Diagnosis and Medical Management of Parkinson Disease

Avner Thaler, MD, PhD; Roy N. Alcalay, MD, MS Movement Disorders p. 1281-1300 October 2022, Vol.28, No.5 doi: 10.1212/CON.0000000000001152
REVIEW ARTICLES
BROWSE ARTICLES
Continuum Audio
KEY POINTS

Older age and male sex are the most established risk factors for Parkinson disease (PD). The most established environmental risk factor for PD is pesticide exposure.

The seven genes clearly associated with PD risk are SNCA, LRRK2, and VPS35 (dominant); PRKN, PINK1, and DJ-1 (recessive); and GBA (risk factor).

The definitive diagnosis of PD is based on pathology. The two key required criteria are atrophy of dopaminergic cells in the substantia nigra and accumulation of α-synuclein.

The clinical diagnosis of PD was historically based on motor symptoms. More recently, nonmotor symptoms were added to the criteria to improve accuracy.

Postural instability, which is a feature of parkinsonism, is not a part of the International Parkinson and Movement Disorders Society criteria for PD diagnosis as it usually appears at later stages of PD.

Clinical red flags raise suspicion to an alternative diagnosis, most often multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies.

The Hoehn and Yahr scale is often used to capture the severity and progression of motor symptoms of PD. The Movement Disorders Society Unified Parkinson’s Disease Rating Scale is used to quantify disease severity.

The diagnosis of PD is primarily clinical. Ancillary diagnostic tests can be useful when the clinical diagnosis remains unclear.

MRI or other structural imaging may detect causes of secondary parkinsonism, such as hydrocephalus or stroke.

Dopamine transporter single-photon emission computed tomography may be helpful in detecting dopamine deficiency but is less useful in tracking the progression of intermediate or advanced stages of PD or in distinguishing PD from other neurodegenerative parkinsonian syndromes.

Exercise and physical activity should be recommended for all patients with PD.

No evidence exists that early pharmacologic (eg, levodopa) treatment of Parkinson disease has disease-modifying properties. However, neither does evidence exist for the benefit of delaying pharmacologic treatment.

Comparing levodopa to dopamine agonists and monamine oxidase type B inhibitors has indicated that although all three therapies are efficacious, levodopa treatment is best tolerated and maximizes improvement in mobility scores.

When impulse control disorder occurs, reduction in the dosage of dopamine agonist therapy is warranted; however, this might be complicated by the development of a dopamine agonist withdrawal syndrome.

When motor symptoms advance, a key consideration is to reduce the motor off time and fluctuations. Continuous levodopa administration or deep brain stimulation should be considered.

Careful adjustment of the dopaminergic treatment is a logical first step in the treatment of nonmotor symptoms in PD.

Hallucinations in PD may significantly impair quality of life and limit the use of dopaminergic intervention. Careful management of hallucinations is indicated.

Although the link between rapid eye movement (REM) sleep behavior disorder and PD is well established, evidence on effective management of REM sleep behavior disorder is insufficient.

PURPOSE OF REVIEW Parkinson disease (PD) is a common neurodegenerative movement disorder, the prevalence of which is rising as the world population ages. It may present with motor and nonmotor symptoms, and symptomatic treatment significantly improves quality of life. This article provides an overview of the workup and differential diagnosis for PD and reviews genetic and environmental risk factors and current treatments.

RECENT FINDINGS Novel treatments for the motor (eg, fluctuations and off times) and nonmotor (eg, hallucinations and orthostatic hypotension) complications of PD have been approved in recent years. In addition, with recent advances in our understanding of the genetics of PD, significant research is focusing on identifying at-risk populations and introducing genetically targeted interventions (precision medicine).

SUMMARY PD is a heterogeneous neurodegenerative movement disorder. Affected individuals may receive substantial symptomatic relief from nonpharmacologic, pharmacologic, and surgical interventions. Although no intervention to modify the progression of PD is currently available, precision medicine and modulation of the immune system are a major focus of ongoing research.

Address correspondence to Dr Roy N. Alcalay MD, MS, 6 Weizman St, Tel Aviv 6423906, Israel, [email protected]

RELATIONSHIP DISCLOSURE: Dr Thaler has received personal compensation in the range of $500 to $4999 for serving as a consultant for AbbVie Inc. The institution of Dr Thaler has received research support from Biogen and The Michael J. Fox Foundation. Dr Alcalay has received personal compensation in the range of $500 to $4999 for serving as a consultant for AVROBIO, Inc; Caraway Therapeutics, Inc; GlaxoSmithKline plc; Janssen Global Services, LLC; Merck & Co, Inc; Ono Pharmaceutical Co, Ltd; and Takeda Pharmaceutical Company. Dr Alcalay has received personal compensation in the range of $10,000 to $49,999 for serving as a consultant for Sanofi. The institution of Dr Alcalay has received research support from Biogen, the Department of Defense, The Michael J. Fox Foundation, the National Institutes of Health, and the Parkinson’s Foundation.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Drs Thaler and Alcalay report no disclosures.

INTRODUCTION

Parkinson disease (PD) is the second most common neurodegenerative disorder, afflicting more than 6.1 million people across the world as of 2016, with effective symptomatic treatment available for decades. The natural history of PD is heterogeneous and includes a wide range of motor and nonmotor symptoms. The traditional definition of PD is based on cardinal motor symptoms, including bradykinesia, resting tremor, rigidity, and gait impairment; however, more recent diagnostic criteria have been developed that integrate nonmotor symptoms, including autonomic, affective, cognitive, and sleep impairments (refer to the section on clinical diagnosis later in this article). Because of the heterogeneity in symptoms and rate of progression, clinical management should be tailored individually.

RISK FACTORS

Age is the single most important risk factor for PD. Juvenile PD, defined as onset younger than 21 years of age, is exceedingly rare, and only 5% to 10% of patients are diagnosed before the age of 50. Mean age at onset is approximately 60 but varies across studies, and women are less often affected than men. To date, most studies have been performed on patients of European decent, thus less is known about PD prevalence and clinical presentation in underrepresented populations. Specifically, it remains unknown whether people of African descent have a lower prevalence and incidence of PD or if prevalence/incidence discrepancies are a result of disparities in health care access.

PD is a genetically complex disorder that can result from genetic alterations, environmental exposures, and the interaction among these factors. Of all environmental risks, exposure to pesticides has been most consistently associated with PD risk; consumption of dairy products, rural living, and traumatic brain injury have also been associated with increased risk. In contrast, consumption of coffee, smoking, physical activity, and use of nonsteroidal anti-inflammatory drugs are associated with lower risk for PD. Several toxins can produce a clinical syndrome resembling PD, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes irreversible damage to dopaminergic neurons in the substantia nigra.

