When is it time for palliative and end-of-life care in status epilepticus?

Status epilepticus (SE) is a neurological emergency characterized by high rates of short-term and long- term morbidity and mortality. Status epilepticus seems to be a marker of the severity of other underlying conditions rather than a determinant of death on its own. Careful diagnosis and acute treatment of com- plications and causes of death to SE or its underlying etiology will enable the differentiation of SE patients that would beneﬁt from different levels of treatment intensity. All SE patients should be treated actively with ﬁrst- and second-line drugs as early as possible. For cases in which seizures continue after second-line treatment, the current guidelines fail to offer possibilities other than the active path with general anesthesia and intensive care unit (ICU) care. However, the intensity of care should be evaluated before starting ICU care or in unclear cases with the time-limited trial at ICU. There are now multiple possibil- ities for specialty palliative SE care that include sequential and add-on use of second-line drugs and palliative sedation at the ward. If ICU care is prolonged, the patient’s status needs to be constantly re- evaluated and communicated to the family. When patients exhibit multiple predictors of mortality and poor functional outcomes, they should be allowed to have a natural death in a peaceful environment without unnecessarily prolonged suffering. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022. (cid:1) 2022 The Authors. Published by


Background
Status epilepticus (SE), in which the hypersynchronous epileptic activity lasts longer than the usual duration of isolated selflimited seizures, is a life-threatening medical emergency caused by diseases that affect the cortical structures of the brain. For adults, the average overall mortality rate for SE is 16%, and it varies depending on age, etiology, and seizure duration [1]. Kantanen et al. [2] investigated the mortality of ICU-treated patients with refractory SE (RSE) and found that the one-year mortality rate was 26%. Older age, super-refractory SE (SRSE), poor baseline function, and signs of organ dysfunction during the ICU stay were independent predictors of one-year mortality. Patients with SRSE had a one-year mortality rate of 35%. The successful management of SE includes both the early termination of seizure activity and the earliest possible identification of a causative etiology, which may require independent acute treatment [3].
When SE is treated in patients with large enough structural and metabolic reserves, the burden of SE and its treatment can be compensated and may lead to increased patient survival, whereas in those with only marginal reserves, medical aggressiveness may in fact lead to a burden of treatment and even increased mortality [3]. A challenge in emergency situations is determining which patients would benefit from aggressive treatment and which are indeed in need of palliative or end-of-life (EOL) care. Palliative care provides symptom relief to improve the quality-of-life of patients and their families, both of whom face the problems associated with life-threatening illness [4]. End-of-life care is given to patients who are no longer responsive to life-prolonging therapies, in whom the goals of care are consistent with a comfort-based approach, and who are likely to die within days or weeks. In

Causes of death
Several factors have been proposed to explain the increased mortality associated with SE. However, studies have mainly reported predictors of mortality in SE; data regarding actual causes of death in hospital and out of the hospital are limited. More detailed data are emerging from multimodal neuromonitoring, but so far it has been difficult to separate the pathophysiological effects of SE leading to neuronal injury from the systemic complications and influence of the etiology [5]. In addition, the development of SE treatment in high-income countries over the last 30 years has not had a demonstrable association with mortality, which remains high [1].
The impact-of-the-burden model integrates structural damage and metabolic derangement, the burden of SE, the success and burden of treatment, and the impact of burden [3]. The seizure burden adds to variable degrees of metabolic exhaustion and the structural damage caused by the underlying brain injury, which may result in functional decompensation leading to neuronal injury and neuronal death.
Recent studies have indicated that deaths seem to result primarily from the underlying neurologic disease and withdrawal of life-sustaining treatment [6,7]. Mortality is higher in convulsive SE in patients without earlier epilepsy and in nonconvulsive SE (NCSE); however, outcomes are impacted not only by semiology at the beginning of SE but also by the evolution of SE semiology [3]. Of the metabolic disturbances, acidosis seems to be one of the most important risk factors for mortality [8]. A recent 13year cohort study conducted at a tertiary teaching hospital identified several factors associated with mortality in patients with SRSE, including generalized convulsive SE, failure of anesthetic tapering, increased number and duration of second-line anesthetic use, and multiple systemic complications [9].

Integrating palliative care decision-making into status epilepticus care
An important gap in current guidelines and treatment algorithms regarding SE treatment is the lack of guidance regarding palliative care in SE. Guidelines for palliative SE treatment are needed for end-stage cancer, such as primary brain tumors and cerebral metastases, for other conditions associated with a dismal prognosis (e.g., severe ischemic stroke, intracerebral hemorrhage, neurodevelopmental and neurodegenerative diseases, and nonneurological conditions such as terminal liver, kidney, or respiratory failure), and for severely frail patients or those suffering from multiple comorbidities simultaneously.
Approaches to palliative care may be classified as either primary (basic) palliative care or specialty palliative care [10]. All patients can and should be treated with first-and second-line anti-seizure medications (ASMs) as early as possible, even in EOL care (Fig. 1). In the future, we may also use the concept of rapid termination of epileptic seizures (REST) immediately when the seizure starts in frail and seriously ill patients to prevent prolonged seizures and SE [11]. The first point in the SE care pathway to evaluate, whether the patient should be treated actively or palliatively (or even with EOL care) is when the first-and second-line medications have failed and the patient has RSE. The second point at which to evaluate when palliative and EOL care should begin is when SRSE continues and the patient exhibits multiple predictors of a poor functional outcome, including comorbid medical illnesses, prolonged duration of a drug-induced coma, and prolonged need for mechanical ventilation.
Palliative SE care does not entail stopping the treatment but continuing the treatment with alternative second-line ASMs and possibly with palliative sedation [12,13]. This specialty palliative care emphasizes the management of more complicated and challenging cases and includes conflict resolution (regarding care goals or treatment methods) within families, between staff and families, and among treatment teams [10]. In EOL SE care, treatment focuses on symptom management while allowing for the natural dying process to occur, but it does not hasten death. Because the decisions to be made may concern patients' family members and society as well as the patients themselves, it is important to protect the rights and dignity of all parties involved in the clinical ethical decision-making process. It is important to determine when a patient might be dying from complications of their serious disease, identify goals of care based on this information, and help to provide goal-concordant care for the patient.
There is no generally accepted process for deciding who should be given care in the ICU. In some situations, later withdrawal of care is considered preferable to the initial withholding of treatments. The idea is to allow the patient to undergo a therapy trial, sometimes referred to as a time-limited trial (TLT). A TLT is an agreement to initiate all necessary treatments or treatments with clearly delineated limitations for a certain period of time to gain a more realistic understanding of the patient's chances of a meaningful recovery or to ascertain the patient's wishes and values [14]. Importantly, if it is decided that a TLT should be conducted, time limits and targets for the trial must be set in advance, and if treatment goals are not met by the allocated time, treatment should be withdrawn according to the plan. To ensure that the purpose of the TLT is clearly understood, good communication with the family is particularly important in this situation. This highlights the importance of defining the intention of SE treatment and the goals of care with surrogate decision-makers at an early stage.
According to the large German SENSE registry, more than 70% of RSE patients were treated without intubation, suggesting that many patients with RSE are indeed currently treated without anesthesia [15]. Intubations occurred more frequently in younger patients with lower levels of dependency, more severe alterations in consciousness, more severe SE semiologies (generalized tonicclonic seizures or NCSE in coma), and acute etiologies. However, at least some of the patients might have been treated without intubation due to the decision to transition to palliative treatment, but the registry has yet to publish this data.
Because third-line therapy with anesthetic drugs is associated with significant side effects and complications, recent Italian SE treatment guidelines advise that aggressive treatment should be reserved for situations in which ongoing SE poses a higher risk than the treatment itself and that the intensity of treatment should be determined on a case-by-case basis [16]. The alternative, less aggressive option recommended by the guidelines is the sequential use of different second-line ASMs. A recent US protocol also recommends avoiding the use of anesthetics in focal SE and patients with preserved consciousness and delaying their use in elderly patients with multiple comorbidities [6]. In NCSE, this protocol recommends trying an additional second-line drug before starting anesthetics.
Recently, family members of deceased SE patients have expressed the view that continued evaluation and communication of patient status, including scheduled objective consultations, align compassionate action with patients' best interests [17].

Advance care planning
Treatment of SE is an essential topic of advance care planning (ACP) for patients with severe epilepsy and other serious diseases with an increased risk of prolonged seizures. ACP enables patients to define their preferences and expectations concerning therapeu-tic options; it is a process that helps adult patients of any age or with any health condition to understand and share their personal values, life objectives, and preferences in terms of future healthcare [18]. Advance directives (ADs) are an essential part of ACP; ADs can include a living will, a do-not-resuscitate order, a donot-hospitalize order, medication restrictions, or feeding and hydration restrictions in the event of future loss of competence.
Given the possibility that patients will become incompetent regarding EOL decision-making in the late stages of their illness, it is important to discuss the subject at a relatively early stage [19].
Providing information about the occurrence and risks of seizures in the EOL phase may reduce distress in both patients and caregivers. In addition, REST methods and alternative methods of administering ASMs can be discussed early in the disease trajec- tory. The earlier SE treatment begins, the higher its likelihood of achieving seizure cessation. It is imperative to involve family members and patients (to the degree possible) in ACP discussions amid the diagnosis of SE. Ideally, it should be determined whether the patient has a desired location in which to die, because this knowledge facilitates discussions of transport to and from the home, hospital, and inpatient hospice settings and prevents unnecessary hospitalizations. Open communication and shared decisionmaking among healthcare providers, patients, and families can obviate many of the ethical dilemmas that arise during EOL care [20].

Prognostication
Four prognostic scores for SE mortality have been developed: the Status Epilepticus Severity Score, the Epidemiology-Based Mortality Score in Status Epilepticus, the modified Status Epilepticus Severity Score, and the ACD score [21][22][23]. These scores may support clinical decision-making by providing a valuable reflection of the full clinical situation, but they should never be relied on as the sole criteria [2,[23][24][25]. Moreover, they were developed to inform clinicians at SE onset, not during its course. Future development should be conducted to get scores to be calculated daily to provide the physician with useful information about the patient's clinical evolution and risk of mortality, allowing for risk stratification and individualized treatment strategies over the course of SE. In the future, we will move to multimodal neuroprognostication as the clinical, EEG, MRI, and biochemical data can be evaluated several times during the hospital stay and with machine learning algorithms the data can be integrated to reflect the course of pathophysiological mechanisms involved in SE excitotoxicity and consequences [26].

Conclusions
Status epilepticus seems to be a marker of the severity of other underlying conditions rather than a determinant of death on its own. A careful adjudication of complications and causes of death to SE or its underlying etiology will enable the differentiation of SE patients that would benefit from different levels of treatment intensity. All SE patients should be treated actively with first-and second-line drugs. The intensity of care should be evaluated before starting ICU care or in unclear cases involving a TLT. If ICU care is prolonged in SRSE, the patient's status needs to be constantly reevaluated and communicated to the family. When patients exhibit multiple predictors of mortality and poor functional outcomes, they should be allowed to have a natural death in a peaceful environment without unnecessarily prolonged suffering.

Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.K. Declarations of interest: has received grants from the Academy of Finland, Saastamoinen Foundation, and Vaajasalo Foundation, speaker's honoraria from Eisai, Omamedical, Orion, Sandoz, Sanofi, and UCB, and honoraria for membership of the advisory boards/consultation from Angelini Pharma, Eisai, Marinus Pharmaceuticals, Orion, and UCB. Z.A. Declarations of interest: has received consulting honoraria from the U.S. Department of State, the UN's International Organization for Migration, The Association for Medical Education in Europe, ReInnovate Group, Orbital Learning Canada. A-M.K. Declarations of interest: nothing to declare.