Parkinson’s disease is an idiopathic, progressive neurodegenerative disorder. It is a clinical diagnosis with the classic features of:
The key pathophysiological feature is loss of dopaminergic neurons from the substantia nigra, as well as other brain stem dopaminergic groups. The exact mechanism for the neuronal loss is not known, but is associated with aging. There is significant neuronal reserve, and so symptoms do not develop until there is loss of around 60-80% of neurons.
Parkinson’s disease is the name given to the idiopathic form of Parkinsonism. Other conditions may be the cause of the Parkinsonism, or have Parkinsonism as a significant part of their symptoms. Other causes include:
Drug induced - particularly the antidopaminergic antipsychotic agents.
The main risk factor for the condition is increasing age. The prevalence in patients over the age of 65 is around 1%. The peak onset is between age 55 and 65
There is a slight preponderance towards males. Pesticide exposure is another recognised risk factor.
As noted above the key features are:
Bradykinesia is a common presenting feature, and may often be mistaken for depression. There is a slowness to voluntary movement and automatic movements (a common example of this being reduced arm swing when moving).
Resting tremor is another common presenting feature. It is slow frequency (4-6 Hz) and coarse. It is maximal at rest, reducing during movement, and can be increased by stress, fatigue, and if mild may be induced by concentration e.g. performing a counting task. The hands are commonly affected first (pill-rolling tremor), and it will also commonly involve the arms and legs, with the face and tongue sometimes being affected.
Muscle rigidity is recognised by increased tone (lead-pipe) on examination. Overlaid tremor may produce a jerky movement when examined (cogwheel rigidity).
The progression of these motor features leads to additional symptoms and signs as the disease course continues:
A ‘Mask like face’ is a common feature, and again may be mistaken for depression. There is a reduction in facial movements and blinking.
Speech disturbance may involve a quiet, monotonous voice, sometimes a dysarthria
Gait disturbance is common with the motor features of the disease. As well as the reduced arm swing, patients can develop a more stooped, shuffling gait. There is difficult initiating and stopping walking (festination), and from activities such as rising from a chair. There is disturbance of postural stability which can lead to falls.
Micrographia refers to the decrease in size a a patients writing.
Associated with all of this are more generalised symptoms such as fatigue, and muscle aches.
Parkinson’s Disease is also associated with a number of non motor features:
Depression is a common associated disease.
Dementia is closely linked with the course of the disease, and is present in 80% after 20 years.
Autonomic nervous system dysfunction is also a feature:
GI disturbance - constipated, impaired swallowing.
This is an excellent video from the Osmosis team. They have loads more open access resources at www.osmosis.org.
The diagnosis is clinical. Further investigations may be indicated to assess for alternative causes of Parkinsonism:
CT head - to look for structural causes
Ceruloplasmin levels (Wilson’s disease)
If there is difficulty with diagnosis, use of I-FP-CIT single positron emission tomography may be useful for specialists.
NICE recommends using the UK Parkinson’s Disease Society Brain Bank Criteria for diagnosis, which has two stages.
Step 1 - diagnosis of a Parkinsonism syndrome Must have bradykinesia plus one other feature of:
Resting tremor (4-6 hz)
Postural instability (not caused by visual, vestibular, cerebellar or proprioceptive causes)
Bradykinesia is clearly defined as a “slowness of initiation of voluntary movements with progressive reduction in speed and amplitude of repetitive actions”
Step 2 - Exclusion criteria for Parkinson’s Disease (evidence of alternative cause)
Repeated CVAs with associated progressive Parkinsonism
Repeated head injury
Presence of a structural lesion
History of definite encephalitis
Neuroleptic (antipsychotic) treatment at the time of onset.
