Parkinson Disease

DEFINITION, Etiology, pathogenesisTop

Parkinson disease (PD) is characterized by degeneration of cerebral structures, including subcortical nuclei, of unknown etiology. It involves atrophy of dopaminergic cells in the substantia nigra leading to striatal dopamine depletion as well as variable degeneration of other neurotransmitter systems. Cardinal motor features of PD include bradykinesia (slowness of movement), muscular rigidity (stiffness), resting tremor, gait dysfunction, and postural instability, which are usually accompanied by autonomic or neuropsychiatric disturbances.

The prevalence of PD is ~120 in 100,000, while the annual incidence is 5 to 24 per 100,000. PD occurs more frequently in men than in women, at a ratio of 3:2. The age of onset is usually >50 years, with an average of 60 years. An onset <40 years suggests a genetic cause. Morbidity in individuals >70 years is 10-fold higher than in the general population.

Etiology has not been clearly identified. In most cases it is probably multifactorial and depends on an interaction between a number of genetic and environmental factors, including polymorphic variants and mutations in selected genes. In ~4% of patients PD can be attributed to single-gene mutations (single-gene hereditary autosomal dominant or recessive PD). Most mutant genes in PD encode proteins associated with mitochondrial function.

Neuropathologic findings always include abnormalities in the substantia nigra, with loss of melanized dopaminergic neurons and proliferation of glial cells. The affected regions of the brain contain Lewy bodies, which are intraneuronal cytoplasmic inclusions containing alpha-synuclein and ubiquitin. However, they are not pathognomonic for PD and also occur in other degenerative disorders of the central nervous system, such as dementia with Lewy bodies. The disease progresses gradually and clinical manifestations correlate with neuropathologic changes. Degeneration is not restricted to the substantia nigra; it involves other brain stem structures, including the locus ceruleus through the substantia nigra into the forebrain structures; the amygdala; medial temporal lobes; and other cortical structures. Pathologic changes have also been identified within the peripheral nervous system.

Currently PD is defined as a systemic synucleinopathy with motor (parkinsonian syndrome) and nonmotor manifestations (olfactory, neuropsychiatric, autonomic, sensory, and sleep disturbances).

CLINICAL FEATURESTop

Types of PD:

1) Akinetic-rigid PD.

2) Tremor-dominant PD.

3) Mixed PD.

Signs and symptomsTop

1. Deficits in primary motor automaticity: Hypokinesia or even akinesia (inability to move), development of synkinesia (voluntary muscle movement causing simultaneous involuntary contraction of other muscles), propulsion, and retropulsion (tendency to fall forward or backward).

2. Increased muscle tone.

3. Resting tremor.

4. Other somatic symptoms: Micrographia (abnormally small handwriting), hypophonic speech, olfactory disturbances, dysphagia, limb pain, fatigue, autonomic disturbances (constipation, drooling, facial and scalp seborrhea, episodes of diaphoresis or excessive cold, orthostatic hypotension, erectile dysfunction, urinary dysfunction).

5. Neuropsychiatric disorders: Depression, anxiety, apathy, cognitive impairment, psychosis.

6. Sleep disturbance: Rapid eye movement (REM) sleep behavior disorder, excessive daytime sleepiness.

NATURAL HISTORYTop

PD is progressive, with increasing motor and nonmotor disturbances over the course of ~15 to 20 years. In advanced PD the combination of movement difficulties—with high risk of falls—and neuropsychiatric symptoms leads to severe disability and complete dependence of the patient on caregivers.

DiagnosisTop

Diagnostic Workup

Diagnosis may be challenging, particularly at an early stage of the disease. Nonmotor manifestations, such as mood symptoms, constipation, and REM sleep behavior disorder, may precede motor manifestations.

There are currently no established diagnostic criteria. Clinical diagnosis of PD is still based on identification of cardinal motor symptoms linked to dopamine deficiency in the nigrostriatal system. The most frequently used diagnostic criteria for idiopathic PD are those developed by the United Kingdom Parkinson’s Disease Society Brain Bank (Table 1), with a 3-step diagnostic process. Step 1 involves diagnosis of a parkinsonian syndrome; step 2, exclusion of signs and symptoms not favoring the diagnosis of idiopathic PD; and step 3, demonstration of typical signs and symptoms of PD. Based on these criteria, bradykinesia (typically asymmetric) is a requirement for the diagnosis of PD and an excellent response to levodopa is a supportive feature.

Clinical manifestations can be used to diagnose only possible or probable PD. A definitive diagnosis requires identification of the characteristic neuropathologic features in a postmortem study (loss of neurons in the substantia nigra, presence of Lewy bodies in the substantia nigra, absence of inclusion bodies in oligodendroglial cells).

