Drilling a hole to shorten the gap: an Aotearoa New Zealand therapeutic algorithm for status epilepticus in NEUROPA (Madrid, Spain)

If you drilled a hole deep enough into the Madrid lake of San Juan, you would eventually resurface from the Manawatū Gorge, near Palmerston North. In 2017, we implemented a clinical practice guideline (CPG) incorporating a therapeutic algorithm to streamline the management of status epilepticus (SE) in Palmerston North Hospital (PNH).¹ Drawing from our previous experience and facing similar challenges at Hospital Universitario Los Madroños (HULM), we adopted the CPG from PNH and adapted it to our local needs.

SE is a neurological emergency defined by continuous epileptic activity lasting more than 5 minutes or by repeated seizures (in clusters) without recovery of consciousness between them. SE results from the failure of the physiological mechanisms responsible for stopping or controlling epileptic activity. A prolonged SE can lead to irreversible neuronal damage, altering neural networks and increasing the risk of future seizures.²

Patients with SE often have a previous diagnosis of epilepsy, which carries a more favourable prognosis. However, the majority of people presenting with SE have no previous history of epilepsy, and the risk of developing epilepsy after SE widely ranges from 22% to about 40%. Poor prognostic indicators include the underlying cause (acute and/or progressive brain lesions), seizure type (bilateral tonic-clonic seizures or convulsive SE being the most frequent and severe), seizure duration and resistance to treatment.³ In an Auckland study on the incidence of SE, two-thirds of the episodes lasted >30 minutes, in keeping with larger epidemiological studies.⁴

Several health organisations worldwide have been involved in the development of CPGs for the management of SE. In spite of this, there still exists a major gap between CPGs for the management of SE and actual clinical practice, which appears to be—to some extent—related to the inherent limitations of the CPGs.⁵ Furthermore, having a CPG is no guarantee that it will be followed. While more research is needed on early seizure detection and agreed therapeutic plans, shortening seizure duration and limiting potential medical complications will ultimately lead to improved clinical outcomes. In this regard, having pragmatic local consensus CPGs tailored to the needs and resources available will help shorten this care gap, especially when 24/7 neurology services are not available.

Acquired severe brain injury

Patients with an acquired severe brain injury are at a significantly increased risk of seizures, SE and epilepsy.^6–8 A single seizure in a patient with a pre-existing structural brain lesion constitutes—by definition—epilepsy, thus requiring chronic pharmacological treatment.^9–10 However, patients with seizures occurring in the first week after a brain injury—so-called acute symptomatic seizures—carry a significantly lower risk of future seizures and, therefore, epilepsy than those presenting with spontaneous seizures after 7 days or more post-injury.¹¹ Both levetiracetam (LEV) and lamotrigine (LTG) have been found to be safe and tolerable as antiseizure medication (ASM) in post-stroke epilepsy,¹² with LTG being the medication of choice in focal epilepsies.¹³ However, LTG can only be taken orally and is therefore not suitable for the management of acute seizures, leaving LEV along with phenytoin or fosphenytoin (fosPHE), valproic acid (VPA) and lacosamide as the main intravenous (IV) ASMs. Furthermore, LEV, fosPHE and VPA have all been found to be comparable in terms of efficacy and tolerability.¹⁴

HULM is well known in Spain for its advanced neurorehabilitation unit and is already linked to the Aotearoa New Zealand EpiNet: an international database facilitating multicentre collaborations in the clinical investigation of epilepsies (www.epinet.co.nz). At HULM there is a multidisciplinary team including neurology, neurophysiology, neurosurgery, rehabilitation and internal medicine, with rapid access to the emergency department and to an intensive care unit (ICU). Most inpatients carry significant neurological sequelae from major traumatic brain injuries, large strokes and post-anoxic, post-surgical and post–infectious lesions, often treated with transcranial magnetic stimulation, with an additional risk of seizures.¹⁵

“Time is brain”

