Introduction

While the motor symptoms of Parkinson disease (PD) dominate the clinical picture – and even define the parkinsonian syndrome – many patients with PD have other complaints that have been classified as nonmotor (Chaudhuri et al., 2006a), and a scale has been developed to quantify them (Chaudhuri et al., 2006b). Also, there is an ongoing modification process to update the Unified Parkinson’s Disease Rating Scale (UPDRS) to include more nonmotor features of PD (Goetz et al., 2007). These include fatigue, depression, anxiety, sleep disturbances, constipation, bladder and other autonomic disturbances (sexual, gastrointestinal), and sensory complaints. Sensory symptoms, including pain, may occur. Orthostatic hypotension can lead to syncope. Behavioral and mental alterations include changes in mood, lack of motivation or apathy, slowness in thinking (bradyphrenia), and a declining cognitive capacity; and these are frequent causes for concern. In one survey of nondemented PD patients, nonmotor symptoms (NMS) were found to occur in the majority of patients (Table 8.1). Genetic as well as sporadic forms of PD have NMS (Kasten et al., 2010).There is even the suggestion that presentation of nonmotor symptoms that commonly occur in PD patients but without any of the cardinal signs of PD may be considered part of the same disease spectrum (Langston, 2006). Lang (2011) uses the term premotor for nonmotor symptoms that are part of PD and precede the motor symptoms. This is based on the Braak hypothesis discussed in Chapter 5. Braak and his colleagues are now estimating that the disease (pathology of Lewy neurites) begins in the olfactory and autonomic system by approximately 20 years before the onset of the motor symptoms of PD, and that many nonmotor symptoms appear (Hawkes et al., 2010).

Table 8.1 Frequency of nonmotor symptoms in Parkinson disease

Data from Shulman LM, Taback RL, Bean J, Weiner WJ. Comorbidity of the nonmotor symptoms of Parkinson’s disease. Mov Disord 2001;16:507–510.

A large collaborative Italian study of more 1072 patients with PD found that 98.6% of patients with PD reported the presence of NMS (Barone et al., 2009). The most common were: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urinary urgency and nocturia (35%), drooling of saliva (31%), and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0–32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity.

Always ask the patient what problems bother him/her; many times a nonmotor symptom is the most troublesome. Helping patients with PD to cope with these difficulties is just as important as manipulating therapy to provide control of their motor symptoms. In addition, antiparkinsonian drugs commonly induce unwanted nonmotor effects and aggravate such complaints. And so-called sensory “offs” are often underappreciated but are usually a greater source of discomfort than are motor “offs.” In this chapter, we cover nonmotor problems inherent to the disease and also those induced by medications to treat the disease. Nonmotor symptoms can become disabling with the increasing duration of the disease (see Tables 6.7 and Table 6.8).

Nonmotor symptoms not uncommonly can be the presenting complaint in PD. In pathologically proven PD 91/433 (21%) of patients presented with nonmotor symptoms, of which the most frequent were pain (53%), urinary dysfunction (16.5%), and anxiety, or depression (12%) (O’Sullivan et al., 2008). Presenting with nonmotor symptoms was associated with a delayed diagnosis of PD. These patients were more likely to be misdiagnosed initially and were more likely to have been referred to orthopedic surgeons or rheumatologists than neurologists. Comparing newly diagnosed patients with a control population, Miller and colleagues (2011) found a statistically significant higher number of autonomic and sensory symptoms in the PD group, especially olfaction, urinary, drooling, constipation, and sensory complaints.

With continuing PD, nonmotor symptoms become more common and can become the major troublesome symptom (Hely et al., 2005, 2008). Also medications to treat the motor symptoms of PD can cause nonmotor symptoms, including impulse control problems, confusion, hallucinations, and paranoid psychosis. Behavioral, mood, and cognitive problems can develop as complications of surgery for PD, such as deep brain stimulation (Voon et al., 2006c), and these are covered in Chapter 7.

Nonmotor symptoms as part of PD fit the pattern of the location of Lewy neurites described by Braak and his colleagues (see review by Braak et al., 2006), and presented in detail in Chapter 6. The Braak hypothesis as an early feature of PD is not uniformly accepted (Burke et al., 2008). As more parkinsonologists are focusing on nonmotor symptoms, there are more publications. Three recent reviews on this topic are recommended: Simuni and Sethi (2008), Lim et al. (2009), Chaudhuri and Schapira (2009), Lang (2011).

