Annals of Movement Disorders

REVIEW ARTICLES
Year
: 2018  |  Volume : 1  |  Issue : 1  |  Page : 30--38

Exploring Parkinson’s disease: A question and answer-based approach


Philippe Rizek1, Niraj Kumar2, Mandar S Jog1,  
1 Department of Clinical Neurological Sciences, Credit Valley Hospital, Trillium Health Partners, University of Toronto, Missisauga, Ontario, Canada
2 Department of Clinical Neurological Sciences, Credit Valley Hospital, Trillium Health Partners, University of Toronto, Missisauga, Ontario, Canada, India

Correspondence Address:
Dr. Mandar S Jog
339 Windermere Road, A10-026, Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Ontario N6A 5A5
Canada

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1%–2% people over the age of 65 years and up to 4% population over 85 years of age. Herein, we present four separate case-based scenarios commonly encountered in the neurology practice and provide the current evidence-based answers to commonly asked questions by patients, caregivers, and primary care physicians regarding the diagnosis and management of patients with PD, separating issues pertaining to early- versus late-onset PD, and management throughout various stages of disease. The discussion points within each case may apply across all cases.



How to cite this article:
Rizek P, Kumar N, Jog MS. Exploring Parkinson’s disease: A question and answer-based approach.Ann Mov Disord 2018;1:30-38


How to cite this URL:
Rizek P, Kumar N, Jog MS. Exploring Parkinson’s disease: A question and answer-based approach. Ann Mov Disord [serial online] 2018 [cited 2022 Aug 18 ];1:30-38
Available from: https://www.aomd.in/text.asp?2018/1/1/30/248383


Full Text



 Introduction



Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It usually affects people in their sixth to seventh decade and involves up to 4% population above the age of 85 years.[1] PD has heterogeneous clinical manifestations in the form of motor and non-motor features. Although motor features such as bradykinesia, rigidity, and rest tremor help in diagnosing PD, various non-motor features such as constipation, depression, anosmia, rapid eye movement (REM) sleep behavior disorders (RBD), and impaired cognition are important factors influencing the quality of life in patients with PD.[1] Development of various therapeutic options in the form of different formulations of dopaminergic medications including levodopa–carbidopa intestinal gel (LCIG) and deep brain stimulation (DBS) has significantly improved the care of patients with PD in the last few decades.[1] We present a case-based review using commonly asked questions by patients, caregivers, and primary care physicians regarding the diagnosis and management of patients with PD, separating issues pertaining to early-onset PD (EOPD) versus late-onset PD (LOPD), and management throughout various stages of disease. The discussion points within each case may apply across all cases.

 Clinical Scenario 1



SP is a 60-year-old woman with stiffness, slowness, and mild tremor in the left upper extremity, who was given a diagnosis of Parkinsonism–possible Parkinson’s disease by her neurologist.

What is Parkinsonism?

Parkinsonism is clinically characterized by bradykinesia, rigidity, rest tremor, gait, and balance abnormality.[1] PD is the most common etiology of parkinsonism. There are many other causes of parkinsonism including medications, as well as other less common disorders such as multiple system atrophy (MSA) or progressive supranuclear palsy (PSP).[1] Although PSP manifests with early eye movement abnormalities and repeated falls, MSA has early cerebellar and autonomic involvement along with parkinsonism. These conditions do not respond well to the PD medications and the prognosis is worse than PD.[1] Dopamine (DA) receptor–blocking agents such as antipsychotics (the phenothiazines and haloperidol) and antinauseants (metoclopramide and prochlorperazine) can cause parkinsonism.[1]

How is PD diagnosed?

