small part of the clinical

phenotype. In reality, PD is better defined as a multisystem neurodegen-

erative disorder causing a large number of motor and non-motor complica-

tions, and both aspects will be covered in this update. Diagnosis remains

largely clinical and there are many potential pitfalls for the unwary clini-

cian. Successful treatment relies heavily on a multidisciplinary approach

with introduction of pharmacological therapy in a gradual, incremental and

monitored setting. In the absence of disease-modifying agents, therapy re-

mains symptomatic and complications increase as time progresses. Many

of the most disabling complications are non-motor, and management of

advanced PD is both complex and challenging.

Keywords basal ganglia; bradykinesia; dementia; dopamine; dyskinesia; extrapyramidal; non-motor symptoms; Parkinsons disease; tremor

DefinitionDefining Parkinsons disease (PD) is a little difficult because of the variability of signs and symptoms present. Broadly speaking, patients exhibit signs of parkinsonism bradykinesia, tremor and rigidity although these clinical features are not unique to PD. Another common term used to describe such symptoms is

Neil Archibald MA BMBCh MRCP is a Clinical Research Fellow at the Institute for Ageing and Health and a Specialist Registrar in Neurology

at Newcastle General Hospital, Newcastle-upon-Tyne, UK. His research

interests include the non-motor complications of Parkinsons disease

in general and visual symptoms specifically. Competing interests: none

declared.

David Burn FRCP MD MA MBBS is Professor of Movement Disorder Neurology at the Institute for Ageing and Health, Newcastle University

and Honorary Consultant Neurologist, Newcastle upon Tyne Foundation

NHS Trust, UK. He is also Director of the Clinical Ageing Research

Unit on the Campus for Ageing and Vitality. He qualified from Oxford

University and trained in general medicine and neurology in Newcastle

upon Tyne and London, UK. His research interests include dementia

and depression associated with Parkinsons disease and also MEDICINE 36:12 63

progressive supranuclear palsy. Competing interests: none declared. extrapyramidal separating 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 extra-pyramidal 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 uncer-tainty 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 popu-lation is 0.3%, with an estimated incidence of 818 per 100,000 person years.1 Both these figures increase with age, and preva-lence 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 of -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 pro-jections 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 cortex, thalamus and other areas of the brainstem. Dopamine deficiency is the hallmark of PD but 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 susceptibil-ity genes in combination with a range of environmental factors play a role in the development of PD and around 90% of cases are sporadic, with no family history. Potential causative envi-ronmental factors are elusive although pesticide exposure has been consistently isolated as an independent risk factor. It seems likely that smoking is associated with a decreased risk of devel-oping PD, although how much of this reduction is due to selec-tive 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 of developing PD for first-degree relatives, this is not a condition that is passed on in the truest sense of the phrase. We still have an incomplete understanding of the role that environmental fac-0 2008 Elsevier Ltd. All rights reserved.

tors play in the development of PD.

MOVEMENT DISORDERSCourse of the disease

PD follows a progressive course with a highly variable tempo. There is no cure nor do we have treatments to reverse or retard the neurodegeneration. Treatment is therefore symptomatic and it is important that patients are aware of this. There is a reduc-tion in life expectancy associated with the diagnosis, with mor-tality 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 situ-ation. Dementia is increasingly recognized as a complication of PD, 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 develop-ing complications. Essentially, developing PD late in life is often associated with other co-morbid conditions and less physiological reserve than younger patients. In addition, the longer you have PD, the more likely you 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 hallucinations) 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

Basal ganglia connections

Cerebral cortex

Caudate

Thalamus

Globuspallidus

Putamen

Subthalamicnucleus

Substantianigra

Corticobasal ganglia thalamocortical loop

Internal regulatory feedback connections

Figure 1 MEDICINE 36:12 631Diagnosis

Despite advances in structural and functional brain imaging, the diagnosis of PD remains clinical. There is great potential for misdi-agnosis and even in patients with advanced disease at tertiary refer-ral centres neuropathological studies suggest an incorrect diagnosis in around 10% of cases.8 In the real world, this diagnostic inaccu-racy 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 diagno-sis and, although not infallible, are at least applicable in a clini-cal environment. It is beyond the scope of this article to cover exhaustively all the clinical features of PD and the numerous potential differential diagnoses. We hope to provide a few clini-cal 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 pres-ence of tremor necessarily suggest PD. Parkinsonism describes the clinical features seen in PD. It does not necessarily imply that the diagnosis is PD. Atypical features (Table 1) should make you question the diagnosis as should a poor response to treatment. Neurologists get it wrong too, and it is often better to leave the diagnosis open if you are not sure.

