Non-motor Symptoms of Parkinson Disease: Update on the Diagnosis and Treatment

Abstract

Objective

To review the prevalence, diagnosis, and treatment of the non-motor symptoms (NMS) associated with Parkinson disease (PD).

Methods

Narrative review of the literature.

Results

The NMS of PD are becoming more frequently recognized as having a critical role in the progression of this neurodegenerative movement disorder. The preponderance of PD patients will be diagnosed with one or multiple NMS during the course of the disease, often with many of these symptoms occurring months or even years prior to receiving the PD diagnosis. Despite the high prevalence and impact on disease burden, they often go undiagnosed due to factors including a lack of reporting by patients or insufficient interrogation by their physicians. Further complicating NMS management, only a few treatments have enough evidence to support their use in addressing NMS.

Conclusions

There is increased recognition of the predominance of NMS in PD, as well as a better understanding that the burden of NMS often supercedes the negative impact seen with motor dysfunction. This has led to significant investigative efforts to identify new or better NMS therapies. Ultimately, it is up to the practitioner to be both knowledgeable of NMS and thorough in patient questioning in order to recognize, diagnose, and address the NMS of PD patients.

INTRODUCTION

Parkinson Disease (PD) is a neurodegenerative movement disorder with an estimated prevalence of 1-2% of the population over the age of 65 years old [1]. Recognition and clinical diagnosis of PD is primarily made based on the cardinal motor features, including rigidity, tremor, bradykinesia, and postural instability. The motor symptoms are neuropathologically associated with accumulation of alpha-synuclein with Lewy body formation and neurodegeneration of the nigrostriatal dopamine system. Postmortem evaluation of PD brains has revealed more widespread degeneration in non-dopaminergic systems including several brainstem nuclei (raphe nucleus, locus ceruleus, dorsal vagal nucleus), limbic and neocortical structures, as well as the peripheral autonomic system [2, 3].

The non-motor symptoms (NMS) of PD are the clinical manifestations of this extensive degeneration, which suggests that NMS are an intrinsic and fundamental features of PD. NMS are exceedingly common and up to 90% of PD patients will experience non-motor features including depression, anxiety, sleep disturbances, cognitive impairment, or dysautonomia [4, 5] (Table 1).

Table 1.