The diagnosis of PD is clinical and requires bradykinesia plus at least one from either rigidity, rest tremor, and postural instability as per the UK Parkinson’s Disease Society Brain Bank Criteria.[2] As early postural instability may suggest an alternative diagnosis such as Parkinson plus syndromes, it has not been included in the definition of parkinsonism in the Movement Disorder Society clinical diagnostic criteria of PD (MDS-PD).[3] Although motor features remain the mainstay in the MDS-PD criteria, non-motor features have been given due significance []. Absence of common non-motor features such as sleep abnormalities, autonomic impairment, hyposmia, and depression for ≥5 years of disease duration has been included as one of the red flags.[3] Clinicopathologic studies have reported approximately 75%–80% accuracy of clinical diagnosis of PD with Parkinson plus syndromes, Alzheimer’s disease and cerebrovascular disease being the most common misdiagnoses.[2],[4] The diagnostic accuracy is lower in the initial stage of the disease and improves with repeat evaluations as the disease progresses.[4] Motor features usually begin unilaterally and are levodopa responsive. Before labeling levodopa non-responsive, a patient with PD must be tried on a levodopa dose titrating up to 1000–1200mg/day for over 6 months, with the maximum dose being tried for at least a month.[5] Various non-motor symptoms (NMS) may precede the motor features by years, including constipation, anosmia, REM-sleep behavior disorder, and depression.[1],[6] Research criteria incorporating such features are being designed to identify patients with prodromal PD for recruitment in research trials investigating potential neuroprotective treatments.[7]

Box 1: MDS Clinical Diagnostic Criteria for Diagnosis of PD[3]

Essential criterion for diagnosing parkinsonism: Bradykinesia + at least one of rest tremor or rigidity.Clinically established PD: Parkinsonism + ≥ two supportive criteria + absence of absolute exclusion criteria and red flags.

Clinically probable PD: Parkinsonism + absence of absolute exclusion criteria + presence of red flags (not more than two) neutralized by equal number of supportive criteria.

Supportive criteria:

Levodopa responsiveness:Patient’s functionality improved to the premorbid state

Significant improvement either reported subjectively by a dependable patient or caregiver or >30% improvement in unified parkinson's disease rating scale-III motor score on clinical examination.

Motor fluctuations with predictable end-of-dose wearing off.

Clinical evaluation revealing resting tremor in a limb

Levodopa-related dyskinesia

Anosmia or metaiodobenzylguanidine scintigraphy suggesting cardiac sympathetic denervation

Absolute exclusion criteria: Any of these following features exclude PD:

Slow downward vertical saccades or downward vertical supranuclear gaze palsy

Presence of clinical features diagnostic of behavioral variant frontotemporal dementia or primary progressive aphasia within 5 year of PD onset

Clear cerebellar signs on examination

Obvious cortical signs on examination such as cortical sensory dysfunction with normal primary sensations],[ progressive aphasia],[ or ideomotor apraxia

Moderate-to-severe PD with poor response to high dose of levodopa (≥600mg/day)

Parkinsonism limited to lower extremities for ≥3 years of disease duration

Drug-induced parkinsonism],[ that is],[ development of parkinsonism clearly correlating with the use of antidopaminergic therapy

Presence of another condition clearly explaining parkinsonism

Normal functional neuroimaging of presynaptic dopaminergic system

Red flags:

Symmetrical parkinsonism at the onset with lack of asymmetry on history and examination

Absence of common non-motor features (sleep abnormalities],[ autonomic impairment],[ hyposmia],[ or psychiatric features of depression],[ anxiety],[ or hallucinations) for ≥5 years of disease duration

Early significant gait abnormality with wheelchair dependency within 5 years of PD onset

Postural instability resulting in repeated (>1/year) falls within 3 years of PD onset

Absent progression of motor features for ≥5 years of disease duration],[ not related to antiparkinsonian therapy

Early significant bulbar involvement (severe dysphonia],[ dysarthria],[ or dysphagia) within first 5 years of PD onset

Inspiratory stridor or incessant inspiratory sighs

Significant dysautonomia within first 5 years of PD onset:Orthostatic hypotension in the absence of dehydration],[ drugs],[ or any other illness known to cause dysautonomia

Severe urinary retention or urinary incontinence unrelated to another cause such as prostate disease and erectile dysfunction in male patients.

