Parkinson's Disease

 

• Background

  Aka idiopathic Parkinson's disease.

  Pathophysiology

  • Formation of intracytoplasmic Lewy bodies – aggregations of α-synuclein bound to ubiquitin – which leads to neuronal death.
  • Especially affects dopaminergic neurons in the substantia nigra pars compacta. Symptoms appear when 70% of dopaminergic neurons loss.
  • Other neurotransmitters also affected, including acetylcholine, serotonin, and norepinephrine.

  Epidemiology

  • 1% prevalence over 65 years old.
  • 5% of patients have onset before 40.
  • Commoner in men.

• Signs and symptoms

  General features:

  • Insidious onset
  • Usually asymmetrical onset, and stays worse on that side.
  • Usually no sensory or power loss.

  Parkinsonism triad

  Tremor:

  • Usually in fingers/hands, classicaly a pill-rolling movement, but can occur elsewhere inc. face and jaw.
  • 4-6 Hz.
  • Worse at rest.

  Rigidity:

  • ↑Tone, known as lead-pipe rigidity or, when combined with tremor, cogwheel rigidity.
  • Subjectively feel 'stiff'.

  Brady/hypokinesia:

  • ↓Initiation of movement, ↓speed, ↓amplitude of repetitive actions, blank face, ↓blinks, monotone speech (later slurred or absent), and micrographia.
  • Altered gait: shuffling, absent arm-swing, flexed trunk, freeze at obstacles.
  • Subjectively feel clumsy or weak.

  Other symptoms

  Autonomic:

  • Urinary frequency and urgency.
  • Constipation
  • Sweating
  • Dribbling
  • Orthostatic hypotension. Contributes to postural instability and falls.

  Neuropsychiatric:

  • Depression.
  • Sleep: fatigue, REM sleep disorder, insomnia, vivid dreams.
  • Visual hallucinations.
  • Parkinson's dementia: dementia starting >1 year post diagnosis. Global cognitive impairment but, unlike Alzheimer's, memory not affected until later. If dementia comes before parkinsonism, it is Lewy Body dementia.

  Sensory:

  • Anosmia
  • Ageusia

• DDx: Parkinsonism

  Neurodegenerative:

  • Parkinson's disease.
  • Parkinson's-plus syndromes.
  • Lewy body dementia.

  Drug-induced parkinsonism.

  Tremor:

  • Physiological tremor: high amplitude, present in all, especially apparent when on stimulants.
  • Essential tremor: symmetrical, postural tremor.
  • Dystonic tremor: coarse, irregular tremor, often in face and neck.

  Others:

  • Multiple strokes (aka vascular Parkinsonism). Upper motor neuron signs also present.
  • Toxin: manganese, MTPT, copper.
  • Trauma

• Diagnosis

  Clinical diagnosis:

  • {Brady/hypokinesia} plus {tremor, rigidity, or postural instability} without identified cause.
  • Should be diagnosed in secondary care.

  Neuroimaging:

  • If diagnosis is unclear or there is poor treatment response, consider CT/MRI or DaTSCAN.
  • DaTSCAN (aka 123I-FP-CIT SPECT) shows striatal dopaminergic neuron loss. It can thus differentiate between PD and drug-induced or essential tremor, but not between PD and LBD or Parkinson's plus syndromes, as they also feature striatal dopaminergic neuron loss.

• Management

  General and supportive

  MDT approach:

  • Specialist nurse.
  • Physiotherapy can improve gait and balance.
  • Occupational therapy to help with work, family role, and ADLs.
  • Speech and language therapy for problems with communication, swallowing, or salivation.

  Patient and carer education, including:

  • Prognosis
  • Treatment options.
  • Need to contact DVLA, but usually can keep driving initially.

  Medical

  In early disease, where symptoms are not causing significant impairment, treatment can be delayed.

  Dopamine modifying drugs for motor symptoms:

  • If motor symptoms are impacting quality of life, begin with levodopa plus dopa-decarboxylase inhibitor.
  • If motor symptoms not yet impacting quality of life, begin with MAO-B inhibitor or dopamine agonist.
  • In later disease, these drugs are used in combination, along with other therapies such as COMT inhibitors.

