Parkinson's
Definition
Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder, with cardinal features include resting tremor, rigidity, bradykinesia, and postural instability
Patients may demonstrate a combination of these motor symptoms, as well as other non-motor symptoms
Risk Factors
Increasing age
Single most important risk factor
From age 0 to 29, the average annual incidence rate of parkinsonism is 0.8/100,000 person-years
Rates increase incrementally to 304.8/100,000 person-years in those aged 80 to 99 years. [4]
History of familial PD
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure
In the early 1980s this neurotoxin produced acute onset parkinsonism in a group of people exposed inadvertently. [29]
It is rarely found outside of laboratory models, and therefore poses minimal risk to populations at large
Other weak risk factors:
Chronic exposure to metals (manganese, iron)
Male gender
Additional genetic risk factors
Head trauma
Geographic influence
Toxin exposure
Occupation as a teacher, healthcare provider, construction worker, carpenter, or cleaner
Differential diagnosis
Progressive supranuclear palsy
Multiple system atrophy (MSA; MSA-A, formerly Shy-Drager syndrome; MSA-P, striatonigral degeneration; MSA-C, olivopontocerebellar atrophy)
Corticobasal degeneration
Alzheimer disease with parkinsonism
Drug-induced parkinsonism
Structural abnormalities
Vascular parkinsonism
Toxin exposure
Infections
Hereditary disorders
Epidemiology
PD is one of the most common neurodegenerative disorders
Western countries' average annual incidence ranges from 4.9 in Sardinia, to 25.6 per 100,000 person-years in parts of the US. [4] [5]
The overall prevalence in the US is estimated at 329/100,000. [6]
The mean age of onset is about 65 years.
Cases occurring in ages 21 to 40 years are considered young onset PD
Those younger than 21 have juvenile parkinsonism. [7]
From ages 0 to 29, the average annual incidence rate of parkinsonism is 0.8/100,000 person-years
Rates increase incrementally to 304.8/100,000 person-years in those aged 80 to 99 years. [4]
Although some studies show a greater prevalence of disease among men, other studies have not shown a clear gender difference. [4] [8] [9] [10]
Some studies show evidence of reduced risk in people with darker skin, but a review showed no consistent difference. [5] [11]
Aetiology
Aetiology is unknown, although several factors have been implicated.
There is probably a genetic predisposition with subsequent environmental factors/exposures contributing to the evolution of clinical disease.
Within this multifactorial model, age is the only undisputed risk factor.
Generally, this is considered a sporadic disorder, with twin studies not clearly showing a genetic basis in those older than 50 years. [12]
Environmental factors are likely involved in the pathogenesis.
Neurotoxic mechanisms have been proposed
Substances such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause selective damage to dopaminergic neurons in the nigrostriatal pathway
By means of mitochondrial poisoning of complex I
Heavy metal exposure also has been implicated as a cause.
Oxidative stress likely has a role in neuronal loss.
The conversion of dopamine into free radicals by numerous mechanisms may contribute to selective substantia nigral damage.
Mitochondrial defects, deficiency of neurotrophic factors, programmed cell death (apoptosis), immune system activation, and infection have all also been implicated
Clinical features
Presence of risk factors
Resting tremor
A 4 to 6 Hz tremor is noted at rest and dissipates with use of the limbs.
A chin tremor may occur as well.
With more advanced disease, this tremor may re-emerge when the arms are outstretched
Bradykinesia
Slowness of movements, delay in initiating movements, and freezing of gait are eventually seen in all patients.
Required sign for many diagnostic criteria. [46]
Rigidity
Hypertonicity defined as unvarying increased resistance within the range of passive movement about a joint. [47]
If tremor is also present, cogwheeling will be noted
Postural instability
Imbalance or falling noted with pull test or spontaneously; retropulsion.
Masked facies
Loss of spontaneous facial movement and expressivity, often noted only by spouse
Hypophonia
Reduced volume of voice
Hypokinetic dysarthria
Related to bradykinesia and rigidity of orobuccolingual and laryngeal musculature
Micrographia
Decrease in amplitude of handwriting/printing
Stooped posture
Related to rigidity
Shuffled gait
Related to rigidity and bradykinesia
Conjugate gaze disorders
Saccadic pursuit and hypometric saccades
Fatigue
Disabling symptom reported commonly
Constipation
Reflection of autonomic dysfunction
Depression
Common neuropsychiatric complaint
Should be sought in patients
Dementia
Non-motor symptom that should be screened for at consultations
Exposure to neuroleptics or antiemetics
Dopamine blocking agents may induce a secondary parkinsonism
Features of atypical parkinsonism
Acute onset
Rapidly progressive disease
Cognitive impairment
Prominent postural instability
Severe autonomic dysfunction
Significant neuropsychiatric features (i.e., hallucinations, fluctuating levels of arousal)
Pathophysiology
The underlying pathophysiology is unknown
Selective loss of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) occurs with findings of intracytoplasmic eosinophilic inclusions (Lewy bodies) and neurites, both of which are composed of the protein synuclein
Loss of striatal dopaminergic output within the circuitry of the basal ganglia (BG) accounts for the constellation of motor symptoms
It is believed that decreased activity of the direct pathway and increased activity of the indirect pathway cause increased inhibitory activity from the globus pallidus internus (GPi)/substantia nigra zona reticulata to the thalamus, and therefore reduced output to the cortex. [17]
Bradykinesia, the most characteristic symptom of BG dysfunction, [18] correlates with dopamine deficiency, as evidenced by reduced striatal fluorodopa update measure by PET scans. [19]
It is the result of excessive stimulation of the subthalamic nucleus (STN) and the GPi. [20]
The resulting slowness and delay initiating movement lead to symptoms including loss of dexterity, drooling, monotonous voice, loss of facial expression, and reduced arm swing.