Genetic Risk Factors

Significant headway has been made in the understanding of PD genetics within the past 2 decades. Genetic risk factors can be crudely organized by the level of risk they convey. Rare pathogenic variants in SNCA, LRRK2, and VPS35 cause dominantly inherited PD, with varying levels of penetrance. Homozygous and compound heterozygous mutations in PRKN, PINK1, and PARK7 (previously known as DJ-1) can cause recessively inherited PD. Glucocerebrosidase (GBA) pathogenic variants are relatively common but convey a lower risk for PD. Combined, pathogenic variants in these seven genes are present in about 10% to 15% of all people with PD.table 2-1 summarizes clinical and phenotypic data on these seven genes. Currently, clinical genetic testing is rarely offered in the workup of PD, but with the rapid evolution of genetic research, clinical genetic testing is on the rise. Various commercial laboratories offer different PD panels that look for mutations among the 5 to 62 genes associated with an increased risk of PD. Most of these panels include the seven genes mentioned above. In addition to mendelian inheritance, many single-nucleotide polymorphisms (SNPs) are associated with a mildly increased risk of PD; combined, these may have a significant role in the development of PD. Recent research studies have analyzed the risk of these SNPs when combined to generate a polygenic risk score, with a high polygenic risk score suggesting a high risk of PD diagnosis. Currently, polygenic risk scores are not commercially available for PD.

DIAGNOSIS OF PARKINSON DISEASE

The gold standard diagnosis of PD is by pathology, which is not, of course, practiced in the clinical setting. This section describes the pathologic and clinical diagnosis of PD.

Pathology: the Gold Standard Diagnosis

The definitive diagnosis of PD is based on pathology, which is obtained by postmortem analysis. The two key criteria for the diagnosis are atrophy of dopaminergic cells in the substantia nigra, not otherwise explained, and accumulation of α-synuclein in Lewy bodies and neurites in the brain. Indeed, many of the motor symptoms that define PD are a result of cell loss in the substantia nigra dopaminergic neurons. This results in an imbalance between the direct and indirect pathways of the basal ganglia, leading to bradykinesia. When PD symptoms appear, up to 60% of the dopaminergic neurons have already been lost. This loss is greatest in the ventrolateral tier of the substantia nigra and in the caudal putamen. The primary cause of this slowly progressive cellular atrophy is unknown. Several mechanisms have been implicated in PD pathophysiology, including mitochondrial, proteasomal, and lysosomal dysfunction; protein aggregation; oxidative stress; and neuroinflammation. In many autopsies of people with PD, and especially in those who died at advanced age, mixed pathology (of Alzheimerlike and vascular changes) may be found. Identifying mixed pathology highlights the role of additional pathologic processes (in addition to α-synuclein deposition) in the development of PD symptoms (eg, cognitive impairment) and may reduce enthusiasm in identifying α-synuclein as a potential target for future PD therapies.

Clinical Diagnosis

Historically, the clinical criteria for the diagnosis of PD were developed in comparison to the gold standard pathologic diagnosis (ie, criteria that will accurately predict the pathologic diagnosis based on motor symptoms). In 2015, the International Parkinson and Movement Disorder Society (MDS) updated its criteria for PD diagnosis (MDS-PD) to improve diagnostic accuracy relative to the previously used Queen Square Brain Bank criteria. In the MDS-PD criteria, the motor syndrome remains the core feature of the disease, but nonmotor features are also included.

The diagnosis of PD is based on major motor manifestations: bradykinesia in combination with either resting tremor or rigidity or both. The assessment of these symptoms should be performed according to the revised MDS-Unified Parkinson's Disease Rating Scale (UPDRS) to encourage interrater reliability among examiners. Bradykinesia is defined as slowness in movement and reduction in amplitude or speed of continuous movements. It should be assessed in each limb separately. Rigidity is defined as increased resistance to passive movement, with cogwheel phenomena usually present on examination. Resting tremor is a 4-Hz to 6-Hz tremor in a fully resting limb. Postural instability, which is a feature of parkinsonism, is not a part of the MDS-PD criteria as it usually appears at later stages of PD.

Supportive criteria for the diagnosis of PD include beneficial response to dopaminergic therapy (ie, to levodopa or dopamine agonists), levodopa-induced dyskinesia, hyposmia, and cardiac sympathetic denervation as demonstrated on metaiodobenzylguanidine (MIBG) scintigraphy. Observations that make the diagnosis of PD less likely include supranuclear gaze palsy (suggesting a diagnosis of progressive supranuclear palsy [PSP]), cerebellar symptoms (indicating a diagnosis of multiple system atrophy [MSA] or PSP), parkinsonism restricted to the lower limbs for more than 3 years (suggestive of vascular parkinsonism), a diagnosis of probable frontotemporal dementia, recent treatment with a dopamine receptor blocker or dopamine depletor, absence of response to high-dose levodopa (>600 mg/d), cortical sensory loss, and normal presynaptic dopaminergic imaging.

In addition, several red flags were proposed to indicate the possibility of an alternative diagnosis:

  • Rapid progression requiring use of wheelchair within 5 years of diagnosis (often seen in MSA and PSP)
  • No motor progression for 5 years (suggesting essential tremor)
  • Early bulbar dysfunction (dysphonia, dysarthria, or dysphagia, suggesting MSA)
  • Inspiratory respiratory dysfunction (stridor, suggesting MSA)
  • Severe autonomic failure within 5 years of diagnosis (orthostatic hypotension or urinary incontinence, suggesting MSA or dementia with Lewy bodies [DLB])
  • Recurrent falls (>1 per year) within 3 years of diagnosis (suggesting PSP)
  • Disproportionate anterocollis within 10 years of diagnosis (suggesting MSA)
  • Absence of nonmotor symptoms (suggesting either dystonic or essential tremor)
  • Unexplained pyramidal signs (seen in PSP and MSA)
  • Bilateral symmetric disease from onset (seen in PSP and MSA)

Diagnostic errors, which depend on the clinical presentation, are common in early stages of PD and improve with longer follow-up as the development of additional symptoms and the time course of symptom progression are considered. Up to 15% of patients with an initial clinical diagnosis of PD are found to be misdiagnosed based on postmortem pathology. When the primary presentation is tremor, essential tremor and other causes of tremor may lead to a diagnostic error. When the primary symptoms are bradykinesia, rigidity, and gait impairment, the differential diagnosis of PD includes vascular parkinsonism, MSA, PSP, and corticobasal degeneration.

Progression of Motor Symptoms

The motor symptoms of PD tend to progress over time. After the initiation of dopaminergic treatment, motor fluctuations may appear, in which the effect of the dopaminergic therapy does not last until the next dose is administered, and an on-off phenomenon develops, in which patients may feel that their symptoms are well controlled in the on state and less controlled in the off state. Further, dyskinesia may appear at the peak of the dopaminergic effect or before or after doses. Freezing of gait is a common PD symptom that may appear later in the disease course; it is defined as a brief episodic absence or reduction of forward progression of the feet despite the intention to walk. Freezing episodes can be triggered by motor, cognitive, or affective causes.

The severity of the motor symptoms of PD can be described using the five-point Hoehn and Yahr scale (table 2-2); however, the rate of motor progression of PD is very heterogeneous and nonlinear. A 2020 study that assessed patients with PD without access to treatment identified that 40% of participants reached Hoehn and Yahr stage 3 after 7 years of disease.

