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Parkinson’s disease

Parkinson's disease
Parkinson's disease

Parkinson’s disease

 Parkinson’s diseaseis a chronic, progressive neurodegenerative condition that occurs secondary to loss of dopaminergic neurones within the substantia nigra.

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Parkinson’s disease is the most common form of parkinsonism. Parkinsonism describes the presence of bradykinesia and at least one of the following:

  • Resting tremor
  • Rigidity
  • Postural instability

Parkinson’s disease tends to present with unilateral symptoms at onset with gradual progression and the development of bilateral signs. In addition to the motor symptoms, non-motor complications like depression, dementia, sleep disturbance and autonomic dysfunction cause significant ill-health.

Management may consist of medical therapy (e.g. levodopa) and surgical interventions (e.g. deep brain stimulation).

parkisons_disease_statistics.jpg

Epidemiology

Parkinson’s disease is one of the most common neurological disorders, it has a lifetime risk of 2.7%.

Parkinson’s disease is slightly more common in men (1.5:1) and the overall prevalence is thought to be increasing, with a projected rise of 27% between 2009 and 2020 in the UK.

The onset of Parkinson’s disease usually peaks between the ages of 55-65 years and generally has a slowly progressive onset.

Anatomy & physiology

The basal ganglia are collections of nuclei found in the subcortical white matter.

Anatomy

The basal ganglia describe a series of cell bodies (i.e. gray matter) that are located together within the deep subcortical white matter of the brain.

The thalamus, though not formally considered part of the basal ganglia, forms extensive connections with the nuclei.

anatomy_of_the_basal_ganglia.jpg

Physiology

The basal ganglia have a number of important roles in movement generation. In simple terms, it helps to kick start and fine tune movement initiated by the motor cortex in a coordinated manner.

Some of the important functions of the basal ganglia include:

  • Inhibition of muscle tone
  • Coordinated, slow, sustained movement
  • Suppression of useless patterns of movement
  • Initiation of movement

Aetiology

Parkinson’s disease is a condition of idiopathic aetiology. 

It is thought that a small proportion (approx 2-3% ) of cases of Parkinson’s disease can be attributed to a monogenic cause (i.e. a single gene variant causing the disease).

In the majority of cases the aetiology is largely unknown and probably related to a complex interaction between a patients genetics and their environment.

Pathophysiology

Parkinson’s disease may not be apparent until a substantial number of neurones (50-80%) have been lost within the substantia nigra.

The basal ganglia are essential for the modulation of pyramidal motor output to allow normal movement. This process of modulation is dependent on two pathways within the substantia nigra, the direct and indirect pathways.

Direct pathway

The direct pathway is mostly a stimulatory pathway (‘on’ pathway) that is shorter, mostly off and predominantly associated with D1 receptors.

Activation of the direct pathway leads to a series of neural connections through the basal ganglia, which eventually leads to the initiation of movement. Dopamine that is released from the substantia nigra via dopaminergic neurones is able to activate the direct pathway via D1 receptors leading to the generation of movement.

Indirect pathway

The indirect pathway is mostly an inhibitory pathway (‘off’ pathway) that is longer, mostly on and predominantly associated with D2 receptors. 

Activation of the indirect pathway is essential in the inhibition of muscular tone to prevent unnecessary movement. Dopamine that is released from the substantia nigra via dopaminergic neurones is able to inhibit the indirect pathway via D2 receptors therefore leading to the generation of movement (i.e. inhibiting the inhibitor)

Summary

Collectively, this shows how the release of dopamine may act on both the direct and indirect pathway to lead to a ‘kick-start’ in movement generation. Importantly, this process is fine-tuned to allow coordinated movement when it is needed by close interaction with the motor cortex via corticonigra fibres. 

It is therefore unsurprising that in Parkinson’s disease there is a problem with the initiation of movement. 

Clinical features

The classic clinical features of Parkinson’s disease are bradykinesia, resting ‘pill-rolling’ tremor and cogwheel rigidity.

