Background

Parkinson disease is a disorder of the basal ganglia and is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. Most cases of idiopathic Parkinson disease (IPD) are believed to be due to a combination of genetic and environmental factors. At both ends of the spectrum are rare cases that appear to be due solely to one or the other. Patients with Parkinson disease exhibit 2 onsets of manifestations: onset of initial clinical manifestations and the onset of motor signs. The initial symptoms typically start insidiously and emerge slowly over weeks or months, with tremor being the most common initial symptom. There are 4 cardinal signs of Parkinson disease: resting tremor, rigidity, bradykinesia, and postural instability. (See Clinical Presentation.) When a patient presents with tremor, the clinician must compare the patient's signs and symptoms with the clinical picture of Parkinson disease in order to differentiate parkinsonian tremor from other types of tremor. In patients with parkinsonism, careful attention to the history is necessary to exclude etiologic factors such as drugs, toxins, or trauma. (See Diagnosis.) No laboratory or imaging study is required in patients with a typical presentation. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. In such cases, the simplest test is a diagnostic trial of levodopa, as the response to low doses of levodopa is nearly complete. (See Workup.) Levodopa coupled with a peripheral decarboxylase inhibitor (PDI) (Sinemet) remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias. (See Treatment Strategies and Management.) Levodopa/carbidopa provides the greatest antiparkinsonian efficacy in moderate-to-advanced disease, with the fewest acute adverse effects. Dopamine agonists (apomorphine [Apokyn], bromocriptine [Parlodel], ropinirole [Requip and Requip XL]) can be used as monotherapy to improve symptoms in early disease or as adjuncts to levodopa in patients whose response to levodopa is deteriorating and those who are experiencing fluctuations in their response to levodopa. MAO-B inhibitors (selegiline [Eldepryl], rasagiline [Azilect]) inhibit the activity of Monoamine oxidase (MAO)B oxidases that are responsible for inactivating dopamine and possibly the conversion of compounds into neurotoxic types. (See Medication.)

Anatomy
Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei situated at the base of the forebrain, shown below.

Stages in the development of Parkinson disease-related pathology. Adapted from Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Cell Tissue Res. 2004 Oct;318(1):121-34. The corpus striatum, composed of the caudate and putamen, is the largest nuclear complex of the basal ganglia. The striatum receives excitatory input from several areas of the cerebral cortex as well as inhibitory and excitatory input from the dopaminergic cells of the substantia nigra pars compacta (SNc). These cortical and nigral inputs are received by the spiny projection neurons, which are of 2 types: those that project directly to the internal segment of the globus pallidus (GPi), the major output site of the basal ganglia, and those that project to the external segment of globus pallidus (GPe), establishing an indirect pathway to GPi via the subthalamic nucleus (STN). For an illustration of the subthalamic nucleus, see the image below.

Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN; lavender). STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease. The complementary actions of the direct and indirect pathways regulate the neuronal output from GPi, which provides tonic inhibitory input to the thalamic nuclei that project to the primary and supplementary motor areas.

Pathophysiology
No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and sensitivity of the characteristic findings have not been established clearly. Individuals presenting with primary dementia may exhibit neuropathologic features indistinguishable from those of Parkinson disease. There are, however, 2 major neuropathologic findings in Parkinson disease:

Loss of pigmented dopaminergic neurons in the substantia nigra

The presence of Lewy bodies

The loss of dopaminergic neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge. Incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of Parkinson disease. Alpha-synuclein is a major structural component of Lewy bodies, and all Lewy bodies stain for alpha-synuclein and most also stain for ubiquitin. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic, of IPD. Lewy bodies also are found in the cortex, nucleus basalis, locus ceruleus, intermediolateral column of the spinal cord, and other areas. Lewy bodies are not specific to Parkinson disease, as they are found in some cases of atypical parkinsonism, Hallervorden-Spatz disease, and other disorders. Incidental Lewy bodies are found at postmortem in patients without clinical signs of parkinsonism. The prevalence of incidental Lewy bodies increases with age.

Motor circuit in Parkinson disease

The basal ganglia motor circuit modulates the cortical output necessary for normal movement (see the following image).

Schematic representation of the basal ganglia - thalamocortical motor circuit and its neurotransmitters in the normal state. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson's disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240. Used with kind permission. Copyright, McGraw-Hill Companies, Inc. Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the GPi and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement. Two pathways exist within the basal ganglia circuit, the direct and indirect pathways:

In the direct pathway, outflow from the striatum directly inhibits GPi and SNr. Striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr. The indirect pathway comprises inhibitory connections between the striatum and the GPe and between the GPe and the STN. Striatal neurons containing D2 receptors are part of the indirect pathway and project to the GPe.

The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (SNc) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr (see the following image).

Schematic representation of the basal ganglia - thalamocortical motor circuit and the relative change in neuronal activity in Parkinson disease. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson's disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:241. Used with kind permission. Copyright, McGraw-Hill Companies, Inc. The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output to the thalamus.

Etiology
Most cases of IPD are believed to be due to a combination of genetic and environmental factors. At both ends of the spectrum are rare cases that appear to be due solely to one or the other. It has been estimated that all currently known genetic causes of Parkinson disease account for less than 5% of Parkinson disease cases.

Environmental causes
Environmental risk factors associated with the development of Parkinson disease include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and

proximity to industrial plants or quarries. Smoking and caffeine consumption are inversely correlated with Parkinson disease risk.

MPTP
Several individuals have been identified who developed parkinsonism after self-injection of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4phenylpyridinium (MPP+) by MAO-B.[6] MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.

Oxidation hypothesis
The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Hydrogen peroxide normally is cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals. Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due to levodopa administration could increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that levodopa accelerates disease progression.

Genetic factors
If genetic factors are important, concordance in genetically identical monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early twin studies generally found low and similar concordance rates for MZ and DZ pairs. Genetic factors appear to be very important when the disease begins at or before age 50 years, according to a study of 193 twins. Overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.

The identification of a few families with apparent familial Parkinson disease sparked further interest in the genetics of the disease. In one large family of 592 members in Salerno, Italy, of whom 50 had Parkinson disease, linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene. Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age 47.5 y), rapid progression (mean age at death 56.1 y), lack of tremor, and good response to levodopa therapy. Five small Greek kindreds also were found to have the PD-1 mutation. In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease. A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease. Several homozygous deletions in a gene dubbed parkin (PARK2), which is located on chromosome 6, have been found to cause autosomal recessive juvenile parkinsonism. This form of parkinsonism differs pathologically from Parkinson disease in that no Lewy bodies are found in the substantia nigra. Several other gene abnormalities have been identified in families with Parkinson disease and these are designated PARK3 -PARK12.

Alpha-synuclein
Alpha-synuclein is a major component of Lewy bodies in cases of Parkinson disease. All Lewy bodies stain for alpha-synuclein, and most also stain for ubiquitin, which conjugates with proteins targeted for proteolysis. Abnormal aggregation of alpha-synuclein into filamentous structures may precede ubiquitination. One hypothesis states that the PD-1 mutation alters the configuration of alpha-synuclein into a beta structure that could aggregate into sheets. All Parkinson disease cases may be associated with abnormal folding of alpha-synuclein, leading to excessive aggregation and neuronal death. Although sporadic Parkinson disease is not caused by a mutation in the alpha-synuclein gene, active investigation is underway into proteins that interact with alpha-synuclein, including those that guide, promote, or prevent aggregation of the protein. Because Parkinson disease, dementia with Lewy bodies, and multiple system atrophy all exhibit Lewy bodies that stain for alphasynuclein, they have been designated "alpha-synucleinopathies." One hypothesis suggests that Parkinson disease is caused by abnormalities of the proteosome system, which is responsible for clearing abnormal proteins.

