J Neurol DOI 10.1007/s00415-014-7361-4

REVIEW

Impulse control disorders in Parkinson’s disease: an overview from neurobiology to treatment Emke Mare´chal • Benjamin Denoiseux • Ellen Thys • David Crosiers • Barbara Pickut Patrick Cras

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Received: 1 February 2014 / Revised: 17 April 2014 / Accepted: 18 April 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder and is characterized by motor symptoms such as tremor, bradykinesia, rigidity and postural instability. A majority of the patients also develop non-motor symptoms. Impulse control disorders (ICD) are behavioural changes that often fail to be detected in clinical practice. The prevalence of ICD in PD varies widely from 6.1 to 31.2 % and treatment with dopaminergic medication is considered to be the greatest risk factor. Management consists mainly of reducing dopaminergic medication. In our experience, ICD has a tremendous impact on the quality of life of the patients and their families and should therefore not be disregarded. Studies addressing the role of ICD in PD caregiver strain are imperative. We attempt to give a comprehensive overview of the literature on the complicated neurobiology of ICD and discuss risk factors, genetic susceptibility, screening modalities and management. E. Mare´chal  D. Crosiers  B. Pickut  P. Cras Department of Neurology, Antwerp University Hospital, Antwerp, Belgium E. Mare´chal (&)  B. Denoiseux  E. Thys  D. Crosiers  P. Cras University of Antwerp, Antwerp, Belgium e-mail: [email protected] D. Crosiers  P. Cras Laboratory of Neurobiology, Born-Bunge Institute, Antwerp, Belgium D. Crosiers Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium B. Pickut Hauenstein Neuroscience Center, Michigan, USA

Keywords Caregiver

Impulse control disorders  Parkinson’s 

Introduction Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder and affects approximately 1 % of the population above the age of 60 years in industrialized countries [1]. Clinically, the disorder is characterized by resting tremor, bradykinesia, rigidity, and postural instability. In addition to these motor symptoms, most patients also develop non-motor symptoms, such as sleep disorders, cognitive deterioration, depression, autonomic dysfunction and behavioural symptoms. Special attention should be paid to impulse control disorders (ICD) in clinical practice. Not only does this disorder cause emotional stress for the patients and their caregivers, but it can also lead to financial problems. One study reported an average loss of 129,000 dollars as a result of pathological gambling [2, 3]. Burkhard and colleagues et al. [4] reported a case in which the patient accumulated a debt of 100000 CHF (82650 euro). ICD is a group of disorders characterized by the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person himself or others [5]. Impulsive behaviours are driven by the prospect of pleasure or gratification whereas compulsive behaviours are performed in order to decrease anxiety and avoid harm [6]. ICD that has been described as a complication of PD includes pathological gambling (PG), hypersexuality, compulsive eating and buying [5]. Punting, hobbyism and walkabout are non-pleasurable or low in risk-reward [5]

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and thus classify as compulsive behaviours. A particular form of behavioural disturbance is dopamine dysregulation syndrome (DDS). Occasional reports also mention kleptomania [7], reckless driving [8] and impulsive smoking [9]. The most frequently studied ICD is pathological gambling (PG). The prevalence in PD patients is 0.3–7.2 % [3, 5, 6, 10–18] as compared to 0.42–1.7 % in the general American population [19, 20]. PG is defined as inappropriate, persistent and recurrent maladaptive gambling behaviour that has repercussions on family, personal and professional life [21]. PD patients with ICD appear to have a preference for slot machines, characterized by a high speed, high reward uncertainty which is characteristic for the tonic ventral tegmental area (VTA) neural activity. This activity is increased when patients are treated with L-dopa and dopamine agonists [22]. Hypersexuality is observed in 1.92–8.9 % of PD patients on dopamine receptor agonist therapy vs. 1 % in the general population [6, 10–12, 14–18]. The behaviour may present itself as a preoccupation with sexual thoughts, demands for sex, desire for frequent genital stimulation, promiscuity, habitual use of sex telephone lines and internet pornography or contact with sex workers. The occurrence of paraphilias and change in sexual preference have also been described [23–25]. According to the McElroy criteria, compulsive buying is defined as an excessive time consuming and irresistible, repetitive compulsion to buy unnecessary goods. This may have financial and social pressure as a result, and can interfere with patient’s everyday activities [26]. The current prevalence among PD patients is 0.7 % [15]. Compulsive eating is characterized by an uncontrollable consumption of a larger amount of food than usual, in excess of that necessary to alleviate hunger [21, 27]. According to DSM-IV, this disorder is associated with characteristics such as eating until feeling uncomfortably full, or solitary eating as a consequence of shame or disgusted self-image about the eaten quantity. It is not associated with an inappropriate compensatory behaviour like purging [21]. In general, PD patients usually lose weight in early stages of the disease [28]. One case report illustrates how a patient lost 5 kg during his first 2 years of illness, then gained 17 kg due to binge eating, resulting in further decrease in mobility [4]. In addition to a denervation of the dorsal striatum, the ventral striatum is also involved in PD [29]. Whereas dorsal striatum denervation causes well-known motor symptoms, ventral striatum denervation can engender dysphoria which can lead to mild immediate reward seeking behaviour: the dopamine deficiency syndrome. This dysphoria can be overcome by the intake of levodopa [29]. In an effort to control dysphoric withdrawal

