1. MOARTEA SUBITA IN EPILEPSIE
CONF. DR. CUCIUREANU DAN
PROF DR FELICIA STEFANACHE
UMF “GR. T. POPA” IASI

2. Semnificatie
”Epilepsy is a very common disease affecting 50 million people worlwide. It is more common than multiple sclerosis, cerebral palsy, muscular dystrophy and Parkinson disease combined.
Epilepsy reprezents more than reccurence of seizures because it is associated with significant comorbidities. Most importantly, over the last few years studies have demonstrated that people with epilepsy have a shorter lifespan with two to three fold increase in mortality, including a 24 fold increase in SUDEP. It has been reported that one in 100 people with epilepsy per year may suffer SUDEP especyally those suffering from frequent convulsive seizures”
Solomon Moshe
President of International League Against Epilepsy, 2011

3. Risc crescut de deces
In primii ani dupa diagnosticare – riscul afectiunii determinante (stroke, tumori)
Epilepsia cronica – riscul crizelor (trumatisme, status epilepticus, SUDEP = Suddeen Unexpected Death in Epilepsy)
SUDEP = “moarte brusca, neasteptata la un pacient epileptic la care nu s-au constatat cauze clare de deces la examinarea completa postmortem”
Survine de obicei postcritic
Cauze : aritmia cardiaca, insuficienta respiratorie, disautonomie sau mecanisme sinergice
Definitii
Nashef Linda 1997 – se concentreaza pe cazuri definite ce implica obligatoriu negativitatea examinarii postmortem (utila in studierea mecanismelor)
Annegers, 1997 – mai generala incluzind si acele cazuri in care nu sunt intrunite toate conditiile (definite,posibile, probabile) utile in studiile epidemiologice
Definitie actuala
“Moarte subita, neasteptata, la un pacient epileptic de cauza nontraumatica, fara axfixie cu sau fara dovada unei crize dar cu absenta documentata a lipsei statusului epileptic si la care examinarea postmortem nu evidentiaza cauze toxice sau leziuni structurale fatale (Nashef Linda 1997 )

4. Incidenta
Rata mortalitatii pacientilor epileptici = mai mare de 1,6 – 9,3 ori fata de populatia generala
Cauzele de deces ale acestora legate de epilepsie = 40%
Boala neurologica de baza (epilepsia simptomatica)
Moartea subita = (SUDEP)
Accidente in timpul crizelor (traumatisme, asfixie, arsuri).
Status epilepticus
Sinucidere,
Accidente terapeutice
Suicide
Treatment-related death
(Téllez-Zenteno JF,2005)
Recunoscut pentru prima data in secolul 19 dar cu studii putine insuficiente.
SUDEP este responsabil de 8- 17% pina la 30% dintre decesele de oricare cauza la pacientii cu epilepsie
(Téllez-Zenteno JF,2005 , Sillanpaa et al, 2012 – studiu retrospectiv pe 40 de ani)
Riscul este mic in primii ani dupa diagnosticare si este mare la pacientii vechi cu forme farmacorezistente candidati pentru tratament chirurgical

5. Date epidemiologice insuficiente datorita lipsei de standardizare a diagnosticului dar si lipsei studiilor focalizate. datele existente provin din: - studii populationale comunitare, - din statisticile spitalelor si a centrlor de referinta acolo unde acesti pacienti (probabil cei cu risc crescut) sunt mai intens monitorizati
Incidenta pare a fi asemanatoare in Europa si SUA: 0,09 – 3,5 cazuri la 1000 pacienti/an crescind pina la cazuri la 1000 pacienti /an in mediul spitalicesc (Tomson T, Nashef L, 2008)
Un studiu singular care a comparat mortile subite din populatia generala cu cele din pacientii epileptici constata ca rata mortii subite este de 24 de ori mazi mare la pacientii epileptici decit in populatia generala (Ficker DM, 1998).
Incidenta SUDEP este mai mare la afro-americani, barbati (7:4) si in decadele II-IV
La copii incidenta se situeaza la valori mici - 0,2 /1000locuitori/an , la copii cu deficite neurologice majore . (Weber P et al, 2005)
Cohorta de copii cu epilepsie urmariti 40 de ani ! SUDEP a survenit in 9% dintre copii reprezentind 38% dintre toate cauzele de deces, mai expusi fiind cei cu deficite neurologice majore, autism, sd Dravet, scleroza tuberoasa, duplicatia cromozomului 15q11-13(Sillanpaa M, Shinnar S, 2010)

