Brain, Vol. 122, No. 12, 2209-2220,
December 1999
© 1999 Oxford University Press
Review article |
Neuropsychological outcome following unilateral pallidotomy
Baylor College of Medicine, Department of Neurosurgery, Houston, Texas, USA
Correspondence to:
Michele K. York, Baylor College of Medicine, Department of Neurosurgery, 6560 Fannin, Suite 944, Houston, TX 77030, USA E-mail: myork{at}bcm.tmc.edu
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Abstract |
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Despite the findings of significantly improved motor functioning following pallidotomy for the treatment of Parkinson's disease, the cognitive sequelae following surgery have yet to be clearly defined. With increasing knowledge of the surgery's effect on frontostriatal circuits, the cognitive processes potentially affected by the procedure require further exploration to evaluate fully the efficacy of the treatment. We reviewed 10 studies on the neuropsychological outcome after pallidotomy that were published in peer-reviewed journals. A general agreement exists that pallidotomy is a relatively safe and effective treatment for ameliorating the motor symptoms of Parkinson's disease, with relatively few cognitive changes reported following surgery. However, a number of conceptual and methodological concerns, including diverse selection criteria, small sample sizes and short follow-up periods, limit the interpretation and generalizability of these findings. These concerns are discussed in detail, along with a summary of the current neuropsychological literature, suggested guidelines for the conduct of research and future research directions. The neuropsychological findings are critically reviewed and tabulated by study, cognitive domain and follow-up period, with particular emphasis on hemisphere-specific cognitive changes.
Parkinson's disease; neuropsychology; outcome; pallidotomy; cognition
GPi = internal portion of the globus pallidus; H and Y = Hoehn and Yahr; UPDRS = Unified Parkinson's Disease Rating Scale
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Introduction |
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TopAbstractIntroductionEvaluating cognition following...Neuropsychological outcome...Methodological issuesReferences |
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Technical advances in stereotactic pallidotomy for the treatment of Parkinson's disease have led to well-documented reductions in dyskinesias, particularly in patients with decreased response to levodopa therapy (Dogali et al., 1995
; Lozano et al., 1995; Fazzini et al., 1997; Kishore et al., 1997; Kopyov et al., 1997; Lang et al., 1997). Moreover, improvements in the ability of patients to perform activities of daily living during both `on' and `off' periods have been reported consistently following pallidal surgery (Kopyov et al., 1997; Lang et al., 1997). However, the cognitive sequelae following pallidotomy in patients with Parkinson's disease have yet to be clearly defined, and in fact the neuropsychological outcome studies that have been conducted have produced inconsistent results. With ~75 centres in the USA performing pallidotomies at present, it is essential to clarify the cognitive consequences of the procedure and to develop more uniform guidelines for the neuropsychological evaluation of patients undergoing this procedure.
The objective of this review is to critically analyse and synthesize the current literature on neuropsychological outcome following pallidotomy in patients with Parkinson's disease. Several researchers (Jacques et al., 1998; Starr et al., 1998) have argued that comparing contemporary pallidotomy series with earlier pallidotomy series is difficult due to recent refinements in lesioning techniques, the widespread use of microelectrode stimulation and recording in later series to locate the target more precisely, and a change from the dorsal to the ventral pallidum as the preferred lesion site. Consequently, this review is confined to the neuropsychological literature published after the sentinel article of Laitinen and colleagues that proposed the posteroventral globus pallidus as the most effective site for the amelioration of motor symptoms in patients with Parkinson's disease (Laitinen et al., 1992). Additionally, the review will be limited to published peer-reviewed articles in English. Consequently, abstracts and book chapters are not included in this review. Furthermore, articles in which cognitive findings are reported without documentation of the specific neuropsychological measures used are not included. Lastly, it is outside the scope of this paper to assess or compare the neurological criteria for patient inclusion, the neurophysiological methodology for target selection or the neurosurgical lesioning techniques. However, several of these aspects may be briefly addressed in order to suggest potential explanations for inconsistencies in the current neuropsychological literature.
The specific aims of this review are to (i) describe briefly the mechanism of the pallidotomy procedure and its implications for evaluating cognition in pallidotomy patients; (ii) summarize the current neuropsychological literature by cognitive domain; (iii) critically analyse the limitations of the current literature in regard to research methodology and suggest ways that these limitations might be overcome; and (iv) propose future research directions and suggest guidelines for advancing the present state of knowledge regarding the neuropsychological consequences of pallidotomy.
