Neuropsychological Outcome of GPi Pallidotomy and GPi or STN Deep Brain Stimulation in Parkinson's Disease

Brain and Cognition 42, 324–347 (2000) doi:10.1006/brcg.1999.1108, available online at http://www.idealibrary.com on

Neuropsychological Outcome of GPi Pallidotomy and GPi or STN Deep Brain Stimulation in Parkinson’s Disease Lisa L. Tre´panier,§,†,‡ Rajeev Kumar,§ Andres M. Lozano,† ,储 Anthony E. Lang,§ and Jean A. Saint-Cyr*,†,‡,储**,§ †Toronto Western Hospital—Research Institute, and 储 Department of Surgery, Division of Neurosurgery, University of Toronto and The Toronto Hospital; §Department of Medicine, Division of Neurology, University of Toronto and Morton and Gloria Shulman Movement Disorder Centre at The Toronto Hospital; ‡Department of Psychology, York University, North York, Ontario, Canada; and **Department of Psychology, University of Toronto, Toronto, Ontario, Canada This paper highlights the neuropsychological sequelae of posteroventral pallidotomy (PVP) and deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) at 3/6 months postoperatively. Results are based on our extensive experience with PVP and our preliminary observations with DBS. Patients with borderline cognitive or psychiatric functioning risk postoperative decompensation. Nonlateralizing attentional and hemisphere-specific impairments of frontostriatal cognitive functions followed unilateral PVP. ‘‘Frontal’’ behavioral dyscontrol was observed in approximately 25% of patients. Three cases of staged bilateral PVP suggest that premorbid factors may predict outcome, although lesion size and location are also critical. Older patients are at risk for significant cognitive and behavioral decline after bilateral STN DBS, while GPi DBS may be safer.  2000 Academic Press Key Words: neuropsychology; Parkinson’s disease; pallidotomy; deep brain stimulation; basal ganglia; subthalamic nucleus; globus pallidus.

INTRODUCTION

The treatment of medically refractory symptoms in advanced Parkinson’s disease (PD) patients by stereotactic neurosurgical interventions has enjoyed a renaissance (Gildenberg, 1995; Goetz & Diederich, 1996; Olanow, 1994). Success with these treatment approaches is attributable to the increasing understanding of the pathophysiology of the basal ganglia, advances in microAddress correspondence and reprint requests to: Lisa L. Tre´panier, Toronto Hospital— Western Division, 399 Bathurst Street, Centre for Movement Disorders, Edith Cavell Wing, 2-026 Toronto, Ontario M5T 2S8, Canada. Fax: (416) 603-5321. E-mail: lisa@playfair. utoronto.ca. 324 0278-2626/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.

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electrode recording, neuroimaging and neurosurgical techniques, and the demonstration of surgical alleviation of experimental parkinsonism, along with the growing awareness of the limitations of pharmacotherapy for PD (Obeso et al., 1997; Wichman et al., 1995). This paper will discuss the neuropsychological impact of two major stereotactic neurosurgical approaches to PD which are coming into widespread use (Baron et al., 1996; Benabid et al., 1996; Dogali et al., 1995; Krack et al., 1997; Laitinen 1995; Lang et al., 1997a, 1997b; Lozano et al., 1995; Kumar et al., 1998a, 1998b; Scott et al., 1998; Siegried & Lippitz, 1994): (1) ablative surgery (i.e., pallidotomy or PVP) and (2) deep brain stimulation (DBS) of the internal globus pallidus (GPi) and subthalamic nucleus (STN). This paper will not deal with neural transplantation or the specific treatment of tremor by thalamic DBS or lesions. In PD, the excessive inhibitory output from the GPi and substantia nigra reticulata (SNr), caused largely by the excessive excitatory drive from the STN, reduces thalamic activation of the primary motor cortex, premotor cortex, and supplementary motor area (Alexander et al., 1990; Grafton & DeLong, 1997; Parent & Hazrati, 1995). Therefore, the functional goals of lesioning or blocking the neural activity of the GPi or the STN with DBS are to improve patients’ parkinsonian symptoms by reducing the inhibitory action of basal ganglia projections to the thalamus (Grafton & DeLong, 1997). Recent clinical outcome studies of unilateral pallidotomy and DBS have demonstrated improvements in contralateral parkinsonian symptoms and levodopa-induced dyskinesias, with ipsilateral and axial benefits being less significant (Baron et al., 1996; Benabid et al., 1996; Dogali et al., 1995; Golbe, 1998; Krack et al., 1997; Kumar et al., 1998a, 1998b, 1998c; Laitinen, 1995; Lang et al., 1997a, 1997b; Lozano et al., 1995; Olanow, 1996; Siegfried & Lippitz, 1994). DBS provides an alternative to pallidotomy and has the potential advantages of reversibility of adverse effects induced by stimulation and adaptability to individual patient needs because of flexibility in stimulation parameters and site (with a quadripolar electrode). Although mostly in the form of conference abstracts, recent preliminary reports of neuropsychological outcome of pallidotomy suggest either a lack of detrimental cognitive changes (Baron et al., 1996; Cahn et al., 1998; Cullum et al., 1997; Soukup et al., 1997) or a negative impact on specific frontostriatal cognitive and functional processes. Specifically, deficits have been fairly consistently observed in verbal phonemic or semantic fluencies, especially after left-hemisphere lesions (Lucas et al., 1997; Manning et al., 1997; Masterman et al., 1997; Rilling et al., 1996; Riordan et al., 1997; Scott et al., 1998; Tre´panier et al., 1998a,b; Uitti et al., 1997). Scott et al. (1998) reported verbal memory declines in their first 3 of 12 (25%) U-PVP patients (side not specified), whose lesions were large and extended vertically, whereas Tre´panier et al. (1998a,b) found 9/15 (60%) of left PVP patients (and 1 right PVP) declined on verbal memory and none recovered by their

