Relationships between deep brain stimulation and impulse control disorders in Parkinson’s disease, with a literature review

Parkinsonism and Related Disorders 18 (2012) 10e16

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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis

Review

Relationships between deep brain stimulation and impulse control disorders in Parkinson’s disease, with a literature review P. Shotbolta, b, *, J. Moriartyb, A. Costelloc, A. Jhad, e, A. Davida, K. Ashkanf, g,1, M. Samueld, e,1 a

Department of Cognitive Neuropsychiatry, Institute of Psychiatry, London, UK Department of Psychological Medicine, King’s College Hospital, London, UK c Department of Clinical Neuropsychology, King’s College Hospital, London, UK d Department of Clinical Neurology, East Kent Hospital NHS University Foundation Trust, Ashford, Kent, UK e Department of Clinical Neurology, King’s College Hospital NHS Foundation Trust, London, UK f Department of Neurosurgery, King’s College Hospital, London, UK g Department of Clinical Neurosciences, Institute of Psychiatry, King’s College, London, UK b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 May 2011 Received in revised form 19 August 2011 Accepted 21 August 2011

Impulse control disorders (ICDs) are behavioural/neuropsychiatric complications of the pharmacological treatment of Parkinson’s disease. Long term motor complications of PD can be effectively treated using deep brain stimulation (DBS) of subcortical nuclei. The relationships between ICDs and DBS treatment of the motor complications of Parkinson’s disease remain unclear. We describe 50 consecutive patients in whom detailed neuropsychiatric assessments were performed as part of our routine pre-operative assessment. Eight had current or past ICDs during pre-operative assessment. These patients were more likely to be male and were younger than those without ICDs. Other psychosocial variables did not predict the presence of ICDs. Detailed neuropsychological examination failed to show any between-group differences. Our prevalence rate of 16% helps raise awareness of ICDs in this specialised clinic population and may reflect common denominators between significant motor fluctuations and dopaminergic drug e related behavioural disturbances. Four patients were deemed suitable for surgery after multi-disciplinary assessment. One had re-emergence of his ICD 18 months post-operatively, the ICD having resolved in the first 18 months. We also review published literature and the evidence regarding post-operative outcomes. We recommend the routine pre-operative examination of patients for psychopathology and emphasize the importance of post-operative psychiatric surveillance. Ó 2011 Elsevier Ltd. All rights reserved.

Keywords: Movement disorders Parkinson’s disease Deep brain stimulation Impulse control disorders

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 4.1. Pre-operative relationships between ICDs/dopamine dysregulation and DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4.2. Post-operative relationships between neuropsychiatric symptoms, ICDs/dopamine dysregulation and DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 4.3. Possible mechanisms and pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 Authors disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

* Corresponding author. Clinical Imaging Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Tel.: þ44 0 208 008 6267; fax: þ44 0 208 008 6491. E-mail addresses: [email protected], [email protected] (P. Shotbolt). 1 Joint last authors. 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.08.016