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Evaluating cognition following pallidotomy |
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Cognitive decline in Parkinson's disease
Any assessment of cognitive function following pallidotomy needs to recognize that cognitive decline is often a major component of the natural course of Parkinson's disease. In a prospective study of Parkinson's disease patients, Jacobs and colleagues found that 21% of their initially non-demented Parkinson's disease subjects were diagnosed with dementia at follow-up evaluation (mean = 2.7 years, SD = 1.03) (Jacobs et al., 1995
). Although the prevalence of dementia in patients with Parkinson's disease continues to be debated, with estimates ranging from 10% to 40% (Lees and Smith, 1983; Brown and Marsden, 1984; Cummings, 1988; Taylor et al., 1985), the characteristics associated with cognitive decline and its progression in Parkinson's disease have been studied extensively using the Cox proportional hazards and regression models (Jacobs et al., 1995; Glatt et al., 1996; Katzen et al., 1998; Mahieux et al., 1998). In general, patients older than 75 years who have predominant bradykinesia, postural instability and/or gait difficulty, a later age of motor symptom onset, a more rapid progression of physical disability, a higher Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale score, less than a high school education, and who fail to respond adequately to dopamine therapy are more likely to become demented than are younger, more educated, early-onset Parkinson's disease patients with predominant tremor and less physical disability and who respond to levodopa therapy (Lieberman et al., 1979; Mortimer et al., 1982; Zetusky et al., 1985; Taylor et al., 1987; Mayeux et al., 1988; Glatt et al., 1996; Katzen et al., 1998; Mahieux et al., 1998). Pallidotomy has been shown to be most effective for patients with levodopa-induced dyskinesias, rigidity, mild tremor (Narabayashi, 1997) and `advanced' Parkinson's disease (severe symptoms during on and off states, and higher UPDRS scores; Hariz, 1999). These characteristics are similar to those associated with dementia in Parkinson's disease; therefore, patients selected for pallidotomy may be at greater risk for dementia compared with the larger population of Parkinson's disease patients.
It has been hypothesized that, when dementia occurs in Parkinson's disease, these cognitive changes are overlaid on specific parkinsonian-related cognitive impairments that already exist in non-demented Parkinson's disease patients. In general, non-demented Parkinson's disease patients demonstrate cognitive impairments in the areas of complex attentional processes, information processing speed, verbal fluency, motor aspects of speech, visuospatial orientation, visuospatial working memory, procedural memory, verbal and visual recent memory, memory retrieval strategies and frontal–striatal executive functioning (Mahurin et al., 1993). At the same time, Parkinson's disease patients show intact cognitive processes in the areas of primary attention, immediate memory, memory storage and consolidation, recognition memory and language comprehension (Mahurin et al., 1993). McFadden and colleagues found that demented Parkinson's disease patients demonstrate unique neuropsychological profiles compared with non-demented Parkinson's disease patients (McFadden et al., 1996), suggesting that the dementia associated with this disease results from a pathogenic process that is distinct from the ubiquitous, but generally mild, cognitive deficits seen in the majority of Parkinson's disease patients. A better understanding of the naturally occurring cognitive changes and dementia in patients with Parkinson's disease is needed in order to counsel patients better on the expected postoperative outcome and to assess pallidotomy-induced neuropsychological changes more accurately.
Medication effects
Levodopa is the most widely used drug for managing the motor symptoms of Parkinson's disease (Growden et al., 1998). The effects of levodopa on cognitive function remain controversial. Several studies of Parkinson's disease patients have associated levodopa therapy with subtle cognitive improvements in executive functioning (Growden et al., 1998), effortful memory processes (Newman et al., 1984), working memory (Cooper et al., 1992), choice reaction time (Pullman et al., 1988) and vigilance (Bowen et al., 1975). Other studies, however, have associated the use of levodopa with declines in memory (Huber et al., 1989), executive functioning (Gotham et al., 1988) and cognitive processing speed (Prasher and Findley, 1991). Other studies have reported that levodopa therapy improves motor function without affecting cognitive performance (Pillon et al., 1989b; Growden et al., 1998). In general, longitudinal studies of the effects of levodopa have found that, following an initial mild improvement, cognitive performance gradually declines to pretreatment levels (Riklan et al., 1976; Portin and Rinne, 1980, 1987). Because pallidotomy patients often require lower doses of levodopa postoperatively, the potential effects of decreased levodopa on cognition should be considered in assessing postoperative neuropsychological change.
The motor symptoms of Parkinson's disease caused by dopamine depletion are generally thought to be disassociable from cognitive functions and psychiatric status (Pillon et al., 1989a, b), suggesting that the motor and cognitive deficits of Parkinson's disease are based on different neuropathological substrates. Research suggests that the cognitive impairment observed in Parkinson's disease patients may be in part dependent on dysfunction of the non-dopaminergic circuitry. Cooper and colleagues have suggested that the dopaminergic and cholinergic systems are both involved in cognitive decline in Parkinson's disease (Cooper et al., 1991). Treatment with anticholinergic drugs, for example, can lead to incidents of confusion (de Smet et al., 1982) and memory loss (Sadeh et al., 1982; Dubois et al., 1987) in Parkinson's disease patients, and poor performance on various verbal and visual immediate recall memory measures is exacerbated by anticholinergic treatment (Cooper et al., 1992). Clearly, medications have an effect on cognitive performance, and any postoperative changes in medication need to be acknowledged when evaluating cognitive changes following pallidotomy.
