In this chapter emphasis will be placed upon those NMS con- sidered to be an intrinsic part of the PD process, including smell disturbances, dysautonomia, pain and other sensory symp toms, sleep disturbances, apathy and depression, and fatigue. Some less common or less disa bling NMS, such as seborrhoeic dermatitis or hyperhidrosis, and particularly those NMS most ly related to treatment, such as skin erosions or skin nodules associated with DBS or apomo rphine are listed in Table 11.2. Th e occurrence Specifi c measures to treat insomnia include modifi cation of antiparkinsonian treatment, s uch as reduction of selegiline or Oxford Textbook of Movement Disorders 100 possible, and depression and anxiety treated. Adding a hypnotic is another option (16). Table 11.1 Non-motor symptoms and presumed neuropathological substrate Non-motor symptoms S mell loss Underlying brain structures Olfactory bulb; anterior olfactory nucleus; amygdala; perirhina l cortex REM sleep behavior disorder RBD is a parasomnia characterized by recurrent episodes of vig- orous dream-enacting behaviors associated with nightmares and abnormally increased phasic and/or tonic electromyographic (EMG) activity during REM sleep. In these dreams, patients a re usually threatened or attacked by people or animals, and they react verbally or physical ly to the off ender (17). Frequency and intensity of abnormal behaviors and dreams may vary during the night (they are usually worst at the end of the night), between diff erent nigh ts, and from one patient to another. In some patients these abnormal dream-enacting behavio rs can be severe and cause injury to the patient or their bed partner, resulting in fractur es, lacerations, or contusions. In other cases, the RBD is less severe in its expression. I n most instances patients are unaware of these behaviors, which are reported by the bed par tner (18). Autonomic dysfunction Amygdala; dorsal nucleus of the vagus; intermediolateral column of the spinal cord; sympath etic ganglia; enteric plexus neurons; autonomic neurons in the thoracic and sacral spinal c ord, heart, and gastrointestinal and genitourinary tracts Sleep disturbances Nucleus subcoeruleus; pedunculopontine nucleus; thalamus; hypothalamus Behavioral/emotional dysfunction Locus coeruleus; raphe nuclei; amygdala; limbic cortex; mesolimbic and mesocortical cortex Hallucinations, psychosis Amygdala; limbic cortex Dementia and cognitive dysfunction Frontal and ventral temporal lobe/neocortex, hippocampus, amygdala, nucleus basalis of Meyn ert, locus coeruleus Polysomnography with audiovisual recording (VPSG), dem- onstrating either abnormal movement s or excessive EMG activ- ity during REM sleep, is needed to confi rm the diagnosis of RBD. VPSG is also helpful in ruling out conditions such as OSA, som- nambulism, nocturnal epile psy, hallucinations, confusional awak- enings, or prominent periodic leg movements, which c an mimic RBD-like behaviors (5, 19). Table 11.2 Pain, cutaneous disturbances, and other less well-known NMS Pain and sensory symptoms \227\206 Non- \202 uctuating: continuous, not related to timing of antiparkinson drugs \227\206 Musculoskeletal or radicular \200\223neuropathic types of neck, lower back, or When diagnosis is based solely on clinical history, RBD fre- quency in PD is 15 \200\22346% (4, 20, 21). If RBD diagnosis is per- formed using VPSG, the frequency is somewhat higher, ranging from 46 to 58% (22 \200\22325). RBD may occur more oft en in the rig- id \200\223a kinetic than in the tremor-predominant subtype of PD (26, 27). Whether RBD is more common i n patients with dementia is unclear, but some studies have suggested that the presence of R BD is associated with cognitive impairment and represents a risk factor for dementia (28). RBD also occurs in patients with PD associated with parkin gene mutations (29). RBD in PD i s probably best explained by dysfunction of the neural systems that regulate REM sleep, par ticularly those located in the brainstem including the locus coeruleus and pedunculopontine tegmental nucleus (17, 30). limb pain \200 Central primary pain in a limb \200 Akathisic discomfort \227\206 Associated with motor \202 uctuations OFF related: central primary pain in limb, low back, unusual body sites; angina-like chest pain; burning mouth syndrome; genital pain; abdominal pain OFF dystonia (usually in the foot) akathisic discomfort RLS-like symptoms ON related: associated to ON-dyskinesias akathisia Cutaneous problems \227\206 Facial seborrhoea (seborrhoeic dermatitis) \227\206 Possible increased risk of skin cancer Most patients with RBD respond to clonazepam at doses of 0.5 \200\2232 mg taken at night in a single dose (17). Th ere is no clear evi- dence that dopaminergic agents infl uence the development, evo- lution, or severity of RBD (26). However, initiation of levodopa has been reported to improve RBD in some patients. In others, reduction