Lawrence W. Elmer, MD, PhD
Robert A. Hauser, MD, MBA
DESCRIPTION 
Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by bradykinesia, rest tremor, and rigidity. As the disease advances, patients may experience gait and balance disturbances as well as nonmotor features including cognitive dysfunction, also known as PD with dementia (PDD). Advances in pharmacological, nonpharmacological and surgical options in the last 2 decades have greatly enhanced our ability to successfully manage PD symptoms for many years, although long-term treatment remains limited as the disease advances and patients exhibit dementia and loss of balance.
EPIDEMIOLOGY
Incidence
Incidence rates of PD vary worldwide with most estimates suggesting 10–20 new cases per 100,000 population annually.
Prevalence
Prevalence rates for PD worldwide vary significantly ranging from <50 to >300/100,000. Since the incidence and prevalence of PD increases with age, rough estimates suggest a prevalence of 1% of people above the age of 65.
RISK FACTORS
- Race: PD prevalence appears higher in Europe and North America, with lower rates in Japan, China, and Africa. In addition, prevalence in the USA is lower among blacks than whites. However, differences in sampling methodology preclude conclusive determination of PD risk based on race (5).
- Age: Increasing age is the single greatest risk factor for developing PD.
- Sex: Most current studies support a greater risk of PD in males; in some cases up to twice as frequent in comparison to females.
- Environment: Current theories of pathogenesis (1) are consistent with observational studies demonstrating increased risk of PD in farming communities, exposure to well water and contact with pesticides and herbicides.
Genetics
A number of mutations have been found in familial PD. Some of these mutations include genes encoding alpha-synuclein, leucine-rich repeat kinase 2, and others (2).
GENERAL PREVENTION
PATHOPHYSIOLOGY
- Understanding of the pathogenesis of PD has changed dramatically in the last 10 years. The classic pathological features include a significant loss of dopamine neurons in the substantia nigra pars compacta, as well as the hallmark finding of Lewy bodies (eosinophilic intracytoplasmic inclusions containing alpha-synuclein, ubiquitin, and other proteins).
- In the early 2000s, Braak and colleagues published the results of their comprehensive neuropathological survey, examining the entire nervous system of 140 patients who died of PD. Immunocytochemically, they identified aggregates of alpha-synuclein in peripheral, autonomic, olfactory, and enteric nervous system structures, in addition to the CNS.
- This landmark research demonstrated that the earliest pathological manifestation of PD, the development of Lewy bodies and Lewy neurites, appears initially in the olfactory bulb and the plexus of the enteric nervous system. In the brain, the alpha-synuclein pathology appears to ascend the brainstem to the midbrain, eventually involving the substantia nigra, sometimes continuing on to reach the cortex, which correlates with PDD.
- These discoveries altered our understanding of the course of PD and provided a pathologic basis for clinical observations supporting pre-motor features that may be identified in people at risk of developing PD.
- The list of premotor features identified to date includes the following:
ETIOLOGY
- The cause of PD is felt to be the result of environmental exposure superimposed on a genetic predisposition. Polygenetic factors may be involved, but are still being elucidated.
- A number of genetic mutations have now been discovered that may cause PD. At this time, it is estimated that known genetic mutations may account for approximately 5–15% of cases of PD. The remaining cases are currently considered “idiopathic.” It seems likely that more genetic mutations associated with PD will be discovered.
COMMONLY ASSOCIATED CONDITIONS
[Outline]
HISTORY
Motor and Nonmotor Abnormalities
- PD symptoms develop insidiously and, when present initially on the nondominant side, may not be noticed by the patient for months or even years. Without the classic rest tremor, the slowness and awkwardness of movement along with muscle rigidity and aching are frequently considered part of the aging process and the diagnosis is delayed, if not missed entirely.
- Pain may be present, typically reported in large muscle groups such as the shoulder girdle, low back, or hip. One international survey confirmed that shoulder pain was the most common symptom shared by patients prior to their formal diagnosis.
- Loss of olfaction, slowing of GI transit times with resultant constipation, and REM sleep behavior disorder may predate the motor symptoms of PD by a decade or more. Increasingly, these symptoms and others are being recognized as part of the PD complex (see “Pathophysiology”).