Nonmotor Symptoms

The nonmotor features of the disease significantly affect patients’ well-being (table 2-3). Dementia often occurs as PD progresses, and up to half of people with PD will report substantial cognitive impairment within 10 years of diagnosis, resulting from neuronal loss and both dopaminergic and cholinergic impairment. The cognitive domains involved include frontal/executive, memory, visuospatial, and, less commonly, language. Patients should be screened yearly for cognitive decline. It should be noted that the MDS-PD criteria do not consider dementia as an exclusion criterion for PD, regardless of when it develops in relation to motor symptoms. Further, the new MDS-PD criteria recommend that for patients with a diagnosis of DLB made according to consensus criteria, the diagnosis can optionally be qualified as PD (DLB subtype). For more information, refer to the article “Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies” by Daniel Weintraub, MD, and David Irwin, MD, in this issue of Continuum.

Autonomic dysfunction is also common in PD, in both early and late stages of the disease. It is associated with both motor symptom severity and cognitive deterioration and is caused by accumulation of α-synuclein within the central and peripheral nervous systems. However, severe autonomic involvement is suggestive of MSA. For more information on MSA, refer to the article “Multiple System Atrophy” by Daniel O. Claassen, MD, MS, FAAN, in this issue of Continuum.

ANCILLARY DIAGNOSTIC METHODS

PD is primarily a clinical diagnosis. However, ancillary diagnostic tests can sometimes assist the diagnosis in cases in which the clinical diagnosis is not clear.

Structural Imaging

Structural MRI is usually normal in patients with PD; however, it can be useful in detecting causes of secondary parkinsonism, such as infarcts, iron deposition, normal pressure hydrocephalus, or space-occupying lesions such as neoplasms. New protocols, including neuromelanin imaging and high-resolution structural scans of the substantia nigra, may hold promise for future structural assistance in diagnosis.

Radiotracer Imaging

Radionuclide tracers can assess presynaptic and postsynaptic striatal dopaminergic functions using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging. Dopamine transporter SPECT detects loss of striatal dopaminergic terminals and can assist in the identification of nigrostriatal degeneration and distinguish these cases from non-neurodegenerative cases (eg, essential tremor, psychogenic or vascular causes) (case 2-1). Dopamine transporter SPECT may also be useful in evaluating patients with parkinsonism who are treated with dopamine blockers. However, dopamine transporter SPECT cannot distinguish between the different neurodegenerative parkinsonian syndromes. A rapid decline in nigrostriatal terminals up to 4 years from diagnosis of PD has been reported, with a floor effect for change in striatal binding afterward. Thus, dopamine transporter SPECT is a good tool for the detection of neurodegeneration but less so for the assessment of progression of disease in intermediate or advanced stages.

CASE 2-1

A 65-year-old woman with a long history of tremor presented with worsening symptoms. She had been diagnosed with essential tremor 27 years earlier because of bilateral hand tremor affecting her handwriting and her ability to eat certain foods like soup. Propranolol provided mild symptomatic effect, and she could not tolerate primidone. More recently, her handwriting, which was always tremulous, became small, and her gait became slower and more effortful. She was concerned she may have developed Parkinson disease (PD) since her father died of PD.

Neurologic examination was significant for bilateral action and postural tremor in her hands. She also had a resting tremor in her right arm and reduced arm swing while walking. Rapid alternating movements, including finger taps and opening and closing her fists, were mildly slower on the right than on the left.

The patient’s diagnosis of essential tremor was confirmed, based on her long-standing action tremor, but given her new symptoms, PD was suspected as well. MRI of the brain was within normal limits. Dopamine transporter single-photon emission computed tomography (SPECT) demonstrated reduced radiotracer uptake in the left and right striata, with more extensive involvement in the putamen relative to caudate. Deficits were more pronounced on the left caudate and putamen compared with the right.

Given the mild PD symptoms, she chose to defer pharmacologic treatment and was referred to physical therapy for gait training and an exercise program. Twelve months later, rasagiline 1 mg was started with mild improvement of motor symptoms.

COMMENT

When the neurologic examination cannot conclusively distinguish between essential tremor and PD, dopamine transporter SPECT imaging can be helpful in establishing a diagnosis. Dopamine transporter SPECT, however, would not help distinguish between PD and other syndromes of dopamine deficiency, such as multiple system atrophy. Physical activity should be encouraged for patients with PD. Nonpharmacologic treatment, such as physical therapy and occupational therapy, can be extremely helpful in alleviating symptoms of stiffness and may improve gait. No evidence supports postponing symptomatic therapy when symptoms are disruptive.

α-Synuclein Tissue Markers

α-Synuclein deposition is the pathologic hallmark of PD; however, no α-synuclein radiotracer is commercially available. Conversion assays that amplify α-synuclein using either real-time quaking-induced conversion (RT-QuIC) assay or protein misfolding cyclic amplification, currently termed synuclein seeding assays, have emerged as promising α-synuclein biomarkers with excellent sensitivity and specificity for distinguishing PD from controls using either CSF or tissue as substrates. These tests are often performed for research purposes, but they are now emerging for clinical use. It is anticipated that when they are more widely clinically available these assays will be very useful in clinically complicated cases (eg, when normal pressure hydrocephalus is suspected or if PD is suspected in patients taking dopamine blockers).

SUBTYPING PARKINSON DISEASE

The heterogeneity of disease progression makes counseling patients on PD prognosis and designing clinical trials challenging. Genetic profiles may explain some of the heterogeneity (table 2-1), but most patients are not carriers of mutations in mendelian genes. Another useful classification of patients is based on the predominant motor symptoms. Patients may be divided into three groups: those with tremor-dominant features, those with postural instability-gait difficulty, and an intermediate group. The differential diagnosis for tremor-dominant PD includes essential tremor and dystonic tremor. In tremor cases in which the diagnosis is not clear, dopamine transporter SPECT may be useful. Patients with PD with the tremor-dominant subtype tend to have slower progression and less cognitive involvement compared to those with postural instability-gait difficulty. When the primary symptoms are postural instability and gait difficulty, dopamine transporter SPECT may not be as useful, because the differential diagnosis includes other causes of parkinsonism, such as PSP or MSA, in which the scan would demonstrate reduced uptake similar to that seen in patients with PD.

MANAGEMENT OF PARKINSON DISEASE SYMPTOMS

Nonpharmacologic interventions for treating the motor symptoms of PD may include physical therapy, occupational therapy, speech-language therapy, and exercise, with mounting evidence of efficacy for each. Assessment and treatment of motor and nonmotor symptoms by a multidisciplinary team is advised. All newly diagnosed patients should be screened for depression and treated as needed. An exercise program and in-person and online support groups may be extremely helpful. Tai chi has been shown to be efficacious for balance issues in PD.

Many factors should be considered when choosing the timing and type of treatment in PD, including age, comorbidities, symptom severity, potential adverse effect profile, cost, and patient preferences. Given that no interventions to slow the rate of progression are available and that all currently available treatments are considered symptomatic, no evidence exists for the added value of early pharmacologic treatment. However, neither does evidence exist for the benefit of delaying pharmacologic treatment.

Levodopa

Levodopa is a precursor of dopamine; when supplemented with a peripheral decarboxylase inhibitor, sufficient levels of dopa enter the striatum and improve motor function. It does not correct the underlying neurodegenerative disruption. Levodopa remains the mainstay of pharmacologic treatment in PD, even 50 years after its discovery.