P. Shotbolt et al. / Parkinsonism and Related Disorders 18 (2012) 10e16

1. Introduction Impulse control disorders (ICDs) and the dopamine dysregulation syndrome are increasingly recognised in Parkinson’s disease (PD) [1e5], with recent reviews reporting their prevalence as between 14 and 24% in treated patients [5,6]. Evidence suggests an association with both dopamine agonists and levodopa [7,8]. The most frequently reported behaviours include pathological gambling, hypersexuality, compulsive shopping, hobbyism and overeating. Excessive use of antiparkinsonian medication over and above that which is felt adequate for control of motor symptoms by the treating physicians [1,9] is referred to as the dopamine dysregulation syndrome. Deep brain stimulation (DBS), particularly of the subthalamic nucleus (STN), is effective in treating advanced motor symptoms of PD. DBS can be considered when medical therapy results in fluctuations, dyskinesia or unpredictable responses [10]. Despite recent publications of the results of large controlled trials for DBS in PD [11e13] and recent reviews on impulse control disorders [7,14,15], the relationship between pre-operative ICDs, other pre-operative psychiatric disorders and post-operative ICDs is unclear. Other pre-existing (non-drug related) active psychiatric disorders such as current depression and psychosis are considered contraindications for DBS [10]. However, with regard to ICDs and dopamine dysregulation syndrome specifically, there is little evidence obtained from prospective studies on which to judge either the prevalence of these symptoms in a pre-operative DBS setting, or the suitability of patients for DBS when these behavioural disturbances co-exist preoperatively with advanced motor fluctuations. Here, we describe our experience of the ICDs seen in this specialised clinic population pre-operatively, possible associations, and surgical outcome in those who proceeded to DBS. Also, we review the literature on ICD/ dopamine dysregulation syndrome and DBS to discuss their preoperative and post-operative relationships, and the potential mechanisms of these relationships. 2. Methods The subjects were 50 consecutive patients with PD referred to our regional multidisciplinary specialist clinic for pre-operative evaluation to determine suitability for DBS. The indications for referral were disabling motor complications of drug treatment (fluctuations and dyskinesias) and medically refractory tremor. Beside neurological and psychological evaluation, all our patients had a routine detailed preoperative neuropsychiatric clinical assessment by a consultant neuropsychiatrist, including aspects specifically related to ICD/dopamine dysregulation syndrome. Other neuropsychiatric aspects include personal, social, forensic and family history, relative psychiatric contraindications (such as active delusions or untreated depression), competency, carer support, expectations from surgery and a qualitative assessment of the patient’s ability for co-operation with demands of DBS and the medication changes which would be required post-operatively should the patient proceed to surgery. The neuropsychiatric examination included a corroborative history from a spouse or carer, obtained with the permission of the patient, either in the presence of the patient or at another time. For the purposes of this report, the diagnosis of ICDs and dopamine dysregulation syndrome were based on previously published criteria for dopamine dysregulation syndrome [1] and with reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for ICDs [16]. ICDs are a specific group of impulsive behaviours, accepted as psychiatric disorders under the DSM-IV-TR, and loosely defined as the failure to resist an impulsive act or behaviour that may be harmful to self or others. The DSM-IV-TR impulsive behaviours refer to violent behaviour, sexual behaviour, gambling, fire starting, stealing, and self-abusive behaviours in the absence of psychosis or other explanatory factors (e.g. illicit drug use or mania). In addition to the above DSM-IV-TR listed behaviours, others in PD are considered to be an ICD by analogy. These more commonly described symptoms in PD include compulsive eating, shopping, and hobbyism. These were included in our assessment with their degree of severity assessed clinically e by analogy e to those published in DSM-IV-TR. There is obviously a potential overlap between ICDs and some features of mania and hypomania; such disorders were therefore carefully screened for and excluded from the ICDs category. The patients with ICD/dopamine dysregulation syndrome were reviewed and compared to those without ICD/dopamine dysregulation syndrome on a variety of neuropsychiatric profiles. Between-group analyses were performed using the

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ManneWhitney U test for numerical data and the Chi-squared test for categorical data. Non-parametric statistics were used given the ICD/dopamine dysregulation syndrome group had only 8 subjects. Significance was accepted at p < 0.05, without correction for multiple comparisons. The levodopa equivalent daily dose (LEDD) at the initial assessment for surgery was calculated with the following conversion, similar to previous reports [17]: Levodopa with decarboxylase inhibitor x1; controlled release levodopa with decarboxylase inhibitor x0.7; levodopa with decarboxylase and COMT inhibitor x1.3; apomorphine and selegiline x10; ropinirole x20; rotigotine x25; rasagiline x1.2; pergolide, pramipexole and cabergoline x100.

