Results

NEUROLOGICAL MEASURES

Baseline

Table 3 shows the means (SD) for the baseline neurological measures for the patients with right or left PVP. Overall, before surgery, patients demonstrated minimally to moderately severe motor disability during the on state, (Hoehn and Yahr: mean=2.66 (SD 0.12); UPDRS: mean=46.2 (SD 2.0)), with severe disability during the off state (Hoehn and Yahr: mean=4.00 (SD 0.12); UPDRS: mean=87.1 (SD 3.0)). During the on state, patients reported mild limitations in their ability to perform activities of daily living (ADLs) (UPDRS ADL: mean=15.6 (SD 0.78); Schwab and England: mean=76.9% (SD 1.9)), while they required moderate to total assistance during the off state (UPDRS ADL: mean=30.3 (SD 1.0); Schwab and England: mean=43.8% (SD 2.3)). Preoperative mean total daily dose of levodopa was 468 mg (SD 241) (range=50 to 1000 mg).

Outcome

Table 3 shows the means (SD) for the neurological measures at the baseline, 3 month follow up, and 12 month follow up evaluations for the patients with right or left PVP in the on and off states. Overall, patients with right or left PVP demonstrated significant improvements in Hoehn and Yahr staging, UPDRS total score, and UPDRS motor score in the on and off states between the baseline and the 3 month and the 12 month follow up evaluations (p=0.01). The 3 and 12 month evaluations did not differ significantly from each other on any of these measures ( Hoehn and Yahr: on, p=0.90, off p=0.31; UPDRS: on p=0.61, off p=0.85; UPDRS motor: on p=0.88, off p=0.79). Three months after PVP, 100% of patients showed motor improvements while in the off state, while 86% of patients showed motor improvements while in the on state. Between the 3 month and 12 month assessments, three patients showed a 10 point decline in UPDRS scores while on (95% maintained improvements from 3 months, n=39), and four patients showed a 10 point decline in UPDRS scores while off (90% maintained improvements from 3 months, n=38).

Furthermore, patients with right or left PVP experienced overall significant improvements in UPDRS ADL scores, and Schwab and England scores in the on and off states post-PVP (p=0.01). The 3 month and 12 month evaluations did not differ significantly from each other on either of these measures (UPDRS ADL: on p=0.81; off p=0.71; Schwab and England: on p=0.34, off p=0.25). Three months after PVP, 74% of patients showed more than a 10 point improvement in Schwab and England scores while on, whereas 88% reported improvements in their ability to perform ADLs independently while in the off state. Between the 3 month and 12 month follow up evaluations, two patients showed a decline (⩾10 point decline in Schwab and England scores) in their ability to perform ADLs independently in the on state (95% maintained improvements from 3 months), whereas 16 patients demonstrated declines (⩾10 point decline in Schwab and England scores) in their ADL ability in the off state (61% maintained improvements from 3 months). In general, improvements in the patients' motor functioning and ability to perform ADLs were maintained for up to 1 year after PVP. These improvements were achieved while most patients were maintained on their pre-PVP mean total daily dose of levodopa (p=0.18; table 3) and there was not a significant change in other anti-parkinsonian drugs.

LESION VERIFICATION

The size and location of the PVP lesion was investigated 1 to 3 days postoperatively and at a 6 month follow up evaluation by MRI studies. A detailed description of the MRI procedure has been published elsewhere.34 In the early phase and late phase images, the lesion was located in the GPi in all instances. The mean volume of the late phase lesions was 22 (SD 28.8) mm³.34

