Parkinson’s disease (PD) is the second most common neurodegenerative condition in the UK (after Alzheimer’s 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 mobility problems, although these features are only a small part of the clinical phenotype. In reality, PD is better defined as a multisystem neurodegenerative disorder, causing a large number of motor and non-motor complications.
Defining PD is a little difficult because of the variability of signs and symptoms. 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 ‘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 extrapyramidal disorders.
To save confusion, I suggest you just call it "PD"
How common is it?
In the UK, prevalence in the general population is 0.3%, with an estimated incidence of 8–18 per 100,000 person years. Both these figures increase with age, and prevalence is estimated at 1% in the over 60s and 4% in the over 80s. An average GP practice will see between two and four new cases per year.
Basically, it’s really common and our PD service looks after over 1000 patients in Teesside and the surrounding areas. I can never remember incidence and prevalence figures so just say – 1 in 100 over 60 and 1 in 20 over 80.
These sorts of figures are pretty useless for patients, as 100% of them has got PD and there is no solace in having a rare, or common, disease.
What’s going on in the brain?
Pathological examination of the brains of PD patients reveals abnormal protein aggregations of α-synuclein, often collected into intracellular inclusions (Lewy bodies). Alpha-synuclein is very useful in it’s normal form but, when it kinks and aggregates, it starts to cause probelms.
We used to think of the Lewy body as the villain of the piece but it may be that we see it in surviving cells, coping with the build up of this toxic, mis-folded protein. It is the smaller aggregates that really bugger up the cells.
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 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.
Whatever you do, don't try and remember all the feedback loops in the basal ganglia structures - that way lies MADNESS (and I would know - I'm better now ... mostly).
Genetic factors play a role in the development of PD, although true Mendelian inheritance is rare. 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 is associated 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.
I'm not saying you should smoke to avoid PD - but when I'm on my fourth cup of coffee of the day by midday, I do console myself with the idea of neuroprotection.
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.
How does it behave?
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.
Unless you are as excited as I am about this little morsel!
Treatment is symptomatic and it is 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.
It used to be said that "you die with PD, not of PD" - but this is patently not true.
Dementia is increasingly recognized as a complication of PD, with cross-sectional prevalence of between 25 and 40% in PD populations, and a cumulative prevalence of 80% in 20-year follow-up.
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, the greater the likelihood of developing 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 (best prognosis)
- those with more marked postural instability and gait disorders (PIGD group).
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 – usually the actual diagnosis is either Progressive Supranuclear Palsy (PSP) or Multiple System Atrophy (MSA). 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
- postural instability
UK Brain Bank criteria (Table 1) are often used to aid diagnosis and, although not infallible, are at least applicable in a clinical environment.
There are a lot of pitfalls but a few useful rules of thumb are:
- Tremor is not needed for a diagnosis of PD, nor does the presence 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
There are lots of PD mimics to catch out the unwary. In brief:
- early falls, gaze palsy, “frontal” behaviour (impulsivity, apathy) – think Progressive Supranuclear Palsy
- early autonomic signs – incontinence, erectile dysfunction, postural hypotension, stridor – think Multiple System Atrophy
- dopamine-blocking drugs (antipsychotics, antiemetics) – think drug-induced
- prominent action tremor – think essential tremor or dystonic tremor
- early cognitive decline, early hallucinations – think Dementia with Lewy bodies (DLB)
- cognitive decline, gait apraxia, urinary incontinence – think Normal Pressure Hydrocephalus (NPH)
- Vascular disease on brain imaging, lower body predominant Parkinsonism – think vascular Parkinsonism
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’. Patients may notice difficulty getting out of chairs and turning over in bed.
Manual dexterity is affected, and writing becomes less legible and smaller across the page (micrographia).
Balance may be affected and PD patients frequently complain of feeling unsteady. Early backwards falls should be considered an atypical feature and suggest an alternative diagnosis (Like PSP, MSA etc.).
Apathy 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 problem.
Depression is a frequent feature in PD and can be considered one of the most common neuropsychiatric features of the disease.
Sleep disorders are frequent, with patients often reporting 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 about 50% of PD patients have some degree of hyposmia), although not frequently volunteered, and both sleep disturbance and loss of sense of smell can pre-date 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 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.
Follow this handy flow-chart to help you assess tremor and ask the right questions in your history.