Non-motor features of PD

NMS	Pathophysiology	Prevalence	Symptomatology	Treatment options
I. Neuropsychiatric
Depression	Degeneration of locus ceruleus and raphe nucleus [3]	30-45%	Somatic complaints, appetite/sleep changes, fatigue, etc.	Pramipexole* [28,29] SSRIs [22,23], TCAs [24-26]
Anxiety	Dysfunction of NA, LC, and limbic structures [34]	40%	Generalized anxiety, panic, phobias	Benzodiazepines [38], SSRIs [37]
Hallucinations	Hypersensitization of DA receptors; dysfunction of visual association cortex; lesion of PPN, LC, RN, and superior parietal [162]	20-40%	Visual hallucinations (animal passing in peripheral vision), tactile hallucination	↓DA-agonists, Clozapine* [48-50], Quetiapine [51.52]
ICD/DDS/Punding	DA-agonist use; ↑activity in VTA, NA, mesolimbic DA system [65]	15-20%	Compulsive behaviors; overuse of levodopa; obsessive handling of objects	↓DA-agonists; Amantadine for gambling [69]; SSRI or atypical antipsychotic for punding [72,73]
Dementia	Dysfunction of ventromedial prefrontal, limbic system, amygdala [163]	20-40%	Cognitive impairment	Rivastigmine* [61], memantine [62,63]
Apathy	Altered cingulate and dopaminergic connections [164]	30-50%	Amotivation, indifference, lack of spontaneous activity	Occasional improvement with early DA therapy [76,80]
II. Sleep disorders
RBD	Degeneration w/ LBs in LC, PPN, reticulospinal tracts, medial medulla [3]	25-50%	Dream enactment, vocalizations	Clonazepam [86,87], melatonin [88]
RLS/PLMS	Unclear; iron deficiency inSN [165,166]	<10%-50%	Urge to move legs, discomfort	Non-pharmacologic [93,95], Pramipexole/ropinerole [97-100], gabapentin enacarbil [95,103,104], opioids [93,95]
Insomnia	Dysregulation of raphe nucleus, LC, and PPN [167]	37-88%	Difficulty with sleep initiation and maintenance	Sinemet CR [49], hypnotics [107], benzodiazepines [105,108], melatonin [49], doxepin [109]
EDS	DA agonist use; Neuro-degeneration of LC, PPN, RAS[168]	15-50%	Daytime somnolence, sleep attacks	Modafinil [112-114], methylphenidate [115]
OSA	Unclear, mechanical obstruction	0-50%	Snoring, daytime fatigue	CPAP application
III. Dysautonomia
Orthostatic hypotension	Degeneration of autonomic centers: ventrolateral medulla, nucleus tractus solitarius, descending para/sympathetics [3,169]	30-60%	Dizziness, drowsiness, palpitations, nausea	Non-pharmacologic [125], fludricortisone [126], midodrine [127], pyridostigmine [128], droxidopa [129,130]
Consitpation/Gastroparesis	Loss of enteric DA cells, degeneration dorsal vagal nuclei [137]	60%	↓# of BMs; early satiety	Macrogol [135], lubiprostone [136], non-pharmacologic
Urinary disturbance	Detrusor hyperactivity: disinhibition of miturition centers in pons [14]	50%	Urinary urgency, incontinence	Oxybutinin, solifenacin, tolterodine [149], botulinum injections [150]
Erectile dysfunction	Hypothalamic dysfunction and dysregulation of DA-oxytocin pathway [151]	60%	Inability to maintain an erection	Sildenafil, vardenafil, tadarafil [151,153], apomorphine [159]
Sialorrhea	Impaired handling of oral secretions [140]	75%	Drooling, impaired speaking/eating	Botulinum injections [143-145], glycopyrrolate [146], gum chewing [147]
IV. Sensory
Pain	BG dysfunction in modulation of sensory input; altered 5-HT pathways [170]	30-85%	Musculoskeletal/shoul der pain; dystonic pain; vague discomfort	NSAIDs/PT; adjust DA therapy or add CR formulation [158,159], DBS [159,160]
Hyposmia	Degeneration of olfactory structures and amygdala [3,171]	40-100% [19]	Inability to distinguish odors	None
Visual disturbances	Retinal DA dysfunction, degeneration of visual cortex [172]	30-40% [172]	Impaired contrast sensitivity, blurred vision, diplopia	None

Abbreviations: BG= Basal ganglia, DA= dopamine, LB= Lewy bodies, LC= locus ceruleus, NA= Nucleus acumbens, PPN= Pedunculopontine nucleus, RAS= Reticular activating system, SN= substantia nigra, VTA= Ventral tegmental area

NMS have a greater impact on quality of life as compared to the motor symptoms [6, 7]; yet are frequently under-recognized. This is in part due to lack of patient reporting, especially of symptoms that may be embarrassing or not recognized as part of PD. Evidence suggests that unless there is systematic and specific interrogation by practioners, NMS will elude recognition [8-10]. Recognizing NMS as part of PD is complicated by the fact that these symptoms are common in the general population and not specific for PD [11, 12]. NMS can occur at any stage of the disease and may predate diagnosis [11], though as PD progresses the NMS become more prevalent with a greater impact on health economics and institutionalization rates than motor features [13, 14].

NEUROPSYCHIATRIC SYMPTOMS

Depression

Epidemiology and Diagnosis

Depression is one of the most common neuropsychiatric manifestations observed in PD patients, with prevalence reports between 4% and 72%, though likely to be closer to 30-45% [15-19]. The onset of depression can occur at any stage of the disease, even pre-dating diagnosis. Additionally, depression has more than twice the impact on health status than other motor symptoms [20].

