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. Th e most extensive evaluation of ICDs in PD is the multicen- tre North American DOMINION c ross-sectional study ( n = 3090 patients), which reported a six-month ICD prevalence of 13. 6%. Th is study demonstrated a strong class association between ICDs Oxford Textbook of Movement Disorders 106 and dopamine agonist use, and a weaker association with higher l -dopa dose, but not with a gonist dose (231). if motor symptoms worsen. Patients with DDS are oft en poorly compliant, and therefore exte rnal control of dosing by pharma- cies and families/caregivers is important. Regarding addi tional pharmacological options, antidepressants for obsessive thoughts, and antipsychotic t reatment for manic or aberrant behavior, may be considered (234). DBS of the subthalamic nu cleus may allow dopaminergic drug reduction and therefore lead to improvement in these symp toms (251, 252); rarely, DDS and ICDs may worsen or develop for the fi rst time aft er DBS surgery (253). ICDs are frequently under-recognized in clinical practice (232). One study found that only 25% of PD patients with an active ICD were identifi ed clinically (232). Risk factors for d evel- opment of ICDs besides treatment with DA agonists, are early age of PD onset, persona l or familial history of alcoholism or gambling, an impulsive or novelty-seeking premorbid personal- ity, and male sex (233). Several mechanisms are implicated in the pathophysiology of ICDs, including interference with the normal pattern of dopamine release, stimulation o f dopamine receptors (specifi cally, limbic D3 receptors), and chronic dopaminergic stimula tion, resulting in neuronal sensitization. Th e pathophysiological mechanisms underlying punding are not well understood, and as a con sequence the optimal therapeutic strategy is unclear. A reduction in the dose of levodopa o r dopamine agonist is the fi rst step. Atypical antipsychotics or select- ive serotonin-reu ptake inhibitors (SSRIs) have been suggested (248, 254). DDS refers to the compulsive use of dopaminergic medication beyond the dose required for op timal control of motor disability and in the face of a mounting number of harmful physical, psychiatric, and social sequelae (234). Th e prevalence of DDS has been reported to be 4% (234). Novelty-seeking personality, high depression score, alcohol intake, and age of PD on set are independent predictors of DDS (235). Th e role of dopamine in the reward system and addic- tion has been proposed to underpin DDS (236). Patients commonly identify aversive d ysphoric OFF mood states as a primary motiva- tion to use their drugs compulsively (237). S upportive of addiction theories, one study utilizing positron emission tomography (PET) sho wed that PD patients with DDS had enhanced levodopa-induced ventral striatal dopamine relea se, perhaps due to sensitization (238). Not all patients with DDS have an ICD, although the majority of those with DDS also exhibit punding (239). Unfortunately, patients with DDS do not recognize the self-induced harm and demand increasing quantities of medication despite the development of complications (i.e. dyskinesias and OFF state dysphoria) (240). NPS and deep brain stimulation . NPS are well known side eff ects of DBS (240). In the imme diate postoperative period they can be related to individual preoperative vulnerability, do paminergic med- ication withdrawal, electrical stimulation eff ects, medication inter- acti ng with stimulation, and psychological changes. At later stages aft er DBS, most NPS are re lated to disease progression (255). Apathy is a relatively common postoperative symptom, with ten studies having found increase d apathy aft er surgery (256 \200\223259). A clear relation between apathy and DBS target \200\224subthalamic nucleus (STN) or globus pallidus internus (GPi) \200\224has not been es tablished. Transient apathy early in the postoperative period is commonly part of the dopam inergic or psychostimulant withdrawal syn- drome, and usually responds to increasing levodo pa (260, 261). Postoperative hypomania \200\223mania has been reported in 4 \200\22315% of patients following STN DBS, generally occurring within the fi rst three postoperative month s (262 \200\223264). Th is commonly improves with a decrease in either stimulation voltage or dopaminergic med- ication (264, 265). Premorbid depression, emotional lability, or a fam ily history of bipolar disorders have been implicated as predis- posing factors (266, 267). Punding is defi ned as the display of aimless stereotyped behav- iours performed for long p eriods of time at the expense of other activities (241). It was fi rst described among amph etamine and cocaine abusers (242, 243). Nowadays, the most frequent cause of punding is dop aminergic drug treatment. In PD, punding preva- lence studies show results ranging from 2 t o 14% (239, 244), though it is considered an under-reported complication (245). It has also