of total daily dose of levo dopa or other dopaminergic agents, such as the MAO-B inhibitors, may improve or eliminate t he symptoms. \227\206 Malignant melanoma (unrelated to dopaminergic treatment) \227\206 Keratosis and basal cell carcinoma \227\206 Adverse event of antiparkinsonian therapy \227\206 Amantadine-induced livedo ret icularis \227\206 Leg oedema (dopamine agonists) \227\206 Erythromelalgia-like (dopamine agonists) \227\206 Subcutaneous nodules related to s.c. apomorphine injections \227\206 S kin erosion over implants in deep brain stimulation Excessive daytime sleepiness Th e presence of EDS in PD has been reported to vary from 12 t o 84% of patients (2, 3, 6, 10). Patients may complain of a constant feeling of sleepiness, or describe episodes of sudden, irresistible, and overwhelming sleepiness without awarenes s of falling asleep, which have been labeled sleep \200\230attacks \200\231 or episodes of sudden onset of sleep (31). Sleep attacks have been reported in 0.5 \200\22320% of patient s with PD on a background of EDS (2, 3, 6, 10). A sub- group of patients (15 \200\22339%) w ith somnolence-present sleep-onset REM periods (SOREMPs) on the Multiple Sleep Latency Test (MSLT) and are said to have a narcolepsy-like phenotype (32, 33). Ocular and visual disturbances \227\206 Dry eyes (xerostomia, related to autonomic dysfunc tion) \227\206 Diplopia, blurred vision Other \227\206 Weight loss, weight gain (possibly drug-induced), rhinorrhoea, ageusia amantadine, or optimization of antiparkinsonian treatment at night to minimize nocturnal mo tor or sensory symptoms. Agents with a long half-life or sustained eff ect, such as rotigot ine or ropinirole 24-hour prolonged release, can be useful for attenuating OFF periods duri ng the night (14, 15). Nocturia has to be improved, if CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease 101 However, in contrast with narcolepsy, hypocretin-1 levels in the cerebrospinal fl uid (CSF) are normal in most PD patients (34 \200\22337). EDS in PD has been attributed to neurodege nerative changes in brain areas that regulate the sleep \200\223wake cycle, including the l ocus coeruleus, the dopaminergic midbrain ventral tegmental area, the pedunculopontine tegm ental nuclei, and the hypocretin-producing neurons in the lateral hypothalamus (38 \200\223 40). Supporting the notion of a \200\230central \200\231 hypersomnia in PD is the fact tha t EDS is more frequent in patients with advanced PD or in those patients in whom the neurop athological process is more extensive, for example PD patients with dementia (6, 7, 37, 41 \200\22342). sodium oxybate, a drug that has been approved for treating nar- colepsy, could improve EDS in PD (53). Smell loss in Parkinson \200\231s disease Smell loss is frequent in PD and involves several functions such as impairment of odor detection, identifi cation, and discrimi- nation. Sme ll loss causes little disability and is rarely mentioned spontaneously by the patient, but if it is specifi cally asked about or tested for, olfactory impairment is demonstrated in u p to 90% of PD patients (54 \200\22357). Th e olfactory defi cit in PD is independent of di sease severity and duration, being present in recently diagnosed and untreated PD patients, and does not vary between the ON and OFF states (54 \200\22355, 58). Hyposmia has been con sidered an early marker for PD, since it can antedate the motor signs of the disease (59, 6 0). Hyposmia in PD is attributed to involvement of the olfac- tory system by Lewy-type path ology. Th e olfactory bulb is the most frequently aff ected area, followed by the anterior olfactory nucleus and the primary olfactory cortex (61). EDS is also a well-known side eff ect of dopamine agonists (43). It has been reported to oc cur with ergot and non-ergot dopamine agonists (44 \200\22346). Levodopa monotherapy can al so induce somno- lence, although less frequently than in combination with dopamine agonists (47, 48). Treatment of EDS in PD will depend on the underlying causa- tive factors (Table 11.3). Howe ver, an important step is to inform the patient about the potential dangers of driving and other activities until the EDS has resolved or improved. Th e next step is to assess whethe r or not EDS is pharmacologically mediated. If sleepiness seems to be related to dopaminerg ic drugs, one should try to reduce the dose, switch to another dopaminergic drug, or even s top the off ending drug, although this may worsen motor function. Other measures that need to be taken are outlined in Table 11.3. EDS can be treated with awake-promoting agents such as modafi nil 200 \200\223400 mg/daily (49). However, the effi cacy of this drug in treati ng EDS in PD has only been assessed in three small double-blind placebo-controlled trials, which have shown con- fl icting results (50 \200\22352). A recent open-label study suggeste d that Some studies have found