Advances in the Study of Postoperative Delirium in Patients with Parkinson’s Disease after Deep Brain Stimulation

Abstract

Objective: Postoperative delirium is a common complication following deep brain stimulation (DBS) surgery, which can prolong hospital stays and potentially impair cognitive function, exacerbating the progression of the disease. The clinical understanding of risk factors, pathophysiology, pathogenesis, prevention, and management of postoperative delirium after DBS is often inadequate, leading to delayed treatment.

Methods: This systematic review aims to summarize key aspects, including definition and incidence, clinical presentation and classification, pathophysiology, risk factors, assessment and prediction, and clinical management, to provide a scientifically rigorous basis for the early identification and intervention of postoperative delirium in DBS surgery patients.

Results: DBS-related delirium typically occurs within 72 hours, with > 50% cases missed. Pathogenesis involves neurotransmitter imbalance, neuroinflammation, mechanical damage to target nuclei, and default mode network dysfunction. Risk factors include advanced age, comorbidities, cognitive impairment, and brain atrophy. Diagnosis relies on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Confusion Assessment Method, and 4 A’s Test. Prophylactic antipsychotics show no benefit; quetiapine is preferred when pharmacotherapy is needed, while haloperidol is contraindicated in Parkinson’s disease (PD).

Discussion: Postoperative delirium following DBS surgery in PD patients is a complex neuropsychiatric complication with multifactorial etiology. The overlapping symptoms between PD and delirium pose significant challenges to accurate identification. Future research should focus on elucidating the specific pathophysiological mechanisms of DBS-related delirium, developing optimized assessment tools tailored for PD populations, and validating the effectiveness of prevention and treatment strategies through large-scale prospective studies. Given the current lack of evidence supporting prophylactic antipsychotic use, emphasis should be placed on non-pharmacological preventive measures and individualized risk stratification to reduce the burden on healthcare providers and caregivers while improving patient outcomes.

Keywords

postoperative delirium / Parkinson’s disease / deep brain stimulation

Introduction

Parkinson’s disease (PD) is a common disabling neurodegenerative disease of the nervous system. The core clinical symptoms include resting tremor, muscle rigidity, bradykinesia, and abnormal postural gait[1]. In the early stages of the disease, drug treatment is significantly effective; however, as the disease progresses, the therapeutic window of medication gradually narrows, efficacy declines, and various motor complications such as wearing-off and dyskinesia are induced. Deep brain stimulation (DBS) achieves symptom control by implanting electrodes in specific brain regions and modulating abnormal neuronal activity through continuous electrical pulses[2]. However, as an invasive therapy, DBS may also trigger a series of side effects. Among them, postoperative delirium, as the most common neuropsychiatric complication, is frequently underdiagnosed clinically, with more complex management and insufficient recognition.

Postoperative delirium is defined as an acute, transient clinical syndrome occurring after surgical procedures, characterized by fluctuating attention and consciousness disturbances, which may be accompanied by memory impairment, disorientation, language expression difficulties, and perceptual disorders[3]. Most studies suggest that the onset time of DBS-related postoperative delirium occurs within the first 72 hours postoperatively[4,5], but some researchers have extended this time window to within one week after surgery or before discharge[6]. This variability may be related to surgical anesthesia methods and target selection for DBS, while inconsistencies in diagnostic criteria, assessment tool selection, and sample size are also important factors. However, more than 50% of PD postoperative delirium cases have been reported to be potentially missed[7]. For PD patients undergoing DBS surgery, the acute episode of postoperative delirium is not only associated with reduced response to drug therapy and worsening of motor symptoms, but also accompanied by accelerated cognitive decline, increased mortality, and various other adverse outcomes[8,9].

This article will systematically review the relevant clinical research evidence on DBS-related postoperative delirium, covering key aspects such as pathophysiology, clinical manifestations and classification, risk factors, assessment and prediction, and clinical management. It aims to provide scientific and effective reference basis for early identification and intervention, thereby reducing the burden on medical staff, management complexity, and family caregivers.