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symptoms in the off-state, patients may tend to take increasing quantities of levodopa despite motor complications, such as dyskinesia, and harmful behavioural consequence: the dopamine dependence syndrome. If this behaviour is complicated by excessive need for levodopa, seeking and hoarding the drug in addition to an unwillingness to reduce levodopa use—despite the associated occurrence of social, legal and occupational problems—the patient suffers from a clinical entity that was defined as the homeostatic hedonistic dysregulation syndrome [30]. This pathological behaviour, that often also includes punding, is now better known as DDS [31]. DDS could be considered as a form of addiction as it is characterized by the same criteria: intoxication with hypomania and impulsivity, persistent use despite social and personal difficulties, withdrawal symptoms such as dysphoria and anxiety following dosage reductions [5]. During the on-phase, these patients may also go on walkabout [23]. The excessive use of levodopa could be engendered by an attempt to alleviate negative non-motor fluctuations (anxiety, low mood). Psychic non-motor symptoms seem to fluctuate more rapidly and more severely and have a negative impact on the quality of life [32]. The prevalence of DDS is about 4 % [30, 33]. Pezzala et al. [33] found a significant correlation between DDS and a previous history of mood disorders and the use of dopamine replacement therapy. Impulsive aggression, for example aggressive demands for medication or sexual intercourse, is often seen in patients with DDS [23]. DDS has been described in relation with all dopaminergic medications, however, levodopa and apomorphine are most commonly involved [30, 33]. In a recent case– control study, DDS was associated with a higher rate of previous depression, a more important difference between ‘on’ and ‘off’ motor symptoms and an earlier age of onset [34]. Punding is a behaviour that is characterized by motor stereotypes, a continuum ranging from simple activities (rearranging things on the table, disassembling objects and putting them back together) to excessive ‘‘hobbyism’’ (collecting objects, cleaning, repairing, playing cards, fishing or excessive computer use, etc.) to disabling stereotyped ritualistic behaviour [2, 23, 24, 35]. These behaviours are classified as compulsive disorders since patients do not experience joy or satisfaction and may even become agitated when interrupted or prevented to carry out their activity. Performing these acts leads to relief [5, 31]. Patients with punding are more likely to have comorbid dyskinesias, suggesting a similar underlying mechanism [36]. Walkabout is characterized by restlessness, which is often accompanied by akathisia and an urge to walk or travel [23].

J Neurol Table 1 Prevalence of ICD in PD Study

N

ICD (%)

Isaias et al. [37]

50 PD, 100 HC

28 vs 20

[1 ICD (%)

PG (%)

HS (%)

BE (%)

CS (%)

4

4

3

7.2*

7.2*

1.4*

2.6

2.6

1.5

6 1.7

8.3 3.5

5.9

0.32

1.92

0.32

Driver-Dunckley [69]

1884

0.05

Pontone [6]

100

9

Voon et al. [15]

297

13.7*

Avanzi et al. [10]

98 PD, 392 HC

Weintraub [143]

272

6.6

Singh et al. [16] Lee et al. [12]

300 404

19.3 14.4

Fan et al. [17]

400

3.53

Weintraub et al. [14]

3090

13.6

3.9

5

3.5

4.3

5.7

Weintraub et al. [18]

157

31.2

15.3

7

8.9

4.5

6.4

Bastiaens et al. [82]

46**

39.1

17.4

2.2

13

DDS (%)

Punding/hobbyism (%)

0.05 2

6.1 vs 0.25

5.2

3.7

6.7 0.64

10.9

\1

10.2/14.6 26.1

N number of patients included, ICD impulse control disorders, PG pathological gambling, HS hypersexuality, BE binge eating, CS compulsive shopping, DDS dopamine dysregulation syndrome, Non-DA percentage in patients not taking a dopamine agonist, PD Parkinson Disease patients, HC healthy controls * Prevalence in patients on dopamine agonists, prevalence in any patient was 6.1 % ** Prevalence in patients on dopamine agonists

Prevalence The prevalence of ICD in PD patients treated with dopamine receptor agonists (DA) ranges between 6.1 and 31.2 % [3, 5, 6, 10–14, 18] and is significantly higher than in the general population [19, 20]. Isaias and co-workers [37] reported that 28 % of the PD patients suffered from at least one ICD, compared to 20 % of healthy controls. There is a great variability in the observed prevalence of ICD between different studies (see Table 1). It should be noted that not all studies screened for all subtypes of ICD and that different screening tools were used. Furthermore, we should keep in mind that the true frequency may be underestimated, due to the patients’ hesitation to acknowledge their ICD.