Clinical Highlights

Consider MAO-B inhibitors for initial treatment of early disease. These drugs provide mild symptomatic benefit, have excellent adverse effect profiles, and according to a Cochrane Review improved long-term outcomes in quality of life indicators by 2025%.[1]

Levodopa combined with a peripheral decarboxylase inhibitor (Sinemet) is the accepted standard of symptomatic treatment of later disease based on 3 well-designed RCTs that showed a 24% benefit in symptom relief over levodopa alone.[2] It is the most efficacious medication for motor signs and symptoms, but its use is associated with the development of response fluctuations (wearing-off) and dyskinesias. Proactively screen patients receiving oral dopamine agonists (pramipexole, ropinirole) for adverse events. A review of the Cochrane and PubMed databases from 1990 to 2008 found that although these drugs provide moderate symptomatic benefit and cause less dyskinesia than levodopa, they caused a 15% increase in adverse events as somnolence, sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic gambling, shopping, and Internet use; hypersexuality; and hoarding).[3] Note that patients may be reluctant to mention these events or may not attribute them to their treatment. Screen Parkinson disease patients for depression, and treat it when present. An evidencebased guideline from the American Academy of Neurology reports that physician recognition of depression is low in Parkinson disease at less than 30% of clinically proven cases; there are many factors that confound its diagnosis in these patients; and depression has the single largest effect on the quality of life of patients with Parkinson disease.[4, 5]

Epidemiology
Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. The incidence of Parkinson disease has been estimated to be 4.5-21 cases per 100,000 population per year, and estimates of prevalence range from 18-328 cases per 100,000 population, with most studies yielding a prevalence of approximately 120 cases per 100,000 population. The incidence and prevalence of Parkinson disease increase with age, and the average age of onset is approximately 60 years. Onset in persons younger than 40 years is relatively uncommon. Parkinson disease is about 1.5 times more common in men than in women.

Prognosis
Prior to the introduction of levodopa, Parkinson disease caused severe disability or death in 25% of patients within 5 years of onset, in 65% in the next 5 years, and in 89% of those who survived for 15 years. The mortality rate from Parkinson disease was 3 times that of the general population matched for age, sex, and racial origin. With the introduction of levodopa, the mortality rate dropped approximately 50%, and longevity was extended by several years. This is thought to be due to the symptomatic effects of levodopa as no clear evidence suggests that levodopa stems the progressive nature of the disease.[7, 8]

Patient Education
For excellent patient education resources, visit eMedicine's Dementia Center. Additionally, see eMedicine's patient education article Parkinson Disease Dementia.

History
Onset of motor signs in Parkinson disease is typically asymmetric, with the most common initial finding being an asymmetric resting tremor in an upper extremity. Over time, patients notice symptoms related to progressive bradykinesia, rigidity, and gait difficulty. The first affected arm may not swing fully when walking, and the foot on the same side may scrape the floor. Over time, axial posture becomes progressively flexed and strides become shorter. Some nonmotor symptoms commonly precede motor signs in Parkinson disease. Most Parkinson disease patients have a substantial reduction in olfactory function (smell) by the time motor signs emerge. However, this is often either not noticed by the patient or he or she may not realize that it is part of the disease. Another common premotor is rapid eye moved (REM) behavior disorder. In this disorder, individuals exhibit movements during REM sleep that are often described as hitting or kicking motions. There are also a number of midlife risk factors for the later development of Parkinson disease. These include constipation and excessive daytime sleepiness, although they are far from specific for Parkinson disease. Initial clinical symptoms include the following:

Tremor A subtle decrease in dexterity, such as a lack of coordination with activities such as playing golf or dressing (about 20% of patients first experience clumsiness in one hand) Decreased arm swing on the first-involved side Soft voice Decreased facial expression Sleep disturbances REM behavior disorder (RBD), in which there is a loss of normal atonia during REM sleep: In one study, 38% of 50-year-old men with RBD and no neurologic signs went on to develop parkinsonism.[4] Patients act out their dreams and may kick, hit, talk, or cry out in their sleep. Decreased sense of smell Symptoms of autonomic dysfunction, including constipation, sweating abnormalities, sexual dysfunction, and seborrheic dermatitis A general feeling of weakness, malaise, or lassitude Depression or anhedonia Slowness in thinking Decreased swallowing, which may lead to excess saliva in the mouth and, ultimately, drooling Regional pain, variously described as coldness, tingling, cramping, or aching; some patients complain of aching or tightness in the calf or shoulder region

The motor signs of Parkinson disease consist of tremor, bradykinesia, rigidity, and dystonia.

Tremor

Tremor is the most common initial symptom, occurring in approximately 70% of patients. It usually is described by patients as shakiness or nervousness. Tremor usually begins in one upper extremity and initially may be intermittent. Upper extremity tremor generally begins in the fingers or thumb, but also can start in the forearm or wrist. After several months or years, the tremor may spread to the ipsilateral lower extremity or the contralateral upper extremity before becoming more generalized; however, asymmetry is usually maintained. Tremor may vary considerably, emerging only with stress, anxiety, or fatigue. Classically, the tremor of Parkinson disease disappears with action or use of the limb, but this is not seen in all patients. Initially, the tremor may be noticed during activities such as eating or reading a newspaper. Although Parkinson disease is a rare cause of tremor affecting the head or neck, tremors of the chin or lip are not uncommon. As with most tremors, the amplitude increases with stress and resolves during sleep.

Bradykinesia
Symptoms of bradykinesia are varied. These may include a subjective sense of weakness, without true weakness, found on physical examination; loss of dexterity, sometimes described by patients as the "message not getting to the limb"; fatigability; or aching when performing repeated actions. Facial bradykinesia is characterized by decreased blink rate and facial expression. The speech may become softer, less distinct, or more monotonal. In more advanced cases, speech is slurred, poorly articulated, and difficult to understand. Drooling is an uncommon initial symptom in isolation but is reported commonly (especially nighttime drooling) in patients with mild disease. Truncal bradykinesia results in slowness or difficulty in rising from a chair, turning in bed, or walking. If walking is affected, patients may take smaller steps and gait cadence is reduced. Some patients experience a transient inability to walk, as though their feet are frozen to the floor. This "freezing" is seen commonly in patients with more advanced disease; it is more prominent in doorways or narrow areas and can result in patients getting trapped behind furniture or being unable to cross a door threshold easily. In the upper extremities, bradykinesia can cause small, effortful handwriting (ie, micrographia) and difficulty using the hand for fine dexterous activities such as using a key or kitchen utensils. In the lower extremities, unilateral bradykinesia commonly causes scuffing of that foot on the ground as it is not picked up, as well during leg swing. This may also be described as dragging of one leg.

Rigidity
Some patients may describe stiffness in the limbs but this may reflect bradykinesia more than rigidity. Occasionally, individuals may describe a feeling of ratchety stiffness when moving a limb, which may be a manifestation of cogwheel rigidity.