6. Criterii de diagnostic US Food and Drug Administration (FDA) and Burroughs-Wellcome 1993
Pacient cu epilepsie (crize recurente, neprovocate)
Pacientul decedeaza neasteptat, in aparenta stare de sanatate
Decesul survine rapid (minute)
Decesul survine in circumstante normale
La autopsie nu se evidentiaza o cauza evidenta a mortii
Decesul nu a survenit ca o consecinta directa a crizei sau aunui status epilepticus
Subcategorii
SUDEP definit = sint intrunite toate conditiile si se cunosc circumstantele mortii si raportul autopsiei
SUDEP probabila = sint intrunite toate conditiile dar nu exista raportul autopsiei
SUDEP posibila = nu poate fi exclus dar datele sunt insuficiente si lipseste raportul autopsiei

7. Witnessed cases of SUDEP
Only a small portion of definite SUDEP cases have been documented as having been witnessed. Langen et al have reported 15 cases of witnessed SUDEP; 80% of these patients had a seizure immediately before death.[7] Terrence[8] reported 24% and Leetsma[9] reported 38% of witnessed deaths to be an immediate consequence of a seizure attack. Kloster reported evidence of recent seizures (ie, witnessed, oral trauma, cyanosis) in 67% of victims.[10]
However, in all witnessed deaths, seizures stopped before death, and in many cases, patients regained consciousness. In a few witnessed cases, the immediate event before death was respiratory arrest (obstructive and central). Most victims were reported to have had difficulty breathing before death. Attempts at cardiopulmonary resuscitation were unsuccessful.
If SUDEP was shown to have occurred during sleep, a variety of circumstances might have contributed. A recent unwitnessed seizure with or without bradyarrhythmias and lack of sympathetic tone to oppose bradyarrhythmias might have contributed. In addition, obstruction of airways and asphyxia are more probable during sleep.
The interaction between the autonomic control of the cardiovascular functions and the seizure phenomenon is very complex.

8. Etiologia
Mecanismele care contribuie la SUDEP sunt variate si probabil intrepatrunse de la pacient la pacient incit in final se poate presupune existenta unui mecanism multifactorial.
Perturbarile respiratorii, inclusiv asfixia obstructiva, apneea de cauza centrala, edemul pulmonar neurogen sunt evenimentele fatale.
Aditional aritmiile cardiace din timpul perioadei ictale dar si interictale ce produc asistolie sau insuficienta cardiaca acuta. Bradiaritmiile se asociaza frecvent cu apneea.
Medicatia antiepileptica reprezinta un alt factor de risc
These interactions can be summarized as the events directly related to seizures (see the first diagram below) and the baseline (see the second diagram below).

10. Factori respiratorii
Edemul pulmonar neurogenic demonstrat in 84% dintre pacienti cu SUDEP si se pare ca este determinat de o stimulare masiva alfa adrenergica, vasoconstrictie generalizata, hipertensiune pilmonara. Se supraspune o lezare importanta a endoteliului alveolar cu o durata mai mare de citeva minute evidentiata printr-o mare concentratie proteica in exudatul alveolar.
Sindromul apneei centrale caracterizat prin oprirea respiratiei in somn,pare a fi determinat de propagarea descarcarii electrice la centrii respiratori. Au fost evidentiate episoade postcritice de apnee cu o durata de sec insotite de o desaturare in oxigen a singelui arterial. Aditional ,asistolia poate determina apnee secundara.
Asfixia secundara obstructiei cailor aeriene superioare mai ales la pacientii gasiti in pozitie anteflectata ( favorizeaza si aspiratia) in momentul decesului.
Se poate supraadauga spasmul laringeal si stridorul postcritic care pot coparticipa la deces (Tavee J, 2008)
Lisa Batterman, monitorizind pacientii spitalizati ce au prezentat iminenta de SUDEP propune urmatoarea secventa patogenica : criza convulsiva determina epuizarea energetica a neuronilor din diferite zone cerebrale avind drept consecinta depresie respiratorie cu hipoxie si hipercapnie care deregleaza functia cardiaca avind drept consecinta finala recuperarea incompleta a neuronilor cerebrali si eventual insuficienta cardiaca acuta.
Ipoteza este sustinuta si de unele studii necrotice umane dar si de experimentele pe babuini epileptici (Szabo L et al, 2009)
Acesta a constatat ca babuinii epileptici decedati se deosebeau de restul babuinilor morti brusc prin prezenta unui edem pulmonar ce nu a putut fi explicat prin anomalii cardiace pentru care babuinii au fost monitorizati.Szabo says, “there is evidence that severe brain injuries can be associated with pulmonary edema, and these cases probably have something to do with a brainstem dysfunction.” The concept of impaired respiration as a cause of death is supported by data from studies in animals and evidence from most witnessed and recorded instances of sudden, unexpected death in epilepsy (Table 2Table 2Suggested Mechanisms of Impaired Respiration in Sudden, Unexpected Death in Epilepsy (SUDEP).) Seizure-induced respiratory changes can be lethal and may involve pulmonary dysfunction and suppression of brain-stem respiratory and arousal centers.40 In sheep, prolonged seizures cause elevated pressure in the left atrial and pulmonary arteries, pulmonary edema, tachycardia, and death from hypoventilation.42 Serotonergic neurons that modulate breathing and arousal may be involved in sudden, unexpected death in epilepsy, as is the case with sudden infant death syndrome.40,43 Some serotonergic neurons stimulate respiratory nuclei in the brain stem, whereas others, activated by hypercapnia, contribute to the ascending arousal system.44 Postictal depression of serotonergic activity can impair respiration and reflexive repositioning if the mouth and nose are obstructed by bedding. In some mouse strains, sound-induced seizure arrests respiration — an effect that is reduced by selective serotonin-reuptake inhibitors (SSRIs) and 5-HT2C–receptor agonists.45 Among patients with epilepsy, use of an SSRI is associated with reduced oxygen desaturation during partial seizure but not during tonic–clonic seizure.46