Dopaminergic pharmacotherapy should be initiated at the lowest dose that provides symptomatic relief when motor symptoms cause impairment in daily function. After a period of good motor response (the “honeymoon”), levodopa-related complications may occur, mainly dyskinesias and motor fluctuations (on-off periods), which are a major source of disability for many patients. Dyskinesias appear in up to 40% of patients treated with levodopa after 4 years, with higher risks among young patients treated with higher doses of levodopa, and can be separated into peak dose (when plasma levels of the drug are at their maximum) and diphasic dyskinesia (which occurs at lower drug levels). Chronic constipation and simultaneous intake of proteinaceous meals might increase off symptoms because of poor medication absorption. Additional strategies to overcome off symptoms, including adjustment of dose timing and introduction of additional drugs (eg, dopamine agonists, catechol-O-methyltransferase [COMT] inhibitors) which might improve on time but potentially with more dyskinesias.

Previous notions that early initiation of levodopa treatment might be deleterious have been disproven and delaying levodopa treatment was not shown to reduce motor complications and dyskinesia. Thus, it is not the duration of levodopa therapy that is associated with the drug-related motor complications but rather the disease progression itself. In addition, levodopa does not seem to have a negative impact on the progression of the neurodegenerative process at the basis of PD; however, it does not seem to have a positive disease-modifying effect either. Certain motor features of PD (eg, bradykinesia and rigidity) respond better than others (eg, postural instability, freezing of gait, and dysarthria) to dopaminergic treatment; however, they all may respond to some extent.

Comparing levodopa to dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors has indicated that although all three therapies are efficacious, levodopa treatment is best tolerated and maximizes improvement in mobility scores.

Dopamine Agonists

Dopamine agonists are synthetic compounds that act as agonists to the dopaminergic D2 receptors within the central nervous system, thus mimicking the function of dopamine. First-generation compounds, which were ergoline derived (pergolide, bromocriptine, cabergoline, lisuride), may cause cardiac valvulopathy and are rarely used. The FDA currently approves dopamine agonists as tablets (pramipexole, ropinirole), patch (rotigotine), sublingual film (apomorphine), and subcutaneous injections (apomorphine). The side effect profile of dopamine agonists includes nausea, leg edema, orthostatic hypotension, sleep attacks, and impulse control disorders such as gambling, hoarding, excessive shopping, binge eating, and hypersexuality. Impulse control disorders may have devastating psychological, social, legal, and economic consequences. When impulse control orders occur, a reduction in the dosage of dopamine agonist therapy is warranted; however, this might be complicated by the development of a dopamine agonist withdrawal syndrome, which is characterized by agitation, anxiety, depression, fatigue, and autonomic symptoms including orthostatic hypotension and irritability, despite compensatory increases in levodopa dosage.

Amantadine

Amantadine, an N-methyl-d-aspartate (NMDA) receptor antagonist, was approved for the treatment of PD in 1973, and its extended-release form was approved for the treatment of levodopa-induced dyskinesia. It has a mild antiparkinsonian effect and may be efficacious in treating resting tremor; it can be administered orally or intravenously (in some countries). Side effects include confusion, hallucinations, ankle edema, constipation, and livedo reticularis.

Monoamine Oxidase Type B Inhibitors

MAO-B inhibitors (rasagiline and selegiline) improve motor symptoms in early PD to a lesser extent than dopamine agonists and levodopa. A potential interaction may occur with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants that might cause serotonin syndrome; however, this is extremely rare. Although the ADAGIO (Attenuation of Disease progression with Azilect GIven Once-daily) study demonstrated a benefit of early-start treatment with rasagiline and a potential for disease modification, a follow-up study failed to substantiate these findings. The MAO-B inhibitor safinamide has been FDA approved as an add-on treatment for patients who are currently taking carbidopa/levodopa and experiencing off episodes.

Anticholinergics

Anticholinergics are effective in relieving some motor symptoms of PD, especially tremor. However, cognitive changes while taking the medications are common, and they should therefore only be considered in younger patients and with extreme caution. In one study, exposure to anticholinergic drugs was associated with increased risk of dementia. Additional side effects include dry mouth, constipation, and urinary retention, making this class of drugs less favorable for use among patients with PD.

TREATMENTS FOR ADVANCED STAGES OF PARKINSON DISEASE

Levodopa is also used to treat advanced PD. In these cases, a shorter time interval between doses, treatment of constipation, and taking the medication on an empty stomach are recommended to improve absorption. Extended-release levodopa formulations are another method for the treatment of fluctuations.

COMT inhibitors, such as entacapone and opicapone, are useful in the treatment of motor complications. They enhance levodopa’s duration of action and reduce motor fluctuations. MAO-B inhibitors (such as safinamide and other medications) and zonisamide have been found useful in treating motor fluctuations; however, zonisamide is not FDA approved for this purpose. Istradefylline, a selective adenosine A2A receptor antagonist, has been approved as an add-on to carbidopa/levodopa for the treatment of off periods in patients with PD.

Another phenomenon that may happen in advanced PD is a sudden off state, for which rescue drugs are indicated. Apomorphine delivered by subcutaneous injection or inhaled levodopa is indicated for treatment of sudden off time. A sublingual form of apomorphine was also recently FDA-approved to reduce off time. Debilitating fluctuations are a reason to introduce device-aided therapies, such as deep brain stimulation, subcutaneous apomorphine and levodopa-carbidopa intestinal gel, discussed in the coming sections.

Deep Brain Stimulation/Focused Ultrasound

Neurosurgical intervention targeting the basal ganglia with high-frequency stimulation (deep brain stimulation) or with lesioning (focused ultrasound) are currently approved for the treatment of motor complications in PD as they have been proven to improve the motor signs and quality of life of patients with PD. Magnetic resonance-guided focused ultrasound targets basal ganglia structures without craniotomy and electrode placement. For more information on deep brain stimulation and focused ultrasound, refer to the article “Surgical Therapies for Parkinson Disease” by Ashley E. Rawls, MD, MS, in this issue of Continuum.

Apomorphine

As mentioned above, apomorphine is a short-acting dopamine agonist. It can be delivered subcutaneously either intermittently via injection or continuously via pump (in some countries but not the United States). It may provide rapid relief from PD symptoms, but intermittent injections have a short half-life.

Levodopa-Carbidopa Intestinal Gel

The use of levodopa-carbidopa intestinal gel via pump aims to reach a steady plasma concentration of levodopa by bypassing the stomach to continuously improve motor performance. It is used for 16 hours daily, with evidence of improved quality of life and improvement in both motor symptoms and nonmotor symptoms such as sleep. Peripheral neuropathy due to vitamin B complex deficiency may become an issue with chronic treatment.

CHOOSING AMONG THE DIFFERENT ADVANCED-STAGE THERAPIES

Currently, no randomized controlled trials have compared the efficacy of the different advanced treatments. However, deep brain stimulation seems to have the most positive effect but with the highest potential for adverse effects.case 2-2 illustrates the complexity of decision making in advanced PD.

