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As usual, read these notes alongside lecture slides

There are two questions in our exam based on this lecture

Revision

  • Parkinson’s disease, named after James Parkinson 1813 “shaking palsy”
    • Initial symptoms:
      • Unilateral rest tremor, stiffness, clumsiness, weakness of one side
    • Signs
      • Tremor (resting, suppressed by action, posture)
      • Bradykinesia – (slowness of movement)
      • Rigidity (cogwheel)
      • Postural changes
  • TRAP = tremor, rigidity, akinesia, postural changes
    • want to make sure they don't have other things (see atypical stuff below)

Introduction

  • Parkinson’s is not just a motor disorder
  • Parkinson’s can be misdiagnosed
    • Features that are atypical (ie, not parkinson’s)
      • Abnormal eye movements
      • Early autonomic nervous system abnormalities (orthostatic hypotension)
      • Early Cognitive impairment
      • Dopaminergic-blocking drugs can produce Parkinsonism
  • Above is because we want to see if they have Parkinson's plus diseases, which are harder to treat
  • Do imaging to check for atypical features e.g. structural problems that could cause parkinsonian-type symptoms
    • He shows an example of a man with just this problem - structural defect in basal ganglia

ParkinsonsDiagnosis.png

Pathology

  • Loss of pigmented neurons in the substantia nigra pars compacta
    • Also, degeneration of the nigro-striatal tract (the major dopaminergic input)
  • Lewy bodies, always present in idiopathic parkinson’s
    • Eosinophilic body
  • Direct pathway is underactive, indirect is overactive
    • Result is reduced activity (bradykinesia) and increased involuntary movements (tremor)
  • Dopamine is not just there for movement, but also psychiatric functions.
  • We wish we could diagnose people in the subclinical phase of PD, before disability becomes severe
  • Early, there is neuron loss, but then the remaining neurons undergo compensation, and later on there are too few neurons to compensate
  • Basal ganglia circuitry - explains PD (too little movement), HD (too much movement) and dystonia (gross uncoordination of movement)
    • Compare this diagram with the notes from
    • Tonic discharge of dopamine sets the excitability of the system (hence L-Dopa can treat the disease)
    • Direct pathway activation --> facilitate movement. Indirect pathway activation --> inhibit movement. Dopamine inhibits indirect and stimulates direct. So lack of dopamine causes PD.

Differential diagnoses

  • Drug induced parkinsonism
  • Parkinson plus syndrome
    • Progressive supranuclear palsy – upper motor neuron problem with eye movement problems
    • Multiple system atrophy – similar posture to parkinson’s
    • Corticobasal degeneration – difficulty in organising movements, rigidity, apraxia (or even alien limb), frontal signs
    • Dementia with lewy bodies – also has alzheimer’s symptoms and cognitive deterioration + hallucinations; visual hallucinations, dementia, fluctuation

Aetiology

  • related to age
  • twin studies
    • onset < 50 some genetic, > 50 non-genetic
  • toxins
  • genetic causes: Park1 (dom) (α synuclein gene mutation)
  • Park2 (AR) (Parkin, juvenile onset)
  • Park3-8 (variable phenotype, incl “ET”)
  • alpha-synuclein hypothesis (ubiquitin pathway) (MSA, DLB)
  • alpha synuclein that causes this change accumulates like a prion and causes ongoing damage

Possible causes of nigra cell loss

  • See diagram

Treatment considerations

  • medication is the main form of treatment in most patients
  • non-pharmacological options – simplify tasks etc (works early in disease)
  • treatment is symptomatic/palliative (doesn't reverse disease)
  • treatment improves life expectancy
  • not all features respond to treatment
  • “more” is not necessarily the answer - avoid complications
  • Start treatment: once motor symptoms esp. bradykinesia causes significant disability (don't start just because of tremor unless patient really wants it)

Treatment types

  • Medications
    • L-dopa + DDC inhibitors (e.g. sinemet, madopar, std, CR, rapid). DDC inhibitor prevents peripheral conversion into dopamine. Dopamine does not cross BBB. Using DDC means we don't need such high doses to get enough across BBB, to avoid ARx.
    • Dopamine agonists – better in younger patients, eg: ergolide (side effects), apomorphine, pergolide, cabergoline
    • MAOI, COMTI – dopamine metabolism inhibitors, prolong the actions of L-dopa – selegiline, entacapone (NB: similar idea to SSRIs in depression)
    • Anticholinergics
      • Useful for tremor, prone to side effects – memory loss, constipation
      • Amantadine – induces dopamine release and is a weak NMDA antag and an anticholinergic
  • Non-pharmacological – simplification of tasks
  • Treatment of symptoms/palliative
  • Improvement of life expectancy


  • Here he showed the diagram we saw in SG

L dopa

  • L-dopa treatment
    • always given with a (peripheral) decarboxylase inhibitor (carbidopa or benserazide)
    • precursor of dopamine
    • taken up into remaining terminals
    • decarboxylated (and stored) in nerve terminals
    • most potent form of treatment, but one also associated with side effects (dyskinesias – involuntary, unwanted movements – 10%/year)
    • side effects may be a result of pulsatile stimulation (plasma t1/2 90-120 min)
    • long acting and rapidly acting formulations (an idea that this might reduce dyskinesias)

