Parkinson's Disease and Parkinson's Plus Flashcards
Parkinson’s Disease - Mx
Currently accepted practice in the management of patients with Parkinson’s disease (PD) is to delay treatment until the onset of disabling symptoms and then to introduce a dopamine receptor agonist. If the patient is elderly, levodopa is sometimes used as an initial treatment.
Parkinson’s Disease - Dopamine Receptor Agonists
Dopamine receptor agonists
Eg: Bromocriptine, ropinirole, cabergoline, apomorphine. pramipexole
ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide*) have been associated with pulmonary, retroperitoneal and cardiac fibrosis. The Committee on Safety of Medicines advice that an echocardiogram, ESR, creatinine and chest x-ray should be obtained prior to treatment and patients should be closely monitored
- Patients should be warned about the potential for dopamine receptor agonists to cause impulse control disorders and excessive daytime somnolence
- Also more likely than levodopa to cause hallucinations in older patients. Nasal congestion and postural hypotension are also seen in some patients
*pergolide was withdrawn from the US market in March 2007 due to concern regarding increased incidence of valvular dysfunction
Parkinson’s Disease - Levodopa
Levodopa:
- Usually combined with a decarboxylase inhibitor (e.g. carbidopa or benserazide) to prevent peripheral metabolism of levodopa to dopamine
- Reduced effectiveness with time (usually by 2 years)
- Unwanted effects: dyskinesia (involuntary writhing movements), ‘on-off’ effect, dry mouth, anorexia, palpitations, postural hypotension, psychosis, drowsiness
- Of no use in neuroleptic induced parkinsonism
Increasing the dose of L-dopa is required when ‘off’ symptoms (bradykinesia, rigidity, freezing) do not respond to the starting dose.
Increasing the frequency of L-dopa, which has a short half-life, is required when patients become ‘off’ in between doses. As the disease progresses the on period after each dose becomes shorter.
Entacapone and selegiline are used as adjuncts to prolong the ‘on’ period after a dose of L-dopa.
Parkinson’s Disease - MAO-B Inhibitors
MAO-B (Monoamine Oxidase-B) inhibitors
e.g. Selegiline
inhibits the breakdown of dopamine secreted by the dopaminergic neurons
Parkinson’s Disease - Amantadine
Amantadine:
- Mechanism is not fully understood, probably increases dopamine release and inhibits its uptake at dopaminergic synapses
- Side-effects include ataxia, slurred speech, confusion, dizziness and livedo reticularis
Parkinson’s Disease - COMT (Catechol-O-Methyl Transferase) inhibitors
COMT (Catechol-O-Methyl Transferase) inhibitors
e. g. Entacapone, tolcapone
- COMT is an enzyme involved in the breakdown of dopamine, and hence its inhibitor may be used as an adjunct to levodopa therapy
- Used in conjunction with levodopa in patients with established PD
Parkinson’s Disease - Antimuscarinics
Antimuscarinics:
- block cholinergic receptors
- now used more to treat drug-induced parkinsonism rather than idiopathic Parkinson’s disease
- help tremor and rigidity
e. g. procyclidine, benzotropine, trihexyphenidyl (benzhexol)
Parkinson’s Disease - Epidemiology
Parkinson’s disease is a progressive neurodegenerative condition caused by degeneration of dopaminergic neurons in the substantia nigra.. This results in a classic triad of features: bradykinesia, tremor and rigidity. The symptoms of Parkinson’s disease are characteristically asymmetrical.