Risk factors Dopaminergic drugs The most important risk factor for developing ICD is the use of dopaminergic drugs. Weintraub and co-workers calculated [14] that the chances of suffering from an ICD were higher in patients treated with a DA than in levodopa-treated patients. At least one ICD was present in 17.7 % of patients taking both DA and levodopa, in 14 % of patients taking a DA, and in 7.2 % of patients taking levodopa. Of the 59 patients not taking DA nor levodopa, only one patient (1.7 %) was diagnosed with an ICD [14]. Some studies concluded that

PG was solely associated with adjunctive DA therapy but not with DA monotherapy [3, 38]. The currently available data support a similar association of the different DA with ICD, suggesting a drug class effect [11, 13, 16, 37, 39]. Most studies reject a DA dosage effect [3, 10, 16, 37, 38, 40], but some suggest otherwise [11, 13, 39, 41]. Hypersexuality seems to be associated with a higher levodopa equivalent dose (LED) but not with a higher LED for DA separately, suggesting a separate levodopa dosage effect [15]. Lee and co-workers [13] concluded that the mean DA LED was significantly higher in the buying-, gambling- and hypersexuality groups whereas the dose of L-dopa was higher in the eating- and punding groups. Studies that investigate the prevalence of ICD in drug naı¨ve PD patients are lacking, which currently leaves the role of PD itself as a risk factor equivocal. The research group of Antonini [42] studied 103 newly diagnosed, drug naı¨ve patients and noted no difference in ICD prevalence when compared to healthy controls. However, all of these patients were in an early disease stage and the study population was rather small. Additionally, this study used general screening instruments that are not validated for PD and binge eating was not included. A more recent study by Weintraub et al. [43] also suggests that suffering from PD does not confer an increased risk to develop an ICD or related behaviours. The authors investigated 186 newly diagnosed and untreated PD patients and 143 healthy controls. In contrary to the study by Antonini et al. [42], the QUIP screening tool was used in this study, which is a validated tool to detect ICD in PD

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[18]. The authors studied the 4 main ICDs (gambling, sexual behaviour, buying and eating) and related behaviours (punding, hobbyism and walkabout) in 3 groups: PD patients treated with medication, de novo and untreated PD patients and in the general population. A similar occurrence of ICD in these 3 groups (approximately 20 %) was observed suggesting that PD does not form a risk factor to develop an ICD or related behaviours [43]. To completely rule out PD as a risk factor for ICD, however, a long-term follow-up cohort is needed. Patients treated with DA for restless legs-syndrome, fibromyalgia or prolactinoma, have as well a higher risk of developing ICD [44–46] which may indicate that the link with PD is weaker than the link with DA use. Non-medication related risk factors Non-medication related risk factors include male gender, younger age, a pre-PD history of ICD symptoms, a personality profile characterized by impulsiveness and noveltyseeking, an immediate family history of alcohol use disorders or gambling, a personal history of alcohol use disorder and a history of substance use or bipolar disorder (see Table 2) [5, 14, 16, 23, 24, 38]. Alcohol use disorders are also associated with PG in the general population, suggesting similar underlying genetic vulnerabilities [20]. Younger age at onset as a risk factor may partially be explained by the more frequent use of DA in this population [38, 47]. Men appear to have an increased risk for developing compulsive sexual behaviour and gambling [13, 14], whereas women have a greater risk for developing compulsive buying and binge eating [14]. Being unmarried, having received a more formal education and cigarette smoking also appear to have a disadvantageous influence [14]. Depressive mood [6, 37], a family history of bipolar disorder [3] and apathy [48] have in addition been reported as potential risk factors. Depression, apathy [48, 49] and bipolar disorder [5] may especially play a role in the development of hypersexuality and DDS. Voon and co-workers [38] demonstrated that noveltyseeking behavioural scores were similar in the general population as in PD patients with PG. Patients lacking PG scored lower on novelty seeking. The authors suggest that the neuropathological process of PD, affecting the ventral striatum, may result in a relative decrease in noveltyseeking which protects them against use of alcohol, cigarettes and other drugs before dopaminergic medication is started [2, 38]. This theory is partly supported by a study of Antonini [42] and associates in which drug naı¨ve PD patients showed slightly lower impulsivity scores, compared to healthy controls. In this study, patients treated with dopaminergic medication obtain higher scores on this subject, which suggests that dopaminergic medication

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Table 2 Risk factors for developing ICD in PD Dopaminergic drugs Dopamine agonists Levodopa Disease-related risk factors Younger age at onset PD-related cognitive disorder Other risk factors Male gender Pre-PD history of ICD symptoms Personality profile characterized by impulsiveness and noveltyseeking Immediate family history of alcohol use disorders or gambling Personal history of alcohol use disorder Personal history of substance use or bipolar disorder Smoking Being unmarried Genetic risk factors DRD2 polymorphism* 48 bp repeat polymorphism DRD4** GRIN2B c.366C[G DRD3 p.S9G * Studied in non PD patients, risk factor for drug abuse, compulsive eating, smoking and PG ** Studied in non PD patients, risk factor for PG

increases the risk of novelty seeking behaviour and impulsivity [37, 42]. Other possibly contributing factors related to the disease, include the effect of the pathological process on cognition [2] and interestingly a weak association has been described between gambling and right-sided PD onset [38]. Genetic risk factors Current knowledge on genetic risk factors for ICD in PD is limited. Studies of impulsive behaviour in patients not suffering from PD indicate an implication of a D2 receptor gene (DRD2) polymorphism in drug abuse, compulsive eating, smoking and PG [50]. Also, presence of a 48 base pair repeat polymorphism in the D4 receptor gene (DRD4) was associated with PG [51, 52]. A number of genetic association studies in PD patients investigated the role of a limited number of genetic variations in genes, encoding for (sub)units of receptors known to have an important role in dopaminergic synaptic transmission. Jee-Young Lee and co-workers [12] studied 404 PD patients and 559 healthy controls. Single nucleotide polymorphisms (SNP) in the DRD3 and GRIN2B gene were shown to confer increased risk for ICD in this genetic association study. A trend for an increased risk for ICD was