3. Results Eight out of the 50 patients (16%) had current or past history of ICDs and/or dopamine dysregulation syndrome on pre-operative assessment. The characteristics of these 8 patients are summarized in Table 1. Three had hypersexuality alone, two had pathological gambling alone, one had pathological gambling and hypersexuality and two had dopamine dysregulation with hypersexuality. Table 2 compares the 8 patients with to the 42 patients without ICDs and/or dopamine dysregulation syndrome on elements of the neuropsychiatric assessment (current psychiatric problems, past psychiatric problems, family history of psychiatric illness, history of alcohol misuse, history of sleep disorders, suicide attempts, levodopa equivalent daily dose (LEDD), Hamilton Depression Scale (HDS) [18], Hamilton Anxiety Scale (HAS) [19] Beck Depression Inventory (BDI) [20]). Significant between-group differences were found for age and sex; patients with ICDs and/or dopamine dysregulation were younger and were exclusively male. In addition there was a trend towards an association between having an ICD and a previous history of alcohol misuse. No significant associations were found between having ICDs and/or dopamine dysregulation and current psychiatric illness, past psychiatric illness, family history of psychiatric illness, sleep disorders and previous suicide attempts. Mean medication doses (LEDD) and proportion of patients prescribed pramipexole were higher in the ICD group overall, but not significantly so. For the two patients who had dopamine dysregulation syndrome during pre-operative assessment, the LEDD for one was 2000e4000 mg/day and the other could not give a figure but admitted to taking extra levodopa preparations from other sources. This was confirmed by family and district nurses subsequently. There were no significant between-group differences in the scores on psychiatric rating scales (HAS, HDS and BDI). All but one of the 50 patients underwent detailed presurgical neuropsychological assessment, which were tailored to the individual’s ethnic and educational ability. The one who did not have any neuropsychology assessment was managed out of region and it became apparent early on that he was developing a dementing illness, so DBS was not considered further. For both groups, the mean scores and standard deviations (SD) for each of the neuropsychological measures for the 5 cognitive domains are given in Table 3. ManneWhitney U tests showed no significant difference on any of the measures between the two groups. Specifically we did not detect an association between patients with frontal executive dysfunction and presence or absence of ICD/dopamine dysregulation. The frontal executive tests used were the Hayling and Brixton Tests [21]. A smaller sample (Table 3) was also given semantic and phonemic verbal fluency tests from the DeliseKaplan Executive Function System [22]. Both groups of patients performed below the normal range on the Brixton executive test, which was the lowest scoring of all the tests. Twenty-nine of the 50 patients proceeded to surgery. Of the 8 patients who had ICDs and/or dopamine dysregulation syndrome, 4 went on to have surgery (see Table 1; patients 1, 2, 3 and 7). All four had bilateral STN DBS. One has shown recurrence after 18 months of being free from ICD. This was managed by further drug reduction. In

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P. Shotbolt et al. / Parkinsonism and Related Disorders 18 (2012) 10e16

Table 1 Characteristics of patients with ICDs. Patient Age Type of ICD

Duration Treated with of PD agonist? (years)

1.

49

Hypersexual

18

2.

63

Hypersexual

8

Initial levodopa equivalent dose mg/day (prescribed)

Follow-up levodopa equivalent dose mg/day (prescribed)

Current psychiatric illness (non-ICD/DDS)

History of psychiatric illness (non-ICD/DDS)

History of History of addiction suicide attempts

Lives with carer?

Yes, pramipexole 1400

500a

No

No

No

No

Yes, pramipexole 1230

1230a

Current depression No

No

Yes

7 15

Yes, ropinirole 1465 Yes, pramipexole 1356

1070 1657

No No

Depression in past No No

No

a

No No

No No

No Yes

12

Yes, rotigotine

2660

2190

No

No

No

No

Yes e wife

12

Yes, ropinirole

660

Not available Mild current depression

No

No

2000e4000c

1600e2200a

No

580

Current visual illusions

Previous alcohol misuse Previous alcohol misuse No

No

13

Non-epileptic seizures, previous epilepsy (childhood) Previous psychosis and depression

3. 4.

47 52

5.

54

6.

53

7.

57

Hypersexual Pathological gambling Pathological gambling Pathological gambling, hypersexual DDS, hypersexual

8.

