Managing Advanced Parkinson Disease

The Care Team

Management of advanced PD requires an aggressive multidisciplinary care team. The team should center on a neurologist, which reduces overall morbidity and mortality. ^9,10 In advanced PD, neurologists with specialized training in movement disorders may offer specialized expertise and experience necessary to implement advanced therapies necessary to improve a patient’s quality of life. ¹¹ The clinician team should include a primary care physician to manage additional medical comorbidities and may also include a psychiatrist (non-motor mood disturbances), a gastroenterologist (GI-related dysautonomia or management of carbidopa-levodopa enteral suspension), an urologist (urinary tract-related dysautonomia), a sleep specialist (sleep-related disorders), or a neurosurgeon (management of surgical adjunctive therapies). In addition, patients unequivocally benefit from engagement of physical therapists, occupational therapists, speech therapists, psychologists, and social workers when appropriate. ^{12 -15} Finally, supplemental educational resources and support provided by nationally accredited patient advocacy programs are critical; examples include the American Parkinson Disease Foundation (www.apdaparkinson.org), Michael J Fox Foundation (www.michaeljfox.org), or the Parkinson’s Foundation (www.parkinson.org).

Pharmacologic Treatment Concepts

The mainstay treatment for motor symptoms in Parkinson disease is dopaminergic repletion. ¹⁶ There are numerous medications that achieve this purpose. ¹⁶ Many clinicians avoid levodopa for early PD management, but evidence does not reinforce this approach. ¹⁷ Dopamine agonists and MAO-B inhibitors are associated with higher overall risk of adverse effects despite reduced efficacy compared to levodopa. ¹⁸ As patients with advanced PD frequently exhibit increased adverse effects related to dose titration, there is particular concern with use of dopamine agonists due to the high frequency of persistent withdraw effects or inability to discontinue dopamine agonists. ¹⁹ Thus, it is generally our institutional preference to prescribe levodopa over alternative options, particularly in advanced PD.

A key concept regarding PD progression relates to inevitable reduction of the therapeutic window with increased duration of disease. With time, effective motor symptom management requires increased dopaminergic dose or frequency and there is concurrent reduction in the threshold for medication-related adverse effects (Figure 1). This concept does not appear related to medication tolerance or loss of efficacy per se, but rather relates to pathophysiological progression and reduced dopaminergic stores in the affected brain. ¹⁹ Progressive reduction of the therapeutic window is best conceptualized when considering advancing motor OFF periods (representing relative sub-therapeutic serum levels of dopaminergic medication) versus development of medication induced ON period dyskinesia (representing relative supra-therapeutic serum levels of dopaminergic medication). At 6 years of treatment, over 50% of PD patients experience motor fluctuations, and 35% have dyskinesias. Disease progression magnifies this effect, where at least 80% develop dyskinesias and motor fluctuations at 10 years. ^20,21 Complicating the notion of motor symptom management is the observation that non-motor symptoms may worsen in both the OFF period (related to dopaminergic benefit for some non-motor symptoms) and the ON period (related to mediation-induced adverse effects). Patient tolerance of this motor and non-motor fluctuation and medication induced adverse effects forms the premise for managing quality of life in the patient with advanced Parkinson disease.

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Figure 1.

Dose response curves in advancing Parkinson disease. In advanced PD, the threshold for motor benefit of dopaminergic medications is increased while the side effect threshold is reduced, and thus reducing the therapeutic window. This concept is critical for understanding and managing motor fluctuations and side effects as disease progresses.

Managing Motor OFF Periods

Managing symptoms related to dopaminergic medication wearing off centers on increasing the area of the pharmacokinetic dose-response curve, while minimizing supra-therapeutic thresholds that may contribute to medication-induced adverse effects (Figure 1). One strategy is to increase the overall levodopa-equivalent dose or to increase the frequency of dosing. The former strategy may breach an effect threshold, while the latter may result in inconvenient or unattainable dosing frequency. Another strategy is to introduce a COMT inhibitor to increase central bioavailability of levodopa, again increasing the area under the dose-response curve. An additional option includes use of controlled or extended release drug formulations, although our institutional experience suggests that such strategies may fall short, frequently resulting in unpredictable dose-response timing that exacerbates medication related fluctuations. Nevertheless, the primary goal in the optimal management of motor OFF periods is to achieve relatively steady-state dopaminergic levels, with careful balance between sub- and supra-therapeutic states.