Other tests, including olfactory testing and transcranial ultrasonography, are very rarely (if ever) done clinically or are reserved for patients with atypical features (magnetic resonance imaging [MRI]). Drug challenge clinical tests are not recommended. Genetic testing is indicated only in selected patients with a positive family history, early age of onset, or both.

In case of diagnostic uncertainty, particularly when attempting to clarify between a neurogenerative parkinsonian condition such as PD and essential tremor, single-photon emission computed tomography (SPECT) with DaTscan (radiolabeled ioflupane with high affinity for dopamine transporters in the presynaptic membrane) may be performed. Decreased expression of presynaptic dopamine transporters, which is typical in PD, is associated with reduced 123I-ioflupane binding in the striatum and manifests as a relatively weaker signal in this area of the brain on SPECT images.

Cardiac scintigraphy with 123I-metaiodobenzylguanidine (123I-MIBG) may also be useful. Cardiac autonomic denervation and reduced MIBG uptake occur in Lewy body diseases. Cardiac scintigraphy facilitates differentiation between PD and other causes of parkinsonism.

Differential Diagnosis

1. Other parkinsonian syndromes: Table 2.

2. Essential tremor.

3. Normal-pressure hydrocephalus.

4. Vascular parkinsonism: Akinesia and muscular rigidity in patients with a history of vascular incidents, frequently with other coexisting neurologic manifestations.

5. Drug-induced parkinsonism.

6. Depression.

7. Dementia.

8. Hemiparesis.

9. Hemisensory syndrome.

TreatmentTop

There is no disease-modifying treatment available to alter the biological course of PD, but symptomatic treatments are used to reduce manifestations of the disease and manage adverse effects of pharmacologic treatments. These include nonpharmacologic techniques, pharmacotherapy, and surgical treatment.

Nonpharmacologic Approach

Patient education, physical therapy and exercise, adequate nutrition and hydration, and participation in mutual support groups for patients with PD.

Pharmacotherapy

Emerging functional impairment or symptom impact on the quality of life are indications for starting symptomatic (dopaminergic) treatment with either levodopa (precursor of dopamine) or a dopamine agonist. Initial treatment with a dopamine agonist may be considered in patients <60 years as, according to some data, it may delay developing dyskinesia (involuntary, unpredictable movements) associated with levodopa treatment. If the response to monotherapy with a dopamine agonist is no longer satisfactory despite using increasing doses, add levodopa. As in older patients the risk of adverse effects of dopamine agonist treatment is higher and early use may not have impact on when dyskinesia may occur after levodopa is started, most patients are started on levodopa from the outset. Dose adjustments over time are expected in PD in order to continue to optimize medication benefit in this progressive condition. Individuals typically begin to report motor complications, including motor fluctuations (fluctuating between “on” time, when symptoms are reasonably controlled, and “off” time, when symptoms recur) and dyskinesia after 3 to 5 years of disease.

In patients treated with levodopa who are experiencing the return of “off” symptoms before each dose is due (ie, “wearing off”), it may be beneficial to add a catechol-O-methyltransferase (COMT) inhibitor or a monoamine oxidase type B (MAO-B) inhibitor, medications that block the degradation of neurotransmitters, including dopamine. Dopamine agonists, COMT inhibitors, and MAO-B inhibitors used as adjunctive therapy to levodopa are more effective than placebo for motor improvement. They also allow for lower levodopa doses, and therefore may mitigate dyskinesia, motor fluctuations, and other adverse effects of long-term levodopa treatment. In some cases with prominent tremor, the use of a nondopaminergic medication, such as a nonselective beta-blocker, or of an anticholinergic medication may be reasonable early in the disease course to postpone the use of the above-mentioned agents.

If the patient does not improve after a treatment is added, the dose or timing of the medication can be slowly increased. If the effect remains minimal despite adjustments, including titration of levodopa up to ~1 g/d, consider alternate diagnoses.

1. Levodopa effectively reduces muscular rigidity and bradykinesia. It also improves the resting tremor of PD, but it may not eliminate it completely or high doses may be necessary to do so. Levodopa is always used in combination with an aromatic L-amino acid peripheral decarboxylase inhibitor (carbidopa or benserazide) to increase dopamine availability in the brain and reduce peripheral adverse effects. The most common adverse effects of levodopa include nausea, orthostatic hypotension, constipation, and dyskinesia (involuntary movements in ~80%-90% of patients after 5-10 years on levodopa treatment). Levodopa treatment often starts at a dose of 50 mg/d. The dose is titrated by 50 mg/d every few days, typically up to 300 to 450 mg/d initially in 3 divided doses, depending on the severity of the patient’s clinical condition. Over time and based on symptom control and medication tolerance, the dose can be increased further to 1200-1500 mg/d (in some cases even higher) in divided doses.