Clinical manifestations of postoperative delirium after DBS surgery

The clinical manifestations of postoperative delirium are complex and diverse, typically including disturbances of consciousness, perceptual disturbances, disorientation, attention deficits, psychomotor agitation, and sleep-wake rhythm disturbances. Based on comprehensive review of previous studies, DBS-related postoperative delirium is more commonly characterized by hallucinations, delusions, and disorientation. Currently, according to psychomotor behavior, postoperative delirium can be classified into three subtypes: hyperactive, hypoactive, and mixed. Patients with hyperactive delirium exhibit altered consciousness with overactive behavior, such as restlessness, hallucinations, and incoherent speech; hypoactive delirium is most commonly manifested as lethargy or drowsiness, which is easily overlooked or misdiagnosed as depression or some form of dementia; the mixed subtype presents with features of both types[3].

Pathophysiological mechanisms of DBS-related postoperative delirium

The pathogenesis of delirium remains unclear, and descriptions in the context of DBS are even more scarce. However, due to its typically complex and variable clinical manifestations, it is unlikely to be explained by a single mechanism or neurochemical pathway. Currently, two classical hypotheses are most frequently mentioned: the neurotransmitter imbalance hypothesis and the neuroinflammation hypothesis. In addition, considering that DBS surgical procedures involve precise target localization, electrode implantation, and continuous electrical pulse stimulation, this suggests that unique pathophysiological mechanisms may also be involved.

Neurotransmitter imbalance hypothesis

The core pathological mechanism of PD is the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by simultaneous involvement of a series of neuronal systems including cholinergic neurons in the basal ganglia, serotonergic neurons in the midbrain nuclei, and noradrenergic neurons in the locus coeruleus[1]. Neurotransmitters such as acetylcholine, dopamine, serotonin, and melatonin play roles in effective cognition, learning, memory, attention, and sleep-wake cycles. Imbalances in the levels of these neurotransmitters or damage to related mechanistic pathways can affect the occurrence of postoperative delirium[10]. Among these, acetylcholine deficiency and dopamine excess are the most prominent. A prospective study by Zhao et al.[11] demonstrated that elderly patients with lower plasma cholinesterase activity after non-cardiac surgery had a higher incidence of postoperative delirium. The therapeutic effect of dopamine receptor antagonists on delirium indicates a close relationship between postoperative delirium and the dopaminergic pathway[12]. Furthermore, variations in dopamine transporter genes and dopamine receptor genes have also been reported to be potentially associated with postoperative delirium[13]. For PD patients, the severe neurotransmitter system disturbance itself constitutes a pathological basis that renders this population highly susceptible to delirium after surgery.

Neuroinflammation hypothesis

The neuroinflammatory hypothesis posits that postoperative delirium is secondary to peripheral inflammatory factors such as interleukin-6 and C-reactive protein, which are released following trauma, infection, surgery, and other injuries. These factors enter the brain through the disrupted blood-brain barrier or via afferent nerve transporters[14], thereby triggering inflammatory responses in the central nervous system. DBS electrode implantation causes initial physical damage that immediately triggers acute inflammatory responses within the central nervous system, directly causing neuronal injury or indirectly activating astrocytes and microglia, ultimately leading to psychiatric and cognitive symptoms associated with postoperative delirium. Studies have reported that preoperative and postoperative plasma C-reactive protein concentrations, as well as cerebrospinal fluid C-reactive protein, neurofilament light chain, and central nervous system-specific protein concentrations, were significantly higher in the DBS postoperative delirium group compared to the control group[15]. Lu et al.[16] also analyzed preoperative plasma from DBS surgical patients and found that a higher fibrinogen-to-albumin ratio was associated with postoperative delirium. Meanwhile, the pathological mechanism of systemic inflammatory response in PD itself can exacerbate microglial reactivity[17].

