Parkinson’s disease

Pathophysiology

Neurodegenerative disease associated with Lewy bodies = intracellular eosinophilic inclusions composed of alpha-synuclein.

Loss of dopaminergic neurons in the substantia nigra pars compacta, which normally project to striatum. The resultant striatal (especially putamen) dopaminergic denervation is thought to lead to the classic motor symptoms of PD.

Loss of dopaminergic innervation is thought to cause an imbalance of dopamine and acetylcholine the striatum – a hypothesis supported by the beneficial effects of anticholinergics in PD.

Additional neurotransmitter deficits (acetylcholine, noradrenaline) are thought to develop, particularly in later stages of the disease, and those affected by Parkinson’s Disease Dementia.

Work by Heiko Braak suggests that degeneration starts in the medulla/olfactory bulb, progressing to the midbrain (SNc) and basal forebrain, before eventually spreading to the cortex (particularly temporal and frontal lobes).

Mechanisms implicated to date include protein misfolding and proteolysis, mitochondrial dysfunction, oxidative stress, defective iron metabolism, as well as immunologic factors, however how these factors interact to lead to cell death is unclear.

Epidemiology and genetics

  • Second most common neurodegenerative disease (after AD)
  • Affects 0.3% of over 40s, prevalence increasing with age
  • Protective factors: Coffee drinking [ref], smoking (big win for cool people everywhere)
  • Risk factors: Family history of PD/tremor, constipation, anxiety/depression, head injury, pesticide exposure/farming

Genetics

  • Familial parkinsonism make up a small minority of patients and is associated with causative mutations in SNCA, Parkin, PINK1, DJ-1 and LRRK-2 (as well as others) – producing mostly young-onset phenotype
  • Meta-analysis of GWAS suggest a number of risk factor loci including glucocerebrosidase (also associated with Gaucher’s disease when homozygous)

Symptoms

  • Motor tetrad
    • “Slowness” – bradykinesia/hypokinesia
    • Resting tremor
    • Rigidity
    • Postural instability
  • Non-motor
    • Lost sense of smell
    • Constipation
    • Urinary frequency/urgency
    • Sleep disorders (REM sleep disorder)
    • Visual hallucinations
    • Sialorrhoea
    • Depression/memory impairment

On examination

  • Face: Hypomimia, seborrheic dermatitis, glabellar tap +ve (don’t do in real life), quiet speech
  • CN: Normal – important finding
  • Lead-pipe rigidity (i.e. velocity independent)
  • Cog-wheeling
  • Resting tremor (4-6 Hz)
  • Brady/hypokinesia
  • Stooped posture
  • Shuffling gait, reduced arm swing, freezing of gait
  • Postural instability

Diagnosis

  • Mostly clinical and response to medications
  • Routine bloods including LFT, B12, Folate
  • MRI head to exclude structural/vascular cause (NPH, lacunar infarcts, tumours)
  • DaTscan (23I-FP-CIT single photon emission tomography) might be useful to distinguish PD from essential tremor or drug-induced parkinsonism,

Treatments

  • See medications
  • Speech therapy
  • Physiotherapy
  • Surgical
    • DBS: permanent implantation of deep brain electrodes targeting usually either the subthalamic nucleus or globus pallidus pars interna. Deep brain regions are stimulated at high-frequency continuously. Useful in those who have developed motor complications of treatment.
    • Ablations: this used to be the surgical option of choice, but has since been almost entirely replaced by DBS. Ablations may be making a comeback however, with the development of focused ultrasound methods allowing “non-invasive lesioning” to deep brain structures [ref].