66

Hypersexual DDS 16

Yes, pramipexole 580b

No

Yes, No very distant No

No

ICD ¼ Impulse control disorder. DDS ¼ Dopamine dysregulation syndrome. PD ¼ Parkinson’s disease. a These patients have had STN DBS. The follow-up levodopa equivalent was calculated at 6e12 months post-operation, once stabilized. b This patient was taking medication in excess of the prescribed dose (see text). c This patient reported that he was varying his intake of levodopa by taking between 20 and 40 sinemet 110 tablets daily.

the remaining three, none has shown recurrence at follow-up ranging from 17 to 41 months. Of the 4 who did not have surgery (Table 1; patients 4, 5, 6 and 8), two chose not to have DBS. Another was considered unsuitable for DBS as within weeks of starting assessment it was clear from his local team that he had a dementing illness. Another was deemed not suitable for DBS. Despite severe dyskinesia and an outward history and appearance from him that indicated no major psychopathology, erratic behaviour led us to offer a period of observation pre-operatively, including a neuropsychiatric inpatient assessment, while additional information was sought. He was shown to have developed a frontal dementing illness, with little insight into his difficulties, but with relatively retained memory. No new cases of ICDs and/or dopamine dysregulation syndrome have developed to date in the patients who had surgery but did not have ICDs and/or dopamine dysregulation syndrome pre-operatively. 4. Discussion Current literature on pre and post-operative prevalence of ICD/ dopamine dysregulation syndrome in relation to DBS is limited to individual reports and a few patients in case series. Data are

sometimes conflicting. The occurrence of ICD and/or dopamine dysregulation pre or post-operatively poses clinicians with challenging management questions. Here we review the pre-operative relationships of ICD/dopamine dysregulation syndrome to DBS, followed by a review of post-operative relationships, before commenting on potential mechanisms and the value of routine neuropsychiatric examination in this population. 4.1. Pre-operative relationships between ICDs/dopamine dysregulation and DBS Our assessments show a prevalence of ICDs/dopamine dysregulation syndrome of 16% in our specialised DBS clinic population of patients for consideration of DBS for their advanced PD motor symptoms. This result is in line with one other recent study [23] specifically in a DBS population, and is also comparable to the figure of 14e18% of medically treated patients [5,24]. These figures are considerably higher than the earlier published figures of 6% in the general PD population [25,26]. The high prevalence in a DBS clinic is possibly related to risk factors which are common to both advanced motoric disease and behavioural disturbances, e.g. young age at onset of PD, long disease duration and a trend towards

Table 2 Comparison of ICD versus non-ICD groups. All subjects assessed are compared, including those who did not progress to have surgery. Group

Age (yrs) Gender Current Past Family History of Sleep Suicide HAS (mean  SD) (M:F) psychiatric psychiatric history of alcohol disorders attempts score illness illness psychiatric misuse illness

ICD (n ¼ 8) 55  8* Non-ICD 63  7 (n ¼ 42)

8:0* 21:21

3/8 8/42

*p < 0.05. **Trend towards significance p ¼ 0.052. HAS ¼ Hamilton anxiety score. HDS ¼ Hamilton depression score. LEDD ¼ levodopa equivalent daily dose.

3/8 19/42

0/8 10/42

2/8** 2/42

4/8 20/42

1/8 3/42

HDS score

Beck’s score

LEDD On mgs/day pramipexole?

8.4  2.9 5.1  3.7 13.0  7.7 1396 7.4  3.7 5.8  3.3 11.9  7.4 1211

4/8 (50%) 11/42 (26%)

P. Shotbolt et al. / Parkinsonism and Related Disorders 18 (2012) 10e16 Table 3 Mean age-adjusted scores and standard deviations () on the neuropsychological tests for the two groups. Tests Intellectual tests: Verbal IQ Performance IQ Full Scale IQ Premorbid IQ Memory tests: Forced choice words Forced choice faces Story recall-immediate Story recall-delayed List learning Language test: Graded naming Perceptual tests: Incomplete letters Object decision Executive tests: Hayling Brixton Verbal fluency-phonemic Verbal fluency-category

N

ICD/DDS

N

Non-ICD/DDS

8 8 8 7

92.87 92.37 92.25 106.42

(8.59) (13.94) (7.66) (10.98)