Prominent neck dystonia (anterocollis) or limb contractures within 10 years of PD onset

Pyramidal weakness or pathological hyperreflexia (excluding mild asymmetrical reflex and isolated extensor plantar)],[ unrelated to another disorder

Key Points

If symptoms are very mild],[ the patient may choose not to begin therapy.

No one medication is recommended for treatment initiation. In LOPD (>60 years)],[ levodopa is generally preferred. In EOPD (<50 years)],[ DA agonists or MAOIs may be used.

Levodopa responsiveness is seen in most of the patients with idiopathic PD for bradykinesia and rigidity; less so for tremor.

Progression of PD is slow],[ and good quality of life can be maintained for 15–20 years with treatment],[ depending on the patient’s age and comorbidities. In advanced stages],[ gait and balance impairment are less likely to respond to dopaminergic therapy.

Most patients will develop motor fluctuations and dyskinesias 5–8 years after onset of PD. Strategies in managing these may include adjusting the medication dose],[ frequency and timing around meals],[ adding adjunct medications],[ and/or surgical treatment.

NMS are present throughout the course of PD and should be addressed at each clinic visit],[ specifically],[ sleep disorders],[ dysphagia],[ orthostatic hypotension],[ bowel/bladder impairment],[ hallucinations],[ and cognitive impairment.

What is the role of neuroimaging in diagnosing PD?

PD is a clinical diagnosis and neuroimaging such as brain magnetic resonance imaging may help exclude structural or vascular causes of parkinsonism.[1] Radionuclide imaging such as positron-emission tomography or single photon emission tomography scans can recognize DA metabolism and deficiency before the onset of motor features.[8] Although presence of normal functional neuroimaging of the presynaptic dopaminergic system has been included as one of the absolute exclusion criteria in MDS clinical diagnostic criteria for PD, functional neuroimaging has not been made mandatory for diagnosing PD.[3]

 Clinical Scenario 2



MA is a 45-year-old, previously healthy, man with a new diagnosis of PD with left upper extremity rest tremor and mild upper extremity bradykinesia and rigidity.

Why me? What caused this? What is the risk of my children developing PD?

PD has no known cause. A variety of environmental and genetic factors have been associated with a risk of developing PD.[1] PD is common in the ageing population and has male predominance (M:F = 1.5:1).[1] Although idiopathic PD more commonly occurs in those over the age of 60 years (LOPD), those with EOPD (between 21 and 50 years) do not show a difference in frequency of a positive family history compared to those with LOPD.[1] First-degree relatives of patients with PD are 2–4 times likely to develop the disorder as compared to general population,[9],[10] Almost 16% of PD cases may have an affected first-degree relative.[11] Although mutation in LRRK2 gene is the most common cause of monogenic PD in North African and Caucasian population,[12] Parkin gene mutation is most commonly reported in Indian studies.[13] Genetic forms account for less than 10% of all patients with PD and they may not significantly affect the management decisions in these patients.[12],[13] Certain environmental exposures, such as urban living; industrial exposure to lead, manganese, and copper; or pesticides, such as rotenone and paraquat; have been associated with a higher risk of developing PD,[1] although most patients with idiopathic PD do not report such a history of exposures. A history of traumatic brain injury may contribute to developing parkinsonism and PD, the amount and degree of injury required to cause this is unknown.[14]

What treatment is available?