In patients with delayed dopaminergic onset or severe OFF periods occurring in an unpredictable nature, it is important to inquire about timing of medication in relation to meals, especially after consuming meat protein, which may delay gut absorption of the drug. Medications that delay gastric emptying should be avoided. Subcutaneous apomorphine injections and inhaled levodopa offer potential rescue therapy for severe unpredictable OFF motor symptoms. However, this rescue effect may be achieved with application of supplemental carbidopa-levodopa dosing crushed and administered with an acidic solution such as orange juice to enhance absorption.

There are currently many ongoing clinical trials that focus efforts to reduce motor fluctuations and medication induced adverse effects in advanced PD. ²² Advancement of these therapeutic efforts, along with development of neuroprotective or curative therapies, remains the holy grail of PD-related research.

Managing Dyskinesias Induced by Dopaminergic Medications

Dopaminergic-induced dyskinesias can be either choreiform or dystonic in nature and can occur relative to the OFF period, biphasic fluctuations, or peak-dose in serum concentration. ^{23 -25} Obtaining a careful history regarding timing of dyskinesias in relation to timing of dopaminergic dose is critical for differentiating whether to increase (diphasic or OFF period dystonia) or decrease dopaminergic medication (peak dose dyskinesia or dystonia). The presence of mild to moderate dyskinesia is often not bothersome to the patient, and unless disabling or contributing to falls, may not require aggressive management. This strategy often requires education for both the patient and family regarding the relative risk and benefit of treating dyskinesia in relation to relieving OFF-state motor symptoms (particularly when this relates to postural instability). Addition of an amantadine formulation (immediate release applied off label, while extended-release formulations are FDA approved) frequently improves dyskinesia, but caution is advised in advanced PD due to its association with hallucinations, cognitive impairment, and concomitant dystonia. If medical management is not sufficient, surgical adjunctive therapy may be considered (see “DBS and Advances in Surgical Management”).

Differentiating Non-Motor Symptoms and Medication Induced Adverse Effects

Non-motor manifestations are prevalent in advanced PD, frequently with detrimental effects on quality of life. Thus, recognition and management of non-motor features is a critical aspect in symptomatic management. There are multiple comprehensive reviews of evidence-based strategies for managing non-motor features of PD. ^{26 -29} We summarize these management strategies in Table 1.

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Table 1.

Nonmotor Features & Corresponding Treatment Strategies of Parkinson Disease.