CASE 2-2

A 68-year-old man presented for a follow-up visit for Parkinson disease (PD). He was diagnosed 9 years earlier when he developed resting tremor in his right hand and stiffness. Since his diagnosis, he had been treated with monamine oxidase type B (MAO-B) inhibitors and levodopa in escalating doses. Four years after diagnosis, he developed fluctuations, with each levodopa dose lasting 4 hours. At the time, entacapone (a catechol-O-methyltransferase [COMT] inhibitor) was added, and the levodopa dose was increased to be taken every 4 hours while awake. When the duration of the on time further decreased to 3 hours, the levodopa formulation was changed to an extended-release capsule; however, dyskinesia developed. Furthermore, he developed spells in which he would abruptly reach an off state. These spells made him hesitate to leave home on his own.

The patient presented for a follow-up visit to check his options for further therapies. The dosage of levodopa was reduced and amantadine extended-release capsule was added to address the dyskinesia, and inhaled levodopa was prescribed for off spells. A discussion about deep brain stimulation was initiated, and the patient was interested in pursuing it. In preparation for the procedure, he had an MRI, which was within normal limits, and neuropsychological testing, which identified deficits that were diagnosed as mild cognitive impairment with executive dysfunction. He chose to pursue genetic testing, which revealed a heterozygous mutation in the glucocerebrosidase (GBA) gene. Because of the cognitive changes, which can represent higher risk for worse outcome for deep brain stimulation, he decided to pursue levodopa-carbidopa intestinal gel treatment. He underwent percutaneous endoscopic gastrojejunostomy for the administration of levodopa-carbidopa intestinal gel successfully, and his fluctuations significantly improved.

COMMENT

In recent years, the treatment of fluctuations and sudden spells of the off state, which are complications of moderate and advanced PD, has improved significantly. Treatment options include pharmacologic and surgical interventions. Combined, these interventions improve the quality of life of patients struggling with the motor complications of PD and levodopa treatment.

Cognitive changes are common as PD advances and can be subtle, mild, or severe, causing PD dementia. Roughly 10% to 15% of people with PD carry a pathogenic variant in one of seven genes linked to PD risk. Carriers of pathogenic variants in glucocerebrosidase are at risk for faster motor and cognitive progression. Clinical trials targeting the biological pathway of the gene are ongoing. Deep brain stimulation surgery may aggravate cognitive changes. Alternative interventions, such as levodopa-carbidopa intestinal gel, may be indicated, as in this patient.

TREATMENT OF NONMOTOR SYMPTOMS

The medications for PD discussed above focus on the motor symptoms of the disease; however, the nonmotor symptoms are often more debilitating and require specific attention. Some of the nonmotor symptoms, such as depression, anxiety, and pain, can fluctuate similarly to the motor symptoms between the on and off states; hence, dopaminergic treatment might be considered as treatment. However, the same treatment might worsen other nonmotor symptoms, such as hallucinations, orthostatic hypotension, and psychosis. Careful adjustment of the dopaminergic treatment is a logical first step in the treatment of nonmotor symptoms in PD. Randomized controlled trials for nonmotor symptoms in PD are lacking, although these symptoms significantly affect the quality of life of patients with PD.

Depression

SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs), specifically venlafaxine and paroxetine, have been found efficacious for the treatment of depression in PD. However, another study did not replicate these findings for SSRIs. The updated MDS task force report on nonmotor treatment in PD lists other SSRIs and SNRIs as possibly useful for the treatment of depression in PD. Pramipexole, a dopamine agonist, has been found to be efficacious for the treatment of depression in PD. Furthermore, the tricyclic antidepressants nortriptyline and desipramine are labeled likely efficacious. A 2021 meta-analysis found electroconvulsive therapy useful for the treatment of refractory depression in PD; however, the number of participants was relatively small.

Hallucinations and Psychosis

Given that most antipsychotic drugs block dopamine receptors, the treatment of hallucinations in PD can be challenging. Both PD itself and its treatment increase the risk for hallucinations. The only FDA-approved drug for the treatment of hallucinations and psychosis in PD is pimavanserin, a selective serotonin 5-hydroxytryptamine, serotonin receptor 2A (5-HT2A) inverse agonist. Although concerns about the safety of pimavanserin have been raised, a recent study of Medicare beneficiaries demonstrated lower mortality among pimavanserin users than those treated with atypical antipsychotic medications. Of the antipsychotic drugs used for schizophrenia, the two that are not primarily dopamine blockers are quetiapine and clozapine. Clinical trials have shown clozapine to be effective in treating PD-related psychosis, but the need for monitoring agranulocytosis hinders its use. Quetiapine, which is widely used in the treatment of PD-related psychosis, has not been demonstrated to be superior to placebo in clinical trials. Other antipsychotic agents block dopamine and should be avoided, if possible, in people with PD.

Urinary Incontinence

Urinary incontinence in PD can have several causes, including motor, sensory, and autonomic function impairments. Thus, the nature and cause of the urinary symptoms should be ascertained before treatment initiation. Many different compounds are used for the treatment of urinary incontinence, several of which have prominent anticholinergic properties that have the potential of affecting both motor and cognitive functions in PD. Solifenacin is used to treat overactive bladder and neurogenic detrusor overactivity. It has been assessed for PD with partial symptomatic improvement; however, it, too, carries peripheral antimuscarinic side effects. Mirabegron, a selective β3 agonist, has also been shown to effectively treat overactive bladder in patients with PD.

Orthostatic Hypotension

Orthostatic hypotension is diagnosed by a drop of 20 mm Hg in systolic or 10 mm Hg in diastolic blood pressure with standing. It is common in patients with PD, may be asymptomatic, and can cause falls. Nonpharmacologic interventions such as increased fluid intake, slow transitions from recumbency to standing, and specific leg-strengthening exercises might be effective in treating this condition.

Droxidopa (a norepinephrine prodrug) and midodrine (an α1 receptor agonist) are considered efficacious for the short-term treatment of orthostatic hypotension in PD and should be taken 20 minutes before upright activity. They should be avoided before supine activity. Fludrocortisone, which is taken daily, is approved for the treatment of orthostatic hypotension and is labeled possibly useful in the updated MDS task force report on the treatment of nonmotor symptoms.

Cognitive Decline

A meta-analysis of cholinesterase inhibitors demonstrated improvement in cognitive functions in patients with PD and dementia; however, this has not been demonstrated for cognitive impairment without dementia in PD. For more information, refer to the article “Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies” by Daniel Weintraub, MD, and David Irwin, MD, in this issue of Continuum.

Constipation

Constipation is prevalent in PD both before and after diagnosis. Many treatments are available for constipation, including adequate hydration, physical activity, and associated medications. Lubiprostone, probiotics, and fibers are considered useful in the treatment of constipation in PD.

Rapid Eye Movement Sleep Behavior Disorder

When patients have rapid eye movement (REM) sleep behavior disorder (RBD), it is important to maintain a safe sleep environment, including the removal of sharp objects near the bed and the addition of bedrails, if indicated. Potential aggravators of RBD should be addressed, including the use of SSRIs, SNRIs, or tricyclic antidepressants. Treatment options for RBD include clonazepam or melatonin, although no firm evidence supports their use.

Impulse Control Disorders

Patients with a premorbid history of behavioral addictions or drug abuse and younger patients are at increased risk for impulse control disorders. A slow decrease of dopamine agonists until discontinuation of use is the mainstay of treatment.