Negative response to large dose of L-dopa
Early severe dementia
Step 3 - supportive prospective positive criteria of Parkinson’s Disease. Three or more needed for confirmation of PD:
Excellent response to L-dopa
Response to L-dopa for 5 years or more
Rest tremor present
Clinical course of 10 years or more
There is often a good response to L-dopa treatment, although this often only for a temporary period. Some common long term problems develop as the disease’s clinical course goes on:
Motor fluctuations are a common problem after several years of treatment, and can often be referred to as ‘off-on’ phenomenon. The ‘off’ state is when patients are experiencing notable stiffness and bradykinesia, whilst the ‘on’ state, is when patients are moving well. With time, the response to treatment may become less predictable, causing motor disturbances relating to this, including:
Reduced time in ‘on’ state after dose of medication (i.e. before next dose)
Random fluctuations between ‘on’ and ‘off’ states
Dyskinesia during ‘on’ state
Axial disturbances can result from non dopamine neuronal degeneration. This may manifest as disturbances with speech and balance, and are not improved by PD medications.
Dementia is an unfortunately feature of the clinical course of PD. Many features are similar to Alzheimer’s disease, but additional symptoms include:
Fluctuations in lucidity
There is no disease modifying treatment for PD and so management is focused on symptom control. Specialist input is often very useful in this, not just for assistance in diagnosis. Management doesn’t just focus on the motor symptoms, but also the common psychological and functional impact of the disease. This often requires MDT involvement - physiotherapy, occupational therapy, SALT.
As the pathophysiology of PD relates to dopaminergic neuron loss, much of the pharmacological management focuses on increasing dopamine levels or activity. The main classes of drug used are:
Monoamine oxidase B inhibitors (MOABIs)
Catechol-O-Methyl transferase inhibitors (COMTIs)
Dopamine Precursors Levodopa is a dopamine precursor molecule that is probably the core drug for PD treatment. Dopamine itself is unable to cross the blood brain barrier (highly polarised, no transport molecule) and so it is given in its precursor form which can. It can then be converted to dopamine by central dopa decarboxylase. To avoid the side effects of peripheral dopamine, and reduce dosage requirements, it is administered with a dopa decarboxylase inhibitor (carbidopa/benserazide) which cannot cross the BBB, and so only inhibits its conversion peripherally.
This can be an incredibly effective treatment for the motor symptoms of PD and nearly al patients respond to it with minimal side effects. The drawback is the increased problems that arise with long term use. These problems are described above and include:
Motor fluctuations - on-off phenomenon, changing duration of symptom control
There is some theoretical concern that some of this may represent neurotoxicity from the drug use, although it is also thought that this is part of the disease progression and a changing response to L-dopa. This changing response relates to depletion of dopamine stores in the relevant neurons, and the increasing dependence on systemic L-dopa. Problems arise because of the fluctuating L-dopa plasma levels associated with itself short half life and variable gut absorption. As such, much of the pharmacological management involves minimising the use of L-dopa to prolong its period of effectiveness. This is often achieved with the other pharmacological agents.
Side effects of L-dopa include: Central effects
It comes in preparations of a fixed ratio with carbidopa, e.g. 10/100, 25/100, 25/250. It is used at the lowest dose that controls symptoms.
Dopamine Agonists The are drugs that act as agonists at dopamine receptors. As such, they can provide effective symptom control in a similar way to L-dopa. Current drugs in this class include:
DAs will often be employed as a monotherapy for motor symptom control. They are often used in this way as a L-dopa sparing agent, to try and prolong the time time of the disease before L-dopa is needed, as mentioned above. As such they are commonly used as an initial therapy in younger patients (under 60 years old), and also as an adjunct in more established disease. In the longer term they are also associated with fewer motor fluctuations and dyskinesias. The side effect profile is similar to L-dopa, but the incidence more common and more severe. This can be a limiting factor in their use. NICE recommend they are considered as a first line treatment in those with less significant motor symptoms (not impacting on their quality of life).
Apomorphine is an injectable preparation which can be very useful in patients as a rescue therapy. It can be given as a single injection or via infusion. It is very potent and must be given as a test dose to establish the suitable subsequent dose if an infusion is planned. Nausea and hypotension are common adverse effects.