Dystonia

Dystonia is a common initial symptom in young-adult Parkinson disease, which is defined as symptom onset before age 40 years. Dystonia produces cramping or aching and a tendency of the extremity (usually the foot) to turn in or the great toe to dorsiflex. Common dystonic symptoms include curling, inversion, or plantar flexion of the foot, and adduction of the arm and elbow, causing the hand to rest in front of the abdomen or chest. Dystonic postures can wax and wane, occurring with fatigue or exertion. One study suggests that this stooped posture may be due to vertebral fractures resulting from vitamin D deficiency with compensatory hyperparathyroidism.[9] Vitamin D supplementation may reduce the risk for stooped posture.

Physical Examination
There are 4 cardinal signs of Parkinson disease, with 2 of the first 3 listed below required to make the clinical diagnosis. The fourth cardinal sign, postural instability, emerges late in the disease, usually after 8 years or more.

Resting tremor Rigidity Bradykinesia Postural instability

Resting tremor
Resting tremor is assessed by having the patient relax his or her arms on the legs while in a seated position. Having the patient count aloud backward from 10 may help bring out the tremor. The arms should also be observed in an outstretched position to assess postural tremor, and kinetic tremor can be observed during the finger-to-nose test.

Rigidity
Rigidity refers to an increase in resistance to passive movement about a joint. The resistance can be either smooth (lead pipe) or oscillating (cogwheeling). Cogwheeling is thought to reflect tremor rather than rigidity and may be present with tremors not associated with an increase in tone (ie, essential tremor). Rigidity is usually tested by flexing and extending the patient's relaxed wrist and can be made more obvious with voluntary movement in the contralateral limb.

Bradykinesia
Bradykinesia refers to slowness of movement but also includes a paucity of spontaneous movements and decreased amplitude of movement. Bradykinesia is also expressed as micrographia (small handwriting), hypomimia (decreased facial expression), decreased blink rate, and hypophonia (soft speech). Thus, the patients blink rate and facial expression should be observed.

In addition, speed and amplitude of movements are assessed by having the patient open his or her hand (each limb is assessed individually) and tap his or her thumb and index finger repetitively, trying to perform the movement as big and as fast as possible. Similarly, the patient should be asked to tap each foot as big and as fast as possible. Finally, the patient should be asked to arise from a seated position with the arms crossed to assess the ability to arise from a chair. The patient is then observed while walking to assess stride length and speed, as well as arm swing.

Postural instability
Postural instability refers to imbalance and loss of righting reflexes. Its emergence is an important milestone, because it is poorly amenable to treatment and a common source of disability in late disease. Postural stability is typically assessed by having the patient stand with eyes open and then pulling his or her shoulders back toward the examiner. The patient is told to be ready for the displacement and to regain balance as quickly as possible. One or 2 steps backward to regain balance is considered normal. The examiner should be ready to catch the patient if he or she is unable to regain balance. Perez et al found that vocal tremor is present in 55% of patients with Parkinson disease. Interestingly, they found that only 35% of patients with Parkinson disease exhibit a resting vocal cord tremor, while the remainder exhibited kinetic tremor. The tremor is primarily a vertical laryngeal movement. Parkinson-plus syndromes (PPS) were found to carry a higher incidence of vocal tremor (64%), with most tremors located in the arytenoids. The authors found no vertical laryngeal tremor in patients with PPS.[10]

Laryngeal Dysfunction and Dysphagia

As the patient is speaking, the vocal loudness, intonation, and quality, including fluidity of speech and articulation, should be assessed. Sustaining vowel phonation (eg, "ah") for maximum duration, counting to 50, and reading a passage that tests articulation (eg, the rainbow passage) provide reasonable speech samples. Closely listening for reduced or diminishing loudness and intonation and increasing breathiness and hoarseness helps to differentiate Parkinson disease from hyperkinetic disorders such as spasmodic dysphonia.[11] A soft, monotone voice, vocal tremor, poor articulation, variable speech rate, trouble with the initiation of speech, and stutteringlike qualities are all characteristics of Parkinson disease. Perhaps the most telling vocal symptom is the marked contrast between habitual vocal volume (soft and diminishing) and the patient's response to a request to increase loudness. A request to "say that again, twice as loud" often results in increased loudness, improved voice quality, and a dramatic improvement in speech intelligibility. Dysphagia is common, especially in advanced Parkinson disease. Manifestations may range from drooling to aspiration. An otolaryngologist can perform a more detailed assessment of laryngeal dysfunction in patients with Parkinson disease, using neurolaryngeal examination and stroboscopy. Because distortion can occur when the tongue is held forward during rigid stroboscopy, the neurolaryngeal examination is best performed by viewing the larynx with a flexible laryngoscope. The larynx is

evaluated for vocal fold mobility, paresis or paralysis, coordination of movement, agility, fatigability, flexibility, and use of accessory muscles during phonation while the patient says various phrases and syllables. Hyperfunctional and hypofunctional disorders can often be differentiated by isolating the abductor and adductor muscle groups. The larynx is also visualized at rest. Rigid stroboscopy plays a key role in the assessment of the vibratory characteristics of the vocal folds, including the presence of masses, lesions, or scar and glottic configuration abnormalities, including an elliptical closure pattern, phase asymmetry, and abnormal phase closure. Stroboscopy and neurolaryngeal examination are complementary in the evaluation of the patient with IPD. Common stroboscopy findings in IPD include true vocal fold atrophy or other evidence of glottal incompetence, including a chasing wave or a shorter closed phase. Pooling of secretions, decreased sensation, and aspiration are also characterizations of the Parkinson disease larynx. A paralyzed vocal fold suggests Parkinson-plus syndrome as the etiology for the parkinsonism if other aspects of the diagnosis are present.

Autonomic Dysfunction
Autonomic dysfunction is common in patients with Parkinson disease. Orthostatic hypotension often becomes a concern in late disease, and impaired intestinal motility can lead to constipation and, sometimes, vomiting or impaired absorption. Urinary incontinence, retention, and bladder infection can occur, and erectile dysfunction is not uncommon. In addition, many patients note episodes of sweating.

Cardiopulmonary Impairment
The flexed posture of patients with Parkinson disease can lead to kyphosis, cause a reduction in pulmonary capacity, and produce a restrictive lung disease pattern.

Depression
Given the high prevalence of mood disorders in Parkinson disease, these patients should be screened regularly for depression. However, assessment of depression in patients with Parkinson disease is complicated by the fact that some symptoms of Parkinson disease overlap with those of depression (eg, masklike facies, insomnia, psychomotor slowing, difficulty concentrating, fatigue). Guilt and self-reproach are less prominent in depression in patients with Parkinson disease, whereas anxiety and pessimism are more prominent.

Dementia
Hoops et al found that in dementia in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for screening for mild cognitive impairment or dementia. MoCA and MMSE demonstrated similar overall discriminant

validity for detection of any cognitive disorder, but as a screening instrument, MoCA was better than MMSE (64% versus 54% correct diagnoses).[12] The prevalence of dementia in Parkinson disease ranges from 20-40%, with the disease conferring a 2- to 6-fold increased risk compared with control populations.[13] Many patients with Parkinson disease have some executive function impairment, even early in the disease.[13] Substantial cognitive impairment and dementia typically occur 8 years or more after the onset of motor features. Dementia generally occurs late in Parkinson disease; substantial cognitive dysfunction within a year of onset of motor features suggests a diagnosis of Lewy body disease, a disease closely related to Parkinson disease and marked by the presence of cortical Lewy bodies. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer disease and cerebrovascular disease, is common. The relatively high prevalence of depression in patients with Parkinson disease is another confounder in the diagnosis of Parkinson disease dementia. Executive function, short-term memory, and visuospatial ability may be impaired in patients with Parkinson dementia, but aphasia is not present.