With disease progression (due to progressive loss of endogenous dopamine) the peak benefit of a levodopa dose diminishes and the duration of effect becomes shorter. This leads to the development of motor fluctuations, where individuals fluctuate between “on” and “off” periods. “Off” periods may include both motor (bradykinesia, rigidity, tremor) and nonmotor (anxiety, autonomic, pain) symptoms. In extreme cases patients may develop freezing (inability to move at all). To manage fluctuations, some or all doses of levodopa may be increased, the interval between doses may be shortened, or another agent may be added. An extended-release formulation of levodopa may be added, but due to unreliable pharmacokinetics, it is often reserved for use at bedtime. In advanced PD (specifically in patients with prominent motor fluctuations despite optimized oral medications) a levodopa/carbidopa gel may be administered continuously (~16 h/d), directly into the jejunum, using a percutaneous endoscopic gastrostomy tube.

2. Dopamine agonists are also effective at improving bradykinesia and rigidity, but they usually do not significantly improve tremor. Most dopamine agonists are administered orally according to applicable regimens, minding the different times of action of individual agents (Table 3); rotigotine is administered via a transdermal system. Apomorphine may provide a shorter time to onset of effect and can be used by patients who experience a significant delay in the time to onset of effect of levodopa (eg, upon awakening, between doses of levodopa, if there are dose failures). Apomorphine has recently been developed as a sublingual film and is also available as a subcutaneous injection, both to be used as needed after the effective dose is determined through a monitored titration protocol. A continuous infusion version of apomorphine is also available.

Dopamine agonists are generally less effective than levodopa, but can be used as monotherapy early on to delay the use of levodopa in an effort to postpone the development of dyskinesia in younger patients. Due to potential adverse effects, including orthostatic hypotension and hallucinations, they are often withdrawn in older individuals (patients in their late 70s and early 80s). Other significant potential adverse effects include impulse control disorders (eg, excessive eating, gambling, sexual behaviors, shopping), hypersomnolence with or without sleep attacks, and lower limb edema. Ergot-derived dopamine agonists (bromocriptine, pergolide, cabergoline) also carry a high risk of fibrosis, especially cardiac valvular fibrosis.

3. COMT inhibitors suppress the enzymatic breakdown of levodopa, thus increasing its plasma concentration. They are used exclusively in combination with levodopa.

1) Entacapone 200 mg with each dose of levodopa, up to a maximum of 2000 mg/d.

2) Tolcapone, a peripheral and central inhibitor, usually 300 mg/d in 3 divided doses. This is a peripheral and central inhibitor. It is contraindicated in some parts of the world due to the risk of hepatotoxicity.

Because entacapone increases the plasma concentration of levodopa, it has the potential to aggravate any adverse effects of levodopa, such as dyskinesia and orthostatic hypotension. A small percentage of individuals who use entacapone may experience diarrhea and have to discontinue this medication.

4. MAO-B inhibitors: Similarly to entacapone, selegiline and rasagiline inhibit the breakdown of levodopa and increase its levels in the brain. When used in monotherapy, they may have minor beneficial effects in early PD and delay the need for dopaminergic treatment. In moderate PD, MAO-B inhibitors added to levodopa reduce motor fluctuations associated with levodopa treatment. Selegiline is used at a dose of 5 mg once daily or bid (it should not be used in the evening because of possible sleep disturbances). Rasagiline is used at a dose of 1 mg/d. Concomitant use of MAO-B inhibitors with antidepressants may increase the risk of serotonin syndrome. Citalopram and sertraline at low doses are the preferred agents when taken with a MAO-B inhibitor.

5. Amantadine causes an increased release of endogenous dopamine in dopaminergic neurons and blocks the glutaminergic N-methyl-D-aspartate (NMDA) receptor. It has minor effects on all symptoms of PD but is most often used to manage levodopa-induced dyskinesia. Amantadine is used at a dose of 100 to 400 mg/d and is available as capsules and liquid formulations. Adverse effects include livedo reticularis, anxiety, lower limb edema, and psychotic disturbances.

6. Anticholinergic agents: Trihexyphenidyl is occasionally used at 2 to 12 mg/d in divided doses, mainly in early PD in patients <60 years with tremor as the dominant clinical feature. The use of trihexyphenidyl and biperiden is restricted by a number of contraindications, adverse effects, and drug interactions.

Surgical Management

Surgical management is used for patients with severe tremor inadequately responsive to oral medications, patients with significant motor fluctuations, and those with debilitating dyskinesia. Deep brain stimulation is most common. In this method electrodes are placed in targeted brain areas (thalamus, globus pallidus, or substantia nigra) and connected to an implantable pulse generator under the skin of the chest. Patients are carefully screened based on age and other medical conditions including dementia, active psychiatric disorders, and comorbid diseases. New and advanced treatment methods are under investigation, including MRI-guided focused ultrasonography, stem cells, and gene therapy.