Two prominent risk factors for mortality in PD are the nonmotor symptoms of psychosis and dementia (Forsaa et al., 2010).

Sensory symptoms

Autonomic dysfunctions: bladder and sexual problems

The listing in Table 8.1 does not include autonomic symptoms, but PD patients also complain more about these, such as gastrointestinal, urinary, cardiovascular, thermoregulatory, and sexual dysfunction, than a control population, with the greatest differences in the gastrointestinal and urinary domain (Verbaan et al., 2008). These symptoms were found to increase with age, disease severity, and medication use.

The autonomic dysfunctions in patients with PD can be segregated into urogenital problems and those that affect other functions, such as blood pressure, the gastrointestinal tract, and skin (Table 8.3). In this section, we discuss bladder problems in patients with PD.

Table 8.3 Autonomic dysfunction in Parkinson disease

The prevalence of bladder symptoms in PD is high; the most common complaint is nocturia followed by frequency and urgency (Fitzmaurice et al., 1985; Winge and Fowler, 2006). Of course PD patients are usually of an age at which prostatic problems in the male and stress incontinence in the female can occur anyway. But PD itself affects bladder control, owing to detrusor hyperreflexia. As a result, premature uninhibited bladder contractions cause frequency and urgency, which can be particularly troublesome at night and during “off” periods. Araki and Kuno (2000) assessed voiding dysfunction in 203 consecutive PD patients and found that 27% had symptomatic voiding dysfunction. Its severity correlated with the severity of PD and not with disease duration, age, or gender.

Prostatic outflow obstruction can add to the problem in the male. Incontinence not explained by immobility when taken by the urge to micturate or by retention with overflow is not, however, a part of PD. True neurogenic incontinence in someone with parkinsonism suggests a diagnosis of multiple system atrophy (MSA) (Stocchi et al., 1997). In this case, sphincter electromyographic studies usually reveal signs of denervation due to involvement of Onuf’s nucleus in the sacral spinal cord, which does not occur in PD.

The diagnosis of significant prostate enlargement in PD is difficult, and prostatectomy by the unwary often leads to disaster. Prostatectomy should be considered only in those with proven outflow obstruction. A simple screening test in patients with PD is noninvasive ultrasonic estimation of post-micturition residual volume, and simple mechanical measurement of urinary flow rate. If there is significant residual volume after urination (>100 mL) or if flow rate is reduced, there may be bladder outlet obstruction and further investigation by more extensive urodynamic studies, and other urologic testing is required. If there is no significant residual volume or reduction of flow rate, urinary frequency and urgency may be helped by a peripheral antimuscarinic drug such as oxybutynin (Ditropan), 5–10 mg at night or 5 mg three times a day. Fluid intake should be reduced at night. A tricyclic antidepressant with anticholinergic properties, such as amitriptyline, may help sleep not only through its sedative actions but also by reducing bladder irritability. Intranasal DDAVP (desmopressin) at night also may reduce nocturia.

Impotence in the male patient with PD causes distress to both partners (as do immobility and other problems in the female). PD itself does not normally cause impotence, although this is a common early complaint in MSA. Loss of libido and failure to gain or sustain erections may have some other cause in this age group, be it psychological, vascular, hormonal or neurogenic, and appropriate investigation is warranted. Some antidepressant drugs, monoamine oxidase inhibitors, and antihypertensive medications can impair sexual performance. Failure of erection can be overcome by a variety of intrapenile or oral medications such as sildenafil (Viagra) (Zesiewicz et al., 2000). Sildenafil can be efficacious in the treatment of erectile dysfunction in both PD and MSA; however, it can unmask or exacerbate hypotension in MSA (Hussain et al., 2001). Parkinsonian symptoms are not affected, but a side benefit of reduced dyskinesias has been reported (Swope, 2000). Hypersexuality, particularly in the male, is a rare and unacceptable side effect of dopamine replacement therapy in PD, both levodopa and dopamine agonists, and usually requires reduction of antiparkinsonian medication.

Levodopa itself can affect the bladder (Brusa et al., 2007). In dopa-naive PD patients challenged with carbidopa/levodopa 50/200 mg, bladder overactivity (neurogenic overactive detrusor contractions) threshold and bladder capacity significantly worsened (32% and 22% of worsening, respectively). But when the same patients were rechallanged after being on levodopa therapy for 2 months, there was improvement of bladder function. Compared to the values obtained earlier, bladder activity and capacity improved 93% and 33%, respectively. Furthermore the sensation of bladder filling had a 120% improvement.