Epidemiology
around twice as common in men
mean age of diagnosis is 65 years
Parkinson’s Disease - Bradykinesia
Bradykinesia
poverty of movement also seen, sometimes referred to as hypokinesia
short, shuffling steps with reduced arm swinging
difficulty in initiating movement
Parkinson’s Disease - Tremor
Tremor
most marked at rest, 3-5 Hz
worse when stressed or tired
typically ‘pill-rolling’, i.e. in the thumb and index finger
Parkinson’s Disease - Rigidity
Rigidity
lead pipe
cogwheel: due to superimposed tremor
Parkinson’s Disease - Other Characteristic Features:
Other characteristic features mask-like facies flexed posture micrographia drooling of saliva psychiatric features: depression is the most common feature (affects about 40%); dementia, psychosis and sleep disturbances may also occur impaired olfaction REM sleep behaviour disorder
Parkinson’s Disease - Autonomic Dysfunction
Patient who presents with hypotensive episodes who is on a PD drug (e.g. Sinemet - Levodopa) = classic non-motor symptom of Parkinsons disease. A significant proportion of patients with PD demonstrate autonomic dysfunction in addition to the classic motor symptoms of rigidity, bradykinesia, resting tremor and postural instability. The patient is likely to demonstrate a significant lying/standing blood pressure difference. Blood pressure lability is a feature of dysautonomia and NO ACTION IS REQUIRED i.e. No pharmacological Mx/IV Fluids (monitor only)
Dopamine Agonists and Impulse Control Disorder - Example Question
A 75-year-old man is referred to you for the management of tremor and mobility issues. On examination, he has a noticeable resting tremor that is worse in the right hand when compared to the left. He also is quite bradykinetic when mobilising and displays mild rigidity. His speech and cognitive function do not appear to be affected. His blood pressure is 125/80 mmHg without any significant postural drop.
You suspect idiopathic Parkinson’s disease. Further history taking reveals that this gentleman has had a previous significant gambling problem which is now well controlled.
Which of the following medications, in particular, should be avoided in this patient?
Rasagiline Levodopa/carbidopa > Pramipexole Entacapone Amantadine
There is an established link between the use of dopamine receptor agonists and serious impulse control disorders. For patients who have a history of habitual behaviours associated with increased risk, this group of medications should be avoided.
PD - Initial Mx of patients <65
Although the treatment of choice should always be individualised to each patient, it is a general rule of starting dopamine agonists such as ropinirole for younger patients under 65, saving L-dopa for later in the disease while reducing the long-term risk of motor complications.
Selegiline is a monoamine oxidase B inhibitor. While it can be a useful adjunct, it does not produce significant functional benefit as a monotherapy and is not commonly used alone for patients with significant motor symptoms.
PD - Initial Mx: Example Question
A 64-year-old male presents with four month history of worsening tremor of his left hand, associated with ‘clumsiness and slowness’ of his left arm. The patient complains that this is limiting his ability to continue to work as a lawyer and is very keen on a treatment. On examination, you notice a slow resting tremor of his left hand, cogwheeling of the left wrist and rigidity of the left upper limb. The right arm is unremarkable. Which drug is the most appropriate treatment?
Selegiline > Ropinirole Pergolide Sinemet (levodopa and carbidopa) Madopar (levodopa and benserazide)
Multiple randomised controlled trials have demonstrated increased efficacy with L-dopa preparations when compared to dopamine agonists, L-dopa is also more likely to produce motor fluctuations of treatment (‘on-off’) and disabling L-dopa-induced dyskinesias. Although the treatment of choice should always be individualised to each patient, it is a general rule of starting dopamine agonists such as ropinirole for younger patients under 65, saving L-dopa for later in the disease while reducing the long-term risk of motor complications.
Sinemet is a combination of levodopa and carbidopa while Madopar is levodopa and benserazide. Both carbidopa and benserazide are peripheral decarboxylase inhibitors combined with the pro-drug to reduce breakdown of L-dopa before reaching the basal ganglia. Selegiline is a monoamine oxidase B inhibitor. While it can be a useful adjunct, it does not produce significant functional benefit as a monotherapy and is not commonly used alone for patients with significant motor symptoms. Pergolide is an older dopamine agonist no longer used in Parkinson’s disease due to associated with cardiac valvular disease, classically tricuspid stenosis.