Apathy

Although apathy has a significant negative effect on both patients and caregivers, no official guidelines for the treatment of this condition are currently available. Some studies detected improvement in apathy scores when treating depression and cognitive impairment with rivastigmine and rotigotine.

Anxiety

Anxiety in PD is often treated with SSRIs and, to a much lesser extent, benzodiazepines because of their adverse effect profile, which includes cognitive impairment and falls. Anxiety and depression are often treated simultaneously with a single agent in PD.

Pain

Several mechanisms are involved in pain in PD, including musculoskeletal, dystonic, radicular, and central mechanisms. The first step in treating pain is to assess which mechanism is involved. One study identified safinamide, a novel MAO-B inhibitor, as efficacious in treating pain in patients with motor fluctuations. Cannabis has also been assessed for pain relief in PD with positive effects.

CONCLUSION

PD is a common neurodegenerative disease with numerous symptomatic treatments for both the motor and nonmotor symptoms but no disease-modifying treatments. Nonmotor symptoms have a large impact on quality of life and require clinical attention similar to the motor symptoms of the disease. The discovery of genetic causes of PD has opened the way for targeted trials; the results of these trials, together with α-synuclein–reducing treatments, are anticipated to change the way we treat the disease.

KEY POINTS

  • Older age and male sex are the most established risk factors for Parkinson disease (PD). The most established environmental risk factor for PD is pesticide exposure.
  • The seven genes clearly associated with PD risk are SNCA, LRRK2, and VPS35 (dominant); PRKN, PINK1, and DJ-1 (recessive); and GBA (risk factor).
  • The definitive diagnosis of PD is based on pathology. The two key required criteria are atrophy of dopaminergic cells in the substantia nigra and accumulation of α-synuclein.
  • The clinical diagnosis of PD was historically based on motor symptoms. More recently, nonmotor symptoms were added to the criteria to improve accuracy.
  • Postural instability, which is a feature of parkinsonism, is not a part of the International Parkinson and Movement Disorders Society criteria for PD diagnosis as it usually appears at later stages of PD.
  • Clinical red flags raise suspicion to an alternative diagnosis, most often multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies.
  • The Hoehn and Yahr scale is often used to capture the severity and progression of motor symptoms of PD. The Movement Disorders Society Unified Parkinson’s Disease Rating Scale is used to quantify disease severity.
  • The diagnosis of PD is primarily clinical. Ancillary diagnostic tests can be useful when the clinical diagnosis remains unclear.
  • MRI or other structural imaging may detect causes of secondary parkinsonism, such as hydrocephalus or stroke.
  • Dopamine transporter single-photon emission computed tomography may be helpful in detecting dopamine deficiency but is less useful in tracking the progression of intermediate or advanced stages of PD or in distinguishing PD from other neurodegenerative parkinsonian syndromes.
  • Exercise and physical activity should be recommended for all patients with PD.
  • No evidence exists that early pharmacologic (eg, levodopa) treatment of Parkinson disease has disease-modifying properties. However, neither does evidence exist for the benefit of delaying pharmacologic treatment.
  • Comparing levodopa to dopamine agonists and monamine oxidase type B inhibitors has indicated that although all three therapies are efficacious, levodopa treatment is best tolerated and maximizes improvement in mobility scores.
  • When impulse control disorder occurs, reduction in the dosage of dopamine agonist therapy is warranted; however, this might be complicated by the development of a dopamine agonist withdrawal syndrome.
  • When motor symptoms advance, a key consideration is to reduce the motor off time and fluctuations. Continuous levodopa administration or deep brain stimulation should be considered.
  • Careful adjustment of the dopaminergic treatment is a logical first step in the treatment of nonmotor symptoms in PD.
  • Hallucinations in PD may significantly impair quality of life and limit the use of dopaminergic intervention. Careful management of hallucinations is indicated.
  • Although the link between rapid eye movement (REM) sleep behavior disorder and PD is well established, evidence on effective management of REM sleep behavior disorder is insufficient.

ACKNOWLEDGMENT

The authors would like to thank Adina Wise, MD, for her careful English editing.