Parkinson-Plus Syndromes
Parkinson-plus syndromes are primary neurodegenerative disorders that have parkinsonian features and are associated with complex clinical presentations that reflect degeneration in various neuronal systems. Patients with Parkinson-plus syndromes typically have a worse prognosis than those with Parkinson disease, and Parkinson-plus syndromes respond poorly to the standard anti-Parkinson treatments. Go to the Parkinson-Plus Syndromes topic for detailed information regarding clinical clues, workup, differential diagnosis, and treatment of such disorders as multiple system atrophy, progressive supranuclear palsy, parkinsonism-dementia-amyotrophic lateral sclerosis complex, corticobasal ganglionic degeneration, and diffuse Lewy body disease.

Diagnostic Considerations
When a patient presents with tremor, the clinician must compare the patient's signs and symptoms with the clinical picture of Parkinson disease in order to differentiate parkinsonian tremor from other types of tremor. For example, an action tremor that is temporarily relieved by drinking alcohol is characteristic of essential tremor, whereas the presence of a pill-rolling rest tremor, bradykinesia, and rigidity is consistent with Parkinson disease and argues against essential tremor. In patients with parkinsonism, careful attention to the history is necessary to exclude etiologic factors such as drugs, toxins, or trauma. Medications that block striatal dopamine receptors, such as metoclopramide and the neuroleptics, can cause drug-induced parkinsonism.

In patients with neurodegenerative parkinsonism, the differential diagnosis includes Parkinson disease and the atypical parkinsonisms (also known as Parkinson-plus syndromes): multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The atypical parkinsonisms are usually associated with little or no tremor, relatively early speech and balance difficulty, and little or no response to dopaminergic medications. MSA is relatively symmetric and characterized by parkinsonism, with additional abnormalities in some combination of autonomic, corticospinal, and cerebellar systems. PSP is relatively symmetric and characterized by parkinsonism with early falls (often in the first year) and a supranuclear gaze palsy in which the patient has difficulty with voluntary down-gaze. CBD is typically very asymmetric and characterized by both cortical (difficulty identifying objects, apraxias) and basal ganglionic (usually marked rigidity in an arm) features. Patients with onset of parkinsonism before age 40 years should be tested for Wilson disease, starting with serum ceruloplasmin measurement and ophthalmologic evaluation for KayserFleischer rings.

Differentials

Alzheimer Disease Cardioembolic Stroke Chorea in Adults Cortical Basal Ganglionic Degeneration Dementia With Lewy Bodies Dopamine-Responsive Dystonia Essential Tremor Hallervorden-Spatz Disease Huntington Disease Lacunar Syndromes Multiple System Atrophy Neuroacanthocytosis Normal Pressure Hydrocephalus Olivopontocerebellar Atrophy Parkinson-Plus Syndromes Progressive Supranuclear Palsy Striatonigral Degeneration Vascular Dementia Wilson Disease

Approach Considerations
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on magnetic resonance imaging (MRI) and computed tomography (CT) scan are unremarkable. Positron emission tomography (PET) and single-photon emission CT (SPECT) may show findings consistent with Parkinson disease, and olfactory testing may provide early evidence of Parkinson disease but are not routinely needed. No laboratory or imaging study is

required in patients with a typical presentation. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. A substantial and sustained response to dopamine medications helps confirm the diagnosis. Over time, diagnostic accuracy improves as the progression of signs and symptoms and response to medications unfolds. When an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are essential tremor and the atypical parkinsonisms (MSA, PSP, CBD). These disorders also do not have laboratory biomarkers, and, therefore distinguishing among them is based on clinical information. In patients with an unusual presentation, diagnostic testing may be indicated to exclude other disorders in the differential diagnosis. Such tests may include serum ceruloplasmin, sphincter electromyography, or lumbar puncture.

Magnetic Resonance Imaging

MRI is useful to exclude multi-infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of diagnostic certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55 years.

PET and SPECT

PET and SPECT are useful diagnostic imaging studies, but they are not widely available and may not be covered by insurance. Moreover, they are not needed for routine clinical diagnosis in patients with a typical presentation. At the onset of symptoms, patients with Parkinson disease show approximately 30% decrease in 18F-dopa uptake in the contralateral putamen. 18F-dopa is taken up by the terminals of dopamine neurons and converted to 18F-dopamine. The rate of striatal 18F accumulation reflects transport of 18F-dopa into dopamine neurons and its decarboxylation to 18F-dopamine, which is stored in dopamine nerve terminals in the striatum. 11C-Nomifensine and cocaine analogues such as [123 I]-beta-CIT and [123 I]FP-CIT bind to dopamine reuptake sites on nigrostriatal terminals and provide an index of the integrity of nigrostriatal projections. Deficits on fluorodopa PET or [123 I]-beta-CIT SPECT indicate a dopamine deficiency syndrome but do not necessarily differentiate Parkinson disease from atypical parkinsonisms, including multiple system atrophy and progressive supranuclear palsy.

Ioflupane I123 (DaTscan) is a radiopharmaceutical indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adults with suspected Parkinsonian syndromes (PSs). This agent may be used to help differentiate essential tremor from tremor due to PSs (idiopathic Parkinson disease, multiple system atrophy, and progressive supranuclear palsy).

Histologic Findings
Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially in the substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called Lewy bodies. The primary biochemical defects are loss of striatal dopamine, which results from degeneration of dopamine-producing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the caudate nucleus. According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem and slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex. Lewy body pathology is also observed in autonomic nerves of the gut and heart.

Serum Ceruloplasmin
Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease in patients younger than 40 years who present with parkinsonian symptoms. If the ceruloplasmin level is low, measurement of 24-hour urinary copper excretion and slit-lamp examination for KayserFleischer rings must be performed.

Sphincter Electromyography
Abnormal results on urinary sphincter electromyography have been noted in patients with multiple system atrophy, which is a Parkinson-plus syndrome.

Olfactory Testing
Olfactory testing can reveal problems with olfaction, which may precede the motor complications of Parkinson disease by several years.[14] However, olfactory loss is not specific and can also occur in Alzheimer disease.

Lumbar Puncture
Lumbar puncture should be performed if signs of normal-pressure hydrocephalus are observed (eg, incontinence, ataxia, dementia). The clinical picture usually improves after removal of about 20 mL of cerebrospinal fluid.

Dopa-responsive dystonia should be considered in patients with juvenile-onset dystonia and parkinsonism, particularly with diurnal fluctuations in symptoms. In such patients, a trial of levodopa is critical. Additional tests for this condition include measurement of cerebrospinal fluid concentrations of biopterin, neopterin, and the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of dopa-responsive dystonia, an altered pattern of decreases in these compounds is observed. Go to the Lumbar Puncture topic for detailed information on indications for the procedure, contraindications, and a step-by-step discussion containing images and video on how to perform the procedure.

Approach Considerations
The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly after diagnosis.[15] Levodopa coupled with a peripheral decarboxylase inhibitor (PDI) (Sinemet) remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. Medications usually provide good symptomatic control of motor signs for 4-6 years. After this, disability progresses despite best medical management, and many patients develop long-term motor complications, including fluctuations and dyskinesias. Additional causes of disability in late disease include postural instability (balance difficulty) and dementia. Thus, symptomatic therapy for late disease requires different strategies. The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment. Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesias. For older patients and those with cognitive impairment, less emphasis is placed on long-term considerations; the focus is on providing adequate symptomatic benefit in the near term with as few adverse effects as possible. For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation, surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely replaced neuroablative lesion surgeries. Experimental surgical approaches include transplantation and gene therapy. In addition to treatment for motor signs, patients with Parkinson disease may require therapy for a host of nonmotor symptoms, including depression, dementia, hallucinations, REM sleep behavior disorder, orthostatic hypotension, and constipation.