signifi cantly better olfactory function in tremor-dominant PD than in akinetic \200\223rigid or postural instabil- ity gait diffi culty predominant PD subtyp es (62, 63). Recent studies suggest that the degree of olfactory dysfunction in PD can corr elate with increased autonomic dysfunction, reduced cognitive func- tioning, and the presen ce of psychotic symptoms (64 \200\22367). Hyposmia can be useful in diff erentiating PD from other parkin- sonian or tremor syndromes since olfactory function is preserved or mildly impaired in atypical parkinsonian disorder s, such as mul- tiple system atrophy (MSA), progressive supranuclear palsy, or cor- ticobas al degeneration (54, 56, 68), or in secondary parkinsonism, Table 11.3 Excessive daytime sleepiness in Parkinson \200\231s disease: causes and manageme nt Causes Management and treatment Dopaminergic drugs EDS occurs more frequently with DA than levodopa Frequency of EDS is sim ilar with all (instead of oral) DA currently in use Consider dose reduction or gradual suppression of DA or other dopaminergic drugs or switchi ng to another DA Risk of worsening of motor symptoms Sedative drugs Neuroleptics, benzodiazepines, antihistamines, etc. Careful check of all current medication Consider dose reduction or suppression of o \200 e nding drug Motor disturbances at night Nocturnal akinesia, rigidity or tremor Dyskinesias Optimize antiparkinsonian treatment (e.g. add a nocturnal dose of levodopa) Nocturnal sensory symptoms Pain: secondary to immobility, rigidity, cramps OFF-period dysto nia (early morning) Restless-legs-like symptoms Optimize antiparkinsonian treatment (e.g. levodopa); extended released or transdermal DA at bedtime OSA syndrome Unclear if this occurs more frequently in PD than in the general population Inquire about intense snoring, gasping, and respiratory pauses during sleep If OSA is suspe cted, nocturnal PSG is indicated CPAP mask eliminates OSA PD-related hypersomnia Sleepiness can be caused by PD itself Some PD patients with EDS may have a narcoleptic-like phenotype PSG followed by a MSLT (presence of > 2 SOREMPs) may be present (narcolepsy-like phenotype) Treatment with wake-promoting agents such as moda \201 nil can be helpful EDS, excessive daytime sleepiness; DA, dopamine agonist; OSA, obstructive sleep apnoea; PSG , polysomnography; CPAP, continuous positive airways pressure; MSLT, Multiple Sleep Latency Test; SOREMP, sleep-onset REM period. Oxford Textbook of Movement Disorders 102 such as vascular or drug-induced parkinsonism (69). Smell is also preserved in essential tr emor (70). Interestingly, patients with parkin- associated PD, which usually demonstrates n igral degenera- tion without Lewy bodies (LB) on neuropathological examination, tend to hav e intact olfactory function (71). In LRRK2 -related PD, another genetic form of parkinsonis m that has heterogeneous neu- ropathology, smell loss also appears to occur less frequently than in idiopathic PD (72, 73). In contrast, and similarly to classic PD, subjects with de mentia with Lewy bodies (DLB) usually present with severe loss of smell (74), supporting th e concept that hypos- mia could be a marker of an underlying LB disorder. Although dysautonomia in PD can sometimes occur as a side effect of treatment, in most case s it can be attributed to the dis- ease process itself. The neuropathological lesions in PD can involve the central and peripheral postganglionic autonomic nervous system, leading to autonomic dysfunction. LB and neu- ronal loss have been found in the dorsal nucleus of the vagus, the intermediate ventrolateral columns of the spinal cord, and Onuf \200\231s nucl eus, and within the cardiac sympathetic plexus and enteric autonomic nervous system (80, 88 \200\22394). Early involve- ment of these structures would explain why some of these dys- autonomic symptoms could occur as a premotor feature of PD (95 \200\22397). Dysautonomia in Parkinson \200\231s disease Dysautonomia in PD is frequent and includes gas trointestinal (GI), urogenital, cardiovascular, and thermoregulatory dysfunction (Table 11. 4) (75, 76). Estimated prevalence of autonomic dysfunction in PD ranges from 14 to 80% (75) , and disabling dysautonomic symp- toms are present in up to 50% of patients (76). Gastrointestinal dysfunction GI symptoms are more frequent in PD than in age-matched contro ls, and include excess salivation, dysphagia, constipa- tion, and other symptoms related to reduced GI motility, such as regurgitation, nausea, and epigastric discomfort or bloating secondary to gastroparesis (98, 99). Nausea is often related to dopaminergic medication, bu t impaired gastric emptying may also play a role (100). Gastroparesis also has relevant pha rma- cokinetic implications in PD, since delayed gastric emptying may cause increased expos ure of levodopa to dopa-decarboxylase in the gastric mucosa and reduce absorption of the dr ug, lead- ing to an