been described in 7% of patients with restless legs syndrome taking dopamine agonists (246 ). Punding is associated with high doses of dopaminergic drugs, but not with any specifi c subtype (233, 247). It has been described more frequently in males (13 \200\22340% higher p ro- portion) and younger patients (239, 248). Th e risk of suicidal behavior has been reported to increase sig- nifi cantly in the fi rst four years aft er STN DBS. Th us, it is one of the most important potentially preventable risks for mortality follow- ing DBS for PD (268). Postoperative depression, being single, a nd a previous history of ICD or DDS are associated with an increased risk of attempted suic ide (268). In the recently reported Veterans Aff airs Cooperative Studies Program 468 study , depression wors- ened with STN DBS but improved with GPi DBS (269). Clinically, pre- and post-DBS psychiatric monitoring is important, especially the appearance of depressive sympt oms (268). Th ere is still no con- sensus on individual psychiatric symptoms as exclusion c riteria for DBS surgery (270). Management of treatment-related complex behavioral disturbances It is important for physici ans to be aware of the neuropsychiat- ric side eff ects of dopaminergic therapy and to acti vely screen for them. Before initiation of therapy with dopamine agonists patients should b e warned of the potential risk of these behaviors, and those considered to be \200\230at r isk \200\231 should be closely monitored (233). ICD behaviors oft en resolve aft er discont inuing agonist treatment (249), but in many patients the parkinsonism worsens and some may develop a dopamine agonist withdrawal syndrome (177). If parkinsonism worsens, it may be pr udent to increase levodopa concomitantly. Th e role of amantadine in managing ICDs is not y et resolved because of contradictory data (250). Cognitive changes and dementia in Parkinson \200\231s disease Cognitive impairment and deme ntia are among the most com- mon non-motor disturbances occurring in PD. Mild cognitive cha nges occur in up to 20% of early untreated patients (271). Th ese changes may underpin comp laints such as memory problems or attention and planning disturbances. Currently, it is fas hionable to categorize these mild changes as mild cognitive impairment (MCI). Depending on the type of cognitive changes present, MCI in PD has been classifi ed as amnestic or non-am nestic (single or In DDS, the strategy is reversed and levodopa should be reduced initially with a subsequent increase in dopamine agonist treatment CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease 107 multiple domain) (272). Of great interest are results of studies sug- gesting that mild cog nitive changes may predict the development of dementia (273). (275) and nursing home placement (208). Th ey may be relatively \200\230benign \200\231 an d non-threatening, but delusional misinterpretation of the hallucinatory phenomena frequent ly occurs when dementia develops. Delusions occur in approximately 30% of PDD patients and are mainly paranoid in type, dealing with persecution and spousal infi delity (284). Apathy is associated with PDD in approxi- mately 25% of subjects (285, 286). Dementia is a serious, typically late, complication of PD and has been termed PD dementia ( PDD). Point prevalence of dementia in PD has been estimated at around 30%, and approximatel y 10% of patients develop dementia annually (274). Two recent longitudinal studies with 12 and 20 years of follow-up, respectively, have shown that over 80% of patients eventually de velop dementia (134, 275). Th e mean duration of PD before dementia develops is approxi- ma tely 10 years, although it can vary considerably. Risk factors for dementia include older a ge, more severe parkinsonism, predomi- nance of gait disturbances and postural instability, presence of hal- lucinations, and MCI documented at fi rst evaluation (276, 277). Th e rol e of genetic factors in the development of dementia in PD is less clear. Variants of the AP OE and MAPT genes have been linked with an increased risk of dementia in PD, but these resu lts are con- troversial (278). Diagnostic investigations Group diff erences between PDD and PD patients without dementia h ave been documented in structural and functional imaging (287), as well as in electrophysio logical studies. However, none of these techniques can be recommended for routine diagnosti c purposes because of inadequate specifi city. Tau-protein levels have been found to be higher and Abeta42 lower in patients with PDD comp ared with PD patients and nor- mal controls (288). Further studies with larger samples and more detailed assessments are needed to clarify the role of CSF markers in the diagnosis of cognitive impairment and dementia in PD. Clinical features Th e clinical features of PDD comprise an insidious onset and slowly prog ressive course of cognitive impairment occurring on a background of loss of response to dop aminergic