REFERENCES

1. Wirdefeldt K, Adami HO, Philip C, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 2011;26(suppl 1):S1–S58. doi:10.1007/s10654-011-9581-6
2. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18(5):459–480. doi:10.1016/S1474-4422(18)30499-X
3. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351(24):2498–2508. doi:10.1056/NEJMoa033447
4. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56(1):33–39. doi:10.1001/archneur.56.1.33
5. Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 2014;29(13):1583–1590. doi:10.1002/mds.25945
6. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet 2021;397(10291):2284–2303. doi:10.1016/S0140-6736(21)00218-X
7. Bailey M, Anderson S, Hall DA. Parkinson’s disease in African Americans: a review of the current literature. J Parkinsons Dis 2020;10(3):831–841. doi:10.3233/JPD-191823
8. Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 2016;15(12):1257–1272.
9. Nonnekes J, Post B, Tetrud JW, Langston JW, Bloem BR. MPTP-induced parkinsonism: an historical case series. Lancet Neurol 2018;17(4):300–301. doi:10.1016/S1474-4422(18)30072-3
10. Skrahina V, Gaber H, Vollstedt EJ, et al. The Rostock International Parkinson’s Disease (ROPAD) study: protocol and initial findings. Mov Disord 2021;36(4):1005–1010. doi:10.1002/mds.28416
11. Kasten M, Klein C. The many faces of alpha-synuclein mutations. Mov Disord 2013;28(6):697–701. doi:10.1002/mds.25499
12. Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 1996;47(1):160–166. doi:10.1212/wnl.47.1.160
13. Valente EM, Bentivoglio AR, Dixon PH, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001;68(4):895–900. doi:10.1086/319522
14. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604):256–259. doi:10.1126/science.1077209
15. Saunders-Pullman R, Mirelman A, Alcalay RN, et al. Progression in the LRRK2-asssociated Parkinson disease population. JAMA Neurol 2018;75(3):312–319. doi:10.1001/jamaneurol.2017.4019
16. Ando M, Funayama M, Li Y, et al. VPS35 mutation in Japanese patients with typical Parkinson’s disease. Mov Disord 2012;27(11):1413–1417. doi:10.1002/mds.25145
17. Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol 2016;80(5):662–673. doi:10.1002/ana.24777
18. Alcalay RN, Kehoe C, Shorr E, et al. Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists. Genet Med 2020;22(3):574–580. doi:10.1038/s41436-019-0684-x
19. Cook L, Schulze J, Verbrugge J, et al. The commercial genetic testing landscape for Parkinson’s disease. Parkinsonism Relat Disord 2021;92:107–111. doi:10.1016/j.parkreldis.2021.10.001
20. Ibanez L, Dube U, Saef B, et al. Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels. BMC Neurol 2017;17(1):198. doi:10.1186/s12883-017-0978-z
21. Chahine LM, Beach TG, Brumm MC, et al. In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease. Neurology 2020;95(9):e1267–e1284. doi:10.1212/WNL.0000000000010404
22. Cagnan H, Mallet N, Moll CKE, et al. Temporal evolution of beta bursts in the parkinsonian cortical and basal ganglia network. Proc Natl Acad Sci U S A 2019;116(32):16095–16104. doi:10.1073/pnas.1819975116
23. Kordower JH, Olanow CW, Dodiya HB, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 2013;136(pt 8):2419–2431. doi:10.1093/brain/awt192
24. Calabresi P, Mercuri NB, Sancesario G, Bernardi G. Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson’s disease. Brain 1993;116(pt 2):433–452.
25. Rocha EM, De Miranda B, Sanders LH. Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 2018;109(pt B):249–257. doi:10.1016/j.nbd.2017.04.004
26. Buchman AS, Yu L, Wilson RS, et al. Progressive parkinsonism in older adults is related to the burden of mixed brain pathologies. Neurology 2019;92(16):e1821–e1830. doi:10.1212/WNL.0000000000007315
27. Espay AJ, Kalia LV, Gan-Or Z, et al. Disease modification and biomarker development in Parkinson disease: revision or reconstruction?Neurology 2020;94(11):481–494. doi:10.1212/WNL.0000000000009107
28. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30(12):1591–1601. doi:10.1002/mds.26424
29. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009;373(9680):2055–2066. doi:10.1016/S0140-6736(09)60492-X
30. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008;23(15):2129–2170. doi:10.1002/mds.22340
31. Adler CH, Beach TG, Hentz JG, et al. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 2014;83(5):406–412. doi:10.1212/WNL.0000000000000641
32. Beach TG, Adler CH. Importance of low diagnostic accuracy for early Parkinson’s disease. Mov Disord 2018;33(10):1551–1554. doi:10.1002/mds.27485
33. Nutt JG, Bloem BR, Nir G, et al. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011;10(8):734–744. doi:10.1016/S1474-4422(11)70143-0
34. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17(5):427–442. doi:10.1212/wnl.17.5.427
35. Cilia R, Cereda E, Akpalu A, et al. Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa. Brain 2020;143(8):2490–2501. doi:10.1093/brain/awaa181
36. Seppi K, Chaudhuri KR, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease-an evidence-based medicine review. Mov Disord 2019;34(2):180–198. doi:10.1002/mds.27602
37. Williams-Gray CH, Mason SL, Evans JR, et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013;84(11):1258–1264. doi:10.1136/jnnp-2013-305277
38. Robbins TW, Cools R. Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov Disord 2014;29(5):597–607. doi:10.1002/mds.25853
39. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018;90(3):126–135. doi:10.1212/WNL.0000000000004826
40. Weintraub D, Irwin D. Diagnosis and treatment of cognitive and neuropsychiatric symptoms in Parkinson disease and dementia with Lewy bodies. Continuum (Minneap Minn) 2022;28(5, Movement Disorders):1314–1332.
41. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci 2017;18(7):435–450. doi:10.1038/nrn.2017.62
42. Anang JBM, Gagnon JF, Bertrand JA, et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 2014;83(14):1253–1260. doi:10.1212/WNL.0000000000000842
43. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24(2):197–211. doi:10.1016/s0197-4580(02)00065-9
44. Claassen DO. Multiple system atrophy. Continuum (Minneap Minn) 2022;28(5, Movement Disorders):1350–1363.
45. Pagano G, Niccolini F, Politis M. Imaging in Parkinson’s disease. Clin Med (Lond) 2016;16(4):371–375. doi:10.7861/clinmedicine.16-4-371
46. Wang X, Zhang Y, Chen Z, et al. The diagnostic value of SNpc using NM-MRI in Parkinson’s disease: meta-analysis. Neurol Sci 2019;40(12):2479–2489. doi:10.1007/s10072-019-04014-y
47. Yomtoob J, Koloms K, Bega D. DAT-SPECT imaging in cases of drug-induced parkinsonism in a specialty movement disorders practice. Parkinsonism Relat Disord 2018;53:37–41. doi:10.1016/j.parkreldis.2018.04.037
48. Scherfler C, Schwarz J, Antonini A, et al. Role of DAT-SPECT in the diagnostic work up of parkinsonism. Mov Disord 2007;22(9):1229–1238. doi:10.1002/mds.21505
49. Strafella AP, Bohnen NI, Perlmutter JS, et al. Molecular imaging to track Parkinson’s disease and atypical parkinsonisms: new imaging frontiers. Mov Disord 2017;32(2):181–192. doi:10.1002/mds.26907
50. Kang UJ, Boehme AK, Graham F, et al. Comparative study of cerebrospinal fluid α-synuclein seeding aggregation assays for diagnosis of Parkinson’s disease. Mov Disord 2019;34(4):536–544. doi:10.1002/mds.27646
51. Stebbins GT, Goetz CG, Burn DJ, et al. How to identify tremor dominant and postural instability/gait difficulty groups with the Movement Disorder Society Unified Parkinson’s Disease Rating scale: comparison with the unified Parkinson’s Disease Rating Scale. Mov Disord 2013;28(5):668–670. doi:10.1002/mds.25383
52. Ogawa T, Fujii S, Kuya K, et al. Role of neuroimaging on differentiation of Parkinson’s disease and its related diseases. Yonago Acta Med 2018;61(3):145–155. doi:10.33160/yam.2018.09.001
53. Mirelman A, Rochester L, Maidan I, et al. Addition of a non-immersive virtual reality component to treadmill training to reduce fall risk in older adults (V-TIME): a randomised controlled trial. Lancet 2016;388(10050):1170–1182. doi:10.1016/S0140-6736(16)31325-3
54. Radder DLM, Nonnekes J, van Nimwegen M, et al. Recommendations for the organization of multidisciplinary clinical care teams in Parkinson’s disease. J Parkinsons Dis 2020;10(3):1087–1098. doi:10.3233/JPD-202078