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demonstrated for a SNP in the HTRA2 gene in the same patient cohort [53]. The A allele of the DRD3 p.S9G substitution was more frequent in the patients with ICD than in other PD patients, as was the C-allele of the GRIN2B c.366C[G polymorphism. The lower binding affinity, which is possibly associated with the AA variant of DRD3 p.S9G variation, may have a synergistic effect on the consequences of neurodegenerative changes in the mesocorticolimbic circuitry [54]. GRIN is a glutamate NMDA receptor, the type 2B subunit is mainly expressed in the striatum. This above-mentioned variant has been associated with ICD, alcohol abuse and schizophrenia. Glutamate is crucial in the transition from reward learning to repetitive behaviours in drug addiction. The level of glutamate in the nucleus accumbens seems to mediate reward-seeking behaviour [55, 56]. Finally, a smaller genetic association study failed to show an effect of the DRD2 Taq1, the COMT Val158Met and the DAT1 30 UTR 40 bp VNTR polymorphisms on the risk for ICD in PD patients [57]. In conclusion, studies with larger sample sizes are needed to accurately identify new genetic risk factors for ICD in PD. A well-designed whole genome association study using a SNP array could therefore be of interest to reveal unknown genetic risk factors.

Neurobiology The pathophysiology responsible for motor impairments in PD consists of progressive loss of dopaminergic neurons in the substantia nigra and the presence of inclusion bodies showing a-synuclein immunopositivity (Lewy bodies) in the surviving neurons [58]. The nigrostriatal pathway, however, is not the only dopaminergic pathway in the human brain (Fig. 1). The mesocortical pathway, which connects the VTA with the prefrontal cortex and on the other hand the mesolimbic pathway, which connects the VTA with the nucleus accumbens through the amygdala and hippocampi, are two pathways that play a crucial role in the pathophysiology of ICD. The brain areas mostly involved in this pathophysiological process include the prefrontal cortex, mainly the ventromedial and orbitofrontal areas, which are involved in planning and judgement; the ventral striatum, in particular the nucleus accumbens, which is crucial for the reward system; and the amygdala, known to be involved in emotions and conditioned response [5]. There are several hypotheses explaining the higher risk in PD patients for the development of ICD. Downregulation of D2 receptor expression PD patients on long-term dopaminergic medication show a downregulation of D2 receptor expression [59]. As a

Fig. 1 Areas playing a role in dopamine pathway: 1 frontal cortex, 2 nucleus accumbens, 3 raphe nuclei, 4 VTA, 5 substantia nigra, 6 striatum. Dopamine pathways: a mesocortical pathway, b mesolimbical pathway, c nigrostriatal pathway

consequence, sensitivity for natural rewards, such as sex, food and money, decreases. The pathological behaviour seen in ICD could be compensatory, as PD patients would seek higher than normal stimuli to obtain sufficient reward. This hypothesis is partly confirmed by an imaging study by Steeves et al. [60]. After administration of DA, PD patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9 %) than control PD patients (8.1 %). Ventral striatal binding during the control task was also lower in PD patients with PG, and this finding could be interpreted to reflect lower baseline levels of D2/D3 receptors. Tonic release of dopamine Phasic release of dopamine occurs when a reward is anticipated and is suppressed when the expected reward is not granted. When the normal pattern of dopamine activity is lost, an anticipation of reward may occur without the feedback signal, indicating the lack of reward [2, 22]. Tonic release occurs with the greatest reward uncertainty, such as in gambling, and this itself may be rewarding [22]. With repeated administration of L-Dopa or DA, tonic release of dopamine will significantly increase [61] resulting in diminished phasic dopamine release. This in turn will lead to a relative dopamine deficit and less reward sensation [62]. Consequently, the person’s behaviour (gambling, eating, buying, sexual activity) or additional stimuli such as psycho-stimulant drugs will have to increase in frequency or intensity to achieve ‘‘spikes’’ of phasic dopamine release and thus experiencing the reward sensation [2, 22].