Diagnosing depression in PD is complicated by the fact that there is overlap between other PD symptoms and clinical features of depression (i.e. amotivation, bradykinesia, fatigue, and sleep disturbances). However, many depressed patients PD are less likely to report feelings of guilt or failure and tend to have higher rates of anxiety [8, 19, 21]. Typically, PD patients are more likely to be diagnosed with minor depression or dysthymia rather than a major depressive disorder [18, 19]. Formal testing through systematic questionnaires are diagnostically useful in the clinic, and serial testing can reveal changes over time to guide more effective treatment. Validated tools to evaluate depression in PD include: Beck Depression Inventory, Hamilton Depression rating scale and Montgomery-Asberg Depression Rating Scale, Geriatric DRS, and Hospital Anxiety and Depression scale [19].

Treatment Options

Treatment of depression in PD demonstrates generally poorer responses by patients to typical antidepressants and side effects that may worsen other PD symptoms. Selective serotonin reuptake inhibitors (SSRIs) have been widely used as there are generally few drug-drug interactions and minimal effect on motor symptoms, though several studies have demonstrated little benefit on depression in PD [22]. However, in a randomized, double-blind, placebo-controlled trial of the antidepressants paroxetine and venlafaxine, both were found to be effective and well tolerated [23]. Tricyclic antidepressants (TCAs) have also demonstrated efficacy, and some studies have found even greater benefit on depressive symptoms as compared to SSRIs [24-26]. The use of TCAs is limited by anticholinergic side effects that occasionally worsen orthostatic hypotension or cognitive impairment [14, 27].

Dopamine agonists have also been studied in depressed PD patients, pramipexole [28, 29] and ropinorole, which have both demonstrated a positive effect on depression [30]. Other therapies have also been tried in pharmacologic-resistant patients. Electroconvulsive therapy has been reported to improve both depression and motor symptoms [31, 32]. Additionally, rehabilitation with video games has demonstrated improvement in depression scores as well as overall quality of life and motor benefits in PD patients [33].

Anxiety

Epidemiology and Diagnosis

The prevalence of anxiety in PD patients is about 40% [34], which is two-times greater than in the general population [8]. Anxiety may worsen PD symptoms, especially tremor and cognition. Risk factors for anxiety include the female gender, greater motor fluctuations, prior history of anxiety, and younger age of PD onset [35]. As with depression, some patients also report worsening of anxious symptoms during their “off” state [36]. Screening tools that have been validated to help practitioners identify anxiety in PD include the Hospital Anxiety and Depression Scale, Beck Anxiety Inventory, Zung Self-rating Anxiety scale, Spielberger State Trait Anxiety Inventory, and Hamilton Anxiety Rating Scale [14].

Treatment Options

The treatment of diagnosed anxiety in PD is primarily with benzodiazepines, and is particularly beneficial in patients whose tremors are exacerbated by anxiety or stress. Other studies have found benefit with serotonergic medications like fluoxetine or citalopram, especially with concomitant depression, as well as optimization of levodopa therapy [37, 38].

Hallucinations, Delusions, and Psychosis

Epidemiology

The prevalence of visual hallucinations in PD patients is about 20-40% [39, 40]. Risk factors for psychotic symptoms include cognitive impairment, advanced age, prolonged duration of disease, depression, severe dysautonomia, and sleep disorders [41-43]. Early recognition of hallucinations is critical because of a strong correlation between the manifestation of psychosis and the need for nursing home placement or hospitalization. With early and effective treatment there is a decreased need for placement and a reduction on caregiver burden [39, 44].

Treatment Options

Hallucinations and other psychotic symptoms may be present in drug-naïve patients or they may be iatrogenically induced with dopaminergic agents. All antiparkinsonian medications are able to induce or worsen hallucinations [8, 45]. Additionally, psychotic symptoms tend to improve when dopaminergic agonists are reduced or eliminated. However, there is no clear relationship between the dose of dopaminergic agents and manifestation of hallucinations [43, 46, 47]. If hallucinations persist or there are motor complications that arise from reduction of dopaminergic agents, initiation of clozapine has been demonstrated to be efficacious [48-50]; however, regular monitoring for neutropenia is required. Quetiapine has demonstrated similar benefit without significant effects on motor symptoms [51, 52]. It is also important to review or eliminate other medications that may contribute to hallucinations.