Mechanical damage to target nuclei

Previous studies have reported that compared to the second implantation of pulse generators, PD patients undergoing their first brain electrode implantation have a higher incidence of postoperative delirium[18], suggesting that the surgical procedure targeting the Subthalamic Nucleus (STN), including mechanical microlesion effects and subsequent stimulation, may contribute to psychiatric effects. Common targets for PD patients include the STN and the globus pallidus internus (GPi); however, no studies have yet investigated the incidence of postoperative delirium based on target selection between GPi and STN. Studies have reported that GPi produces fewer side effects such as cognitive impairment and mood-related neuropsychiatric symptoms[19]. The possible reason is that the GPi itself has a larger volume, with its posterolateral region responsible for sensorimotor functions being spatially distant from the anteromedial region, and fewer motor nerve fibers near the GPi compared to the STN.

The STN serves as a relay station in the basal ganglia circuit, participating in the control of motor, cognitive, motivational, and affective functions. Direct damage to the STN by DBS electrodes may trigger abnormal synchronization or desynchronization of neuronal signals in the cortico-thalamo-subthalamic network, disrupting normal information processing[20]. Furthermore, although the STN is anatomically divided into sensorimotor, cognitive, and limbic regions, at the microscopic level, multiple overlapping domains exist within it[21]. Therefore, during DBS implantation, the associative and limbic portions should be avoided as much as possible, as these parts of the STN are closely connected to the limbic circuit and may affect emotional and behavioral control[22].

Damage to brain functional areas

DBS-related postoperative delirium may be associated with regional brain functional damage. The default mode network is a network activated during resting state and deactivated during task state, including the medial prefrontal cortex, posterior cingulate cortex, precuneus, inferior parietal lobule, and temporal cortex[23]. Luo et al.[24] utilized functional neuroimaging to analyze brain functional area status during the acute phase after DBS, suggesting that DBS electrode implantation significantly reduces activity and connectivity in the prefrontal cortex and default mode network regions. Studies have also found that excitatory discharge in the medial prefrontal cortex decreases after general anesthesia surgery, which is significantly correlated with postoperative delirium-like behavior[25]. Tanaka et al.[26] found through voxel-based morphometric analysis that reduced total white matter volume was significantly associated with the duration of postoperative delirium. Song et al.[27] also used functional magnetic resonance imaging and diffusion tensor imaging to analyze brain function and structure in patients with postoperative delirium, revealing structural changes and functional abnormalities in the frontal lobe, temporal lobe, corpus callosum, hippocampus, and cerebellum. Additionally, an atlas-based study reported that patients with postoperative delirium showed significantly reduced gray matter volume in the temporal lobe and limbic lobe, which may be involved in the occurrence of postoperative delirium[28].

Risk factors for DBS-related postoperative delirium

Patient-related risk factors

Advanced age

Due to decreased physiological reserve function and degeneration of brain structure and function, advanced age is considered an independent risk factor for postoperative delirium. Although a study on the impact of aging on DBS outcomes showed that increased age (> 75 years) had no significant effect on overall 90-day complication rates[29], multiple study results still indicate a close association between advanced age and postoperative delirium[30,31]. Currently, the number of DBS surgeries in elderly PD patients remains relatively small, and relevant Chinese guidelines or consensus recommendations suggest that the age of surgical patients should be limited to under 75 years. Whether advanced age should be regarded as a contraindication for DBS surgery still requires further discussion.

Comorbidities

The presence of preoperative comorbidities, such as diabetes, cortical cerebral infarction, and pulmonary inflammation, significantly increases the incidence of postoperative delirium by affecting the patient’s overall health status and increasing surgical risk. Therefore, postoperative comorbidities are considered the strongest predictor of increased readmission rates[32]. Paim et al.[33] found that after adjusting for multiple confounding factors, the comorbidity index remained significantly associated with postoperative delirium. Lu et al.[6] also noted in their study that patients with higher comorbidity burden, especially those with diabetes, had a higher incidence of postoperative delirium. Furthermore, a prospective study indicated that patients with preoperative cortical cerebral infarction and complex white matter hyperintensities were more likely to develop postoperative delirium[34].

