Parkinson disease

Parkinson's 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
  • 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's 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-plus syndromes.
• Parkinson's disease: parkinsonism for which no cause can be determined (idiopathic)

References:^[1][2]

• 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 body dementia.
• 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

References:^[11][1][3]

General

• Clinical course > 10 years; unilateral onset with persistently asymmetrical course (i.e. unilaterally pronounced symptoms) but may progress to the contralateral side
• Parkinsonism
  • Bradykinesia/akinesia
    • Slowness of movement in combination with decreased amplitude or speed during a sequence of movement
    • Bradydiadochokinesia
  • Resting tremor (4–6, rarely up to 9 Hz)
    • Pill-rolling tremor that subsides with voluntary movements, but increases with stress
    • Typical in hands; may involve the legs, jaw, lips, and tongue
  • Rigidity
    • Increased and persistent resistance to passive joint movement that is independent of speed of movement
    • 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.
      • Not to be confused with Froment's sign in palsy of the ulnar nerve!
    • Special form: cogwheel rigidity
• Postural instability
  • 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, Rigor, Akinesia, and Postural instability

Other clinical features

• Early
  • Prodromal PD and/or Lewy body dementia: rapid eye movement sleep behavior disorder (RBD)
  • Sensory
    • Hyposmia or anosmia (potential early symptom )
    • Dysesthesias: muscle and joint pain (often in the shoulder/arm region)
  • Motor: reduced swinging of arms while walking
  • Personality changes: e.g., withdrawal, apathy
• Late
  • Motor
    • 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
  • Autonomic
    • Waxy complexion , dysphagia, constipation , impotence, hypersalivation, orthostatic dysregulation, hyperhidrosis
    • Bladder emptying disorders may emerge as a late symptom
  • Depression, dementia

Parkinsonism is required for the diagnosis of Parkinson's disease! Unilateral onset is characteristic of Parkinson's disease!

References:^{[12][13][14][15][16]}

Parkinson's disease is a clinical diagnosis!

Clinical diagnostic criteria for Parkinson's disease

The Movement Disorder Society (MDS) defines absolute exclusion criteria, red flags, and supportive criteria for the clinical diagnosis of Parkinson's disease. Application of the criteria require the observation of parkinsonism as a clinical picture. The criteria distinguish between two levels of diagnostic certainty.

• Criteria
  • 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)

Pharmacological

Levodopa challenge test: (alternatively apomorphine test): The result is positive if administration of levodopa/apomorphine relieves symptoms.

Imaging

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)
  • Advanced MRI techniques (e.g., diffusion-weighted imaging) allow PD to be distinguished from atypical parkinsonian syndromes in some cases.
• DaTSCAN^TM
  • A radiopharmaceutical (I123 ioflupane) is used to visualize striatal dopamine transporters via single-photon emission computed tomography (SPECT).
  • 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

References:^[14][17][18]

Differential diagnosis of parkinsonism
	Parkinson's disease (PD)	Secondary parkinsonism	Parkinson-plus syndromes
Etiology	Idiopathic Various factors (genetic, environmental, inflammation, immune response, oxidative stress) appear to play a role.	Drug-induced (e.g., haloperidol) Toxin-induced (e.g., exposure to manganese) Metabolic (e.g., Wilson's disease) Structural (e.g., vascular disorders) Normal pressure hydrocephalus (NPH) Infections (e.g., HIV)	Multiple system atrophy (MSA) Dementia with Lewy-bodies (DLB) Corticobasal degeneration (CBS) Progressive supranuclear palsy (PSP)
Pathophysiology	Degeneration of dopaminergic neurons chiefly in the substantia nigra → dopamine deficiency in the striatum → reduced excitatory input to the motor cortex → bradykinesia Serotonin, norepinephrine, and acetylcholine metabolism are also affected → depression, dementia Depigmentation, atrophy, gliosis Lewy bodies	Variable, depends on the cause	MSA Secondary neuronal degeneration as a result of Lewy body deposition in glial cells (and subsequent glial and myelin dysfunction) Particularly in the putamen, the pons, and the cerebellum DLB Cerebral atrophy due to deposition of Lewy bodies, amyloid plaques, and neurofibrillary tangles in neurons Occurs in cortical layers throughout the brain; the frontal and temporal lobes are particularly affected. CBS: asymmetric frontoparietal atrophy and gliosis PSP: neuronal loss and gliosis particularly of the basal ganglia, midline thalamic nuclei and the brainstem
Clinical features	Parkinsonism: bradykinesia plus either resting tremor or rigidity (or both) Postural instability Parkinsonian (shuffling) gait Course: Unilateral onset Progression usually over > 10 years	Parkinsonism: bradykinesia plus either resting tremor or rigidity (or both) Course: variable, depends on the cause	Atypical parkinsonism: Generally poor response to levodopa Dementia, oculomotor dysfunction, and early onset of autononomic dysfunction and gait instability are common. Particular syndromes show further characteristic symptoms. Course: The progression is usually faster and the prognosis is usually worse than in PD.
Additional diagnostic tests	Parkinson's disease is a clinical diagnosis (MDS criteria)! Levodopa challenge test: Symptoms usually improve with levodopa administration. Imaging to rule out other causes MRI DaTSCAN IBZM-SPECT	To confirm specific etiologies: Laboratory: drugs, toxins, infections, metabolic disorders Imaging: NPH, vascular disorders, tumors	May be distinguished from PD with the help of the clinical picture or via the levodopa challenge test and/or imaging studies (see the additional diagnostic tests for PD on the left). Distinction from Alzheimer's disease MSA: dementia is possible, but not common DLB: frequent visual hallucinations CBS: cortical atrophy more pronounced in supplementary motor area and superior frontal gyrus PSP: dementia usually only in later stages

References:^[19]

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 Parkinson's disease medication).

General measures

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

Medical therapy

For details on effects, administration and side effects, see medication for Parkinson's disease.

• Levodopa is the drug of choice for the symptomatic therapy of Parkinson's 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
  • Non-ergot 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)
  • NMDA antagonists (e.g., amantadine): used to reduce levodopa-induced dyskinesias
  • Anticholinergics/muscarinic antagonists (biperiden, benztropine, trihexyphenidyl): useful in patients < 65 years with tremor as the main complaint

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

Patients over the age of 65 or multimorbid patients of any age

• First-line treatment: levodopa + decarboxylase inhibitor (carbidopa)
• Second-line treatment
  • Jejunal levodopa infusion
  • Parenteral apomorphine administration

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

• Duodopa^TM 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)

Deep brain stimulation (DBS)

• 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.
• Effects
  • Only ameliorates symptoms that respond to levodopa therapy (e.g., tremor)
  • Can reduce necessary medication significantly.
  • In some patients, the effects of DBS are more beneficial than pharmacotherapy.
• Adverse effects
  • Related to procedure and material: infections, hemorrhages, breakage or displacement of the electrode(s) or the lead(s)
• Criteria of exclusion:
  • Presence of motor symptoms that do not respond to levodopa therapy (e.g., postural instability, speech disorders)
  • Presence of significant comorbidities, including mental health problems (e.g., depression)

References:^{[13][1][10][20][21][22][23][24][25][26]}