Rotigotine can be given as a transdermal patch. As such it can be very useful as a bridging therapy for when the enteral route is not available e.g. perioperatively. A problem can be is that they may struggle to be potent enough if the patient is on a high dose of enteral medications.
MOABIs By blocking the MAOB enzyme which is involved in dopamine breakdown, these drugs act to increase the synaptic levels of dopamine. Drugs in this class include:
They can also be used as a monotherapy for symptom control to delay the initiation of L-dopa therapy, though their effectiveness appears to be a little less than the dopamine agonists. Similarly, they may be used in an adjunct role in more advanced disease. NICE recommend they are considered as a first line treatment in those with less significant motor symptoms (not impacting on their quality of life). Side effects include: Nausea, headache, confusion, hallucinations.
COMTIs These reduce the methylation of levodopa and dopamine and so prolong the plasma half life and stability of the drug. As such they are only used as an adjunct with L-dopa frequently in patients to try and reduce the off phenomenon. Examples include:
Other Antimuscarinics may be used in some patients, but the evidence is poor Amantadine is a drug with some weak antiparkinsonism activity, but again has a fairly poor evidence base.
Abrupt withdrawal of medications in PD can precipitate some serious complications and so must be avoided. This is of particular relevance for anaesthetists in the perioperative period. Adverse features may include:
Dopamine agonist withdrawal syndrome
The correct timing of medication is also essential. In hospital, this may sometimes mean it is beneficial for patients to self administer their medication.
Dopamine Agonist Withdrawal Syndrome Reported to occur in around 10-20% of patients who take dopamine agonists and who stop stop abruptly. The clinical picture is described as being similar to that of cocaine withdrawal:
The symptoms are only treatable by recommencement of a dopamine agonist agent, with even L-dopa not being effective.
Parkinsonism-Hyperpyrexia Syndrome This is a neuroleptic malignant syndrome presentation that can occur in the context of stopping or reducing the dose of L-dopa. Symptoms include: muscle rigidity, fever, CNS disturbance (coma, agitation, confusion), CVS instability. Management involves the replacement of the missed medication. This may include an atypical approach if patients have missed drugs because of GI disturbance:
Levodopa can be infused IV (50-100mg over 3 hours QDS - UpToDate)
Apomorphine injection or infusion
Supportive care is also required, which will usually involve a critical care environment. Alternative (though unproven) options in patients who are not responding to treatment include: dantrolene, amantadine, bromocriptine.
Options for avoiding medication withdrawal in the planned setting e.g. major abdominal surgery include:
These will require specialist input to establish, including on aspects such as doses conversion.
Surgical treatment was the initial management option of PD prior to the introduction of effective medical management. Currently surgical treatment is only considered in those patients in whom medical therapy is no longer providing a good quality of life. Surgical procedures include:
Deep brain stimulation (DBS)
The majority of these surgeries have been replaced by DBS.
Deep brain stimulation This is an possible surgical option for these patients who are not getting good control of symptoms with medical therapy, and is the most common surgical procedure for it. Electrodes are inserted into the basal ganglia, generally targeting the subthalamus An electrical stimulator is attached and placed subcutaneously below the clavicle. The aim is to suppress the activity in the neuronal pathways that are causing the symptoms. This can provide good symptom relief of motor fluctuations and dyskinesia. The patients need close management follow up to adjust their treatment. Risks include infection and bleeding.
Patients with PD may not uncommonly require surgery related to another pathology, or in some cases for the surgical management of PD itself. PD is recognised to increase the risk for patients undergoing surgery:
Delirium (up to 60% of patients)
These problems can contribute to an increased mortality, morbidity and length of stay.
Some of the key factors in anaesthetic management for patients with PD include:
Recognising adverse physiological effects of PD
Minimising the disturbance to the patient’s medication regime.
Due to the complexity of these patients, optimal preoperative preparation should be undertaken. In an elective setting this will involve the early involvement of the anesthetic, PD nurse specialists and PD physicians.
