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Cognitive changes in Parkinson’s disease during subthalamic stimulation: a clinicopathologic study
  1. F Valldeoriola1,
  2. E Tolosa1,2,
  3. M Alegret1,
  4. M J Rey2,
  5. O Morsi3,
  6. M Pilleri3,
  7. J Rumià4
  1. 1Parkinson’s Disease and Movement Disorders Unit, Department of Neurology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Suñer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
  2. 2Banco de Tejidos Neurológicos, Universitat de Barcelona-Hospital Clínic, Barcelona, Spain
  3. 3Parkinson’s Disease and Movement Disorders Unit, Department of Neurology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Suñer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
  4. 4Department of Neurosurgery, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
  1. Correspondence to:
 Dr Francesc Valldeoriola
 Neurology Department, Hospital Clínic, C/ Villarroel, 170, 08036-Barcelona, Spain; fvallde{at}clinic.ub.es

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It is well established that patients with Parkinson’s disease (PD) can develop cognitive, behavioural, and mood changes.1 Cognitive decline has been reported to be present in up to 84% of patients who survive for 15 years after diagnosis.2 Several mechanisms may underlie these clinical problems including cholinergic deficiency, dopaminergic dysfunction, prefrontal-caudate nucleus disconnection, and intrinsic limbic and cortical pathology (Lewy bodies, Alzheimer-like changes). Concerns have been raised about the possibility that subthalamic deep brain stimulation (STN-DBS) could also produce cognitive changes and mood and behavioural alterations.3,4 We report the clinical and neuropathological features of a patient with advanced PD who developed behavioural changes and dementia while on STN-DBS.

CASE REPORT

A 74 year old man suffering from PD for 11 years presented troublesome dyskinesias and unpredictable motor fluctuations that did not respond to multiple changes in medication. The Hoehn and Yahr stage was IV while “off” and III while “on” medication. The Schwab and England scale score was 40% in the “off” and 80% in the “on” condition. The UPDRS-III score was 56 while “off” and 21 while “on”. No clinically evident signs of cognitive impairment were present. The Mini-Mental State Examination (MMSE) score was 28/30. Neuropsychological assessment was considered to be normal except for the presence of mild cognitive processing slowness and free recall impairment (table 1).

Table 1

 Neuropsychological performance before and 6 months after STN-DBS

Dyskinesias and motor fluctuations had disappeared 3 months after STN-DBS. The Hoehn and Yahr stage was III and the Schwab and England score was 70%. Dopaminergic medication was initially reduced to 20% but the patient later developed restless legs syndrome (attributed to the reduction in dopaminergic medication) and levodopa was reintroduced (400 mg/day). Motor performance remained stable during the following months. There were no significant changes in neuropsychological performance 6 months after STN-DBS (table 1). However, shortly afterwards the patient developed mood changes consisting of apathy, anhedonia without sadness, and diurnal hypersomnolence. Levodopa was then increased and antidepressants were started. Changing stimulation electrical parameters and stimulation poles did not change the patient’s mood.

The patient developed fluctuating confusion, visual hallucinations, and paranoid ideations 1.5 years after surgery. The MMSE score was 22/30. He became violent with his relatives. Clozapine (100 mg/day) reduced aggression but confusion persisted. The possible role of STN-DBS on these cognitive and behavioural changes was assessed by switching off the stimulators for 1 week. Mental status remained unchanged but parkinsonism worsened until the stimulators were again switched on. Later in the course of the disease, the patient received galantamine which improved psychiatric symptoms and temporal-spatial orientation. The patient died from bronchopneumonia 3.5 years after surgery. The patient was a donor of the Bank of Neural Tissues of the University of Barcelona-Hospital Clinic.

PATHOLOGICAL EXAMINATION

Macroscopic examination of the brain disclosed important loss of pigmentation in the substantia nigra pars compacta and locus coeruleus. The electrode tips were placed within the boundaries of the subthalamus on both sides. On microscopic examination moderate inflammatory infiltrates of T lymphocytes and mild astrocytic gliosis were observed surrounding the leads. Lewy bodies (LB) and Lewy neurites were found in the substantia nigra pars compacta, locus coeruleus, raphe nuclei, the dorsal nucleus of the vagus, and the hypoglossal nerve. Dystrophic neurites and cytoplasmatic inclusions were found in the nucleus of Meynert and the subthalamus. Cortical type LB were observed in the gyrus cinguli, transentorhinal cortex, the amygdala, and the parietal and temporal cortex. The density of LB was maximal in the sub-cortical nuclei and the limbic areas. A few neurons showing neurofibrilar degeneration were found in the transentorhinal and entorhinal cortex, amygdalar complex, locus coeruleus, and raphe nuclei. Neocortical senile plaques were scarce and signs of amyloid angiopathy were absent. The pathological diagnosis was diffuse Lewy body disease, transitional type.

DISCUSSION

Recently, concerns have been raised in relation to the possible negative effects of STN-DBS on cognition and behaviour.3,4 We report a patient with advanced PD who developed cognitive impairment and behavioural changes while on STN-DBS. The patient was judged to be cognitively normal before surgery. After death from bronchopneumonia, post-mortem examination of the brain disclosed pathological changes typical of diffuse Lewy body disease.

The present report is the second clinicopathological description of a patient with PD, dementia, and STN-DBS. The first report by Jarraya et al5 described a parkinsonian patient who had some cognitive impairment before STN-DBS and whose mental condition worsened after surgery. Post-mortem examination confirmed the diagnosis of PD. The authors concluded that the bad outcome after surgery was due to the inadequate selection of a candidate who had cognitive deterioration before surgery, but the cause of the worsening mental status after STN-DBS remained unclear. In the case reported here, post-mortem examination disclosed changes typical of diffuse Lewy body disease. In addition, the cognitive and behavioural alterations were not thought to be related to STN-DBS since mental problems appeared late after STN-DBS and changes in stimulation parameters or even disconnection did not result in any mental or behavioural change. The clinical manifestations, the course of the disease, the presence of hallucinations, and the good response to cholinesterase inhibitors were also typical of so called Parkinson’s disease-dementia in which the main pathological substrate is the presence of LB in limbic and neo-cortical areas.6 The development of neuropsychiatric symptoms is common in advanced PD and becomes more prevalent with disease progression.2 STN-DBS has not been shown to cause progressive cognitive deterioration so far. The present case report supports the view that mental problems observed after STN-DBS in some patients are not related to STN-DBS and suggests alternative explanations. Several predictive factors for dementia in PD have been identified, such as older age at onset of symptoms, longer duration of motor symptoms, predominance of akinesia, rigidity, and gait disturbances, depression, early hallucinations, and impairment of memory and language function1 but, in general, it is difficult to foresee which patients are more likely to develop behavioural and cognitive problems. A better understanding of the predictive factors for the development of dementia in PD will help to improve candidate selection for STN-DBS.

ACKNOWLEDGEMENTS

Dr O Morsi was granted a fellowship for specific training in movement disorders by the Spanish Neurological Society.

References

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Footnotes

  • Competing interests: none declared

  • Patient details are published with consent

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