Long-term cognitive profile and incidence of dementia after stn-dbs in parkinson's disease

Movement DisordersVol. 22, No. 7, 2007, pp. 974-981 2007 Movement Disorder Society Long-Term Cognitive Profile and Incidence of Dementia After Selma Aybek, MD,1 Aline Gronchi-Perrin,1 Alexandre Berney, MD,2 Sabina Catalano Chiuve´,3 Jean-Guy Villemure, MD,4 Pierre R. Burkhard, MD,3 and Franc¸ois J.G.Vingerhoets, MD1* 1Service de Neurologie, CHUV, Lausanne, Switzerland2Service de Psychiatrie, CHUV, Lausanne, Switzerland 3Service de Neurologie, HUG, Gene`ve, Switzerland 4Service de Neurochirurgie, CHUV, Lausanne, Switzerland Abstract: An effect of subthalamic nucleus deep brain stimu-
operative differences between PDD and PD included older age lation (STN-DBS) on cognition has been suspected but long- (69.2 Ϯ 5.8 years; 62.6 Ϯ 8 years), presence of hallucinations term observations are lacking. The aim of this study was to and poorer executive score (10.1 Ϯ 5.9; 5.5 Ϯ 4.4). The evaluate the long-term cognitive profile and the incidence of incidence of dementia over 3 years after STN-DBS is similar to dementia in a cohort of Parkinson’s disease (PD) patients the one reported in medically treated patients. The PDD pre- treated by STN-DBS. 57 consecutive patients were prospec- sented preoperative risk factors of developing dementia similar tively assessed by the mean of a neuropsychological battery to those described in medically treated patients. These obser- over 3 years after surgery. Dementia (DSM-IV) and UPDRS I vations suggest dementia being secondary to the natural evo- to IV were recorded. 24.5% of patients converted to dementia lution of PD rather than a direct effect of STN-DBS. 2007 over 3 years (incidence of 89 of 1,000 per year). This group of patients cognitively continuously worsened over 3 years up to Key words: dementia; subthalamic; DBS; Parkinson’s
fulfilling dementia criteria (PDD). The rest of the cohort re- mained cognitively stable (PD) over the whole follow-up. Pre- Subthalamic nucleus (STN) deep brain stimulation disability with an almost 6-fold increased risk when (DBS) for Parkinson’s disease (PD) has been validated: compared with normal controls.8 Prevalence and inci- STN deep brain stimulation (STN-DBS) provides good dence of dementia in surgically treated patients is un- motor outcome,1 and allows significant reduction of an- known, as cognitive data on the long-term impact of tiparkinsonian medication.2 There has been much debate as to whether STN-DBS may cause adverse effects on In this prospective study, we examined the long-term cognition and behavior3-7 with suspicion of a negative evolution of cognition after STN-DBS, including the impact on cognition, particularly executive functions.
incidence of dementia, and we studied potential risk In medically treated PD, the prevalence of dementia is factors for postoperative cognitive decline.
now considered to be much higher than previously thought, reaching 60% after 10 to 15 years of motor We studied 57 (36 men, 21 women, age 63.8 Ϯ 8 years, PD duration 15.7 Ϯ 5 years) consecutive nonde- *Correspondence to: Francois Vingerhoets, Service de Neurologie, mented PD patients who underwent bilateral STN-DBS CHUV, Rue Bugnon 44, 1011 Lausanne, Switzerland.
and who potentially reached at least their two years follow-up. Inclusion criteria were the presence of PD Received 4 December 2006; Revised 20 February 2007; Accepted 23 following the United Kingdom Parkinson’s1 Disease So- Published online 18 April 2007 in Wiley InterScience (www.
ciety Brain Bank Criteria, with untreatable motor fluc- interscience.wiley.com).
