Intensive care treated refractory status epilepticus : incidence and outcome in Finland 2010-2012

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DISSERTATIONS | ANNE-MARI KANTANEN | INTENSIVE CARE TREATED REFRACTORY STATUS... | No 420

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ANNE-MARI KANTANEN

INTENSIVE CARE TREATED REFRACTORY STATUS EPILEPTICUS

Incidence and Outcome in Finland 2010–2012

ANNE-MARI KANTANEN

Status epilepticus (SE) is a neurological emergency that may cause death and marked

neurological deficiency. There is paucity of population-based epidemiological studies

especially on the refractory and super- refractory forms of SE. This thesis provides

new information on the incidence and long- term outcome (one-year) of most severe forms of SE: Intensive Care Unit- (ICU) and anaesthesia-treated refractory and super-refractory SE. The Finnish Intensive

Care Consortium (FICC) national ICU benchmarking programme was used as the population based data source for this study.

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Intensive Care Treated Refractory Status Epilepticus – Incidence and Outcome in

Finland 2010–2012

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ANNE-MARI KANTANEN

Intensive Care Treated Refractory Status Epilepticus –

Incidence and Outcome in Finland 2010-2012

To be presented with permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Kuopio University Hospital Auditorium, Kuopio, on Saturday, May 20^th 2017,

at 13.00 hours

Publications of the University of Eastern Finland Dissertations in Health Sciences

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Department of Neurology and Department of Anaesthesiology and Intensive Care, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland

Kuopio 2017

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Institute of Clinical Medicine, Clinical Radiology and Nuclear Medicine Faculty of Health Sciences

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Department of Nursing Science Faculty of Health Sciences Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences

Associate Professor (Tenure Track) Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

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III

Author’s address: Neurocenter, Epilepsy Center, Kuopio University Hospital and Department of Neurology, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences

University of Eastern Finland KUOPIO

FINLAND

Supervisors: Professor Reetta Kälviäinen, M.D., Ph.D.

Department of Neurology, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences

FINLAND

Docent Matti Reinikainen, M.D., Ph.D.

Department of Intensive Care, North Karelia Central Hospital JOENSUU

FINLAND

Docent Ilkka Parviainen, M.D, Ph.D.

Department of Intensive Care, Kuopio University Hospital KUOPIO

FINLAND

Professor Esko Ruokonen, M.D.,Ph.D.

Department of Intensive Care, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences

FINLAND

Reviewers: Professor Jukka Peltola, M.D, Ph.D.

Department of Neurology, Faculty of Medicine and Life Scinces University of Tampere

TAMPERE FINLAND

Docent Lauri Soinne, M.D., Ph.D.

Department of Neurology, Institute of Clinical Medicine Helsinki University

HELSINKI FINLAND

Opponent: Professor Simon Shorvon, M.A., M.D., F.R.C.P.

Institute of Neurology University College of London LONDON

UNITED KINGDOM

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V

Kantanen, Anne-Mari

Intensive Care Treated Refractory Status Epilepticus – Incidence and Outcome in Finland 2010-2012 University of Eastern Finland, Faculty of Health Sciences

Publications of the University of Eastern Finland. Dissertations in Health Sciences ŚŘŖ. ŘŖŗŝ. ŗŗř p.

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ABSTRACT

Status epilepticus (SE) is a neurological emergency that may cause death and marked neurological deficiency. The condition is called refractory status epilepticus (RSE) if the first- and second-line medications fail to terminate the seizure, and super-refractory status epilepticus (SRSE) if it continues beyond 24 h after the administration of first anaesthesia.

Data on long-term outcomes of SE are scarce, particularly in the cases of RSE and SRSE, and are based on small patient cohorts. I analysed the first population-based, nationwide cohort showing the incidence and long-term outcome (one-year) of Intensive Care Unit- (ICU) and anaesthesia-treated RSE and SRSE.

The Finnish Intensive Care Consortium (FICC) is a body responsible for a national ICU benchmarking programme and database in Finland. All 20 major central and university hospitals providing secondary and tertiary care, ICUs, and neurological services for their referral population in Finland have joined the consortium. I used the FICC database and medical records to identify adult (16 years or over) RSE patients treated in ICU with general anaesthesia) in a population-based cohort in Finland, during a 3-year period of 2010–2012.

Patients with postanoxic aetiologies were excluded.

Altogether, 395 incidents of RSE fulfilled the final inclusion criteria, 87 (22%) were diagnosed as SRSE. The incidence of RSE was 3.4/100,000/year, and 0.7/100,000/year for SRSE. The one-year mortality of all RSE and SRSE patients was 25% and 36% respectively.

Super-refractoriness, dependence on activities of daily living (ADL) functions, severity of organ dysfunction at ICU admission, and higher age predicted long-term mortality. In Kuopio University Hospital special responsibility area, (population 840 000) nearly 50% of the ICU-treated RSE patients recovered to baseline function, whereas 30% showed new functional defects, and 20% died. The outcome was worse in older patients and in patients with progressive or fatal etiologies.

ICU treated refractory status epilepticus is a rare yet lethal medical emergency with high mortality rate (25%) especially in the elderly population. More population-based prospective studies of SE are needed not only to understand this entity but also improve the long-term outcome of patients with RSE.

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VII

Kantanen, Anne-Mari

Tehoitoa vaativa pitkittynyt epileptinen kohtaus Suomessa – ilmaantuvuus – ja kuolleisuus vuosina 2010 - 2012

Itä-Suomen yliopisto, Terveystieteiden tiedekunta

Publications of the University of Eastern Finland. Dissertations in Health Sciences ŚŘŖ. ŘŖŗŝ. ŗŗř s.

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TIIVISTELMÄ

Pitkittynyt epileptinen kohtaus, eli status epilepticus, on neurologinen hätätilanne, joka vaatii välitöntä hoitoa ja johon liittyy merkittävä kuolleisuuden ja vammautumisen riski.

Pitkittynyttä epileptistä kohtausta kutsutaan hoitoresistentiksi, jos kohtausoire ei vastaa annettuun ensimmäisen – ja toisen linjan lääkehoitoon, ja potilas joudutaan hoitamaan yleisanestesiassa teho-osastolla. Mikäli oireet jatkuvat yli 24 tuntia ensimmäisen yleisanestesian aloittamisesta, pitkittynyttä epileptistä kohtausta kutsutaan erittäin hoitoresistentiksi. Hoitoresistentin, pitkittyneen epileptisen kohtauksen pitkäaikaisennusteesta on hyvin vähän tutkimustietoa ja olemassa oleva tieto perustuu pieniin tutkimusotoksiin. Tutkimuksessa analysoidaan väestöpohjaisen potilaskohortin pohjalta hoitoresistentin ja erittäin hoitoresistentin status epilepticuksen ilmaantuvuutta ja pitkäaikaisennustetta. Tutkimukseen otettiin mukaan yhden vuoden ajalta tehohoidetut ja hoitoresistentit suomalaiset status epilepticus -potilaat.

