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Super Refractory Status Epilepticus

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Going beyond the algorithm, what can we do when a child is still fitting despite appropriate treatment?

Four-year-old Fern is a previously healthy girl who presents with a febrile illness and seizures.

Seizure activity did not respond to either first or second-line treatments, so she needed rapid sequence induction and transfer to PICU for ongoing anaesthesia and management.

Whilst in PICU, amplitude-integrated EEG monitoring is commenced and reveals ongoing seizure activity.

Burst suppression is only achieved after an escalation of anti-epileptic drugs and commencing a ketogenic diet.

Extensive screening for infection, auto-immunity, and metabolic diseases finds no underlying cause.

What is Super Refractory Status Epilepticus (SRSE)?

Super Refractory Status Epilepticus (SRSE) is a life-threatening neurological emergency with high morbidity and mortality.

SRSE is defined as status epilepticus that: 

Does not respond to first and second-line antiepileptic treatment 

Persists at least 24 hours after the onset of anaesthesia, either without interruption despite appropriate treatment with anaesthesia, recurring while on appropriate anaesthetic treatment, or recurring after withdrawal of anaesthesia and requiring anaesthetic reintroduction. 

SRSE is primarily seen in the PICU, given that SRSE occurs after failure of second-line anti-epileptic drugs and anaesthesia. Recognising and understanding this thankfully rare but potentially devastating complication of seizures is important for all of us involved in the care of children.

Status epilepticus is estimated to occur in 17-23/100,000 children, with 10%-40% developing refractory status epilepticus and a small proportion of these then going on to develop SRSE. 

SRSE may present with generalised convulsive status epilepticus, focal status epilepticus with impaired consciousness, or subtler presentations such as non-convulsive status epilepticus (NCSE).

What causes Super Refractory Status Epilepticus?

Causes are also variable, including infections, autoimmunity, malignancy, pre-existing seizure disorders, and traumatic brain injury.

SRSE can also occur in previously healthy school-aged children without epilepsy or a pre-existing neurological disorder. This is called New-Onset Refractory Status Epilepticus (NORSE). When precipitated by fever, it is known as Febrile Infection-Related Epilepsy Syndrome (FIRES).

Although NORSE and FIRES are rare epilepsy syndromes, they are frequent amongst the SRSE population.

The cause of SRSE is relatively complicated, with many different pathophysiological mechanisms implicated.

Essentially, failure to respond to the body’s normal ways of stopping seizures leads to the seizure becoming self-sustained and unresponsive to treatments.

A reduction in the effectiveness of seizure inhibition, including the internalisation of GABA receptors into the brain cells (reducing the receptor’s availability for anti-epileptic drugs to act upon) coupled with brain hyperexcitability (due to mitochondrial failure, blood-brain barrier damage, or neuroinflammation) are potential mechanisms.

What is the problem with SRSE?

Once a child is mechanically ventilated, or if they are having NCSE, seizures can be difficult to recognise.

Unfortunately, SRSE is more likely to occur and persist if this is the case and treatment is delayed or inadequate.

Mortality is high, between 16-43.5%, and neurological outcomes are generally poor amongst survivors. Children who survive SRSE are less likely to return to their baseline neurological function and often go on to develop drug-resistant epilepsy. These poor outcomes are related to both the SRSE itself and as a result of the prolonged PICU stay. One case-series of children with SRSE showed a median PICU stay of 27 days and hospital length of stay of 62 days. PICU-related co-morbidities include but are not limited to, hypotension, respiratory failure, hospital-acquired infections, and prolonged immobility.

What are our treatment goals?

Initial treatment in PICU involves using anaesthetic agents to induce a pharmacological coma and achieve rapid seizure control and neuroprotection. There is no evidence on the choice of anaesthetic agent, and treatment is often individualised based on the child, the clinical condition, and the potential adverse effects of each agent (shown in the table below).

The anaesthetic agent should be titrated to achieve seizure cessation (which will require EEG monitoring) and is generally maintained for at least 24-48 hours before being weaned. Adjunctive treatments may also be used.

Some children will enter a chronic phase of illness where the seizure activity cannot be completely suppressed. Here, the goal of treatment, without an identifiable and treatable cause, is to move to a mitigation strategy where the child lives with chronic drug-resistant epilepsy.