55. Li F, Hamer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson’s disease. N Engl J Med 2012;366(6):511–519. doi:10.1056/NEJMoa1107911
56. Espay AJ. The final nail in the coffin of disease modification for dopaminergic therapies: the LEAP trial. JAMA Neurol 2019;76(7):747–748. doi:10.1001/jamaneurol.2019.0974
57. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16(3):448–458. doi:10.1002/mds.1090
58. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA 2020;323(6):548–560. doi:10.1001/jama.2019.22360
59. Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med 2019;380(4):315–324. doi:10.1056/NEJMoa1809983
60. Cilia R, Akpulu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain 2014;137(pt 10):2731–2742. doi:10.1093/brain/awu195
61. Gray R, Ives N, et alPD Med Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014;384(9949):1196–1205. doi:10.1016/S0140-6736(14)60683-8
62. Patel S, Garcia X, Mohammad ME, et al. Dopamine agonist withdrawal syndrome (DAWS) in a tertiary Parkinson disease treatment center. J Neurol Sci 2017;379:308–311. doi:10.1016/j.jns.2017.06.022
63. Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 2005;25(13):3312–3322. doi:10.1523/JNEUROSCI.4262-04.2005
64. Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2018;33(8):1248–1266. doi:10.1002/mds.27372
65. Richard IH, Kurlan R, Tanner C, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Parkinson Study Group. Neurology 1997;48(4):1070–1077. doi:10.1212/wnl.48.4.1070
66. Rascol O, Hauser RA, Stocchi F, et al. Long-term effects of rasagiline and the natural history of treated Parkinson’s disease. Mov Disord 2016;31(10):1489–1496. doi:10.1002/mds.26724
67. Brocks DR. Anticholinergic drugs used in Parkinson’s disease: an overlooked class of drugs from a pharmacokinetic perspective. J Pharm Pharm Sci 1999;2(2):39–46.
68. Coupland CAC, Hill T, Tom D, et al. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med 2019;179(8):1084–1093. doi:10.1001/jamainternmed.2019.0677
69. Ferreira JJ, Lees A, Rocha JF, et al. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol 2016;15(2):154–165. doi:10.1016/S1474-4422(15)00336-1
70. Schapira AH, Fox SH, Hauser RA, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol 2017;74(2):216–224. doi:10.1001/jamaneurol.2016.4467
71. Hauser RA, Hattori N, Fernandez H, et al. Efficacy of istradefylline, an adenosine A2A receptor antagonist, as adjunctive therapy to levodopa in Parkinson’s disease: a pooled analysis of 8 phase 2b/3 trials. J Parkinsons Dis 2021;11(4):1663–1675. doi:10.3233/JPD-212672
72. Olanow CW, Factor SA, Espay AJ, et al. Apomorphine sublingual film for off episodes in Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurol 2020;19(2):135–144. doi:10.1016/S1474-4422(19)30396-5
73. Vitek JL, Jain R, Chen L, et al. Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson’s disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study. Lancet Neurol 2020;19(6):491–501. doi:10.1016/S1474-4422(20)30108-3
74. Rawls A. Surgical therapies for Parkinson disease. Continuum (Minneap Minn) 2022;28(5, Movement Disorders):1301–1313.
75. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2018;17(9):749–759. doi:10.1016/S1474-4422(18)30239-4
76. Trenkwalder C, Chaudhuri KR, Garcia Ruiz PJ, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease–clinical practice recommendations. Parkinsonism Relat Disord 2015;21(9):1023–1030. doi:10.1016/j.parkreldis.2015.06.012
77. Fernandez HH, Boyd JT, Fung VSC, et al. Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson’s disease. Mov Disord 2018;33(6):928–936. doi:10.1002/mds.27338
78. Tsunemi T, Oyama G, Saiki S, et al. Intrajejunal Infusion of levodopa/carbidopa for advanced Parkinson’s disease: a systematic review. Mov Disord 2021;36(8):1759–1771. doi:10.1002/mds.28595
79. Romagnolo A, Merola A, Artusi CA, Rizzone MG, Zibetti M, Lopiano L. Levodopa-induced neuropathy: a systematic review. Mov Disord Clin Pract 2019;6(2):96–103. doi:10.1002/mdc3.12688
80. Nijhuis FAP, Esselink R, de Bie RMA, et al. Translating evidence to advanced Parkinson’s disease patients: a systematic review and meta-analysis. Mov Disord 2021;36(6):1293–1307. doi:10.1002/mds.28599
81. Richard IH, McDermott MP, Kurlan R, et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology 2012;78(16):1229–1236. doi:10.1212/WNL.0b013e3182516244
82. Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72(10):886–892. doi:10.1212/01.wnl.0000336340.89821.b3
83. Barone P, Poewe W, Albrecht S, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9(6):573–580. doi:10.1016/S1474-4422(10)70106-X
84. Takamiya A, Seki M, Kudo S, et al. Electroconvulsive therapy for Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 2021;36(1):50–58. doi:10.1002/mds.28335
85. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2014;383(9916):533–540. doi:10.1016/S0140-6736(13)62106-6
86. Mosholder AD, Ma Y, Akhtar S, et al. Mortality among Parkinson’s disease patients treated with pimavanserin or atypical antipsychotics: an observational study in Medicare beneficiaries [published online June 15, 2022]. Am J Psychiatry. doi:10.1176/appi.ajp.21090876
87. Weintraub D, Chiang C, Kim HM, et al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol 2016;73(5):535–541. doi:10.1001/jamaneurol.2016.0031
88. Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004;75(5):689–695. doi:10.1136/jnnp.2003.029868
89. Shotbolt P, Samuel M, Fox C, David AS. A randomized controlled trial of quetiapine for psychosis in Parkinson’s disease. Neuropsychiatr Dis Treat 2009;5:327–332. doi:10.2147/ndt.s533
90. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008;9(6):453–466. doi:10.1038/nrn2401
91. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015;175(3):401–407. doi:10.1001/jamainternmed.2014.7663
92. Zesiewicz TA, Evatt M, Vaughan CP, et al. Randomized, controlled pilot trial of solifenacin succinate for overactive bladder in Parkinson’s disease. Parkinsonism Relat Disord 2015;21(5):514–520. doi:10.1016/j.parkreldis.2015.02.025
93. Fanciulli A, Campese N, Goebel G, et al. Association of transient orthostatic hypotension with falls and syncope in patients with Parkinson disease. Neurology 2020;95(21):e2854–e2865. doi:10.1212/WNL.0000000000010749
94. Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson’s disease (nOH306B). Mov Disord 2015;30(5):646–654. doi:10.1002/mds.26086
95. Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry 2015;86(2):135–143. doi:10.1136/jnnp-2014-307659
96. Fasano A, Visanji NP, Liu LWC, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015;14(6):625–639. doi:doi:0.1016/S1474-4422(15)00007-1
97. Ondo WG, Kenney C, Sullivan K, et al. Placebo-controlled trial of lubiprostone for constipation associated with Parkinson disease. Neurology 2012;78(21):1650–1654. doi:10.1212/WNL.0b013e3182574f28
98. Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: an RCT. Neurology 2016;87(12):1274–1280. doi:10.1212/WNL.0000000000003127
99. St Louis E, Boeve A, Boeve B. REM sleep behavior disorder in Parkinson’s disease and other synucleinopathies. Mov Disord 2017;32(5):645–658. doi:10.1002/mds.27018
100. Antonini A, Siri C, Santangelo G, et al. Impulsivity and compulsivity in drug-naive patients with Parkinson’s disease. Mov Disord 2011;26(3):464–468. doi:10.1002/mds.23501
101. Hauser RA, Slawek J, Barone P, et al. Evaluation of rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson’s disease. BMC Neurol 2016;16:90. doi:10.1186/s12883-016-0610-7
102. Pontone GM, Williams JR, Anderson KE, et al. Pharmacologic treatment of anxiety disorders in Parkinson disease. Am J Geriatr Psychiatry 2013;21(6):520–528. doi:10.1016/j.jagp.2012.10.023
103. Defazio G, Gigante A, Mancino P, Tinazzi M. The epidemiology of pain in Parkinson’s disease. J Neural Transm (Vienna) 2013;120(4):583–586. doi:10.1007/s00702-012-0915-7
104. Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of safinamide on pain in fluctuating Parkinson’s disease patients: a post-hoc analysis. J Parkinsons Dis 2017;7(1):95–101. doi:10.3233/JPD-160911
105. Shohet A, Khlebtovsky A, Roizen N, Roditi Y, Djaldetti R. Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson’s disease. Eur J Pain 2017;21(3):486–493. doi:10.1002/ejp.942
© 2022 American Academy of Neurology.