  Treatment of non-motor features, after considering non-pharmacological measures and reversible causes (e.g. drug side effects) first:

  • Psychosis: quetiapine or clozapine, though treatment not needed if not distressing or problematic.
  • Sleep problems: modafinil for daytime sleepiness, clonazepam or melatonin for REM sleep disorder.
  • Orthostatic hypotension: midodrine or fludrocortisone.
  • Depression and dementia are treated as for those without PD, paying close attention to any possible drug side effects.

  Surgical

  Deep brain stimulation:

  • Either bilateral subthalamic nucleus stimulation, or bilateral globus pallidus interna stimulation.
  • Criteria: refractory motor symptoms, otherwise well, previously levodopa responsive, no cognitive or mental health problems.

• Prognosis

  • Better prognosis if tremor main feature.
  • Death usually 10-15 years from diagnosis. Pneumonia is commonest cause.

• Levodopa

  Mechanism

  Levodopa is the drug name for L-DOPA, the amino acid precursor of catecholamines (dopamine and (nor)adrenaline).

  Use in Parkinson's disease

  • Most effective drug for motor symptoms but also most likely to cause motor complications.
  • Start low but will later require increasingly higher doses (with increased side effects).
  • Give with a dopa-decarboxylase inhibitor (DDCI) to reduce peripheral conversion of levodopa to dopamine, thus minimizing nausea and vomiting and prolonging therapeutic effect. Options: carbidopa-levodopa (co-careldopa, Sinemet), benserazide-levodopa (co-beneldopa, Madopar).

  Side effects and complications

  Short term:

  • Nausea and vomiting. Treat with domperidone.
  • Postural hypotension.
  • Oedema
  • Neuropsychiatric: confusion, visual hallucinations, delusions, impulse control disorders.
  • Sleep disturbance: vivid dreams/nightmares, daytime drowsiness.
  • Red urine.

  Long-term:

  • Dyskinesia (50%): involuntary movement, including chorea and dystonia.
  • Wearing-off before next dose due.
  • Unpredictable on-off: sudden, random wearing off leading to bradykinesia.
  • Freezing: unlike an 'off', only one specific movement affected.

  Managing later side effects and treatment-resistance:

  • Fractionate the dose i.e. frequent small doses.
  • Motor complications: give dopamine agonists, amantadine, or continuous apomorphine infusion if severe.
  • Reducing off time: give COMT inhibitors or intermittent apomorphine infusion.
  • Duodenal infusion (Duodopa) if other options not effective.

• Adjuncts and alternatives to levodopa in Parkinson's disease

  Dopamine agonists

  Mechanism:

  • Bind D1 and/or D2 receptors in the striatum.

  Drugs:

  • Oral: ropinirole, pramipexole.
  • Subcut: apomorphine.
  • Transdermal: rotigotine.
  • These are all non-ergot agents, which are preferable to ergot-derived drugs like bromocriptine.

  Indications:

  • Alternative or adjunct to levodopa.
  • Apomorphine can be used intermittently for freezing, or continuously for dyskinesia.

  Side effects:

  • Fatigue, including sudden onset of sleep.
  • GI: nausea and vomiting (especially apomorphine), and constipation.
  • Impulse control disorders (10%): pathological gambling, sex, eating, and shopping.
  • Other neuropsychiatric: confusion, hallucinations.
  • Peripheral oedema.
  • Dyskinesia (though less than levodopa).
  • Apomorphine can cause uncomfortable subcutaneous nodules.

  Monoamine oxidase B (MAO-B) inhibitors

  • Mechanism: block dopamine degradation within the cell.
  • Drugs: rasagiline, selegiline.
  • Use: an alternative initial treatment option, or for levodopa wearing-off.
  • Side effects: anticholinergic.
  • Contraindications: SSRI (serotonin syndrome risk).

  Catechol-O-methyltransferase (COMT) inhibitors

  Mechanism:

  • Blocks dopamine and L-DOPA degradation outside the cell.