erratic pharmacological response (99). Reduced GI motility may worsen w ith disease progression, and eventually can be life-threatening in some patients in associa tion with fatal gastroparesis, Ogilvie \200\231s megacolon, and sigmoid volvulus (101, 102) . Th e presence of dysautonomia in PD has been correlated with age, disease severity, and use of dopaminergic drugs. Symptomatic dysautonomia is more severe as the disease advances; ho wever, dysautonomia is also frequent in recently diagnosed and untreated PD (77, 78). In so me early PD patients, dysautonomic symptoms can be prominent, mimicking pure autonomic fail ure or MSA (79, 80). In addition, some dysautonomic symptoms may even predate the developme nt of the cardinal motor signs of the disease (81). Dysautonomia is also frequent in geneti cally determined PD vari- ants, including alpha-synuclei n , PINK- 1 , and LRRK2 gene muta- tions (82 \200\22385), and even in cases of parkinsonism related to parkin gene mutations which usually lack LB pathology (86, 87). Constipation is very common and is present in up to 60% of PD patients (76, 103). Slowed or delayed colonic transit seems to be the main pathophysiological mechanism underpinning dec reased bowel movement frequency (99). PD patients may also have additional diffi culties wi th the act of defecation, such as painful or incomplete emptying, because of hypertonus in the perianal musculature, poor ability to voluntarily contract the external anal sphincter, or poor ability to activate pelvic muscles during OFF periods (104 \200\223106). In additi on, problems with def- ecation can be aggravated by associated puborectalis dystonia or ani smus (107, 108). Table 11.4 Dysautonomic symptoms in Parkinson \200\231s disease Gastrointestinal dysfunction Hypersalivation (also related to swallowing di \203 culties) Dysphagia Regurgitation, nausea Epigastric discomfort or bloating, heavy digestion (gastrop aresis) Constipation Incomplete emptying, painful defecation, anismus Bowel pseudo-occlusio n (Ogilvie \200\231s s y ndrome), sigmoid volvulus Treatment of constipation should include general measures of bowel hygiene such as dietary modifi cations, with increase in dietary fi bre and fl uid intake, and reduction or discont inuation of anticholinergic drugs. Some laxatives (macrogol, dietary herbal extracts) and p rokinetic drugs (tegaserod, mosapride) have been specifi cally tested in PD in double-blind controlled randomized trials or observational short series, with promising results (49, 10 6, 109 \200\223112). Domperidone, a peripheral dopamine antagonist, may improve gastric emp tying and reduce dopaminergic-drug-related GI symptoms (113). Dopamine receptor blockers wi th cen- tral activity, such as metoclopramide and clebopride, should be avoided. Other pro- kinetic drugs, such as erythromycin or ondansetron, could be useful but have not been speci fi cally tested in PD. Treatment with botulinum toxin in pelvic musculature may have some b enefi t in cases with anismus (114). If GI symp- toms are refractory, one should consider r eferral for additional investigations to rule out other causes, including common and readil y treatable conditions such as Helicobacter pylori infection or peptic ulceration. Urinary dysfunction Urinary frequency and urgency Urge incontinence Nocturia Di \203 culty with initiation of urination Urinary retention Sexual dysfunction Erectile dysfunction Impaired ejaculation Reduced vaginal sensitivity an d decreased mucosal lubrication Cardiovascular dysfunction Orthostatic hypotension Postprandial hypotension Th ermoregulatory dysfunction Sweating abnormalities (can be localized and asymmetric) Hype rhidrosis (may occur in association with OFF periods, ON dyskinesias, or unrelated to motor \202 uctuations) Hypohidrosis Heat/cold intolerance CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease 103 Genitourinary dysfunction Poor bladder control can be one of the most troublesome non- moto r symptoms of PD. Increased frequency, urinary urgency, urge incon- tinence, nocturia, and voiding diffi culties are common in PD (115 \200\223 117). Urinary symptoms are particularl y frequent in the advanced stages and appear with a mean latency in relation to the onset o f motor symptoms of about 144 months, in contrast with 12 months in MSA (118). However, a r ecent study in early untreated PD found storage problems (urinary urgency, day- and night-t ime urinary frequency (nocturia), and urge/stress/mixed incontinence) in 64% of subjects (1 19). Urinary symptoms have also been reported to antedate the onset of motor signs (120). OH can contribute to falls and other accidental trauma. Cardio- vascular dysautonomia worse ns with disease progression. In the Sydney Multicentre Study of PD, a cohort of newly diagn osed patients was followed over 20 years (133). At 15 years follow-up, symptomatic postural hypotension occurred in 35%, increasing