PD patients will usually have a rather expressionless face with reduced blink frequency (hypomimia).
For Pete's sake do not call this a "mask-like face" as this is insulting Also, if I find you trying to do the glabellar tap, I will hunt you down and tap you in the face repeatedly to see if you like it!
Assessing gait will reveal reduction in arm swing and, perhaps, a slight stoop and shuffle. This video is from an apomorphine trial – a subcut dopamine agonist (and nothing to do with morphine). You can see the difference between “off” and “on” medication – these videos are taken minutes apart.
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.
I rarely do this anymore as it is a bit dangerous for all concerned. If the history is of backwards falls, what are you trying to prove?
Tremor is at a 4–6 Hz frequency (i.e you can roughly count the beats in a second) and will usually diminish when the limb is used. The tremor often re-emerges after a second period of rest so watch out for this feature. Not always present, but very suggestive of PD.
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). It is not enough for it just to be slow – it has to decrement in amplitude too.
subtle resting tremor, subtle bradykinesia, subtle reduction in arm swing - all on the right.
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 (paint a wall, play the piano) 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.
As previously mentioned, 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.
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.
Structural brain imaging (computed tomography or magnetic resonance imaging) is indicated for atypical features, and the most common findings are the hallmark changes of cerebrovascular disease.
When it proves difficult to differentiate clinically between movement disorders, or when there is a 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. These projections degenerate in PD (and other disorders such as MSA, PSP 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 between more closely linked conditions, such as PD and MSA. Unhelpfully, it is possible to have a normal DaT scan and still have PD, but such cases are fortunately rare.
It is my belief that all patients with presumed PD should be seen, at least initially, by a clinician skilled in the diagnosis and management of movement disorders.
Ideally, given the multi-system nature of the condition, and its complications, they should have access to a multidisciplinary team including specialist nurses, physiotherapists, occupational therapists, pharmacists, mental health workers, 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 Carer 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 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 online.
The mainstay of treatment for PD is dopaminergic replacement therapy.
It used to be the case that patients were discouraged from starting treatment at the point of diagnosis, and it is still true to say that not everyone needs therapy straight away, but my practice has changed in recent years, and I now like to see my newly-diagnosed patients offered some form of treatment as early as possible.
The main options are:
- levodopa – co-careldopa, co-beneldopa
- dopamine agonists – ropinriole, pramipexole, rotigotine, apomorphine
- monoamine-oxidase inhibitors (type B) – rasagiline
No treatment is without potential complications and it is sometimes a “gut feeling” as to what medication to start with.
Because of the risk of developing levodopa-induced additional movements (dyskinesias) after prolonged or high-dose therapy, initial treatment often consists of levoddopa-sparing drugs (agonists, MAOIs), unless there are contraindications.
Unfortunately, the use of these agonists is limited by side-effects such as somnolence, 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 and hypersexuality). These can be a total nightmare and patients need to be counseled in advance.
This flow chart summarises a fairly well-accepted approach to drug selection.
DO NOT GET HUNG UP ON DOSES – THIS IS COMPLEX STUFF AND ALL YOU NEED IS THE BASICS
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, particularly in narrow spaces, such as doorways, and a prolonged time to onset of action (delayed on). In addition, involuntary movements when “on” (dyskinesia) can become problematic.
These are the 3 “W’s” of complex PD:
- wearing off
To some extent, these problems can be overcome with judicious increments in medication dose, or with additional agents to prolong the effect of levodopa, such as Catechol-O-methyltransferase (COMT) inhibitors.
If motor fluctuations become intolerable despite optimizing oral therapies, then consideration can be given to parenteral routes (jejunal infusions of levodopa gel or subcutaneous apomorphine) or even deep brain stimulation procedures (particularly of the subthalamic nucleus).
Here is a great example of "off" and "on" with dyskinesia. Peter continues to do really well on an intestinal infusion of levodopa gel (Duodopa)
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 timings, to suit their daily existence. They may also choose odd meal times to avoid interactions with their drugs.
Needless to 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 senior ward staff as well as patients and caregivers can help to minimize these problems.
This link will take you to an example of a “nil by mouth” protocol for patients in hospital with their PD.
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) is, sadly, very common, 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.
PDD patients can respond well to cognitive enhancers (e.g. rivastigmine, donepezil, memantine), 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. The atypical antipsychotic, clozapine, can be effective if other options have failed.
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 patient’s 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.