Surgical mechanism
Pallidotomy attempts to interrupt the neural circuitry believed to be responsible for the abnormally patterned motor activity in Parkinson's disease. The basal ganglia-thalamocortical motor circuit is thought to be responsible for hypokinetic and hyperkinetic states depending on the specific neural pathways involved (Starr et al., 1998). The rigidity and bradykinesia of Parkinson's disease are thought to be caused by excessive inhibitory outflow from the internal section of the globus pallidus (GPi), the major efferents of which terminate in the ventrolateral and ventroanterior nuclei of the thalamus, which in turn project to the premotor and prefrontal cortices (Starr et al., 1998). Destruction of a portion of the GPi is thought to reduce abnormal motor patterns by freeing efferent targets from the excessive inhibitory neural activity, thus restoring more normal thalamocortical activity and improving motor functioning.
Although the GPi is primarily involved in sensorimotor activity, lesioning of this area may also lead to cognitive changes. Other axons that pass through the globus pallidus and their associated targets, other efferent targets of the globus pallidus, and/or other pathways of the basal ganglia-thalamocortical motor circuit might also be affected by the ablative surgery. In addition, differences in lesion placement and size may lead to varied results in both motor functioning and cognitive outcome. Table 1 shows some of the neurosurgical factors reported in the current neuropsychological literature, including lesion size, lesion location, targeting method, and whether or not the lesions were verified postoperatively using neuroimaging. Green and Barnhart (1999) hypothesized that impingement of the lesion into more anterior or external portions of the globus pallidus may account for some of the subtle, transient neuropsychological deficits reported in the current neuropsychological literature. The studies included in this review that verified the lesion site using neuroimaging (Table 1) reported numerous lesions that were not confined to the GPi (Baron et al., 1996; Cahn et al., 1998; Scott et al., 1998; Trepanier et al., 1998). This finding suggests that at least some of the inconsistencies found in the neuropsychological literature may be due to differences in lesion placement or size. Consequently, more precise postoperative information, including lesion verification using neuroimaging, on the size and location of the pallidal lesion is necessary to select appropriate neuropsychological measures and to evaluate accurately the cognitive outcome of pallidotomy.
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Strategy of neuropsychological assessment
The selection of measures to evaluate the neuropsychological outcome in patients with Parkinson's disease who undergo pallidotomy is currently being debated. Scott and colleagues have argued that, due to the limited research on cognitive effects of pallidotomy, the neuropsychological test battery should screen all major domains of cognitive function (Scott et al., 1998
). On the other hand, Trepanier and colleagues have argued that the neuropsychological test battery should focus on the cognitive functions believed to be involved in Parkinson's disease and/or potentially affected by pallidotomy (Trepanier et al., 1998). Their argument is derived from a hypothesis-testing approach that advocates selecting tests designed to evaluate the underlying mechanism rather than choosing more global tests selected from the traditional clinical neuropsychological literature. With increasing knowledge of the neurological mechanism of the pallidotomy procedure, a more specific hypothesis-testing approach may be preferred for choosing a neuropsychological test battery for this population. Due to the profuse connections from the GPi to the thalamus and then to the prefrontal cortex, tests designed to measure cognition related to prefrontal and frontal cortical functioning, such as verbal fluency, working memory and planning/sequencing, may particularly advance our present state of knowledge in this area. |
Neuropsychological outcome findings |
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Although the number of articles investigating the neuropsychological effects of pallidotomy has increased steadily per year over the past 5 years, a consistent pattern of cognitive findings following pallidotomy has not been identified. Recent studies have reported significant changes in cognitive functioning postoperatively, particularly when lesion laterality is taken into account. Variability in outcome measures, length of follow-up and other methodological problems (see Methodological issues, below) complicates synthesis of the outcome studies. To structure this review, we have limited the neuropsychological findings depicted in Table 2
to statistically significant effects, and have summarized the findings across studies, measures, length of follow-up and cognitive domains. Significant neuropsychological findings are discussed below according to cognitive domain.
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Motor function
Assessments of motor function in Parkinson's disease patients are routinely conducted by neurologists using the UPDRS motor subscale, a dyskinesia evaluation, and several simple timed motor tasks such as finger-tapping and grooved pegboard tests. In general, studies of motor function have found significant and stable improvements in the cardinal motor symptoms of Parkinson's disease, i.e. dyskinesias, rigidity, tremor and bradykinesia (Lozano et al., 1995
, 1998; Dogali et al., 1995; Fazzini et al., 1997; Kishore et al., 1997; Kopyov et al., 1997; Lang et al., 1997; Desaloms et al., 1998; Jankovic et al., 1999; Kondziolka et al., 1999). Although the majority of neuropsychological studies that included timed motor tasks studies reported similar motor improvements following pallidotomy (Soukup et al., 1997; Uitti et al., 1997; Cahn et al., 1998), several studies have also reported motor weakness, as measured by grip strength, in the hand contralateral to surgery (Riordan et al., 1997; Cahn et al., 1998).