A full anaesthetic history should be taken. This will aim to understand in more detail the impact of PD in this case. Certain systematic features to be aware of are described below.
Upper airway dysfunction may lead to aspiration, laryngospasm, impaired secretion clearance.
Chest wall rigidity (or bradykinesia) may act as a restrictive deficit
Motor disturbances of the neck may result in intubation difficulty
Obstructive sleep apnoea is a common overlying condition
Postural (orthostatic) hypotension is a common feature of the condition. Intraoperative hypotension is more likely.
Cardiac arrhythmias may occur.
Impairment of GI function from surgery (e.g. ileus) can notably impact on ant-PD drug absorption
Dysphagia may be present - can contribute to aspiration
Sialorrhea (drooling) is a feature of advanced PD. Glycopyrrolate may be needed
Oesophageal reflux is more common
Post operative delirium is more common
GA may be needed for other indications due to tremor e.g. GA is needed for patients to have an MRI to stop movement.
Patients may also have coexisting disease which needs careful assessment.
Anaesthetic technique needs to be considered carefully in these patients.
A key principle is maintenance of PD medication administration. Patients should be first on the list. They should continue to take their usual medication right up to the initiation of anaesthesia (with a small sip of water). In prolonged general anaesthesia when a dose is due, NG insertion and administration of the drug should be undertaken.
Regional anaesthesia may provide benefits over GA if the surgery is suitable. Medication can continue to be given orally intraoperatively. There are also a lower risk of postoperative nausea and vomiting that may impair postoperative administration. The downside primarily relates to the motor features of PD, which will only be abolished along with motor blockade. Tremor and tone can therefore make surgery challenging or impossible. Patients with autonomic dysfunction may have an exaggerated hypotension response to spinal anaesthesia.
Full AAGBI monitoring is essential. Resting tremor can notably interfere with ECG
General anaesthesia requires a few disease specific considerations. There is no strong preference for a particular IV induction agent, with propofol, thiopentone and ketamine all being used. Theoretical assessment may put propofol as have a slightly better profile. Volatile agents are similarly all viable options (historically halothane has an increased risk of exacerbating PD arrhythmias, but is now very rarely used).
All muscle relaxants are suitable, but reversal with neostigmine can result in thickened secretions and so potential problems with clearance post operatively. The combination of rocuronium and sugammadex has a nice ‘clean’ approach.
The choice of airway management technique should be guided by the symptoms of the patient. Specific factors of PD which may impact are noted above and include: sialorrhea, dysphagia (indication intubation), oesephageal reflux (intubation and potentially RSI).
There are a few classes of drug that will be relatively contraindicated in PD:
Antiemetics - the classes that work through dopamine antagonism (phenothiazines, butyrophenones, benzamides) will all have a significant risk of worsening Parkinsonism.
Atropine - centrally acting anticholinergics may precipitate a central anticholinergic syndrome
Pethidine - interacts with MOABIs to produce serotonin syndrome
Opioids - fentanyl and alfentanil may induce chest wall rigidity in large doses.
Sympathomimetics - direct acting sympathomimetics may produce an exaggerated response in those patients taking MOABIs.
There should be strong consideration given to a critical care admission for these patients, unless the surgery is very minor. Stronger indications include; cough/swallow involvement, autonomic dysfunction, OSA. A clear management plan about anti-PD medication needs to be in place. An appropriate analgesia plan should be as per the surgery they have undergone, but it is important to note that effective use of a PCA pump may be impaired.
Delirium is common and the management should follow optimal delirium treatment as with other patients i.e. minimise pharmacological intervention, orientation etc. Clearly the typical antipsychotics are contraindicated as a management option in these patients who are very agitated/distresses. Benzodiazepines will therefore the sedative of choice if absolutely essential (noting their deliriogenic properties). Quetiapine has also been used in some settings of psychosis, but with little evidence.
Links & References
Parkinson’s Disease. The Merck manual (18th ed). 2006.