41 40 40 38

97.95 91.20 95.22 103.44

7 8 8 8 8

9.85 10.25 9.00 8.37 7.25

(4.22) (3.84) (3.20) (2.77) (3.24)

40 40 39 36 39

9.80 8.55 7.82 7.94 6.53

8

11.87 (2.90)

40

10.47 (3.74)

8 8

12.5 (6.14) 9.25 (4.16)

40 38

11.75 (4.83) 9.16 (3.67)

38 39 19 16

7.68 4.58 11.68 10.81

8 8 3 2

8.75 6.00 14.33 14.00

(1.83) (4.89) (4.08) (4.24)

(15.91) (14.18) (14.83) (13.03) (4.07) (4.26) (2.78) (2.60) (2.78)

(3.05) (3.65) (5.24) (4.47)

The IQ scale used was the standard WAIS-111 with a mean ¼ 100 and a standard deviation ¼ 15. All other scores are age-adjusted scaled scores with mean ¼ 10 and a standard deviation ¼ 3.

a history of alcohol misuse, all potentially indicating susceptible individuals. Additionally, patients attending for DBS assessment typically have taken high amounts of dopaminergic drugs which can drive both dyskinesias and ICD/dopamine dysregulation syndrome. Patients who elect to seek advice for DBS for motor symptoms may also have personality traits towards higher risktaking, although we are not aware of evidence for this. Our high prevalence may also reflect detection by specific enquiry by a neuropsychiatrist. We found no association between ICD/dopamine dysregulation and current or past psychiatric symptoms, suicide attempts or family history, even allowing for our low statistical thresholds. Active psychiatric symptomatology is a contraindication to surgery, which may affect how representative our patients are. The small numbers mean we should be cautious in interpretation. All of the patients in our ICDs and/or dopamine dysregulation syndrome group were male. This association has been reported by others [1], and is considered to be a risk factor for ICDs and/or dopamine dysregulation syndrome. The finding of a trend towards an association with previous alcohol use in the ICDs and/or dopamine dysregulation syndrome group suggests that a previous history of substance misuse may also be a risk factor. Further, from the literature, a small proportion of impulse control disorders may also remain covert at the time of DBS [27,28]. Lim et al. [29] recently described a patient who admitted to one neurologist that he was taking four times as much medication as he admitted to another. One of our cases who did not proceed to surgery required extended pre-operative neuropsychiatric assessment before the full extent of his psychopathology and medication misuse became apparent. Unrecognised active ICD/dopamine dysregulation at the time of DBS may be one potential risk factor for a poor post-operative outcome [29,30], and long term outcome for such patients remains to be studied in detail. 4.2. Post-operative relationships between neuropsychiatric symptoms, ICDs/dopamine dysregulation and DBS Despite publication of recent large randomised trials of DBS in PD [11e13], and cohort series on related topics [29,30], there