In 2010, the American Academy of Neurology released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following[16] :

Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction. Polyethylene glycol may be considered to treat constipation. Modafinil should be considered for patients who subjectively experience excessive daytime somnolence. For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms. Evidence is also insufficient to support or refute the use of melatonin for poor sleep quality. Levidopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease. Methylphenidate may be considered for fatigue. Note: methylphenidate has the potential for abuse and addiction. Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, and anxiety.

Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of dopamine neurons. Currently, no proven neuroprotective therapies exist for Parkinson disease. If a neuroprotective therapy were available for Parkinson disease, it would be administered from the time of diagnosis onward. At the current time, the greatest interest in possible neuroprotection resides with the MAO-B inhibitors selegiline and rasagiline. Other agents of interest include coenzyme Q10 and creatine.

Selegiline
Selegiline (Eldepryl) was shown conclusively to delay the need for levodopa therapy in early Parkinson disease, according to the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study. The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/d) or placebo and tocopherol (2000 IU/d) or placebo. Patients who received selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy. Patients who received placebo required levodopa at a projected median of 15 months from enrollment, while those who received selegiline required levodopa at a projected median of 24 months after enrollment. Tocopherol had no effect on progression of disability.[17] Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not possible to determine whetheraneuroprotective effect contributed to the delay in need for levodopa in this study. In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less clinical progression and required less levodopa than patients receiving placebo. In the study, patients with early Parkinson disease were randomized to selegiline or placebo and levodopa was added as needed.[18] After 5 years, subjects treated with placebo had UPDRS scores that were 35% higher (worse) than those treated with selegiline, even as they

were receiving 19% higher doses of levodopa. This is a striking finding considering that as monotherapy in early disease, selegiline only provides modest symptomatic improvement. Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease. Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP toxicity, even when the agent was administered after a delay sufficient to allow the oxidation of MPTP to MPP+,[19] an effect that cannot be attributed to MAO-B inhibition. In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and antiapoptotic proteins. Evidence indicates that one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's amphetamine metabolites may interfere with its neuroprotective actions.

Rasagiline
Rasagiline (Azilect) is an MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. Possible disease-modifying effects of rasagiline were studied in 2 large, delayed-start studies. In delayed-start studies, subjects are randomized to treatment with the active study medication or placebo (phase I), followed by the active study medication (phase II). In the second phase of the study, subjects in both arms are receiving active study medication, and if this period is long enough to allow full wash-in of symptomatic effects, any differences between the groups should be due to enduring benefits (ie disease modification) that accrue only to the group receiving the active study medication during the first phase of the study. Treatment with rasagiline 2 mg/d for 1 year provided significantly greater improvement than treatment with placebo for 6 months followed by rasagiline 2 mg/d for 6 months, in the TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) study, a clinical trial of patients with early Parkinson disease.[20] When patients were followed long term (5.5-6 y), those who started rasagiline at the beginning of the study experienced 16% less progression of disability than those who started it after 6 months.[21] Similarly, patients who received rasagiline 1 mg/d from the start of the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) trial, a large and rigorous delayed-start study of rasagiline, had less progression of clinical disability over 18 months than those who received rasagiline 1 mg/d after a delay of 9 months.[22] These results are potentially consistent with a disease-modifying effect of rasagiline. However, 18 months of treatment with rasagiline 2 mg/d did not provide a better outcome than treatment with placebo for 9 months followed by rasagiline 2 mg/day for 9 months.[22] The reason for the conflicting results of the 1 mg/d and 2 mg/d delayed-start comparisons in the ADAGIO study is not known. However, a subanalysis evaluating the most affected quartile at baseline was positive for both 1 mg/d and 2 mg/d.[23] This suggests the possibility that a

symptomatic floor effect could have interfered with the studies ability to assess disease modification in these very early patients using the higher dose.

Co-enzyme Q10
In a preliminary study, coenzyme Q10, 1200 mg/d, slowed progression of Parkinson disease disability. Coenzyme Q10 is a scavenger of free radicals.[24]

Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit in early Parkinson disease include MAO-B inhibitors, dopamine agonists, and levodopa.

MAO-B inhibitors
MAO-B inhibitors provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients. When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (eg, a dopamine agonist or levodopa) can be added.

Levodopa
Levodopa coupled with a PDI (Sinemet) remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. Levodopa/PDI is introduced at a low dose and escalated slowly. Currently available levodopa preparations in the United States include levodopa/carbidopa, levodopa/carbidopa CR, levodopa/carbidopa orally disintegrating tablet, and levodopa/carbidopa/entacapone (Stalevo). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa but dissolves on the tongue without the need to swallow it with water. In the STRIDE-PD study, patients with early Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more dyskinesia than patients treated with levodopa/ carbidopa; therefore, it is not recommended for treatment of early disease.[25] Levodopa is started at a low dose and slowly titrated to control clinical symptoms. Most patients experience a good response on a daily dosage of 400-600 mg/d (usually divided tid or qid) for 35 years or more. Doses higher than those necessary to control symptoms adequately should be avoided because higher doses increase the risk for the development of dyskinesia. If nausea occurs, the levodopa dose can be taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone (available outside the United States).

Dopamine agonists
Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, has been shown to cause less development of motor fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these studies indicate that the benefit of dopamine agonists in delaying motor complications is due to their ability to delay the need for levodopa/PDI.[26, 27] Dopamine agonists provide symptomatic benefit reasonably comparable to levodopa/PDI in early disease but lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. They provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they have more adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders. However, these adverse effects resolve upon lowering the dose or discontinuing the medication. Dopamine agonists are commonly reserved for younger individuals (< 65-70 y) who are cognitively intact. When the dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, the authors then often add levodopa/PDI. However, dopamine agonists may provide good symptom control for several years. For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to treat with a dopamine agonist prior to levodopa and add levodopa/PDI when necessary. For patients who are demented or older than 70 yearswho may be prone to adverse effects, such as hallucinations, from dopamine agonistsand for those likely to require treatment for only a few years, the authors may elect not to use a dopamine agonist and instead depend on levodopa/PDI as primary symptomatic therapy. When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects become problematic. The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, somnolence, and impulse control disorders. Nausea usually can be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the United States, is very helpful in relieving refractory nausea. Patients on dopamine agonists should be routinely asked about sleepiness, sudden onset of sleep, and impulse control disorders such as pathologic gambling, shopping, Internet use, or sexual activity. Patients should be warned not to drive if they are experiencing undue sleepiness. In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with Parkinson disease.[28] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of impulse control disorders, including gambling.[29] Thus, further research is needed to understand the role of amantadine as a treatment or cause of impulse control disorders in patients with Parkinson disease.

Anticholinergic agents
For patients who have disability due to tremor that is not adequately controlled with dopaminergic medication, an anticholinergic agent can be used. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not another, a second anticholinergic usually can be tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in elderly persons.