Neuroleptic Malignant Syndrome in Parkinson’s Disease
Neuroleptic malignant syndrome is a rare but dangerous condition seen in patients taking antipsychotic medication. It carries a mortality of up to 10% and can also occur with atypical antipsychotics. It may also occur with dopaminergic drugs (such as levodopa) for Parkinson’s disease, usually when the drug is suddenly stopped or the dose reduced.
Features more common in young male patients onset usually in first 10 days of treatment or after increasing dose pyrexia rigidity tachycardia
A raised creatine kinase is present in most cases. A leukocytosis may also be seen
Management
stop antipsychotic
IV fluids to prevent renal failure
dantrolene* may be useful in selected cases
bromocriptine, dopamine agonist, may also be used
*thought to work by decreasing excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor, and decreasing the release of calcium from the sarcoplasmic reticulum
Example Question:
A 79-year-old is brought into hospital with muscle cramps, fevers and passing dark urine. He is known to have previously had Parkinson’s disease and takes Sinemet 125 five times a day. His daughter, who normally picks up his medicine for him from the pharmacy has been called away on business for the past 5 days. As a result, the patient’s supplies ran out and he has not taken his PD meds for 3 days. His blood pressure is fluctuant, from 77/52 mmHg to 150/88mm Hg. On examination, his temperature is 39.2 degrees, his heart sounds are quiet but present and chest auscultation is unremarkable. You note rigid muscles in four all limbs, no obvious superficial evidence of head injury and new confusion, with abbreviated mental test 0/10. You start intravenous fluids, intravenous broad spectrum antibiotics, catheterise the patient and insert a nasogastric tube to administer his regular medications. What is the underlying diagnosis?
Urosepsis Restrictive pericarditis Idiopathic Parkinson's disease progression L-dopa dyskinesia > Neuroleptic malignant syndrome
The history gives a clear history of lack of access to regular Parkinsonian medications associated with pyrexia and muscle cramps. This would point towards a diagnosis of Parkinsonism-hyperpyrexia syndrome, a form of neuroleptic malignant syndrome observed when PD medications are withdrawn or changed. A key feature to be noted here is the labile blood pressure, suggesting autonomic instability, suggesting the need for careful intensive care monitoring and supportive therapy. Treatment is by replacing the original dose of withdrawn medication, either orally or via a nasogastric tube. If this is not possible intravenous L-dopa is possible while dopamine agonists can be given parenterally: rotigotine can be applied as a transdermal patch while apomorphine is available as an intravenous or subcutaneous infusion.
Treatment of ‘off’ periods: Example Question
A 72-year-old male presents to the Parkinson’s clinic with his wife, reporting increasing frequency and duration of ‘off’ periods. The couple finds these episodes extremely debilitating and occurs up to 11 times a day. The patient was diagnosed with Parkinson’s disease 12 years ago. As a relatively young patient on diagnosis, he was commenced on ropinirole, which he continued for 5 years, before being prescribed Sinemet 6 times a day and entacapone for the following 7 years. Over past 2 years, the ‘off’ episodes have gradually increased in frequency in addition to the development of very mild involuntary jaw movements. He is very low in mood and has presented to the emergency department with two episodes of attempted paracetamol overdoses. He would like a more effective treatment. What would you recommend?
Deep brain stimulation > Subcutaneous apomorphine Reintroduce ropinirole at higher doses Palliative care involvement Trihexyl
The treatment of ‘off’ symptoms is particularly important in patients who have been diagnosed with Parkinson’s disease for a long time. The introduction of ropinirole would not help off periods. Trihexyl is an anti-cholinergic therapy for PD patients where tremor is the predominant symptom. In the context of suicidal behaviour, the patient would not be a candidate for deep brain stimulation, which for unknown reasons, increases the risk of suicide. Subcutaneous apomorphine is a reasonable option, administered as an infusion after a test bolus, which can be used to alleviate but not cure off symptoms.
Tremor - Predominant Parkinson’s Disease - Mx
Tremor-predominant Parkinson’s disease can be highly disabling and tremor may persist despite standard treatment with dopaminergic agents, which primarily improve bradykinesia. First-line treatment is such cases is the addition of an anticholinergic drug such as procyclidine, orphenadrine, or trihexyphenidyl.