Dopaminergic medications form the backbone of PD treatment [Table 1]. In EOPD, dopamine (DA) agonists or monoamine oxidase inhibitors (MAOIs) are preferred as initial treatment because of the high risk of developing motor fluctuations on levodopa. But this early benefit of DA agonists declines over approximately 10 years.[15] Motor complications are seen less frequently with DA agonists and MAOIs,[16] however, non-motor side effects, such as nausea, hallucinations, edema, sleep disturbance, and impulse control disorders (ICDs), are common with DA agonists.[1],[17] Levodopa has been shown to have a better symptomatic efficacy compared to DA agonist, pramipexole,[18] and the majority of patients need levodopa after 2–5 years.[19] Early use of levodopa may help patients PD derive the maximum benefit out of it.[20]{Table 1}

Do I need to be treated?

Treatment may be deferred if symptoms are not functionally disabling.[1] Dopaminergic medications used in PD neither accelerate nor slowdown disease progression.[1] Anticholinergics may be used as an adjunct, but not as a first option, in the treatment of tremor.[15]

My sleep is fragmented. Are sleep disturbances related to PD?

Sleep dysfunction is the most common non-motor complaint and includes insomnia, excessive daytime somnolence (EDS), RBD, restless legs syndrome (RLS), and sleep disordered breathing.[21] Insomnia may be primary due to impaired sleep maintenance in PD or secondary due to medications such as selegiline and amantadine, motor impairment such as “off” period and tremor, or nocturia.[21] Sleep disordered breathing can occur in 48% of patients.[22] Almost half of the patients with PD have EDS.[21] Although dopaminergic medications contribute to EDS in early PD, it may be disease related in later stages. Apart from the antiparkinsonian medications, the drug list should be reviewed for antihistamines, H2 antagonists, antipsychotics, and sedatives.[1] If EDS persists, methylphenidate[23] or modafinil[24] may be tried. RBD involves acting out dreams, that is, kicking, punching, and yelling while asleep.[21] It affects approximately 50% of patients with PD, and may appear as an early premotor feature.[6] Medications such as selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors may worsen RBD.[21] Precautionary measures such as bed safety, that is, bed rails, mattresses on the floor near the bed, and sleeping alone may prevent injury to the patient and his partner.[21] Clonazepam in a dose of 0.5–2mg at bedtime is effective in 90% of patients.[21] Melatonin in a dose of up to 12mg/day can also be tried as an alternative to clonazepam.[21] RLS is very common in the general population and seen in up to 50% of patients with PD, even predating motor features in PD,[25] however, no data are available to suggest that having RLS is linked to causing PD. The intriguing link lies in the involvement of dopaminergic system as levodopa and DA agonists are used in the treatment of RLS.

What should I expect in the future? Are there stages of PD?

Patients with EOPD have a slower disease progression, delayed onset of falls, and longer survival.[26] In the Hoehn and Yahr rating scale of PD, five stages are defined traditionally.[27] The first stage is unilateral disease, the second stage is bilateral disease, followed by third stage, where balance is affected. The fourth stage involves substantial disability, requiring a wheelchair, and the fifth stage is when patients are unable to do most tasks (bedbound). This is a very general classification and often fails to describe the severity of disease (e.g., patients may have mild bilateral symptoms and rated stage 2 vs. having fairly substantial unilateral symptoms and rated stage 1 PD). In addition, the staging can change depending on whether the patient has a good “on” response to medications versus “off.” Therefore, it is common for someone to drop a stage going from being unstable to having great improvement with medications. Generally, we recommend patients not to depend on staging specifically but rather discuss prognosis with their physician. It takes approximately 5–7 years to progress from one stage to the next.[27] Caregiver requirements will gradually change from minimal to substantial as PD progresses.

 Clinical Scenario 3



JP is a 65-year-old man with a new diagnosis of tremor-dominant PD.

What are the treatment options?