drugs, including levodopa. Behavioral and neuropsychiatric symptoms, including de pression, also occur frequently in patients with PDD. Neuropathology Recent studies have reported the presence of abundant LBs in the cerebral co rtex PDD (289, 290). However, although the presence of cortical and subcortical Lewy pathol ogy is likely to be causa- tive, this link is controversial. Braak et al. (291) showed that even in stage 3 (i.e. in the virtual absence of cortical LB involvement), a third of patie nts already had impaired cognition, mostly of moder- ate severity. Colosimo et al. (292) de scribed a series of PD patients with considerable limbic and/or neocortical LB involvement but without major cognitive impairment. In autopsy studies, PDD has been associated with ne uronal loss in the locus coeruleus, medial SNc, ventral tegmental area, and nucleus basalis of Meynert. Although some authors have emphasized impaired mesolimbic and mesocortical dop aminergic function in PDD, a severe cortical cholinergic defi cit, independent of co-existi ng Alzheimer disease changes, is the most consistent neurochemical fi nding associated with PDD (293). Additional Alzheimer pathological burden in PDD is generally low but probably e xacerbates the overall disease process, as does ageing (294). Cognitive changes PDD is best summarized as a \200\230dysexecutive \200\231 syndrome (defi cits in abstract thinking, planning, mental fl exibility, judgment, and ini- tiative) with impairment of visuospatial abilities and memory. Defi cits in attention are also consistently present in PDD, and attention may fl uctuate w ith waxing and waning of vigilance simi- lar to that described in DLB (279, 280). Memory im pairment is a common feature, and memory complaints are the presenting cog- nitive problem in 67% of patients with PDD. Memory defi cits aff ect verbal, non-verbal, and visual domain s (279, 281). Impairment of learning of new information is less severe than that reported f or Alzheimer \200\231s disease (AD). PDD patients consistently show impairment in visuospatial functions (282, 283) with poor dr awing ability that correlates with the Mini Mental State Examination (MMSE) score. Language and praxis, so-called instrumental functions, are aff ected to a lesser degree than in AD. Signifi cant dysphasia or dyspraxia is very un usual in PDD and should call the diagnosis of PDD into question. Diagnosis and assessment In clinical practice, PDD oft en goes unrecognized and, as a resul t, is not appropriately treated. Cognitive changes occur gradually and it is frequently dif fi cult to separate early dementia from the cog- nitive changes occurring in elderly subjec ts. Diffi culties also arise since the clinical presentation is heterogeneous. Delusion and hal- lucinations may be prominent in some patients, while apathy and somnolence accompany early dementia in others. Th e presence of motor defi cits (e.g. dysarthria, bradykinesia) interferes with the assessment of cognition and also makes it diffi cult to assess the func tional consequences of the cognitive changes. In any event, it is not uncommon to overestim ate the cognitive status of the patient on a routine clinical visit. Conversational speech and content of conversation may seem normal, and only a more detailed cogni- tive assessmen t, which may require considerable time, highlights the presence of cognitive changes. Behavioral and neuropsychiatric disturbances Hallucinations and delusions commonly occur in PDD patients, as do depression and apathy. In a community-based study major depression occ urred in 13% of PDD subjects (284). Major depres- sion with suicidal ideation is rare. Sad aff ect, apathy, and loss of interest are widely encountered. Anxiety also occurs frequentl y and may overlap with depression in the same subject. Hypomanic mood disorders are uncommo n, as are problems with anger or aggression. Psychotic symptoms are common in PDD. Visual hallucinations occur in up to 55% of PDD patie nts (284) and are infrequently reported spontaneously in the clinic. In PD patients without demen- tia, hallucinations are a major predictor of subsequent dementia Dementia diagnosis in PD has been commonly based on the DSM-IV criteria for dementia, and a standard bedside test is the Oxford Textbook of Movement Disorders 108 MMSE. However, DSM-IV criteria fail to capture several of the core features of PDD. Functio nal decline related to cognitive dysfunc- tion, as required by DSM criteria, may be diffi c ult to discern because of motor diffi culties. Th e MMSE does not detect dysexecutive dis- turbances well. Th e Mattis Dementia Rating Scale and the Montreal Cognitive Assessment (Mo CA) are probably more appropriate than the MMSE for this group of subjects. Th e Neuropsych iatric Inventory is a scripted interview of caregivers, providing ratings of ten behaviors common in dementia syndromes (295), and is fre- quently used in the evaluation of PDD patie nts. to maintain control of motor