Cognitive Impairment

Epidemiology

Cognitive dysfunction can be detected early in PD through neuropsychological testing; however, impairment of cognition is often insidious and may not be appreciated until symptoms become severe. Dementia is a substantial burden for the caregiver and is a significant contributor to mortality in PD patients [53]. Cognitive impairment often presents with other behavioral symptoms, which further hastens placement outside the home and increases cost of caring for PD patients [44, 54].

The prevalence of dementia in the PD population is 20-40% [55], though almost 80% of PD patients ultimately develop cognitive decline [56]. Overall, a PD patient is 6 times more likely to develop dementia than the general population [57]. There may be parallel progression of cognitive impairment and motor symptoms, but there is no correlation with overall duration of disease [57, 58]. Risk factors linked with the presence of dementia include older age at onset of PD, presence of hallucinations, and male gender [59, 60].

Treatment Options

Rivastigmine has demonstrated modest improvement in cognitive performance in PD patients with dementia in a large multicenter, placebo-controlled study [61]. Other cholinesterase inhibitors (i.e. donepezil or galantamine) are not recommended at this time due to limited studies or contradictory results in the literature [27, 49]. Caution is advised with use of cholinesterase inhibitors as they may worsen tremor or autonomic dysfunction; and often use is limited by nausea or other gastrointestinal symptoms. Memantine, an NMDA receptor antagonist, has also been investigated and demonstrated modest improvement of cognition and is generally well tolerated [62, 63].

Compulsive Disorders: Impulse Control Disorders, Dopamine Dysregulation Syndrome, and Punding

ICD: Epidemiology and Treatment

Impulse control disorders (ICDs) are inappropriate behaviors resulting from a failure to resist an impulse, which leads to pleasure-seeking activities at the expense of relationships and ability to function socially. In PD, ICDs are expressed as pathologic gambling, hypersexuality, binge eating, compulsive shopping, and excessive spending [8, 54]. The prevalence of all ICDs in PD is 15-20% and a patient may be diagnosed with multiple ICDs [64]. Dopamine agonist use has been implicated in the development of ICDs and this risk is further increased with the addition of levodopa [65, 66]. Clinical features associated with ICDs include young age of onset, male gender, family history of addiction, depression or anxiety, and disinhibition or impulsive traits [67, 68].

Traditionally, treatment consists of modifications to dopamine agonists or adjustment of levodopa therapy. Amantadine as an adjunct therapy has been shown to reduce impulsivity in a few patients with pathologic gambling [69].

DDS: Epidemiology and Treatment

Dopamine dysregulation syndrome (DDS) is characterized by compulsive use of dopaminergic medications, beyond what is needed to treat parkinsonian symptoms, and is associated with social impairment. Patients describe addictive symptoms like craving or intense desire to obtain more dopaminergic medication [8, 64]. Like ICDs, treatment of DDS consists of modification to dopaminergic medications, though patients with DDS may also require psychiatric evaluation and treatment.

Punding: Epidemiology and Treatment

Punding is another compulsive disorder that is defined as an intense fascination with objects, and is associated with repetitive handling, manipulation, sorting, or arrangement of the items [70]. Occurrence of punding has been associated with higher total daily levels of levodopa, though one study has also implicated dopamine agonists [14, 71]. As with the other compulsive disorders, punding also tends to respond well to reduction or discontinuation of levodopa. Studies have demonstrated modest benefit with SSRIs or atypical antipsychotics [72, 73], though one study reported worsening of punding with quetiapine [74].