Treatment of Nonmotor Disturbances

Increasing attention is being paid to treatment of nonmotor symptoms of PD (depression, anxiety, dementia, sleep disturbances, autonomic disturbances, sensory symptoms), which may worsen the quality of life to a greater extent than motor disturbances, especially given that they frequently remain undiagnosed and untreated.

1. Erectile dysfunction may occur as an early sign of PD in men. Phosphodiesterase inhibitors may be effective.

2. Orthostatic hypotension may be prevented by increasing the intake of fluids, adding salt to foods, sleeping with an elevated head (10-15 cm), and reducing or eliminating hypotensive agents (including antihypertensive agents and dopamine agonists). Domperidone may be helpful for levodopa-induced orthostatic hypotension. Pharmacotherapy with mineralocorticoids and alpha-adrenergic agents may also be effective.

In patients with coexisting orthostatic hypotension and supine hypertension, therapeutic decisions should include consideration of the risk of falls, cognitive impairment (associated with orthostatic hypotension), stroke, and myocardial infarction (associated with supine hypertension).

3. Constipation: A fiber-rich diet, increased intake of fluids, and physical activity are the key methods to prevent constipation. Discontinuation of anticholinergic agents and use of laxatives, in particular macrogol or lactulose (10-20 g/d), should be considered.

4. Urinary incontinence: Anticholinergic agents such as oxybutynin, tolterodine, and solifenacin may be effective. However, they are contraindicated in patients with cognitive impairment due to the risk of confusion and hallucinations. Mirabegron is also used with some success.

5. Drooling: Anticholinergic medications including atropine drops, ipratropium bromide spray, and glycopyrrolate tablets can be helpful, but these are generally contraindicated in patients with dementia, hallucinations, or both. Botulinum toxin injections into the salivary glands (parotid and submandibular glands) may be effective.

6. Sleep disturbances: The quality of sleep may be improved by drugs ensuring prolonged activation of dopamine receptors throughout the night, such as extended-release levodopa or dopamine agonists.

7. Somnolence: The subjective sensation of daytime somnolence may be reduced by modafinil. However, the use of this drug may be limited in some jurisdictions due to its relatively high cost.

8. Chronic fatigue: Methylphenidate and amantadine may be used to relieve chronic fatigue.

9. Pain may be secondary to muscle stiffness during an “off” period and may therefore respond to alterations in the dose and timing of dopaminergic medications. Over-the-counter analgesic agents, muscle relaxants, opioids, and anticonvulsant medications may also be helpful. Painful dystonia, often of the toes and feet, may also be effectively managed by botulinum toxin injections.

10. Mood symptoms, including depression and anxiety, are managed with nonpharmacologic approaches, including cognitive behavioral therapy; and with pharmacologic therapies with effects on serotonin, norepinephrine, or both.

11. Psychosis: Hallucinations and delusions may be managed with quetiapine and clozapine. Other antipsychotic medications are contraindicated due to the risk of worsening parkinsonism.

12. Dementia: Improvements in cognitive function, behavioral symptoms, and motor function may result from treatment with cholinesterase inhibitors. Memantine may possibly also have a positive effect.

ComplicationsTop

1. Pneumonia is the most frequent direct cause of death. The rigidity of respiratory muscles is associated with an impaired cough reflex and susceptibility to infection. Additionally, dysphagia leads to food aspiration and aspiration pneumonia.

2. Urinary tract infection due to dysfunction of the urinary bladder and urinary retention.

3. Sequelae of falls.

Special considerationsTop

Akinetic Crisis (Neuroleptic Malignant-Like Syndrome; Parkinsonism-Hyperpyrexia Syndrome)

Akinetic crisis is a life-threatening deterioration of the patient’s condition (eg, as a result of a sudden discontinuation of antiparkinsonian agents). Akinetic crisis requires aggressive treatment with antiparkinsonian agents, cooling of the body, and systemic treatment tailored to the patient’s condition (adequate fluid volume, correction of electrolyte disturbances, thromboembolism prophylaxis, antibiotics where appropriate).

PrognosisTop

After 7 to 10 years of symptoms, most people with PD experience disability related to imbalance and increased risk of falls, and by 10 years, 50% of patients have dementia. The clinical course of PD lasts ~15 to 20 years, although individuals who are younger at disease onset typically have a more prolonged course, while elderly patients may progress more quickly. Other adverse prognostic factors (faster deterioration of motor function and shorter survival) include significant comorbidities and muscular rigidity and bradykinesia as presenting symptoms of PD.

TablesTop