to 48% at 20 years follow-up (134). Symptomatic OH can occur even early in the course of the disease (135). Bonuccelli found a decrease of mo re than 20 mmHg in systolic blood pressure on standing in 7/51 (14%) patients with PD. Prom inent OH in a parkinsonian patient is considered a red fl ag for MSA, and dif- ferentiation of early PD with symptomatic OH and MSA can be challenging. OH and postprandial hypotension can be attributed to sym- pathetic neurocirculatory failure from generalized sympathetic denervation secondary to PD pathology (136 \200\223137), alth ough dopaminergic medications may cause, or even aggravate, OH and postprandial hypotension (138). Cardiovascular abnormalities can occur in the absence of OH in PD, as shown by asym ptomatic cardiac and vasomotor sympathetic dysfunction demonstrated by studying heart rate variability and 24-hour blood pressure monitor- ing (137, 139, 140). Extensive cardiac symp athetic denervation has been shown in most PD patients, using meta-iodobenzyl guanidine (MI BG) SPECT, even in the early stages of the disease (141 \200\223145). Th e degree of tracer uptake seems to correlate with disease progres- sion (146, 147) and the rigid \200\223akin etic PD subtype (148), but not with dysautonomic symptoms (144, 149). Several MIBG and path - ological studies indicate that impaired sympathetic postganglionic function constitutes a marker of LB disorders compared with other parkinsonian syndromes without underlying LB pa thology (97, 150 \200\223152). MIBG SPECT can be useful in the diff erentiation of PD with prominent OH from MSA. Increased frequency, urinary urgency, and urge incontinence result from detrusor over activ ity. Th e cause of nocturia, which occurs in about 60% of patients, has not been well estab lished (115, 121). Less frequently, detrusor hypoactivity may result in delayed bladder emp tying and diffi culty with initiation of urina- tion. Urodynamic testing may be helpful in identifying the type of urinary dysfunction and guiding appropriate treatment (115, 121). B oth urinary retention and incontinence may lead to recurrent urin ary infections. Sexual dysfunction in PD occurs frequently in both men and women. Erectile dysfunction and impairment of ejaculation can be present in up to 79% of PD males (76, 121 \200\223123). In a recent retro- spective study in 32 000 subjects, erectile dysfunction was associated wit h a higher risk of developing PD (124). Less frequently, exagger- ated penile erection can occur as a consequence of dopaminergic treatment (125, 126). Reduced vaginal sensitivity an d decreased mucosal lubrication has also been described in women with PD. Diminished libido and hypersexuality are also frequent, but these types of sexual dysfunction in PD appear t o be related to mood disorders or behavioral abnormalities in the setting of an impulse con trol disorder and dopaminergic drugs. includes pharmacological and non- pharmacological measures used in the management of other condi- tions, alhough there are insuffi cient data to support or refute these treatments in PD (49). General measures include frequent small meals, increased salt and fl uid intake, head-up bed tilt (by 10 \200\22330 ) at night, thigh- or waist-high elastic stockings, por table chairs, and avoiding triggers or aggravating factors, such as alcohol intake, a warm environment, and increments of antihypertensive drugs (153 \200\223155). If OH is related t o, or aggravated by, dopaminergic medications dose reduction of these drugs can be useful, although it may lead to worsening of motor symptoms. Domperidone may be of help in dopamine -agonist-related OH (155, 156). Agents that increase blood pressure, such as salt-retaining mineralocorticoids (e.g. fl udrocortisone) or the alpha-adrenergic agonist midrodrine, can be useful (156 \200\223159). It is important to monitor blood pres- sure when using these agents, as they may cause supine or noc- turnal hypertension. Th e anticholinesterase agent pyridostigmine has been reported to improve neurogenic OH without worsening supine hyperte nsion (160), but this drug has not been formally tested in PD. Octreotide, a somatostatin a gonist, may be of help in treating postprandial hypotension, but also has not been specifi - cally studied in PD (161). Treatment of OH Standard agents to treat neurogenic bladder dysfunction, such as peripherally acting antich olinergic drugs (oxybutinin, tolterodine, darifenacin, solifenacin, and trospium) and alpha -1 agonists (pra- zosin), can be used for urinary urgency and incontinence in PD, although controlled clinical trials in this population are lacking (49). Care should be exercised to avoid exacerbating existing cogni- tive impairment by prescribing drugs which have minimal \200\230central \200\231 anticholinergic actions. Urological referral should be considere d, particularly in refractory or severe cases, to detect primary