Suomen tehohoitokonsortio ohjaa ja koordinoi suomalaisten teho-osastojen laadunvalvontaa ja vertaisarviointia laatutietokannan avulla. Konsortioon kuuluvat nykyisin kaikkien suomalaisten keskus – ja yliopistosairaaloiden yleisteho-osastot.

Hyödynsimme tutkimuksessa tehohoitokonsortion laatutietokantaa ja sairauskertomustietoja kaikkien suomalaisten yleisanestesiassa ja teho-osastoilla kolmen vuoden aikana (2010-2012) hoidettujen hoitoresistenttien status epilepticus - aikuispotilaiden (16-vuotiaat ja vanhemmat) tunnistamiseen. Tutkimuksen ulkopuolelle suljettiin hapenpuutteesta johtuvan aivovaurion aiheuttamat kohtausoireet. Tutkimukseen valikoitui kaikkiaan 395 sisäänottokriteerit täyttävää hoitojaksoa, joista 87 (22%) oli erittäin hoitoresistenttejä potilaita. Väitöskirjatutkimuksessa havaittiin, että hoitoresistentin status epilepticuksen ilmaantuvuus oli 3.4/100 000 tapausta vuodessa ja kuolleisuus 25%, kun taas erittäin hoitoresistentin status epilepticuksen ilmaantuvuus oli 0.7/100 000 ja vuosikuolleisuus nousi aina 36%:iin saakka. Kuolleisuutta ennusti oirekuvan pitkittyminen erittäin hoitoresistentiksi, aiempi alentunut omatoimisuusaste päivittäistoiminnoissa ja eri elinjärjestelmien toimintahäiriöt ensimmäisen tehohoitovuorokauden aikana. Kuopion Yliopistollisen Sairaalan erityisvastuualueen sairaaloissa (väestömäärä 840 000) tehdyissä arvioissa ilmeni seuraavaa: Vuoden kohdalla lähes 50% potilaista oli palautunut

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voinniltaan lähtötasoon, 30%:lle jäi toiminnallista haittaa ja kaikkiaan 20% kuoli. Ennuste oli huonompi iäkkäämmillä potilailla ja niillä, joiden hoitoresistentin status epilepticuksen syynä oli etenevä tai vaikea kuolemaan johtava sairaus.

Luokitus:

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IX

‘Success is not final, failure is not fatal: it is the courage to continue that counts.’

Anonymous

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Acknowledgements

This doctoral thesis was carried out in the Departments of Neurology and Anesthesiology and Intensive Care in Kuopio University Hospital and Institute of Clinical Medicine at University of Eastern Finland and in collaboration with Finnish Intensive Care Consortium during the years 2014 – 2017. This study was supported by grants from Kuopio University Hospital Special Government Funding (VTR, 507 T006), Finnish Epilepsy Research Foundation, Finnish Cultural Foundation and Saastamoinen Foundation.

I wish to express my deepest gratitude to my principal supervisor, Professor Reetta Kälviäinen. I am privileged to say that you wise, intelligent, strong and warmhearted woman, are my supervisor in this thesis. It would have never been started or finished without you and your participation.

There would not have been this project and thesis without my co-supervisor Professor Esko Ruokonen, Intensive Care Specialist and one of the “grand old men in intensive care”. You had the original idea of this study and pushed us gently to start it. I am happy to say that you also have been the Godfather of my professional life: I would not be here and now if it wasn´t your influence. It is such a privilege to have met you early enough in life!

Docent Ilkka Parviainen, my dear co-supervisor, or “subvisor” as you like to say, Intensive Care head of department at Kuopio University Hospital. You are a remarkable professional and such a charming personality. You had all the contacts needed to have the FICC data cleared: without your help it would not have been possible. The most important thing I want to thank you for is “the best time of the day” – having lunch and extremely bad coffee in KUH cafeteria on daily basis.

I am also very grateful to docent Matti Reinikainen, from North Karelia Central Hospital, who I have had a privilege to get to know better with this project and having you my co- supervisor also. You are brilliant and intelligent, true scientist and amazing lecturer and supervisor and very talented intensive care physician. Your knowledge of statistics and consortium data and the way you can teach things to other people is so valuable and important. I value your advice, views and friendship.

Professor Pekka Jäkälä, Head of Neurocenter, thank you very much for being a collegue, a co-worker, a good boss and also a friend for over 15 years. Thank you for giving me great opportunities in the field of neuroacutology and stroke, training young neurologists and so much more than average clinician job includes. You also know the two words: “Thank You”, and use them in great amounts.

Professor, Dean Hilkka Soininen: I want to thank you for giving me the possibility to specialize in Neurology and also work on behalf of colleagues in different meetings, projects and associations alongside the clinical work during the early years.

Docent Harri Hyppölä. You have absolutely nothing to do with my thesis, but you have been a great head of the Emergency Department and it has been great working with you and for you. You are a multitalented person, who can do what ever you set your mind to.

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Most of all I wish to thank you for your friendship, it has been very important to me and always will be.

Thank you for all co-writers Marika Ala-Peijari, Tom Bäcklund, Juha Koskenkari and Ruut Laitio for giving a valuable input in this project by clearing the majority of the data and your comments on the two of the articles. I also want to thank all the colleagues all around Finnish ICUs for making data clarification possible. I owe you big time. Thank you also for Juuso Tamminen, for helping me with the figures and tables! One can really tell which are the ones you draw.

I am indebted to the wonderful reviwers of this thesis, Professor Jukka Peltola and Docent Lauri Soinne. Thank you for your time and effort and kindness during the process. Your comments improved this thesis greatly.

I would also like to express my deepest gratitude to all of my colleagues: specialists and juniors in the Department of Neurology: you are wonderful, hardworking and modest people that are not afraid to change along with the speciality requirements. Thank you for your friendship and putting up with me during this project and everyday life. I surely enjoy the team spirit, caring and family like atmosphere and sense of humor we share. I would also like to thank other professionals in our clinic: intelligent neuropsychologists, all the nurses for being there for the patients and hard work, the best ever text-writers and ward secretaries and housekeeping personnel for your kindness and good work.