Other autonomic symptoms

Lewy body degeneration affects the autonomic nervous system in PD. Both sympathetic ganglion neurons and parasympathetic myenteric and cardiac plexi can be involved (Qualman et al., 1984; Kupsky et al., 1987; Wakabayashi et al., 1988). The postganglionic sympathetic nerves to the heart degenerate early and in a centripetal manner, with synuclein accumulation, not only in PD but also in persons with incidental Lewy bodies (Orimo et al., 2008). The loss of these sympathetic neurons is reflected in the reduced cardiac uptake of ¹²³I-meta-iodobenzylguanidine (MIBG), a physiologic analog of norepinephrine, in patients with PD and dementia with Lewy bodies (Oka et al., 2007a). In contrast, postganglionic sympathetic fibers remain intact in MSA, and so MIBG uptake is normal in MSA. Central autonomic nuclei, such as those of the hypothalamus and dorsal motor nucleus of the vagus, can also be affected in Lewy body degeneration (Eadie, 1963).

Orthostasis: Control of blood pressure may be compromised by sympathetic failure with impaired vasoconstriction and inadequate intravascular volume. Faintness on standing (pre-syncope) and frank loss of consciousness on standing (postural syncope) can occur owing to orthostatic hypotension (OH). OH can also cause posturally induced fatigue and weakness, blurring of vision, and “coat-hanger” neck and shoulder aching. Hypotension also may occur postprandially due to gastrointestinal vasodilatation. Levodopa, dopamine agonists, and selegiline (Churchyard et al., 1999) may aggravate postural hypotension. Oka and colleagues (2007b) compared PD patients with and without OH and found a greater association with male gender, older age, longer disease duration, posture and gait instability phenotype, low Mini-Mental State Examination (MMSE) scores, and visual hallucinations. Cardiac ¹²³I-MIBG uptakes were lower in patients with OH.

Prominent early symptoms of postural hypotension are, of course, one of the hallmarks of MSA, so such complaints may raise concern over the diagnosis of PD. The severity of postural hypotension in PD rarely is as severe as that seen in MSA. Nevertheless, treatment might be required. A selective peripheral dopamine antagonist such as domperidone sometimes helps, as does increasing fluid and salt intake, with head-up tilt at night which reduces nocturnal polyuria. Intranasal DDAVP (desmopressin) (5–40 µg) at night also reduces nocturnal polyuria, but can cause hyponatremia. However, a small dose of fludrocortisone (0.1–0.5 mg) (to promote salt retention), or midodrine (ProAmatine) (a selective α-agonist) (2.5–5 mg three times a day), might be required to maintain adequate blood pressure. Pyridostigmine was found to improve orthostatic hypotension, probably due to enhanced sympathetic ganglionic neurotransmission and a vagal shift in cardiac sympathovagal balance (Singer et al., 2006).

Gastrointestinal problems cause significant disability in PD (Edwards et al., 1991, 1992). Dysphagia is due mainly to poor masticatory and oropharyngeal muscular control making it difficult to chew and propel the bolus of food into the pharynx and esophagus (Bushman et al., 1989; Edwards et al., 1994). Soft food is easier to eat, and antiparkinsonian medication improves swallowing.

Parasympathetic failure may contribute to gastrointestinal problems in PD, causing delay in esophageal and gastric motility. A sense of bloating, indigestion, and gastric reflux are common in PD (Edwards et al., 1992). Many factors contribute to delayed gastric emptying, including immobility, parasympathetic failure, constipation, and antiparkinsonian drugs (both anticholinergic and dopamine agonists). Levodopa is absorbed in the upper small bowel, so gastric stasis may slow or prevent levodopa assimilation, leading to “delayed-ons” and “no-ons” (dose failures) after single oral doses (either there is an excessive interval before the drug works, or it does not work at all).