Mental status
Traditional and expanded measures of mental status have not revealed a consistent pattern of change following pallidotomy. Yokoyama and colleagues found a transient decline in orientation on the Mini-Mental Status Examination 1 month after pallidotomy for right pallidotomy patients (Yokoyama et al., 1999). Furthermore, in a pilot study, Baron and colleagues reported a decline in the Memory and Initiation/Perseveration subscales of the Mattis Dementia Rating Scale between the preoperative assessment and the 1-year follow-up (Baron et al., 1996). However, these subscale scores did not decline significantly between the presurgical assessment and the initial postoperative evaluation, and did not reach significance when two patients with postoperative frontal subdural haematomas were excluded from the analysis. Thus, the reported decline may have been due to natural disease progression or to postoperative complications. As noted earlier, the natural progression of cognitive decline in Parkinson's disease should be taken into account when assessing the efficacy of pallidotomy; however, low scores on brief mental status examinations are not an entirely satisfactory method of diagnosing or tracking dementia in Parkinson's disease.
Attention/information processing
Performance on measures of attention and information processing following pallidotomy depends on the specific outcome measures tested and the length of follow-up (Baron et al., 1996; Uitti et al., 1997; Cahn et al., 1998; Trepanier et al., 1998). The findings for digit span (i.e. repetition of increasingly longer number sequences in the forward and backward directions) were inconsistent, particularly in the backward condition. Findings ranged from no change to a mild improvement between the preoperative and 3-month evaluations to a mild decline between the preoperative and 6-month evaluations (Baron et al., 1996; Trepanier et al., 1998; Yokoyama et al., 1999). Although performance on the digit symbol test (i.e. timed transcription of numbers) improved in two studies between the preoperative and the 3-month follow-up evaluations (Uitti et al., 1997; Cahn et al., 1998), this improvement did not remain significant at longer follow-up periods (Riordan et al., 1997; Perrine et al., 1998). Neuropsychological measures that impose more complex information processing demands (i.e. the Paced Auditory Serial Addition Test, the Stroop Color–Word Test and the Trail Making Test, Part B) did not reveal a consistent pattern of change at any of the postoperative evaluations (Riordan et al., 1997; Trepanier et al., 1998). Because of the heavy reliance on timed responses for the measures testing attention/information processing, the inconsistencies in the findings for this cognitive domain may be explained partly by the influence of both practice and medication effects. Measures of attention that do not rely heavily on timed responses may need to be developed to evaluate this cognitive domain in Parkinson's disease patients more accurately.
Language
Significantly decreased verbal fluency (i.e. word generation from a specified letter) was one of the more consistent findings across studies carried out 3 months postsurgery, particularly in patients who had undergone a left-sided pallidotomy (Riordan et al., 1997; Uitti et al., 1997; Cahn et al., 1998; Trepanier et al., 1998). This finding was also consistent across the few studies that investigated performance 6 months postsurgery (Riordan et al., 1997; Trepanier et al., 1998). Nonetheless, although Trepanier and colleagues found a significant decline in verbal fluency between the preoperative baseline and various time points up to 6 months (Trepanier et al., 1998), this decline did not remain significant at 12 months, suggesting that the verbal fluency deficit may be transient. Although tests of semantic fluency demonstrated a similar decline between the preoperative scores and the scores 6 months postsurgery (Riordan et al., 1997; Masterman et al., 1998), the findings between the baseline and the 3-month postsurgery scores were not consistent across studies (Uitti et al., 1997; Soukup et al., 1997; Cahn et al., 1998; Scott et al., 1998; Trepanier et al., 1998; Yokoyama et al., 1999). Further long-term outcome research is needed to examine the stability of these changes in verbal fluency. Confrontational naming does not appear to be affected significantly by pallidotomy during the first postoperative year (Baron et al., 1996; Riordan et al., 1997; Soukup et al., 1997; Uitti et al., 1997; Cahn et al., 1998; Masterman et al., 1998; Scott et al., 1998).
Memory
Postpallidotomy changes in verbal and visual memory performance are dependent on the side of the surgery (Baron et al., 1996; Riordan et al., 1997; Trepanier et al., 1998). Some evidence exists for a decline in spatial memory performance 3 months after a right pallidotomy (Riordan et al., 1997; Trepanier et al., 1998), with improvement in baseline levels of performance 12 months postsurgery (Trepanier et al., 1998). In individuals who underwent left-sided surgery, verbal learning of word lists and prose passages was worse at the 3-month and 6-month follow-up assessments than at the preoperative testing session (Riordan et al., 1997; Trepanier et al., 1998), and this pattern did not resolve to baseline by the 12-month follow-up. Conversely, a pattern of improved verbal memory was found for right-sided pallidotomy patients ~3–6 months after surgery (Trepanier et al., 1998), with a trend for improvement in verbal learning for the 12-month follow-up. Due to the small sample sizes (11 right and 7 left), caution should be used when interpreting the hemisphere-specific findings at the 12-month follow-up evaluation. Further evaluation of both the short-term and long-term effects of pallidotomy on specific aspects of memory (e.g. recognition, working and procedural memory) is needed to clarify these results.
