Pathophysiology of Parkinsonism and Chorea
Parkinsonism: Core Pathophysiological Mechanisms
Parkinsonism results from degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to striatal dopamine deficiency that disrupts the basal ganglia-thalamo-cortical circuit, with symptoms manifesting after approximately 40-50% neuronal loss. 1
Molecular and Cellular Basis
Alpha-synuclein aggregation forms the pathological hallmark, with abnormal cytoplasmic inclusions (Lewy bodies) accumulating in neurons, classifying Parkinson's disease as a synucleinopathy 1
Mitochondrial dysfunction, particularly decreased Complex I activity in the respiratory chain, drives progressive neurodegeneration 1
Dopamine depletion in the corpus striatum is the primary biochemical abnormality underlying motor symptoms, as dopamine normally cannot cross the blood-brain barrier but its precursor levodopa can 2
Circuit-Level Dysfunction
The parkinsonian state shifts basal ganglia activity toward inhibiting cortically generated movements by increasing gain in the globus pallidus externa-subthalamic nucleus-globus pallidus interna network while reducing activity in direct cortico-putaminal-globus pallidus interna projections 3
Abnormal synchronous oscillating neuronal activity within basal ganglia-thalamo-cortical loops generates parkinsonian symptoms, with weakly coupled neural networks producing pathological oscillations 4
The globus pallidus externa emerges as the main regulatory station of output activity in the normal basal ganglia network, with its dysfunction central to parkinsonian pathophysiology 3
Clinical Manifestations
Cardinal motor symptoms include bradykinesia (essential for diagnosis), rigidity, resting tremor (4-6 Hz "pill-rolling"), and postural instability, all resulting from striatal dopamine deficiency 1, 5, 6
Symptoms typically appear 5 years after initial neurodegeneration begins, when 40-50% of dopaminergic neurons have been lost 1, 6
Chorea: Pathophysiological Mechanisms
All forms of chorea, regardless of origin, share a common underlying neural mechanism centered on disordered activity of the subthalamic nucleus within the basal ganglia-thalamo-cortical circuit. 7
Subthalamic Nucleus Dysfunction
Disordered subthalamic nucleus activity is central to generating choreic movements across all etiologies 7
In levodopa-induced dyskinesia (a form of chorea), the putamen is the site of action where dopaminergic agents trigger choreiform movements 7
Physiological inhibition of the subthalamic nucleus occurs through disinhibition of lateral pallidal neurons, which become overactive 7
Mechanism in Dopaminergic Treatment
Long-term exposure of the dopamine-depleted parkinsonian putamen to exogenous dopaminergic agents creates the specific pathophysiological state conducive to chorea 7
Chronic dopaminergic treatment causes preferential inhibition of putaminal neurons projecting specifically to the lateral globus pallidus, leading to disinhibition of lateral pallidal neurons 7
This creates a paradoxical situation where treatment for parkinsonism (dopamine replacement) can induce chorea through circuit-level changes 7
Distinguishing Features from Parkinsonism
Rapid, jerky movements characterize chorea, with higher skewness and kurtosis for velocity compared to parkinsonian dyskinesia 8
Choreic movements show similar randomness and lack of coordination to parkinsonian dyskinesia but with distinct frequency compositions—parkinsonian dyskinesia concentrates more in the 1.0-1.5 Hz range 8
Both conditions involve abnormal basal ganglia-thalamo-cortical circuit function but represent opposite ends of the movement disorder spectrum 9
Drug-Induced Movement Disorders
Tetrabenazine-Induced Parkinsonism
Tetrabenazine, used to treat chorea, can paradoxically cause parkinsonism (bradykinesia, hypertonia, rigidity) by reducing dopaminergic transmission 10
This drug-induced parkinsonism may be difficult to distinguish from disease progression in conditions like Huntington's disease where rigidity develops naturally 10
Levodopa-Induced Dyskinesia
Standard pharmacological treatments fail to restore functional balance between direct and indirect corticostriatal pathways, leading to motor complications including dyskinesia 3
These treatments do not mimic normal dopaminergic system physiology, explaining why motor complications develop despite symptomatic improvement 3
Common Pitfalls in Understanding
Do not confuse the mechanisms: Parkinsonism involves excessive inhibition of movement through basal ganglia output, while chorea involves excessive disinhibition through subthalamic nucleus dysfunction 7, 3
Recognize that treatment-induced dyskinesias can persist even after stopping medication in multisystem degenerations, unlike pure Parkinson's disease where they resolve 11
Understand that peripheral factors play only a minor role in parkinsonian tremor and other signs—the pathophysiology is primarily central nervous system-based within basal ganglia circuits 4