Can you explain Parkinson disease, including its clinical features, diagnosis, and treatment options?

Parkinson's Disease: Clinical Overview

Definition and Pathophysiology

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra, characterized by the cardinal motor features of bradykinesia plus either resting tremor, rigidity, or both. 1, 2

• PD is the most common form of parkinsonism, affecting more than 6 million individuals worldwide, with peak onset between 60-70 years of age 1, 2
• The disease is a synucleinopathy—neuronal deposits of Lewy bodies (composed predominantly of alpha-synuclein and ubiquitin) accumulate in specific brain regions 1, 3
• Clinical symptoms appear only after approximately 40-50% of dopaminergic neurons in the substantia nigra have been lost, typically about 5 years after neurodegeneration begins 1, 3
• The pathological progression follows a predictable pattern: Lewy bodies initially deposit in the medulla oblongata, pontine tegmentum, and olfactory system, then involve the substantia nigra (corresponding to motor symptom onset), and finally spread to the cortex 1

Clinical Features

Motor Symptoms (Cardinal Features)

Bradykinesia is the essential diagnostic feature and must be present, accompanied by at least one of the following: 4, 2

• Resting tremor - typically begins unilaterally and spreads to the contralateral side as disease progresses 1, 5

• Rigidity - constant resistance throughout passive range of motion (lead-pipe rigidity), often with cogwheel phenomenon when combined with tremor 4, 5

• Postural instability - appears later in disease progression and contributes to falls 1, 5

• Bradykinesia affects all voluntary movements including fine motor tasks (buttoning clothes, writing), gross motor activities (walking, turning), facial expressions, and speech 4

• The disease typically begins asymmetrically, affecting one side of the body before spreading to involve the other 5

• Additional motor features include flexed posture, "freezing" episodes, and loss of postural reflexes 5

Non-Motor Symptoms

• Prodromal features (may precede motor symptoms): rapid eye movement sleep behavior disorder, hyposmia (reduced sense of smell), constipation 2, 6
• Neuropsychiatric symptoms: depression, anxiety, anhedonia, lack of novelty-seeking behavior, cognitive decline, and dementia 2, 6
• Autonomic dysfunction: including various regulatory impairments 1
• These non-motor symptoms may be related to defective adult neurogenesis in the subventricular zone and hippocampus 6

Diagnosis

Clinical Diagnosis

The diagnosis of PD is primarily clinical, based on history and neurological examination demonstrating bradykinesia with tremor, rigidity, or both. 4, 2

• A general neurologist or movement disorder specialist should confirm the diagnosis, as correctly diagnosing parkinsonian syndromes on clinical features alone is quite challenging 4
• Look for prodromal features in the history: REM sleep behavior disorder, loss of smell, and constipation 2
• Examine for characteristic asymmetric onset and progression of motor symptoms 5

Diagnostic Imaging

When clinical presentation is unclear, obtain MRI brain without contrast first, followed by I-123 ioflupane SPECT/CT (DaTscan) if the diagnosis remains uncertain. 4

• MRI brain without contrast is the optimal initial imaging modality to rule out structural causes, focal lesions, or vascular disease, though it is often normal in early PD 4
• I-123 ioflupane SPECT/CT (DaTscan) is the gold standard nuclear medicine study for differentiating PD from essential tremor or drug-induced tremor 4
  • Shows decreased radiotracer uptake in the striatum, typically progressing from posterior putamen to anterior caudate 4
  • A normal DaTscan essentially excludes parkinsonian syndromes 4
  • Abnormal in neurodegenerative parkinsonian syndromes (PD, MSA, PSP, CBD) but normal in essential tremor and drug-induced parkinsonism 4
  • Cannot differentiate among specific parkinsonian syndromes 4
• FDG-PET/CT has limited utility for initial evaluation but can help differentiate PSP from idiopathic PD by showing characteristic hypometabolism patterns 4
• CT has limited utility due to poor soft-tissue characterization compared to MRI 1

Workup for Early-Onset Parkinsonism (Age < 50)

Before diagnosing idiopathic PD in younger patients, systematically exclude secondary and reversible causes: 4