Symptom:	General treatment:	Reviews:
Neurologic		30 –32
Cognitive impairment	Avoid offending medications; consider cholinesterase inhibitors
Dementia	If acute onset/worsening, consider workup for infectious etiology
Inattention delirium	Cognitive training & physical exercise
Pain or paresthesia	Dopaminergic agents for OFF period pain; botulinum toxin injections for dystonia; pain management referral
Sleep:		33,34
Excessive daytime somnolence	Decrease PD dopaminergic dose; consider caffeine or modafinil; sleep specialist referral
REM behavior sleep disorder	Melatonin or low-dose clonazepam; avoid serotonergic antidepressants
Insomnia	Sleep hygiene, cognitive behavior therapy, & relaxation training; melatonin
Sleep fragmentation	Levodopa at bedtime
Restless legs syndrome	Gabapentin > dopamine agonists
Psychiatric:		35,36
Anxiety	SSRI, SNRI, mirtazapine, or bupropion for low mood and anxiety
Depression	Psychologist referral; cognitive behavior therapy
Apathy	Psychiatrist referral; electroconvulsive therapy for refractory symptoms
Illusions	Wean dopaminergic (Table 3)
Hallucinations Delusions Compulsive behavior	Consider antipsychotic (quetiapine, pimaveserin, clozapine) or cholinesterase inhibitor
Ophthalmologic:
Dry eyes	Artificial tears & ample ambient light	37
Blurred vision	Optometrist referral; refraction exam, & appropriate corrective lenses
Diplopia	Ophthalmologist referral; prism lenses for convergence insufficiency
Blepharospasm or eyelid apraxia	Journal dopaminergic dose timing; botulinum toxin injections
Cardiovascular		38,39
Postural hypotension	Wean anti-hypertensives Avoid sudden postural change, salt-rich diet, light exercise, & raise head of bed while sleeping Caffeine, fludrocortisone, midodrine, droxidopa
Supine hypertension	Avoid evening meds for orthostatic hypotension; consider short-acting anti-hypertensives (captopril, clonidine, losartan, transdermal nitroglycerin) at bedtime
Cardiac dysrhythmias	Cardiology consultation, electrocardiogram, & cardiac event monitoring
Olfactory: Hyposmia		40
Oral:		41,42
Hypophonia	Speech therapy referral: video assisted swallow therapy & strength training
Dysphagia	Speech therapy referral; consider enteric feeding via gastrostomy
Sialorrhea	Botulinum toxin injections
Xerostomia	Avoid xerogenic medications. Frequent water sipping, swallow timers, & sugar-free candies; ubiquinol
Gastrointestinal:		43,44
Reduced gastric emptying	Avoid dopamine receptor blockers (e.g., metoclopramide)
Nausea & vomiting	Take dopaminergics with meals; supplemental carbidopa; domperidone; ondansetron
Constipation	Increase dietary fiber, laxatives, & secretagogue; pelvic floor training
Genitourinary		45 –47
Urinary frequency or urgency	Consider UTI if acute onset. Avoid antimuscarinic agent use Urology referral for post-void residual study; mirabegron Consider intra-detrusor injection of botulinum toxin
Nocturia	Low-dose desmopressin
Erectile dysfunction or reduced libido	Review medications; sildenafil

Many dopaminergic adverse effects may overlap with non-motor features of advanced PD (Table 2). ⁴⁸ Patients with advanced PD are often sensitive to small changes in dopaminergic medications, thus it is important to discern whether adverse effects are due to progression of disease, induced by dopaminergic medications, or a combination of both. If dopaminergic adverse effects are suspected, or if this remains unclear, the first management strategy should include a trial of gradually reduced dopaminergic burden. We propose a prioritized approach to weaning multiple dopaminergic drugs in this instance (Table 3). If weaning dopaminergic burden is not appropriate or tolerated, we briefly discuss strategies for managing adverse effects that may occur independently or exacerbate similar non-motor symptoms. ⁴⁹

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Table 2.

Common Non-Motor Dopaminergic Adverse Effects.

Neurologic:

Confusion

Inattention

Psychiatric:

Illusions, hallucinations, or delusions

Psychosis

Impulse control disorder

Punding

Cardiovascular:

Postural hypotension

Peripheral edema

Sleep:

Daytime somnolence

Vivid dreams/RBD exacerbation

Gastrointestinal:

Nausea and vomiting

Other:

Dopamine dysregulation syndrome

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Table 3.

PD Medications Can Worsen Psychosis & Cognition.^a

Anticholinergics

Dopamine agonists

Amantadine

Monoamine oxidase inhibitors

Catechol-o-methyl transferase inhibitors

Levodopa/carbidopa

^a In order of elimination if on multiple agents.