symptoms may be less eff ective than in the earlier stages of PD, while the risk of precipitating or aggravating cognitive and psychiatric symptoms is in creased. Non-pharmacological measures are important, as well as provid- ing adequate information to the patient and family. Th ese measures include appropriate physical and mental activation, and avoidance of aggravating factors (e.g. inappropriate environment). Conditions which ca n trigger or aggravate mental dysfunction should be excluded (e.g. depression, adverse eff ects of drugs given for PD, or co-morbid conditions) (297). Th e management of sleep disturbances and dysautonomia, as well as specifi c treatments for psychiatric and behavioral symp- toms, is outlined in earlier sections of this chapter. Th e Movement Disorder Society has recently published guide- lines that provide practical h elp to diagnose PDD (296). Th ese guidelines emphasize the use of bedside tools that do not require neuropsychological expertise to administer or interpret. Th e infor- mation needed to arrive at the diagnosis requires the clear demon- stration that cognitive impairment ne gatively impacts daily living. Acute confusion, major depression, or features compatible wi th vascular dementia preclude the diagnosis of PDD. Cholinesterase inhibitors are the main class of drugs available for the specifi c treatment of cognitive impairment. Th ey inhibit the enzyme acetylcholinesterase which results in an increase of acetyl- choline half-life and enhances cholinergic transmission. Two small dou ble-blind placebo-controlled trials appeared to demonstrate modest cognitive benefi ts for donepezil (298, 299). However, only one large ( n = 541) double-blind placebo-controlled ch olinesterase inhibitor trial has been published to date (300). Statistically signifi - cant eff ects of rivastigmine capsules versus placebo on a range of primary and secondary outco me measures were observed, includ- ing cognitive performance, attention, executive function , activities of daily living (ADLs), and behavioral symptoms. Management Attention to motor, cognitive, neuropsychiatric, and sleep domains needs special attention in patients with PDD (Box 11.1). In many subjects the response to levodopa is re duced, and trying Box 11.1 Management of dementia in PD Donepezil, rivastigmine, and galantamine are widely approved for the treatment of AD, but r ivastigmine is the only pharmaco- logical agent currently approved for the treatment of mil d to moderate PDD in Europe, the USA, and Canada. In the USA, a patch containing rivastigmi ne was the fi rst transdermal treatment approved for both AD and PDD (301). Th e cholineste rase inhibi- tors are generally well tolerated. In addition, to the GI side eff ects, hyper salivation, rhinorrhoea, and lacrimation occur in 15% of PDD patients, and postural hypoten sion, falls, and syncope in up to 10%. Worsening of parkinsonism (tremor) can occur, but is rarely clini- cally signifi cant (302). General measures Maintain the patients in a familiar structured setting. \227\206 Judicious use of day care centers and caregivers at home. \227\206 Minimize pharmacological treatment. \227\206 Manage behavioral distrubances. \227\206 Pharmacological treatment of associated behavioral disturbances Th e N -methyl- d -aspartate (NMDA) antagonist memantine is approved for the treatment of m oderate to severe AD. Two relatively small randomized trials in patients with either PDD or DLB demon- strated benefi t for memantine, although the eff ects were very mod- est (303, 304). A larger randomized double-blind placebo-controlled study in subjects with mild to mo derate PDD or DLB failed to show signifi cant diff erences between the two treatments in pa tients with PDD. Th e drug was well tolerated in both studies (305). Reduce doses of antiparkinsonian drugs as much as pos- sible. Th e majority of these drugs can induce or worsen psy- chosis in demented patients. Monotherapy with levodopa is recomme nded. \227\206 Atypical antipsychotics quetiapine (12.5 \200\223125mg/day) or cloza- pine (50 \200\223100m g/day) for management of hallucinations, con- fusion, and other psychotic symptoms. \227\206 Acetylcholinesterase inhibitors can attention disturbances, and sleep disturbances. lessen hallucinations, \227\206 A joint task force of the European Federation of Neurological Societies and the European Se ction of the Movement Disorder Society provided their recommendations for the therapeutic m anagement of PDD in 2011. Most of the recommendations are off -label, and include (a) disco ntinuation of potential aggravators (e.g. anticholinergics, amantadine, benzodiazepines), ( b) adding a cholinesterase inhibitor (rivastigmine, donepezil, galantamine), and (c) adding or substituting memantine if cholinesterase inhibi- tors are not tolerated or lack effi ca cy (306). Antidepressants: SSRIs and SSNIs can improve depression and anxiety. 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