Symptomatic Therapy, Advanced Disease

Patients initially experience stable, sustained benefit through the day in response to levodopa. However, after several months to years, many patients notice that the benefit from immediaterelease levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened duration of response becomes more fleeting, and clinical status fluctuates more and more closely in concert with peripheral levodopa concentration. Ultimately, benefit lasts only 1-2 hours. The time when medication is providing benefit for bradykinesia, rigidity, and tremor is called "on" time, and the time when medication is not providing benefit is called "off" time. For patients on CR levodopa/carbidopa, switching to immediate-release levodopa/carbidopa often provides a more consistent and predictable dosing cycle and allows finer titration. In general, smaller levodopa doses are administered more frequently. A dose should be sought that is sufficient to provide benefit without causing troublesome dyskinesia. The time to wearing-off then determines the appropriate interdose interval. The extreme of this strategy is using liquid levodopa, a solution with which the dose can be titrated finely and administered every hour. Amantadine (Symmetrel) may also be of benefit to reduce dyskinesia. COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD), thereby prolonging the levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a longer time. Because of the potential risk of hepatotoxicity with tolcapone (Tasmar), liver function test monitoring is required, and it should be used only in patients who are experiencing motor fluctuations on levodopa that cannot be adequately controlled with other medications. If dyskinesia emerges, the levodopa dose should be reduced. In patients who already have dyskinesia, the levodopa dose often is reduced by 30-50% at the time tolcapone is introduced. Entacapone (Comtan) is a COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with this medication. A combination tablet of levodopa/carbidopa/entacapone is now available.

Dyskinesia
By several months to years after the introduction of levodopa, many patients develop peak-dose dyskinesia consisting of choreiform, twisting/turning movements that occur when levodopaderived dopamine levels are peaking. At this point, increasing dopamine stimulation is likely to worsen peak-dose dyskinesias and decreasing dopamine stimulation may worsen Parkinson

disease motor signs and increase off time. The therapeutic window lies above the threshold required to improve symptoms (on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia threshold). The therapeutic window narrows over time because of a progressive decrease in the threshold for peak-dose dyskinesia. Although many patients prefer mild dyskinesia to off time, the clinician should recognize that dyskinesias can be sufficiently severe to be troublesome to the patient, either by interfering with activities or because of discomfort. Asking patients how they feel during both off time and time with dyskinesia is important in titrating medication optimally. Having patients fill out a diary may be helpful; the diary should be divided into half-hour time periods on which the patient denotes whether they are off, on without dyskinesia, on with nontroublesome dyskinesia, or on with troublesome dyskinesia (see image below). The goal of medical management is to minimize off time and time on with troublesome dyskinesia.

Parkinson disease diary. The patient or caregiver should place 1 check mark in each half-hour time slot to indicate the patient's predominant response during most of that period. The goal of therapeutic management is to minimize off time and on time with troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with permission.

Motor fluctuations
Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several different strategies, either alone or in combination, can be used to provide more sustained dopaminergic therapy. Possible strategies include adding a dopamine agonist, catechol-O methyltransferase (COMT) inhibitor, or MAO-B inhibitor; dosing levodopa more frequently; increasing the levodopa dose; or switching from immediate-release to controlled-release (CR) levodopa/carbidopa or levodopa/carbidopa/entacapone. Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be increased until off time is eliminated.

Motor fluctuations with dyskinesia

The treatment of patients with both motor fluctuations and troublesome peak-dose dyskinesia can be difficult. The goal of treatment in this situation is to provide as much good functional time through the day as possible. This is accomplished by maximizing on time without troublesome dyskinesia. An attempt is made to reduce both off time and time with troublesome or disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time and an increase in dopaminergic therapy may worsen peak-dose dyskinesia. For patients who have

motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation, surgery is considered

Tremor
Levodopa/PDI, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50% of patients. If a patient is experiencing troublesome tremor and symptoms are not controlled adequately with one medication, another should be tried. If the tremor is not controlled adequately with medication, thalamotomy or thalamic stimulation surgery may be considered at any time during the disease.

Deep Brain Stimulation

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease because it does not involve destruction of brain tissue; it is reversible; it can be adjusted as the disease progresses or adverse events occur; and bilateral procedures can be performed without a significant increase in adverse events. Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease largely because of long-term complications of levodopa therapy resulting in significant disability despite optimal medical management. A better understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity. Until recently, surgery for movement disorders involved predominantly destructive lesioning of abnormally hyperactive deep brain nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to lesioning procedures. Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed the focus of movement disorder surgery to 3 key gray matter structures: the thalamus, the globus pallidus, and the subthalamic nucleus (STN). (See the image below.)

Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN; lavender). STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease. A randomized controlled trial in 255 patients with advanced Parkinson disease found that bilateral DBS was more effective than best medical therapy in improving on time without troublesome dyskinesias, motor function, and quality of life at 6 months; however, DBS was associated with an increased risk of serious adverse events.[30] A study by Foltynie assessed 79 consecutive patients who underwent bilateral subthalamic nucleus DBS at the National Hospital for Neurology and Neurosurgery using an MRI-guided surgical technique without microelectrode recording.[31] At a median follow-up period of 12 months and 14 months, a mean improvement of 27.7 points (standard deviation, 13.8) was noted in the off-medication motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III), equivalent to a mean improvement of 52%. Significant improvements in dyskinesia duration, disability, and pain were noted. This confirms that image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability and improvements of quality of life in well-selected patients with Parkinson disease, with very low morbidity. In Australia, guidelines have been developed to help neurologists and general physicians identify Parkinson disease patients who may benefit from referral to a specialized DBS team; these teams assess the likely benefits and risks of DBS for each referred patient.[32] Please go to the topic Deep Brain Stimulation in Parkinson Disease for a more extensive discussion of deep brain stimulation in this setting, including mechanisms of action, advantages and disadvantages, and stages of the procedure.

Neuroablative Lesion Surgeries

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease. Lesion surgeries for Parkinson disease have largely been replaced by DBS. During neuroablation, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion.

The 2 most commonly performed neuroablative procedures are thalamotomy and pallidotomy, in which lesions are created in the VL thalamus and the GPi, respectively.

Ventrolateral thalamotomy
The VL thalamus receives afferent innervation from 2 primary sources: the GPi via the ansa lenticularis and thalamic fasciculus and the contralateral cerebellum via the superior cerebellar peduncle. These cerebellar fibers synapse primarily in the VIM and ventral oral posterior (VOP), the most posterior segments of the VL. Oscillating excitatory input from the cerebellum may be responsible for the tremor observed in Parkinson disease, as cellular activity synchronous with the frequency of parkinsonian tremor can be recorded in VL. These data support the clinical observation that lesions placed within VL (and specifically within VIM/VOP) arrest parkinsonian and essential tremors. VL thalamotomy was the most frequently performed procedure for movement disorders in the prelevodopa era because tremor responds best to thalamotomy and can be monitored more easily in the operating room than gait abnormalities, rigidity, and akinesia. Thalamotomy involves destruction of a part of the thalamus, generally the VIM, to relieve tremor. VIM almost unanimously is considered the best target for tremor suppression, with excellent short- and long-term results in 80-90% of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including GPi and STN, are preferred. Thalamotomy is indicated in patients with Parkinson disease who are disabled by medically refractory tremor. The anticipated benefit of tremor reduction or elimination must be considered carefully. Rest tremor alone is rarely disabling, and bradykinesia and rigidity can reduce dexterity irrespective of tremor. Most patients with Parkinson disease who undergo thalamotomy have significant improvement in tremor of the limbs contralateral to the side of the lesion. Bilateral thalamotomy is generally avoided because complications, especially speech and cognitive impairment, are common. The reported morbidity rate for thalamotomy ranges from 9-23%. The predominant complication is speech impairment with dysarthria and hypophonia. The risk of speech abnormalities is 30% for unilateral thalamotomy and greater than 60% following bilateral lesions. Other complications include memory loss, contralateral hemiparesis, and, more rarely, hemineglect, dystonia, hemiballismus, athetosis, and dyspraxia. Preoperative memory and language evaluation can help identify patients who are at greatest risk for postoperative cognitive and language dysfunction. In the largest series, the mortality rate for thalamotomy ranged from 0.5-1%. Death results almost exclusively from intraparenchymal hemorrhage.

