PD is a progressive neurodegenerative disorder resulting from the loss of dopamine-producing neurons. The physical symptoms—tremor, muscle rigidity, slowness of movement (bradykinesia), and difficulty with balance—are collectively known as parkinsonism. While PD is the most common cause, a diagnosis of parkinsonism does not automatically confirm PD. Many other conditions mimic these motor features by affecting the same brain circuitry, necessitating a careful differential diagnosis. Distinguishing the specific underlying cause is challenging because the initial presentation of several disorders can appear remarkably similar.
Medication Effects
One frequent cause of a Parkinson’s disease-like syndrome is exposure to certain prescription drugs, known as drug-induced parkinsonism (DIP). This occurs because these medications block dopamine receptors, mimicking the dopamine deficiency seen in PD. Antipsychotic medications, designed to modulate dopamine pathways, are the most common culprits, along with certain anti-nausea drugs. Symptoms like slowness, stiffness, and gait instability usually emerge acutely or subacutely, often within weeks or months of starting the drug. A distinguishing feature of DIP is that symptoms are frequently symmetrical, affecting both sides of the body equally, unlike the typical unilateral onset of classic PD. The symptoms are often reversible, gradually improving or resolving entirely once the medication is stopped or the dosage is lowered.
Atypical Neurodegenerative Syndromes
Atypical parkinsonian syndromes (APS), or “Parkinson’s-plus” syndromes, are challenging mimics of PD because they involve similar neurodegeneration. These progressive disorders feature additional symptoms and a generally more rapid course than PD.
Multiple System Atrophy (MSA)
MSA is characterized by the accumulation of alpha-synuclein in the brain’s glial cells, unlike PD where it accumulates in neurons. MSA typically presents with early and severe failure of the autonomic nervous system, leading to prominent symptoms such as urinary incontinence and orthostatic hypotension (a sudden drop in blood pressure upon standing). Patients with MSA show a poor or transient response to levodopa and experience faster disease progression than those with classic PD.
Progressive Supranuclear Palsy (PSP)
PSP is marked by the accumulation of the tau protein. A hallmark of PSP is an inability to move the eyes vertically, particularly downward, which is uncommon in PD. People with PSP also experience balance problems and falls very early in the disease, often falling backward due to axial rigidity. PSP shows minimal or no benefit from levodopa therapy.
Corticobasal Syndrome (CBS)
CBS is a tau-related disorder that often presents with markedly asymmetrical symptoms. CBS is associated with apraxia—the inability to perform familiar, purposeful movements. Affected limbs may also exhibit dystonia (painful, sustained muscle contraction) or the “alien limb phenomenon,” where the limb seems to act on its own.
Lewy Body Dementia (LBD)
LBD shares the same alpha-synuclein pathology as PD. The distinguishing factor is the timing of cognitive decline. In LBD, significant cognitive issues, fluctuating alertness, and recurrent visual hallucinations occur before or at the same time as motor symptoms. In contrast, dementia in PD typically develops only after motor symptoms have been present for many years.
Structural and Vascular Causes
Some forms of parkinsonism are caused by physical damage rather than a progressive proteinopathy. Vascular Parkinsonism (VaP) results from multiple small strokes that damage subcortical areas controlling movement. VaP is sometimes called lower body parkinsonism because symptoms—gait difficulty, freezing, and balance issues—predominantly affect the legs. VaP often presents with an abrupt onset or a stepwise progression, unlike the gradual onset of PD. The tremor associated with VaP is often absent or less pronounced, and the condition generally does not respond to levodopa treatment.
Normal Pressure Hydrocephalus (NPH) is another mechanical issue, involving the accumulation of excess cerebrospinal fluid in the brain’s ventricles. The classic triad of NPH symptoms includes a magnetic or shuffling gait disturbance, cognitive impairment, and urinary incontinence. The gait problem can resemble parkinsonism, but the full symptom triad helps differentiate NPH from PD. NPH is one of the few causes of parkinsonism treatable with the surgical placement of a shunt to drain the excess fluid.
Other Neurological Conditions That Cause Overlap
Other neurological disorders can be mistaken for PD because they share one or two prominent motor symptoms. Essential Tremor (ET) is the most common movement disorder, characterized by shaking. The ET tremor is an action tremor, most apparent when the person is actively using the limb (e.g., writing or eating). Conversely, the PD tremor is typically a resting tremor, noticeable when the hand is at rest and subsides upon movement. Unlike PD, ET does not cause the bradykinesia, rigidity, or severe postural instability characteristic of parkinsonism.
Dystonia is a movement disorder characterized by sustained or repetitive muscle contractions causing twisting and abnormal postures. While dystonia can occur in PD, it can also be a primary disorder mistaken for parkinsonism rigidity. In primary dystonia, muscle spasms are the main feature, without the accompanying slowness of movement seen in PD. Finally, rare metabolic or toxic exposures, such as prolonged contact with heavy metals like manganese, can damage the brain’s movement centers, resulting in parkinsonism.