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first year follow-up. Lang et al. (1997c), Masterman et al. (1997), and Scott et al. (1998) each noted further cognitive decline in 1 patient who was considered preoperatively cognitively borderline. Riordan et al. (1997), Stebbins et al. (1997), and Tre´panier et al. (1998a) reported further decline in executive functions, such as cognitive flexibility, working memory, abstract reasoning, or speed of processing. Baron et al. (1996) only noted these types of executive changes in 2 of 12 patients who had iatrogenic small frontal subdural hematomas. Frontal behavioral dyscontrol has also been observed in some patients (Dogali et al., 1995; Fazzini et al., 1997; Lang et al., 1997c; Shannon et al., 1998; Tre´panier et al., 1998a,b). With regard to the neuropsychological outcome of DBS, findings have only been reported following unilateral GPi stimulation in nine patients (six left and three right) (Tro¨ster et al., 1997). Declines were reported in semantic fluency and visuoconstructional abilities and were also seen in individuals for phonemic fluency and the short- and long-term delayed free recall trials of the CVLT (verbal learning). Except for our long-term follow-up study of 42 PD patients postpallidotomy (Tre´panier et al., 1998a), these outcome studies are unfortunately limited by small sample sizes, short-term follow-up, combining data from right and left hemisphere pallidotomy surgeries, or potential practice effects. This paper highlights our experience assessing the neuropsychological and behavioral outcomes of unilateral posteroventral pallidotomy (U-PVP), staged bilateral pallidotomy (B-PVP), and most recently of bilateral deep brain stimulation of the globus pallidus (GPi-DBS) and subthalamic nucleus (STN-DBS) in advanced PD patients after their first follow-up evaluation (3 or 6 months). A few comments regarding our long-term follow-up data will be included. The preliminary nature of our DBS data must be emphasized. We are interested in examining which processes are differentially sensitive to these procedures. Therefore, where sample size permits, highlights of statistically significant cognitive effects within patient groups and average test scores pre- and 3/6 months postoperatively for the different groups will be reported. In order to provide a clinical overview of individual trends in the data, incidence of declining cognitive performance (⬎1 SD, except the PASAT, see Subjects and Methods) and frontal lobe behavioral changes following these procedures will also be presented. SUBJECTS AND METHODS

Selection Criteria Patients with idiopathic Parkinson’s disease were considered for GPi pallidotomy or bilateral GPi or STN DBS implantation if they met the following inclusion criteria: substantial disability due to motor fluctuations and levodopa-induced dyskinesias, despite optimization of antiparkinson medications, and compliance with pre- and postoperative assessments. Exclusion criteria included: dementia, other neurological or unstable medical disorders, prior neurosurgical

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procedure, MRI evidence of other CNS disease, or current psychiatric complications compromising cooperation, failure to obtain informed consent, or incapacity to deal with management and adjustment of the DBS device postoperatively.

Patients Three groups of patients (demographics in Tables 1 and 2) who underwent either PVP or DBS, as well as a smaller number (n ⫽ 3) who underwent staged bilateral PVP, are reported here. In the latter group, it should be noted that two patients had a history of diabetes and one of these had a history of clinical depression, treated with anti-depressant medication and electroconvulsive shock therapy (ECT). These three patients were 47, 50, and 59 years of age; the first two had completed grade 12 and the latter had 24 years education. Premorbid/current WAIS-R VIQs were 117/110 (modified slightly due to differences in cultural background), 108/88 (difference due to depression, not dementia), and 125/128 preoperatively.

Surgical Procedures The technique for microelectrode-guided PVP has been described in detail elsewhere (Lozano et al., 1996). Usually one or, rarely, two or three overlapping radiofrequency lesions, approximately 6 mm in diameter, were made with a thermistor-coupled probe, using temperatures up to 90°C for 60 s. For STN or GPi DBS, the initial methods used for target selection were the same as those for pallidotomy (Lozano et al.,1996). Once the target was selected, a permanent four-channel DBS macroelectrode was implanted and then intraoperative test stimulation was carried out to optimize clinical effects and reduce adverse effects. After 1 week, the electrode cables were internalized and connected to an internal pulse generator. Details of the procedures and equipment employed are described elsewhere (Kumar et al., 1998a, 1998b).

Clinical Motor Evaluation A full description of the neurological evaluation protocol and related results from the patients of the current pallidotomy and DBS studies (in part or in full) have been published elsewhere (Lang et al., 1997a, 1997b; Lozano et. al., 1995; Kumar et al., 1998a, 1998b).

Neuropsychological Evaluations: Baseline or Preoperative Evaluation In order to assess suitability for trial inclusion, as well as to establish a baseline cognitive profile, a thorough neuropsychological evaluation was completed preoperatively on all patients. Patients were then reassessed at 3, 6, and/or 12⫹ months postoperatively (long-term follow-up data are yet to be fully collected for the STN DBS trial). Not all patients were seen on all occasions, nor was it always possible to assess patients on all measures, but patients reported in this review had at least one short-term follow-up assessment at 3 or 6 months. Patients were always evaluated in their optimal behavioral state on medication (i.e., in the ‘‘on’’ state). Patients with DBS devices had their stimulators turned on during all assessments. There were no significant changes in the dosage of total dopaminergic medication postpallidotomy (Lang et al., 1997a, 1997b) or with bilateral GPi DBS (Kumar et al., 1998b), although total drug dosage was decreased for the bilateral STN DBS group (Kumar et al., 1998a). Components of the full neuropsychological test battery were selected with three considerations in mind: the battery had to be relatively brief (3–4 h), evaluate the range of cognitive domains often affected by PD, and include tests assessing aspects of cognitive, behavioral and emotional processes that were shown in the older literature to be affected by thalamotomy and/or pallidotomy (Kocher, Siegfried, & Perret, 1982; Ricklan et al., 1960; Vilkki & Laitinen,

42

Unilateral pallidotomy Bilateral STN DBS Bilateral GPi DBS

58 (8.2) (42–73) 67.4 (7.5) (55–75) 56 (10.9) (43–69)

Age 12.6 (5) (5–27) 14 (4.9) (3–20) 11 (1.2) (10–12)

111 (13.3) (78–132) 116.4 (12.3) (87-128) 109.8 (7.2) (101–117)

Estimated premorbid IQ 108 (14.2) (82–138) 112.2 (12.9) (94–130) 103.5 (9) (95–115)

Current WAIS-R VIQ 12.8 (5) (4–25) 14.3 (3.5) (11–22) 15 (5.3) (10–22)

Disease duration (years) 3.6 (0.9) (2.5–5) 4 (1.2) (2.5–5) 3.9 (1) (2.5–5)

Preoperative Hoehn and Yahr (off)

2.6 (0.7) (1.5–5) 2.6 (0.3) (2–3) 2.6 (1) (2–4)

Preoperative Hoehn and Yahr (on)

1140.90 (506) (200–2250) 1497 (659) (650–2375) 1457 (261) (1220–1806)

Preoperative dopa equivalents (mg/day) a

Note. Demographic characteristics are presented as the mean (standard deviation) with the (range) below. a Total dopa equivalents ⫽ dose of regular levodopa/carbidopa (or benserazide) ⫹ 0.75⫻ dose of controlled-release levodopa/carbidopa ⫹ 10⫻ dose of bromocriptine ⫹ 100⫻ dose of pergolide.