Death from this syndrome, typically, is because of withdrawal from life-sustaining treatment or because of the complications of prolonged PICU stay and mechanical ventilation. 

Potential adjunctive therapies

Treatment decisions around the use of adjunctive therapies mainly relies on case-series or expert opinion and a formalised comparison between different strategies has not been evaluated in a robust way. Below there is a brief overview of some of the adjunctive treatments that may be considered and the evidence behind them. 

Ketogenic diet

The ketogenic diet is a high-fat, low-carbohydrate diet which is thought to have anti-inflammatory and anti-seizure properties. This has shown benefit for drug resistant epilepsy with a Cochrane review demonstrating that children were up to three times more likely to be seizure free, and up to six times more likely to achieve a reduction in seizure frequency compared to children given their usual care. Studies into the use of the ketogenic diet for SRSE have also been promising, with some studies demonstrating over 50% of children achieving remission, particularly in the FIRES group of children. However, at present these studies are largely small to moderate case series. 

It is important to note that the ketogenic diet is contraindicated in children with certain metabolic defects. Additionally, treatment can be difficult due to feed intolerance and side effects such as hypertriglyceridaemia and pancreatitis, which may require cessation of treatment.

Immunomodulators

Anakinra is a human recombinant IL-1β blocker which on a first principles basis may be beneficial in treating FIRES. Raised levels of IL1-α and IL1-β have been found in CSF of children presenting with FIRES suggest a strong auto-inflammatory response which may be amenable to immunomodulation. Currently there are case-series which seem to demonstrate a beneficial effect. 

Tocilizumab has also been trialled in a few small case series. One study suggests remission in 6 out of 7 patients where it was used, but long-term clinical outcomes remained poor. There was, however, a suggestion of increased benefit with earlier initiation. 

IVIG has been used as a treatment in SRSE but there are no trials delineating its effectiveness in FIRES. It has been shown to be useful in auto-immune mediated SRSE. 

There is also no strong evidence to support the use of steroids in SRSE, but they may have some benefit in reducing inflammation contributing to seizure activity. 

Allopregnanolone is a neuro-steroid, which is secreted by glial cells within the brain which modulates the activity of GABA receptors. The first human trials for children with SRSE were conducted in 2014 where 2 patients responded well to the treatment and there have been encouraging results in open label adult trials more recently. 

Therapeutic cooling

Amongst adults, the HYBERNATUS trial demonstrated short-term reduced seizure activity in the cooled group compared to controls, but no difference in 90-day outcome. Smaller studies trialling therapeutic cooling in paediatric patients seem to have demonstrated benefit but are restricted to small case series. 

Magnesium 

Little evidence exists for the use of magnesium in SRSE but it is a well-tolerated drug with a history of clinical efficacy in eclampsia and Alpers syndrome. There are small scale case series of its use in FIRES with some success. 

Cannabidiol

Cannabidiol has shown efficacy in the treatment of Lennox-Gastaut and Dravet syndrome and is a potentially promising treatment option for SRSE. Of note cannabidiol is an enzyme inhibitor so may interact with other drugs

Take-home messages

SRSE is a rare but life-threatening complication of seizures

Early recognition and treatment are essential 

Management is focussed on the suppression of seizure activity to reduce irreversible damage to the brain, either to reset the brain after breaking the seizure, or to allow time for adjunctive therapies to suppress seizure activity to a level where anaesthetic treatments can be withdrawn

The outcome for children with SRSE is poor and most children have a degree of neurodisability and drug-resistant epilepsy

About PICSTAR

PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care.  We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.

If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to get in touch with us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/

References

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Breu M, Häfele C, Glatter S, Trimmel-Schwahofer P, Golej J, Male C, Feucht M, Dressler A. Ketogenic Diet in the Treatment of Super-Refractory Status Epilepticus at a Pediatric Intensive Care Unit: A Single-Center Experience. Front Neurol. 2021 Jun 3;12:669296. doi: 10.3389/fneur.2021.669296. PMID: 34149600; PMCID: PMC8209375.

Broomall E, Natale JE, Grimason M, Goldstein J, Smith CM, Chang C, Kanes S, Rogawski MA, Wainwright MS. Pediatric super-refractory status epilepticus treated with allopregnanolone. Ann Neurol. 2014 Dec;76(6):911-5. doi: 10.1002/ana.24295. Epub 2014 Nov 11. PMID: 25363147; PMCID: PMC4534165.