DA agonists

  • Dopamine agonists:
    • have a direct action on the postsynaptic receptor - include bromocryptine, pergolide, cabergoline, pramipexole and rotigitine (patch that is not on PBS)
    • limited potency but associated with fewer dyskinesias
    • use initially in younger patients
    • (rare, but serious -ergolide) S/E: retroperitoneal fibrosis, heart valve abnormalities (restrictive valvopathy, incompetence), behavioural
    • apomorphine – potent but has to be given by injection or infusion

Metabolic inhibitors

  • have little or no effect alone
  • prolong the action of co-administered L-dopa
  • more stable levels of L-dopa may be an advantage - MAO-B inhibitor – selegiline (more recently - rasagiline) ?neuroprotective
  • COMT inhibitor – entacapone (with L-dopa & carbidopa = Stalevo)

Anticholinergics

  • limited application
  • useful for tremor but prone to cause side effects (memory loss, constipation)

Amantidine

  • weak antiparkinsonian effect
  • reduces dyskinesias (unwanted invol. movements)

Transdermal

  • rotigotine (not PBS)

Complications of treatments

  • Effects wear off
    • Pharmacokinetics don't change but response changes, ie, effects on the pre-post synaptic terminals
      • as it progresses, the effect of drug lasts shorter period
  • Dyskinesia – abnormal movements (peak dose effect, biphasic effect (when levels are rising/falling), early morning effect, end of dose effect)
  • Delusions/hallucinations
  • Hypotension/addiction/fatigue
    • Valvular changes
    • Pulmonary fibrosis (ergolides)

Late complications of disease

  • Often can’t be treated and can be exacerbated by treatment
    • Postural instability – falls
    • Bulbar (NB bulb = medulla) function (speech, swallowing; doesn't respond to increased dose) – aspiration + pneumonia
    • Cognitive impairment – hallucinations (hallucinations are a limit to the max dose you can give - they're caused by Dopa)
  • May be due to other dopaminergic pathways and the lack of dopamine

Treatment of non-motor and balance disorders

  • Orthostatic hypotension – fludrocortisone (replaces aldosterone which causes increased resorption of water)
  • Dementia – centrally acting cholinesterase inhibitors – to reduce effects of dementia (like with AD)
  • Urinary urgency – anticholinergics
  • Constipation – bulking agents
  • Falls – walking frames

Behavioural changes due to treatment

  • Dopamine is involved in the reward system of the limbic region
    • Thus, treatment can cause:
      • Behavioural addiction
      • Dopamine dysregulation syndrome – cravings/addiction for dopamine; demand higher and higher doses
      • Punding – repeated meaningless tasks (dopamine may exacerbate these behaviours); become obsessed with sorting buttons, for example
      • Hypersexuality
      • Pathological gambling/shopping

Surgical treatments

  • DBS - expensive
  • Thalamotomy – reduce tremor (rarely done now)
  • Pallidotomy – unilateral/bilateral
    • Now the trend Is to stimulate instead thus regulating the GPi and reducing the STN activity
    • pallidal stimulation
  • bilateral STN stimulation (now preferred method) - this blocks the activity of STN (see diagram)
  • direct GDNF (glial derived neurotrophic factor) infusion – not effective
  • Transplant – stem cells (research)/foetal, no longer done
  • Vim in thalamus = for tremor
  • GPi = for dystonia
  • STN = for PD (usually bilateral, or else only get unilateral improvement)
  • PPN = research target for improvement of gait

Stimulation

  • Need careful selection of patients
    • Need to have response to L-dopa
    • reduces dose, but doesn't reverse the disease
    • Some people fluctuate wildly, very disabling – suitable treatment (people with periods of both rigidity and prominent dyskinesias)
      • Don’t know how to treat, can’t increase or decrease dose
    • Intact cognition
    • No active neuropsychiataric conditions – treatment may cause psychiatric problems like apathy
    • Social support
    • Fitness for procedure
  • Preferred method: bilateral STN
    • Needs careful targeting
    • Need intraoperative and postoperative adjustment and followup
    • Can be turned ‘on’ and ‘off’ to regulate akinesia/dyskinesia
  • At the moment, disease modifying treatment is not yet available, we need a better understanding of the underlying causes
  • (both) stimulators need replacement
  • best “on” is usually not better than can be achieved with medication (BUT it's sustained)
  • is particularly effective for “off” periods alternating with dyskinesias
  • following successful STN stimulation, required dosage of DA may fall
  • no evidence that underlying disease is affected
  • post op problems include neuropsychiatric complications

Summary

  • “Falls, deteriorating bulbar function and dementia remain the major therapeutic challenges in Parkinson’s disease.” (Lees 2002)
  • True disease modifying treatment is not yet available and may require a more fundamental understanding of the underlying cause.