Parkinson's Disease (Yvonne Mbaki) Flashcards
What is the definition of Parkinsons?
Neurodegenerative; death of dopamine containing cells of the substantia nigra
What is the substantia nigra?
The origin of dopaminergic afferents implicated in Parkinson’s disease
What is the pathophysiology associated with Parkinson’s disease?
Domaine neurons in the substantia nigra in normal cells compared to the loss of noradrenergic and serotonergic neurons.
How do Lewy bodies form?
Aggregation of protein deposits in substantia nigra, locus coeruleus and other brain regions
Alpha-synuclein aggregation.
How is Parkinson’s disease linked to genetics?
The earlier the age of onset, the greater the familial occurrence
Odds of inheritance are increased if parent or sibling has PD
Which specific genes are the causative agents of PD?
- a-synuclein (autosomal dominant)
Major constituent of Lewy bodies
In familial Parkinson’s, too much or abnormal amounts of a-synuclein are produces.
It is thought that it inhibits neurotransmitter release - LRRK2 (autosomal dominant)
Leucine-rich repeat kinase 2
High prevalence in North African Arabs / Central/Eastern European Jews. - Parkin (autosomal recessive)
Juvenile parkinsonism - onset <30 yrs
Acts as a ubiquitin-protein ligase; labels dead / damaged neurons to be cleared up
How can rural living increase risk of PD?
Some pesticides are known to be potent mitochondrial inhibitors
Mitochondrial complex 1 extracts energy from NADH; this complex is deficient in patients that have died from PD.
Infusion of insecticide rotenone in rats caused dopamingergic cell death, Lewy body formation and motor defecit.
How does mitochodrial inhibition cause PD?
Mitochondrial complex 1 extracts energy from NADH; this complex is deficient in patients that have died from PD.
Which insecticide has shown to cause PD effect in rats?
Rotenone
Dopaminergic cell death, Lewy body formation and motor defecit
Which two environmental factors can cause PD?
Pesticides that lead to mitochodrial inhibition
MPTP
What is MPTP?
MPTP (1- methyl - 4-phenyl - 1, 2, 3, 6 - tetrahydropyridine)
How was MPTP discovered?
By accident when synthetic heroin was the target
A student accidentally manufactured a neurotoxin MPTP
The student developed Parkinson’s disease smptoms but was responsive to treatment.
Autopsy showed destruction of substantia nigra but not Lewy body formation
What does increased prevalence of Parkinson’s Disease suggest?
Age is a factor associated with development of PD.
Loss of striatal dopamine (dopamine from the striatum) and dopamine cells in the substantia nigra
The precise role of aging is still unclear.
What are the motor symptoms associated with PD?
Bradykinesia: slowness of movement
Resting tremor: Shaking that disappears during active use of the affected body part
Rigidity: Increased resistance to passive movement
Postural instability: instability when standing, or impaired balance / coordination.
What other motor symptoms are included in PD?
Drooling Fatigue Loss of facial expressions Speech problems Dysphagia
What are the non-motor symptoms / autonomic symptoms of PD?
GI dysfunction Genitourinary dysfunction Cardiovascular dysfunction Cognitive dysfunction Sleep disorders Mood disorders Pain
What GI dysfunction is associated with PD?
Parasympathetic NS
Constipation
Incomplete bowel evacuation / bowel incontinence
What genitourinary dysfunction is associated with PD?
Urinary urgency, frequency and incontinence
Sexual dysfunction presents in erectile dysfunction in men
What cardiovascular dysfunction is associated with PD?
Cardiac sympathetic denervation = loss of nerve supply
Responsible for light headedness and hypotension.
More commonly, postural hypotension related to medication for PD.
What cognitive dysfunction is associated with PD?
Slowness of thought and executive dysfunction
Parkinson’s Disease Dementia
What sleep disorders are associated with PD?
Rapid eye movement disorder Restless legs syndrome Periodic limb movement of sleep Insomnia Excessive daytime sleepiness
What are the mood disorders associated with PDD?
Depression
Psychosis (potentially due to too much dopamine as a result of Tx)
Anxiety - GAD, agoraphobia, panic disorder, social phobia
What are the pain symptoms associated with PD?
Muscoskeletal pain; cramping aching deformities
Radicular neuropathic pain; radiates into the lower extremity directly along the course of a spinal nerve root
Dystonic pain; pain in the neck muscles (effect of medication)
Centra/primary pain; stabbing burning scalding pain
What is the management strategy for treating PD?
Treat symptoms by replenishing dopamine
Prevent, delay, reverse neurodegeneration
What is the first line therapy for PD?
First line therapy is Levodopa
How does Levodopa treat PD?
Treats bradykinesia and rigidity
Mechanism of action - levodopa is converted to dopamine via DOPA-decarboxylase.
What is often concomittantly given with Levodopa and why?
Dopa-decarboxylase inhibitor such as carbidopa (Sinemet) or benserazide (Madopar)
Given in order to reduce peripheral side effects such as nausea, vomiting, cardiovascular
What is the first line treatment in younger patients?