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remains limited and sometimes conflicting data on the prevalence of these disorders after DBS. Although noted, the frequency of rare neuropsychiatric side-effects may not reach significance in large trials. For general neuropsychiatric syndromes, Witt et al. [31] reported an overall incidence of 10/63 in operated patients:suicide in 1 patient, apathy in 1 patient, depression in 4 patients (6%) and psychosis in 4 patients (6%). This is comparable to the 11/121 cases in the trial of Weaver et al. [12] (some with STN DBS, others GPI DBS). In the latter study [12] the main psychiatric sideeffects were anxiety, depression and confusional states. Thobois et al. [32] prospectively examined 63 patients who had STN DBS and reported higher rates of psychiatric morbidity. Thirty-four patients (54%) developed apathy after surgery, 17 (27%) developed transient depression (all except one also had apathy) and2 attempted suicide. A systematic review by Kleiner-Fisman et al. [33] reported the rates of post-operative depression at 6.8%, hypomania at 1.9% and ‘other psychiatric disorders’ including psychosis, ICDs and emotional lability at 3.5%. A later review [34] reported postoperative depression in 8%, hypomania in 4%, anxiety disorders in less than 2% and personality changes, hypersexuality, apathy and aggression in less than 0.5%. In case series of 24 patients 25 postoperative depressive disorders were reported in 4 (15%), generalized anxiety in 18 (75%) and mild to moderate emotional hyperreactivity in 15 (63%) with 2 (8%) patients having ICDs. Information on post-operative general psychiatric issues is supplemented by individual case reports of deleterious post-operative behaviours, including acute depression [35], laughter [36], aggression [37], mania with psychosis [38,39], and pseudobulbar crying [40]. These data concentrate mainly on general neuropsychiatric syndromes but do give information, albeit limited, specifically on ICDs/dopamine dysregulation. Collectively, they suggest that neuropsychiatric syndromes can be identified by post-operative surveillance and emphasize this aspect of DBS management as they may be treatable. Whether or to what degree these represent deterioration in pre-operative problems, technical DBS or targeting issues, or reflect underlying disease progression, is hard to determine. Specifically, ICDs described post-operatively include hypersexuality [27,41], pathological gambling [28,42], and aggressive behaviour [43]. Recurrent DBS lead fracture due to repetitive manipulation of the lead connector has also been reported [44]. This compulsive behaviour could be considered to be an ICD, analogous to trichotillomania as described in DSM-IV [16]. In contrast to these isolated reports, improvement has been suggested in ICDs post-operatively in some patients [30,45]. For dopamine dysregulation syndrome, Witjas et al. [46] reported a cessation post-operatively in two patients, plausibly due to post-operative medication reduction. Both patients had their drugs stopped immediately post-operatively, rather than in a more gradual titration. In addition, the Thobois study [32] found that the ICD present in one third of their sample at baseline disappeared postoperatively following a mean reduction in dopaminergic therapy by 82% over 2 weeks. In contrast, a recent questionnaire-based publication [29] reported variable outcomes for the dopamine dysregulation syndrome: 5/17 patients who had their dopamine dysregulation syndrome detected pre-operatively had good motor and behavioural outcomes, while 12/17 had a poor behavioural outcome and variable motor outcome. It is not clear if all patients were specifically asked to, or were able to, reduce medication postoperatively, but in the group in whom dopamine dysregulation either did not improve or worsened, the total levodopa equivalent dose post-operatively remained high. Patient reluctance to reduce medication (or even to reduce DBS settings if required) and the effects of high drug maintenance post-operatively could potentially lead to poor motor and psychiatric outcomes or dopamine dysregulation [28,29].

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In the study by Lim et al. [29], two other patients were reported to have developed dopamine dysregulation for the first time postoperatively. In one patient, the appearance of dopamine dysregulation occurred 8 years after STN DBS and co-incided with the death of a spouse. This emphasizes two important points. Firstly, that short term follow-up may fail to detect these syndromes. Secondly, the role of carer supervision. The patient had a history of nonpathological gambling and it was hypothesised that the spouse’s surveillance role for 8 years maintained the ICD at an acceptable level, until death of the spouse. This highlights the potential role of post-operative surveillance, either by spouse or clinical teams, which may not only detect post-operative symptoms but also potentially lead to significant reduction of symptoms to an acceptable level. Patients’ insight and expectations of both motor and behavioural outcomes after DBS may also be important in relation to both subjective and objective assessment of outcome [47,48]. An explanation of the possible need for gradual dopaminergic drug reduction post-operatively after STN DBS should be performed. Patients who are unwilling to accept this at pre-operative counselling may present difficult post-operative management issues as they could continue to have both dyskinesia (i.e. a poor motor outcome) and drug-related compulsions (i.e. a poor behavioural outcome) [29], especially if the dopamine dysregulation syndrome was unrecognised pre-operatively. 4.3. Possible mechanisms and pathophysiology Impulsive behaviours in PD are postulated to result from inappropriate activation of dopamine receptors, namely in the limbic system and/or prefrontal cortex. Dopaminergic ventral tegmental projections to the ventral striatum are involved in motivation and reward prediction, while D3 receptors in the limbic regions are thought to be the substrate of pathological gambling [49]. The neurodegenerative process in PD mainly affects the substantia nigra whereas the ventral tegmental area can be relatively spared, potentially leading to differential stimulation following administration of dopaminergic medication. Deep brain stimulation of dorsal STN is considered to be relatively specific for the motor improvement, and therefore theoretically may be considered less likely to lead to unwanted behavioural effects if electrical stimulation effects can be confidently confined to this zone. If postoperative drug reduction is the mechanism for improvement in ICD/dopamine dysregulation post-operatively, then dorsal STN DBS would currently be the only potentially effective DBS target as the other forms of DBS (pallidal or thalamic) do not usually lead to significant drug reduction post-operatively. There are currently insufficient data on relationships of ICD/dopamine dysregulation syndromes with DBS in thalamic, pallidal or other areas of STN to allow further comment. While drug reduction (leading to resolution of ICD/dopamine dysregulation) appears to be important, another potential mechanism has been put forward for post-operative improvement of ICD/ dopamine dysregulation. In the post-operative period, the pulsatile dopaminergic stimulation of medication is at least partially replaced with chronic (non-pulsatile) electrical stimulation. Pulsatile dopaminergic stimulation is thought to be associated with behavioural symptoms in PD [1]. If pulsatility is significant in the generation of ICDs, then avoidance of pulsatility by switching from pulsatile dopamine agonist to a continuous mode of treatment could be hypothesised to lead to improved ICDs, but clinical evidence of this is awaited. For levodopa therapy, switching from pulsatile oral levodopa to non-pulsatile delivery of levodopa via percutaneous jejunostomy is at a relatively early phase and its role in impulse control disorders/dopamine dysregulation syndrome is yet to be determined.