Constipation is another frequent complaint in PD (Edwards et al., 1992, 1994; Kaye et al., 2006), and is multifactorial. Again, immobility, drugs, reduced fluid and food intake, and parasympathetic involvement prolonging colonic transit time may all contribute. In addition, malfunction of the striated muscles of the pelvic floor due to the PD itself can make evacuation of the bowels difficult (Mathers et al., 1988, 1989). Constipation may exacerbate gastric stasis. Anticholinergic drugs should be stopped and physical exercise should be increased. The role of levodopa in causing or treating constipation is uncertain. This drug usually does not relieve the problem, and some patients believe that it worsens the problem. Constipation is ameliorated by adequate fluid intake, fruit, vegetables, fiber, and lactulose (10–20 g/day) or other mild laxatives. The following “rancho recipe” provided by Dr Cheryl Waters has been found useful for many patients: Mix together one cup each of bran, applesauce, and prune juice; take two tablespoons every morning; the mixture can be refrigerated for one week, then should be discarded. Polyethylene glycol powder (marketed as MiraLax) can be effective to overcome constipation; the usual dose is 17 g/day dissolved in a glass of water at bedtime. Refractory constipation may be helped by apomorphine injections to assist defecation (Edwards et al., 1993; Merello and Leiguarda, 1994).

Pyridostigmine by enhancing parasympathetic tone can also aid peristalsis and help in the treatment of constipation. For patients who have abdominal bloating due to suppression of peristalsis when they are “off”, keeping them “on” with levodopa or other dopaminergics is beneficial.

Excessive sebum (seborrhea) probably is due more to facial immobility that to overproduction. The greasy skin contributes to seborrheic dermatitis and dandruff. Medicated soaps and shampoos help. Blepharitis also is common, due in part to reduced blinking. Artificial teardrops can help.

Excessive sweating can be a problem, particularly in the form of sudden drenching sweats (sweating crises). These seem to occur as part of an “off” phenomenon (Sage and Mark, 1995; Swinn et al., 2003; Pursiainen et al., 2007). Sweating can cause physical, social, and emotional impairment.

Excessive salivation (sialorrhea) is due more to failure to swallow saliva frequently than to overproduction (Bateson et al., 1973). Drooling of saliva can be helped by chewing gum (which also helps those with dry mouth) or by using peripherally-acting anticholinergic drugs, which are quaternary ammonium compounds that do not cross the blood–brain barrier. Two such compounds are glycopyrrolate and propantheline. The former was tested in a controlled clinical trial and found to be effective and safe therapy for sialorrhea in PD (Arbouw et al., 2010). If these are unsuccessful, intraparotid injections of botulinum toxin B can sometimes be effective in reducing salivary secretions and drooling (Lipp et al., 2003; Racette et al., 2003; Ondo et al., 2004). Chewing gum has also been found useful to increase swallow frequency, and it decreases latency of swallowing in PD (South et al., 2010), which are common problems in advanced PD and contribute to weight loss in PD.

Rhinorrhea is not infrequent in patients with PD and has been reported to occur in almost 50% (Friedman et al., 2008). Patients with PD with rhinorrhea were older and had a higher Hoehn and Yahr stage. Duration of disease was not different between those with and without rhinorrhea. Most patients with rhinorrhea reported that it worsened with eating.

Respiratory distress

Respiratory distress such as dyspnea can occur as a symptom of PD in some patients, including during the “off” period in some (Ilson et al., 1983). It can also occur as a complication of dystonia, usually peak-dose dystonia (Braun et al., 1983), and with some dopamine agonists, particularly pergolide. Removing the offending drug is required. “Off” period dyspnea is difficult to treat, other than attempting to keep the patient “on.” Despite the sensation of dyspnea, oxygen saturation is not affected because the patient will have a voluntary sigh or transient deep breathing when feeling short of breath. Some forms of parkinsonism-plus syndromes may have an accompanying apnea that is life-threatening, such as postencephalitic parkinsonism (Strieder et al., 1967; Efthimiou et al., 1987), frontotemporal dementia (Lynch et al., 1994), MSA (Chester et al., 1988; Salazar-Grueso et al., 1988), Joseph disease (SCA3) (Kitamura et al., 1989), and other familial parkinsonian syndromes (Perry et al., 1990).