I also would like to thank the Neurosurgeons, our companions in Neurocenter everyday life. Thank you for the expertise and skills you have and also for the great tolerance of me.

We surely are like old married couple: can not live with or without each other and evidently together we are stronger. Let us continue until death do us apart and before that – let us watch many new NeuroCenter movies together.

A neurologist never walks alone. Our work would be impossible without everyday collaboration with other groups of specialists. Since I know that KUH is the best ever hospital in Finland, I want to express my gratitude to our talented radiologists, clinical neurophysiologists that provide us the best services in the country and our lovable cardiologists, collegues in EMS and emergency department and for me most of all: ICU specialists for keeping up the good work 24/7 and sharing the best and darkest moments of clinical work. I also would like to thank all the personnel of ED and ICU for your support and good work you do. You are all awesome!

I wish to thank my “adopted sisters in life” – Viiteryhmän akat – for the friendship that has lasted for over 20 years now, starting from the medical school. With you I can be myself, nothing more nothing less. There is no joy that great or sorrow that deep that I could not share with you – and life really has been full of them for us all and there will be many to conquer. I admire you all as modern academic women who just have done it all: having a career, wonderful children and absolutely great husbands, having talent in different fields of life as well. It is not easy, but it is a way of life. With you I sometimes believe that men and women are equal in life.

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My dear friend Leena Jutila, you are so many things to me: a friend, a excellent co-worker and professional, a neighbor, step-aunt to Leevi – you name it. We are so different and yet the same. I am very grateful for your endless support and friendship for many years and I hope there will be many more to come. I also want to thank the dear EB team of Kuopio:

Maarit Lång (we eat ten), Riikka Kettunen and Outi Vanha-Kämppä for being there virtually every day. Also EB Finland – the Evilest of them all Tinja, Marjo and Suvi for friendships that lasts even after NLY years. Let there be a lot of shared champagne in our life.

I am a blessed person for having so many friends over the years. I want to thank all of you for your friendship and tolerance and being there for me. With some we have had good meetings, with some the best travels, with all the funniest dinners and endless conversations over the years.

I would like to thank my father Matti Kantanen, for being absolutely the best father. You have always been encouraging me to do what ever I wish to do in life. My dear little brother Olli I would like to thank you for being such a great guy. I am very proud of you and your lovely family. My oldest little brother Ville I would like to thank for the love and kindness and showing me that there is diversity in life. I also would like to thank my little sister Maria for being such a fine young lady. I am very proud of you. I would also like to thank my mother Helena († 2011), for believing in me and teaching me the best way to cherish your loved ones: cooking tasty meals.

Most of all I would like to thank my ”peculiar extended family”. My dear son Leevi (Pöllykkä, Pampula, Pörrö), you are the sunshine of my life and the best thing that has happened to me, I love you so much. I also would like to thank Leevi’s father Olli for the friendship that has survived over the years and your spouse Outi for loving Leevi as one your own. I would like to express my gratitude to my spouse Pasi for the years together so far. Thank you for your love and patience and understanding during this project and let there be life, love and many happy moments after this dissertation.

Kuopio, April 2017 Anne-Mari Kantanen

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List of the original publications

This dissertation is based on the following original publications:

I Kantanen A-M, Reinikainen M, Parviainen I, Ruokonen E, Ala-Peijari M, Bäcklund T, Koskenkari J, Laitio R, Kälväinen R. Incidence and mortality of super-refractory status epilepticus in adults. Epilepsy&Behavior 2015 Aug; 49:

131-4

II Kantanen A-M, Kälviäinen Reetta, Parviainen Ilkka, Reinikainen Matti. Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus: a population based study. Critical Care 2017 Mar 23; 21 (1): 71-7

III Kantanen A-M, Reinikainen M, Parviainen I, Kälviäinen R. Long term outcome of refractory status epilepticus: Apopulation-based study. Epilepsy Research 2017 Apr 2; 133: 13-21

The publications were adapted with the permission of the copyright owners.

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6.3.2 Clinical factors ... 51 6.3.3. Statistics ... 52 6.3.4 Standard protocol approvals, registrations, and patient consents ... 52 6.4 Results ... 52 6.4.1. Incidence, mortality and morbidity ... 52 6.4.2. Demographics and predictors by 1–year outcome in RSE ... 54 6.4.3 Adherence to AED and EEG guidelines ... 57 6.4.4. Super-refractory status epilepticus ... 58 6.5 discussion ... 60 6.5.1 Main findings ... 60 6.5.2 Limitations and need for future work ... 62 7 GENERAL DISCUSSIONS ... 63

7.1 Incidence of intensive care treated refractory and super-refractory status epilepticus 63 7.2 Predictors of short- and long-term mortality of refractory status epilepticus ... 64 7.3 Long-term functional outcome of refractory and super-refractory status epilepticus .. 65 7.4 Adherence to current care guideline and practical implications ... 66 7.5 Strengths and weaknesses of the study ... 67 7.6 Future perspectives ... 68 8 CONCLUSIONS ... 69 9 REFERENCES ... 71

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Abbreviations

ADL activities of daily living

AED antiepileptic drug

AMPA ΅-amino-3-hydroxy-5-methyl-

4-isoxazolepropionic acid

aOR Adjusted odds ratio

APACHE Acute Physiology and Chronic Health Evaluation cEEG

CI CNS COI CSF DNA ECG ED EEG EMS EMSE

ER FICC

GABA

continuous

electroencephalogram confidence interval central nervous system cost of illness

cerebrospinal fluid Deoxyribonucleic acid electrocardiogram emergency department electroencephalogram Emergency Medical System theȱ epidemiologyȱ based mortality score in status epilepticus

emergency room Finnish Intensive Care Consortium

gamma-aminobutyric acid

GCS Glasgow Coma Scale

GOS Glasgow Outcome Scale

GOS-E Glasgow Outcome Scale

Extended

ICU intensive care unit

ILAE International League Against

Epilepsy

IQR interquartile range

IV intravenous

IVA intravenous anaesthetic

KUH Kuopio University Hospital

LOS length of stay

MELAS mitochondrial

encephalopathy with lactic acidosis and stroke-like episodes

MS multiple sclerosis

NMDA N-methyl-D-aspartate

NCSE Nonconvulsive status

epilepticus

NSE nonrefractory status

epilepticus

NYHA New York Heart Association

functional classification

mRS modified Rankin Scale

PRIS propofol infusion syndrome

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RNA ribonucleic acid RSE refractory status epilepticus SAPS The Simplified Acute