In LOPD, levodopa (combined with carbidopa or benserazide) is the preferred therapy, with prolonged clinical response in the early stages. The lowest possible effective dose and schedule should be used[15] to minimize the risk of developing motor fluctuations, that is, levodopa/carbidopa, 100/25mg, 1 tab oral qid (titrated to this dose over 4 weeks to watch for side effects, such as nausea and orthostasis).[1] Although levodopa improves bradykinesia and rigidity, tremor fails to show a consistent response.[28] Anticholinergics for the treatment of tremor should be used with caution in the elderly.[15] Surgical therapies including DBS may help manage such cases.[1] Recent literature shows the efficacy of kinematically determined botulinum toxin injection pattern to the upper limb to treat tremor in PD with minimal side effects.[29]

Can any medication slow down the disease?

No proven neuroprotective therapies are available at present, and trials with antiparkinsonian medications such as rasagiline, selegiline, amantadine, pramipexole, and ropinirole have failed.[1] Some controversial evidence was reported for neuroprotection with the MAOI, rasagiline, at the 1mg daily dose, which was not seen in the same study at a higher dose of 2mg daily.[30] Other drugs such as creatine, vitamin E, and ibuprofen, and thalamotomy have also failed.[1] Although recent evidence suggests the possible neuroprotective role of statins in PD,[31],[32] further trials are required for confirmation. Exercise does show promise as a neuroprotective strategy, although not confirmed, and is recommended for all patients.[33],[34]

I have been experiencing constipation for over 5 years. Is this associated with PD? What is recommended?

Constipation is seen in 40%–50% of patients with PD and is thought to be one of the earliest non-motor features.[35] It is related to early degeneration of peripheral autonomic ganglia, thereby increasing transit time in the gut. Some patients develop dyssynergic defecation where pelvic floor muscles fail to relax on straining to defecate.[36] Antiparkinsonian medications including dopaminergic therapies, amantadine, and anticholinergics may contribute to constipation.[1] Treatment recommendations include increasing water intake, using bulk agents or stool softeners, and lactulose for moderate-to-severe constipation.[15],[37] Reduce or discontinue drugs with anticholinergic activity. Domperidone (10mg po, tid) may be used[15] and may help with nausea associated with PD medications.[16] Avoid metoclopramide or prochlorperazine, as they have antidopaminergic properties and may worsen motor symptoms of PD.[1] Biofeedback and botulinum toxin injection in the anal sphincter may help dyssynergic defecation.[36]

I have been experiencing severe pain in my hips and back area, it is excruciating to bend over. Is this a common symptom of PD?

Pain is a very common symptom in PD, occurring in more than 80% patients, but commonly under-recognized and inadequately treated.[38] Although the pathogenesis of pain in PD is still unclear, DA is felt to increase the cortical pain threshold.[39] Pain may involve the more severely affected side of the body.[38] Although pain in patients with PD is commonly musculoskeletal or dystonic, they may also develop radicular, central, or akathitic pain.[38],[39] Usually, patients experience a deep aching pain in the shoulder, neck, back, or any other body part. Frozen shoulder characterized by shoulder pain and limited range of motion may be a presenting symptom.[38] Early morning pain along with abnormal posturing in the foot or during “wearing off” later in the day may result from dystonia because of reduced brain DA level.[39] Oral and genital pain, responsive to dopaminergic therapy, may occur in the “off-period.”[40] Sometimes more diffuse pain such as abdominal or leg cramping can be present.[40] Along with peak-dose dyskinesia, pain may also appear during “on-periods.”[40] Pain can also result from the presence of RLS.[38] Because of the fact that pain is such a common entity in the general population, investigations must be carried out to rule out common causes such as arthritic or degenerative disc disorders.[38],[39]

 Clinical Scenario 4



CJ is a 70-year-old man with PD of 10 years duration. He is on 1600mg/day of levodopa, with motor fluctuations requiring dosing every 2h.

What are fluctuations? Why is this happening?