  Drugs:

  • Entacapone. Taken with levodopa/DDCI combinations e.g. with Sinemet as Stalevo.
  • Tolcapone

  Indications:

  • Wear off.
  • Dyskinesia

  Side effects:

  • As with the other dopaminergic drugs.
  • Also: diarrhoea, orange urine, dyskinesia.
  • Tolcapone can be hepatotoxic, so check LFTs.

  Amantadine

  • Mechanism: increases dopamine release and reduces reuptake. Originally an antiviral drug.
  • Indication: dyskinesia (if other agents ineffective).
  • Side effects: insomnia, hallucinations, livedo reticularis, ankle oedema.

• Parkinson's plus syndromes

  Conditions featuring parkinsonism plus additional distinctive features.

  Progressive supranuclear palsy

  • Eye symptoms: vertical gaze palsy, reduced/absent blinking or eyelid closure.
  • Pseudobulbar palsy: dysphagia, dysarthria, dysphonia.
  • Falls are an early feature, including falling over backwards.
  • Rigidity of trunk more than limbs.
  • Frontal lobe symptoms, including reduced verbal fluency.
  • Unlike PD, symmetrical at onset, and tremor is uncommon.

  Multiple system atrophy

  • Early ANS symptoms, including postural hypotension and bladder dysfunction.
  • Cerebellar and pyramidal signs.
  • Rigidity more than tremor.
  • Aka Shy-Drager syndrome.

  Cortico-basal degeneration

  • Akinetic rigidity in 1 limb.
  • Sensory loss.
  • Apraxia, possibly with alien limb sensation.

  Lewy body dementia

  May or may not be considered a Parkinson's plus syndrome. See dementia for more info.

• Drug-induced parkinsonism

  Causes

  • Anti-dopamine drugs: antipsychotics, antiemetics.
  • Other psychiatric drugs: valproate, lithium, fluoxetine.
  • CV drugs: calcium channel blockers, amiodarone.

  Clinical features

  The following help differentiate from Parkinson's disease:

  • Bilateral symptoms.
  • Subacute onset.
  • Postural tremor i.e. worse on moving/holding.

  Management

  • Stop drug.
  • Symptoms may persist for up to months.
  • Consider levodopa only if there are severe, disabling symptoms.

• Other common movement disorders

  Essential tremor

  Pathophysiology unclear, though possibly due to excess GABA activity.

  Epidemiology
  

  • Bimodal onset: early adulthood and >60 years old.
  • 50% have family history.

  Tremor characteristics:

  • Bilateral 7-12 Hz tremor of hands, sometimes with slight asymmetry. Less commonly affects head or voice.
  • Postural (worse when arms outstretched) and/or kinetic (worse with movement).
  • Often improves with alcohol, though unclear if increased risk of dependency.

  Management:

  • Propranolol or primidone (a barbiturate) are 1st line.
  • Focused ultrasound thalamotomy if refractory.

  Restless legs syndrome

  Pathophysiology unclear, though possibly due to reduced dopaminergic activity.

  Epidemiology:

  • Onset usually in 20s or 30s, commoner in women.
  • Associated conditions: iron-deficiency anaemia, pregnancy, CKD, depression, anxiety, ADHD.

  Presentation:

  • Uncomfortable sensations in lower legs, worse at rest, with intense urge to move and with movement providing relief.
  • Worse in evening and often affects sleep, though doesn't tend to result in severe daytime sleepiness.
  • Periodic leg movements (repetitive flexor movements) during sleep.

  Investigations for alternative and treatable causes:

  • Basic bloods: CBC, U&E, Ca2+, LFT, glucose.
  • Metabolic and endocrine: ferritin, B12, folate, TFT.
  • Further neuro investigations (e.g. MRI, EMG) if neuropathy suspected.

  Management:

  • Gabapentin or pregabalin are 1st line, and should be started when treatment affects quality of life, functioning, or sleep.
  • Dopamine agonists – ropinirole, pramipexole, or rotigotine – are effective 2nd line drugs, though may worsen symptoms long-term.
  • Treat any iron-deficiency.