Physiology Score

SE status epilepticus

SOFA Sequential Organ Failure Assessment

SRSE super-refractory status epilepticus

STESS the status epilepticus severity score

Sz seizure

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1 Introduction

An epileptic seizure is a transient occurrence of signs and symptoms due to abnormal, excessive or synchronous neuronal activity in the brain (Fisher et al. 2005). Epileptic seizures are usually short and self-terminating. Seizures of any type can, however, continue persistently, and they are then considered as a separate condition known as status epilepticus (SE) (Shorvon 1994). In half of the cases SE occurs de novo, without prior epilepsy. Status epilepticus can have long-term consequences including neuronal death, neuronal injury and alteration in neuronal networks (Trinka et al. 2015). Treatment of SE is aimed at stopping seizures rapidly in order avoid neuronal damage, other morbidity and mortality (Shorvon & Ferlisi 2011).

All current treatment protocols acknowledge a staged approach to treatment with first-, second- and third-line medications, and emphasize prompt recognition and termination of seizure activity (Trinka & Kälviäinen 2017). Refractory status epilepticus (RSE) occurs if the first- and second-line medications fail to terminate the seizure. RSE is treated at the Intensive Care Unit (ICU), with general anaesthesia used as a third-line medication, unless the intensive care is considered futile, and only second-line treatments are continued as palliative measures. Super-refractory status epilecticus (SRSE) occurs if RSE continues beyond 24 h from the onset of administering the first anaesthesia at the ICU (Shorvon &

Ferlisi 2011). The long-term mortality of RSE is 35% (Shorvon & Ferlisi 2012), and depends on the underlying aetiology and the duration of SE (Neligan & Shorvon 2011). Although being a life-threatening condition necessitating complex critical care, there is an alarming paucity of population-based epidemiological and long-term outcome data on RSE and SRSE.

The present study aims to investigate the incidence and long-term mortality and mortality related to ICU- and anaesthesia-treated RSE and SRSE, using the Finnish Intensive Care Consortium (FICC) national ICU benchmarking programme as the population-based data source.

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3

2 Review of the Literature

2.1 STATUS EPILEPTICUS

2.1.1 History

SE is a fatal condition that was first mentioned as early as 718-612 B.C., in the Babylonian diagnostic manual called Sakikku (Shorvon 1994). Apart from a few sporadic notes, like from Caelius Aurelian in the fifth century, about poor prognosis of “epileptic attacks that extend to a second day”, SE was not mentioned until the 1850s, when the concept of the status was truly formulated, although epilepsy itself was widely mentioned and studied (Shorvon 1994). The first term to describe SE was “état de mal”, published by Luis Calmeil in 1824; the term was originally used by his patients for a severe and often fatal seizure in the Parisian asylum of Salpêtrière. Calmeil and later Delasiauve in 1854 recognized that the real danger lies not in the number or duration of individual seizures in the cluster, but the succession of seizures without recovery in between. Desiré Magloir Bourneville (1869) was the first to describe the secondarily generalized tonic-clonic status and the two periods of SE: The convulsive and what we now call subtle status. Bazire translated “ètat de mal” to Latin-English as “status epilepticus” in 1868. The first series of studies on SE was conducted from 1903-1904 by Clarke and Prout, and stated that: “Status epilepticus is the maximum development of epilepsy in which one paroxysm follows another so closely that coma and exhaustion are continuous between seizures” (Neligan & Shorvon 2009). They also recognized de novo SE in the presence of brain trauma. In his textbook of 1907, Turner was the first to recognize SE in three circumstances: As the first manifestation of epilepsy, as a recurrent phenomenon in established epilepsy, and as a recurrent event without other symptoms of epilepsy. He also noted that SE in patients with epilepsy could result from sudden cessation of sedatives or bromides (Neligan & Shorvon 2009).

The International League Against Epilepsy (ILAE) was founded in 1909, and the new journal Epilepsia, had a profound impact on the SE concept, definition, and use of electroencephalogram, (EEG) and treatment protocols both in Europe and US. William Shanahan published the first review of SE in 1915, estimating the mortality of SE to be around 20-25%, and claiming “prompt and energetic treatments” for SE. During the First and Second World Wars, interest in SE diminished, but after the wars, publishing of clinical features and prognosis of SE increased again. After the wars, one of the important milestones was the Xth Marseille Colloquium in 1962, which was solely devoted to SE, and was led by Henri Gastaut. A review of the lectures of the colloquium by Janz (1967) includes the basic principles of the SE definition, and the first suggestion of a modern treatment protocol for SE, for pre– and inhospital use. Artificial ventilation, curarisation,

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EEG monitoring, pharmacokinetics and different routes of rapid medication administration were mentioned (Janz 2013). The recognition that prolonged (82 min or longer) SE causes cerebral damage via excitotoxicity, and that early therapy is important in preventing this brain damage by Brian Meldrum in the 1970s (Meldrum & Horton 1973; Meldrum 2007) was an important milestone. Urgent therapy of febrile SE to prevent longer-term neurologic damage was recognized through the work of Aicardi and his colleagues in the 1970s (Aicardi & Chevrie 1970).

The medical treatment of SE before 1909 was derived from various sources including mustard flour, lavement purgatives (laxatives) and quinine sulphate; however, these treatments had very little effect on seizures (Janz 2013; Shorvon 2013). The first few treatments that were used and thought to be effective included the vasodilator amyl-nitrate (1876), and later the use of bromides. Inhalation of chloroform, small doses of morphia, amyl-nitrate and venesections were thus used as treatments. The idea of administering antiepileptic agents in high enough amounts as anaesthetic treatments is an approach used from 1850, after the invention of bromides (Neligan & Shorvon 2009). The use of anaesthesia became safe and more common only 100 years later in 1950, after treatments such as curarisation, intravenous (IV) anaesthesia, and positive pressure ventilation became possibilities (Neligan & Shorvon 2009). Phenobarbital was introduced in 1912 to treat epilepsy, and SE, although the use of bromides continued. Barbiturates were invented in the 1930s; thiopental and pentobarbital are still used as third-line treatment of SE. Propofol invented in 1977, and midazolam in 1978 are contemporary drugs used to treat SE (Janz 2013; Shorvon 2013). Similarly, intravenous phenytoin hit the market in 1958 and benzodiazepines were introduced in the 1960s. Diazepam became drug of choice for out-of- hospital treatment in rectal formulations during the 1970s (Shorvon 2013). Benzodiazepines, phenytoin, propofol and barbiturates are currently the main medications used to treat SE.