Surgical and technical DBS issues also need consideration as potential causative factors. The aetiology of post-operative appearance of, or worsening of abnormal behaviours is confounded by several factors which will require careful analysis to elucidate the relative contribution of each potential factor. Misplaced stimulation or current spread is likely to lead to motor and psychiatric clinical findings which may not be anticipated by the patient or physician, through stimulation outside STN [35,37] or differential effects on dorsal and ventral STN [39,40] or anteromedial STN [50]. In addition general surgical effects, oedema at target, or oedema along the frontal white matter tracts may play a role in the transient behavioural changes (or hypomania) which may occur in the first few days post-operatively. It seems likely that impulsivity should be reflected in abnormalities of cognitive function. One group reporting development of pathological gambling post DBS found that STN DBS affected performance on decision making tasks [28]. Although impaired decision making has been previously reported in pathological gambling [51], it is not clear if frontal (dysexecutive) dysfunction, at least as detected by standard neuropsychological testing, will be a risk factor for the development of or decompensation of ICDs and/or dopamine dysregulation following STN DBS. In a small study of decision making under conditions of high and low conflict [52], it was proposed that STN DBS may also lead to loss of the STN’s ability to control unwanted decisions when high conflict exists within the decision, suggesting that a patient may have an inability to avoid an action by acting too quickly. This is in contrast to their proposed drug-induced pathophysiology of ICD, in which patients were less able to learn from negative feedback. This highlights the potential for more than one mechanism for the pathophysiology of ICD. In our series, patients with and without ICD/dopamine dysregulation syndrome, had scores below the normal range on the Brixton executive test. It is well established that executive dysfunction frequently occur in PD patients even in the early stages of the disease [53]. Examination of the relationship between performance on decision-making tasks and executive functions in PD has yielded heterogeneous findings. Where decision-making tasks involve risks that are not explicitly stated, some authors report impaired decision making which is unrelated to executive dysfunction [54] while others report poor performance which is correlated with executive dysfunction [55]. However there is greater consensus for the correlation between executive functions in decision-making situations where risks are explicitly known [56]. The relationship between the Brixton executive test and decision-making tasks however is as yet not established. 5. Conclusion When the severity of the motor symptoms warrant consideration of DBS, ICDs and dopamine dysregulation syndromes may coexist, with a pre-operative prevalence of 16%. The high prevalence rate in our DBS clinic may be the result of shared common driving factors for ICDs and refractory motor symptoms or because of specific enquiry. Potential benefits of a detailed neuropsychiatric assessment pre-operatively could include identifying an ICD/dopamine dysregulation syndrome which may otherwise go un-noticed until it becomes apparent post-operatively. In addition, other psychopathologies, which themselves may warrant specific treatments or influence the timing or decision on DBS, may be identified. If present, patients could be offered other forms of therapy preoperatively before proceeding to DBS at a later date, or possibly avoid DBS, or be provided with mechanisms for post-operative surveillance should they proceed to surgery. In addition, although these items can be detected pre-operatively, their clinical relevance to post-operative outcome is currently poorly studied and the