Severity and phenotype of motor symptoms

The more severe the motor symptoms in PD patients, the stronger their susceptibility to postoperative delirium. Lu et al.[35] found that the unified Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part III was directly associated with the occurrence of postoperative delirium. Abboud et al.[36] also supported this view, noting that for every 1-point increase in the preoperative Unified Parkinson’s Disease Rating Scale Part III score, the incidence of postoperative delirium increased by 10%. Additionally, they found that axial-dominant symptoms, as well as preoperative falls or balance dysfunction, were also associated with postoperative confusion. However, this conclusion still lacks further evidence support. A possible explanation for this association is that patients undergoing DBS surgery are mostly in the advanced stages of the disease, with severe neurotransmitter disturbance and significant drug side effects, making them more prone to postoperative delirium. Meanwhile, patients with axial-dominant symptoms often receive complex drug regimens and have stronger resistance to medications.

Cognitive impairment

PD patients with pre-existing severe cognitive impairment are more likely to develop delirium after surgery. Zhou et al.[37] investigated the correlation between baseline cognitive scores and postoperative delirium in DBS surgical patients, demonstrating that the Mini-Mental State Examination and Clinical Dementia Rating Scale scores were independent influencing factors for postoperative delirium after STN-DBS in PD patients. More notably, certain special types of cognitive impairment may carry higher risk of concurrent postoperative delirium. Jahanshahi et al.[38] found that patients with more severe preoperative executive dysfunction and poorer memory were more likely to develop postoperative delirium. Such patients, due to attention deficits and slowed information processing speed, are often more susceptible to environmental interference and therefore require greater attention in clinical practice.

Other non-motor symptoms

Studies have shown that PD patients with preoperative hallucinations, anxiety, depression, and other non-motor symptoms have an increased risk of postoperative delirium, possibly related to high expression of inflammatory factors under stress states and damage to the blood-brain barrier[39,40]. Meanwhile, studies have found that sensory deprivation caused by symptoms such as hyposmia or visual dysfunction may make DBS surgical patients more susceptible to postoperative delirium[41,42]. A 2025 meta-analysis on risk factors for postoperative delirium in PD patients undergoing DBS surgery also indicated that the Non-Motor Symptoms Scale score was an independent predictor[43]. A study by Kim et al.[44] on PD patients after spinal surgery showed that rapid eye movement sleep behavior disorder was also an independent risk factor for postoperative delirium. Furthermore, orthostatic hypotension caused by autonomic nervous system dysfunction in the elderly is also associated with postoperative delirium, possibly due to chronic cerebral hypoperfusion leading to cognitive impairment[40].

Brain atrophy

Brain atrophy, as an independent risk factor for DBS-related postoperative delirium, reflects more severe pathophysiological changes in the central nervous system and poorer cognitive reserve. The caudal middle frontal gyrus is considered to be associated with transient psychiatric disorders in PD[45], and its atrophy may damage intra-lobar connections and top-down input to other brain structures[46]. Radziunas et al.[47] found that although DBS postoperative delirium patients showed significant differences in white matter and cortex in many brain regions, significant reductions in white matter volume and cortical area were only found in the left caudal middle frontal gyrus. Bourn et al.[48] demonstrated that the minimum width of the lateral ventricles in DBS postoperative delirium patients was significantly greater than in the control group, and for patients requiring higher levels of care and those with complications, their ventricular width was also significantly greater than in the control group. Katsumi et al.[49] reported that baseline anterior midcingulate cortex thickness was negatively correlated with the severity of postoperative delirium. These indicators can all reflect the degree of brain atrophy to some extent, indicating that brain atrophy not only increases the risk of postoperative delirium but may also affect the recovery of neurocognitive function.

