On long-term follow-up, we found that Parkinson’s disease patients continued to receive motor benefit from unilateral pallidotomy; however, they demonstrated mild neurocognitive declines. Although the primary focus of this investigation was the cognitive outcome of unilateral pallidotomy, a thorough analysis of the cognitive outcome cannot be carried out without a description of the patients’ clinical motor functioning. Our findings of improved UPDRS scores in the "off" state and control of dyskinesias in the “on” state five years following unilateral pallidotomy are consistent with previously reported results with shorter follow-up periods. [4
] Our patients continued to experience significant clinical benefit from the surgery, particularly in regard to a dramatic reduction in their dyskinesias and improved ADL scores five years following unilateral pallidotomy. Overall, our motor outcome is consistent with the literature. [14
Whereas the patients retained motor benefit, mild neurocognitive declines were found on long-term follow-up, specifically in oral and motor information processing speed, verbal recognition memory and general mental status. These cognitive declines experienced by our patients 5 years post-pallidotomy are not entirely consistent with the neuropsychological profile associated with the progression of Parkinson's disease. Cognitive changes associated with Parkinson’s disease include declines in frontal lobe functioning, including the Wisconsin Cart Sorting Test, Trails B and the Stroop, verbal memory, information processing speed, and verbal fluency. While the decline in information processing speed is consistently associated with a diagnosis of Parkinson's disease and is not an unexpected finding, we did not find the expected declines in verbal fluency and memory as reported in previous studies including Alegret and colleague’s (2003) 4-year cognitive outcome study. [1
] Consequently, further analyses are warranted to examine the relationship between age, disease progression and unilateral pallidotomy at long-term follow-up. Moreover, the lack of significant findings by lesion side and declines in general mental status and recognition memory suggest a more generalized cognitive decline 5 years following surgery rather than a decline related specifically to the surgical intervention.
Significant differences were not found on measures of information processing for a sub-sample of 10 of the 18 patients at an interim period (1.3 years post pallidotomy). However, scores on the MMSE and on the CVLT discriminability measure showed a significant decline between short and long-term follow-up. Results suggest that the sub-sample experienced their significant cognitive decline toward the end of the study evaluation period and not 6 months or 1 year post pallidotomy. This preliminary analysis indicates that the cognitive decline is likely due to the progression of Parkinson’s disease and not their surgical intervention.
Individual MMSE scores at long-term follow-up suggest that one third (6/18) of the pallidotomy patients reached the cut-off for dementia (MMSE<23). Overall, our unilateral pallidotomy sample lost 3 points on the MMSE from the baseline to the 5-year follow-up evaluation. Second, all of the information processing speed measures administered showed declines at the long-term follow-up; both oral and visuomotor information processing speed were impaired. Patients showed increased bradyphrenia, which may be due to the progression of the disease over time or may be a long-term consequence of the surgery. The interplay between the disease and the sequelae of unilateral pallidotomy was not investigated due to the lack of a comparison group. A pallidotomy surgery wait list group matched on age, educational attainment and disease duration would provide us with a better understanding of the impact of the surgery on both motor and neurocognitive abilities. However, it would be difficult, if not impossible and unethical, to maintain a long-term, matched comparison group given the efficacious surgical treatments available to individuals with Parkinson's disease currently.
Several studies have reported that age may be a confounding factor in the cognitive outcome of pallidotomy, with older patients at time of surgery performing worse on neuropsychological outcome than younger patients. [4
] Our patients were on average 57 years old at the time of surgery, with only 2 patients being over 70. The two older patients' performance was consistent with the remaining unilateral pallidotomy sample. Due to the small sample size of older patients, we were unable to analyze independently the role of age in our cognitive outcome. However, our findings of cognitive decline in our young sample suggest that age cannot be the only factor resulting in cognitive decline following pallidotomy. It should be noted that patients who were lost to follow-up were significantly older than our sample. Consequently, the influence of demographic variables must be considered.
The long-term cognitive declines found in the current study suggest a further progression of the disease affecting frontostriatal circuits. While pallidotomy interrupts the “motor” neural circuitry believed to be responsible for the abnormally patterned motor activity in Parkinson’s disease, our findings suggest that cognitive dysfunction following pallidotomy may be a consequence of disruption in not only the primary motor circuit but a number of interconnected pathways from the basal ganglia to the cortex.[27
] Specifically, dopamine depletion in the lateral orbitofrontal and the dorsolateral prefrontal circuits has been suggested as a possible mechanism of cognitive impairment in Parkinson’s disease and may be affected by pallidotomy.[2
] However, dopamine depletion in the nigrostriatal pathways and in the ascending pathways from the ventromedial tegmentum.[2
] may not be the only pathways involved in non-motor functioning of Parkinson’s disease patients, but non-dopaminergic systems may also play an important role. [27
] Future longitudinal neuroimaging studies may be able to provide additional information as to the mechanism of action for the reported long-term cognitive decline following pallidotomy.
Several methodological issues complicate interpretation of this study. First, our sample size is relatively small, thus limiting our power to detect significant differences. Additionally, the small sample size limited our ability to conduct additional statistical investigations of subgroups of patients (e.g., age). Second, our attrition rate for the long-term follow-up was 38%, which is moderately high. We were able to account for the patients who were lost to follow-up and the majority of these patients were unable to return for testing because they were from out-of-state or had changed neurology clinics. Only one local patient who was followed by BCM PDMDC refused to complete further neuropsychological testing. In addition, our attrition group was significantly older than our long-term follow-up sample. The older age of the attrition group likely contributed to their lack of long-term follow-up. Third, the lack of a comparison group limited our ability to make conclusive statements regarding the effects of the progression of Parkinson’s disease on neurocognitive abilities and its interaction with the surgical procedure.
In summary, our results suggest that patients who underwent unilateral pallidotomy continued to receive long-term motor benefits from the surgery, while showing only mild neuropsychological declines. Although currently deep brain stimulation has become the primary treatment choice for patients with Parkinson’s disease, the procedure and subsequent follow-up evaluations can be cost prohibitive. [15
] Pallidotomy is still widely performed in many parts of the world because it is effective, much less costly, and does not require extensive follow-up evaluations. In these cases, unilateral pallidotomy should be considered a treatment option for Parkinson’s disease patients who suffer from severe unilateral disabling motor symptoms or dyskinesias. However, patients should be counseled as to the potential long-term cognitive risks of the procedure to make an informed decision.