DOI: 10.1002/mds.21478
tuations and dyskinesia, without any sign atypical for PD *Use of different variant of the same tests at each evaluation (see at clinical examination and with at least 25% improve- COGNITIVE PROFILE AND INCIDENCE OF DEMENTIA ment of the Unified Parkinson’s Disease Rating Scale cific cognitive domains, i.e., language, praxis, visual (UPDRS) motor scale by levodopa (L-dopa) tests.2 Ex- perception, calculation, memory, and executive func- clusion criteria included overt ongoing psychiatric dis- tions, using standardized tests (see Appendix) were as- ease, severe depression (MADRS Ͼ 19), general contra- sessed. Potential test–retest bias was considered minimal indication to surgery, and dementia following DSM-IV because of the large time interval between each assess- criteria (i.e., memory impairment plus decline in one ment. In addition, we used different variant of the same other cognitive field with impact on daily living) or tests at each evaluation, when available. For internation- severe impairment (score below the 5th percentile of the ally validated tests and for locally developed tests (“Ex- healthy population: ՅC5) in two or more tested domains amen Neuropsychologique du CHUV”: French version commercially available at Division Autonome de Neu- Clinical evaluations were made prior to surgery (mean ropsychologie Lausanne, Switzerland),11,12 the impair- 1.7 Ϯ 2.4 months) during the “on” medication state and ment criterion was based on the distribution (percentile) at 3, 6, 12, 18, 24, and 36 months and once a year of a corresponding normative sample stratified by age, postoperation with STN-DBS turned on and under the education, and gender. Standardization of our test battery current medication. UPDRS I to IV and the total L-dopa was performed on 10 healthy subjects for each decade, equivalent dose (LED) were computed2: 100 mg* L-dopa from 20 to 80 years old and for each education level; with dopa-decarboxylase inhibitor ϭ 130 mg controlled level I: Ͻ9 years of education, level II: 9 to 12 years, release L-dopa* preparations ϭ 83 mg L-dopa with dopa- level III: Ͼ12 years. To obtain comparable categorical decarboxylase and COMT inhibitors (i.e., the L-dopa data for each test we defined a 0 to 3 score: 0 ϭ normal dosages marked by * were increased by 20% when an performances (ϾC25: above the 25th percentile of the inhibitor of COMT was associated) ϭ 1 mg pergolide ϭ healthy population), 1 ϭ limited performances (ϾC10 – 1.5 mg cabergoline ϭ 1 mg lisuride ϭ 1 mg C25: between the 25th and the 10th percentile of the pramipexole ϭ 10 mg bromocriptine ϭ 3 mg ropinirole.
healthy population); 2 ϭ moderate impairment (ϾC5– Presence of hallucination was assessed with the UPDRS C10: between the 10th and the 5th percentile), 3 ϭ I (item 2) (scores 0 and 1 ϭ absence of hallucinations, severe impairment (ՅC5: below the 5th percentile). Fi- scores 2, 3, and 4 ϭ presence of hallucination). This nally, for each cognitive domain, we obtained a Cogni- dichotomization was done since vivid dreams (score 1) tive Index (CI), corresponding to the sum of the related seem less specific for PD and more related to medica- subtests. In 19 PD patients who underwent both assess- tion.10 At each follow-up, clinical criteria for dementia ments the same day (including 11 of the present study), were reviewed by the neurologist and the impact of our CI correlated linearly (r ϭ 0.89) with the Mattis cognition on daily living was carefully discussed with dementia rating scale (MDRS); based on this correlation, estimated MDRS of all patients at inclusion in the Neuropsychological tests were performed at baseline for the 57 patients, at 6 months (5.1 Ϯ 2.3 months, range: A trained psychiatrist made a structured clinical eval- 1.1–11.2 months) for 53 patients and at 3 years (34.3 Ϯ uation and scored patients on the Hamilton Anxiety 13.5 months, range: 13.0 –73.9 months) for 50 patients Rating Scales (HARS) and the Montgomery Asberg De- (Fig. 1) by the same trained neuropsychologist. Six spe- Statistical Analyses
Results are presented as mean Ϯ standard deviation.
Student t tests were used for normally distributed para-metric values, the Wilcoxon signed-rank test and Mann–Whitney U test were used for nonparametric data. Bon-feroni correction was applied for multiple comparisons.
Significance level was established at P Ͻ 0.05. Thecumulative proportion of patients becoming dementedwas estimated using Kaplan–Meier survival analysis.
The event of interest was the occurrence of dementia.
The proportion of patients “surviving” at each time point FIG. 1. Follow-up of patients. E, evaluated with detailed neuropsy-
was the proportion of patients not demented at that time.
chological testing; NE, nonevaluated with detailed neuropsychologicaltesting; PD, patients without dementia; PDD, patients with dementia.