Apathy

Epidemiology and Treatment

Apathy is often characterized by a loss of motivation or inability to initiate goal-directed behavior, which results in dependence on others for activities of daily living and increases caregiver burden [75]. Patients demonstrate indifference, lack of interest, or inability to express or describe emotion. The apathetic patient will lack spontaneous and voluntary activity and their affect display is often flattened [76].

With a prevalence of 30-50% [77], apathy is as common as depression in PD patients [54, 78]. Risk factors associated with apathy include advanced age, severity of depression, severity of motor dysfunction, and dementia [79]. Apathy is frequently mistaken for depression given the significant overlap in symptoms; however, the patient with pure apathy will deny sadness or depressed feelings. It is also important to distinguish apathy from motor impairment or cognitive dysfunction that could explain the behavioral changes. No medications have reliably been shown to improve apathy, though it may be improved with initiation of dopaminergic therapy, especially early in the course [76, 80].

SLEEP DISORDERS

The original report of PD by James Parkinson describes sleep disturbances and daytime somnolence [81], which suggests that sleep disorders may be an intrinsic feature of the neurodegenerative process of PD itself.

REM Behavioral Disorder

Epidemiology and Diagnosis

Rapid Eye Movement Behavioral Disorder (RBD) is a parasomnia characterized by vocalizations and motor activity during dreaming due to loss of normal atonia associated with Rapid Eye Movement (REM) sleep. Patients enact their dreams, which may lead to violent behaviors that can injure the patient or their bed partner. RBD is seen in 25-50% of PD patients [82, 83], with variability depending on diagnostic technique and patient selection. Polysomnography is the most important diagnostic tool and demonstrates increased chin tone and limb movements during REM sleep in RBD [84, 85]. Diagnosis can also be made clinically with patient and bed partner reports, though sensitivity is only approximately 30% [14].

Interestingly, many studies are now investigating the relationship between presence of RBD and later onset of neurodegenerative disorders. Multiple studies have shown that 40-65% of patients diagnosed with idiopathic RBD later develop an alpha-synucleinopathy which includes PD, dementia with Lewy bodies, or multiple system atrophy within 10 years [82, 85]. Idiopathic RBD is now being investigated as a prodrome to a neurodegenerative synucleinopathy, with reports that as many as 90% of patients with idiopathic RBD develop neurodegenerative disease when followed over 14 years [86]. If RBD is an early marker for neurodegenerative disease, it may be used to identify patients for neuroprotective trials as treatments are developed.

Treatment options

Low dose clonazepam (0.25-1mg) is the mainstay therapy, especially for patients with injurious behaviors during sleep. Use of clonazepam may be limited by daytime sedation, confusion, or psychomotor agitation [27, 87, 88]. Melatonin has also demonstrated benefit in RBD at doses between 3-12mg at bedtime, with fewer side effects and no addiction potential as compared to clonazepam [89]. Case reports also support the use of several other effective medications, including cholinesterase inhibitors (rivastigmine and donepezil) and dopaminergic agents (pramipexole and levodopa) [14, 19].

Restless Leg Syndrome and Periodic Limb Movements in Sleep

Epidemiology

Restless leg syndrome (RLS) and periodic limb movements in sleep (PLMS) cause disruptions of sleep and have an important impact on quality of sleep in PD patients. RLS is described as strong urge to move the legs, accompanied by an uncomfortable sensation that is exacerbated at rest and relieved by movement. RLS is more frequently diagnosed in patients with PD, though prevalence reports vary widely [14]. Secondary causes for RLS should be investigated including iron deficiency, uremia and polyneuropathy. Several case reports demonstrate onset or worsening of RLS with use of antidepressants [90, 91] or antipsychotics like risperdone, aripiprazole, and quetiapine [92, 93].

PLMS occurs in approximately 80-90% of patients with RLS, though may be present independently, and when seen on polysomnography is supportive of RLS [94]. PLMS is characterized by repetitive dorsiflexion of the foot, extension of the great toe, and may be accompanied by flexion of the knee and hip. The prevalence of PLMS in PD is approximately 60% and correlates with severity of PD motor features [95].