- Modern diagnostic criteria require the presence of bradykinesia along with rest tremor and/or rigidity. In addition, PD is an asymmetric disorder, usually beginning on one side and remaining worse on that side throughout the course of the illness. In addition, in almost all cases, bradykinesia and rigidity clearly improve with the introduction of dopamine replacement medications [levodopa (LD) or dopamine agonists] at appropriate doses. Postural instability (loss of balance) is a late feature of PD and is not expected at presentation.
- Supportive prospective diagnostic criteria for a diagnosis of PD:
- Unilateral onset
- Rest tremor present
- Progressive disorder
- Persistent asymmetry primarily affecting side of onset
- Excellent response (70–100%) to LD
- LD response for ≥5 years
- Severe LD-induced chorea
- Clinical course of ≥10 years
Cognitive and Mood Disorders
- Criteria for a diagnosis of PDD have been published (3). These criteria are nearly identical to that for dementia with Lewy bodies (DLB).
- Mood disorders are a common complication of PD with or without dementia, but depression and anxiety are more commonly seen in PDD.
- Hallucinations and delusions are seen frequently in PDD, but the overlap between drug-induced psychosis and that induced by the disease burden makes accurate diagnosis and treatment difficult at times.
PHYSICAL EXAM
Motor Features
- Patients classically present with asymmetric slowness (bradykinesia) in movement on the affected side. Typical exam features include reduced amplitude and/or inability to sustain ongoing movements such as finger tapping, open–closing hand, and pronation–supination. In addition, there will typically be micrographia (reduced size of handwriting), which progressively worsens as the patient continues to write. While walking, there may be reduced natural arm swing and shortened stride length on the affected side.
- Rest tremor is also asymmetric, when present, and is slower than most other forms of tremor, typically in the range of 3–5 Hz. There may be a “pill-rolling” characteristic with the thumb, index, and middle fingers moving against each other.
- Rigidity is part of the early motor symptom triad and may be best described as increased resistance to passive manipulation. Other terms include “lead-pipe” or “cogwheel” rigidity, although the ratcheting sensation is primarily the result of the tremor superimposed on the rigidity.
- Postural instability is typically a late manifestation of PD, but may be seen early in the other parkinsonisms [see multiple system atrophy (MSA), progressive supranuclear palsy (PSP)].
- Inability to resist blinking when the examiner taps the glabella (Myerson's sign) is considered suggestive of PD, but this primitive reflex may be seen with other degenerative disorders and/or medical conditions.
- Patients may have masked facies (reduced spontaneous facial movement), hypophonia (reduced voice amplitude), and difficulty initiating movement from a seated to standing position without supporting the movement with their arms.
- Eye movements are typically abnormal due to saccadic pursuits.
- As the disease progresses, symptoms of bradykinesia, rigidity, and/or tremor spread to the contralateral side. In advanced cases, patients develop a stooped posture and increased difficulty maintaining their balance if given a postural challenge. Gait becomes more difficult with “shuffling” and periods of “freezing”, during which the initiation of gait is markedly inhibited.
Cognitive and Autonomic Signs
- Autonomic dysfunction with orthostatic hypotension may be present on blood pressure testing.
- PDD is characterized on exam by features common to DLB. Patients may have myoclonus. Cognitive testing demonstrates problems with attention and concentration (serial 7’s, spelling WORLD backwards) along with visuospatial dysfunction (drawing intersecting pentagons and/or clock drawing test) usually well before difficulties with orientation or memory become prominent.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Bloodwork: There are no specific blood tests to diagnose PD, but the following tests should be considered to identify potential underlying secondary causes of parkinsonism: Serum vitamin B12 and D levels and thyroid function tests.
Imaging
- DaTscan™ can now be used as an aid in the diagnosis of PD. Single-photon emission computed tomography (SPECT) scanning is utilized to image a ligand that binds to dopamine transporters on dopamine terminals. This provides a visual index of the number of remaining dopamine neurons. It is decreased in PD, as well as in other degenerative parkinsonisms such as MSA and PSP. It is normal in ET, DIP, healthy individuals, and psychogenic parkinsonism. This test should be reserved for those individuals in whom the diagnosis is uncertain.