POSTOPERATIVE IMAGING STUDIES

Three study participants had adverse events on postoperative imaging studies. Two patients had small ischaemic infarctions involving the corona radiata, and in one a venous infarction at the entry site of the electrode was detected. These findings were incidental in two patients, but ischaemic infarction resulted in mild transient Broca's aphasia in one instance. Patient 1 was a 62 year old white man with a 15 year history of Parkinson's disease. After left PVP, he had a mild aphasia that was found to be secondary to a small ischaemic infarction involving the corona radiata, the periventricular white matter, and the dorsal thalamus. Patient 2 was a 71 year old white woman who underwent a left PVP to relieve her contralateral motor symptoms. A frontal cortical subcortical venous infarction was detected on the routine postoperative MRI at the entry site of the electrode which, however, was asymptomatic clinically. Patient 3 was a 61 year old white woman who had a right PVP after 8 years of PD. The incidental finding of an asymptomatic small ischaemic infarction extending from the pallidal lesion into the corona radiata was also noted on routine postoperative imaging. Despite these adverse events on postoperative imaging studies all three patients benefited from improvement in their motor function and ADLs up to the 1 year clinical follow up. To determine whether these adverse events on postoperative imaging studies affected cognitive outcome after PVP, the neuropsychological data were analysed a second time excluding these three patients. Significant changes in neuropsychological outcome based on the second analyses are discussed below by cognitive domain (see neuropsychology measures section).

Table 4 shows the neuropsychological measures that demonstrated decline (greater than 1SD) from baseline for the three patients with adverse events on postoperative imaging studies. Patients 1 and 2 showed subtle declines in verbal memory, verbal fluency, information processing, and executive functioning up to 1 year after PVP. Whereas the performance of patient on trails A showed a stable improvement from his baseline testing, his performance on trails B declined, suggesting difficulty with set shifting rather than the motor or information processing aspects of the task. Patient 3 showed more subtle and transient declines after PVP in information processing and executive functioning with an improvement in her affective functioning 1 year after surgery.

NEUROPSYCHOLOGICAL MEASURES

Baseline

Table 5 shows the means (SD) for the baseline neuropsychological scores for the patients with right or left PVP. When the patients' baseline scores were compared with published norms for age and education matched non-Parkinson's disease groups, average to low average performance was shown on confrontational naming (BNT), visuospatial organisation (Hooper), verbal new learning (CVLT total), verbal fluency (COWAT), and mental flexibility (WCST). Information processing tasks (SymDigit, trails A) were borderline impaired and executive functioning tasks requiring a verbal or motor output and switching set or interference (Stroop, trails B) were borderline to mildly impaired. Patients reported a minimal level of depressive symptoms before surgery. This pattern of cognitive impairment is common in patients with Parkinson's disease and suggests involvement of the frontostriatal cognitive system.35

Outcome by cognitive domain

Table 5 shows the means (SD) for the 3 month and 12 month follow up evaluations for the patients with right or left PVP. To distinguish between improvements due to practice effects and improvements due to the effects of surgery, alternate test forms of the CVLT were administered in a counterbalanced fashion. Alternate forms were not available for the remaining tests; therefore, significant improvements in these tests may be due to practice effects and, in the absence of a non-surgical control group, must be viewed with caution.

Mental status

No significant differences were found between the baseline, 3 month, and 12 month evaluations on the MMSE (p=0.91) and the time×lesion side interaction effect was non-significant (p=0.33).

Verbal learning

Between the baseline and 3 month follow up evaluation, patients showed a significant decline in the total number of words recalled over five trials on the CVLT (p=0.004). There was not a significant difference between the baseline and 12 month scores on this measure (p=0.42); but the 3 month and 12 month scores differed significantly (p=0.04). The time×lesion side interaction was not significant (p=0.73). Time accounted for 22% of the variance in CVLT total scores, which is a moderately large effect size. Patients showed a transient decline in verbal learning and memory at 3 months post-PVP with a return to baseline performance by the 12 month evaluation. When the three patients with adverse events on postoperative imaging studies were excluded from this analysis, the decline in total number of words recalled on the CVLT remained significant but the magnitude decreased from the p<0.01 level to the p<0.05 level. Scores on the CVLT long delay did not differ significantly across time periods (p=0.18), and the time×lesion side interaction effect was non-significant for CVLT long delay (p=0.70).

Language

Scores on the BNT improved significantly between the baseline and the 3 month evaluations and between the baseline and the 12 month evaluations (p=0.01 and p=0.001, respectively). Time accounted for 40% of the variance in BNT scores, which is a large effect size. The 3 month and 12 month scores on the BNT did not change significantly (p=0.29) and the time×lesion side interaction effect was not significant (p=0.75).