Difficulties at night and daytime sleepiness

Table 8.4 lists some of the sleep problems seen in PD. Patients often have troubled nights for many reasons (Factor et al., 1990; Askenasy, 1993; Van Hilten et al., 1994; Bliwise et al., 1995). The most common problem is difficulty with sleep maintenance (so-called sleep fragmentation). Frequent awakenings may be caused by tremor reappearing in the lighter stages of sleep, difficulty in turning in bed due to nocturnal akinesia as the effects of daytime administration of dopaminergic drugs wear off at night, and nocturia. In addition, periodic leg movements in sleep (sometimes associated with restless legs), fragmentary nocturnal myoclonus, sleep apnea, REM sleep behavioral disorders (intense dream-like motor and behavioral problems), and parasomnias (nocturnal hallucinations and nocturnal wandering with disruptive behavior) may all disrupt sleep in PD. Reversal of sleep rhythm with sundowning also is common in PD (Bliwise et al., 1995). Many of these conditions probably occur more frequently in PD than in other aged populations. As a result, PD patients and their caregivers face disrupted nights, which lead to poor quality of life and worse parkinsonism the next day. In fact, along with depression, poor sleep is a major factor in a PD patient’s assessment of having a poor quality of life (QoL) (Karlsen et al., 1999b). Rating scales to assess severity of sleep disturbances have been developed (Trenkwalder et al., 2011). A good night’s sleep reduces the severity of daytime parkinsonism, and many patients comment on sleep benefit, describing better mobility the morning after a restful night. Indeed, patients with marked sleep benefit might not require antiparkinsonian medication for some hours after they awaken, and some PD patients find that a daytime nap “charges the batteries.” These may be the young-onset PD patients with mutations in the parkin gene for they typically show sleep benefit (Elibol et al., 2000).

Table 8.4 Sleep problems in Parkinson disease

Another cause of disturbed sleep is the return of parkinsonian symptoms during the night after the last dose of medication has worn off. Nocturnal tremor and akinesia due to the PD and nocturia in the elderly can cause arousals. Depression, which is common in PD, can cause insomnia and is a major factor associated with nighttime sleep problems (Verbaan et al., 2008). Drugs given to treat PD symptoms can interfere with sleep.

PD pathology can also be associated with REM sleep behavior disorder (RBD) and parasomnias, especially in patients with incipient or frank dementia. RBD, described initially by Schenck and colleagues (1986), is a condition in which there is lack of somatic muscle atonia, thus enabling such individuals to move while they dream (acting out their dreams). The animal model of REM sleep without atonia indicates that lesions to the perilocus coeruleus disrupt the excitatory connection to the nucleus reticularis magnocellularis in the descending medullary reticular formation and disable the hyperpolarization of the alpha spinal motoneurons (Ferini-Strambi and Zucconi, 2000). The development of RBD may be an early marker for the later onset of PD (Schenck et al., 1996; Tan et al., 1996; Postuma et al., 2006).

RBD may precede or develop after PD. RBD is suspected of arising in the pons–medulla area, and therefore the Braak scheme would have RBD occurring before PD, if RBD is a component of PD. In the survey of their PD patients, Scaglione and colleagues (2005) found that only 33% had RBD. Of these, PD preceded RBD in 73%, an average of 8 years before onset of RBD. In another study, RBD preceded PD in only 22% (De Cock et al., 2007). Postuma and colleagues (2009) followed patients with idiopathic RBD and found that the risk for developing any neurodegenerative disease (PD, dementia with Lewy bodies, MSA, or Alzheimer disease) is 17.7% by 5 years, 40.6% by 10 years, and 52.4% by 12 years. Only 14 out of 93 developed PD. With longer follow-up, approximately 50% of idiopathic RBD cases will develop PD and the more severe the loss of atonia on baseline polysomnograms, the better the prediction of the development of PD (Postuma et al., 2010).

RBD is usually successfully treated with a bedtime dose of clonazepam (Schenck et al., 1987); 0.5 mg is often sufficient, but sometimes a higher dosage is required to obtain complete relief.

The treatment of sleep disorders in PD is important. Attention to sleep hygiene by avoiding alcohol, caffeine, and nicotine, and excessive fluid intake at night is helpful. Deprenyl (selegiline), which is metabolized to methamphetamine and amphetamine, should not be given at night. Treatment of depression might be required. A sedative antidepressant, such as amitriptyline (10–25 mg at night), mirtazapine, or trazodone, can be very useful, not only to induce and maintain sleep, but also to reduce urinary frequency. A dose of a long-acting levodopa preparation last thing at night may improve nocturnal akinesia (Laihnen et al., 1987; Lees, 1987). However, levodopa given at night may provoke excessive dreaming and disrupted sleep in some patients (Nausieda et al., 1982). A benzodiazepine, especially clonazepam, may lessen REM sleep behavior disorders. A low dose of 0.5 mg at bedtime is usually effective. Propoxyphene is useful for periodic leg movements of sleep and restless legs (Hening et al., 1986). A small bedtime dose of clozapine (Rabey et al., 1995) or quetiapine may be very effective in improving sleep. For patients who have no problem falling asleep, but awaken in 2–3 hours, the short-acting hypnotic zolpidem is useful when taken after the awakening. It helps the patient get back to sleep quickly and still be refreshed in the morning.