Pallidotomy

Svenillson and Leksell described ventral posterior pallidotomy in the 1960s;[33] however, their report was largely overlooked. The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial pallidotomy effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al reported reduced tremor, rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy, prompting a reappraisal of the procedure performed with more modern techniques.[34] The negative symptoms of Parkinson disease (ie, rigidity, bradykinesia) are caused, in part, by excessive inhibitory output from the GPi to the VL thalamus (see Pathophysiology). Lesioning of the sensorimotor region of the GPi, which lies ventral and posterior in the nucleus, decreases this hyperinhibition of motor thalamus. Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have demonstrated significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant reduction in dyskinesia. Tremor improvement is less consistent than with thalamotomy. The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode recording. Less frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed. Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment.

Subthalamotomy
Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of Parkinson disease. Subthalamotomy involves destruction of a part of the STN. Although lesioning the STN usually has been avoided out of concern of producing hemiballismus, results obtained by experimental lesions of the STN in animals and humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically. Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson disease, as well as the reduction of motor fluctuations and dyskinesia.

Preoperative Evaluation
Good surgical outcomes begin with careful patient selection and end with attentive, detailoriented postoperative care. The authors believe that this level of care is best provided by a multidisciplinary team comprising a movement disorder neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential.

At the authors' movement disorder center, patients are evaluated for surgery as follows: 1. 2. 3. 4. Neurologist evaluation Neurosurgeon evaluation to identify potential surgical candidates Psychiatrist evaluation Medical evaluation

First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for successful STN DBS because a number of factors concur to determine positive surgical outcome.[35, 36] These can be summarized as follows:

A diagnosis of IPD Positive response to levodopa Absence of atypical parkinsonian features Advanced disease, virtually unmanageable with dopaminergic medications Relatively young age; however, advanced age (>75 y) is not an absolute contraindication to surgery (if a patient otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery should be offered) Normal cognition Absence of active psychiatric disease Good social support and access to programming

Potential surgical candidates then are evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:

Brain MRI to rule out comorbid conditions and to assess the degree of brain atrophy; significant atrophy may increase the risk of perioperative hemorrhage Detailed neuropsychological testing to rule out subtle cognitive impairment, which can be worsened by the surgical procedure

A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression, suicidality). A fluorodopa PET scan may be performed in the unusual circumstance that an alternative diagnosis of multiple system atrophy cannot be ruled out clinically. A medical evaluation is performed to determine the patient's general fitness for surgery. Surgery is reserved for patients with medically refractory Parkinson disease with disabling problems. Currently, the authors' center adopts the following surgical recommendations for patients with medically refractory Parkinson disease:

Unilateral pallidotomy is offered to patients with asymmetric Parkinson disease who develop fluctuations in their response to levodopa, including disabling dyskinesias and off-state dystonia. Bilateral pallidotomy is avoided, although investigations are underway to evaluate contralateral GPi DBS in patients who have undergone a successful pallidotomy and are experiencing disease progression in the untreated side. Thalamotomy or thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling tremor (more commonly, this procedure is performed on patients with disabling essential tremors). Thalamic DBS is preferred over thalamotomy, particularly in young patients with Parkinson disease who are disabled solely by tremor early in the course of their disease, because it gives the option of removing the stimulator if more effective therapies are developed or if symptom progression necessitates DBS at another target such as STN. Bilateral STN DBS is offered to patients with advanced Parkinson disease with bilateral levodopa-induced dyskinesia, significant gait disturbances and axial symptoms, or medically refractory rigidity and akinesia. Prior to surgery, the patient should be informed that these procedures do not cure Parkinson disease and that progression is expected.

Transplantation
Neural transplantation is a potential treatment for Parkinson disease because the neuronal degeneration is site and type specific (ie, dopaminergic), the target area is well defined (ie, striatum), postsynaptic receptors are relatively intact, and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function. Transplantation of autologous adrenal medullary cells and fetal porcine cells have not been found to be effective in double-blind studies and have been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded promising results, 3 randomized, double-blind, sham-surgerycontrolled studies found no net benefit. In addition, some patients receiving these transplants developed a potentially disabling form of dyskinesia that persisted even after withdrawal of levodopa. Features such as gait dysfunction, freezing, falling, and dementia are likely due to nondopaminergic pathology and hence are unlikely to respond to dopaminergic grafts.[37] Lewy bodylike inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions stained positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting that Parkinson disease may affect grafted cells.[38] Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have been implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgerycontrolled study of this technique is under way.[39] In one case study, however, postmortem examination in a patient who died 6 months after surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.[40]

Gene Therapy
Several studies have demonstrated the safety of gene therapy as a treatment for Parkinson disease, and larger studies have been initiated to examine the efficacy of this procedure. The goal of these studies is to modify genes involved in the development of Parkinson disease. In a phase I trial of gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2), the safety and efficacy of intraputaminal AAV2-neurturin was not superior to sham-surgery, but further study should focus on the possibility of a benefit with additional targeting of the substantia nigra.[41] However, a double-blind, phase II, randomized, controlled trial of patients aged 3075 years, who had progressive levodopa-responsive Parkinson disease and an overnight off-medication UPDRS motor score of 25, found that the efficacy and safety of bilateral infusion of AAV2GAD in the subthalamic nucleus suggested promise for gene therapy for neurological disorders.[42]

Management of Psychiatric Comorbidities

Dementia
Although no specific therapy exists for dementia, the American Academy of Neurology evaluated the evidence regarding the use of cholinesterase inhibitors in Parkinson disease dementia.[43] Based on their review, they suggested that rivastigmine (Exelon) and donepezil (Aricept) are probably effective in treating the dementia. The risk of potentially exacerbating motor symptoms may limit their widespread use. Anticholinergic drugs used for the treatment of motor manifestations of Parkinson disease may exacerbate memory impairment. When possible, avoid these medications.

Depression
Depression affects as many as 40% of patients with Parkinson disease. This may be due in large part to neurochemical changes associated with the disease. Limited studies suggest that tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants have efficacy in depression in this setting. Case reports exist of worsening of Parkinson disease motor features by SSRIs, but this has not been demonstrated in population studies. The combination of selegiline and an SSRI potentially can cause the serotonin syndrome, with symptoms of mental status changes, myoclonus, tremor, diaphoresis, incoordination, and possibly coma or death. This appears to be very rare and might be due to individual variations in metabolic pathways. The combination of selegiline at an oral dose of 10 mg/d or less and an SSRI generally is considered safe, although clinical monitoring is warranted.

Psychotherapy can play an important role in the treatment of depression,[44] and, in severe refractory cases, electroconvulsive therapy may be effective.[45] There is limited evidence showing any benefit with dopamine agonists[46] and monoamine oxidase inhibitors.[47] One study suggests that dopamine agonist treatment of Parkinson disease carries a substantial risk of pathological behaviors, which occurred in 16% of patients receiving these agonists.[48] The vast majority of affected cases (94%) were concurrently taking carbidopa/levodopa, suggesting concurrent therapy with a dopamine agonist appeared to be an important risk factor.