urinary pathology such as prostatic hypertrophy. Coff ee and other natural diuretics, as well as a large water intake before bedtime, should be avoided in order to minimize nocturia. Evidence in support of in tra- nasal desmopressin spray for nocturia is lacking (127). Sildenafi l has been found to be effi cacious in the treatment of erectile dysfunction and can be considered in patients with PD (49, 128, 129). Cardiovascular dysfunction Orthostatic hypotension (OH) is the main cardiovascular symp- to m. It is defi ned as a drop in more than 20 mmHg systolic pres- sure or 10 mmHg diastolic p ressure when changing position from lying to standing (130). OH occurs in 20 \200\22350% of patients with PD; postprandial hypotension can also occur, but is less common. Except for the diff erent circumstances in which they occur, the symptoms are similar, with somnolence , light-headedness, coat-hanger neck pain, and syncope (131, 132). Neuropsychiatric symptoms Neuropsychiatric symptoms (NPS) occur in the majority of patients at some point during the disease course, sometimes even before the diagnosis of PD has bee n established (162). Th e most common Oxford Textbook of Movement Disorders 104 recent double-blind placebo-controlled study showed that prami- pexole had a mild but signi fi cant antidepressant eff ect in PD, 80% of which could be attributed to a direct eff ect on depression and 20% to an indirect eff ect via improvement in motor function (174). A goo d strategy in the management of depression in PD is to optimize dopaminergic treatment fi r st before adding an anti- depressant (175). and important NPS are depression, anxiety, apathy, and psychosis (163). Th ey have importan t consequences for the patient \200\231s qual- ity of life and daily functioning (164), and they also have a nega- tive impact on the quality of life of caregivers. Th ey are frequen tly under-recognized and, consequently, are undertreated. Biological and psychological fact ors have been implicated in the pathogenesis of NPS in PD; frequently they occur as a compl ication of dopamin- ergic therapy. Th ere are certain situations in PD in which depression is particu- larly prominent and sho uld be carefully looked for. Th is includes reactive depression at the time of fi rst diagn osis, OFF period depression in patients with motor fl uctuations (176), depression occurrin g in the setting of dopamine agonist cessation (dopamine agonist withdrawal syndrome) (177) , and DBS-related depression (178) which on rare occasions may lead to suicide. Disease-associated NPS Depression Th e diagnosis of depression in PD may be diffi cult beca use of over- lapping symptoms in the two disorders. Th e clinical \200\230gold-standard \200\231 diagnosis is frequently based on the application of the criteria of the Diagnostic and Statistical Manual Version IV (DSM-IV). Th ese criteria may underestimate the real pre valence of depression in PD. To improve diagnostic assessment, the National Institute of Ne urological Disorders and Stroke (NINDS) \200\223National Institute of Mental Health (NIMH) working group on depression and PD has given specifi c recommendations (Table 11.5) (165). Anxiety and apathy Anxiety disorders are common in PD (179, 180), with many studies showing a high co-morbidity with depression. Th e most frequent anxiety disorders observed are gen eralized anxiety disorder, panic attacks, and phobias (181). Increasing anxiety has been as soci- ated with non-motor fl uctuations, occurring particularly during OFF periods (179, 18 0). Th erefore PD medication adjustment to avoid OFFs can decrease the duration and severit y of anxiety (182). Occasionally, anxiety syndromes and mania have been reported as a side eff ect of dopamine agonists and high-dose levodopa treatment. A recent systematic review (166) of 36 studies concluded that, in PD, major depressive diso rder is present in 17%, depressive symp- toms in 22%, and dysthymia in 13%. Depression incr eases disability and caregiver distress and is the strongest predictor of quality of life i n PD patients (167). Th e identifi cation of depressive symp- toms in PD by the treating ne urologist is less accurate than in other groups of patients. Furthermore, once diagnosed, o nly 20 \200\22326% of depressed PD subjects will receive appropriate pharmacological treatm ent (168). Ravina and colleagues have shown that depression may cause patients to appear wo rse than they are, may cause doc- tors to start antiparkinsonian treatment before it is nee ded, and can cause poor daily functioning (169). Apathy is defi ned as a set of behavioral, emotional, and cog- nitive features that involve reduced interest and motivation in goal-directed behaviors, indiff erence, and fl attened aff ect (183). It is a common non-motor disturbance in PD, reported to occur in up to 70% i n some studies (184, 185). It can be present early in the disease course and is