Parkinson disease

Parkinson disease (PD) is a neurodegenerative condition that involves the progressive depletion of dopaminergic neurons in the basal ganglia, particularly the substantia nigra. The disease most commonly manifests at approx. 60 years of age. Although PD is considered an idiopathic disease, genetic factors play a role in about 10–15% of cases and, accordingly, familial clustering has been observed. A core clinical feature of PD is parkinsonism, a syndrome that comprises bradykinesia along with resting tremor and/or rigidity. Postural instability is another frequent finding in PD. Parkinsonism that results from medication, intoxication, or head trauma is referred to as secondary parkinsonism. Parkinsonism due to neurodegenerative disorders other than PD is considered atypical parkinsonism, which manifests with features that are not characteristic of PD such as vertical gaze palsy in progressive supranuclear palsy, and apraxia and agnosia in corticobasal degeneration. There is currently 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 surgery may be beneficial.

• Prevalence: second most common neurodegenerative disorder following Alzheimer disease ^[1]
• Age of onset: ∼ 60 years in sporadic cases ^[2]
• Risk factors
  • Genetic factors: 10–15% of all cases are familial. ^[3]
  • Environmental factors (e.g., exposure to manganese and other substances)
  • Diet/metabolism (e.g., low levels of vitamin D, high iron intake, obesity)
  • History of traumatic brain injury

Epidemiological data refers to the US, unless otherwise specified.

Parkinson disease

• Idiopathic
• Contributing genetic factors include:
  • α-Synuclein (SNCA)
  • Glucocerebrosidase (GBA): A mutation in the GBA gene (the same gene associated with Gaucher disease) is the most common genetic risk factor for PD. GBA mutations are associated with altered autophagy and lysosomal function, potentially resulting in impairment of α-synuclein clearance.
  • Dardarin (LRRK2): A mutation in LRRK2 gene is the most common cause of dominantly inherited PD.
  • Parkin (PARK2): A mutation in PARK2 gene is the most common cause of recessively inherited PD.

Secondary parkinsonism

• Medication (drug-induced parkinsonism or pseudoparkinsonism)
  • Most frequent cause of secondary parkinsonism ^[3]
  • Frequent use of drugs with considerable antidopaminergic effects: typical antipsychotics (e.g., haloperidol), some antiemetics (e.g., metoclopramide), some calcium channel blockers (e.g., flunarizine), amiodarone, valproate, and lithium ^[3][4]
  • MPTP: an illegal drug that metabolizes to MPP⁺, damaging the substantia nigra
• Metabolic disorders: e.g., Wilson disease, hemochromatosis, Niemann-Pick disease
• Toxins: e.g., manganese, carbon monoxide, carbon disulfide
• Cerebrovascular disease (vascular parkinsonism): subcortical arteriosclerotic encephalopathy
• CNS infections
  • Viruses: e.g., herpes simplex virus, human immunodeficiency virus
  • Bacteria: e.g., Treponema pallidum, Mycobacterium tuberculosis
  • Protozoa: e.g., Toxoplasma gondii, Plasmodium spp.
  • Prion agents: Creutzfeldt-Jakob disease
• Atypical parkinsonism: depends on the underlying disease (e.g., genetic abnormalities in Huntington disease)

• 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 ^[5]
• Indirect pathway of the basal ganglia is affected (see “Basal ganglia” in “The cerebral cortex, meninges, basal ganglia, and ventricular system”)
• Serotonin and noradrenaline depletion (in the raphe nuclei): likely cause of depressive symptoms
• Acetylcholine surplus (in the nucleus basalis of Meynert): likely cause of dyskinesia

References:^[3][5]

Overview

• Signs of PD gradually progress over time: The course is usually > 10 years.
• Motor signs are unilateral at onset but may progress to the contralateral side.
• Motor signs are asymmetrical (i.e., more pronounced on one side than on another).
• Preclinical (prodromal) stage with nonmotor signs may precede the onset of motor signs (clinical phase).

Preclinical stage ^[6]

• Constipation
• Anosmia
• Sleep disturbances
  • REM sleep behavior disorder
  • Restless leg syndrome
  • Excessive daytime sleepiness
• Mood disorders (most commonly depression, apathy, and/or anxiety)

Clinical stage

Motor signs ^[7]