- There is no evidence to suggest that structural imaging studies (CT, MRI) can assist in the diagnosis of PD. MRI imaging may reveal evidence of other causes of parkinsonism such as vascular insults, mass lesions, calcium or iron deposition in the striatum, atrophy in the posterior fossa suggestive of multiple system atrophies, and cortical atrophy patterns suggestive of other dementing illnesses.
Diagnostic Procedures/Other
Pathological Findings
DIFFERENTIAL DIAGNOSIS
- DLB
- Essential tremor
- Drug-induced parkinsonism (e.g., antipsychotics, antiemetics, and other dopamine-blocking agents)
- MSA
- PSP
- Corticobasal degeneration
- NPH
- Vascular parkinsonism
[Outline]
MEDICATION
A primary goal in the treatment of PD is to provide good motor benefit through the day. This is generally accomplished by restoring dopamine levels as close to normal as possible. This can be accomplished through the use of LD (used in combination with a dopa-decarboxylase inhibitor [DDCI] to prevent peripheral breakdown to dopamine), dopamine agonists, or monoamine-oxidase type B (MAO-B) inhibitors. In addition, catechol-O-methyl transferase (COMT) inhibitors, when combined with LD/DDCI, increase the bioavailability of LD, thereby enhancing brain levels of dopamine. Additional available medications include anticholinergic agents and amantadine. All of these treatments have specific potential benefits and side effects.
Levodopa
- The most effective and widely used treatment option for the motor features of PD is LD (combined with a DDCI). LD is taken up by remaining dopamine neurons, converted to dopamine, and released over time to restore normal stimulation of striatal neurons. However, long-term use of LD is associated with motor fluctuations, such that patients notice benefit for a few hours after LD administration and then experience a “wearing-off” of its effect. In addition, many patients develop twisting, turning chorea movements that typically occur when LD-derived dopamine is peaking in the brain. The usual dose of carbidopa/levodopa (C/L) is 25/100, 3–4 times daily, typically given at 4-hour intervals and apart from meals. A common side effect when initiating LD therapy is nausea, which may be ameliorated by the co-administration of C/L with food at the beginning. Days to weeks later, the medication may be moved to 30–60 minutes prior to meals.
- It has been hypothesized that dyskinesias are the result of nonphysiologic peaks and troughs of dopamine brain concentrations that result from the short serum half-life of LD. The development of dyskinesias correlates with the total dose of LD and, therefore, unnecessarily high doses of LD should be avoided.
- Carbidopa/levodopa (C/L) (brand name Sinemet®, multiple generic formulations) is the preparation that provides the standard of care for people with idiopathic PD. While its use is controversial as a first-line agent due to predictable development of motor fluctuations after prolonged exposure to LD, it is the most efficacious and biologically effective medication available.
- Controlled-release form of C/L (Sinemet CR® or C/L ER) is only 70% bioavailable on average compared to immediate release C/L, and thus there is a tendency to underdose patients when using this formulation.
Dopamine Agonists
Dopamine agonists, such as pramipexole, ropinirole, and rotigotine, are moderately effective in controlling motor features of PD as monotherapy in early disease and as adjuncts to LD in more advanced disease. Large, controlled clinical trials have demonstrated that the initial use of a dopamine agonist to which LD is added when the agonist alone is no longer sufficient delays the development of fluctuations and dyskinesias. However, dopamine agonists are associated with more somnolence (including sudden onset sleep), hallucinations, edema, and impulse control disorders than LD. Because younger PD patients are more likely to develop fluctuations and dyskinesias, the strategy of starting dopaminergic therapy with an agonist and/or an MAO-B inhibitor and then adding LD when necessary may be beneficial in this population (<65 years).
MAO-B Inhibitors
- MAO-B inhibitors (selegiline and rasagiline) provide mild symptomatic benefit as monotherapy in early disease and as adjuncts to LD in more advanced disease. There has been controversy regarding whether this class of agents may slow clinical progression and improve long-term outcome. Both agents are generally well tolerated.