Thus the modern era of SE treatment has begun (Neligan & Shorvon 2009). Historical milestones of SE shown in figure 1.

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5

Figure 1. Historical milestones that have influenced status epilepticus definition and treatment.

ILAE (International League Against Epilepsy), SE (status epilepticus), IV intravenous.

2.1.2 Definitions

The definition of SE has evolved through the years, although the fundamental idea of abnormally prolonged epileptic seizures has remained the same. The first modern definition dates to the Marseilles Colloquium (1962) by the ILAE stating that: “Status epilepticus is a term whenever a seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring condition” (Gastaut 1970).

Although no duration was specified in Marseilles, Gastaut later specified the duration of 60 min to define SE. The definition was modified slightly by the ILAE in 1981 to be: “A seizure persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur” (The Commission on Classification and Terminology of the International League Against Epilepsy 1981). Both the ILAE definitions lack a precise specification for the duration of SE, and therefore different definitions have been provided.

The work of Meldrum (Meldrum & Horton 1973) led to the conclusion that irreversible neuronal damage may occur after 30 min of ongoing seizure activity; therefore the commonly used definition for SE specifies the seizure duration to be 30 min (The Epilepsy Foundation of America's Working Group on Status Epilepticus 1993). However, there was an obvious discrepancy between this evidence-based definition, and the need to start the treatment early and effectively; thus the currently accepted operational definition of SE has a shorter duration (Bleck 1991; Treiman et al. 1998; Lowenstein et al. 1999).

700 – 600 BC Sakikku manual

Babylon 400 Long epileptic seizures

Caelius Aurelian

1824 Etát de mal

Calmeil 1850’s Bromides

1868 Status Epilepticus

Bazire 1876 Amyl-nitrate

1903 First study on SE

1909 ILAE

1912 Phenobarbital

1930’s Barbiturates

1950 Intensive Care:

curarisation and

positive pressure ventilation, IV anaesthetics

1958 IV Phenytoin

1960’s Benzodiazepines

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The 2015 ILAE Task force on Classification of SE defines SE as ‘a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation mechanisms, which lead to abnormally prolonged seizures’. The definition consists of two significant timeframes of SE, t1 and t2, pointing out the time after seizures are not self–limited, and the timeframe for developing potential neuronal injury, neuronal death and alteration of neuronal networks. The definition provides a timeframe for when the emergency treatment should be considered and started; t1 for generalized tonic-clonic seizures is 5 min, and 10 min for focal seizures with or without impairment of consciousness. The timeframe t2 is only suggested for generalized tonic-clonic seizures; SE should be controlled by the time of 30 min to avoid permanent neuronal damage. (Trinka et al. 2015). Evolution of the definition is shown in Figure 2.

Figure 2. Evolution of the definition of duration of status epilepticus.

In its most serious form SE is defined as refractory, if the seizures persist or are repetitive after administering the first- and second-line medication (Trinka et al. 2015; Stecker et al.

1998; Mayer et al. 2002; Holtkamp et al. 2005). RSE patients are treated in the ICU with general anaesthesia, to eliminate the seizure activity, unless intensive care is considered futile and only second-line treatments are continued as palliative measures. The term SRSE was first used in the Third London-Innsbruck Colloquium on SE, held in Oxford on 7–9 April 2011 (Shorvon & Trinka 2011). SE is called super-refractory if the seizure activity continues after 24 h of administering the first anaesthetic treatment, or reoccurs shortly after the treatment (Shorvon & Ferlisi 2011).

1962 (Gastaut)

60 min

1973 (Meldrum)

30 min

1991 (Bleck) 20 min

1998 (Treiman)

10 min

1999 (Lowenstein)

5 min

2015 (ILAE) 5 min

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2.1.3 Classification

The 2015 ILAE task force on SE published a new diagnostic classification of SE, based on the four axes of SE: Semiology, cause, EEG-correlates and patients’ age (Trinka et al. 2015).

The semiology axis is the backbone of the classification and is based on two main features:

The presence of motor activity in the seizure type, and the degree of impairment of consciousness during the seizures. The clinically most common and relevant status-types fall into these two categories: The ones that have both prominent motor symptoms, and impairment of consciousness (generalized convulsive forms), and the ones that have a severe degree of consciousness impairment without motor signs (subtle) , or nonconvulsive status epilepticus (NCSE), with coma. Both these status types carry a risk of refractoriness, and poor outcomes compared to those NCSE without a severe degree of coma, and focal motor seizures without impairment of consciousness. (Sutter et al. 2013; Rossetti et al. 2008;

Rossettiet al. 2006). This category helps clinicians decide whether to pursue a more aggressive treatment strategy with the patient.

The second axis of classification is aetiology, that is, the most likely cause of SE.

Recognizing the underlying aetiology and the appropriate treatment is the key to treating patients with SE. Aetiology can be divided to known (symptomatic) and unknown (cryptogenic) categories. The symptomatic group can be divided to four categories: 1) Acute symptomatic, 2) remote symptomatic, 3) progressive symptomatic, and 4) SE caused due to electroclinical syndromes; a list of underlying aetiologies is provided and available for clinicians to use (Trinka et al. 2015).

The third axis presents EEG correlates of SE. There are many different EEG patterns related to SE, along with clinical status that can be used to diagnose and differentiate SE from other conditions, especially in the case of NCSE. The classification recommends that EEG is described as: Name of pattern, morphology, location, time-related features, modulation and effect of intervention (i.e. medication), and the use of American Clinical Neurophysiology Society’s criteria (Hirsch et al. 2013), and Salzburg criteria for NCSE terminology (Trinka &

Leitinger 2015; Beniczky et al. 2013; Leitinger et al. 2015).

The fourth axis, age, points out the typical SE types presented in different age groups (Trinka et al. 2015).