Dopamine agonists such as Ropinirole, Pramipexole, Rotigotine
What is the factor that means young people have a different first line treatment?
They have fewer motor complications
Which drugs are dopamine agonists?
Ropinirole, Pramipexole, Rotigone
How do dopamine agonists work?
Agonists selective for D2 and D3 post synaptic receptors
What can dopamine agonists be given in combination with?
Levodopa for effective treatment
What are the side effects associated with dopamine agonists?
Nausea, sleepiness, dizziness, hallucinations and psychiatric disorders due to increased dopamine
How do monoamine oxidase-B inhibitors treat PD?
Prevents the degradation of dopamine
Which drugs are MAOi’s?
Selegiline, Rasagaline
What are the side effects associated with MAOi’s?
Selegilline; excitement, anxiety or insomnia
Generally well tolerated
What is the mechanism of action of amantadine?
Mechanism is unclear but has mixed dopaminergic and anti-glutamatergic effects
Initially used as an anti-viral
Which drugs are COMT inhibitors?
Entacapone
What is the mechanism of action of COMT inhibitors?
Prevents degradation of dopamine
How can PD medication compliance be improved?
Levodopa + Carbidopa + Entacapone
Stalevo
How can the cognitive function of PD be treated?
Rivastigmine for demention
Acetylcholinesterase inhibitor ; treats hallucinations more than amnesia
How can mood orders be treated in PD?
Dopamine agonist - pramipexole
TCA SSRi
How can pyschosis in PD patients be treated?
Atypical neuroleptics i.e clozapine (needs close monitoring due to bone marrow suppression).
How can the cognitive function of PD be treated?
Rivastigmine for dementia
Acetylcholinesterase inhibitor ; treats hallucinations more than amnesia
How can PD be managed surgically?
Deep brain stimulation
What criteria must be met in order for deep brain stimulation to be suitable for patients?
Excellent response to levodopa
Younger age
No / mild cognitive impairment
Absence / well controlled psychiatric disease
How does deep brain stimulation work?
Permanent implantation of leads into the subthalamic nucleus (basal ganglia) or globus pallidus
Leads deliver high frequency electrical impulses contolled by stimulator
Shown to alleviate motor problems
Presents opportunity to reduce levodopa dose
What is cell replacement therapy?
No therapies currently available but current research focusses on embryonic, mesenchymal, neural, pluripotent stem cells
+long stability of grafted cells
+long lasting function recovery
+ effective restoration of dopamine release in vivo
What lifestyle factor can help in management of PD?
Dance, martial arts are considered useful as an adjunct to medication.
What vitamin is associated with the non-pharmacological treatment of PD?
Vitamin D Low in patients with PD Related to bone health in PD Appears related to severity of symptoms Neuroprotective role in animal studies
What are the complication in treating PD with levodopa?
Dyskinesia
Fluctuations in clinical state
Nausea
What is dyskinesia (complication of levodopa)?
How can it be treated?
Involuntary writhing which develops in most patients
Amantadine or clozapine to treat
What are fluctuations in clinical state (complications in levodopa)?
How can it be treated?
Hypokinesia (reduced body movement) and rigidity worseding for a few minutes/hour then improving
Levodopa-SR or levodopa and COMT combined Tx
How can nausea (induced by levodopa) be managed?
Administer levodopa with food; combination with carbidopa/benserazide
Domperidone anti-emetic (peripheral dopamine antagonist).
What are the complications with treating PD with dopamine agonists?
Impulsive compulsive behaviour - exacerbated in a patient with a history of OCD, impulsive personality or addictive behaviour
What action is taken when impulsive compulsive behaviour arises in people taking dopamine agonist medication for PD?
Reduce / discontinue dopamine agonists
Anti-convulsant zonisamide; reduces impulsive behaviour
What are the benefits that arise in patients treating PD with clozapine?
Observed to improve psychosis
What needs to be monitored in patients taking clozapine and why?
Agranulocytosis (lowered WBC count)
Blood monitoring is needed
What are the co-morbities associated with Parkinson’s disease?
Depression, cognitive impairment, orthostatic hypotension
How can PD related depression be treated?
SSRi and TCA
How does depression present as a co-morbidity in PD?
Widespread in patients with early onset of PD
Abnormalities of serotenergic, noradrenerfic and dopaminergic function
Why is it hard to diagnose depression in PD?
Challenging diagnosis due to symptoms overlapping e.g. weight loss and insomnia
How does cognitive impairment arise in PD?
Cholinergic dysfunction observed in patients over time
How can cognitive impairment be treated as a PD comorbitiy?
Clinical trials; acetylcholinesterase inhibitor (rivastigmine, donepezil)
How does orthostatic hypertension manifest in PD patients?
Exists as manifestation of autonomic dysfunction or adverse effect of dopaminergic medication
What medications are in clinical trials for PD related postural hypotension?
Corticosteroid; fludrocortisone
Cholinesterase inhibitor; pyridostigmine
NSAID; indomethacin
Domperidone
What non-pharmacological advice can help alleviate orthostatic hypotension in PD?
Increase intake of fluid and salt –> Monitor for hypotension