- Selegiline (5–10 mg/d) and rasagiline (Azilect® 0.5–1 mg/d) are both selective MAO-B inhibitors that delay or decrease the breakdown of dopamine in the brain, resulting in symptomatic benefit. Selegiline has been approved for adjunctive therapy in PD along with LD/DDCI therapy while rasagiline has been approved for both monotherapy in early PD and adjunctive therapy in advanced PD.
- A large, controlled, multicenter study was completed in 2009 comparing early versus delayed start of rasagiline as monotherapy for PD. While controversial, the results suggested the possibility that rasagiline slows disease progression in early PD. Further studies are expected.
COMT Inhibitors
- COMT inhibitors are useful as adjuncts to LD/DDCI. The COMT inhibitors reduce the peripheral metabolism of LD, thereby allowing more LD to enter the brain over a longer time. The addition of a COMT inhibitor to a LD/DDCI regimen in a patient with motor fluctuations extends the clinical benefit of each LD administration and reduces “off” time, the time when LD is not providing benefit. The most common COMT inhibitor in use worldwide is entacapone. Tolcapone is a highly effective COMT inhibitor, but it can rarely cause fatal hepatotoxicity and liver function test monitoring is required.
- Tolcapone (Tasmar® 100–200 mg t.i.d.) had the adverse side effect of lethal hepatic damage in several patients worldwide, resulting in a black-box warning on the package insert. There is an absolute requirement for liver function monitoring and, thus, this medication should be prescribed only by specialists familiar with its use and contraindications.
- Entacapone (Comtan® 200 mg with every dose of C/L) has not shown any evidence of hepatic toxicity. A combination pill incorporating carbidopa/LD/entacapone – Stalevo® – is also available with multiple different doses of LD/DDCI along with a fixed dose of 200 mg of entacapone in each tablet.
MISCELLANEOUS
- Anticholinergic agents, such as trihexyphenidyl, benztropine, and others, are generally reserved to ameliorate tremor that has not adequately responded to dopaminergic medications. Side effects include dry mouth, dry eyes, constipation, and cognitive dysfunction. They must be used cautiously in older individuals and avoided in those with dementia.
- Amantadine, initially developed as a treatment for influenza, provides mild benefit as monotherapy in early PD. In more advanced PD, it can reduce dyskinesias and motor fluctuations. Common side effects include hallucinations and confusion. It must be used cautiously in older individuals and those with cognitive impairment.
- Treatment of cognitive and behavioral symptoms in PD and PDD replicates the strategies of similar symptoms in DLB.
ADDITIONAL TREATMENT
General Measures
- Dopaminergic replacement is the mainstay of PD and PDD therapy. However, there is increasing evidence that specialized exercise therapies positively impact the functional capacity of people with PD.
- Management of cognitive and behavioral features of PDD is complicated, involving most, if not all, of the treatments outlined in the chapter on DLB.
- One medication of the cholinesterase inhibitor class, rivastigmine, has been demonstrated in a large, controlled clinical trial to improve cognitive deficits in PD patients with dementia. Other potential benefits of this medication include a reduction of hallucinations, depression, anxiety, and other neuropsychiatric manifestations of PD.
- Hallucinations are usually improved by reducing and/or discontinuing PD medications other than LD. If the LD dose necessary to maintain motor function causes hallucinations, treatment with quetiapine (Seroquel® 12.5–25 mg q.h.s. or b.i.d.) can be considered.
- Depression in PD is extremely common – a recent study demonstrated significant improvement of depression and good tolerability of 2 commonly prescribed agents paroxetine and venlafaxine.
- Other nonmotor features of PD that may require symptomatic treatment include insomnia, anxiety, and constipation.
- Surgical treatment of PD may dramatically improve motor symptoms in PD and reduce side effects of other dopaminergic therapies by allowing significant reductions and/or elimination of those medications. Success of deep brain stimulation (DBS) correlates with careful patient selection by a movement disorder specialist along with high-precision placement of the DBS electrodes by an experienced neurosurgeon.
Issues for Referral
- Patients with atypical symptoms or who fail to respond to conventional therapies and doses of dopaminergic agents may be referred to a movement disorder specialist. Patients experiencing significant side effects from their medications and/or those who have disabling “off” times or dyskinesias may be candidates for DBS surgery.