Visuospatial performance
Riordan and colleagues observed a significant decline in Wechsler Adult Intelligence Scale—Revised Block Design scores ~4.5 months postsurgery for patients who underwent a right-sided pallidotomy (Riordan et al., 1997). Overall, assessment of visuospatial functioning using a wide variety of traditional visuoperceptual measures has revealed few significant changes in performance following pallidotomy (Baron et al., 1996; Perrine et al., 1998).
Executive functioning
Although the mechanism of pallidotomy suggests an interruption in the frontostriatal neural circuits, very few thorough investigations of executive functioning have been conducted. Yokoyama and colleagues reported a transient decline in serial sevens for left pallidotomy patients 1 month after surgery (Yokoyama et al., 1999). The majority of the studies in this review included at least one measure of higher cognitive function, generally the Wisconsin Card Sorting Test (Baron et al., 1996; Riordan et al., 1997; Uitti et al., 1997; Masterman et al., 1998; Perrine et al., 1998; Trepanier et al., 1998). These studies did not reveal significant changes in executive functioning following pallidotomy. However, the Wisconsin Card Sorting Test has an easily conceptualized solution and is influenced considerably by practice effects (see Methodological issues). Trepanier and colleagues, using the Spatial Conditional Associative Learning Test, which is thought to measure cognitive and behavioural processes dependent on the frontostriatal circuits, did not find direct evidence of executive functioning deficits (Trepanier et al., 1998). Nonetheless, these researchers reported evidence of a decline in executive function based on observed changes in `frontal' behaviour on the Frontal Lobe Personality Scale and clinical interview. These findings were supported by a decline on measures that indirectly test executive functioning, in particular Digit Span—Backwards, California Verbal Learning Test-encoding of trials 1–5, verbal fluency, and the Rey–Osterrieth planning score. Experimental measures may need to be designed or existing cognitive psychological measures may need to be modified in order to identify more subtly and accurately the changes in executive functioning caused by surgical interruption of the frontostriatal circuitry.
Mood
Evaluation of emotional functioning has revealed inconclusive evidence of improved mood following pallidotomy. Of the 10 neuropsychological studies reviewed, seven included at least one measure of mood. While two studies found significantly decreased depression following pallidotomy (Riordan et al., 1997; Masterman et al., 1998), the remaining five studies did not detect any significant changes in mood (Baron et al., 1996; Uitti et al., 1997; Cahn et al., 1998; Perrine et al., 1998; Scott et al., 1998; Trepanier et al., 1998). However, because ~40% of patients with Parkinson's disease suffer from depressive symptomatology (Menza and Mark, 1994), further investigation of the emotional functioning of pallidotomy patients is necessary not only to evaluate the contribution of depression to Parkinson's disease in general, but also to assess more accurately any gains in neuropsychological test scores attributable to improvements in mood following pallidal surgery.
Hemisphere-specific cognitive changes
Evidence for hemisphere-specific cognitive changes following pallidotomy has been documented in the current neuropsychological literature (Table 2
). Patients who have undergone a left pallidotomy demonstrate a disproportionately greater degree of cognitive impairment than do right pallidotomy patients, particularly in language processing and verbal learning (Riordan et al., 1997; Uitti et al., 1997; Cahn et al., 1998; Masterman et al., 1998; Trepanier et al., 1998; Yokoyama et al., 1999). Patients with a left pallidotomy were consistently impaired across studies on tests of verbal fluency and, to a lesser degree, category fluency. Verbal learning in patients with a left pallidotomy was observed to be impaired significantly 3 and 6 months postsurgery compared with preoperative levels (Baron et al., 1996; Riordan et al., 1997; Trepanier et al., 1998), with evidence of a return to baseline levels of performance by the 12-month follow-up. Although attention and information processing measures have shown a general trend towards improvement following pallidotomy surgery, Trepanier and colleagues reported a significant decline in digit span scores between the preoperative and the 6-month follow-up evaluation for left-sided pallidotomy patients (Trepanier et al., 1998). Several authors have suggested that the subtle cognitive deficits associated with left pallidotomy were transient findings associated with frontal lobe dysfunction (Green and Barnhart, 1999; Yokoyama et al., 1999). Green and Barnhart hypothesized that the cognitive decline observed following left pallidotomy may be due to encroachment of the lesion into non-motor circuits of the globus pallidus (Green and Barnhart, 1999).