With the exclusion of the three patients with adverse events on postoperative imaging studies, verbal fluency scores on the COWAT showed an overall non-significant trend for decline over time (p=0.08). When these three patients were included in the analyses, verbal fluency showed a significant decline between the baseline and 3 month evaluations and between the baseline and 12 month evaluations (p=0.04 and p=0.03, respectively). The 3 month and 12 month scores on the COWAT did not differ significantly (p=0.77) and the time×lesion side interaction effect was non-significant (p=0.25). Time accounted for 14% of the total variance in COWAT scores, which is a small effect size.

Visuospatial

Visuospatial organisation ability as measured by the Hooper improved significantly between the baseline and the 3 month evaluations and between the baseline and 12 month evaluations (p=0.02 and p=0.05, respectively). Time accounted for 15% of the variance in Hooper scores, which is a small effect size. There was not a significant difference between the 3 month and 12 month evaluations (p=0.99) and the time×lesion side interaction effect was not significant (p=0.99).

Information processing

SDMT and trails A did not show significant differences across time periods (SDMT: p=0.85; trails A: p=0.77) and the time×lesion side interaction was not significant for either measure (SymDigit: p=0.74; trails A: p=0.12). Patients did not show any significant changes in their information processing abilities after surgery.

Executive functioning

The total number of errors on the WCST decreased between the baseline and 12 month evaluations and the 3 month and 12 month evaluations (p=0.01 and p=0.04, respectively). The time×lesion side interaction effect was not significant for the WCST total error score (p=0.45). Time accounted for 20% of the variance in WCST total error scores, which is a small effect size. Patients with right or left PVP also demonstrated delayed improvement in the ability to resist interference from competing stimuli as measured by the Stroop test between the pre-PVP and 12 month evaluations and between the 3 month and 12 month evaluations (p=0.01 and p=0.01, respectively). The time×lesion side interaction effect was not significant for the Stroop test (p=0.26). Time accounted for 21% of the variance in Stroop interference scores, which is a small effect size. Time to completion of trails B, WCST categories, and WCST perseverative errors did not show significant changes over time (trails B: p=0.82; WCST categories: p=0.42; WCST perseverative errors: p=0.21) and the time×lesion side interaction effect was not significant for any of these variables (trails B: p=0.32; WCST categories: p=0.29; WCST perseverative errors: p=0.68).

HEMISPHERE SPECIFIC CHANGES

No significant main effects for lesion side or time×lesion side interaction effects were found for any of the neuropsychological measures. The patients with right or left PVP did not differ on any neuropsychological measure between the preoperative and follow up evaluations or between the 3 month and 12 month assessments. A second series of repeated measures ANOVAs were performed to test the interaction of sex and lesion side on neuropsychological outcome. The analyses did not show any significant sex×lesion side interactions. Male and female patients with right or left PVP did not differ significantly on any neuropsychological variables.

AFFECTIVE FUNCTIONING

Scores on the BDI improved significantly between the baseline and 3 month post-PVP evaluations and the baseline and 12 month follow up evaluations (p=0.02 and p=0.02, respectively), but not between the 3 month and 12 month evaluations (p=0.84). The time×lesion side interaction showed a non-significant trend (p=0.07). In general, the improvement in BDI scores was unrelated to any alteration in antidepressant drug regimen. When the three patients with adverse events on postoperative imaging studies were excluded from the analysis, the time×lesion side interaction was not found to be significant (p=0.14; table 5).