2.1.4 Genetics

SE as a heterogenic disorder has a complex genetic background. A direct relationship between genes and SE is not easily found. Genes with mendelian inheritance “falling in the families” are not seen in SE; also susceptibility genes would need a homogeneous phenotype of SE, and would need to be a more common disorder to have enough power to find a significant genetic link. With SE there is always the influence of intrinsic factors and provoking ones, time related factors, and chance. It is said that “seizures beget seizures”,

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meaning that epilepsy and seizures are dynamic processes, modifying the brain networks whilst happening. However, it is possible to identify genes in which mutations are strongly associated with status epilepticus. A recent review by Bhatnagar and Shorvon (Bhatnagar &

Shorvon 2015) identified 122 genes with an SE association. Mutations were divided in five different categories: i) Genes with mutations causing malformation of cortical development (cortical dysplasia) or other gross cerebral structural changes, ii) genes with mutations causing inborn errors of metabolism and other congenital conditions, iii) mitochondrial genetic disorders, iv) genes associated with early childhood epileptic encephalopathies and idiopathic forms of other childhood epilepsy syndromes, and v) genes with mutations occurring in cases without gross structural cerebral disorders, inborn errors of metabolism, early childhood epileptic encephalopathy or epilepsy syndromes. Other genetic mechanisms such as chromosomal abnormalities like the ring chromosome (e.g. 20), and trisomy (e.g. 21) also play a role in the aetiology of SE.

Currently, the genetics of SE has little impact on clinical treatment decisions, apart from genetic counselling and avoiding of certain of therapies in certain specific epileptic encephalopathies and progressive disorders (like avoiding valproate in mitochondrial diseases), and the use of certain therapeutic solutions in rare metabolic disorders. Defining the genetic syndrome may also be of prognostic value in RSE and SRSE, and help to direct the treatment.

2.1.5 Pathophysiological mechanisms

SE results from failure of mechanisms that terminate seizures, or from seizure initiation mechanisms that lead to abnormally prolonged seizures (Trinka et al. 2015). This failure of endogenous mechanisms to terminate seizure activity is thought to start after excessive excitation that is caused by loss of inhibitory mechanisms. Thus there is a failure of processes that usually “push” the seizure towards the post-ictal state (Walker 2016).

Reinforcing these mechanisms with medication, for example gamma-aminobutyric acid (GABA) inhibition can drive the brain toward a post-ictal state.

Failure to terminate the seizure leads to a prolonged seizure, which is self-perpetuating.

Initially, in both animal models and humans, SE can be suppressed or terminated with drugs. However, the longer the SE lasts, the harder it is to treat. SE thus becomes drug- resistant. The most studied hypothesis of SE drug resistance is the internalization of synaptic (γ-subunit) containing GABAA receptors (Kapur & Macdonald 1997, Goodkin et al. 2008). Studies show that protein phosphorylation, ion-channel opening and closing, and neurotransmitter release starts the process in the first milliseconds of seizure initiation, and is followed by receptor trafficking, which includes decreases in GABAA, β2/3 and γ2 subunits, and increases in excitatory N-methyl-D-aspartate receptor (NMDA) receptors and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) –type glutamate receptors (Chen et al. 2007; Naylor et al. 2005; Goodkin et al. 2007). After some

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time, ranging from minutes to hours, neuropeptide expression is observed, as there is an increase in the excitatory substance Phosphorous (P), and an insufficient replacement of inhibitory neuropeptide γ (Lado & Moshe 2008). In the final phase of the cascade, in the days and weeks following the seizures, genetic and epigenetic changes are observed; gene expression, DNA methylation and micro-RNA regulation are observed and are also the mechanisms believed to cause neuronal damage after SE thus leading to epileptogenesis (Jimenez-Mateos & Henshall 2013).

Drug resistance during SE can also develop towards receptors other than GABAergic or glutamate receptors, that are targeted by antiepileptic drugs. Both molecular and functional changes in voltage–dependent sodium channels, and decrease in surface expression in potassium channels have been studied after SE. Cholinergic mechanisms are possibly also involved in neuronal damage after SE; abnormal release of acetylcholine has been reported in animal models with SE, and treatment with anticholinergic scopolamine in combination with benzodiazepine and phenobarbital has irreversibly terminated SE in rodents, and has prevented hippocampal neurodegeneration and epileptogenesis (Loscher 2015; Hillert et al.

2014; Adams et al. 2002).

The most prominent impact of SE is neuronal death and prolonged convulsive seizures that can lead to hypotension, hypoxia and acidosis contributing to neuronal damage (Walker 2016). Some specific groups of neurons are more susceptible to neuronal damage than others; cells in the hippocampus, in the CA3 and CA1 regions are particularly vulnerable (McKhann et al. 2003; Sloviter et al. 2003). Seizure activity itself can cause neuronal damage via calcium entry and accumulation in neurons (Meldrum & Horton 1973).

Pathofysiological changes and clinical changes of SE are shown in figure 3.

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Figure 3. The pathofysiological changes and clinical manifestations in status epilepticus. Original figure adapted from Grover et al 2016. GABA (gamma-aminobutyric acid), NMDA (N-methyl-D- aspartate), Sz (seizure), SE (status epilepticus).

2.1.6. Aetiology

The underlying aetiology of SE is considered the most important prognostic factor of the SE outcome. Half of the patients presented with SE do not have a pre-existing epilepsy syndrome, and SE is an acute symptom of another underlying disease. SE can be caused by many different aetiologies. The ILAE has introduced guidelines on SE aetiology to make SE study results more comparable, and to clarify the role of aetiology of SE in their outcomes.

The underlying cause of SE is categorized as symptomatic (known) or cryptogenic (unknown), by Trinka et al. (2015) and Sutter et al. (2013). Symptomatic aetiologies are divided into four subcategories: acute, remote, progressive, and SE in defined electroclinical syndromes. These terms are established and are used in clinical life, differing slightly in terminology and classification used with the epileptic syndrome. Acute aetiologies consist of various acute (less than a week) insults of the central nervous system or metabolism like strokes, traumatic brain injury, intoxication, encephalitis or meningitis.

Contrastingly, remote aetiologies are considered when SE occurs after a week from the cerebral insult, and include poststroke, posttraumatic, and postencephalitis type of aetiologies (Trinka et al. 2012). Progressive aetiologies are malignant, progressive diseases of central nervous system like brain tumours, or progressive myoclonic epilepsies. SE in defined electroclinical syndromes consist of selected electroclinical syndromes as per

Inhibition Failure GABA-responsive

Excess Exitation GABA-unresponsive

Reseptor Trafficking:

↓ GABA (endocytosis)

↑ NMDA upregulation

Rapid Synaptic Plasticity:

GABA Receptor composition changes

Altered Gene Expression:

Multi-Drug Efflux Transporters (i.e. P-Glycoprotein) Drug Resistance Proteins

Drug Target Alterations

Super-refractory SE Refractory SE

Established SE Early SE

Acute Sz

Pathologic Mechanism

Pathophysiology

Clinical Stages

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patients’ age, like febrile SE or myoclonic SE in Dravet syndrome, myoclonic SE in juvenile myoclonic epilepsy or myoclonic SE in Alzheimer’s disease. The term cryptogenic or

“unknown” is used when the underlying cause of SE for an individual patient cannot be found or classified (Trinka et al. 2015, Trinka et al. 2012). Table 1a and table 1b show the aetiologies that may cause SE.