One might expect disruption of the neural circuitry at the level of the left pallidum to yield a consistent pattern of communicative dysfunction, similar to the subcortical aphasia syndrome demonstrated with thalamic lesions. However, lesions in the left globus pallidus have failed to produce reliably speech and language dysfunction other than reduced verbal fluency. Some left pallidum-lesioned patients, for example, have demonstrated either fluent or non-fluent and transient or persistent language deficits consistent with both Broca's and transcortical motor aphasia, whereas others have developed dysarthric speech without significant language impairment (Crosson, 1985; Robin and Schienberg, 1990). Some authors have argued that language and cognitive functions depend on the integrity of the neural circuitry of the pallidum (Damasio, 1983; Lieberman et al., 1986), whereas more recently Nadeau and Crosson have argued that the basal ganglia do not play a direct role in language formulation, but rather regulate the selection and timely release of language segments (Nadeau and Crosson, 1997). Clearly, the involvement of the left globus pallidus in language function, along with other cognitive domains, deserves further exploration. Moreover, this debate underscores the overwhelming need for knowledge regarding the complex neurophysiology of the basal ganglia and their role in psychomotor and cognitive functioning.
Patients who have undergone a right pallidotomy have demonstrated disproportionate declines on measures of visual memory and visuospatial processing compared with left pallidotomy patients (Riordan et al., 1997; Trepanier et al., 1998). However, these cognitive areas are under-represented in the current pallidotomy literature and further research regarding the processing and retention of visual material following right pallidotomy is needed for corroboration. The published literature is inconsistent concerning verbal learning and information processing speed following right pallidotomy. Several studies have observed subtle declines in verbal memory performance in patients who have undergone a right pallidotomy. However, Trepanier and colleagues reported a significant improvement in verbal learning performance between the preoperative and postoperative evaluations in patients with a right-sided lesion (Trepanier et al., 1998). Riordan and colleagues found a significant performance decline in right pallidotomy patients on a task that required complex information processing abilities and set shifting (Riordan et al., 1997); however, this finding was not confirmed by several other studies (Baron et al., 1996; Soukup et al., 1997; Uitti et al., 1997; Cahn et al., 1998; Masterman et al., 1998; Perrine et al., 1998).
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Methodological issues |
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In evaluating studies for potential inclusion in this review, it became increasingly apparent that the usefulness of many of the studies was limited by their failure to report sufficient information to allow interstudy comparisons, and by various methodological concerns. Of particular methodological concern when conducting serial neuropsychological assessments with pallidotomy patients are practice effects, follow-up periods, attrition, statistical power, selection criteria and examiner effects. Each of these methodological issues and suggested alternative solutions will be discussed in turn.
Patient selection criteria
Patient selection criteria for pallidotomy vary widely among different centres (Table 1). First, the diagnostic criteria for Parkinson's disease differ among studies. De Rijk and colleagues compared eight sets of diagnostic criteria for Parkinson's disease (all included cardinal signs of Parkinson's disease, while some had additional requirements related to duration of symptoms, asymmetry of signs or response to medication) and concluded that the choice of diagnostic criteria affects research results (de Rijk et al., 1997). Secondly, not only do the selection criteria for pallidotomy differ among studies, but also many studies fail to report the specific neurological inclusion criteria used to select patients for surgery (Soukup et al., 1997; Uitti et al., 1997, Yokoyama et al., 1999). Although Hoehn and Yahr (H and Y) staging scores for Parkinson's disease are often used to describe symptom severity and to help select subjects for surgery, these scores have not been reported consistently in the neuropsychological literature (Perrine et al., 1998), and the threshold score for inclusion has not been consistent across studies (H and Y score 
3 off medication: Baron et al., 1996; score 2 off medication: Cahn et al., 1998; Soukup et al., 1997; score 1 off medication: Masterman et al., 1998; Scott et al., 1998). These inconsistencies, both in the choice of specific inclusion criteria and in the reporting of these criteria, complicate the comparison of patient characteristics and outcome across studies.
Exclusion criteria also vary widely across studies, limiting the generalizability of the findings. For example, studies have typically excluded older patients; however, the specific age at which patients are excluded varies widely across studies. Although several studies have included patients older than 75 years (age range 34–82 years: Masterman et al., 1998; age range 43–82 years: Soukup et al., 1997; age range 49–78 years: Uitti et al., 1997), Trepanier and colleagues excluded patients older than 75 years (Trepanier et al., 1987).
The presence of significant preoperative cognitive impairments on brief mental status examinations is another common exclusion criterion (Uitti et al., 1997; Perrine et al., 1998; Trepanier et al., 1998). According to Scott and colleagues, `dementia is widely accepted as a contraindication' for pallidotomy surgery (Scott et al., 1998). However, few studies have investigated patients with varying degrees of dementia at pre- and postoperative evaluations in order to address this issue adequately. Based on two patients with low scores preoperatively on the Mattis Dementia Rating scale, Baron and colleagues concluded that moderate to severe dementia may be associated with poor surgical outcome (Baron et al., 1996). Similarly, Masterman and colleagues noted that their two patients with a borderline preoperative cognitive performance demonstrated a significant cognitive decline postoperatively (Masterman et al., 1998). On the other hand, Riordan and colleagues have challenged the premise that dementia should be used as an exclusion criterion (Riordan et al., 1997). They did not find a significant relationship between preoperative cognitive performance and neuropsychological outcome, even though one-third of their patients demonstrated moderate to severe preoperative cognitive impairment. These authors argue that excluding patients based on dementia-screening batteries may result in unrepresentative samples and that there may be a potential selection bias if only patients without comorbidities are offered the surgery. No clear consensus has been reached on the utility of dementia as an exclusion criterion and on the appropriate threshold measure for exclusion.