Treatment Options

Treatment of RLS should be initiated with non-pharmacologic therapies including good sleep hygiene, exercise, leg massage, and heat or ice packs [94, 96]. DA agonists are the primary treatment for RLS; however, even modest adjustments in levodopa can be helpful. One drawback to levodopa therapy is augmentation (a worsening or reappearance of symptoms) when serum levels fall due to the short half-life of levodopa [96, 97]. DA agonists are less likely to cause augmentation. Both pramipexole and ropinirole have been extensively studied with benefits in 70-90% of patients with RLS and PLMS, though there is a risk of developing compulsive behaviors [98-101]. Another option for PD patients is rotigotine, which is a partial dopamine agonist and may also help with motor symptoms [102, 103].

More recently, gabapentin enacarbil has demonstrated improvement of moderate to severe RLS and was well tolerated [96, 104, 105]. Lastly, opioids (tramadol, oxycodone, codeine) have been shown to be effective, especially in the treatment of RLS that is refractory to other treatments [94, 96].

Insomnia

Epidemiology

The most common sleep disorder in PD is insomnia, with a prevalence between 37-88% [13, 106]. Insomnia is associated with difficulty in initiation or maintenance of sleep. Disruption of sleep typically leads to daytime somnolence and patient reports of a strong impact on motor disability and overall quality of life. There are several contributors to insomnia in PD patients including nocturia, depression, RLS, dystonia, and akinesia/rigidity/difficulty turning in bed [107].

Treatment Options

The use of carbidopa/levodopa controlled-release formulations at bedtime is associated improved sleep duration and nocturnal akinesia, though does not demonstrate a significant improvement in overall sleep ratings [49]. Hypnotics like eszopiclone and zolpidem have also demonstrated improved quality of sleep, but use is limited by sedation, dizziness, and falls [49, 108]. Benzodiazepines improve sleep latency, though there is a risk of cognitive impairment, tolerance, and falls [106, 109]. Melatonin at 3 to 5 mg and 50mg doses have been investigated, although there is insufficient evidence to support their use [49]. Nevertheless, melatonin is well tolerated and may be tried with minimal risk [49]. More recently, doxepin has demonstrated improvement of insomnia scores and was generally well tolerated [110].

Excessive Daytime Sleepiness and Abrupt Sleep Onset

EDS: Epidemiology and Treatment

A common complaint by PD patients is excessive daytime sleepiness (EDS), and verified by a Multiple Sleep Latency Test, which demonstrates a decreased latency of time to sleep with frequent periods of daytime sleep. EDS frequency varies in the literature, but is seen in approximately 15-50% of PD patients [4, 111]. The etiology is usually multifactorial, with insomnia, dysautonomia, and depression as contributing factors to EDS [106]. A longer duration of symptoms, greater total load of levodopa, cognitive decline, and male gender are all risk factors for EDS [111, 112]. The evidence for the use of stimulants for EDS is lacking. The few studies conducted with modafinil have not demonstrated a robust improvement of EDS [113-115]. Other stimulants like methylphenidate have been studied with improvement of Epworth Sleepiness Score, though no randomized control trials have been undertaken [116].

Sleep Attacks: Epidemiology and Treatment

Abrupt sleep onset, or “sleep attack,” occurs when transition from wake to sleep is unavoidable and may occur without warning. Sleep attacks are three-fold more likely to occur in patients using DA agonists with an associated dose-related increase in this risk [117]. Adjustment or elimination of DA agonists often improves sleep attacks, though it is important to address concurrent EDS if present. Non-pharmacologic treatments to consider include mild exercise, early morning bright light exposure, and a stimulating environment [106].