RELATION BETWEEN PREOPERATIVE MOTOR SYMPTOM SEVERITY AND COGNITIVE OUTCOME

To assess the effect of preoperative level of motor symptom severity on cognitive outcome, a repeated measures ANOVA with time (baseline, 3 months, 12 months) as the within subject factor and motor impairment (severe versus mild to moderate) as the between subject factor was conducted for each of the cognitive variables that demonstrated a significant difference at either 3 months or 12 months post-PVP. The patients were divided into two subgroups based on their preoperative Hoehn and Yahr scores both in the on and off states. Patients who were severely impaired before PVP (Hoehn and Yahr on⩾3 and Hoehn and Yahr off⩾4, seven patients) were compared with patients with less severe preoperative motor impairments ( Hoehn and Yahr on⩽2 and Hoehn and Yahr off⩽3, 28 patients). The mild to moderately motor impaired patients did not differ from the severely impaired patients on any demographic variable (p>0.05). As expected, the severely impaired patients showed significantly worse preoperative neurology scores while in on and off states (p<0.05). Table 6 shows the means (SD) of each neuropsychological variable for the severely impaired and mildly to moderately impaired groups on the preoperative, 3 month, and 12 month follow up evaluations. A significant time×motor impairment interaction was found for CVLT Total 1–5 (F(2,32)=3.19, p=0.05). Post hoc analyses showed that the severely impaired group had lower scores on the CVLT at the 3 month evaluation than the mild to moderate group (p=0.05). However, patients with severe preoperative motor impairments scored higher than those patients with mild to moderate preoperative impairments on verbal learning at the 12 month evaluation, with scores for both groups returning to baseline 1 year after surgery (p=0.05; figure). No other significant time×motor impairment interaction effects were found for any of the other neuropsychological variables. Patients with mild to moderate preoperative motor impairment did not differ on cognitive outcome from the patients with severe preoperative motor impairment, with the exception of the CVLT total score.

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Impairment of verbal learning before and after pallidotomy.

RELATION BETWEEN PREOPERATIVE COGNITIVE FUNCTIONING AND COGNITIVE OUTCOME

To assess the effect of preoperative cognitive functioning on neuropsychological outcome, a repeated measures ANOVA with time (baseline, 3 months, 12 months) as the within subjects factor and mental status (impaired v intact) as the between subjects factor was conducted for each of the neuropsychological variables that showed a significant change from baseline at either 3 months or 12 months post-PVP. The sample was divided into two subgroups based on their preoperative MMSE scores. Patients who registered preoperative impairment on the MMSE (MMSE⩽26) were compared with patients in the normal range (MMSE⩾27).36 No significant time×mental status interaction effects were found for any of the neuropsychological variables. Patients with intact preoperative mental status did not differ significantly on cognitive outcome from patients who showed below expected mental status scores preoperatively.

Discussion

This study of 42 patients with advanced Parkinson's disease who underwent preoperative, 3 month post-PVP, and 12 month post-PVP evaluations is the largest long term follow up study of cognitive outcome after PVP reported to date. While in the off state, all patients showed significant improvements in motor symptoms 3 months post-PVP, with these improvements being maintained by 95% of the patients for up to 1 year after surgery. These motor improvements were achieved while maintaining patients on essentially the same levodopa dosage as before PVP. Therefore, the motor and cognitive changes after the surgery are not likely attributable to increases in medication regimens. The neuropsychological testing was conducted during the patient's best on state to optimise patient performance and to allow for completion of the neuropsychological testing battery. Consequently, conclusions drawn from the results cannot be generalised to a patient's cognitive performance during the off state.

SUMMARY OF NEUROPSYCHOLOGICAL IMPROVEMENTS

Patients with right or left PVP showed significant improvements in confrontational naming and visuospatial organisation up to 1 year after PVP. Executive functioning tasks produced an inconsistent trend toward improvement 12 months after PVP. Whereas performance did not change over time on trails B, patients were better able to resist interference from competing stimuli on the Stroop test and made fewer errors on a task of hypothesis generation. It is difficult to determine the clinical significance of these improvements without a clear consensus of the influence of practice on these measures. Consistent with previous reports, patients reported lower levels of depressive symptoms after surgery.9 11 Patients reported minimal levels of depressive symptoms after PVP, which was an improvement from the mild symptoms they reported before surgery.

SUMMARY OF NEUROPSYCHOLOGICAL DECLINES

Our patients showed a transient decline in learning verbal material 3 months post-PVP, with this deficit returning to baseline scores by the 12 month evaluation. This finding of cognitive decline after unilateral PVP is generally consistent with previous reports of neuropsychological outcome after PVP.11 12 The finding of transient declines in learning verbal material may be clinically significant to patients after PVP. Memory compensation techniques (for example, memory journals, computerised medication prompts) may be initiated before surgery to prepare patients for these transient memory problems after surgery.