History

Motor featuresPatients 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 getting out of chairs and turning over in bed. Their balance may be affected and they frequently complain of feeling unsteady. Early backward falls should be considered an atypical feature and suggest an alternative diagnosis (Table 2).

Non-motor featuresApathy and low mood are frequent, although not often reported by patients. We have already mentioned dementia as a potential complication and psychosis, either in association with cognitive impairment or as a result of medication, is also a common prob-lem. Depression is a frequent feature in PD and can be consid-ered one of the most common neuropsychiatric features of the disease. Sleep disorders are frequent, with patients often report-ing sleep fragmentation rather than initial insomnia (i.e. 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 punch their 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 2008 Elsevier Ltd. All rights reserved.

MOVEMENT DISORDERS

more atypical disorders here.sense of smell can predate 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 and frank visual hallucinations. The early develop-ment 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.

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 them back may reveal retropulsion or even a tendency to fall stiffly like a felled tree. Tremor is at a 46 Hz fre-quency 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 the movements may be very slow (bradykinesia). Unlike spasticity, increase in

UK Brain Bank diagnostic criteria for Parkinsons disease

Step 1 Diagnosis of Parkinsonian syndrome

Bradykinesia plus at least one of the following:

rest tremor

rigidity

postural instability

Step 2 Exclusion criteria, includingHistory of:

repeated strokes

neuroleptic medication use

head injury

definite encephalitis

Presence of atypical features (such as):

early falls

supranuclear gaze palsy

ataxia and cerebellar features

early autonomic features

early cognitive decline

Poor response to l-DOPA

Step 3 Supportive clinical features (at least three required)Unilateral onset

Rest tremor

Evidence of progression

Persistent asymmetry

Excellent response to l-DOPA

l-DOPA-induced dyskinesias

l-DOPA response for 5+ years

Clinical course of 10+ years

Table 1MEDICINE 36:12 632muscle tone (rigidity) is not velocity dependent, but rather more constant throughout the range of movement. It can be accentu-ated 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, ratcheting feel when moving the joint. Such abnormal tone is best examined using a combination of flexion, extension and rotation at the wrist joint.

Investigations

As previously mentioned, the diagnosis of PD remains largely clinical. Tests are therefore employed to avoid an incorrect diag-nosis being made rather than to confirm a clinical suspicion. You will note from Table 2 that there is a broad range of neurode-generative disorders that feature parkinsonism as part of their clinical phenotype. We will not discuss the investigation of these

Differential diagnosis for tremor disorders

Diagnosis Clinical features

Physiological tremor Anxiety disorder

Symptoms/signs of thyrotoxicosis

Fine tremor

Essential tremor Positive family history

Alcohol responsive

Rest and action tremor

Cerebellar disorders Intention tremor (not rest)

Broad-based gait

Nystagmus, dysarthria, etc.

Vascular parkinsonism Step-wise progression

Often lower > upper bodyMultiple cerebrovascular risk factors

Drug-induced

parkinsonism

Frequently symmetrical (not always)

Temporally associated with drug use,

haloperidol, anti-emetics, valproate

Atypical parkinsonian

disorders PSP, MSA

and CBD

Early backward falls

Eye movement problems

Cognitive decline

Autonomic or cerebellar features

Dementia with Lewy

bodies

Early cognitive decline

Marked fluctuation and drowsiness

Visual hallucinations

Neuroleptic sensitivity

Functional (non-organic) Variable features

Distractible

Uncommon

Normal pressure

hydrocephalus

Dementia

Urinary incontinence

Gait disorders (not necessarily

parkinsonism)

Others Wilsons disease

Familial parkinsonism

PSP, progressive supranuclear palsy; MSA, multiple system atrophy; CBD, corticobasal degeneration.