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The overdosing theory In PD, there is a dopamine shortage in the nigrostriatal pathway, whereas the mesolimbic and mesocortical pathways maintain relatively intact. Using brain perfusion SPECT, PD patients with active PG have been examined [63]. The authors report a resting overactivity in brain areas involved in reward and reward-based learning, motivation, impulse control, decision making and memory processing [63]. Joutsa et al. [64] also found increased monoaminergic function in the medial orbitofrontal cortex in ICD patients using fluorodopa PET. Several studies on drug addiction [65, 66] suggest that the non-physiological compensation by giving DA therapy, will lead to an excessive dopaminergic stimulation in the relatively intact prefrontal cortex and ventral striatum [24, 67, 68]. Therefore this theory is known as the ‘‘overdosing theory’’. Additionally, DA seem to have a binding preference to D3 receptors, rather than the D2-receptors. D2 and D1 receptors are abundant in the dorsal striatum whereas D3 receptors exclusively exist in the ventral striatum. PG in PD could be the result of a disproportionate stimulation of D3 receptors, which are more present in the limbic area [5]. Pramipexole, which has a relative selectivity for the D3 receptor, confer an especially high prevalence of pathological gambling in some studies [69, 70] The dopaminereceptor binding profile of levodopa on the other hand, demonstrates greater selectivity for D1 and D2 receptors [14]. This might explain why the prevalence of ICD in patients taking DA is greater than those on levodopa monotherapy. Cognition A study of Cools et al. [71] supports the overdosing theory on cognitive aspects. It has been proposed that dopaminergic stimulation of dopamine-deficient dorsal striatal receptors is associated with cognitive enhancement on tasks that require activation of this area, whereas dopaminergic activation of the relative intact ventral striatum is associated with impairment of the cognitive functions related to ventral striatal activation, e.g. the ability to modify behaviours by outcomes [71]. Observations have demonstrated that patients with PG have better cognitive and executive functions than PD without PG. This is in contrast with studies of Santangelo and Voon [3, 38, 49], in which a dysfunction in the prefrontal cortex and the limbic system is suggested, which is responsible for less cognitive flexibility, planning capability, more inappropriate behaviour and poor feedbackprocesses [3, 38, 49]. Djamshidian et al. [72] investigated impulsivity in PD patients using the beads task and found that PD patients

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with ICD made more impulsive choices compared to PD patients lacking ICD, while results from working memory tasks and MMSE were similar in both groups. This hypothesis is supported by Voon and co-workers [73] who compared 14 PD patients suffering from ICD with 14 PD patients lacking ICD, both ‘off’ and ‘on’ DA. Subjects had a chance of winning money in two different situations: ‘Gain’ (in which they started with 0$) and ‘Loss’ (in which they started with a negative amount). In the ICD group, DA ‘on’ state was associated with riskier choices, especially in the ‘Gain’ condition, suggesting the risky choice is independent of loss aversion. The authors suggest that the sensitivity to risk is enhanced by impaired risk evaluation in the ventral striatum, orbitofrontal cortex and anterior cingulate, as shown by decreased activity in these areas on functional MRI. Dopamine agonist withdrawal syndrome Rabinak and Nirenberg [74] defined dopamine agonist withdrawal syndrome DAWS as a severe cluster of physical and psychological symptoms that lead to significant distress or social/occupational dysfunction, caused by DA withdrawal in a dose-dependent manner and which cannot be attributed to other clinical factors [74]. It is considered a drug-specific syndrome because of the observed lack of symptomatic response when replaced by levodopa, antidepressants and anxiolytics. An improvement is however observed with DA replacement. This is in contrast with the wearing off or ‘off’ state phenomena, where an improvement should be observed with any form of dopamine replacement therapy [74, 75]. It is associated with higher peak DA doses and greater cumulative DA exposure, as can be observed in other drug withdrawal syndromes. The severity and long-term prognosis of DAWS is also associated with cumulative DA exposure, sometimes resulting in severe cases where DA can never be discontinued, leading to chronic ICD [74]. DAWS can manifest itself with psychiatric symptoms (anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain) or with drug cravings and autonomic symptoms (orthostatic hypotension, dizziness, nausea and diaphoresis) [74]. Rabinak and Nirenberg [74] suggest that patients with DAWS belong to a ‘mesocorticolimbic variant’ of PD, with disproportionate mesocorticolimbic (vs. relatively preserved nigrostriatal) dopaminergic dysfunction and therefore exhibit an increased vulnerability to DAWS and ICD. Pondal et al. [75] conducted a retrospective chart review on 487 PD patients to analyse the frequency, predictors and outcomes of DAWS. Out of 487 PD patients, 84 were withdrawn from DA and were evaluable. Thirteen of them (15.5 %—comparable with other conducted studies [74,

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76]) developed DAWS. ICD was the main reason for DA withdrawal in all of them (100 %) in contrary to the minority of the DAWS-negative patients (41 %). The most common symptoms were depressed mood, fatigue, anxiety and insomnia. No significant difference in frequency of occurrence was found between pergolide, pramipexole and ropinirole [76]. The authors suggest that developing an ICD in response to exposure to any DA may be the major determinant in the development of DAWS, which was also confirmed in several other studies [74, 76]. Smoking history and higher LED in the ICD group may increase the likelihood of developing DAWS and can be seen as additive predictors [75, 76].