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Table 1a. Aetiologies that can cause status epilepticus. Adapted and modified from Trinka et al.

2015.

1. Cerebrovascular diseases a. Ischemic stroke b. Intracerebral hemorrage

(ICH)

c. Subarachnoid hemorrage (SAH)

d. Sinus venous thrombosis and corical venous thrombosis e. Posterior reversible

encephalopathy syndrome (PRESS)

f. Vascular dementia 2. CNS infections

a. Bacterial meningits (acute and chronic)

b. Viral encephalitis c. Atypical bacterial infections d. Tuberculosis

e. HIV-related diseases f. Prion diseases (Creuzfeldt –

Jacob disease, CJD) g. Progressive multifocal

leucoencephalopathy h. Protozoal infections i. Fungal diseases 3. Neurodegenerative diseases

a. Alzheimer’s disease b. Corticobasal degeneration c. Frontotemporal dementia 4. Intracranial tumors

a. Glial tumors b. Menigeomas c. Metastases d. Cerebral lymphoma e. Ependymoma f. Ependymoma

g. Primitive neuroectodermal tumor (PNET)

5. Cortical dysplasias a. Focal cortical dysplasia

(FCD), tuberous sclerosis complex (TSC), hemimegalencephalia b. Ganglioglioma,

gangliocytoma, dysempryoplastic

neuroepithelial tumor (DNET) c. Periventricular nodular

heterotopia (PNH) and other heterotopias

d. Subcortical heterotopias e. Lissencephaly f. Polymicrogyria g. Schizenecephaly

h. Infratentorial malformations 6. Traumatic brain injury

a. Subdural hemorrage

b. Epidural hemorrace c. Intracerebral hemorrage d. Subarachnoid hemorrage e. Diffuse axonal injury (DAI)s 7. Alcohol related SE

a. Withdrawal

b. Late alcohol encephalopathy with seizures

c. Wernicke encephaly 8. Intoxication

a. Drugs/Medication overdose b. Neurotoxins

c. Heavy metals 9. Withdrawal or low levels of

antiepiletic drugs

10. Cerebral hypoxia or anoxia 11. Metabolic disturbancies

a. Electrolyte imbalances b. Hypo – or hyperglycemia c. Acidosis

d. Organ failure e. Renal or hepatic failure

(encepahlopathy) 12. Autoimmune disorders causing

SE

a. Multiple sclerosis b. Paraneoplastic encephalitis c. Hashimoto’s encephalopathy d. Anti-NMDA (n – methyl-d-

aspartate) receptor encephalitis e. Anti-voltage- gated

potassium channel reseptor enecephalitis

f. Anti-glutamic acid decarboxylase antibody associated encephalitis g. Anti – alpha – amino-3-

hydroxy-5-methylisoxazole – 4 – propionic acid receptor encephalitis

h. Seronegative autoimmune encephalitis

i. Rasmussen encephalitis j. Cerebral lupus (sytemic lupus

erythematosus)

k. CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, teleangiectasia) syndrome l. Adult onset Still’s disease m. Goodpasture syndrome n. Thrombotic thrombosytopenic

purpura

13. Neurocutaneus syndromes a. Sturge-Webersyndrome

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13

Table 1b. Genetic aetiologies and chromosomal aberrations that can cause status epilepticus.

Adapted and modified from Bhatnagar & Shorvon 2015.

1. Genes with mutations causing malformation of cortical development (cortical dysplasia) or other gross cerebral structural changes (see Table 1a)

2. Genes with mutations causing inborn errors of metabolism of:

a. Amino-acid (D2HGDH, L2HGDH,GLYCTK) b. Citric acid (FH)

c. Copper (ATP7B) d. Creatine (GAMT)

e. Cytosolic protein synthesis (QARS) f. Fatty acid oxidation (GTPBP3) g. Cerebral folate transport (FOLR1) h. GABA transaminase deficiency (ABAT) i. Aspargine linked glycosylation defect (ALG13)

3. Genes with lipid strorage disorders and other congenital conditions a. Gauchers type 3 (GBA)

b. GM2 Gangliosidosis, Tay-Sachs (HEXA), GM2 Gangliosidosis, Sandhoff (HEXB) c. Metachromatic leukodystrophy (ARSA)

d. Urea cycle defects (SLC25A13) e. Aicardi-Coutierés syndrome (ADAR) f. Alexander disease (GFAP)

g. Angelman syndrome (UBE3A, MECP2), Angelman like syndrome (CDKL5) h. Neuronal ceroid lipofuscinoses 3 and 6 (CLN3,CLN6)

i. Rett syndrome (FOXG1, MECP2) j. Sialidoses type 1 and 2 (NEU1, PPGB) 4. Mitochondrial genetic disorders:

a. Nuclear gene defects

i. IOSCA (infantile spinocerebellar ataxia) (TWNK) ii. Alpers disease (POLG1, RRM2B, SLC25A13, SLC25A22) b. Mitochondrial gene defects

i. Leigh syndrome (MTND4)

ii. MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes)( MTND1, MTND5)

iii. NARP (Neuropathy, ataxia, retinitis pigmentosa) MTATP6 5. Genes associated with early childhood epileptic encephalopathies 6. Genes associated with other epilepsy syndromes

a. Dravet syndrome (CHD2, GABRG2, PCDH19. SCN1A, SCN1B, SCN2A)

b. Lennox-Gastaut (ARX, CDKL5, CHD2 DNM1,FOXG1,GABRB3, PLCB1, PNKP, SCN8A, SPTAN1, STXBP1) c. Malignant migration partial seizures of infancy (KCNT1, PLCB1)

d. Progressive myoclonic epilepsies (PME)

i. Unverricht-Lunborg disease (CSTB, EPM1) ii. Lafora disease (EPM2A, EPM2B)

iii. PME types 3-7 (KCTD7. SCARB2, PRICKLE2, COSR2, KCNC1)

iv. Myoclonic epilepsy and ragged red fibers (MERFF) (MTTF, MTTK, MTTH, MTTL1, MTTS1, MTTS2)

7. Genes with mutations in other neurological diseases

a. CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) NOTCH3

8. Chromosomal aberrations

Ring Chromosome 20 and 17, Wolf-Hirschen syndrome, Fragile X – syndrome, Down syndrome (trisomy 21).