Table 2 2008 Elsevier Ltd. All rights reserved.

DISORDERSMOVEMENT

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 is worth 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 investi-gation of movement disorders outside the specialist setting.

Structural brain imaging (computed tomography or magnetic resonance imaging) is indicated for atypical features and the most common findings are the hallmark changes of cerebrovas-cular disease.

When it proves difficult to differentiate clinically between movement disorders, or when there is a poor response to treat-ment, 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. These projections degenerate in PD (and other disorders such as multiple system atrophy, progressive supranuclear palsy, etc.) but are preserved in vascular parkinsonism, drug-induced par-kinsonism and essential tremor (ET). An abnormal dopamine transporter (DaT) scan can therefore distinguish between con-ditions such as ET and PD but is unhelpful in differentiating between more closely linked conditions such as PD and 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 man-agement of movement disorders. Ideally, given the multisystem nature of the condition and its complications, they should have access to a multidisciplinary team including 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 educationIn 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 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 PDAny discussion of PD treatment should begin with the statement that not all patients need to commence on treatment at diagnosis. It is only when symptoms begin to interfere with daily life that pharmacotherapy is necessary. The mainstay of treatment for PD MEDICINE 36:12 63

is dopaminergic replacement therapy. The two most common classes of drugs are the dopamine agonists, which stimulate dopa-mine 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. Because of the risk of developing l-DOPA-induced additional movements (dyskinesias) after prolonged or high-dose therapy, initial treat-ment often consists of dopamine agonist therapy unless there are contraindications. Unfortunately, the use of these agonists is lim-ited by side effects such as somnolence, confusion and hallucina-tions, 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 disor-ders (for example, pathological gambling and hypersexuality). Treatments for PD are comprehensively discussed in the NICE guidelines for management of PD9 and summarized in Table 3 and Figure 3.

Initial treatment of PD is usually effective and well tolerated but, as time and the disease progress, patients begin to develop problems. 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 of the drug effect before the next dose, unexpected freezing, par-ticularly 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 the effect of l-DOPA, such as Cate-chol-O-methyltransferase (COMT) inhibitors. If motor fluctuations

DaT scan images in essential tremor a and idiopathic PD b. Note

the asymmetrical reduction in dopamine transporter labelling,

particularly in the putamen in PD, giving a full stop as opposed

to a comma appearance.

Figure 23 2008 Elsevier Ltd. All rights reserved.

MOVEMENT DISORDERSPharmacological treatment of PD

Drug class Examples Mode of action Benefits Drawbacks Side-effects

Levodopa Co-careldopa

(Sinemet)

Co-beneldopa

(Madopar)

Uptake by remaining

dopaminergic neurons

Conversion to dopamine

Release by nerve terminals

Safe

Usually well tolerated

Easily titrated

Multiple preparations

standard release

controlled/modified

release

dispersible

Short half-life (t 60 minutes)

Quickly metabolized,

therefore combined with

dopa decarboxylase

inhibitor Motor

complications

End-dose effect

Dyskinesias

Typical dopaminergic

side effects:

nausea, vomiting

postural

hypotension

somnolence

vivid dreams

confusion

visual

hallucinations

Oral dopamine

agonists

Ropinirole

Pramipexole

Cabergoline

Pergolide

Directly stimulate

dopamine receptors

(largely D2 receptors)