The timing variable was the time from baseline to the Movement Disorders, Vol. 22, No. 7, 2007 visit at which dementia was diagnosed and to the last 12.3% (Fig. 1). Incidences of dementia in the 50 patients who underwent serial detailed neuropsychological exam-ination are 214 of 1,000 per year at 6 months and 98 of 1,000 per year (Fig. 2) at 3-years with prevalences of 9.4 At baseline, except for poor executive performance as usually encountered in advanced PD, cognitive perfor- At 6 months, the cognitive profile for the 53 patients mances were normal (Table 1), and, by definition, no who underwent neuropsychological testing declined in patient was demented according to DSM-IV, in particu- executive functions (especially for initiation, inhibition, lar their cognitive status did not interfere with daily and reasoning), for encoding and free recall capacities living activities and they did not present significant im- (Table 1). The 5 patients who converted to dementia pairment in more than one cognitive field.
worsened in almost all cognitive domains, significantly At 6-months evaluation, 5 of 57 patients (prevalence for the global memory score (1.8 Ϯ 1.3; 7.4 Ϯ 4.2; P Ͻ 8.7%) fulfilled dementia criteria when examined by the 0.05). They ended up significantly worse than nonde- neurologist. This represents an incidence of 202 of 1,000 mented PD in all fields (Table 2) except for the direct per year. At 3-years, fourteen patients (prevalence of digit span and ideomotor praxis. The 48 nondemented 24.5%) were demented, representing an incidence of 89 patients worsened in executive functions only (6.2 Ϯ 5.0; of 1,000 per year from baseline. Between 6 months and 7.3 Ϯ 5.2; P Ͻ 0.05) [particularly initiation (1.7 Ϯ 2.1, 3 years, 5 patients died without having the long-termdetailed neuropsychological evaluation. They were clin- ically evaluated in average 8.5 months before their death: At 3-years, the 50 patients who underwent neuropsy- none presented DSM-IV criteria of dementia at that time.
chological testing worsened significantly in memory, They did neither differ from PD for the cognitive profile particularly encoding capacities and inverse digit span, at baseline and at 6 months, nor for its evolution between executive functions, inhibition, attention, and in con- structive praxis (Table 1). The 14 patients who converted Four of the nondemented patients were not examined to dementia significantly worsened from baseline in all with detailed neuropsychological testing at the 6-months tested functions (Table 2) except for the language, direct follow-up (3 refused, 1 had systemic infection): all were digit span, and calculation; they performed significantly examined at 3-year and were not demented at that point.
worse than PD in all fields (Table 2). After excluding At 3-years, 7 patients were not examined in detail (5 these 14 patients, the remaining 36 PD patients who did died, 1 refused, 1 moved to another country), represent- not develop dementia had a neuropsychological profile ing a drop out for detailed neuropsychological testing of (Table 2) similar to the preoperative evaluation except TABLE 1. Cognitive profile of the whole cohort
aP Ͻ 0.05 compared to baseline.
bP Ͻ 0.05 comparing 6 mo to 3 yr.
cP Ͻ 0.01 compared to baseline.
dP Ͻ 0.01 comparing 6 mo to 3 yr.
CI, cognitive index; ϾC10, with scores above the 10th percentile.
Movement Disorders, Vol. 22, No. 7, 2007 COGNITIVE PROFILE AND INCIDENCE OF DEMENTIA The 14 patients developing dementia worsened in allcognitive fields, significantly for constructive praxis,ideomotor praxis, calculation, inverse digit span, mem-ory (particularly encoding). The rest of the cohortshowed only a significant worsening for executive func-tions (inhibition) and inverse digit span.
Patients who developed dementia were similar to the rest of the cohort for gender, duration of PD, baselineUPDRS III, LED, psychiatric profiles (except hallucina-tions) and the preoperative cognitive evaluation exceptexecutive functions (Table 2). The two groups had sim-ilar evolution for anxiety (HARS), depression (MADRS)and motor outcomes (Table 3). Correct electrodes posi-tioning were confirmed in the 12 patients who developeddementia and who were controlled by postoperative MRI(performed routinely since 2000). No persistent compli-cation occurred in either group. Transient complicationscomprised 4 confusions (1 in PDD, 3 in PD), one hypo-natremia and one acute paranoid state, both in PD.