Managing Non-Motor Symptoms Versus Medication Induced Adverse Effects

Cognitive dysfunction and decline frequently occur in PD, representing a spectrum from mild cognitive impairment (MCI) to Parkinson disease dementia (PDD). MCI and PDD represent deficits on formal neuropsychological examination, differentiated by patient or informant reports of impaired functional independence in the latter. ^{50 -52} Thus, PDD represents clinically significant cognitive decline with functional impairment, representing a prevalence rate of 20% at 5 years, 46% at 10 years, and 80% at 20 years of Parkinson disease duration. ^{50 -52} Cognitive dysfunction in PD is often stereotyped, most commonly involving dysfunction of executive planning, visuospatial attention, or memory domains, and is often accompanied by neuropsychiatric symptoms. Routine screening for cognitive dysfunction should occur in all patients with advanced, including a collateral source, and cognitive testing to monitor progression of symptoms. In PD patients with cognitive complaints, potentially offending medications require frequent review and aggressive weaning (see related section below).

There have been conflicting studies regarding levodopa in PD as to whether it has a positive or negative effect on cognition. It appears that levodopa may improve attention and visuospatial tasks as well as frontal lobe functioning in patients with mild cognitive impairment. ^{49,53 -55} However, levodopa may also contribute to cognitive worsening in patients with moderate cognitive impairment. ⁵⁶ There are no disease-modifying treatments to reduce the risk of dementia or progression, but cholinesterase inhibitors such as donepezil and rivastigmine may provide modest cognitive and psychiatric benefit in a small proportion of patients and may be considered on an individual basis. ⁵⁷ Evidence remains inconsistent regarding efficacy of memantine, a glutamatergic modulator, for treating cognitive impairment in PDD that may additionally result in worsening delusions and hallucinations. ^{58 -62} Non-pharmacological interventions like cognitive training and exercise may provide positive effects on mental flexibility, processing speed, sustained attention and cognitive function and should be recommended for patients with cognitive decline given it is safe and may improve global cognition, but there are no large randomized trials demonstrating efficacy of these interventions in preventing further cognitive decline. ^63,64

Visual hallucinations, delusions, or illusions are quite common in advanced PD, affecting up to 25% in the outpatient setting. ^{65 -67} Treatment strategies should begin with conservative environmental and behavioral cues and elimination of non-essential medication. ⁶⁸ Acute onset should prompt immediate review of recent medication changes and screening for acute infectious etiologies, including asymptomatic urinary tract infections. There are many medication classes that may contribute or worsen existing neuropsychiatric symptoms in advanced PD (see related section below), including medications used to treat motor symptoms of PD (Table 3). Presence of hallucinations and psychosis often limits the ability to further increase the levodopa dose for motor symptom management. When removal of dopaminergic medications fails to improve psychosis or motor symptom severity prohibits wean of carbidopa-levodopa, the treatment strategy includes off-label addition of cholinesterase inhibitors in cognitively impaired PD patients (rivastigmine, donepezil, or galantamine) and antipsychotic agents such as clozapine or quetiapine. Clozapine requires weekly lab monitoring for granulocytopenia at initiation and periodic monitoring thereafter. Pimaveserin is FDA approved to treat hallucinations and delusions associated with PD, although benefits remain modest and long-term follow-up data is lacking.

Orthostatic hypotension is the most common cardiovascular symptom reported by patients with advanced PD, occurring in over half of affected patients. ⁶⁹ This symptom is considered intrinsic of PD, but is worsened by extrinsic factors including dopaminergic medications. ⁷⁰ While loss of consciousness is rare, serious injury may result. Prior to initiating therapeutic attempts for symptomatic orthostatic hypotension, one should carefully review medications and eliminate potential contributors (e.g., longstanding antihypertensives, alpha-blockers commonly prescribed for associated urinary symptoms, etc). First-line management remains conservative, including elevated position of the head during sleep, sufficient oral hydration, and sodium-enriched diets when permissible. ⁷¹ Compression stockings provide only modest benefit, prompting consideration of reduced dexterity and fall risk associated with substantial donning requirements. If a post-prandial component is noted, one may encourage more frequent, smaller meals or snacks. Additionally, patients and caregivers must be educated to avoid rapid changes in posture or prolonged standing and manual attempts to increase cardiovascular preload prior to position changes. Reduction of dopaminergic therapy must be balanced with potential risk of motor symptoms. If reduction in dopaminergic therapy is not permitted, there are few pharmacologic approaches. Midodrine is generally effective, but the prescriber should caution against evening doses due to concern of supine hypotension. Fludrocortisone is also commonly used, with consideration of adverse effects related to increased intravascular volume. ⁷² Droxidopa, an orally active synthetic precursor of norepinephrine, is FDA approved for neurogenic orthostatic hypotension, although data regarding long-term outcomes remain limited. Domperidone may also provide benefit in addition to its anti-nausea effects. ⁷³