Screening In 2009, Weintraub et al. [18] validated the QUIP (Questionnaire for Impulsive-Compulsive disorders in Parkinson’s disease). It is a brief, self-completed screening questionnaire and contains 30 questions. The first section assesses the following ICD: gambling, sexual, buying and eating behaviours. The second section evaluates other compulsive behaviours (punding, hobbyism and walkabout). The last section questions compulsive medication use. The questionnaire was shown to be 100 % sensitive when filled out by both patients or informants [77]. A more compact version with a 5-point rating scale as a response, the QUIP-RS, is also available and has been validated [78]. The latter also assesses severity and can be used to monitor changes over time. The SCOPA-PC is a validated screening instrument for psychiatric complications in PD. It contains seven questions concerning symptoms occurring over the last month. Apart from questions about hallucinations, illusions, paranoid ideation, altered dream phenomena and confusion, it also contains one question about sexual preoccupation (only asking about sex drive) and one concerning compulsive behaviour (shopping/gambling) [79]. The QUIP questionnaire and SCOPA-PC appear to be the only validated instruments for use in PD patients. The modified Minnesota Impulsive Disorders Interview (mMIDI) includes sections for compulsive gambling, sexual behaviour, eating, buying and punding [80]. Several other screening instruments and scales also exist. The South Oaks Gambling Screen [81] is a validated screening instrument for compulsive gambling and has been used in PD. It contains 20 items and is based on the DSM III-R criteria for pathological gambling. A punding questionnaire is also available [35]. DSM-IV diagnostic criteria for pathological gambling [27] and McElroy criteria for compulsive buying [26] have been established. In 2006, the Voon [15] criteria for

compulsive sexual behaviour were created. The sensitivity of these criteria is not known [15]. None of the above-mentioned screening instruments have, to our knowledge, ever been cross-validated. A comparison of different screening instruments would be of help to disentangle the apparent discrepancy in ICD prevalence across different studies.

Management There is a paucity of studies regarding the management of ICD in PD and there is an urgent need for well-designed clinical trials in this field. First of all, patients should be screened for pre-existent ICD and predisposing risk factors before starting dopaminergic drugs in order to avoid this invalidating adverse effect. During treatment, neurologists should actively ask for the past and current presence of ICD. Questioning family members should play an important role in this screening process. Dose reduction In most cases, management will mainly consist of dosereduction. When ICD arises during DA therapy, discontinuing treatment will often be required [69, 70]. Weintraub and coworkers [11] examined 18 ICD patients who were taking DA. Four of them became asymptomatic after discontinuation of DA treatment and two after reduction of DA dosage. Driver Dunckley et al. [69] noticed that all of the PD patients with PG, treated with pramipexole, improved when switched to ropinirole or having reduced pramipexole. Burkhard and co-workers [4] reported two cases in which symptoms disappeared or decreased when DA was replaced by other treatments (subthalamic stimulation—COMT inhibitor). Bastiaens et al. [82] reported that in 18 patients with ICD, symptoms resolved in all 10 patients who discontinued DA therapy. This strategy, however, is not always successful. Some patients are reluctant to stop their dopaminergic treatment due to the motor or non-motor benefits they experience. In a long-term follow-up study on ICD in PD, Mamikonyan and co-workers [83] noted that 83.3 % of their patients no longer met diagnostic criteria for an ICD after discontinuing or decreasing DA treatment. They demonstrated that it is possible to adequately manage motor symptoms in ICD patients by shifting the balance away from DA treatment to L-dopa treatment without a change of UPDRS motor score [83]. Sohtaoglu and co-workers [84], however, found an increase in UPDRS score but 73 % of patients (n = 22) completely recovered after reducing dosage of DA. In 60 % of the patients an antipsychotic or antidepressant drug was also added. Holman studied 21 fibromyalgia patients with ICD. Symptoms resolved in all

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of them after 3 months, and in 19 patients, it took even less than 10 days [45]. Deep brain stimulation Conflicting results exist considering the role of deep brain stimulation (DBS). Ardouin and co-workers [85] found improvement in all 7 PD patients with PG after STN DBS (subthalamic nucleus DBS) surgery. Two case reports, published by Bandini and co-workers [86], support these data. Eusebio et al. observed 18 patients with compulsive dopaminergic medication use, of whom 90 % also had concurrent ICD. Only one subject had persistent compulsive dopaminergic medication use after STN stimulation and ICD were reduced in all patients [87]. On the other hand, in another study, ICD persisted or worsened in 12 out of 17 patients with pre-operative DDS and developed for the first time in 2 patients, after DBS surgery [23]. However, a minority of patients (5/17) improved dramatically. Smeding and associates [88] also described one patient who developed PG after successful STN stimulation. PG disappeared after changing the stimulation parameters and discontinuation of pergolide. In the past 2 years, a handful of larger studies concerning this controversial subject were reported. Moum et al. [89] performed a retrospective chart review on 159 patients who underwent DBS surgery. Of the five pre-operative DDS patients, none showed a resolution of their symptoms. Of the seven preoperative ICD patients, one patient’s symptoms resolved after unilateral STN stimulation, and one after bilateral globus pallidus interna (GPi) stimulation. There was no significant decrease in DA usage. Interestingly, 17 patients developed ICD after implantation with no change in DA usage. These symptoms were seen with either unilateral or bilateral and with either STN or GPi stimulation. Limitations of this study, hampering the clinical usefulness, include the retrospective design and the relatively small sample size of ICD patients. Kim and co-workers [90] evaluated 89 patients who underwent bilateral STN DBS in a large retrospective study. Twenty patients had preoperative ICD, six patients experienced complete resolution of their disorder and another seven showed improvement (total of 65 %). However, three of those 20 ICD patients worsened and nine patients developed de novo ICD after STN-DBS. The group that improved showed no differences in LED compared to the group with a negative outcome. One patient even developed de novo ICD, while he was not treated with any dopaminergic medication. No significant impairment in response inhibition by the Stroop interference task was documented. The first prospective study was performed by the group of Lhomme´e et al. [91] who investigated 30 patients with