SE is a medical emergency with a high morbidity and mortality, requiring prompt recognition and early treatment. Nevertheless, most seizures resolve spontaneously within 2–3 minutes without requiring any pharmacological intervention; therefore, particular care must be taken not to overtreat seizures that are going to be self-limited. Moreover, seizures presenting to emergency departments can be dissociative (DS) in nature, where particular care must be taken not to escalate treatment unnecessarily. In 2015, the International League Against Epilepsy taskforce defined the time periods for SE as 5 minutes for bilateral tonic-clonic seizures, 10 minutes for focal seizures and 10–15 minutes for absence seizures. The commonly proposed guidelines for the treatment of SE include first-line IV benzodiazepines, followed by second-line IV ASM at adequate doses. Around two-thirds of patients will respond to this therapeutic regimen.²

An international audit collected information from 776 cases of refractory SE in 50 countries, including cases treated with continuous IV anaesthetic drugs in an intensive care unit (ICU) setting, through online questionnaires using active surveillance. The audit ran over the course of 4 years. Control of SE was achieved in 74% of the cases. Neurological outcomes were poor in 41% of patients, and 24% died. A good outcome was associated with younger age and a previous history of epilepsy. Aetiology strongly influenced the outcome.¹⁶ After 30 minutes (for bilateral tonic-clonic seizures) or 60 minutes (for focal, non-convulsive epileptic activity), if seizures continue despite the use of two ASMs, patients are considered to have refractory SE. At this point, mortality rates as high as 38% have been reported. Without strong evidence to support a specific action plan, most guidelines and protocols suggest treatment with a continuous infusion of IV anaesthetics in this situation.¹⁷ Of all modifiable factors, early administration of appropriately dosed medication has demonstrated a positive impact on clinical outcomes, including the rapid initiation of supportive measures, assessment of the cause of the seizure and starting first-line treatment with benzodiazepines, as highlighted in recent reviews carried out across Aotearoa New Zealand¹⁸ as well as overseas.^17,19

With the aim of optimising the management of patients with seizures and borrowing from the stroke motto “time is brain”, seizure codes have been proposed and are being implemented. In the region of Madrid, an epileptic seizure and SE code has recently been established to better organise care across different levels of the healthcare system, facilitate therapeutic decision making and improve response times and patient outcomes.²⁰ Such an arrangement not only raises awareness about epileptic seizures and SE as a time-dependent urgent medical condition requiring a prompt and co-ordinated multidisciplinary therapeutic intervention, but may also contribute to shortening the gap between CPGs and actual clinical practice in the management of SE. On the other hand, a seizure code will result in a resource diversion away from other sick patients and could indeed have an impact on increasing treatment delays in the ED. Furthermore, it can potentially become a “magnet” for other seizure-like events, namely DS, potentially leading to unnecessarily harmful treatments. However, a seizure code can also be very beneficial when used knowledgeably for life-threatening conditions such as SE, and ultimately it will come down to clinical judgment and available resources at a local level to decide on the priority of care and management, regardless of codes, guidelines or algorithms.

Based on international CPGs and taking into consideration the characteristics of our centre and available resources, a pragmatic algorithm tailored to local needs where all staff are trained to become confident and competent using it can be particularly useful.

Buccal midazolam (MDZ)

Early administration of benzodiazepines (e.g., MDZ) along with second-line treatment intravenously (e.g., LEV) at adequate doses is key in the management of SE.^17–21 Lorazepam is currently unavailable in Spain intravenously and has often been used sublingually whenever the established risk of seizures is high, or in preventing clusters of seizures. Clonazepam is used in some centres but rarely by paramedics, who have IV or intramuscular MDZ and IV or rectal diazepam (DZP) as the main benzodiazepines available. Traditionally used in paediatrics, there is now significant evidence supporting the use of buccal MDZ as a therapeutic alternative to rectal DZP in adults in nursing homes, hospitals and community settings.²² Easy to use, effective, water soluble and not acidic (like the nasal form), it is also a more dignified route for the patient—healthcare professionals and caregivers can administer it in cases where IV access is not immediately available and/or proves difficult. Should more than one dose be needed to abort ongoing seizure activity or indeed to stop SE, even in a well-known patient with drug-resistant epilepsy and good adherence to treatment, admitting to ICU under observation for further management is generally advisable, given the increased risk of respiratory depression. In Spain, both DZP and MDZ are available for use and we have adopted buccal MDZ at HULM as the alternative drug of choice to first-line IV or intramuscular medication over intranasal or rectal benzodiazepines, considering its comparable efficacy and tolerability.

