- Clinical science
Parkinson disease (PD) is a neurodegenerative disease involving a progressive depletion of dopaminergic neurons in the basal ganglia, particularly the substantia nigra. PD usually manifests at approximately 60 years of age. Although PD is considered an idiopathic disease, genetic factors seem to play a role in about 10–15% of cases and, accordingly, familial clustering has been observed. The typical clinical picture seen in PD is called parkinsonism and features the classical cardinal symptom of bradykinesia along with resting tremor and/or rigidity. Postural instability is another frequent finding. While PD is the main cause, parkinsonism may also result from other factors, e.g., medication (secondary parkinsonism). Atypical parkinsonism may appear similar to PD, but often features additional or atypical symptoms. To date, there is no cure for PD. Symptomatic treatment includes physical therapy and, depending on patient age and individual symptoms, various medications (e.g., levodopa, dopamine agonists). In specific cases, deep brain stimulation (DBS) surgery may be beneficial.
- Parkinsonism is a syndrome featuring bradykinesia and either resting tremor or rigidity (or both).
- However, research suggests that a constellation of resting tremor, asymmetric movement disorders, and responsiveness to levodopa treatment correlates better with PD-specific neuropathological changes than classic parkinsonism.
- Secondary parkinsonism: parkinsonism with secondary causes such as medication, intoxication, and head trauma
- Atypical parkinsonism: parkinsonism that occurs as a feature of neurodegenerative diseases other than Parkinson disease; , usually due to different or more extensive neuropathological changes and featuring additional or uncommon symptoms (e.g., early-onset postural instability). Disorders featuring atypical parkinsonism are termed .
- Parkinson disease: parkinsonism for which no cause can be determined (idiopathic)
- Sex: ♀ ≅ ♂
- Prevalence: increases with age (up to ∼ 1,600/100,000 in patients 70–79 years old)
- Age of onset: ∼ 60 years
- Risk factors
Epidemiological data refers to the US, unless otherwise specified.
- Parkinson disease: PD is commonly considered idiopathic, although several etiologic factors (e.g., genetic predisposition) are being investigated.
Secondary parkinsonism (pseudoparkinsonism)
Medication (drug-induced parkinsonism or “pseudoparkinsonism”)
- Most frequent cause of secondary parkinsonism
- Frequently used drugs with considerable anti-dopaminergic effects: typical antipsychotics (e.g., haloperidol), some antiemetics (e.g., metoclopramide), some calcium channel blockers (e.g., flunarizine, amiodarone), valproate, and lithium
- MPTP: Illegal drug, metabolized to MPP+, damages substantia nigra
- Metabolic disorders: e.g.,
- Toxins: e.g., manganese, carbon monoxide, carbon disulfide
- Cerebrovascular disease (vascular parkinsonism): e.g., subcortical arteriosclerotic encephalopathy
- CNS infections:
- Medication (drug-induced parkinsonism or “pseudoparkinsonism”)
- depends on the underlying disease (e.g., genetic abnormalities in ) :
- Earlier disease onset type: onset < 55 years
- Tremor dominant type: onset ≥ 55 years with tremor as sole initial (or generally predominating) symptom
- Non-tremor dominant type: onset ≥ 55 years with predominating bradykinesia/rigidity
- Rapid disease progression without dementia type: rapid progression of motor symptoms and death within 10 years
- Progressive dopaminergic neuron degeneration in the substantia nigra (part of the basal ganglia) and the locus coeruleus → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of PD. Neuromelanin-containing neurons are at particular risk of degeneration, and depigmentation suggests a progressive stage of the disease.
- A further pathological hallmark of PD is the appearance of Lewy bodies (hyaline eosinophilic globules), which are also seen in ; . Lewy bodies are aggregates of misfolded α-synuclein and other proteins.
- Serotonin and noradrenaline depletion (in the Raphe nuclei): likely cause of depressive symptoms
- Acetylcholine depletion (in the nucleus basalis of Meynert): likely cause of dementia
- Clinical course > 10 years; unilateral onset with persistently asymmetrical course (i.e. unilaterally pronounced symptoms) but may progress to the contralateral side
- Slowness of movement in combination with decreased amplitude or speed during a sequence of movement
- 4–6, rarely up to 9 Hz) (
- Increased and persistent resistance to passive joint movement that is independent of speed of movement
- The patient is asked to perform repetitive movements in the contralateral extremity (e.g., opening and closing of the left fist if the right side is examined) → Subclinical rigidity becomes more pronounced and may be detected.