At baseline, patients who subsequently developed de- Kaplan-Meier curve of the incidence of dementia. y-axis: mentia differed from the rest of the cohort only by an Proportion of PD without dementia; x-axis: Time course after the older age, presence of more hallucinations, and poorer operation (months). Each step down represents one patient who devel-oped dementia and each cross represents the time point of the last executive functions especially inhibition and initiation follow-up for each patient who did not develop dementia.
(Tables 2 and 3). However, there was important overlapsbetween PDD and PD groups for these scores preventing for inhibition, which significantly worsened (3.2 Ϯ 2.7; them to be good preoperative predictors (Fig. 3). Even score combining these three risk factors did not reach Over the 28 Ϯ 14 months between the two postoper- 40% sensitivity for prediction of postoperative dementia.
ative follow-ups, the whole cohort had a worsening of We analyzed the risk profile of the 5 patients who died inhibition, inverse digit span, memory (particularly rec- before the long-term neuropsychological testing; they were ognition), constructive praxis, and calculation (Table 1).
older (mean 68.6 years), none of them had hallucinations.
TABLE 2. Cognitive differences between PD and PDD at 6 mo and at 3 yr
aP Ͻ 0.05 between PD and PDD.
bP Ͻ 0.01 between PD and PDD.
cP Ͻ 0.05 compared to baseline.
Movement Disorders, Vol. 22, No. 7, 2007 TABLE 3. Neurological and psychiatric data
aP Ͻ 0.05 comparing PD and PDD.
cognitive tests potentially leading to different exclusion We found that, in spite of current selection criteria, criteria for cognition. However, CAPSIT17 criteria, pub- excluding demented patients from STN-DBS, 28% de- lished after we started our long-term prospective follow- veloped dementia over three-year follow-up, leading to a up, proposed a cut-off score of 120 on the MDRS. This postoperative dementia incidence between 89 and 98 of corresponds to a clinical state of dementia that is very 1,000 per year (clinical versus detailed neuropsycholog- similar to what we obtain by applying the DMS-IV ical evaluation). Potential confounders, such as depres- criteria for dementia in addition to our extensive battery sion or anxiety,13 were excluded by psychiatric exami- of neuropsychological tests (patients with a severe deficit nations and mood scores. These estimated incidences are (ՅC5) in more than one domain being excluded).
higher than those reported in other studies with a range Such variability in the estimates of dementia incidence between 24 and 46 of 1,000 per year over 3 to 5 in PD has also been observed, with similar range, in years.1,9,14 An explanation for such differences relies in studies dealing with medically treated patients (42.6 to the average age of these cohorts (55 to 59 years), 112 of 1,000 per year).8 Even if comparison with com- younger than our (64 year): age being one of the main munity-based studies should be regarded cautiously, determinant for the future development of dementia.15,16 such similarities of incidence estimates may suggest that Another possible factor involves the use of different the occurrence of dementia after STN-DBS corresponds FIG. 3. Baseline findings associated
with postoperative dementia. Patients
who did not develop dementia (PD: black
circles) are compared with those who
developed it (PDD), at 6 months (white
circles) or thereafter (crosses). (A) Base-
line Executive function score; (B) Base-
line Hallucination score; (C) Age at op-
eration. Although means (black squares)
and SD (error bars) lead to significant
differences, there is a substantial overlap,
preventing discrimination between the
two groups. In addition, there is no dif-
ference between PDD developing de-
mentia at 6 months and those developing
it at 3 years.
Movement Disorders, Vol. 22, No. 7, 2007 COGNITIVE PROFILE AND INCIDENCE OF DEMENTIA to the natural evolution of PD rather than as a conse- Stroop test. Here again the interpretation of this execu- quence of the surgery. This is also supported by the tive decline in operated PD should be cautious as med- stability over 3 years of the neuropsychological profile in ically treated patients may also display such a decline patients not developing dementia with only minimal im- and the operation may have only precipitated it.