- Physical and occupational therapists can assess and recommend treatment of mobility issues or difficulties in activities of daily living. Occupational therapists perform driving evaluations in patients at risk of having motor vehicle accidents, especially those in whom visuospatial skills are impaired (PDD).
- Neuropsychologists may determine whether depression and/or anxiety is a confounding component of a PD/PDD patient's presentation.
- Social workers assess caregiver stress and coordinate home health care services. They also address medico-legal issues pertinent to PDD such as driving.
- Referral to geriatric psychiatry, cognitive or movement disorder neurology, or other specialists in dementia is frequently warranted due to the complications of disease progression and medication management seen in patients with PDD.
Additional Therapies
Physical therapy, occupational therapy, and voice therapy play an important therapeutic role in the management of PD patients with disability. Big and Loud® therapy and the Theracycle® have significantly improved disability, especially involving gait and balance, in controlled clinical trials (e.g., 4).
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Co-enzyme Q10 was recently studied as a potential disease-modifying treatment in a large, placebo-controlled clinical trial. While no safety issues emerged, the use of 1,200–2,400 mg/d of CoQ10 demonstrated no evidence of slowing disease progression.
SURGERY/OTHER PROCEDURES
- High-frequency DBS of the subthalamic nucleus or the internal portion of the globus pallidus is an effective treatment to treat most motor symptoms of PD, reducing motor fluctuations and dyskinesias in patients on LD whose clinical symptoms cannot be adequately managed by medications alone. Candidates for DBS are those who experience a meaningful improvement with LD but are unable to adequately sustain the response through the day.
- Another surgical option, intestinal infusion of LD (Duodopa®), using an external pump has also been demonstrated to better maintain LD benefit through the day and reduce dyskinesias.
IN-PATIENT CONSIDERATIONS
Admission Criteria
- PD is usually managed in an outpatient setting. Not uncommonly, concomitant illnesses (e.g., pneumonia, UTI) can lead to an acute exacerbation of PD symptoms, requiring hospitalization for dysphagia, airway management, and issues of decreased mobility. Psychosis in the setting of idiopathic PD with excessive dopaminergic medication may precipitate hospitalization and/or institutionalization. If hospitalized, careful attention to dopaminergic dosages and timing of doses is critical to enhance positive outcomes.
[Outline]
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Patients with idiopathic PD are seen usually 2–3 times per year in an outpatient setting. These visits are typically more frequent when medications are adjusted.
- By its very nature, idiopathic Parkinson's disease (IPD) typically requires steadily increasing doses of medications, for the treatment of dopaminergic deficiency or the side effects of (exogenous) dopaminergic therapy.
- Patients with PDD may need to be seen more frequently, up to 4–6 times per year, due to the additional complications of cognitive and/or behavioral changes superimposed on the motor disturbances.
- Patients with PD and prominent nonmotor symptoms (dysautonomia, sleep disturbances, bowel/bladder disturbances, etc.) may also need to be seen more often or referred to appropriate subspecialists for the management of these symptoms.
DIET
- As dysphagia develops, use of pureed foods may be indicated to avoid aspiration pneumonia. Patients may require PEG tube placement in order to maintain nutritional status.
PATIENT EDUCATION
- Support groups for PD are available locally in many areas of the country. There are several large national organizations that provide educational materials to patients and their families. Numerous internet-based resources are available as well.
PROGNOSIS
Over time, patients with PD may develop gait and balance disturbances leading to falls along with or complicating cognitive and/or behavioral abnormalities. Recent studies suggest that PD without cognitive changes does not shorten lifespan, while dementia shortens lifespan, commonly associated with reduced therapeutic alternatives for the management of motor symptoms and/or institutionalization.
COMPLICATIONS
Dysphagia with resultant aspiration pneumonia and falling are 2 common causes of morbidity and mortality in PD and especially in PDD.
[Outline]
Hallucinations in drug-induced psychosis or associated with PDD are commonly visual in nature and typically make no sound, in contrast to the auditory hallucinations seen in schizophrenia.