4

9

n

Group

Education (years)

TABLE 1 Patient Characteristics by Group

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5. Short delay free recall (SDFR) 6. Long delay free recall (LDFR) 7. Long delay cued recall (LDCR)

Verbal learning (CVLT) 4. Total score (trials 1–5)

2. Digit SpanBackward (raw score) Executive functions 3. Trailmaking test—B (seconds)

Attention 1. PASAT–3″ (% correct)

Psychometric tests/ domain

54.3 ⴞ 8.9 46.4 ⴞ 7.2* (n ⴝ 14) 11.7 ⴞ 2.2 9.7 ⴞ 2.3* 12.1 ⫾ 2 11.3 ⫾ 2.2 12.4 ⫾ 2.2 11.6 ⫾ 2.2

120.7 ⫾ 62.9 135.7 ⫾ 103.3 (n ⫽ 15)

151.2 ⫾ 95.6 158.0 ⫾ 109 (n ⫽ 34) 48.3 ⴞ 12.7 45.4 ⴞ 10.0* (n ⴝ 30) 9.7 ⴞ 3.8 8.8 ⴞ 3.3 a 10.2 ⫾ 4 10.3 ⫾ 3.3 10.9 ⫾ 3.3 10.6 ⫾ 2.9

63.4 ⫾ 35.9 68.1 ⫾ 37.7 (n ⫽ 10) 7.2 ⴞ 2.4 6.3 ⴞ 1.6* (n ⴝ 15)

Unilateral left pallidotomy (n ⫽ 18) (posthoc analyses)

53.88 ⴞ 38.8 61.00 ⴞ 37.4* (n ⴝ 24) 6.7 ⴞ 2.5 6.1 ⴞ 2.2* (n ⴝ 35)

Unilateral pallidotomy (R & L) (n ⫽ 42)

43.1 ⫾ 13.4 44.5 ⫾ 12.1 (n ⫽ 16) 7.9 ⫾ 4 8.1 ⫾ 3.8 8.5 ⫾ 4.6 9.4 ⫾ 3.9 9.5 ⫾ 3.5 9.8 ⫾ 3.2

175.3 ⫾ 110.9 175.6 ⫾ 112.9 (n ⫽ 19)

47.1 ⫾ 40.6 55.9 ⫾ 37.8 (n ⫽ 14) 6.4 ⫾ 2.6 6.0 ⫾ 2.6 (n ⫽ 20)

Unilateral right pallidotomy (n ⫽ 24) (posthoc analyses)

41 35.7 (n 7.9 5.7 8.7 5.3 9.6 6.9

⫾ ⫾ ⫽ ⫾ ⫾ ⴞ ⴞ ⴞ ⴞ

12.3 17.5 7) 3.7 5.3 4 5.3* 3.3 4.7*

101.9(30.5) 135.7(38)* (n ⴝ 7)

56 ⫾ 35.0 48.8 ⫾ 22.2 (n ⫽ 8) 5.7(2.3) 4.7(2.1) a (n ⴝ 6)

Bilateral STN DBS (n ⫽ 9)

40.2 33.4 (n 7.4 5 7.4 4.8 9 6

⫾ ⫾ ⫽ ⴞ ⴞ ⴞ ⴞ ⴞ ⴞ

13.1 18.5 5) 4.4 5.4 a 3.8 5.6 a 3.2 4.6 a

88.5(27.1) 134.5(36.8)* (n ⴝ 5)

40.4 ⫾ 35.2 42 ⫾ 24.8 (n ⫽ 5) 6(2.8) 5.5(3.5) (n ⫽ 2)

Bilateral STN DBS (age ⬎69) (n ⫽ 5)

TABLE 2 Neuropsychological Outcome 3/6 Months Following Unilateral PVP and Bilateral DBS of STN or GPi

47.5 49.5 (n 12 10 11.5 10.5 11 11.5

⫾ ⫾ ⫽ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

0.7 5 2) 1.4 1.4 2.1 0.7 4.2 2.1

87(32) 88(26) (n ⫽ 4)

57.9 ⫾ 17.1 66.7 ⫾ 20.4 (n ⫽ 3) 6.8(2.2) 5.5(1.3) a (n ⴝ 4)

Bilateral GPi DBS (n⫽ 4)

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329

6.8 8.3 (n 6.8 7.8 (n

2.6 1.9 4) 1.9 1.8 3)

⫾ ⫾ ⫽ ⫾ ⫾ ⫽

2.3 2.2 a 8) 1.9 1.3 6)

⫾ ⫾ ⫽ ⫾ ⫾ ⫽

6.3 7.7 (n 6.6 7.8 (n

47.1 ⫾ 8.5 49.7 ⫾ 15.3 (n ⫽ 3)

39.9 ⴞ 15.3 27.1 ⴞ 12.1** (n ⴝ 15)

46.7 ⫾ 10.4 47 ⫾ 10.6 (n ⫽ 6)

33.4 ⴞ 16.2 27.3 ⴞ 13.6** (n ⴝ 35)

5.8 7.1 (n 6.3 7.8 (n

⫾ ⫾ ⫽ ⫾ ⫾ ⫽ 2.1 2.7 4) 2.4 1.0 3)

46.3 ⫾ 14.1 44.3 ⫾ 4.9 (n ⫽ 3)

28.5 ⫾ 15.4 27.5 ⫾ 14.9 (n ⫽ 20)

8.9 7.5 (n 7.3 5.3 (n

ⴞ ⴞ ⴝ ⴞ ⴞ ⴝ 2.4 2.4* 8) 1.8 2.5* 8)

47.2 ⴞ 12.5 41.6 ⴞ 13.1* (n ⴝ 8)

33.5 ⴞ 11.7 21.8 ⴞ 12.2* (n ⴝ 8)

Note. In each data cell, the top line is the pre- mean ⫾ SD and the second line is the post- mean ⫾ SD. a Indicates trends toward significant changes, .05 ⬎ p ⱕ .10. * Indicates that the differences are statistically significant at p ⬍ .05. ** Indicates that the differences are statistically significant at p ⬍ .005.