The analyses were run excluding the two patients with a previous neurosurgical history and the three patients with adverse events after surgery. When the two patients who had had a previous neurosurgical procedure were excluded from the analyses, the findings did not change. Thus, these patients were included in the current analyses. When three patients who had adverse events on postoperative imaging studies were excluded from the analysis, a decline in verbal fluency performance after PVP was not found to be significant. This finding suggests that larger lesions that may have encroached on adjacent structures (for example, internal capsule, putamen) may affect cognitive outcome after PVP. Patients with satisfactory lesion placement and without adverse events on postoperative imaging studies did not show a decline in verbal fluency after PVP. When Baron et alexcluded the data from two patients with small frontal subdural haematomas, none of their neuropsychological variables showed a significant change at 3 or 12 months post-PVP.8 Our current findings, along with those of Baron et al, highlight the need to investigate the relation between the specific nuclei and fibre bundles interrupted after PVP and cognitive outcome.8

Our results differ from previous reports in that the expected hemisphere-specific decline in verbal fluency for patients with left PVP compared with patients with right PVP was not found in the present study. Verbal fluency has been shown in patients with head injury to have high sensitivity to frontal lobe damage regardless of the side of lesion.37 The overall lack of hemisphere-specific cognitive changes in a patient population of adequate size to detect differences suggests that cognitive deficits after PVP may be due to changes in the basal ganglia thalamocortical circuitry regardless of the side of lesion placement. However, the lack of findings may also be due to limitations in the scope of the test battery. Future long term outcome research utilising more comprehensive neuropsychological test batteries with repeated measures multivariate analyses is needed to replicate and validate the current findings.

The vast literature on the dissociation in performance between verbal fluency and confrontational naming allows for further investigation of the cognitive processes that may be negatively affected by PVP. When the total sample was included in the analyses, the current study found a significant decline in verbal fluency and a significant improvement in confrontational naming 12 months post-PVP. Firstly, this dissociation suggests that the decline in verbal fluency is not likely due to word finding difficulties, which the BNT often shows.38 39 Secondly, Huff argued that a dissociation between these tasks may be due to the automatic processing required by the BNT compared with the effortful processing required by the verbal fluency task.40 Thirdly, Margolin et al argued that the tasks differ in the type of verbal processing that is required, with a decline in verbal fluency suggesting phonological processing dysfunction, rather than semantic processing, which is required by the naming task.41 Fourthly, the verbal fluency task emphasises response speed whereas the naming task is not timed, suggesting that the dissociation is related to general information processing speed abilities. Fifthly, whereas verbal fluency has been shown to be sensitive to frontal lobe damage and mental flexibility impairment, naming is dependent on frontal and temporal lobe functioning and memory retrieval.42 43 Declines in verbal fluency after PVP may be due to failures in several cognitive areas including effortful processing, lexical processing, general speed of information processing, and mental flexibility.44 45The total number of words generated from the verbal fluency task (the current measure of analysis) does not provide information on these specific underlying components of the task. Future research into these components, including semantic versus lexical processing, timed versus untimed responding, and clustering (for example, generating words within subcategories) versus switching (shifting between subcategories), may lead to a clearer understanding of the specific cognitive processes affected by PVP.46

Patients with severe versus mild to moderate preoperative motor impairment and those with impaired versus intact preoperative mental status were investigated separately to further clarify the efficacy of PVP for subgroups of patients with Parkinson's disease. With the exception of a transient decline in verbal learning performance at 3 months post-PVP, patients with severe motor impairment did not differ on cognitive outcome from patients with less severe preoperative motor impairment. Likewise and consistent with the findings of Riordanet al patients with impaired preoperative mental status did not differ on cognitive outcome from patients with intact mental status.11 Patients with varying motor symptom severity and mental status received equal benefit from PVP with minimal changes in cognitive outcome. It has been stated that “dementia is widely accepted as a contraindication” for PVP.14 We think that patients with mild to moderate dementia with MMSE scores above 20 should not be denied surgery automatically. Patients with more severe dementia, on the other hand, are not suitable candidates for surgery as they might not gain sufficient benefit in daily activities even though their motor symptoms might be improved. Future research considering the utility of preoperative cognitive status as an exclusion criterion for PVP is needed for a consensus to be reached.