Sample size, power and attrition
Due to a lack of reported power analyses in the pallidotomy literature, uncertainty remains as to whether the studies were convincing beyond reasonable doubt. Small sample sizes, particularly studies with 
20 subjects, result in low power and a greater chance of not detecting a significant difference (Kraemer and Thieman, 1987). Moreover, administering large neuropsychological batteries to a small sample increases the risk of a type II error dramatically. Although a few studies have used Bonferroni correction to control for error, the majority of the neuropsychological studies to date have not addressed the issue of small sample size and its effect on statistical power. Studies with larger samples and power analyses are needed to address this issue adequately.
Serial studies must also contend with the effect of attrition on statistical power. Attrition is inevitable in serial assessment research, particularly in a medically ill population. Many studies to date have not reported attrition rates for their samples, nor have they commented on the demographic differences between the respondents and those who were lost to follow-up to adjust for potential biases (Collins and Horn, 1991). Because some erosion of sample size is expected in neuropsychological outcome studies following pallidotomy, investigators should design their studies for greater statistical power, as well as calculating the effects of subsequent attrition on the power of their studies (Lipsey, 1990).
Follow-up periods
The current neuropsychological literature on cognitive outcome after pallidotomy has reported relatively brief follow-up periods, only three studies reporting findings 1 year postsurgery (Baron et al., 1996; Perrine et al., 1998; Trepanier et al., 1998). In the longest follow-up evaluation to date, Fazzini and colleagues followed 11 patients for up to 4 years; however, neuropsychological findings were not reported in this article (Fazzini et al., 1997). In addition to brief follow-up periods, the interpretation of the literature is complicated by investigators merging data from different follow-up periods to maximize sample size (Riordan et al., 1997; Perrine et al., 1998; Trepanier et al., 1998). This practice makes it difficult to compare findings across studies and to assess changes across time. Further exploration of the long-term effects of pallidotomy surgery in Parkinson's disease and of the patterns of change over time are needed in order to track the cognitive consequences of the surgery effectively.
Examiner effects
Another methodological concern is the effect that the examiner may have on the outcome when the examiner is not blinded to patient status. As an alternative to blinding, which may be impracticable, Soukup and colleagues have suggested the use of computerized testing to minimize the effects of non-blinded examiners on outcome (Soukup et al., 1997).
Practice effects
Test/retest evaluations raise the issue of practice. It is well documented that an overall pattern of improved performance on serial assessments may be demonstrated as a function of task familiarity, especially with short test-retest intervals (Lezak, 1995). Practice effects may mask subtle cognitive deficits secondary to pallidotomy or may result in spurious cognitive improvements. Several factors that are thought to mediate practice effects require consideration when conducting multiple assessments. One such factor is task selection. Practice effects are task-specific, with tests such as vocabulary, abstract reasoning, naming and oral fluency showing a less pronounced effect than timed tasks and those tasks with a specific, easily conceptualized solution (Quereshi, 1968; Dodrill and Troupin, 1975). The subject's age and intelligence are also mediating factors in the role that practice effects play in cognitive performance (Matarazzo et al., 1980; Shatz, 1981; Rapport et al., 1997).
The most commonly used approach for mitigating practice effects in serial neuropsychological assessments is the use of normed and counterbalanced alternative forms. Several pallidotomy studies have included alternative forms of neuropsychological measures in their test protocols, while acknowledging that the remaining tests were also susceptible to practice effects (Scott et al., 1998; Trepanier et al., 1998). Although alternative forms are in widespread use, this approach is not an entirely satisfactory answer to this methodological concern (Soukup et al., 1997). First, the usefulness of the approach is restricted by the limited availability of psychometrically sound alternative forms for many of the traditional neuropsychological measures. Secondly, parallel forms of neuropsychological measures may not be equivalent in level of difficulty. For example, Hannay and Levin demonstrated that one alternative form of the Buschke Selective Reminding Test is more difficult than another, even when the parallel forms were matched on word frequency (Hannay and Levin, 1985). Thirdly, parallel forms do not address the potential gains that may be attributed to general learning or to improved test sophistication.