Visuospatial encoding/ learning 9. Battery for memory efficiency (BEM) (total score) 10. BEM-RIE (immediate recall of complex figure) 11. BEM-AL (serial learning—12 designs in three trials)

Language: Fluency 8. Phonemic fluency (FAS/CFL)

9.1 7.1 (n 7.2 4.9 (n

ⴞ ⴞ ⴝ ⴞ ⴞ ⴝ

2.7 3.1* 5) 2.4 3* 5)

46.6 ⴞ 16.2 39.7 ⴞ 16.1 a (n ⴝ 5)

37.6 ⴞ 12.3 23.8 ⴞ 14.2* (n ⴝ 5)

9.2 8 (n 7.7 7.8 (n

⫾ ⫾ ⫽ ⫾ ⫾ ⫽

0.8 1.4 2) 0.3 0.4 2)

48.7 ⫾ 2.1 48.8 ⫾ 3.9 (n ⫽ 2)

32 20 (n ⴝ 1)

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1976) and which are commonly used in the neuropsychological evaluation of PD (Brown & Marsden, 1990; Dubois et al., 1991;Taylor & Saint-Cyr, 1995; Taylor, Saint-Cyr, & Lang, 1986). Based on our experience with our evaluation of the U-PVP patients (Tre´panier et al., 1998a), a selection of tests thought to be sensitive to the integrity of striatal circuits functionally linked to the frontal lobes were chosen from the overall battery for the present comparison of outcome of PVP and DBS.

Neuropsychological Tests and Questionnaires: A full outline of the test battery can be found in Tre´panier et al. (1998a). However, tests reported on here are as follows. Intelligence. These measures were used only to establish premorbid and current verbal intellectual level (IQ) and to estimate cognitive weaknesses at baseline relative to the expected PD cognitive profile (see Table 1): (i) American New Adult Reading Test (AMNART) and (ii) Wechsler Adult Intelligence Test—Revised: Verbal (WAIS-R VIQ). Frontal executive tasks including attention, concentration, and problem solving. These included (i) the Paced Auditory Serial Addition Test (PASAT), 3″; (ii) the Digit Span—Backward (verbal subtest from the WAIS-R); (iii) the Trailmaking Test—part B; and (iv) the Spatial Conditional Associative Learning Test (four-disk version). Language. For language we used (i) the Semantic Category Fluency (‘‘Animals’’ trial) and (ii) the Controlled Oral Word Association Test (FAS & CFL versions). Verbal memory and learning. We used the California Verbal Learning Test (CVLT: Forms 1 and 2). Visual memory and learning. This domain of function proved to be difficult to assess due to the dyskinesias exhibited in many patients’ drawing hand as well as test sensitivity. In an attempt to circumvent these limitations, alternate methods for assessment of these functions were explored over these series. (i) the Rey-Osterrieth (R/O) Complex Figure (copy) (used only for U-PVP-R group). (ii) the Battery for Memory Efficiency- 7 visual spatial subtests (BEM) make up the total score, and results from the immediate recall of a complex figure (RIE) and serial learning of 12 designs in three trials (AL) (both examining aspects of initial encoding). Questionnaires. We used (i) the Frontal Lobe Personality Scale (FLOPS) and (ii) A clinical follow-up questionnaire regarding subjective experience of surgery by patient and caregiver. Descriptions of these tests can be found in Spreen and Strauss (1998), Signoret (1991), or in the publications of Taylor, Saint-Cyr, and Lang, (1986, 1990). Care was taken not to confound practice effects with improvement in cognitive processing by using alternate forms (order randomized across patients), where available, to examine verbal memory (CVLT—forms 1 and 2), and verbal phonemic fluency (FAS and CFL).

Statistical Analyses Details regarding the analyses for the unilateral pallidotomy data are found in Tre´panier et al. (1998a). In brief, pre- and postanalyses (i.e., 2 ⫻ 2 ⫻ 2 ANOVAS; side of lesion X prevs posttest score ⫻ time of post score; i.e., 3 or 6 months or paired t tests) were carried out. For the two DBS groups, the nonparametric Wilcoxon signed ranks test was used. In order to maximize postoperative data for each measure and group, patients’ first follow-up scores from either 3 or 6 months were employed.

Individual Patterns of Change To evaluate test score changes among individual patients at their first follow-up evaluation, each reported test score was transformed to a standard (z) score, using published normative

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data for all measures except the PASAT 3″, where a conservative 20% decline in number correct was considered clinically significant (≅ 0.5–1 SD, depending on the group; see Table 2). This criterion was used for the PASAT due to high variability at baseline, because it is greater than the mean change in our larger PVP group, and the fact that it is an experimental but clinically valid measure for this population. The clinical criterion of ⬎ ⫾ 1 SD was employed to tally improvements and declines, respectively, over the 3- to 6-month follow-up. Both levels of analyses were completed for the whole bilateral STN DBS group and for the older (ⱖ 69) subgroup.

RESULTS

Baseline Neuropsychological Profile As seen in Table 1, there were no statistically significant differences between premorbid and current IQs within the U-PVP and DBS study groups. Examination of other selected baseline psychometric tests indicated that the study groups had evidence of mild-moderate executive dysfunction), which affects processing across many cognitive domains, a neuropsychological profile comparable to that seen in other groups of PD patients with on/off fluctuations (eg. within 1 SD on CALT, TMT-B, FAS, and CVLT of means and SDs presented in Taylor, Saint-Cyr, & Lang, 1986; 1987). Postoperative Course As reported elsewhere (Lang et al., 1997a, 1997b; Lozano et. al., 1995; Kumar et al, 1998a, 1998b), clinically significant improvements in motor function were observed in patients undergoing each of the different surgical procedures, as of the first postoperative assessment. In summary, U-PVP results in approximately 30% improvement in off-period ADL and motor UPDRS scores (with most of the improvement contralateral to the lesion). Although dyskinesias are reduced by 80% contralateral and 40% ipsilateral to the lesion, on-period motor functioning is otherwise not improved compared to the preoperative state. The results of bilateral PVP have not been reported in large carefully studied groups of patients. Most centers have found approximately 10% additional improvement in off-period functioning with a second lesion and striking elimination of virtually all remaining levodopa-induced dyskinesias, but again no significant improvement in on-period motor functioning. The effects of unilateral and bilateral GPi DBS are similar to those of pallidotomy. In contrast, bilateral STN DBS has a greater effect on motor function and benefit may approximate that of levodopa, with 60% improvement in off-period motor scores and 30–40% improvement in offperiod ADL scores. Unlike pallidal surgeries, bilateral STN DBS improves on-period motor scores by about 40%. The acute cognitive morbidity of surgery may differ when operating on the pallidum and the STN. Postoperative confusion was very uncommon even in elderly patients undergoing pallidal surgery. However, there was a

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tendency toward intraoperative and postoperative confusion in the elderly (ⱖ 70 years) STN DBS patients (Kumar et al., 1998a, 1998b). Confusional states lasting 1 to 2 weeks postoperatively developed in 4 of our first 16 STN DBS patients (all ⱖ 70 years), and 2 of these patients were still experiencing confusional episodes at their 3-month follow-up assessment. Neuropsychological Effects Posthoc analyses indicated significant age effects in the STN DBS group. Therefore, separate analyses are presented for the elderly subgroup. Highlights of our statistical results are reported by group in Tables 2 and 3. Table 4 provides a summary of only the significant findings. Results will be presented by functional domain. In Table 2, pre- and postoperative means, standard deviations, sample sizes, and symbols denoting whether the group comparisons demonstrated trends toward significance (used when sample size was small) or where statistically significant results are reported (i.e., @ ⫽ 0.06 ⱖ p ⱕ .10; * ⫽ p ⱕ .05; ** ⫽ p ⱕ .005). Table 3 indicates the incidence of declining cognitive performance following the different procedures. The following applies to all groups except B-PVP. Attention and Working Memory As measured by the 3″ PASAT, attention significantly improved with UPVP and a similar trend was seen in GPi DBS. No significant group changes were noted with STN DBS but it should be mentioned that 37.5% of these patients and 20% of older STN DBS patients ⬎69 declined in performance ⬎ 1 SD, although the elderly group started off at a lower level of performance. It is also worth mentioning that postoperative performance of the younger patients from this group was similar to that of the other groups. Working memory, as measured by Digit Span Backward, declined in all groups but the change was significant only for U-PVP and for the left PVP subgroup. Executive Functioning Set switching, as indicated by performance time on Trails B, declined for the whole STN DBS group as well as for the older STN DBS subgroup. There were no significant group changes in executive functioning, as measured by the number of errors made on the Conditional Associative Learning Test (CALT ⫺ number of errors). However, Table 3 indicates that many of the STN and GPi DBS patients had more difficulty with the task postoperatively. Verbal Learning Verbal learning effects were seen with the CVLT. The patients with left pallidotomies had increased difficulty with initial encoding. In addition, they

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were poorer in free recall at a short delay. By comparison, the STN DBS group (no age effect) were poorer in both free and cued recall at long intervals (consolidation phase) and generally had more difficulties with retrieval (Trials 1–5, LDFR) (see Tables 2–4). In contrast, although sample size was limited, the GPi DBS patients did not experience encoding difficulties postoperatively but were similar to the STN DBS patients in that they were poorer in retrieval and the consolidation phase of learning (long delay free and cued recall). Language (Phonemic and Semantic Category Fluency) Controlled phonemic verbal fluency was significantly reduced for all patient groups except the right PVP subgroup (Tables 2 and 4). This reduced performance appears to be long-term in some patients, as indicated in 5/6 U-PVP, 3/3 B-PVP, 2/5 STN DBS (both elderly), and 2/3 GPi DBS patients who have had 12⫹ month follow-up evaluations and at least one previous postoperative assessment. Table 3 indicates that left PVP, STN DBS, and STN DBS ⬎69 patients are most susceptible to these difficulties. This may also be true of the GPi DBS but the numbers are too few to draw any conclusions. In contrast, no groups had significant difficulties with semantic fluency, when only the ‘‘Animals’’ trial was given. Table 3 indicates that about 1/4 of the U-PVP patients (regardless of lesion side) had difficulties. Although not reported here, significant reductions were found in the STN DBS group and the elderly subgroup when all three trials (Animals, Fruits, and Vegetables) were employed. Visual Learning & Memory Visual–spatial functions were assessed with both the Rey-Osterrieth (R/O) Complex Figure (right PVP subgroup) and with the BEM (DBS groups and some PVP patients who were later in our series). After a right pallidotomy, patients had more difficulty accurately drawing the complex figure (n ⫽ 8; t ⫽ 2.771, p ⫽ .028) but this improved to baseline levels after 6 months. None of the small number of U-PVP patients tested with the BEM subtests had postoperative difficulties. After STN DBS, the total score from six subtests, the immediate recall of a complex figure (simpler than the R/O), as well as the learning of a list of nonsense shapes were significantly reduced. One of two GPi DBS had more difficulty recalling the BEM complex figure; otherwise, their performance was preserved. Cognitive Effects of Staged B-PVP Within the three cases of B-PVP at baseline, one patient demonstrated a 1⫹ SD (⬎15 points) difference between these IQ estimates. Two of our

Attention 1. PASAT-3″ (% correct) a 2. Digit Span-Backward (raw score) Executive functioning 3. Trailmaking test— B (seconds) 4. Conditional associative learning test (No. errors) Verbal Learning (CVLT) 5. Total Score (trials 1–5) 6. Short delay free recall (SDFR) 7. Long delay free recall (LDFR) 8. Long delay cued recall (LDCR)

Psychometric tests/domain

(0%)

8/14 (57%) d 7/14 (50%) 7/14 (50%) 5/14 (36%)

10/30 (33.3%) d 9/30 (27%) 9/30 (27%) 5/30 (17%)

2/15 (13%)

2/34 (6%) 2/30 (7%)

(0%) 2/15 (13%) c

Declined (⬎1 SD)

Declined (⬎1 SD) 1/24 (4%) 6/35 (17%) c

Unilateral left pallidotomy (n ⫽ 18)

Unilateral pallidotomy (R & L) (n ⫽ 42)

(0%)

1/16 (6%) 1/16 (6%) 1/16 (6%)

(0%) b 2/17 (12%)

1/14 (7%) 4/20 (20%) c

Declined (⬎1 SD)

Unilateral right pallidotomy (n ⫽ 24)

3/7 (43%) 3/7 (43%) 3/7 (43%) 6/7 (86%)

3/5 (60%) 2/5 (40%) 1/5 (20%) 4/5 (80%)

5/5 (100%) b 4/5 (80%)

(0%)

(0%) 5/7 (71%) b 5/8 (62.5%)

2/5 (40%) b

Declined (⬎1 SD)

Bilateral STN DBS (age ⬎69) (n ⫽ 5)

3/8 (37.5%) b

Declined (⬎1 SD)

Bilateral STN DBS (n ⫽ 9)

TABLE 3 Incidence of Declining Cognitive Performance Following Unilateral PVP and Bilateral DBS of STN or GPi

(0%) 2/2 (100%) 1/2 (50%) 1/2 (50%)

(0%) 2/3 (66.7%)

(0%) 1/4 (25%)

Declined (⬎1 SD)

Bilateral GPi DBS (n⫽ 4)

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10/15 (60%) b 4/14 (29%)

(0%) (0%)

(0%)

11/35 (31%) 7/27 (26%)

(0%) (0%)

(0%)

(0%)

(0%)

(0%)

2/20 (10%) 3/13 (23%) (0%)

(0%)

4/5 (80%) 3/5 (60%) 4/5 (80%)

6/8 (75%) 4/8 (50%) 5/8 (62.5%)

(0%)

(0%) 1/2 (50%)

1/1 (100%)

3/5 (60%)

5/8 (62.5%) 1/8 (12.5%)

b

a

A 20% decline in the number correct was considered clinically significant for the PASAT-3″ (equivalent to ⱖ 1 SD). On these measures, postoperative floor or ceiling effects were observed for one patient, making their data appear like ‘‘no change’’ when in fact, test scores changed in the expected directions; thus, an underestimate of percentage. c Group analyses indicated that it took 6 months to fully observe improvements on the PASAT-3″ and declines on Digit Span–Backward. Therefore, tallies of percentage declined were made with the 6-month scores, if available. d With regard to verbal learning, one patient received the Hopkins Verbal Learning Test (a similar but easier CVLT due to education limitations) and so was taken from the group analyses but a decline of 5.4 SD was observed at the first follow-up evaluation (making n ⫽ 15, 60% declining on total score).

Language: fluency 9. Phonemic fluency (FAS/CFL) 10. Category fluency (Animals only) Visuospatial encoding/ learning 11. (BEM) (total raw score) 12. BEM-RIE (immediate recall of complex figure) 13. BEM-AL (serial learning—12 designs)

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↓

↓

↓

↓

↑*

↓

↓

↑

Unilateral left pallidotomy (n ⫽ 18)

Unilateral right pallidotomy (n ⫽ 24)

↓ ↓

↓

↓*

↓ ↓

↓

↓*

↓ ↓

↓*

↓

Bilateral STN DBS (age ⬎69) (n ⫽ 5)

↓

↓

↓*

Bilateral STN DBS (n ⫽ 9)

↓

↓*

Bilateral GPi DBS (n⫽ 4)

Note. (↓) Indicates a decline in performance. (↑) Indicates an increase in performance. * Refers to a trend in the data (i.e., 0.1 ⱕ p ⱖ .051) and presented due to the preliminary nature of the DBS data and the small cell sizes for some measures/groups.

Attention 1. PASAT-3″ (% correct) 2. Digit SpanBackward (raw score) Executive functioning 3. Trailmaking Test-B (seconds) Verbal learning (CVLT) 4. Total score (Trials 1–5) 5. Long delay free recall (LDFR) 6. Long delay cued recall (LDCR) Language: fluency 7. Phonemic Fluency (FAS/CFL) Visuospatial encoding/ learning 8. (BEM) (total raw score) 9. BEM-RIE (immediate recall of complex figure) 10. BEM-AL (serial learning—12 designs)

Psychometric tests/domain

Unilateral pallidotomy (R & L) (n ⫽ 42)

TABLE 4 Summary of Significant Changes in Cognition Following Unilateral PVP and Bilateral DBS of STN or GPi

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TABLE 5a Prevalence of Behavioral Complaints Post–Unilateral PVP Prevalence of Complaint (x/N; %) Behavioral description I. Environmental Dependency (i) Perseveration on actions or ideas II. Psychosocial/emotional control (i) Unawareness of deficits (ii) Social judgment (iii) Lability (unipolar or bipolar) (iv) Depression (not reactive to PVP) (v) Impulsivity (vi) Sexually inappropriate behaviors (vii) personality change III. Executive/cognitive (i) Word finding (fluency/quantity) a

(ii) Overall memory (iii) Concentration/distractibility (iv) Organizational abilities (v) increased confusion (vi) dementia (general cognitive decline)

By patient

By caregiver(s)

6/32 (19%)

11/27 (41%)

2/32 1/32 6/32 7/42 2/32 1/42 1/42

11/27 (41%) 8/27 (30%) 9/27 (33%) 7/27 (26%) 8/28 (29%) b 3/27 (11%) 1/27 (4%)

(6%) (3%) (19%) (17%) (6%) (2%) (2%)

17/42 (40%) 12/18 (67%) (L) 6/24 (25%) (R) 12/42 (29%) 8/42 (19%) 5/32 (16%) 2/42 (5%) (R only) b

9/29 (31%) b 4/10 (40%) (L) 5/19 (26%) (R) 9/29 (31%) b 5/29 (17%) b 5/27 (19%) 2/29 (7%) b 1/29 (3%) b

Note. L, left PVP; R, right PVP; otherwise, R ⫹ L. It was not until spontaneous reporting of complaints occurred that more systematic inquiry via the FLOPS and more detailed clinical interviewing was carried out, allowing for the possibility of an underestimate of the true incidence. a These complaints were spontaneously reported during the clinical interview to have worsened postoperatively. b Data jointly collected from clinical interview and FLOPS. N’s increase if clinical interview available, but not FLOPS.

three B-PVP patients experienced significant global cognitive decline subsequent to their second pallidal lesion. Preoperatively, both of these patients had atypical cognitive profiles for PD (i.e., impaired confrontational naming and extremely poor visual spatial integration or serial list learning and one had functionally impaired intellectual capacities). Postoperatively, in all cognitive domains but especially executive functioning, performance for both patients was 1–3 SD below that seen prior to their second lesion. Both of these patients had problematic premorbid medical histories involving diabetes. One of the patients also had a history of psychiatric disturbance, along with a current verbal IQ ⬎1 SD below premorbid estimates. This patient was one of the earliest patients in our pallidotomy series. In contrast, the last case in our series, who had a small second lesion, experienced only transient declines in certain aspects of executive functioning (working memory, increased perseveration, and encoding of new material) post- second

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TABLE 5b Prevalence of Behavioral Complaints Post–Bilateral DBS of STN and GPi Prevalence of complaint (individual tallies) STN Behavioral description

GPi

Patient (n ⫽ 9)

Caregiver(s) (n ⫽ 9)

Patient (n ⫽ 4)

Caregiver(s) (n ⫽ 3)

2

1

1

1

0 1 1 1 2 0 1

1 1 1 1 1 0 1

0 0 3 0 1 0 0

0 0 1 0 1 0 0

2 8 5 0 2 1 3

1 4 2 1 2 1 2

0 1 1 1 0 0 0

1 1 1 0 0 0 0

I. Environmental dependency (i) perseveration (actions/ideas) II. Psychosocial/emotional control (i) Unawareness of deficits (ii) Social judgment (iii) Lability (unipolar or bipolar) (iv) Depression (not reactive to DBS) (v) Impulsivity (vi) Sexually inappropriate behaviors (vii) Personality change III. Executive/cognitive (i) Word-finding (fluency/quantity) (ii) Overall memory (iii) Concentration/distractibility (iv) organizational abilities (v) Increased confusion (vi) ‘‘General cognitive decline’’ (vii) Increased mental slowing