frequently, but not always, associated with depression and cognitive impairment (186). Apathy in PD is more likely to be a consequence of neurodegeneration than psychologi- cal reaction or adap tion to disability, and was rated one of the most distressing behavioral features by caregi vers of demented patients with PD (184, 185). Disruption of non-motor basal ganglia con- ne ctions to the mesial frontal anterior cingulate cortex has been suggested to underpin apath y in PD (187). Management is oft en diffi cult because patients are indiff erent to the nee d to attend to their own health (188). Improvement in apathy may be eff ected by managing o ther conditions such as depression and dementia (189). Apathy occurring in the setting of c hronic stimulation of the sub- thalamic nucleus can improve with dopamine agonists (190). Depression in PD is thought to refl ect disturbances in the monoaminergic pathways between brainstem nuclei and prefrontal and orbitofrontal cortical areas (170). A combination of do pamin- ergic, norepinephrinergic, and serotonergic pathways in the limbic system has been a lso implicated (171). Few controlled studies exist with regard to the effi ciency of antidepressants in PD. Tricy clic antidepressants may be more eff ective than SSRIs in the treatment of depression in PD , but the benefi ts are limited by a higher rate of side eff ects (172). Th e dopamine agon ist pramipexole has been shown to have antide- pressant eff ects in both unipolar and bipol ar depression (173). A Fatigue Fatigue is defi ned by two components: a feeling of tiredness, weari- ness, or exha ustion, and a reduction in the capacity to perform a task as a result of continuous perform ance of the same task (191). It is considered pathological when it is chronic, brought on b y no or minimal exertion, does not fully improve with rest, and causes disability (192). Fa tigue as defi ned above can be one of the most disabling symptoms reported by PD patients. Despite its preva- lence (reported to occur in up two-thirds of patients) (193, 194) and ne gative impact, it is under-recognized clinically (195). It may be present early in the cour se of PD and may even predate the onset of motor features (196, 197). Table 11.5 NINDS/NIMH Work Group recommendations for improving the diagnosis of depression in PD (165) (a) Use the inclusive approach rather than an aetiological strategy (b) Eliminate \200\230the e \200 ects of a medical general condition \200\231 as a criter ion of exclusion (c) Subsyndromal depression should be included as a diagnostic category in research studies (d) Specify the timing of assessment (ON versus \200\223 OFF periods) (e) Anhedonia should only be diagnosed based on loss of pleasure rather than loss of intere st (as it overlaps with apathy) for diagnosis of minor depression/ subsyndromal depression (f) Informants should be used if possible when assessing cognitively impaired In PD, fatigue onset and duration is not related to type of motor symptoms or disease sever ity, and is oft en exacerbated by physical, patients CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease 105 psychological, or social stressors (194, 196). Fatigue cannot be explained by EDS or poor s leep. In a recent study, the strongest predictors of fatigue in PD were symptoms of anxiety , depression, and impaired motivation (198). Th e Parkinson \200\231s Fatigue Scale (PFS) w as developed as a disease-specifi c scale and has been validated in several countries (199) . Alterations of the hypothalamic \200\223pit- uitary \200\223adrenal axis and dysfunction of frontal striatothalamocorti- cal loops have been proposed as mechanisms underlying fatig ue in PD (200, 201). Fatigue lacks specifi c treatment. An important step is to clarify to the patient and their caregivers that the symptom is a genuine and frequent manifestation o f PD (202). Non-pharmacological strategies are of the utmost importance in the management of psychotic symptoms in PD. Th ese include: a) identifi cation and management of co-morbid medical condi- tions such as pain, dehydration, or infection (216); b) psycho-educative approaches such as distraction or redirecting attention; c) environmental interventions such as improving ambient light conditions and providing visual aids (217). Reduction of polypharmacy should be considered, since this is an independent risk factor fo r the development of psychotic symp- toms in PD. Narcotics, hypnotics, antidepressants, and anxiolyt- ics, as well as dopaminergic medications, may contribute to the expression of ps ychosis. A gradual removal of anti-PD drugs is rec- ommended: initially anticholinergics, M AO-B inhibitors, amanta- dine, and dopamine agonists, then catechol- O -methyltransferase ( COMT) inhibitors, and fi nally levodopa. Psychosis Psychotic symptoms are very common in PD, with increased risk in those with highe r age at onset and need for high doses