Gastrointestinal symptoms. Nausea, vomiting, or both are common adverse effects of dopaminergic therapy. This may additionally result from reduced gastric emptying or severe constipation reflecting non-motor manifestations in advanced PD. Thus, specific history regarding dose changes and symptoms related to GI motility are imperative in guiding management decisions when dopaminergic-induced nausea or vomiting is expected, particularly in a patient with prior tolerance to dopaminergics in advanced PD. Dopaminergic adverse effects contributing to nausea or vomiting result from stimulation of the area postrema, the chemoreceptor trigger zone for the vomiting center. The blood-brain barrier does not protect this brain region, thus supplemental carbidopa (a peripheral dopa-decarboxylase inhibitor) paired with levodopa reduces prevent peripheral decarboxylation and subsequent nausea. Strategies to dose supplemental carbidopa 30 minutes prior to the first daily dose of carbidopa/levodopa, then with subsequent doses may be effective. Additional conservative approaches may be considered, including advising that the patient take carbidopa-levodopa with a small amount of food. Domperidone, a D2 receptor antagonist that cannot cross the blood-brain barrier, may be considered with caution as it can prolong QT interval and is associated with arrhythmias. Antiemetics with mechanisms of action that rely on blockade of dopamine receptors should be strictly avoided. Ondansetron, a serotonin 5-HT3 antagonist, is generally well-tolerated and does not appear to worsen PD related motor symptoms.

Medications Classes to Avoid in Advanced Parkinson Disease

There are many medication classes that should be used with caution when treating individuals with advanced PD. In particular, attention must focus on medication classes that may be prescribed for non-motor symptoms in advanced PD. For instance, medications including anticholinergics, benzodiazepines, and narcotics may potentiate fall risk, cognitive decline, or neuropsychiatric manifestations (including impulse control related disinhibition). In a patient with impaired mobility and fall risk due to inherent motor symptoms, this combination may prove increasingly more dangerous as PD motor symptoms advance with regard to postural instability. It is imperative that the managing clinician regularly review each medication, weighing potential benefits and risks.

Agents that block dopamine receptors such as typical antipsychotics or antiemetics should be strictly avoided in PD as antagonism of D2 dopamine receptors can irreversibly exacerbate motor symptoms. Atypical antipsychotics such as quetiapine also block D2 receptors but dissociate faster and are frequently successfully used off-label with caution.

Medications with anticholinergic properties have the strongest association for inducing psychosis and have been closely correlated with delirium in PD. ^{74 -76} This medication class is broad, and may be prescribed to manage motor or non-motor (e.g., select antipsychotics, tricyclic depressants, antihistamines, urinary and GI antispasmodics, bronchodilators, antiemetics, or anticholinergics for sialorrhea) symptoms associated with advanced PD. In the patient with cognitive or neuropsychiatric complaints, careful review and appropriate discontinuation of all medications with anticholinergic properties is advised. The selective beta3-adrenergic agonist, mirabegron, and botulinum toxin are commonly considered for urinary symptoms, while botulinum toxin is a safe and reliable therapy for sialorrhea.

Benzodiazepines are frequently used for management of REM-behavior sleep symptoms in PD. The prescribing clinician should balance the risk of self-injury associated with REM-behavior sleep disorder with fall risk in the patient with advanced PD and postural instability, particularly when nocturnal ambulation may be more frequent secondary to nocturia. Otherwise, there are generally safer alternatives for the management of mood related disorders, insomnia and other related symptoms. Many studies consistently demonstrate a temporal relationship with delirium and balance impairment with initiation of benzodiazepines in advanced PD. Long-term benzodiazepine use in the geriatric and PD population can increase the risks of cognitive impairment, daytime somnolence, falls and fractures and thus should be avoided. ^77,78

Narcotics are commonly used in the general population to treat pain. It is particularly imperative to avoid narcotics in advanced PD due to increased risk of delirium and falls in the elderly population. ^{79 -81} Moreover, narcotics can exacerbate orthostatic hypotension and constipation, 2 prevalent problems in many patients with advanced PD.