Note. Data were jointly collected from clinical interview and FLOPS.

lesion. Phonemic fluency had declined after the first lesion, never recovered prior to the second lesion, but did not deteriorate further after the second lesion. ‘‘Frontal Lobe’’ Behavioral Changes Behavioral changes, in the three domains of Environmental Dependency, Psychosocial/Emotional Control, and Executive/Cognitive, are presented by group in Tables 5a–5c. Complaints were organized in this fashion based on correlations with frontal lobe/executive functioning and the consistency of observations reported by caregivers and some patients in the clinical interview and the FLOPS. Although most marked and persistent in two of the three B-PVP, four U-PVP, and one STN DBS patient(s), behavioral changes, sufficiently noticeable to cause disturbance of family or social interactions, have been observed in all groups. Notably, lack of patient insight can be problematic. Problems can vary from impulsivity and poor judgment to apathy and loss of initiative. Patients who became more physically independent postoperatively, and who consequently attempted to resume their previous activities, appeared to be the ones who experienced limitations and frustrations in this regard.

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TABLE 5c Behavioral Complaints 3/6 Months Post–Staged Bilateral PVP Prevalence of Complaint (individual tallies) (patient) Behavioral description I. Environmental dependency (i) Perseveration (actions/ideas) (ii) Utilization behavior II. Psychosocial/emotional control (i) Unawareness of deficits (ii) Social judgment (iii) Lability (unipolar or bipolar) (iv) Flattened affect (v) Impulsivity (vi) Personality change (psychic akinesia: abulia, anhedonia, akinesia) III. Executive/cognitive (i) Word finding (fluency/quantity) (ii) Overall memory (iii) Concentration/distractibility (iv) Organizational abilities (v) Increased confusion (vi) ‘‘General cognitive decline’’ (vii) Increased mental slowing (viii) Instability of mental set

1

2

3

o/x o/o

o/x o/x

x/x o/o

o/o o/o x/x o/o o/o o/o

o/x o/x o/o x/x o/o o/x

o/o o/o x/o o/o o/o o/o

x/x x/x x/x x/x x/x x/x o/o x/x

o/x o/x o/x o/x o/x o/x o/x o/x

x/o o/o o/o o/o o/o o/o o/o o/o

Note. Data jointly collected from clinical interview and FLOPS. (o), not endorsed; (x), endorsed; (patient/caregiver(s) endorsement). Patients are presented in the order in which they were operated upon. Patient 2 was in intensive speech, behavioral, and occupational therapies postoperatively, making an evaluation of insight into personal changes problematic.

It should also be mentioned that, in our experience with pallidotomy patients, despite thorough explanation of what constitutes realistic expectations of these procedures, many patients remained overly optimistic about postoperative resolution of their parkinsonian symptoms. For those patients, despite a generally favorable postoperative clinical outcome, depressive reactions and despondency were often experienced. DISCUSSION

This paper highlights our experience assessing the neuropsychological and behavioral outcome of U-PVP, staged B-PVP, bilateral GPi DBS, and bilateral STN DBS in advanced PD patients 3/6 months postoperatively. Cautious interpretations are warranted due to the preliminary nature of our B-PVP and GPi DBS data.

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Summary of Neuropsychological Effects Patients with U-PVP lesions can experience improvements in allocation of attentional resources but can also suffer declines in working memory, certain aspects of executive functioning, and lateralized declines in verbal learning and fluency post- left and visuoconstructional abilities post- right lesions. In our limited experience, staged B-PVP appears to potentially be the most psychologically toxic procedure. Two of three patients suffered major cognitive decompensation across all domains, but especially in the area of executive functioning. However, optimal lesion placement and reduced lesion size may make this a viable option for selected patients (Scott et al., 1998). Many aspects of cognitive functioning decline after STN DBS. Working memory, speed of mental processing, set switching, error rate on a conditional associative learning task (trend only), long delay free and cued recall of verbal material, phonemic fluency, and encoding of visuospatial material can decline in a clinically significant proportion of patients. Patients ⬎69 years of age are much more at risk for these cognitive changes (4/5 in our series so far), which appear to be progressive supranuclear palsy (PSP)-like in nature, especially with regard to the slowness of mental processing (see next section for further discussion). Our four GPi DBS patients (all ⬍ 70 years old) showed fewer of the deleterious effects (working memory, executive functioning, long delay free and cued recall on CVLT, FAS, RIE-BEM) seen in the other groups but these observations are too preliminary to draw any conclusions. Plausible Neuroanatomical Explanations for Neuropsychological Sequelae These findings are consistent with the explanation that lesions or chronic stimulation within the frontal-striatal circuits (i.e., GPi and STN) are capable of causing further deterioration of processes normally thought to be dependent on the functional integrity of these circuits. Specifically, these cognitive and behavioral/emotional changes may be due to alterations of ‘‘nonmotor’’ pathways involving ‘‘dorsolateral’’ (affecting problem-solving, flexibility), ‘‘orbitofrontal’’ (affecting inhibitory processes), or ‘‘anterior cingulate’’ (affecting initiation, motivation, and drive) striato-thalamo-cortical circuits (see Alexander et al., 1990). Correlations between PVP lesion location and these cognitive changes in a subset of our U-PVP patients have now been demonstrated (Lombardi, Gross, Tre´panier, Lang, Lozano, & Saint-Cyr, in press). For a further discussion of this topic, please refer to Tre´panier et al. (1998a). It should be mentioned that these neuropsychological changes were found in our initial and consecutive series of pallidotomy patients. Subsequent patients have had smaller and more carefully placed lesions, which may likely result in different motor and psychological consequences. The PSP-like cognitive changes (especially mental slowness) observed