- Not to be confused with ulnar nerve! in palsy of the
- Special form: cogwheel rigidity
- Imbalance and tendency to fall
- Pull test
- Parkinsonian gait: shuffling gait with quickened and shortened steps
- Unhabituated glabellar reflex
- Signs of dystonia
- Pyramidal signs (but normal tendon reflexes)
- Good response to levodopa
TRAP – Tremor, Rigidity, Akinesia, and Postural instability
Other clinical features
- Freezing : sudden inability to start or continue movements (e.g., while walking)
- Festination: gait pattern characterized by small, increasingly quick steps
- Propulsion: forward-leaning gait with risk of patient falling forward
- Micrographia: size of handwriting is reduced
- Low degree of facial expression (hypomimia), decreased blinking
- Depression, dementia
Parkinsonism is required for the diagnosis of Parkinson disease! Unilateral onset is characteristic of Parkinson disease!
Parkinson disease is a clinical diagnosis!
The Movement Disorder Society (MDS) defines absolute exclusion criteria, red flags, and supportive criteria for the clinical diagnosis of Parkinson disease. Application of the criteria require the observation of parkinsonism as a clinical picture. The criteria distinguish between two levels of diagnostic certainty.
- Absolute exclusion criteria (e.g., downward vertical supranuclear gaze palsy)
- Red flags (e.g., rapid progression of gait impairment)
- Supportive criteria (e.g., good response to dopamine treatment)
Levels of certainty
- Clinically probable PD (absence of absolute exclusion criteria, maximum of two red flags that are balanced by an at least equal number of supportive criteria)
- Clinically established PD (absence of absolute exclusion criteria and red flags, two or more supportive criteria)
Imaging is not routinely required for diagnosis, but should be considered in an atypical presentation or to rule out other underlying disorders.
- Iodobenzamide single-photon emission computed tomography (IBZM-SPECT): measures D2 receptor density in striatum and, in contrast to atypical parkinsonism, usually appears normal in PD or shows increased receptor density
|Differential diagnosis of parkinsonism|
|Parkinson disease (PD)||Secondary parkinsonism|
|Pathophysiology|| || || |
|Clinical features|| |
To confirm specific etiologies:
The differential diagnoses listed here are not exhaustive.
To date, there is no cure for PD. Treatment is aimed at relieving symptoms and should generally begin once patients develop significant functional disability (see ).
- Speech and language therapy
- Occupational therapy
- Support groups
For details on effects, administration, and side effects, see .
is the drug of choice for the symptomatic therapy of Parkinson disease.
- Dopaminergic therapy should be considered at an early stage if motor symptoms begin to substantially affect a patient's activities of daily living. The age of 65 should be considered a general point of reference rather than a fixed limit for beginning levodopa therapy.
- In the early phase; of levodopa treatment, patients may experience a "honeymoon period" with relief of symptoms.
- “On” (parkinsonism is relieved by the levodopa) and “off” (levodopa effect wears off, parkinsonism returns) episodes are another common phenomenon.
- Dopamine agonist in patients under the age of 65
Patients under the age of 65 with no significant comorbidities
- First-line treatment
- Normally combined with a peripheral carbidopa like
- Most effective symptomatic treatment but carries a higher risk of dyskinesias than other medications
- (e.g., )
- NMDA antagonists (e.g., ): used to reduce levodopa-induced dyskinesias
- Anticholinergics/ (, , t): useful in patients < 65 years with tremor as the main complaint
Patients over the age of 65 or multimorbid patients of any age
- First-line treatment: levodopa + decarboxylase inhibitor (carbidopa)
- Second-line treatment
Levodopa is best taken between meals (e.g., 30 minutes before a meal). High protein binding properties are responsible for decreased activity!
Patients with severe motor fluctuation
- DuodopaTM pump
- Deep brain stimulation (see below)
Treatment of associated symptoms
- Depressive moods: SSRIs (e.g., citalopram) or SNRIs (e.g., venlafaxine)
- Dementia: cholinesterase inhibitors (e.g., donepezil)
- Psychotic episodes: atypical neuroleptics (e.g., clozapine)
- Dyskinesias: anticholinergics with CNS effects (e.g., trihexyphenidyl, benztropine)
- Detrusor hyperactivity: anticholinergics without significant CNS effects (e.g., trospium chloride)
- Indication: primarily recommended for patients with severe motor symptoms who respond to levodopa treatment but are not sufficiently controlled by it (or if a decrease in dosage is necessary due to side effects)
- Procedure for DBS
- Sterotactic implantation of a stimulating electrode in the subthalamic nucleus or the globus pallidus (in rare cases, in the thalamus)
- Usually performed bilaterally
- DBS normally does not lead to extensive neuronal damage, and electrodes can be safely removed if necessary.
- The stimulating electrode(s) can be controlled from the outside via a special device.
- Adverse effects
- Related to procedure and material: infections, hemorrhages, breakage or displacement of the electrode(s) or the lead(s)
- Criteria of exclusion: