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Management of post-operative delirium following stereoelectroencephalography electrode placement for drug resistant epilepsy: Lessons learned from two case reports

Highlights • Post-operative delirium poses unique challenges in neurosurgical patients.• Substance use is a modifiable risk factor for post-operative delirium after SEEG.• SEEG patients have increased risk of harm when experiencing post-operative delirium.


Introduction
Post-operative delirium (POD) is an acute, fluctuating disruption in attention and cognition that is associated with altered perception, inappropriate behavior, changes in awareness, and disorganized thinking [1][2][3]. Often expression of POD cannot be explained by a pre-existing disorder and can impair ability to comply with medical care [4,5]. Diagnosis and treatment are complicated by a multitude of interactions between pre-operative vulnerabilities with intra-operative and post-operative precipitating factors [6,7].
Patients undergoing neurosurgical interventions are at unique risk for POD [4]. They require frequent neurologic checks, have baseline deficits with neurologic and metabolic derangements, and neurosurgical related brain injury [2,5,8]. In this population factors such as age, functional and neurologic impairment, and structural comorbidities of the brain (epilepsy, ischemia, etc.) have all been shown to be predisposing factors to delirium [3,9].
Contributing to POD is potentially a direct psychotropic effect of surgical implantation of electrodes suggested by research investi-gating POD in Parkinson's patients with deep brain stimulation [10]. Yet, there has been little research in patients undergoing stereoelectroencephalography (SEEG) surgery, where depth electrodes are implanted directly into the brain for localization of epileptic foci. While the outcome of a complex interplay of a multitude of factors, hyperactive delirium is of particular interest in this population because of the potential for self-harm.
Although there is the potential for self-harm when the patient is delirious, aborting the SEEG procedure before epileptic foci localization can prevent patients from receiving subsequent epileptic surgery aimed at seizure control. This is often their last therapeutic option for seizure control after several failed medical management trials. Thus, pre-operative risk mitigation and discussing the potential for POD can allow therapeutic alignment between patient, family and treatment team about delirium management and preserve this therapeutic option. This paper reviews two cases of POD in patients undergoing SEEG neuromonitoring out of 62 SEEG neuromonitoring cases between 2018 and 2019 at the University of Colorado Hospital and proposes how to mitigate complications post-operatively if a patient becomes acutely delirious.  A 20-year-old female patient presented to the University of Colorado Neurology Department in 2015 with a 4-year history of drug resistant focal epilepsy. Due to two non-diagnostic phase 1 video-EEG (VEEG) sessions, she ultimately underwent three phase 1 VEEG sessions in the epilepsy monitoring unit (EMU) over a seven-month span. During the first session, the patient had an altercation with her parents and asked for security to escort them from her room. She then was adamant about leaving herself. She had completed the VEEG session but her final magnetic resonance imaging (MRI) had to be completed as an outpatient. Two subsequent phase 1 evaluations were without further altercations. VEEG helped localize seizure onset to the right posterior temporal lobe along with MRI findings of heterotopic gray matter along the right hippocampus and medial right temporal lobe.
In 2019 the patient presented to the University of Colorado Neurology Department for surgical consideration. A multidisciplinary team recommended phase 2 invasive neuromonitoring using SEEG to further localize seizure onset given the lack of clear posterior margin and the uncertainties regarding involvement of hippocampus and overlying neocortical tissue in the epileptogenic zone. In part due to known previous substance abuse issues with methamphetamines and current cannabis use, psychiatric evaluation was performed prior to surgery and the patient was deemed an appropriate surgical candidate. Electrodes were implanted in the temporal occipital pole, anterior temporal pole, amygdala, anterior, middle and posterior hippocampus, posterior periventricular nodular heterotopia, temporal occipital junction and insula.
On post-operative day 1, the patient demonstrated severe agitation. She attempted to remove her electrodes and slam her head against the bed aiming at the surgical site. The patient was physically restrained by multiple individuals and given 5 mg Haldol and 4 mg Ativan to sedate her and address her POD. She was subsequently started on risperidone 0.5 mg twice daily after for POD management.
An emergent consultation with psychiatry deemed the patient lacked decision making capacity and was a potential active harm to herself and staff. The treatment teams deemed it prudent to remove electrodes over safety concerns. The family and patient showed unwillingness to consent for explantation surgery. Ultimately consent was obtained, though family expressed a strong preference the electrodes remain. Legal counsel advised the neurosurgical team to not remove the electrodes unless necessary. Thus, the patient and family were advised that the next incident of any agitation/antagonism would result in immediate removal.
The patient was left in the intensive care unit (ICU) for better control of environment. She was given a sitter for monitoring of her POD and safety. She had successful capture of seizures and was explanted uneventfully on hospital day 23 without further incident.