We have already highlighted potential contributions of dopaminergics to adverse effects in advanced PD. In addition, amantadine may contribute to cognitive dysfunction or neuropsychiatric manifestations in advanced PD and should be weaned if such symptoms develop. Furthermore, one must consider that reduced amantadine clearance in impaired renal function can worsen cognition. ⁸² Amantadine withdrawal has also been reported to cause acute delirium, so a slow taper should be initiated when discontinuing. ^83,84

Non-pharmaceutical Approaches

PD treatment usually involves both pharmacologic and nonpharmacologic approaches. There is increasing evidence that exercise and physical, occupational, and speech therapists offer substantial improvements in quality of life of the advanced PD patient. ⁸⁵ Dance and group fitness classes may additionally complement more formal treatment modalities and are generally well accepted by patients in context of social engagement and a nurturing environment that enhances motivation. ⁸⁶ Family and social support also play an important role in the mood symptoms of the PD patient. ⁸⁷

Speech therapy is critical in the management of hypophonia and dysphagia. Dysphagia occurs commonly in at least a third of patients of PD; about 82% demonstrate signs of abnormal swallowing through formal imaging evaluation. ^{88 -90} Swallow modifications and exercises can decrease the risk of aspiration. Behavioral steps can be first implemented by limiting bite size, eating during the motor ON phase, sitting up, removing distractions during meals, or sipping small amounts of water between bites. As dysphagia progresses, modified diets may become necessary to further reduce aspiration risk. When dysphagia is marked, the option of a gastrostomy tube should be considered for enteric feeding to combat aspiration risk, malnutrition and weight loss. The primary clinician best guides these informed discussions regarding aspiration risk, nutritional needs, and personal quality of life considerations in such decisions.

As motor and non-motor symptoms progress, there are often reductions in cognitive function, social and psychological autonomy, and communication. Social isolation as a result from PD is often a result of chronic illness and loss of mobility. Coping and social support have been shown in multiple studies to play an important role in patient autonomy and communication. ^91,92 Psychologists play an important role in providing coping skills and stress management techniques which can reduce psychological and social stress (that notably may contribute to worse motor and non-motor symptoms). Moreover, as there are high incidences of depression and dysthymia in PD, routine screening is imperative. Mood is often correlated to perception of motor symptoms. Low mood in PD is most commonly treated with SSRIs or SNRIs. Cognitive behavior therapy alone or in combination with pharmacotherapies can improve mood symptoms in PD. ^{93 -96} When depressive symptoms are refractory to medications, electroconvulsive therapy is a good choice for PD patients as there is often improvement not only in the mood symptoms, but also a transient improvement in motor symptoms. ^97,98 There have also been ongoing studies regarding repetitive transcranial magnetic stimulation as an alternative to ECT for medication refractory depression. ^99,100

DBS and Advances in Surgical Management

Deep-brain stimulation (DBS) was approved by the Food and Drug Administration (FDA) in 2002 “as an adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive Parkinson’s disease that are not adequately controlled by medication.” DBS applications in PD are discussed in a companion manuscript in this journal, ¹⁰¹ and have been extensively reviewed elsewhere. ¹⁰² Briefly, DBS is indicated for management of motor fluctuations and adverse effects related to dopaminergic therapy. DBS developed on the heels of successful neurosurgical lesioning techniques (subthalamotomy and pallidotomy) contributing to the latter falling out of favor due to relatively increased intraoperative risk and reduced therapeutic flexibility. ^{103 -105} However, experimental application of non-invasive lesioning techniques, such as focused ultrasound, represents an area of growing consideration in the potential management of advanced PD. ¹⁰⁶