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advantage of their pre-operative detection needs to be weighed against the complexity, costs and practicality of performing such assessment pre-operatively by a neuropsychiatrist. Following DBS, there is currently limited and sometimes conflicting data on the prevalence and outcomes. Further larger prospective studies, extended over longer follow-up periods, will continue to inform us. Authors disclosures Paul Shotbolt, Angela Costello, John Moriarty and Anthony David have nothing to disclose. Dr Michael Samuel has received honoraria for lectures/educational material form UCB and Medtronic. He has received unrestricted educational grants from Solvay and Ipsen. He has received funding for educational trips from Ipsen, Medtronic and UCB. Mr. Keyoumars Ashkan has received funding for educational trips from Medtronic. References [1] Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000;68:423e8. [2] Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422e3. [3] Evans AH, Lees AJ. Dopamine dysregulation syndrome in Parkinson’s disease. Curr Opin Neurol 2004;17:393e8. [4] Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64:1089e96. [5] Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson’s disease: a cross-sectional study of 3090 patients. Arch Neurol 2010;67(5):589e95. [6] Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, et al. Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies. Parkinsonism Relat Disord 2011;17:260e4. [7] Ferrara JM, Stacy M. Impulse-control disorders in Parkinson’s disease. CNS Spectr 2008;13:690e8. [8] Szarfman A, Doraiswamy PM, Tonning JM, Levine JG. Association between pathologic gambling and parkinsonian therapy as detected in the Food and Drug Administration Adverse Event database. Arch Neurol 2006;63:299e300. [9] O’Sullivan SS, Evans AH, Lees AJ. Dopamine dysregulation syndrome: an overview of its epidemiology, mechanisms and management. CNS Drugs 2009;23:157e70. [10] Lang A, Houeto J, Krack P, Kubu C, Lyons K, Moro E, et al. Deep brain stimulation: preoperative issues. Mov Disord 2006;21(Suppl. 14):S171e96. [11] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896e908. [12] Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks Jr WJ, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 2009;301:63e73. [13] Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol 2010;9(6):581e91. [14] Lim SY, Evans AH, Miyasaki JM. Impulse control and related disorders in Parkinson’s disease: review. Ann N Y Acad Sci 2008;1142:85e107. [15] Halbig TD, Tse W, Frisina PG, Baker BR, Hollander E, Shapiro H, et al. Subthalamic deep brain stimulation and impulse control in Parkinson’s disease. Eur J Neurol 2009;16:493e7. [16] American Psychiatric Association. Diagnostic and statistical manual of mental disorders; 2000. [17] Evans AH, Katzenschlager R, Paviour D, O’Sullivan JD, Appel S, Lawrence AD, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19(4):397e405. [18] Hamilton M. Rating depressive patients. J Clin Psychiatry 1980;41:21e4. [19] Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50e5. [20] Beck A, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561e71. [21] Burgess PW, Shallice T. The Hayling and Brixton tests. Pearson assessment. London, UK: PsychCorp; 1997. [22] Delis DC, Kaplan E, Kramer JH. The DeliseKaplan executive function system. Pearson assessment. London, UK: PsychCorp; 2001. [23] Azulay J-P, Witjas T, Delfini M, Henry J, Fakra E, Regis J, et al. Dopamine dysregulation syndrome: clinical manifestations and response to subthalamic stimulation. Mov Disord 2008;23:1345. [24] Bostwick J, Hecksal K, Stevens S, Bower J, Ahlskog J. Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of Idiopathic Parkinson disease. Mayo Clin Proc 2009;84:310e6.

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