Bradykinesia

  • A general slowing of voluntary movements
  • Reduced arm swing
  • Reduction in amplitude with repetitive movements

Tremor

  • Traditionally resting and described as ‘pill-rolling’
  • 4-6 Hz in frequency
  • Can be induced by distraction

Rigidity

  • Increase resistance to passive movement
  • Cogwheel due to superimposed tremor

Other

  • Expressionless face (‘Parkinsonian mask’)
  • Micrographia – small writing
  • Soft voice
  • Drooling of saliva
  • Shuffling gait (festinating gait)
  • Glabellar tap – repeated tapping of forehead associated with persistent blinking (patient should stop blinking in the absence of pathology)
  • Depression
  • Bowel & bladder symptoms (urgency, incontinence, constipation)
  • Sleep disorder
  • Sexual dysfunction

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clinical_features_of_parkinsons_disease.jpg

Diagnosis

Parkinson’s disease is a clinical diagnosis and should be suspected based on the presence of bradykinesia and one or more of the other major features of parkinsonism. 

Patients suspected of Parkinson’s disease based on the clinical features should be referred to specialist for assessment and diagnosis. Parkinson’s disease may be diagnosed using the UK Parkinson’s Disease Society (PDS) Brain Bank Clinical Diagnosis Criteria.

Step 1

Step 1 involves the identification of features of parkinsonian syndrome. 

Bradykinesia and one of the following:

  • Muscular rigidity
  • Postural instability
  • Resting tremor (4-6 Hz)

Step 2

Step 2 identifies exclusion criteria for Parkinson’s disease. 

  • Repeated strokes and stepwise progression. 
  • History of trauma (head injury)
  • Definite encephalitis
  • > 1 relative affected
  • Sustained remission
  • Unilateral features after 3 years
  • Oculogyric crisis
  • Antipsychotic or dopamine-depleting drugs
  • Exposure to neurotoxin
  • Cerebral tumour or hydrocephalus
  • Other atypical neurological features
  • Negative response to levodopa

Step 3

Step 3 involves the identification of supportive criteria of Parkinson’s disease. 

Three or more of the following:

  • Progressive disorder
  • Unilateral onset
  • Resting tremor 
  • Persistent asymmetry 
  • Excellent response to levodopa
  • Severe levodopa induced chorea
  • Levodopa response ≥ 5 years
  • Clinical course of ≥ 10 years

MDS diagnostic criteria

More recently, the movement disorder society (MDS) have released a new diagnostic criteria that outperformed the UK brain bank criteria.

This diagnostic criteria follows a similar methodology to the UK brain bank criteria for reaching a diagnosis.

The diagnosis of clinically established PD is based on:

  • Confirmation of Parkinsonism: must be evidence of ‘motor’ parkinsonism (bradykinesia + tremor or rigidity)
  • No absolute exclusion criteria present: multiple exclusion criterias exist. Examples include unequivocal cerebellar abnormalities, vertical supranuclear gaze palsy, parkinsonism restricted to lower limbs ≥3 years, suspected frontotemporal dementia, others.
  • ≥2 supportive criteria: dramatic response to dopaminergic drugs, levodopa-induced dyskinesia, rest tremor of limb (typically unilateral onset), others.
  • Absence of red flags: rapid development gait impairment, early bulbar dysfunction, non-progressive motor symptoms ≥ 5 years while not on treatment, respiratory dysfunction, early severe autonomic dysfunction, others.

The diagnosis of clinically probable PD is based on:

  • Confirmation of Parkinsonism
  • No absolute exclusion criteria
  • Presence of red flags, but counterbalanced by supportive criteria: no more than two red flags allowed.

Parkinsonism

Parkinson’s disease is considered an idiopathic cause of parkinsonism.

The main differential diagnoses for Parkinson’s disease include other causes of parkinsonism, which described the presence of bradykinesia associated with one or more features from tremor, rigidity and postural instability.

There are numerous causes of parkinsonism, which can be broadly divided into four groups to aid memory: idiopathic Parkinson’s disease, drug-induced, other medical pathology and the Parkinson-plus syndromes.