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some form of an addictive habit who underwent STN-DBS and all of them were free from addiction one year post-op. There was an overall decrease of 73 % in dopaminergic treatment. The authors explain these results, which are very different from previous studies, by proper reduction in dopaminergic treatment and the use of STN stimulation in all patients. GPi stimulation, however, does not always allow for a decrease in dopaminergic medication [92]. STN-DBS can indeed also induce ICD because of functional deactivation of the limbic STN-DBS. The risk of developing ICD after STN-DBS depends on the concurrent dopaminergic therapy. In this study, only one patient developed DDS. The problem resolved after replacing the electrodes and thus allowing for further tapering in dopaminergic medication [91]. Rogers and co-workers [93] studied loss-chasing behaviour in a group of 22 PD patients treated with STNDBS and who were not known with any history of gambling behaviour. In their loss-chasing game, patients had a choice throughout the game to either continue gambling to recover a loss or to quit when losing money. The results indicated that PD patients with DBS had a tendency to increase the value of losses that they were willing to play for when shifting from the DBS-off to DBS-on conditions. We can conclude that DBS patients are usually younger, have a longer disease duration and have a higher agonist LED. These characteristics could explain why DBS patients have a higher a priori risk for developing ICD. The ambivalence of outcome options after DBS surgery, suggests the involvement of different mechanisms, needing further clarification. Implementation of DBS usually implies a reduction in LED, often resulting in ICD improvement [85, 90]. On the other hand, functional deactivation of the limbic STN may occur, resulting in higher risk of ICD [85, 90]. Amantadine The role of amantadine in the treatment of ICD is another controversial issue. A double-blinded placebo controlled study [94] investigated the therapeutic possibilities of amantadine as a treatment for PG in a small population of 12 patients who were resistant to reduction or abolishment of DA. Amantadine abolished or reduced expenditures, due to gambling, by 75–90 % in 2–3 days. Once amantadine was withdrawn, the disorder reappeared after a few days [94]. These results should be interpreted with great caution, because when adjusted to clinical variables, including PD duration and medication dosages, the risk of PG tended to increase in the group treated with amantadine [95]. Walsh et al. [96] recently presented a 50 year old woman, suffering from for 15 years, who developed multiple ICD after amantadine was associated as a treatment

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for dyskinesias. Symptoms disappeared 1 month after amantadine was discontinued. Other studies confirm a higher frequency of ICD in amantadine users [95, 97], in particular compulsive gambling, sexual behaviour and buying [97]. Possible explanations could be the dopamine-enhancing effects of amantadine or the fact that PD patients treated with amantadine often are treated with higher dosages of levodopa as well. The authors concluded that the dopamineenhancing effects of amantadine can be a potential risk factor to the development of a new ICD, while the antiglutaminergic effect, which could be a protective factor in the development of ICD, can be beneficial for patients with ICD [97].

A possible explanation could be that by pharmacological manipulation of the opiate system, it is possible to target core symptoms of PG [109] such as ‘‘craving’’ and to create higher cognitive resistance to the addiction. Another explanation could be that the natural endorphins, that are elevated when experiencing a reward, are antagonised [110]. Studies about naltrexone, another opioid antagonist, and N-acetylcysteine, a glutamate-modulating agent, suggest they are both efficacious in the treatment of PG in general population [109, 111]. However, it is advised to interpret the results with caution due to the small number of participants.

Impact of ICD and PD on caregivers Further treatment options Psychotherapy has been proposed as an adjunctive treatment, but the results appear to be disappointing [25, 69, 85]. Weak evidence supports the use of psychotropic drugs for ICD in PD but ICD may improve with treatment of concomitant depression [5]. A positive result for following treatments have been suggested: SSRI [98], atypical antipsychotics [99] (e.g. risperidone [100], olanzapine [101], clozapine [102] or quetiapine [103]) and a few antiepileptic drugs. Hicks and co-workers [104] reported a series of 3 PD patients whose ICD improved after treatment with valproate in dosages ranging from 500 to 1000 mg/day, without any observed worsening of tremor. Most likely, the effects of valproate on ICD are due to its GABAergic and serotonergic effect. Use of topiramate showed marked improvement on severity of impulsive behaviours and global impulsiveness with only marginally elevated UPDRS scores, in a small open label study [105]. Bermejo and associates [106] found that zonisamide, an antiepileptic drug, led to a marked reduction in global impulsiveness and severity of ICD without any effect on motor complications. Rotondo and co-workers [102] reported three cases in which olanzapine was beneficial in treating patients with persistent ICD after discontinuation of DA therapy. Larger studies are needed to confirm this result. Gerschlager and Bloem [107] described one patient whose symptoms of pathological gambling and punding had completely disappeared 1 year after switching to continuous enteral infusion of levodopa gel, despite an increased daily LED. The authors suggest that this case demonstrates the role of pulsatile dopaminergic stimulation in PG in PD. Nalmefene [108], a long-acting opioid antagonist, showed beneficial effects on PG in low dose (25 mg/day).