Sleep Disordered Breathing/ Obstructive sleep apnea

Epidemiology and Treatment

Sleep disordered breathing (SDB) consists of either a deficit in the drive to breathe as in central sleep apnea, or may be due to an blockage of the airway as seen in obstructive sleep apnea (OSA). Apnea leads to oxygen desaturations that consequently trigger awakenings throughout the night, which in turn is experienced by the patient as daytime somnolence [106]. The prevalence of SDB and OSA is variable in the literature ranging from no increased risk in PD patients [118, 119], to a 50% prevalence in PD patients [120, 121]. Discussions with bed partners, history of snoring, and clinical reports of EDS or daytime fatigue are important indicators of SDB. Polysomnography confirms the diagnosis and can direct treatment, which frequently includes application of CPAP devices during sleep.

AUTONOMIC DYSFUNCTION

Orthostatic Hypotension

Epidemiology and Diagnosis

Orthostatic hypotension (OH) is defined as a 20mmHg fall of systolic blood pressure or 10mmHg drop of diastolic blood pressure within 3 minutes of a change in position. The prevalence of OH in PD patients is 30-60% [122, 123]. Symptoms of OH can occur early in the disease and often precede diagnosis of PD [123]. Patients experience OH as dizziness, drowsiness, palpitations, nausea, or loss of consciousness. Additionally, falls and supine hypertension that accompany OH are associated with increased risk of morbidity and mortality in PD patients [124]. Several medications used in the treatment of PD can exacerbate OH, including levodopa, DA agonists, MAO-B inhibitors, and TCAs [125].

Treatment Options

First-line therapies for OH includes non-pharmacologic methods such as compression stockings, sleeping with head elevated to 30 degrees, increased water and salt intake, more frequent small meals, and slowly changing position [126]. Fludrocortisone, a mineralacorticoid, and domperidone (a peripheral dopamine antagonist not currently approved for use in the United States), both modestly improve OH in PD patients [127]. Other effective treatments include midodrine [128], pyrdiostigmine [129], and droxidopa [130, 131]. Currently there is insufficient evidence to support the preferential use of any specific agent in the treatment of OH in PD.

Gastrointestinal (GI) Dysmotility

Constipation: Epidemiology and Treatment

Constipation is common amongst PD patients, reported by nearly 60% of PD patients [132]. Constipation can precede the development of motor symptoms of PD, and the prevalence of GI disturbances increases with age and longer duration of disease. Nearly one third of patients will have been diagnosed with a GI disturbance within the year prior to PD diagnosis [133], and is associated with an increased risk for PD [134]. People without a PD diagnosis, but with <1 bowel movement per day had more nigral Lewy body degeneration postmortem [135] compared to people without constipation.

Treatments for constipation include dietary modification, increased fluid intake, and mild exercise. Macrogol significantly improves constipation in PD patients and is very well tolerated [136]. Lubiprostone, a GI active prostaglandin, is also effective in the short-term treatment of constipation [137].

Gastroparesis: Epidemiology and Treatment

Gastroparesis, like constipation, is related to enteric dopaminergic cell loss and degeneration of the dorsal motor nucleus of the vagus [138]. Patients experience gastroparesis as early satiety, full sensation, and nausea. Decreased gastric motility leads to retention of food as well as medications, which can slow absorption and delay onset of action for many medications including levodopa. Domperidone has both prokinetic and antiemetic properties, which have been beneficial in the treatment of gastroparesis [139]; though its use is not approved in the United States.

Dysphagia: Epidemiology and Treatment

Dysphagia is associated with more advanced stages of PD as well as a significant increase in morbidity. Swallow exercises have demonstrated improvement of dysphagia [140]. The impact of levodopa therapy on dysphagia is controversial. For some patients, enteral nutrition is needed and placement of nasogastric tubes or percutaneous endoscopic gastrostomy tubes are an option.

Sialorrhea (Drooling)

Epidemiology

Difficulty handling oral secretions due to impaired or infrequent swallowing results in sialorrhea in up to 75% of PD patients [141], which is a significant embarrassment for most patients [142]. PD patients with drooling have difficulty speaking, eating, and engaging in social interactions, which significantly impacts perceived quality of life [143].