The main side-effect which limits the use of anticholinergics in older patients is cognitive dysfunction, and dementia is a relative contra-indication. Other side effects include blurred vision, urinary retention, nausea, constipation, and dry mouth.
Second-line treatments for persistent tremor include amantidine, clozapine, and propranolol. Deep brain stimulation may be used in refractory cases.
Parkinson’s Resting Tremor - Mx: Example Question
A 56 year-old consultant surgeon has recently been diagnosed with idiopathic Parkinson’s disease, and attends clinic for review.
You read the previous clinic letter and see that he presented with tremor affecting mainly the right hand, which forced him to stop operating. On examination he also had some bradykinesia and rigidity of the right hand. He was started on co-beneldopa 100/25, initially one tablet three times daily, with instructions to up-titrate as tolerated.
When you see him today, he is concerned that there has been no improvement in the tremor. This is causing him considerable distress as he hopes to return to clinical work. His motor control is otherwise good, and throughout the day and night he has no difficulty with ‘off’ periods or freezing. He currently takes co-beneldopa 100/25, two tablets three times daily, and reports no complications.
On examination there is a resting tremor of the right hand. There is no discernable rigidity or bradykinesia.
What is the best treatment option?
Increase dose of co-beneldopa Increase frequency of co-beneldopa > Add procyclidine Add entacapone Add selegiline
Tremor-predominant Parkinson’s disease can be highly disabling and tremor may persist despite standard treatment with dopaminergic agents, which primarily improve bradykinesia. First-line treatment is such cases is the addition of an anticholinergic drug such as procyclidine, orphenadrine, or trihexyphenidyl.
The main side-effect which limits the use of anticholinergics in older patients is cognitive dysfunction, and dementia is a relative contra-indication. Other side effects include blurred vision, urinary retention, nausea, constipation, and dry mouth.
Second-line treatments for persistent tremor include amantidine, clozapine, and propranolol. Deep brain stimulation may be used in refractory cases.
Increasing the dose of L-dopa is required when ‘off’ symptoms (bradykinesia, rigidity, freezing) do not respond to the starting dose, however this patient is taking a reasonable dose of L-dopa (600mg) and is not troubled by ‘off’ symptoms.
Increasing the frequency of L-dopa, which has a short half-life, is required when patients become ‘off’ in between doses. As the disease progresses the on period after each dose becomes shorter.
Entacapone and selegiline are used as adjuncts to prolong the ‘on’ period after a dose of L-dopa.
Progressive Supranuclear Palsy
Overview
aka Steele-Richardson-Olszewski syndrome
a ‘Parkinson Plus’ syndrome
Features impairment of vertical gaze (down gaze worse than up gaze - patients may complain of difficultly reading or descending stairs) parkinsonism falls slurring of speech cognitive impairment
Management
poor response to L-dopa
Example Question:
A 76 year old male is referred by the GP to your Parkinsons disease clinic. The patient and his wife described an increasing frequency of falls, the most frightening of which occurred when he fell 4 steps down a flight of stairs last week, luckily with no lasting damage. On examination, you note a slow pill rolling tremor equally on both hands and bilateral cog-wheeling. His cranial nerves are unremarkable except a poverty of upwards gaze. His speech appears distinct and nasal in character. What is the diagnosis?
Idiopathic Parkinsons disease Vascular Parkinsonism > Progressive supranuclear palsy (PSP) Multi-system atrophy (MSA) Corticobasal degeneration (CBD)
PSP is most likely in this scenario. A number of features should alert you to a Parkinsons-plus syndrome instead of idiopathic Parkinsons disease: bilateral, symmetrical symptoms are uncommon, particularly in early PD. In addition, eye sigsn are very unusual. PSP patients classically present with increasing falls near the stairs due to an impaired vertical gaze and a nasal ‘Donald-Duck’ voice secondary to pseudobulbar palsy. MSA patients classically present with significant cerebellar or autonomic symptoms. CBD present with higher order dysfunction such as apraxia and aphasia, but classically with ‘alien hand syndrome’, thought to be as prevalent as 60% of CBD patients, when the patient has no control over their own hand movements.