Variable affinities for

receptor subtypes

Variable half-life

Ropinirole 35 hours

Pramipexole 812 hours

Cabergoline 65 hours

Levodopa-sparing

therefore fewer motor

complications later

Ergot-derived agonists

(cabergoline and

pergolide) can cause

cardiac valvulopathy

Potent side effects

Less well tolerated in the

elderly

Typical dopaminergic

side effects*

Transdermal

dopamine

agonists

Rotigotine Directly stimulate

dopamine receptors

No tablets needed Less familiar to patients

and doctors

Typical dopaminergic

side effects

Skin site reactions

Subcutaneous

dopamine

agonists

Apomorphine Stimulates D1 and D2

receptors

Useful in patients with

distressing dyskinesias

and off periods

No tablets required

Rapid onset

Specialist administration

required

Costly

Very short half-life,

therefore prolonged

infusion required

Typical dopaminergic

side effects

Potently emetogenic

Severe skin site

reactions

Monoamine

oxidase

inhibitors

Selegiline

Rasagiline

Inhibit MAO-B in neurones

and glial cells

Increases available

dopamine in synaptic cleft

Safe

Well tolerated

Once-a-day dosing

Levodopa sparing

No convincing evidence

of neuroprotection

Only effective for mild

symptoms

Dry mouth

Headache

Urinary symptoms

Depression

Agitation

Postural hypotension

COMT inhibitors Entacapone

Tolcapone

Inhibit catechol-O-methyl

transferase

Increase half-life of

levodopa

Inhibit COMT in gut wall

Tolcapone also inhibits

COMT centrally

Reduce overall

levodopa dose

Reduce motor

fluctuations in more

advanced disease

More tablets for patients

Modest effect

Tolcapone can cause liver

damage therefore needs

regular monitoring of

liver function tests

Typical dopaminergic

side effects

Diarrhoea

Orange

discolouration of

urine

Dyskinesias

Anticholinergics Trihexyphenidyl

(Benzhexol)

Orphenadrine

Muscarinic receptor

antagonists

May help suppress

severe tremor

Significant cognitive side

effects, even in young

patients

Generally to be avoided

Confusion

Hallucinations

Cholinergic features

Amantadine Unclear actions on

dopaminergic, cholinergic

and glutaminergic systems

Originally an antiviral agent

Mild effect on

parkinsonian symptoms

May help reduce

dyskinesias

Limited role in PD

management

Confusion

Hallucinations

Ankle oedema

Livedo reticularis

*Occur more frequently than with levodopa.MEDICINE 36:12 634 2008 Elsevier Ltd. All rights reserved.

Table 3

MOVEMENT DISORDERSbecome intolerable despite optimizing oral therapies, then con-sideration can be given 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 com-plex routine of medication dosage and timing to suit their daily existence. They may also choose odd meal times to avoid interac-tions with their drugs. Needless to say, the busy general medical ward is not the place to accommodate these regimens. In addi-tion, 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 senior ward staff as well as patients and caregivers can help to minimize these problems.

Treatment of PD complicationsComplications are universal in PD and one can sometimes feel overwhelmed by the daunting array of complaints. Even in very

Young onset

biologically fit

Minimal co-morbidities

Mild symptoms

Monoamine oxidase

inhibitor (rasagiline,

selegiline)

Dopamine agonist

(non-ergot)

L-DOPA therapy (sinemet,

madopar)

COMT inhibitor

(entacapone, tolcapone)

Newly-diagnosed Parkinsons disease

Dyskinesia

Severe motor fluctuations

despite optimal oral therapy

Severe resistant tremor or

severe motor fluctuations

Reduce L-DOPA dose

Add amantadine

Consider subcutaneous

apomorphine or Duodopa

Deep brain stimulation

Treatment algorithm for Parkinsons disease

Biologically frail

Co-morbidities

Cognitive impairment

L-DOPA therapy

(sinemet, madopar)

Monoamine oxidase

inhibitor (rasagiline,

selegiline)

COMT inhibitor

(entacapone, tolcapone)

Figure 3 MEDICINE 36:12 63advanced 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 con-sensus diagnostic criteria,10 the key features being a progressive cognitive decline impacting on daily life with associated fluctuating drowsiness, 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 (e.g. 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.

RBD can be effectively treated with clonazepam or melatonin, sometimes with resulting improvements in 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 involves symptomatic 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 co-morbidities and other medications. 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 consideration and investigation.

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Parkinsons diseaseDefinitionEpidemiologyPathology and pathogenesisCourse of the diseaseDiagnosisHistoryMotor featuresNon-motor features

ExaminationInvestigationsManagementPatient and caregiver educationPharmacological therapy for PDTreatment of PD complications

References