Management

The major pharmacological agents for PD/LBD are outlined below:

  1. Levodopa
  2. Dopamine agonists
  3. MAO B inhibitors
  4. Anticholinergic agents
  5. Amantadine
  6. COMT inhibitors

Levodopa

  • Widely regarded as the most effective drug for bradykinesia/akinesia
  • Some improvement in tremor/rigidity might be reported, but rarely improves postural instability
  • Combined with peripheral decarboxylase inhibitor to prevent metabolism to dopamine systemically (which would cause nausea & postural hypotension)
    • levodopa + carbidopa = sinemet
    • levodopa + benserazide = madopar
    • Immediate release and modified release are available for each
  • Commonly produces nausea at first – advise to take meds with meals
  • GI absorption will vary with protein meal content – the drug competes with other amino acids for absorption.
  • Motor fluctuations:
    • Patients typically develop fluctuations in their motor response to l-dopa <10 years of starting. These include:
      • Dyskinesia
      • Wearing-off
      • Dystonic posturing
    • Evidence suggests this is more common in younger-onset PD
    • Controversy exists as to whether the drug itself is causal to these complications via neurotoxic oxidative stress mechanisms – the guidance is to prescribe the minimum dose that prevents symptoms from impacting on their daily activities.
    • Some advocate starting young-onset PD on agonists instead.

Dopamine agonists (DAs)

  • DAs directly stimulate DARs and do not require metabolic activation.
  • Generally longer duration of action vs. immediate release l-dopa.
  • Different medications tend to have varying affinities to DAR subtypes:
    • pramipexole – D2R > D3R
    • ropinirole – D3R > D2R > D4R
    • bromocriptine – D2R
    • cabergoline – D2R
    • transdermal rotigotine
    • injectable apomorphine – D2R
  • D1R & D2R are more abundant in the dorsal (motor) striatum
  • D3R, D4R, and D5R are more abundant in the mesolimbic brain (D3R, D4R) and hippocampus/hypothalamus (D5R)
  • Given the controversy noted above regarding motor fluctuations  and their relationship to l-dopa, some advocate initially using DAs as a monotherapy to postpone the use of l-dopa, especially in younger-onset patients – the evidence for this is currently unproven.
  • AE: nausea, somnolence, valvular heart disease (for ergot-derived medications), withdrawal syndrome
  • Dopamine dysregulation syndrome & impulse control disorders
    • Compulsive use of DA medications, despite worsening drug-induced dyskinesia
    • Associated with mood disorders and impulse control disorders including pathological gambling and hyper-sexuality

Monoamine oxidase (MAO) B inhibitors

  • Inhibit the breakdown of DA (and other monoamines) that have been taken up in the pre-synaptic terminal, effectively boosting DA concentrations in the synaptic cleft.
  • Meta-analysis suggests that MAO B inhibition can be used as an effective monotherapy in early disease, and might delay the need to start l-dopa.
  • Longterm use when combined with l-dopa has also been found to be beneficial.

Anticholinergic agents

  • Acetylcholine (ACh) is synthesised in the striatum by the non-spiny striatal neurons, where it has a mostly excitatory effect on spiny striatal neurons
  • The therapeutic mechanism of blocking ACh is not understood. It is thought to be due to a rebalancing the proportions of DA and ACh in the striatum.
  • Used most often in patients with tremor that has not improved with l-dopa.
  • Centrally acting anticholingerics that are sometimes used (all roughly equally effective)
    • Trihexyphenidyl
    • Benztropine
    • Procyclidine
    • Orphenadrine
  • Beware of using anticholinergics in older/cognitively impaired patients, particularly those with hallucinations
  • Classic anticholinergic side effects usually limit their use (dry mouth – can be useful in PD, blurred vision, nausea, constipation, urinary retention etc.)

Amantadine

  • Originally an antiviral agent, later found to have mild efficacy in PD possibly due to increasing DA in striatum, possibly due to anticholinergic effects, possibly due to anti-glutamatergic effects?
  • Mostly used as a short term single therapy for those with mild disease.
  • Can be used to help those with l-dopa induced dyskinesia and motor fluctuations
  • Can cause confusion/nightmares in older adults.

Catechol-O-methyl transferase (COMT) inhibitors

  • Used in combination with l-dopa to extend the drug effect by inhibiting inactivation of DA and l-dopa
  • Useful in patients with motor fluctuations experiencing “wearing off phenomenon”
  • No added benefit in patients without motor fluctuations
  • Examples include entacapone
  • Patients may require a lowering of their l-dopa dose on commencing entacapone, as the entacapone increases the drug half-life
  • Discolours urine orange, can worsen liver function tests.