• Parkinsonism: a triad of signs (bradykinesia, rigidity, and resting tremor) that is consistent with impairment of the extrapyramidal system
  • A core feature of PD
  • Can be also seen in a variety of other disorders, e.g. multiple system atrophy, corticobasal degeneration (see “Atypical parkinsonism”)
  • Bradykinesia: slowed movements in combination with decreased amplitude/speed when moving
  • Resting tremor (4–6 Hz)
    • Pill-rolling tremor that subsides with voluntary movements but increases with stress
    • Most common in the hands but may involve the legs, jaw, lips, and tongue
  • Rigidity: increased and persistent resistance to passive joint movement that is independent of speed
    • Froment maneuver: 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.
    • Cogwheel rigidity
      • A phenomenon caused by the overlay of increased muscle tonus and resting tremor in PD patients.
      • It may manifest before tremor becomes clinically apparent.
      • Muscles in an extremity (most commonly the arms) are passively stretched, eliciting a jerking-like motion.
      • Muscle tone should be tested with at least two joints.
• Postural instability
  • Imbalance and tendency to fall
  • Evaluated with the pull test
• Gait abnormalities
  • Parkinsonian gait: shuffling gait with quickened and shortened steps
  • Freezing: sudden inability to start or continue movements
  • Festination: gait pattern characterized by small, increasingly quick steps
  • Propulsion: forward-leaning gait with a risk of a patient falling forward
  • Decreased arm swing
• Other motor findings
  • Unhabituated glabellar reflex
  • Signs of dystonia
  • Stooped posture
  • Abnormal flexor posturing of hands and feet (i.e., striatal deformities)
  • Micrographia: size of handwriting is reduced
  • Hypomimia: low degree of facial expression

Parkinsonism is required for the diagnosis of Parkinson disease. Unilateral onset is characteristic of Parkinson disease.

Parkinsonism TRAPs the patient: Tremor, Rigidity, Akinesia, and Postural instability.

Nonmotor signs

• Autonomic symptoms
  • Orthostatic hypotension
  • Oily skin
  • Urinary urgency
  • Impaired sexual function
• Neuropsychiatric symptoms
  • Depression
  • Cognitive problems, e.g., decreased attention and concentration, executive dysfunction, impaired memory (Parkinson dementia): develop in advanced disease ^[5]
  • Apathy
  • Behavioral changes (e.g., irritability, impulsivity)
• Disordered sleep (sleep fragmentation, vivid dreams)
• Fatigue
• Hyposmia, anosmia

Approach

• PD diagnosis is based on the presence of typical parkinsonian features (see “Clinical features” above).
• Criteria from the Movement Disorder Society criteria, such as absolute exclusion criteria, red flags, and supportive criteria, can be used to facilitate the diagnosis. ^[8]
• Additional tests, including imaging, are not routinely required for diagnosis but should be considered in an atypical presentation or to rule out other underlying disorders.
• Definitive diagnosis can only be made upon postmortem examination showing the typical Lewy pathology (see “Pathology” below).

Parkinson disease is a clinical diagnosis.

Clinical diagnostic criteria for Parkinson disease

• Diagnostic certainty: The criteria distinguish between two levels of diagnostic certainty.
  • Clinically probable PD: a maximum of two red flags (balanced by an at least equal number of supportive criteria) plus the absence of absolute exclusion criteria
  • Clinically established PD: two or more supportive criteria plus the absence of both red flags and absolute exclusion criteria
• Supportive criteria
  • Clear response to dopaminergic therapy (i.e., improvement with dose increase and worsening with dose decrease and/or presence of on/off fluctuations)
    • Levodopa challenge test: The result is positive if the administration of levodopa relieves symptoms.
  • Levodopa-induced dyskinesia
  • Resting tremor of a limb
  • The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy
• Absolute exclusion criteria
  • Cerebellar abnormalities, including oculomotor dysfunction (e.g., cerebellar gait, limb ataxia, gaze-evoked nystagmus, hypermetric saccades)
  • Downward vertical supranuclear gaze palsy or selective slowing of downward vertical saccades
  • Diagnosis of probable frontotemporal dementia in the first 5 years of the disease
  • Parkinsonian features restricted to the lower limbs for > 3 years
  • Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism
  • Absence of observable response to high-dose levodopa despite at least moderate severity of the disease
  • Unequivocal cortical sensory loss (i.e., graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia
  • Normal functional neuroimaging of the presynaptic dopaminergic system
  • Potential alternative condition associated with parkinsonism and plausibly connected to the patient's symptoms.
• Red flags
  • Rapid progression of gait impairment that eventually requires frequent use of a wheelchair
  • Stability of motor symptoms or signs for ≥ 5 years
  • Early severe bulbar dysfunction in the first 5 years of disease (e.g., dysphonia, dysarthria, dysphagia)
  • Inspiratory dysfunction (e.g., inspiratory stridor, dyspnea)
  • Early severe autonomic dysfunction in the first 5 years of disease (e.g., orthostatic hypotension, urinary incontinence)
  • Recurrent falls because of impaired balance in the first 3 years of disease
  • Severe dystonia in the first 10 years of disease (e.g., disproportionate anterocollis, orofacial dystonia)
  • Absence of common nonmotor symptoms in the first 5 years of disease (e.g., sleep dysfunction, autonomic dysfunction, hyposmia, neuropsychiatric symptoms)
  • Otherwise unexplained pyramidal tract signs (excluding brisk reflexes in affected limbs and isolated extensor plantar response)
  • Bilateral symmetric parkinsonism

Imaging ^[9][10]

Imaging is not routinely required for diagnosis but should be considered in an atypical presentation or to rule out other underlying disorders.