Case 2
A 34-year-old male presented to the University of Colorado Neurology Department in 2018 with a 12-year history of drug resistant focal epilepsy. He was scheduled for a phase 1 EMU study which was rescheduled on the day of admission as the patient believed he was only having a half day test opposed to a multiday study. His reasoning for rescheduling was that he was ''not in the right mental space to tolerate the test". He was later admitted for his phase 1 evaluation in the EMU using VEEG and completed the study with no disturbances. The pre-surgical hypothesis was left temporal lobe, non-lesional epilepsy with no obvious anatomical abnormalities on MRI.
In 2019 a multi-disciplinary team recommended SEEG to further localize seizures for potential surgical intervention. Prior to surgery the patient was evaluated by psychiatry due to concern over prior substance use and competence and was deemed an appropriate surgical candidate.
Starting on post-operative day 1, while under observation in the EMU after electrode implantation, the patient had multiple episodes of agitation suspected to be secondary to nicotine and marijuana withdrawal and expressed interest in leaving against medical advice (AMA). During these POD episodes he threatened to pull out his electrodes. He was counseled on the adverse and potentially life-threatening outcome of electrode tampering and subsequent ineligibility for future epilepsy surgery. Psychiatry noted that during periods of agitation the patient lacked capacity to understand the consequences of leaving the hospital with electrodes in place. He was given 2 mg Ativan once and put on Quetiapine 25 mg on post-operative day 1 in response to POD that was increased to 50 mg on post-operative day 2. The patient went on to have multiple target seizures and was successfully explanted on hospital day four.
Following explantation, the patient was still severely agitated and expressed interest in leaving the hospital. He was counseled on the post-operative risks and informed that leaving AMA would prevent future surgical interventions due to concern over treatment compliance. The patient was able to calm down, though had repeated cycles of agitation where he threatened to leave until discharged 24 hours later.

Discussion
Well known risk factors for POD include increased age, cognitive impairment, substance abuse, and many others. [11,9]. These vulnerabilities interact with intra-, peri-, and post-operative factors to result in an acutely delirious state [12,13,5]. SEEG has been demonstrated to have a low complication rate with few reports of a variety of psychiatric changes as a complication of this neuromonitoring modality [14]. The post-electrode implantation psychiatric consequences of SEEG monitoring is multifactorial with factors such as substance withdrawal, potential epileptic psychosis, baseline mood disturbances, and a variety of other factors all contributing. Of consequence, intracranial electrodes provide an external conduit in patients following SEEG placement thus providing a mechanism by which hyperactive delirium can result in devastating intracranial damage via electrode tampering. Thus, patients following SEEG placement are a particularly vulnerable population, but no guidance exists on POD in this population.
Pre-operative substance use is a modifiable risk factor for POD. In our two case reports, both patients had significant substance use with abstinence contributing to agitation while hospitalized. Additionally, both of these patients had documented issues tolerating previous phase 1 studies and difficulty abstaining from substances for recommended periods of time (e.g. prior to WADA testing). More thorough documentation of these occurrences may enlighten the care team to the possibility of such situations during phase 2 studies. We propose detailed documentation regarding prior studies, duration of substance abstinence prior to hospitalization and patient tolerance of the prior monitoring to be part of the discussion at epilepsy surgery patient care conferences. This documentation and neuropsychiatric evaluation can be used synergistically to generate a level of suspicion of potential POD in patients preoperatively. This increased level of suspicion can help guide postoperative management to avoid use of known delirium contributing drugs. For instance, our first patient received diphenhydramine and oxycodone and our second patient received hydrocodoneacetaminophen and acetaminophen-codeine for pain management, which are known to contribute to POD. Avoidance of delirium contributing medications in patients with a high baseline suspicion for POD would benefit the patient.
As well, patients and families need to be informed of the potential of POD and the risk it poses to a patient before electrode placement. Identification of surrogate decision makers and assent for electrode removal if needed for safety concerns can be obtained pre-operatively. Thus, patients and families are able to make better informed decisions and allows for alignment of the patient, family and treatment team on the surgical treatment plan.
Post-operatively, if a patient develops POD re-orientation and modification of risk factors is necessary. As well, decision making capacity should be evaluated using standard hospital protocol. If the patient lacks decision making capacity then the predetermined medical durable power of attorney (MDPOA) should be reached for treatment discussion. If the MDPOA is not available or no one is designated, legal should be involved, particularly if there is a disagreement about explanation over safety concerns between the treatment team and patient/family. Escalation to this point is hoped to be avoided by the pre-emptive conversations and decrease in substance use before surgery.
As demonstrated in these case reports, patients that have hyperactive delirium after SEEG can pose unique risk of harm to themselves. By having an external conduit via the electrodes, pulling at the electrodes and aggressive movement of the head can result in neurologic damage that can have devastating consequences. Thus, we propose several steps that can mitigate the risk of POD and lessen the decision making burden post-operatively in the event the patient becomes delirious.

Conclusion
Patients undergoing SEEG neuromonitoring for drug resistant epilepsy are at risk of POD and have unique safety concerns. Yet, there is a paucity of literature about POD in patients undergoing SEEG monitoring. Thus, we propose several steps pre-operatively that can help reduce the risk of POD and ways post-operatively that POD can be mitigated and addressed by the treatment team.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent
For this type of study formal consent is not required.