Epilepsy New Zealand (www.epilepsy.org.nz) distributes a one-page user-friendly guideline on the use of MDZ for the emergency management of seizures, supported by the Epilepsy Foundation, and is available at https://epilepsy.org.nz/wp-content/uploads/2022/07/Use-of-Midazolam_NZ-2022.pdf. Anybody, including family members, carers and health professionals, can easily be trained to use it in plastic ampoules like the ones available in Aotearoa New Zealand (Figure 1) or in plastic syringes, which are particularly user friendly and are now approved for use in adults (Figure 2).

Not all seizures are convulsive (or even) epileptic

Often diagnostically complex, but quite frequently found in a brain injury unit, is non-convulsive SE, usually of focal onset,²³ where access to electroencephalogram (EEG) is particularly helpful. Refractory and super-refractory convulsive SE can be subtle and may resemble non-convulsive SE, carrying a particularly poor prognosis and often requiring a pharmacologically induced coma to achieve burst suppression with ongoing or frequent EEG monitoring. The prognosis of SE will largely depend on the aetiology (e.g., a meningioma causing continuous seizures with impairment of consciousness will usually have a better prognosis than a new-onset refractory SE in the context of a limbic encephalitis, for instance), seizure duration and resistance to treatment.³ The main differential diagnosis of epileptic seizures, apart from syncope, are DS. Starting an ASM often implies a diagnosis of epilepsy, with significant clinical, psychosocial and economic consequences. Furthermore, a misdiagnosis of epilepsy is not rare and can occur in up to one in four patients, with DS accounting for the largest proportion.²⁴ The same applies to DS presenting as pseudo-SE, ideally requiring rapid access to a neurologist and to EEG whenever possible. Distinguishing SE from pseudo-SE is particularly relevant in order to minimise unnecessary treatments and potential iatrogenicity.

Drilling a hole to shorten the gap: the NEUROPA algorithm

A therapeutic algorithm should not be used to replace clinical experience or judgement. Furthermore, having a protocol or guideline in-house is no guarantee that it will be followed, especially when clinicians, nurses and paramedics are not familiar with or comfortable using it. In this regard, a flowchart adapted from a consensus guideline can be a very useful tool for the management of seizures and SE. Considering the universal to be the local without boundaries and in order to expedite in-hospital and pre-hospital treatment, with the collaboration of emergency services, paramedics and medical staff including internal medicine and ICU, we transposed to HULM the CPGs originally used at PNH.¹ The flowchart was tailored to the hospital’s resources and characteristics, with clinical observation along with an ongoing internal audit, both retrospective and prospective, already showing preliminary poorer outcomes in those cases where the treatment had been delayed or medication was administered below recommended doses, in line with the medical literature.

Taking into account the European Academy of Neurology (EAN) recommendations along with more up-to-date proposed pocket cards, protocols and guidelines,^25–26 while considering the treatments readily available in the hospital pharmacy and the circumstances of our centre, the PNH algorithm was adapted to a consensus-based CPG at HULM (which happens to be its exact antipode, at 40 degrees of latitude in the Northern Hemisphere [Figure 3]). Key points in the management of SE, therefore, include an early intervention (treatment should begin within 5–10 minutes of the onset of seizures) with ongoing monitoring in ICU as required.

Conclusion: go early, go hard and go local

SE is a life-threatening condition, one in which bold and early treatment significantly improves prognosis. Conversely, most seizures are self-limited and do not require pharmacological treatment. The risk of overtreating patients must, therefore, be carefully balanced against the risk of under-recognising and hence undertreating SE. Shortening the therapeutic gap by incorporating site-tailored, multidisciplinary CPGs for the management of seizures and SE with a streamlined flowchart is a straightforward, potentially life-saving hospital-centred tool.

To conclude, an acquired severe brain injury predisposes patients to seizures, epilepsy and SE. We adapted a pragmatic CPG from Aotearoa New Zealand to local needs on the opposite side of the world in order to help bridge the care gap in the clinical management of SE and improve the chances of better patient outcomes.

View Figure 1–3.