Clarkson BDS, LaFrance-Corey RG, Kahoud RJ, Farias-Moeller R, Payne ET, Howe CL. Functional deficiency in endogenous interleukin-1 receptor antagonist in patients with febrile infection-related epilepsy syndrome. Ann Neurol. 2019 Apr;85(4):526-537. doi: 10.1002/ana.25439. Epub 2019 Mar 8. PMID: 30779222; PMCID: PMC6450741.

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM; GWPCARE3 Study Group. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018 May 17;378(20):1888-1897. doi: 10.1056/NEJMoa1714631. PMID: 29768152.

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S; Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020. doi: 10.1056/NEJMoa1611618. PMID: 28538134.

Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open. 2019;4(2):344-350. doi:10.1002/epi4.12317

Hirsch LJ, Gaspard N, van Baalen A, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia. 2018;59(4):739-744. doi:10.1111/epi.14016

Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol. 2018 Dec;84(6):940-945. doi: 10.1002/ana.25374. Epub 2018 Nov 30. PMID: 30408233.

Legriel S, Lemiale V, Schenck M, Chelly J, Laurent V, Daviaud F, Srairi M, Hamdi A, Geri G, Rossignol T, Hilly-Ginoux J, Boisramé-Helms J, Louart B, Malissin I, Mongardon N, Planquette B, Thirion M, Merceron S, Canet E, Pico F, Tran-Dinh YR, Bedos JP, Azoulay E, Resche-Rigon M, Cariou A; HYBERNATUS Study Group. Hypothermia for Neuroprotection in Convulsive Status Epilepticus. N Engl J Med. 2016 Dec 22;375(25):2457-2467. doi: 10.1056/NEJMoa1608193. PMID: 28002714.

Martin-McGill KJ, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2020 Jun 24;6(6):CD001903. doi: 10.1002/14651858.CD001903.pub5. PMID: 32588435; PMCID: PMC7387249.

Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51(10):2033-2037. doi:10.1111/j.1528-1167.2010.02703.x

Ochoa JG, Dougherty M, Papanastassiou A, Gidal B, Mohamed I, Vossler DG. Treatment of Super-Refractory Status Epilepticus: A Review. Epilepsy Curr. 2021 Mar 10;21(6):1535759721999670. doi: 10.1177/1535759721999670. Epub ahead of print. PMID: 33719651; PMCID: PMC8652329.

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Rosenthal ES, Claassen J, Wainwright MS, Husain AM, Vaitkevicius H, Raines S, Hoffmann E, Colquhoun H, Doherty JJ, Kanes SJ. Brexanolone as adjunctive therapy in super-refractory status epilepticus. Ann Neurol. 2017 Sep;82(3):342-352. doi: 10.1002/ana.25008. Epub 2017 Sep 11. PMID: 28779545; PMCID: PMC5639357.

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Tan, W. W., Chan, D. W. S., Lee, J. H., Thomas, T., Menon, A. P., & Chan, Y. H. (2015). Use of Magnesium Sulfate Infusion for the Management of Febrile Illness-Related Epilepsy Syndrome: A Case Series. Child neurology open2(1), 2329048X14550067. https://doi.org/10.1177/2329048X14550067

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Visser, N. A., Braun, K. P., Leijten, F. S., van Nieuwenhuizen, O., Wokke, J. H., & van den Bergh, W. M. (2011). Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. Journal of neurology258(2), 218–222. https://doi.org/10.1007/s00415-010-5721-2

Authors

  • Owen Hibberd is an Emergency Medicine Trainee in Cambridge, currently studying on the QMUL PEM MSc. Interested in Paediatric Emergency Medicine, Pre-Hospital Emergency Medicine and Medical Education. He/him.

  • Alex is an ST8 PICM GRID trainee originally from Nottingham and the East Midlands, now completing training at Birmingham Children's Hospital. His interests are how and why we make the clinical decisions we do, how we know what we think we know and expressly not doing things "because that's the way we have always done it".

  • Spyridon is a Paediatric Resident in Athens, interested in Paediatric Emergency Medicine, reducing antibiotic use in paediatric patients and in Medical Education. Currently studying on the QMUL PEM MSc. He/him.

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