Motor fluctuations are characterized by predictable or unpredictable drop in the beneficial motor response to dopaminergic therapies.[40] Motor fluctuations affect almost 10% of patients with PD per year after starting levodopa.[40] Thus, up to 50% of patients with PD develop motor fluctuations and dyskinesias within 5 years of chronic levodopa therapy and 70%–80% in 10 years.[16],[41],[42] Longer duration and increased severity of PD at the time of levodopa initiation along with a higher daily levodopa dose increases the risk of developing early motor fluctuations.[40] Motor fluctuations occur early in the disease course in patients with EOPD and in women.[18],[40]

What can be done to reduce “off” periods throughout the day?

Irregularities in gastrointestinal absorption and rapid enzymatic degradation of levodopa are the two major factors contributing to motor fluctuations.[43] Transportation of levodopa across the gut wall and the blood–brain barrier uses sodium-dependent large-neutral amino acid transport system, and levodopa has to compete with other large-neutral amino acids, especially those coming from the dietary proteins.[43] Therefore, we generally recommend taking levodopa 1h before or 2h after meals. Depending on the onset, quality, and time duration of “on” achieved after a dose of levodopa, a patient of PD with motor fluctuations may be categorized with “no on,” “delayed on,” “transient on,” “sudden/early off,” and “unpredictable on.”[1] In addition to increasing the dose and frequency of levodopa, introducing dopaminergic agonists and drugs potentiating the levodopa action may help manage the motor fluctuations.[1] Catechol-O-methyltransferase inhibitor (COMTI), such as entacapone, improves the duration of antiparkinsonian effect by up to 30min for each dose of levodopa[43] and reduces the motor fluctuation.[1],[44] The MAO-B inhibitors, rasagiline or selegiline, increase the DA concentration, thereby, reducing the “off” time.[45] DA agonists, pramipexole or ropinirole, may add up to 1.5h per day of the “on” time.[45] Rotigotine, a DA agonist, available as a transdermal patch has been found to be effective in reducing the “off” time with doses above 8mg/24h.[46],[47],[48],[49] Levodopa-carbidopa-controlled release may reduce motor fluctuations, but not as a first choice.[15] It may be used at bedtime to manage the nocturnal “off” as it has a delayed “on.”[50]

Since increasing his dose of levodopa, he developed abnormal movements of the upper extremities, suggestive of levodopa-induced dyskinesias

Dyskinesias are unwanted intrusive hyperkinetic involuntary movements related to chronic levodopa use.[1],[40] The dyskinetic movements include chorea (most common), dystonia, ballism, and less likely myoclonus.[1],[40] Although dyskinesias are less likely to occur when the total daily dose of levodopa is less than 400–500mg,[51] most patients require higher doses after 5 years of disease, thus dyskinesias are difficult to avoid. Patients with EOPD and women have higher risk of developing early dyskinesias.[26],[40] Dyskinesias may indicate better levodopa responsiveness.[1] Depending on its relation with the preceding levodopa dose, dyskinesias can be categorized as peak dose (PDD), beginning or end of dose (BOD or EOD), diphasic dose (DD; both at BOD and EOD), and square-wave dose (SWD; throughout the “on” period).[1] Treatment is required only if dyskinesias are functionally disabling and bothersome as most patients prefer to be “on” and dyskinetic than “off.”[18],[40] Reduction in levodopa dose may improve PDD and SWD, increase in dose frequency may help BOD or EOD, and increase in each dose and frequency both may be required in DD.[1] Although stopping MAOI and COMTI may help PDD, DD may be benefited by adding a COMTI.[1] Amantadine, an anti-glutamatergic agent, reduces dyskinesias in 60%–70% of patients.[52]

It is difficult to take medications as frequently as prescribed. Are there other options to manage motor fluctuations?