Excessive daytime sleepiness (EDS) occurs in about 15% of patients with PD, and is associated with more severe PD and patients with cognitive decline (Tandberg et al., 1999). In one study, EDS was found in 50% of patients (Shpirer et al., 2006). EDS is determined by short sleep latency and sleep-onset REM periods. When studied with tests determining these two criteria, PD patients with EDS were found to correlate not with variables related to disease severity or to total sleep time or sleep stage percentages, but rather those related to primary impairments of waking arousal and REM-sleep expression (Rye et al., 2000). Dopamine agonists are more likely than levodopa to be associated with EDS (Ondo et al., 2001; Gjerstad et al., 2006). The antisoporific agent modafinil can sometimes be beneficial in overcoming EDS in patients with PD (Happe et al., 2001). Oxybate has been reported to reduce EDS (Ondo et al., 2008).

Some patients who sleep a lot during the day may have their problem related to drowsiness following a dosage of levodopa. This phenomenon is usually seen in patients with developing or more pronounced dementia. With post-levodopa drowsiness, patients can sleep during much of the day and are then awake at night. This altered sleep–wake cycle can make life unbearable for the caregiver, who requires adequate sleep at night. If a patient becomes drowsy after each dose of medication, this is a sign of overdosage. Reducing the dosage can correct this problem. Sometimes, substituting Sinemet CR for standard Sinemet will help because this provides for a slower rise in plasma and brain levels of levodopa.

If the patient’s sleep problem has advanced to that of an altered sleep–wake cycle, it is important to get the patient onto a sleep–wake schedule that fits with that of the rest of the household. To correct the problem, it might be necessary to use a combination of approaches. Efforts must be made to stimulate the patient physically and mentally during the day and force the patient to remain awake, otherwise he or she will not be able to sleep at night. At night, the patient should then be drowsy enough so that he or she will be able to sleep. If this fails, it might be necessary to use stimulants in the morning and sedatives at night to reverse the altered state. This should be done in addition to prodding the patient to remain awake during the day. Drugs such as methylphenidate and amphetamine are usually well tolerated by patients with PD. A 10 mg dose of either of these two drugs, repeated once if necessary, may be helpful. To encourage sleep at night, a hypnotic might be necessary in addition to using daytime stimulants. It should be noted that strong sedatives, such as barbiturates, are poorly tolerated by patients with PD. Milder hypnotics, such as benzodiazepines, are usually taken without difficulty. Short-acting benzodiazepines would be preferable, but if the patient awakens too early, a longer-acting one might need to be used.

Fatigue

Although fatigue can be a symptom of sleepiness or depression, it is also a symptom that may be unassociated with these states. The clinician should probe the patient to distinguish between fatigue and sleepiness. In patients with PD, fatigue is often a complaint during the earliest phase of the disease, before motor symptoms, such as stiffness and slowness, become prominent. As these other features of PD develop, with their important contribution to disability, these become more of a complaint than does fatigue. But when patients are specifically asked, fatigue remains a common feature in PD. In a community study of elderly people in Norway, 44% of PD patients and 18% of healthy controls reported fatigue (Karlsen et al., 1999a). In a Japanese study involving 361 PD patients, fatigue was present in 41.8% and depression was not a contributing factor (Okuma et al., 2009). In newly diagnosed patients with PD, fatigue was discerned in 36% and was less likely to worsen if the patient received levodopa compared to a placebo (Schifitto et al., 2008). Treating depression and daytime sleepiness would be helpful, but when fatigue is an independent symptom, no treatment has been found to be satisfactory. Despite the claimed benefit of amantadine in treating fatigue in multiple sclerosis, neither this drug nor the monoamine oxidase inhibitor selegiline has been found particularly beneficial in treating fatigue in PD. Neither has modafinil in a small controlled trial (Lou et al., 2009). Methylphenidate 30 mg/day has been reported to reduce fatigue in a controlled clinical trial (Mendonça et al., 2007) and in fatigue in patients with prostate cancer (Roth et al., 2010). Oxybate at bedtime has also been reported to help (Ondo et al., 2008). Friedman and colleagues have published a thorough review of fatigue in PD (Friedman et al., 2007).

Depression, anxiety, and change in personality