Surgery-related risk factors

Anesthesia

It has been reported that 20% of patients experience postoperative confusion after local anesthesia surgery[33]. Ishii et al.[50] found that for elderly patients, the incidence of postoperative delirium was lower with total intravenous anesthesia compared to inhalation anesthesia, a result that was also validated in patients undergoing STN-DBS[51,52]. The possible reason is that surgery under total intravenous anesthesia may proceed more efficiently and can shorten operative time. However, other studies[53] suggest that these two methods did not show significant differences in postoperative neuropsychiatric symptom assessment results, and intraoperative sedation time, depth, and specific dosages of anesthetic drugs should receive greater attention[54]. Overall, general anesthesia offers certain advantages in specific populations, helping to reduce puncture risks and expand the applicable population. Currently, preoperative MRI precise localization and intraoperative verification techniques have also provided more reliable technical support for general anesthesia, but its clinical application still requires weighing against individual circumstances.

Surgical approach

The impact of surgical approach on postoperative delirium remains controversial. In 2011, Gologorsky et al.[55] conducted a study on 81 PD patients and found that compared to traditional methods, transventricular DBS lead implantation increased the risk of postoperative delirium by traversing the lateral ventricle wall. However, in 2019, Ray et al.[56] reached contradictory conclusions, finding that only 1.5% (156 cases) of patients developed postoperative delirium, and therefore considered this approach unlikely to significantly increase risk.

Postoperative complications

Studies indicate that hemorrhage and edema at DBS stimulation sites are closely related to the occurrence of postoperative delirium, and these pathological changes significantly increase the risk of postoperative delirium[57]. Although intraoperative microelectrode pass counts and surgical laterality have also been investigated, studies have shown that they are not directly correlated with the occurrence of postoperative delirium[58]. This suggests that the surgical procedure itself has a relatively small direct impact on the occurrence of postoperative delirium, while complications resulting from surgery have a more significant effect.

Diagnosis and assessment of DBS-related postoperative delirium

Currently, the diagnosis of postoperative delirium is based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by the American Psychiatric Association[59]. However, because this standard is overly complex and requires experienced specialist physicians to administer it, more convenient scales are commonly used in clinical practice, such as the Confusion Assessment Method (CAM)[60] and the 4 A’s Test (4-AT)[61]. CAM is suitable for non-psychiatric physicians and nurses, generally detecting postoperative delirium through four features: (1) acute onset and fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. If patients exhibit the first two features plus either disorganized thinking or altered consciousness, they are classified as having postoperative delirium. The 4-AT consists of four items: Item 1 assesses alertness level; Items 2 and 3 are brief cognitive screenings; Item 4 assesses acute changes or fluctuations in mental status. A score of 0 indicates no postoperative delirium, 1–3 indicates possible cognitive impairment, and ≥ 4 indicates signs of postoperative delirium.

DBS-related postoperative delirium often has a fluctuating course and is associated with poorer patient status in PD, leading to many postoperative delirium events being missed. Furthermore, because there are many overlapping symptoms between PD disease symptoms and postoperative delirium (e.g., impaired attention, hallucinations, and delusions), postoperative delirium identification becomes more difficult. One study found that simple bedside attention and arousal tests have high sensitivity in detecting delirium superimposed on PD and dementia, which may open new avenues for postoperative delirium identification in neurodegenerative diseases[62]. Future development of assessment scales more suitable for identifying DBS-related postoperative delirium in PD patients is needed in larger cohorts.

Clinical management of DBS-related postoperative delirium

Preventive measures

Preoperative assessment and risk stratification are key to preventing postoperative delirium. Before surgery, comprehensive evaluation of the patient’s nutritional, cognitive, and emotional baseline status is required to screen appropriate candidates for surgery and optimize their baseline condition. For high-risk patients such as the elderly, those with poor cognitive function, and those with multiple comorbidities, treatment planning and risk education for patients and families should be conducted in advance. During surgery, direct damage to brain tissue, especially critical regions such as the STN, should be minimized to reduce the incidence of postoperative delirium. A randomized study also indicated that intraoperative use of general anesthesia with careful titration of anesthesia depth under processed electroencephalography monitoring guidance helps reduce the risk of postoperative delirium[63]. After surgery, repeated assessment of the patient’s sleep quality, pain level, and cognitive status is still needed for timely detection of conditions. Furthermore, early resumption of PD-related medications should be encouraged to avoid postoperative delirium triggered by delayed administration or sudden discontinuation.