Treatment Options

Botulinum toxin (A and B) injections into the submandibular or parotid glands have demonstrated efficacy in the treatment of sialorrhea in PD patients, though injections are associated with greater invasiveness and cost [144-146]. Glycopyrrolate, an anticholinergic drug, is also efficacious in the treatment of sialorrhea in the short term [147]. Alternatively, gum chewing increases swallow frequency, improves drooling, and also shows a benefit with dysphagia [148].

Genitourinary Disturbances

Bladdery dysfunction: Epidemiology and Treatment

Bladder dysfunction in PD is often secondary to hyperactivity of the detrusor muscle leading to urinary urgency, increased urinary frequency, and nocturia. Less commonly, hypoactive detrusor muscle causes difficulty with initiation of urination, delayed bladder emptying, and recurrent infections. Urinary disturbances may occur before the onset of motor symptoms or early on in the disease course [11]. Disease severity is associated with greater urinary disturbances, and more than 50% of advanced PD patients report severe bladder symptoms [149].

Anticholinergic medications such as oxybutinin, solifenacin, and tolterodine are commonly used in the treatment of detrusor hyperactivity and demonstrate significant improvement in detrusor pressure [150]. PD patients on these agents should be closely monitored for side effects including cognitive impairment, somnolence, hallucinations, confusion, and blurred vision. Other treatments include botulinum toxin injections into the detrusor muscle [151].

Erectile dysfunction: Epidemiology and Treatment

Erectile dysfunction (ED) is reported by more than 60% of male PD patients [132] and is thought to be related to hypothalamic dysfunction and modification of the dopamine-oxytocin pathway [152]. Effects of PD medications, cognitive impairment, fatigue, apathy, and low testosterone contribute to loss of libido and ED [19, 153]. Phosphodiesterase inhibitors such as sildenafil, vardenafil, and tadalafil are possibly useful in the treatment of ED in PD patients, though randomized trials have been limited [152, 154]. Apomorphine sublingually is another medication that has demonstrated improvement of ED and can be considered for patients with contraindications to phosphodiesterase inhibitors [155].

SENSORY SYMPTOMS

Pain

Epidemiology

Sensory disturbances in PD include diminished ability to identify odors, visual abnormalities (blurred vision, abnormal color perception, double vision), and pain. Pain is the most disabling sensory disturbance, though frequently underreported. Nearly two-thirds of PD patients report pain, [156], though only half of patients receive any treatment [157]. Pain may also be a presenting symptom that precedes the clinical diagnosis of PD [158, 159].

Treatment Options

There are several types of pains in PD patients, the most common of which is musculoskeletal, typically involving the shoulder. Other types include dystonic, radicular, and central pain [160]. First-line treatment of musculoskeletal complaints includes non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. Modification of levodopa regimen (including altering timing and frequency or adding controlled release formulations) can often provide relief for dystonic pain, and also for central pain for some patients [159, 160]. Deep brain stimulation, with subthalamic nucleus or globus pallidus targets, has demonstrated improvement with dystonic, central, and musculoskeletal pain [160, 161].

CONCLUSIONS

NMS is an intrinsic part of PD, may predate diagnosis, and substantially affect the preponderance of patients with PD. For many of these patients, NMS have a greater impact on quality of life and healthcare costs than the cardinal motor symptoms that define the disease. NMS includes cognitive changes, psychological disturbances, sleep derangements, autonomic and sensory disturbances. Many of these symptoms are not recognized by practioners and are often not volunteered by PD patients, raising the importance for practitioners to routinely and directly inquire about NMS.

Management of NMS in PD is challenging and can often be compromised by the importance of addressing the co-existing motor symptoms, thereby complicating the balance needed to alleviate NMS while maintaining sufficient control of motor symptoms. Many treatments are available for NMS including a variety of pharmacologic and non-pharmacologic means. Nevertheless, it is important to first recognize the presence of these symptoms so as to not lose an opportunity to make a positive and potentially significant impact on the Parkinson patient’s quality of life.