Levodopa-carbidopa enteral suspension is another advanced surgical option in the management of motor fluctuations and dopaminergic induced adverse effects. ¹⁰⁷ This enteral suspension requires placement of a percutaneous transgastric jejunal feeding tube providing a slow, continuous infusion of low-dose levodopa resulting in more steady serum levels compared to oral dosing. ^{108 -111} Adverse effects stem from technical device-related problems (dislocation of enteral tubes) or surgical complications (infections). ¹¹²

Treatment of the Hospitalized Parkinson Disease Patient

Patients with PD are more likely to be hospitalized, experience prolonged hospitalizations, and are less likely to be discharged home. ¹¹³ Specifically, they are at higher risk of falls, aspiration pneumonia and motor decline. ^114,115 If outpatient alternatives are available and appropriate, particular effort should be made to avoid hospitalization of the patient with advanced PD. Aminoff et al. provides an excellent review of PD management during hospitalization, emphasizing resumption of home medications dosing, early recognition and management of infections, and reduction of risks associated with aspiration and mobility. ¹¹⁶ Additionally, it is imperative to educate or alert staff regarding risk of medications contraindicated in the hospitalized patient with PD. ^117,118 There are several reviews addressing the risk of PD patients receiving antidopaminergic medication during hospitalization and this should be avoided. ¹¹⁹ It may be important to initiate enteral feeding via nasogastric tube for PD patients who cannot adequately continue their home dosing regimen. Sublingual administration of disintegrating formulations of carbidopa-levodopa may be useful, but it should be noted that such formulations still require enteral absorption for efficacy. If available, transdermal rotigotine or subcutaneous apomorphine may be considered; the latter is associated with increased cardiovascular risk and peripheral side effects if not paired with a dopa-decarboxylase inhibitor. When available, a neurologist and specialized nursing service should be engaged in the care of hospitalized patients with Parkinson disease.

End-stage Parkinson Disease

The management of PD remains largely palliative throughout the entire course of disease in absence of any curative treatment. Thus, principles of palliative care are not limited to the terminal end-of-life period. However, one may anticipate a strategic shift in care from a “therapeutic” pharmacological approach to one with greater emphasis on quality of life when one recognizes the shortened remaining lifespan and inadequate ability of medications to meet increasing physiologic demands. Clinicians play an important role in continuously educating the patient and primary caregivers regarding natural progression of disease and realistic expectations of treatment response. Clinical decisions should focus on patient-centered values regarding quality of life. As disease progresses, this becomes more imperative as treatment options may diverge across strategies to improve motor symptoms and mobility, provide mental clarity, reduce neuropsychiatric burden, emphasize pain control, or target overall comfort above all else. In late stages of PD, there may be a need to withdraw dopaminergic drugs due to lack of efficacy or increasing sensitivity to adverse effects. When possible, withdrawal should occur gradually to achieve the balance between symptom relief and minimal withdraw effects.

Advanced PD often contributes to advanced dysphagia, prompting decisions regarding parenteral supplementation to reduce aspiration risk, provide sufficient caloric intake, or both. ¹²⁰ Discussions regarding patient desires of such decisions are nearly always beneficial prior to acute needs, in turn because advanced stage PD is associated with cognitive and neuropsychiatric symptoms that may limit interpretability of such individual desires. It is important to note that dementia and hip fractures are strongly associated with skilled-nursing home placement in the PD population. ¹²¹ Hospice services should be involved if enteric feeding is not pursued and when nutritional status declines. ^122,123 The National Association for Home Care and Hospice provides information on how to locate hospice services: https://agencylocator.nahc.org (last accessed, 1/15/2021).

Increased efforts to provide specialist care to dependent individuals with PD may improve end-of-life care. ¹²¹ The neurologists role is imperative to provide nuanced management decisions in end-of-life care. With the increase in available technology, telemedicine offers additional consultative and therapeutic approaches for patients with advanced PD. ^{124 -127}