pairment of executive functions as can be expected from With such potential precipitating effect of STN-DBS the natural evolution of medically treated nondemented on dementia in at-risk patients, it might be desirable to refine selection criteria to avoid operating patients at risk In contrast to the long term follow-up results, we of such poor cognitive outcome. We were not able to found that 9.4% of patients developed dementia within 6 identify predictors of early dementia (6 months) and this months from implantation (36% developing postopera- might be due to the small number of patients involved tive dementia) representing an incidence of 214 of 1,000 (Fig. 3). For long-term dementia (3 years) the patients per year, twice as high as the biggest rate ever reported who will develop dementia were significantly older, in medically treated patients. Those early-demented pa- scored worse in executive functions and presented more tients did not suffer from specific surgery complication frequently hallucinations preoperatively than those who (transient confusion or infection) and this raises the ques- did not develop dementia. These risk factors are similar tion of a direct impact of STN-DBS on cognition, at least to those predicting dementia in medically treated PD.20,27 in some patients. Such early postoperative increase of However none of them allows discriminating between dementia incidence has been reported in other series with pre-PDD and PD patients, as substantial overlap exists figures between 5.8% at 13 weeks postop21 and 30% at 3 (Fig. 3). Even the combination of 3 risk factors allowed months.6 Direct comparison to medically treated PD has prediction of only part of the occurrence of dementia also recently confirmed a larger decline in executive when excluding any nondemented PD was avoided. As function at 6 months in DBS treated patients,22 in keep- we found hallucinations, based only on UPDRS defini- ing with our observation. In this latter study, three cases tion, having the better discriminating potential, an ex- of dementia resulted from surgical complications (2 elec- panded evaluation of this risk factor seems desirable in trode misplacements, 1 hemorrhage) but the larger de- cline in DBS treated patients was maintained after ex- Such potential baseline predictors may help us in the clusion of these patients. These results suggest that the evaluation of the risk for further development of demen- operation itself may trigger the occurrence of dementia tia after STN-DBS to better inform patients and caregiv- in at-risk patients. Such effect might be nonspecific as ers. They should not be understood yet as exclusion cognition has been showed to be altered in all types of criteria, since such criteria should also take into account surgery (not only brain surgery)23 leading to a transient global evaluation of quality of life and daily function of cognitive decline followed by a recovery at 2 years in patients and balance these risks with the benefits from healthy elderly populations. With PD leading to progres- motor improvement. Our study does not include such sive cognitive decline in the vast majority of patients, systematic analysis but 5 of the patients who developed such return to the baseline of the cognitive status cannot dementia where included in our recently published pro- be expected in our patients but rather a return to the spective study28; in contrast to the improvement of qual- natural evolution, including persistence of dementia.
ity of life as measured by the Parkinson’s disease Ques- In addition to such potential effect of the intervention, tionnaire (39)29 reported by the other PD patients, the 5 we found a slow worsening of executive functions in the patients who developed dementia reported a trend to whole cohort over the 3 years, in agreement with other authors. Saint-Cyr et al. evaluated eleven patients be- In conclusion, the 3-year cognitive follow-up of our tween 3 and 12 months postoperation5 and demonstrated longitudinal cohort revealed an incidence of dementia a negative impact of STN-DBS on executive functions, after STN-DBS similar to those reported in medically mostly letter fluency (initiation) and Trail making test treated patients. However, 36% of patients developing (TMT) B (inhibition). Those two functions have been dementia did so within 6 months from implantation sug- reported to be sensitive to STN-DBS implantation since gesting a precipitating effect of the stimulation either it might interfere with frontal cortico-subcortical loops24 nonspecifically or by interference with the frontal cog- as shown by PET studies.25 However a direct effect of nitive loops. The identification of predictors (older age, the stimulation itself is still a matter of controversy22,26 presence of hallucination, and poorer baseline executive since no differences were seen when stimulation was functions) may help a better patient selection and infor- turned OFF to ON, 3 and 12 months postoperatively for mation concerning the risk of poor cognitive outcome.
verbal fluency and even an improvement was seen in However the low sensitivity of the prediction calls for Movement Disorders, Vol. 22, No. 7, 2007 further studies to better delineate risk factors for devel- Reasoning: Similarities subtest of the WAIS-III, Piaget’s reasoning task (patient is asked to draw the liquid levelof four bottles in different positions).
Cognitive Assessment
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15. Athey RJ, Porter RW, Walker RW. Cognitive assessment of a Initiation: Verbal fluency: literal (M words) and categor- representative community population with Parkinson’s disease ical (animals) (number of items stated in 1 min), (PD) using the Cambridge Cognitive Assessment-Revised (CAM- Nonverbal fluency: drawing of different figures (num- 16. Hobson P, Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson’s disease in the United Kingdom.
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Movement Disorders, Vol. 22, No. 7, 2007

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