of dopaminergic drugs. Psychotic symptoms in PD incl ude hallu- cinations, illusions, and paranoid delusions (203, 204). Reported prevalence rat es of hallucinations vary, probably because of dif- ferences in patient selection and study design, ranging from 16 to 75% in prospective cross-sectional studies. Delusions aff ect 1 \200\22335% of subjects with PD (205).Visual hallucinations (VHs) are the most common psyc hotic symptoms observed in PD, but hal- lucinations can occur in all sensory domains (206). Th ey tend to be persistent and progressive (207). Th eir prevalence increases with durati on of disease, particularly if dementia develops. Th e presence of VHs in PD patients is a strong predictor of functional impairment, greater caregiver stress, and higher admission r ates to nursing homes (208). Two atypical neuroleptics, quetiapine and clozapine, are fre- quently used in the managemen t of psychosis in PD. Quetiapine is an atypical antipsychotic with a similar structure to c lozapine, but it has the advantage of not requiring blood monitoring. It combines a strong antagonism for 5-HT2 receptors with a weak antagonism for D2 receptors. Four of fi ve place bo-controlled studies found that quetiapine was not eff ective in PD psychosis (218 \200 \223222). Th e only positive study excluded patients with delusions. Despite this, many phy sicians believe that quetiapine is eff ective and the American Academy of Neurology \200 \231s task force on PD treatment recommends quetiapine as a treatment option aft er clozapi ne has been considered (223). Clozapine improves psychotic symptoms without worsening motor symptoms (224, 225). Nevertheless, its use is limited because of the risk of agranulocytos is and the requirement for regular blood monitoring. Th e recommended initial daily dose is 6.25 \200\22312.5 mg, with an increase of 12.5 mg every 4 \200\2237 days. Risperidone and olan- zapine are eff ective in psychosis, but are not recommended because of signifi cant m otor worsening (226, 227). Some positive outcomes with cholinesterase inhibitors have been reported in a small series of PD patients with psychosis, with or without signifi cant cogn itive impairment. Further studies to assess the effi cacy of these agents are required (228 , 229). VHs are initially oft en minor, but may become formed; they are usually non-threatening, an d insight is oft en retained with a clear sensorium. However, they may become severe and fr ight- ening, and insight can be lost. Typical VHs consist of human forms and animals, oft e n mobile, which appear and vanish sud- denly. Th e fi gures do not usually disturb the pati ents, who rarely involve themselves in the activities of the hallucinations (209). Th e awa reness of the presence of another person ( Anwesenheit ) and the sensation of movement in t he peripheral visual fi eld ( pas- sage hallucinations ) are sometimes considered pre-hallu cinatory symptoms (203). Delusions, which occur in approximately 5% of non-demented and 15% of demented patients wit h PD (163), are most commonly paranoid with contents of persecution, jealousy, spousal infi delity, and fears of impoverishment. Usually these beliefs are held with strong conviction , and such delusions can be extremely disruptive for the relationship between caregiver and patient. Th ey almost always require treatment. Treatment-related NPS Antiparkinsonian medication can produce or worsen psychosis (see prev ious section), but may also cause delirium (e.g. amanta- dine and anticholinergics), mood d isturbances (e.g. hypomania secondary to levodopa), impulse control disorders (ICDs), and a variety of related behavioral disorders such as the dopamine dys- regulation syndrome (DDS ) and punding. Th e pathophysiology of psychosis in PD is complex. Multiple external and internal factors may interact to produce the psychotic symptoms, such as visual impairment (210), sleep dysr egulation with intrusion of REM fragments into wakefulness (211), overac- tivation of mesol imbic systems, and monoaminergic \200\223cholinergic imbalance (212, 213). VHs occur mostly on medication. However, the dose and duration of treatment do not greatly infl uence the d evelopment of hallucinations, suggesting that other factors are more important. Th e most c onsistent risk factor has been cogni- tive impairment (214). Age, duration of disease, dise ase severity, depression, REM sleep disorder or daytime somnolence, and poor visual acuity have been associated with hallucinations only in some studies (215). ICDs are defi ned by DSM IV criteria as the failure to resist an impulse, drive, or temptat ion and to perform an act that is harm- ful to the person or to others (230). Several such behaviors have been described in PD, including pathological gambling, compulsive shopping, hypersexuality, and compulsive eating. Th ey oft en occur without causing distress and are frequently hidden by patients.