L-Dopa Dyskinesia
Involuntary movements on a background of chronic and substantial use of L-dopa is a phenomenon known as L-dopa dyskinesias (LID). The pathophysiology of LIDs remains unclear but the key is to minimise L-dopa dosage if at all possible.
Example Question:
An 80-year-old male presents to the Parkinson’s disease (PD) clinic complaining of jerking and flailing movements of his arm. He says he has no control of them and finds them embarrassing and disabling. However, he reports very few other PD symptoms, with minimal problems with ‘off’ periods. His past medical history includes PD, diagnosed 8 years ago, and type 2 diabetes. He currently takes Sinemet 250 for Parkinson’s disease 5 times a day and metformin 500mg TDS, he has been on the same dose of Sinemet for past 18 months. What is your most appropriate management?
> Reduce dose of Sinemet Increase dose of Sinemet Start entacapone Start ropinirole Deep brain stimulation (DBS)
The patient describes involuntary movements on a background of chronic and substantial use of L-dopa, a phenomenon known as L-dopa dyskinesias (LID). The pathophysiology of LIDs remains unclear but the key is to minimise L-dopa dosage if at all possible. As the patient reports minimal other motor symptoms, this is possible in this case. Entacapone smooths the motor profile of L-dopa but does not help with LIDs. DBS is a possible treatment for LIDs changes to L-dopa dose is not possible or if symptoms remain refractory despite L-dopa dose changes.
Mx of Psychosis in Parkinson’s Disease - Example Question
A 75 year old man with Parkinson’s disease is brought to see you in clinic by his son. He has become increasingly concerned that his neighbours have been watching him, and have put wiring throughout his walls to monitor his movements. He has also been describing visual hallucinations of animals climbing up his walls. His son is concerned that he has become increasingly anxious. He is currently on co-careldopa, ropinirole, and rasagiline. What is the best course of action?
Initiate a 'drug holiday' withholding all but co-careldopa for 1 week > Reduce ropinirole Reduce rasagiline Refer for cognitive behavioural therapy Start quetiapine
This gentleman is displaying psychotic symptoms. Psychosis in Parkinson’s disease (PD) can be due to the disease process itself (non-motor feature of PD), or medication side effect. It is sensible to perform a medication review and alter any potentially precipitating drugs.
Ropinirole is a dopamine agonist and is associated with psychosis, and in particular visual hallucinations. It is also important to warn all patients initiated on dopamine agonists of the potential for impulsive behaviour disorders including gambling and excessive spending.
Abrupt discontinuation of medication is never indicated in Parkinson’s disease since this can lead to rapid deterioration and worsening of symptoms.
Parkinson’s Dementia vs Lewy Body Dementia - Example Question
A 72-year-old male diagnosed with dementia after a one-year history of progressive cognitive decline, particularly in planning, cognitive flexibility, attention, visual memory and visuospatial manipulation on detailed neuropsychological assessments. His mini-mental state examination scores 15/30. His past medical history includes Parkinson’s disease, for which he was started on Madopar 6 years ago. His son attends clinic with his father and both are very keen to start some treatment. What is the most available treatment?
No treatment > Rivastigmine Donepezil Increase Madopar dose Deep brain stimulation
The patient describes a syndrome of executive and visuospatial dysfunction on a background of PD diagnosis more than 12 months before diagnosis of cognitive impairment. This represents PD dementia (instead of Lewy Body dementia). The only licensed proven treatment for PD dementia demonstrated in a randomised clinical trial is rivastigmine. Donepezil is also useful for PD dementia but is not currently licensed in the UK. Neither DBS nor increasing PD medications improve cognitive impairment.