Our investigation attempted to address several methodological limitations present in published reports of the neuropsychological outcome after PVP, including sample size, follow up periods, attrition rates, and practice effects, as well as to correlate accurate placement of the lesion and the presence of additional adverse events on postoperative imaging studies with outcome. By contrast with several preliminary reports, the present study investigated a large sample of patients who each received two follow up evaluations; thus allowing for the use of repeated measures multivariate statistical analysis to assess significant differences over time and between right and left PVP.8 10 15 Furthermore, the current 12 month follow up evaluation of cognitive outcome was based on an adequate sample size to draw more definite conclusions regarding the long-term efficacy of the surgery.

The reporting of rates of attrition in the sample, along with the differences between the study participants and those patients who were lost to follow up, aids in describing the sample and allows for more specific comparisons across sites. To date, attrition rates have not been considered in the pallidotomy literature. The moderate attrition in the current sample points out the main limitation of the study and highlights the need to report rates of attrition in future studies. Further analysis showed that most of those patients who were lost to follow up were restricted by long travel distances and elected to receive follow up evaluations closer to home. The significant differences found between the study participants and those who dropped out may pose a threat to the external validity of the study. Whereas study participants did not differ presurgically from those who dropped out either with motor problems or in their ability to perform ADLs while in the off state, study participants were significantly less impaired in motor function and more able to perform ADLs independently while on than those who did not return for both follow up evaluations. Thus, the interpretation of the current findings may be limited to patients who demonstrate distinct on and off states, with mild to moderate impairments while on and more severe impairments while in the off state. The presurgical differences between the study participants and those who dropped out may become more salient after surgery; therefore, home visits may need to be implemented to obtain follow up data on a larger number of patients and to help reduce attrition rates.

Cognitive improvements were found for several tasks in which alternate forms were not available, raising the question of the role of practice effects on outcome. However, some of these measures have been shown to be relatively resistant to the effects of practice. The Hooper test and the BNT have high test-retest reliabilities without a significant shift in scores after repeated administrations (Hooper, 0.86; BNT,0.94).45 47 Although experience with the Stroop test does affect performance, this executive functioning measure is more resistant to practice effects than the WCST, which has a specific, easily conceptualised solution.48 49 However, the Stroop test requires a timed verbal response; therefore, an improvement in performance may be in part secondary to the marked motor improvement seen after surgery. The SDMT and trails A and B, which are tests with a prominent motor component, failed to show the expected improvement with practice, which may be evidence of a negative outcome. On the other hand, rather than showing the expected practice effects on the COWAT, patients showed a decline in verbal fluency performance, suggesting that the main effect of time on COWAT scores may have been underestimated in our study. Although the effects of practice cannot be ruled out in the current study, it is unlikely that the demonstrated cognitive improvements after PVP are due entirely to previous experience with the measures. Alternative methods for contending with practice effects in serial assessment, such as non-surgical comparison groups and statistical methods (for example, growth curves and change scores), need to be employed.

Due to the lack of a non-surgical comparison group, we were unable to consider the role of cognitive decline as a component of the natural course of Parkinson's disease after PVP. With prevalence estimates of dementia ranging from 10% to 40% in patients with Parkinson's disease, PVP superimposes an intervention on a progressive and highly variable disease.50-52 To determine the proportion of changes after PVP that are related exclusively to the surgery and those that are related to natural cognitive decline due to the progressive nature of the disease, a systematic study including a non-surgical comparison group and a more comprehensive neuropsychological battery would be an invaluable addition to the literature.

Nonetheless, the current findings suggest that male and female patients with right or left PVP with varying preoperative mental status and motor symptom severity receive equal benefit from PVP for up to 1 year after surgery. Although three patients showed subtle cognitive decline subsequent to postoperative adverse events, these patients received considerable motor benefit from the surgery allowing them more independence in their ability to perform ADLs. In the largest long term follow up study of PVP reported to date, the cognitive changes after unilateral PVP are minimal compared with the robust improvements seen in motor function.