Anxiety
SSRIs and venlafaxine (Effexor) can be beneficial. Buspirone is well tolerated but has not been studied in this population. Benzodiazepines may help severe anxiety, but adverse effects such as cognitive impairment and balance problems may be concerning. Behavior modification techniques can play an important role in the treatment of anxiety.[49] However, the 2010 American Academy of Neurology practice parameter on the treatment of nonmotor symptoms in Parkinson disease found insufficient evidence to support or refute the treatment of anxiety in Parkinson disease with levodopa.[16]

Sleep disturbances
Benzodiazepines can be helpful in the treatment of rapid eye movement sleep behavior disorder (RBD), and obstructive sleep apnea can be treated with positive airway pressure with either continuous pressure or bilevel pressure. Sleep hygiene techniques include avoiding stimulants/fluids near bedtime, avoiding heavy late-night meals, and following a regular sleep schedule.[49, 50] The 2010 American Academy of Neurology practice parameter found insufficient evidence to support or refute beneficial effects from the treatment of RBD in Parkinson disease. Other sleep disorders may benefit from treatment. Levodopa/carbidopa should be considered to treat periodic limb movements of sleep. Modafinil may improve patients subjective perceptions of excessive daytime somnolence (EDS), and methylphenidate may be considered in patients with fatigue.[16]

Hallucinations
Hallucinations usually occur in the presence of an underlying dementia. Mild, nonthreatening hallucinations may be tolerated, but an effort should be made to eliminate more severe or threatening hallucinations. In patients who experience hallucinations, minor agents such as amantadine and anticholinergics should be titrated down and discontinued. If hallucinations are still present, dopamine agonists should be discontinued slowly, and levodopa/PDI should be titrated to see if hallucinations can be resolved while still maintaining adequate control of motor symptoms. If hallucinations persist, an atypical neuroleptic should be added. These agents reduce hallucinations and induce little or no worsening of parkinsonian motor features.

Quetiapine (Seroquel) is the most widely used medication to treat hallucinations in Parkinson disease. It is generally effective and does not require blood monitoring. It is introduced at a dose of 25 mg and increased to 50-300 mg/d as needed. Clozapine (Clozaril) can be introduced using a chip (approximately one eighth) of a 25-mg tablet. The dose can be escalated slowly, and most patients experience good benefit at a dose of 12.5-25 mg/d. Weekly blood tests are required because of the risk of agranulocytosis. Olanzapine (Zyprexa) and risperidone (Risperdal) appear to have slightly more parkinsonian adverse effects than clozapine or quetiapine.

Speech Therapy
The laryngeal manifestations of Parkinson disease often lead to decreased participation in the activities of daily living because of an inability to communicate effectively. During the course of the disease, 45-89% of patients report speech problems, and more than 30% find speech problems to be the most debilitating part of the disease. Medications and surgery cannot effectively treat the laryngeal manifestations of Parkinson disease. For this reason, speech therapy plays the key role in the disease's vocal treatment regimen. Speech therapy is effective in treating the laryngeal manifestations of Parkinson disease, but despite the significant number of patients with vocal symptoms, only an estimated 34% of patients with Parkinson disease undergo speech therapy. The Lee Silverman Voice Treatment (LSVT) is a program designed to increase vocal intensity in patients with IPD. The treatment focuses on a simple set of tasks that are practiced intensively, 4 sessions per week during a 4-week period, resulting in maximization of phonatory and respiratory functions. The goal of LSVT is to improve vocal performance for 6-24 months without interval intervention. LSVT focuses on maximizing vocal effort ("think loud, think shout") and maximizing sensory perception of vocal effort and loudness by therapists. Therapists who quantify results give constant feedback to patients during sessions and encourage patients to self-monitor and internally calibrate their loudness. After LSVT, patients with IPD speak at a normal volume and with a healthy voice quality despite the need to "think loud, think shout." In studies with a 2-year follow-up, patients who received LSVT maintained or improved vocal intensity compared with pretreatment levels. Glottal incompetence and swallowing ability both improve after LSVT without any significant change in supraglottal hyperfunction. Preliminary PET scans after LSVT training in patients with IPD show reduced activity in the globus pallidus, an effect similar to pallidotomy. LSVT may also stimulate coordination of motor output beyond the phonatory system in the form of increased orofacial expression. Other therapies have been suggested for the treatment of the vocal symptoms in IPD, but most data so far support LSVT as the promising therapy for IPD laryngeal symptoms. Alternative methods of delivering therapy that do not involve 16 face-to-face sessions with a therapist are currently being studied. These methods incorporate webcam delivery of LSVT (eLOUD) and software programs that patients can perform at home. These technologically enhanced methods,

when used to replace half of the face-to-face sessions, have documented outcomes that are equivalent to classic LSVT. The hope is that such alternatives will be implemented to allow a less transportation-intensive therapy course for the patient and to allow follow-up review of the LSVT techniques as needed.

Dietary Considerations
Proper nutritional support is essential for patients with Parkinson disease, including adequate dietary fiber to prevent the common problem of constipation. Protein-restricted diets may be useful in patients who are experiencing motor fluctuations with long-term levodopa treatment. Levodopa is transported into the brain by a carrier protein that also transports large neutral amino acids found in dietary protein. Consequently, high-protein meals can compete for the transport of levodopa and reduce or eliminate its effects. A proteinrestricted diet can therefore improve the response to levodopa and can be useful in patients with otherwise refractory motor fluctuations. Two general approaches are used for a protein-restricted diet. In one, the total daily protein intake is spread more or less equally over the day. The other approach is consuming food very low in protein or not containing protein during the day and eating a high-protein meal in the evening. Generally, these diets are difficult to follow; however, in patients with severe, unpredictable motor fluctuations, this approach may be worthwhile.

Consultations
Generally, patients with Parkinson disease are best treated and monitored by a neurologist, except in the early stage of the disease. Depending on the patient, consultations may include the following:

Neurosurgeon Psychiatrist Urologist Physiatrist Nutritionist Otolaryngologist Gastroenterologist Speech therapist

Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia refractory to medical treatment. However, patients with dementia or significant psychiatric or behavioral problems are not candidates for the current neurosurgical treatments for Parkinson disease.

Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with refractory depression or psychosis. A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction. A physiatrist, physical therapist, and occupational therapist may be able to improve the patient's ability to perform activities of daily living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb dystonia can be very helpful and are administered by specially trained physiatrists or neurologists. A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse effects of levodopa. An otolaryngologist can offer vocal fold bulking procedures in the form of vocal fold injection or Gore-Tex thyroplasty as a possibility in treating refractory true vocal fold bowing. Bilateral injections to medialize the vocal fold can offer improvement, unless the patient is already aphonic due to advanced disease. Bilateral collagen, gel, fat and hydroxyapatite injections have been used for this purpose.[51] Articulatory problems can persist, and the result of surgery can be disappointing. A gastroenterologist and speech therapist may be needed to evaluate dysphagia, a common complication in patients with more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the salivary glands, usually administered by otolaryngologists. In some patients, a gastrostomy may be needed to maintain adequate nutrition.

Long-term Monitoring
Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral abnormalities. Once patients are stable on medications, provide follow-up care at least every 3-6 months and periodically adjust medication dosages as necessary. Medication management provides the most effective treatment of Parkinson disease for the first 4-6 years. Thereafter, this disabling disease advances despite continuing medication management.