Consequently, alternative methods for contending with practice effects in serial assessments may need to be employed, including the use of a non-surgical comparison group, multiple baseline assessments, change scores and growth curves. Perrine and colleagues conducted the first reported study to use an unoperated group of Parkinson's disease patients as a comparison group in an attempt to control for confounding factors and practice effects (Perrine et al., 1998). However, recruitment of unoperated or surgical waiting list control subjects presents a logistical limitation that is inherent in this approach. The pallidotomy group of Perrine and colleagues received more frequent follow-up evaluations and overall had a longer mean follow-up period than the unoperated group (Perrine et al., 1998); therefore, the length of time between the baseline and follow-up testing had to be included as a covariate in the analyses. Additionally, the selection bias of the patients in a control group composed of patients who chose not to undergo surgery or who were not considered surgical candidates presents a second limitation of this approach. Although researchers can statistically correct for differences in numerous demographic and medical factors between control and experimental groups, biases due to selection cannot be fully addressed statistically.
The use of multiple baseline assessments has been proposed as another method of reducing the influence of practice effects on test scores after pallidotomy. General learning effects are most pronounced between the initial and the second assessment (Hannay and Levin, 1985). Thus, obtaining multiple baseline scores would allow a stable baseline to be reached before the surgical intervention was introduced, and would mitigate the pronounced learning effect of the first assessment on subsequent testing (Hersen and Barlow, 1976). However, this approach may not be practicable for many researcher/practitioners.
The use of change scores, growth curves/recovery curves, generalized estimating equations and other statistical methods to reduce practice effects is becoming more widespread. Change scores, which are conceptualized as difference scores between pre- and post-test assessments for a given patient, have gained popularity with the increased interest in outcome studies. Riordan and colleagues used difference scores to analyse change in neuropsychological summary scale scores and functional activities of daily living scores over time in a pallidotomy population (Riordan et al., 1997). However, caution must be used when comparing and interpreting the meaning of change scores because of differences in base rates and reliabilities of measures.
With the development of hierarchical linear modelling, growth curves have become an interesting approach to studying change over time and potentially to addressing the issue of practice effects. Growth curves can be applied to estimate a mean growth curve, while taking into account individual variations in growth trajectories, including the progression of Parkinson's disease. However, growth curves cannot be generated from simple preoperative/postoperative test designs, as a minimum of three to four postoperative assessments are necessary (Bryk and Raudenbush, 1992). Green and Barnhart discussed the advantages of using generalized estimating equations, which account for correlations among repeated test scores for each patient, in pallidotomy patients (Green and Barnhart, 1999). These authors note that this statistical approach does not assume normally distributed data and is robust to unbalanced experimental designs.
Future research directions and suggested guidelines
Although several of the studies reviewed have addressed a number of the conceptual and methodological concerns noted herein, other studies have failed to acknowledge the potential role these factors may play in the neurobehavioural outcome. By addressing specific factors germane to the evaluation of cognition in Parkinson's disease and to methodological issues pertinent to conducting serial assessments, future studies should be able to delineate more clearly the neuropsychological outcome of the surgery and obtain more consistent findings.
When evaluating cognition following pallidotomy, future research needs to address: (i) the natural history of cognitive decline in Parkinson's disease and its potential effect on cognitive outcome following surgery; (ii) the effect of medication changes; and (iii) the selection of cognitive tests, including tasks designed to test specific cognitive functions believed to be affected by the surgical procedure. To the extent that current tests are inadequate, new tests may need to be designed.
In addition to these issues related to cognitive evaluation, several methodological issues need to be addressed and reported when conducting research with pallidotomy patients, including: (i) the diagnostic criteria for Parkinson's disease and the selection criteria for pallidotomy; (ii) the exclusion criteria; (iii) the characteristics of the sample, particularly the sample size, the lesion location and size, and the symptom severity and aetiology; and (iv) the detailed reporting of drugs and doses before and after surgery. When serial assessments are conducted, issues related to practice effects, follow-up periods, attrition and the use of comparison groups need to be addressed in addition to the reporting of power analyses and the use of blinded examiners.
Although the amount of research focused on the neuropsychological consequences of pallidotomy has increased steadily over the past 5 years, numerous questions require further investigation. The impact of lesion laterality on the neuropsychological outcome following pallidotomy has become widely accepted. Future research needs to focus on these hemisphere-specific cognitive changes and develop a priori hypotheses based on the surgical mechanism and the neurophysiology of the pallidum. Delineation of hemisphere-specific cognitive changes in consecutive bilateral pallidotomy patients may be able to add to our understanding of these mechanisms. More attention also needs to be directed towards the investigation of subgroups of Parkinson's disease patients. Parkinson's disease patients with dementia and depression may need to be investigated separately in order to understand better the impact of cognitive impairment and mood disorder on the surgical outcome. Multicentre investigations of unilateral and bilateral pallidotomy using Parkinson's disease comparison groups may be able to advance our understanding of the effects of this procedure on cognition by increasing sample sizes, by creating more standardized procedures across centres and by addressing the natural history of cognitive decline in Parkinson's disease.
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Acknowledgments |
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We wish to thank Dr Sharon Brown for her valuable advice on the manuscript. This work was supported in part by NIH Postdoctoral Medical Rehabilitation Research Training Grant HDO7465.
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Received April 12, 1999. Revised June 8, 1999. Accepted June 14, 1999.
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