Non-pharmacological management

Given the complex risk factors for postoperative delirium, multi-component non-pharmacological management is an effective strategy for preventing postoperative delirium. First, for benign hallucinations or confusion, a familiar environment and family companionship are more conducive to patients recovering from postoperative delirium as soon as possible[39]. Therefore, discharge may be recommended for patients with stable conditions. Second, the Hospital Elder Life Program, as the most classic intervention method, helps reduce the risk of postoperative delirium, and its components mainly include: cognitive activation, early mobilization, improved sensory stimulation, reduced sleep disruption, and adequate fluid and nutritional intake. Additionally, strict medication review is necessary for PD patients. For some medications with low anti-Parkinson efficacy and high potential for inducing postoperative delirium, dose reduction or discontinuation may be appropriate[64], while carefully adjusting levodopa dosage.

Pharmacological management

Non-antipsychotic medications

Non-antipsychotic medication management includes the following two aspects: (1) avoiding or reducing the use of medications prone to inducing postoperative delirium; (2) optimizing the types and dosages of medications used by patients. Benzodiazepines should be avoided preoperatively as they may worsen postoperative delirium[65]. However, prophylactic intraoperative use of dexmedetomidine is considered safe and effective. Su et al.[66] conducted a study on 700 non-cardiac surgical patients, showing that low-dose dexmedetomidine significantly reduced the incidence of delirium during the first 7 postoperative days. Postoperative analgesia is an important method for reducing delirium incidence. Considering that opioids themselves are prone to inducing postoperative delirium, it is recommended to use multimodal analgesia with acetaminophen and non-steroidal anti-inflammatory drugs to reduce opioid use, thereby lowering the risk of postoperative delirium[67]. Furthermore, although melatonin has a role in treating circadian rhythm reversal, there is no consistent conclusion indicating that prophylactic melatonin use can reduce the incidence of postoperative delirium[68,69].

Antipsychotic medications

Whether prophylactic use of antipsychotic medications can reduce the incidence of postoperative delirium remains undetermined. Neufeld et al.[68] compared patients receiving prophylactic antipsychotic medications with control groups, showing no significant benefit in the antipsychotic medication group. Evidence-based guidelines and consensus on postoperative delirium in adult patients recommend considering antipsychotic medications only when non-pharmacological treatments are ineffective, and even greater caution should be exercised for PD patients[70]. Haloperidol is the most widely used antipsychotic medication, but due to its extrapyramidal side effects and risk of acute dystonia, it is generally considered contraindicated in PD[71]. Currently, atypical antipsychotics are the mainstay for treating neuropsychiatric symptoms in PD patients[72]: Clozapine is the only fully recommended medication for treating PD psychosis, but white blood cell counts need to be monitored; Olanzapine is considered ineffective and can cause motor deterioration; Quetiapine is considered to have insufficient evidence, but due to its minimal side effects, no specialized monitoring is required. Currently, studies have confirmed the efficacy of quetiapine in DBS-related postoperative delirium patients[4]. A case report also found that naloxone may help alleviate psychiatric symptoms, improve cognitive dysfunction, and reduce irritability in PD patients[73]. Future prevention and treatment strategies for DBS-related postoperative delirium require further research and validation.

Conclusion

In summary, the management of DBS-related postoperative delirium is a complex and ongoing process that requires comprehensive consideration of individual differences, surgical characteristics, and other factors for prevention and management. Future research should further explore the pathogenesis of DBS-related postoperative delirium, optimize delirium assessment tools using multi-dimensional approaches combining biochemistry, imaging, and electrophysiology, and validate the effectiveness of prevention and treatment strategies to improve patient treatment outcomes and quality of life.

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