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2.1.7 Diagnosis

Diagnosis is based on the clinical presentation and symptoms, patient history from medical records and family members, seizure onset and semiology, timeframes from Emergency Medical Service (EMS) personnel, and possible eyewitnesses of the seizure onset. Typical findings include altered consciousness, arrest of speech, and motor signs or symptoms that persist or are recurrent. The most common type of SE is the convulsive type (70%), with tonic – clonic jerks, although prolonged seizure activity could be presented only with impairment of consciousness as subtle SE (DeLorenzo et al. 1996). NCSE with impaired consciousness and no motor signs is the second most common type of SE in adults (Kaplan 2003).

In all patients, basic diagnostic measures should be taken, including computed tomography for the CNS insults like strokes and tumours, laboratory tests and basic parametres of circulation (Fung et al. 2017) (Figure 4). RSE diagnostics should include EEG along with clinical judgement, to differentiate between seizure and postseizure activity, and medication-derived conditions, as well as nonepileptic seizures (NES). Patients can also be presented to the emergency department (ED) after having been sedated and intubated by paramedics and emergency doctors; therefore, evaluation of ongoing seizure activity and clinical presentation is necessary (Kälviäinen et al. 2014, Kälviäinen et al. 2005). Further diagnostic measures should be taken based on a patient’s clinical history and examination;

these measures include cerebrospinal fluid (CSF) samples for detection of infection, and later if suspected for autoimmune encephalitis antibody-diagnostics, gene mutations (in the case of POLG and other mitochondrial diseases), toxicology screen and brain MRI (enhanced) (Fung et al. 2017; Webb et al. 2016; Sutter et al. 2016) (Figure 4).

2.1.8 Differential diagnosis

Approximately 20% of epileptic patients are misdiagnosed, and the most common misdiagnoses are syncope and psychogenic NES. Differential diagnoses include exclusion of NES, strokes, movement disorders, CNS infections like encephalitis or bacterial meningitis, metabolic disorders (low sodium levels, hepatic dysfunction, uraemia), and cardiac arrhythmias (Smith 2012; Xu et al. 2016).

Psychogenic non-epileptic seizures (PNES) should be differentiated from SE. PNES are common, and present as paroxysmal time-limited alterations in motor, sensory, autonomic, and/or cognitive signs and symptoms. Unlike epilepsy, PNES are not caused by ictal epileptiform activity. The incidence of PNES in the adult population varies from 3.4-4.9/100 000 in different reports (Duncan 2011; Sigurdardottir & Olafsson 1998; Szaflarski et al.

2000). Between 5% and 20% of the patients referred to neurological or epilepsy polyclinics have PNES. The peak age of PNES patients is 20–30 years, and females dominate this group. It is estimated that 5–20% of patients with epilepsy present with PNES as well

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15

(Asadi-Pooya & Sperling 2015, Benbadis & Hauser 2000). Seizure semiology and clinical presentation leads to diagnosis with a combination of ictal EEG, if uncertain. Symptoms of PNES include unresponsiveness without movement, or the type of seizures that are not constant, do not follow the “homunculus” neuroanatomical spreading of symptoms, with asynchronous extremity movement, forward pelvic thrusting, geotropic eye movements, and resting in between seizures or motor function (Mostacci & Bisulli et al. 2011).

Patients with continuous focal motor or sensory symptoms, without impairment of consciousness should also be considered in patients with strokes, transient ischemic attacks (TIA), migraines, tumours or other focal processes; such patients should be thoroughly examined with imaging and ictal EEG. Seizures with impairment of consciousness, without motor signs include differential diagnosis with symptoms like postictal stage strokes, transient global amnesia (TGA), delirium of diverse aetiologies, encephalitis and metabolic disorders like hyperammonemia and uraemia provoking toxic encephalopathy, as well as and low blood sodium levels resulting in altered consciousness. Diagnostic EEG is a valuable tool that differentiates these entities from each other, along with clinical examination, measurement of blood samples, ECG and sufficient imaging (Webb et al. 2016;

Sutter et al. 2016). A staged diagnosis and treatment of SE is shown in Figure 4.

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Figure 4. Staged diagnosis and treatment of status epilepticus.

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2.2 EPIDEMIOLOGY OF STATUS EPILEPTICUS 2.2.1 Early phase of SE

A majority of convulsive seizures end spontaneously in 4 min (Theodore et al. 1994;

Shinnar et al. 2001). Emergency medical services are contacted due to seizures, seizure clusters or prolonged seizures 340 times per 100 000 inhabitants per year (Kälviäinen et al.

2016). Many of these seizures terminate without treatment, or with emergency treatment at home. A recent study on delays in the acute treatment of seizures in Finland in adults over 16 years old showed 80 seizures / 100 000 inhabitants per year lasted over 5 min, and needed acute treatment (Sairanen et al. 2016).

2.2.2 Established SE

Established SE (second stage) lasts over 30 min or has a recurrence, without regaining consciousness, as per the criteria used in most epidemiological studies on SE. The age- adjusted incidence of SE has been determined in different patient cohorts and hospital- based series, ranging from 4.61–18.3/100 000 in different parts of the world; the lowest occurrence of SE is in Asia, and the highest is in the US (Ong et al. 2015; Hesdorffer et al.

1998). The incidence of SE in different European cohorts is 10–16/100 000 (Knake et al. 2001, Coeytaux et al. 2000); these estimates are for SE that lasts over 30 min. Table 2 provides an overview of relevant data from established SE from various geographies.

Intensive care treated refractory status epilepticus : incidence and outcome in Finland 2010-2012

uef.fi

Dissertations in Health Sciences

ANNE-MARI KANTANEN

INTENSIVE CARE TREATED REFRACTORY STATUS EPILEPTICUS

ANNE-MARI KANTANEN

Intensive Care Treated Refractory Status Epilepticus – Incidence and Outcome in

Finland 2010–2012

Intensive Care Treated Refractory Status Epilepticus –

Incidence and Outcome in Finland 2010-2012

Acknowledgements

List of the original publications

Contents

Abbreviations

1 Introduction

2 Review of the Literature