Surgical options such as DBS and LCIG, by delivering continuous dopaminergic stimulation, help manage motor fluctuations in patients with advanced PD.[1] The subthalamic nucleus (STN) and globus pallidus interna are accepted targets for DBS in patients with PD.[1],[45] Thalamus may be targeted in tremor-dominant patients with PD where STN-DBS cannot be performed.[1] Ideal DBS candidates include levodopa-responsive patients with PD below the age of 70 years with motor complications of chronic levodopa therapy, without cognitive impairment or significant mood or psychiatric illness.[45],[53] Although levodopa responsiveness is the best guide for a beneficial response to DBS,[45] levodopa-refractory PD tremor also improves with DBS.[54] DBS fails to improve impairment in cognition and axial features such as gait, balance, and speech.[1],[53] In fact, patients with PD with significant psychiatric features or impaired cognition are poor candidates for DBS.[1] The side effects related to dopaminergic medications improve as STN-DBS allows for the reduction in their doses.[55] Although STN-DBS may fail to provide the non-motor benefits of medications,[56] few studies have reported reduction in pain, neuropsychiatric and sensory symptoms, along with improvement in non-motor fluctuations.[57] A recent study has reported survival advantage in patients with advanced PD who received STN-DBS (n = 106) versus those who continued with medical therapy (n = 41) (hazard ratio = 0.29, 0.13–0.62; P = 0.002).[58] Another study raised the possibility of early DBS when patients start having motor fluctuations (average duration of PD = 7.5 years; mean age, 52 years).[59] Although axial symptoms including postural instability and speech along with cognition may worsen with disease progression, improvement in motor fluctuations, dyskinesia, and rigidity may continue for more than 10 years after DBS.[54],[60],[61] Most of the literature reports a 3%–5% risk of seizure, bleeding in the brain, stroke, infection, and potentially death, together.[1]

LCIG has been recently approved in the management of motor fluctuations in patients with PD. It is an option for patients unsuitable for or refusing DBS. The gel is a combination of levodopa (20mg/mL) and carbidopa (5mg/mL) and is delivered continuously into the jejunum via a percutaneous transgastric jejunostomy tube.[62],[63] Increased age or presence of neuropsychiatric illness is not a limitation for LCIG.[51] LCIG administration improves levodopa absorption, has comparable bioavailability, and low intrasubject variability in levodopa concentrations compared to oral preparations of levodopa–carbidopa.[64] LCIG improves mean “on” time without bothersome dyskinesia by approximately 4h per day.[65]

What should I expect from the disease?

Older age at onset and longer disease duration are associated with greater disability.[66] The duration of disease is as important as the age of onset of disease. Many patients maintain a good response on dopaminergic treatment for 15 or more years from the onset of motor symptoms, with appropriate adjustment in dosages and scheduling of medications to minimize motor fluctuations,[1] after which axial features such as gait impairment and postural instability predominate and are less responsive to dopaminergic therapy.[1] Appearance of non-levodopa-responsive non-motor features in advanced PD such as dysphagia (50% at 15 years),[67] neuropsychiatric manifestations (50% at 15 years),[67] including hallucinations, sleep disturbance, and dementia, as well as autonomic dysfunction (70–80%),[37],[68] including sweating, orthostasis, sialorrhea, and urinary dysfunction, may significantly affect the quality of life. Dysphagia,[66] orthostatic hypotension,[69] falls, and cognitive impairment[70] are poor prognostic indicators in patients with PD.

Financial support and sponsorship

Dr. Rizek receives research grants from Allergan and AbbVie. He also receives speaker honoraria from Merz, Abbvie and UCB. Dr. Kumar reports no disclosures relevant to manuscript. Dr. Jog receives speaker and consultant honoraria from Merz Pharmaceuticals, Allergan, and AbbVie. He also receives research grants from Canadian Institutes of Health Research, Academic Medical Organization of Southwestern Ontario, Allergan, Merz Pharmaceuticals, and Lawson Health Research Institute and is part of the AGE-WELL Network of Centers of Excellence of Canada program. From time to time, he serves on advisory boards of Allergan, Boston Scientific, AbbVie, and Merz Pharmaceuticals.

Conflicts of interest

There are no conflicts of interest.

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