• MRI
  • Conventional MRI is usually used to rule out other possible causes of parkinsonism (e.g., strokes, tumors)
  • In some cases, advanced MRI techniques (e.g., diffusion-weighted imaging) allow PD to be distinguished from atypical parkinsonian syndromes.
• DaTSCAN
  • A radiopharmaceutical (I123 ioflupane) is used to visualize striatal dopamine transporters via single-photon emission computed tomography.
  • Indicated as a means of differentiating between parkinsonian tremor and essential tremor
• 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

• Lewy bodies
  • Aggregates of misfolded α-synuclein and other proteins, such as ubiquitin and neurofilament protein within the neural cell bodies
  • Appear histologically as intracellular hyaline eosinophilic globules
  • May be found in brainstem, substantia nigra, and cortex ^[6]
  • Also seen in Lewy body dementia
• Loss of dopaminergic neurons in substantia nigra pars compacta, causing depigmentation of substantia nigra on gross and microscopic examination
• Reactive gliosis is found within the areas of neural degeneration. ^[5]

The differential diagnoses listed here are not exhaustive.

General measures

• Physiotherapy
• Speech and language therapy
• Occupational therapy
• Support groups

Medical therapy

Approach

For details on therapeutic effects, administration, and side effects, see “Medication for Parkinson disease.”

• Drug classes for initial treatment of motor symptoms in Parkinson disease include nonergot dopamine agonists, MAO-B inhibitors, and levodopa combined with carbidopa.
• Although levodopa is the most effective drug for the management of motor symptoms in Parkinson disease, its use is associated with unavoidable motor complications.
  • There is usually a dramatic beneficial effect of levodopa in the early phase of treatment ("honeymoon period").
  • All patients treated with levodopa eventually develop drug-related motor fluctuations (see “Side effects” in “Medication for Parkinson disease”).
• Since levodopa is associated with inevitable motor complications that require treatment modification, younger (< 65 years) patients might benefit from initial treatment with dopamine agonists.

Overstimulation of D2-receptors by levodopa or dopamine agonists may induce psychosis and hallucinations, especially in elderly patients with concurrent dementia or other psychiatric disorders.

Levodopa can increase intraocular pressure, therefore it is not recommended in patients with glaucoma.

Patients < 65 years with no significant comorbidities

• First-line treatment
  • Nonergot dopamine agonists (e.g., pramipexole, ropinirole, apomorphine): as monotherapy or in combination with levodopa/carbidopa
  • MAO-B inhibitors (e.g., selegiline): may be used as a monotherapy or in combination with dopamine agonists or levodopa/carbidopa
  • COMT inhibitors (e.g., entacapone): in combination with levodopa/carbidopa
• Alternatives
  • Levodopa
    • Normally combined with a peripheral decarboxylase inhibitor like carbidopa
    • Most effective symptomatic treatment but carries a higher risk of dyskinesias than other medications
  • Ergot dopamine agonists (e.g., bromocriptine): due to significant side effects (e.g., pulmonary fibrosis) have mostly been replaced by nonergot agonists
  • NMDA antagonists (e.g., amantadine): used to reduce levodopa-induced dyskinesias
  • Anticholinergics; /muscarinic antagonists (biperiden, benztropine, trihexyphenidyl)
    • Indicated in
      • Patients < 65 years with tremor as the chief concern and no significant bradykinesia or gait disturbance
      • Patients with advanced disease and persistent tremor despite treatment with levodopa
    • Not recommended in
      • Patients > 65 years
      • Patients with glaucoma

Administration of anticholinergics may worsen existing psychiatric symptoms (particularly dementia). There is also a risk of ischuria.

Patients > 65 years or multimorbid patients of any age

• First-line treatment: levodopa PLUS decarboxylase inhibitor (carbidopa)
• Other antiparkinsonian medications are used to control motor fluctuations and dyskinesias

Patients with severe motor fluctuations

• Duodenal levodopa infusion 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, quetiapine, pimavanserin) ^[15]
• Dyskinesias: anticholinergics with CNS effects (e.g., trihexyphenidyl, benztropine)
• Detrusor hyperactivity: anticholinergics without significant CNS effects (e.g., trospium chloride)

Deep brain stimulation (DBS) ^[16]

• 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) ^[16][17]
• Targets: subthalamic nucleus or internal globus pallidus
• Adverse effects: infections, hemorrhages, breakage or displacement of electrodes or the leads