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following STN DBS may be specifically due to chronic stimulation of the STN, recalling that it is involved in the neuropathology of PSP (Parent & Hazrati, 1995; Weiner & Lang, 1989). Current spread to adjacent structures as well as remote antidromic and orthodromic actions must also be considered. Finally, nonspecific effects of surgery may also explain some of the cognitive changes. Specifically, bilateral frontal lobe trajectories or bilateral trajectories through the thalamus, rather than specific stimulation of the STN, may be contributing factors. In order to determine if a microlesion/trajectory effect exists, patients would need to be tested off stimulation. However, in our practical experience, this would be very difficult as most patients have not wanted their stimulators turned off due to the resumption of their motor symptoms. Comparisons with Other Studies Unilateral pallidotomy. Our findings have been previously reported (Lang et al., 1997c; Saint-Cyr et al., 1996; Tre´panier et al., 1997, 1998a, 1998b) for this group and are indicative of some further postoperative decline in already weakened frontal-striatal cognitive and functional processes. There are other centers also reporting some negative impact on specific aspects of frontal-striatal processes, such as cognitive flexibility, working memory, abstract reasoning, or speed of processing (Riordan et al., 1997; Stebbins et al., 1997) (see Introduction for further details). Also similar to our findings, some centers have reported rare cases of frontal behavioral dyscontrol (i.e., sexual disinhibition; see Tables 5a–5c for further examples) (Dogali et al., 1995; Fazzini et al., 1997; Shannon et al., 1998). Scott et al. (1998) is the only other group who reported any patients who had difficulties with free recall of verbal material. Last, similar to our observations, Masterman et al. (1997) and Scott et al. (1998) each noted further cognitive decline in a patient who was preoperatively considered borderline cognitively, indicating a need for caution when considering these surgical procedures for such patients. Deep brain stimulation. With regard to the neuropsychological outcome of DBS, findings have only been reported following unilateral GPi stimulation in nine patients (six left and three right) (Tro¨ster et al., 1997). Declines were reported in semantic fluency and visuoconstructional abilities and were also seen in individuals for phonemic fluency and the short- and long-term delayed free recall trials of the CVLT (verbal learning). These findings are concordant with our observations following bilateral GPi or STN DBS, except in the latter group, wherein we found patients’ difficulties to be more extensive, especially if they were ⬎69 years old (i.e., speed of processing, working memory, and executive functioning). Staged-bilateral pallidotomy. The effects of staged bilateral pallidotomy have not been well studied from either a neurological or a neuropsychological perspective, but our experience with three cases (Kumar, Tre´panier, et

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al., in preparation; Galvez-Jiminez et al., 1996), along with the report of six cases by Roberts and Heilbrun, (1997), suggests that although some aspects of motor improvement can be seen, this procedure can carry a high risk of unacceptible adverse effects in other aspects of motor, cognitive, and behavioral functioning. This is in direct contrast to the very recent and more optimistic study of Scott et al. (1998), reporting on the outcome of eight simultaneous bilateral pallidotomy cases who, as a group, only experienced reductions in phonemic and semantic verbal fluencies as well as decreased speech articulation rates. Their group also demonstrated significant improvements in functional outcome (similar to two of our three cases), although they did report that one of eight patients (12.5%) suffered generalized cognitive impairment postoperatively. Possible Explanations for Differential Findings Differences between the neuropsychological outcome of PD patients operated on in different centers may lie largely in the location and extent of lesions, on the one hand, or there may be other factors, such as age and preoperative cognitive status, which influence outcome, on the other. Comorbidity with other conditions (e.g., psychiatric history and diabetes, in our group) probably plays an important role as well. Also of importance will be consideration of test sensitivity and the use of alternate test forms, when available. For example, we used the PASAT 5″ and 3″, the CVLT (two alternate forms), BEM subtests, phonemic fluency (FAS and CFL forms), and the FLOPS, which have revealed impairments (or improvements) across all procedures. In our own studies, lack of group effects (despite significant individual changes) could also be attributed to large variances (and SDs) and floor effects on measures such as the Conditional Associative Learning Test, Digit Span-Backward, and Trailmaking Test—B. When assessing semantic fluency, it appears more sensitive to use all three categories (i.e., Animals, Fruits, & Vegetables), rather than just ‘‘Animals’’ alone. When monitoring the behavioral impact of these surgeries, a structured questionnaire, such as the FLOPS, is needed, along with consultation with caregivers and patients. Sometimes, patients lack insight or the caregivers have some difficulty articulating the nature of the behavioral problems, other than to report that they are having more problems coping at home with their spouses, despite their being more mobile, etc. Conclusions

(1) Patients who have preexisting atypical cognitive profiles for PD or who are borderline demented appear to be at high risk for postoperative behavioral or cognitive decompensation. (2) Unilateral GPi PVP is still clinically useful but caveats with regard to

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preoperative status and the likelihood of neuropsychological sequelae must be taken into account. Our findings suggest that PVP can induce a further decompensation in cognitive and behavioral areas which show preexisting impairment in PD and can be hemisphere-specific. In our series, patients with right lesions experienced fewer and only transient difficulties compared to those with left lesions. (3) In our experience, staged B-PVP can be the most problematic surgical procedure but careful patient selection with regard to premorbid cognitive, medical, and psychiatric profiles and care with lesion placement and/or size may make this a viable option. (4) STB DBS is gaining the reputation of being the most clinically effective method but older patients appear to be at risk for significant cognitive and behavioral decline. We are still collecting long-term follow-up data to determine whether these changes are permanent, but so far, speed of processing and verbal fluency appear to remain impaired. Larger patient samples are also required to confirm these preliminary findings. (5) The least neuropsychologically detrimental procedure may possibly be bilateral GPi DBS but the numbers are too few to draw any conclusions. This treatment should probably be investigated further using random, blinded surgical trials and evaluations. (6) When deciding on any of these neurosurgical treatments, one needs to weigh the potential benefits and risks and hopefully to be prepared to offer sustained and intensive postoperative follow-up, support, and management for any difficulties that arise. Education of patients and caregivers regarding strategies to minimize cognitive losses has been very helpful. Also, when patients have experienced frontal lobe behavioral changes postoperatively, it has also been helpful to teach caregivers and family environmental management skills to help organize and guide them so as to better manage potentially problematic situations. REFERENCES Alexander, G. E., Crutcher, M. D., & DeLong, M. R. 1990. Basal ganglia thalamocortical circuits parallel substrates for motor, oculomotor, ‘‘prefrontal’’ and ‘‘limbic’’ functions. [Review]. Progress in Brain Research, 85, 119–146. Baron, M. S., Vitek, J. L., Bakay, R., Green, J., Kaneoke, Y., Hashimoto, T., Turner, R., Woodard, J., Cole, S., McDonald, W., & DeLong, M. 1996. Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Annals of Neurology, 40, 355–366. Benabid, A. L., Pollack, P., Gao, D. M., Hoffmann, D., Limousin, P., Gay, E., Payen, I., & Benazzouz, A. 1996. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. Journal of Neurosurgery, 84, 203– 214. Brown, R. G., & Marsden, C. D. 1990. Cognitive function in Parkinson’s disease: from description to theory. Trends in Neurosciences, 13, 21–29. Cahn, D., Sullivan, E., Shear, P., Heit, G., Lim, K., Marsh, L., Lane, B., Wasserstein, P., &

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