In our quest to establish a comprehensive picture of ICD, we consider it important to point out the caregivers’ burden, especially since ICD can cause severe psychological, social and financial problems and thus must have a significant impact. Strikingly, studies concerning the quality of life of caregivers are scarce. Recently, one study was published in which 71 caregivers were interviewed, of which 21 took care of a PD patient with an ICD [112]. Carers of PD patients with ICDs carried a significantly greater burden (p \ 0.002) compared with carers of other PD patients. Dopaminergic load and depression were the most important risk factors. We reviewed more extensive literature concerning general aspects of caregiving in dementia and PD. The majority of studies confirmed that caregivers have to deal with an increased amount of stress. Taking care of a PD patient is a full time occupation and can take up to more than 40 h a week. Studies suggest that caring for a patient with mental problems is more stressful than caring for a person with physical problems [112]. In review of A’Campo and co-workers [113] that not only the quality of life of the patient gradually declined during the progression of the disease, but also of the caregiver [114]. Negative consequences of caregiving consist of lack of social contacts, reducing or giving up employment [115] psychological burden (anxiety and depression) [116–125], physical problems [diabetes, cardiovascular problems, infections (e.g. flares of herpes)]. Higher stress hormone levels have been reported in several studies [125–133] Financial burden is highly prevalent in caregivers, partly due to high medical and non-medical costs [134–137]. On the other hand, caring has also been associated with positive feelings: enjoying togetherness, sharing activities, increased faith [137]. If PD on its own has such an impact on the life of a caregiver, we can only imagine the supplementary burden of an ICD.

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There has been one study of interest concerning caregiver burden in PG in the general population by Shaw et al. [139]. This group extensively reviewed the financial, physical and psychological impact of pathological gambling on the spouse/partner and offspring. A higher family life dissatisfaction was reported in the gambling group with loss of trust as main cause, and after abstinence male partners showed more improvement in their views of family life than female partners [140]. This dissatisfaction was confirmed by the higher divorce rate in the pathological gambling group (53.5 %) than in the non-gambling group (18.2 %) [138]. Spouses of pathological gamblers are described to be 10.5 times more likely a victim of partner violence [141] and the most frequently endorsed emotions are anger or resentment (74 %), depression (47 %), isolation (44 %), and guilt about contributing to the gambling (30 %). Frequently reported physical complaints include chronic or severe headaches, stomach and bowel ailments and disturbed or unsatisfactory sexual relations [139]. The gambling behaviour often results in devastating consequences on the life of the offspring with greater risk of developing health-threatening behaviours such as smoking and alcohol or drug use; psychosocial problems such as an unhappy childhood; educational difficulties and emotional disorders including dysphoria and suicidal behaviour [142].

Discussion The extent of the problem of ICD in PD patients has long been underestimated. Recently, a rising number of studies are being published, revealing an increasing amount of data on pathophysiology, genetics and risk factors of ICD. Gambling has long been one of the most investigated ICD. A thorough review of the literature revealed that gambling is just a tip of the iceberg. ICD that have been described as a complication of PD include pathological gambling (0.3–7.2 %), hypersexuality (1.92–8.9 %), compulsive eating (0.32–4.5 %), compulsive buying (1.4–6.4 %), punding (10.2 %), hobbyism (14.6 %), walkabout and DDS (0.64–4 %). All studies seem to come to one common conclusion: treatment with dopaminergic medication, especially DA, is the strongest risk factor for ICD in PD. Extensive debate is still on-going concerning the dosage effect in DA. This discussion is very important in the choice for an adequate management strategy of ICD. Is it useful to reduce DA dosage or should we stop DA treatment completely in these patients? Furthermore, one could argue about the feasibility to reduce dopaminergic medication. One study proved that it was possible to reduce DA dosage without influencing

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UPDRS motor scores [83], however several non-motor symptoms (e.g. depression) could also deteriorate after reduction of DA dosage. The rising number of studies dealing with the subject of ICD in PD is a clear indication of the increased awareness and can catalyse further research. Numerous questions concerning treatment remain unanswered. Conflicting results concerning DBS need further elucidation, reflecting different possible effects on ICD. Larger studies are needed in order to improve outcome prediction and selection of suitable patients. Occasional reports provide some evidence for neuroleptics or antidepressants as potential treatment but the results are often disappointing or inconclusive. An alternative strategy with more investment in the prevention of ICD could be designing an ICD risk profile before starting DA. In newly diagnosed PD patients, it certainly would be valuable to ask a few simple questions to estimate the risk of developing an ICD, before the clinical decision is made to start DA treatment. One aspect that was largely absent in literature comprises the extent in which ICD in PD affects the lives of caregivers. Social and financial consequences can be tremendous. We can only imagine the heavy burden resting on caregivers’ shoulders. Studies addressing the role of impulse control disorders in PD caregiver strain are urgently needed in order to give an insight on the impact of ICD on caregivers. In addition of the management of the patient, we could in this way also alleviate part of the caregivers’ burden. Acknowledgments We thank Disha Shah for her linguistic support in the writing of this paper. Conflicts of interest

None.

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