• Wilson's disease screening (mandatory in patients < 50 years): serum ceruloplasmin, 24-hour urinary copper excretion, slit-lamp examination for Kayser-Fleischer rings 4
• Metabolic screening: thyroid function tests (TSH, free T4), calcium-phosphorus metabolism, blood glucose, serum bilirubin 4
• Structural imaging: MRI brain to exclude vascular disease, structural lesions, hydrocephalus, or basal ganglia calcifications 4

Differential Diagnosis: Red Flags for Atypical Parkinsonism

Certain clinical features suggest diagnoses other than idiopathic PD and warrant consideration of atypical parkinsonian syndromes: 1, 4, 3

• Progressive Supranuclear Palsy (PSP): vertical gaze palsy (especially downward), early falls with axial dystonia, lurching gait, slow saccades 1, 4
• Multiple System Atrophy (MSA): early severe autonomic dysfunction, cerebellar signs (ataxia), pyramidal signs, urinary incontinence 1, 4, 3
  • MSA is also a synucleinopathy but differs from PD in that alpha-synuclein accumulates in oligodendroglia rather than neurons 3
• Corticobasal Degeneration (CBD): asymmetric rigidity with alien limb phenomenon, apraxia, cortical sensory deficits 1, 4
• Vascular parkinsonism: multiple lacunar infarcts, diffuse white-matter disease on MRI 4
• Drug-induced parkinsonism: history of dopamine-blocking medications (antipsychotics, antiemetics) 4, 2

Common Diagnostic Pitfalls

• Skipping structural MRI before ordering functional imaging—always obtain MRI first to exclude alternative diagnoses 4
• Missing atypical parkinsonian syndromes (PSP, MSA, CBD) that have different prognoses and treatment responses 4
• Failing to screen for Wilson's disease in patients under 50 years 4
• Not recognizing drug-induced parkinsonism, which has a normal DaTscan and resolves with medication discontinuation 4

Disease Variants and Prognosis

PD has multiple disease variants with different prognoses: 2

• Mild motor-predominant subtype (49-53% of patients): mild symptoms, good response to dopaminergic medications, slower disease progression 2
• Diffuse malignant subtype (9-16% of patients): prominent early motor and non-motor symptoms, poor medication response, faster disease progression 2
• Intermediate subtype: falls between the above two categories 2

Treatment Overview

Pharmacologic Treatment

Treatment is symptomatic, focused on improving motor and non-motor symptoms; no disease-modifying therapies are currently available. 2

• Dopamine-based therapies (levodopa-carbidopa, dopamine agonists) typically help initial motor symptoms and are the mainstay of treatment 2
• Non-dopaminergic approaches for non-motor symptoms: selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition 2
• Drug-induced parkinsonism (when PD mimics must be treated): anticholinergic or mild dopaminergic agents such as amantadine 4

Advanced Therapies for Complications

Patients experiencing motor complications benefit from advanced treatments: 2

• Deep brain stimulation for medication-resistant tremor, "off periods" (worsening symptoms when medication wears off), and dyskinesias 2
• Levodopa-carbidopa enteral suspension for similar complications 2

Non-Pharmacologic Treatment

• Rehabilitative therapy and exercise complement pharmacologic treatments and are essential components of management 2
• Palliative care is an integral part of PD management throughout the disease course 2

Etiology and Risk Factors

PD is a multifactorial disorder involving interplay among aging, genetic susceptibility, and environmental factors. 7

• Aging is the strongest risk factor—prevalence rises exponentially with age, though most individuals over 80 do not develop PD 7
• Genetics: rare mutations and common variants in genes such as SNCA, LRRK2, and GBA are associated with PD risk, but Mendelian causes account for only 5% of cases; heritability is estimated at 30% 7
• Environmental factors: various toxins and exposures have been studied, but causality is not conclusively established for most 7
• Converging pathways: mitochondrial dysfunction, impaired autophagy, oxidative stress, neuroinflammation, and DOPAL toxicity contribute to dopaminergic neuron loss 7, 8

Assessment and Monitoring

• The Unified Parkinson's Disease Rating Scale (UPDRS) is the standard clinical assessment tool, with the Movement Disorder Society-UPDRS (MDS-UPDRS) providing improved evaluation of non-motor aspects, freezing of gait, and tremor subtypes 4
• Regular monitoring of nutritional and functional status is essential, including body weight, vitamin status, dysphagia screening, and nutritional risk assessment, as 15% of community-dwelling PD patients are malnourished 4