The pathophysiology of rigidity is not well understood, but enhancement of long latency stretch reflexes is a generally accepted hypothesis. [21]
Postural instability is due to loss and/or dysfunction of postural righting reflexes. [22]
No definitive cause of the resting tremor (4 to 6 Hz) is known.
Research suggests that synuclein pathology may actually begin in the lower brainstem (dorsal motor nucleus of the vagus in the medulla oblongata) and progress in a predictable caudal to rostral pattern. [26]
There is also evidence that pathology may begin distally in the enteric and peripheral autonomic nervous systems. [27] [28]
Investigations
Dopaminergic agent trial
Improvement in symptoms
Sensitivity of 70.9%; specificity of 81.4%
Olfactory testing
Hyposmia or anosmia
MRI brain
Normal image in most patients with idiopathic PD
Age-related changes such as mild small vessel disease acceptable
Similarly acceptable if patient has appropriate history to explain other abnormalities (i.e., stroke, trauma)
In advanced disease with dementia, may see cortical atrophy
Genetic testing
Specific mutation would be identified
Neuropsychometric testing
Executive dysfunction can occur in PD with dementia
Serum ceruloplasmin
Low in Wilson's disease, which must be excluded
24-hour urine copper
Elevated in Wilson's disease, which must be excluded
Brain biopsy (postmortem)
Nigrostriatal degeneration and Lewy bodies
Functional neuroimaging
Decreased basal ganglia dopamine uptake using either positron emission tomography (PET) or single photon emission tomography (SPECT)
Sonography, basal ganglia
Hyperechogenicity of substantia nigra
Cardiac sympathetic innervation using iodine-123 meta-iodobenzylguanidine (MIBG)
Decreased heart to mediastinum average count ratio
Management
a) conservative
Treatment is symptomatic as no curative or disease-modifying agents are available.
Treatment is designed to supplement depleted dopamine stores in the substantia nigra, thus minimising or eliminating symptoms and improving quality of life. [61]
Initiation of treatment is based on severity of symptoms.
Patients with mild disease may elect to postpone treatment until disability occurs.
Research is underway to develop agents that slow disease progression, reverse neuronal loss, and even prevent neuronal loss by identifying at-risk patient groups and administering neuroprotective agents
b) medical
Levodopa is considered the definitive treatment, and research suggests that it does not appear to accelerate disease progression. [62]
However, due to the increased risk of developing dyskinesias, other dopaminergic medications should be considered when initiating treatment, particularly in younger patients.
First-line treatment for mild symptoms in any age group can vary, [61] but a reasonable starting point for mild symptoms would be a trial of a monoamine oxidase-B (MAO-B) inhibitor
These agents have modest symptomatic benefit, and rasagiline was shown to have possible disease-modifying effects, with smaller increase in UPDRS scores in those patients started earlier on this treatment. [64]
However, no treatment has been shown to be neuroprotective. [62]
If MAO-B inhibitors are ineffective, a dopamine agonist or carbidopa/levodopa may be instituted adjunctively.
Adverse effects are monitored and can limit usage, particularly in older people.
Either carbidopa/levodopa or dopamine agonists are also effective first-line treatment options
Ergot derivatives
Non-ergot derivatives
Can be used at a later stage to reduce L-DOPA side-effects
Patients who do not respond to dopaminergic agents are unlikely to have idiopathic PD. [61]
Anticholinergic agents may also be effective in treating mild symptoms, but adverse effects often limit their use
Amantadine
c) surgical
n/a
Prognosis
This is a neurodegenerative disease with no cure or disease-modifying agents.
Therefore, the course is progressive.
Unilateral symptoms ultimately become bilateral.
Rates of progression vary between patients, but the typical course is as follows:
A period of 2 to 3 years when treatment with dopaminergic agents results in resolution of symptoms.
After 5 years of levodopa treatment, motor complications develop
Eventually after a number of years, the emergence of symptoms such as freezing, falling, and dementia, which do not respond to levodopa, cause significant disability.
The disease course varies between patients, with many living a normal life span.
Young patients may accumulate sufficient disability to lead to an early death.
Certain features can predict a slower progression, such as tremor predominance. [43]
Factors to predict more rapid rate of progression: [43]
Older age at symptom onset
Rigidity/hypokinesia as presenting symptoms (versus rest tremor)
Associated co-morbidities
Presentation with rigidity and bradykinesia
Decreased response to dopaminergic medications.