11. Cerebral Shutdown
Seizure and the postictal state can affect brain-stem respiratory centers. Central apneas or hypopneas complicate most seizures.38 In one study, patients with epilepsy who died suddenly had longer periods of postictal generalized EEG suppression than did patients with epilepsy who did not die suddenly.21 Respiration depends on brain-stem activity; prolonged suppression of activity stops respiration. Postictal shutdown of cerebral and brain-stem function may be related to the mechanisms that stop seizures. Postictal hypercapnia and hypoxemia can occur despite increased respiratory effort, possibly from ventilation–perfusion inequality, which is caused by right-to-left pulmonary shunting or neurogenic pulmonary edema.47 Sudden, unexpected death has been reported in a patient with epilepsy who had postictal pulmonary edema.36 Postictal hypercapnia can cause severe acidosis that is arrhythmogenic.48 The effects of prolonged postictal EEG suppression, apnea, pulmonary shunting and edema, suffocation in the prone position, impaired arousal to hypercapnia, laryngeal spasm, and respiratory acidosis probably combine and cascade with cardiac factors to cause many cases of sudden, unexpected death in patients with epilepsy (Table 2 and Figure 2).
Cardiac Factors

12. Factori cardiaci
Aritmii fatale intracritic dar si postcritic
Modificari ictale: tahicardia, aritmia, alungirea intervalului Q-T au fost documentate in epilepsia de lob temporal
Iar bradicardia urmata de tahicardie in toate cazurile de crize convulsive generalizate (Erickson T, 1939)
Inregistrari simultane ale EKG si EEG au relevat tahicardie in 74-92% dintre crizele focale complexe.
Pornind de la aceste constatari se presupune ca aritmia precede SUDEP reprezentind cauza decesului.
Lathers J, et al (2009) au demonstrat o sincronizare a descarcarilor ictale si interictale cu cresterea activitatii simpatice a cordului.
In timpul crizei pacientii prezinta o reducere a frecventei cardiace care de multe ori se prelungeste si postictal determinind o scadere marcata a perfuziei cerebrale si deces potential.
Se presupune ca frontul electric se propaga la amigdala si de aici prin eferentele sale (prin nucleii centrali) spre centrii cardioreglatori medulari pe care ii poate bloca sau determina aritmii.
Furtuna simpatica si puternica inhibitie vagala intraictala pot constitui un mecanism alternativ al mortii prin cresterea activitatii ectopice ventriculare si respectiv asistolie.
Interictal aritmia cardiaca poate deveni fatala

13. Testele functionale reflexe cardiace releva interictal disfunctii simpatice si parasimpatice in special la mpacientii cu epilepsie refractara.
Scaderea variabilitatii frecventei cardiace determina o crestere a vulnerabilitatii centrilor cardioreglatori determinind astfel o crestere a automatismului cardiac si a posibilitatii aparitiei aritmiilor.
Disfunctia autonoma la pacientii epileptici este determinata multifactorial. Sistemul vegetativ este supus , in urma descarcarilor ictale dar si interictale la modificari fiziologice (hipometabolism interictal perifocar) si anatomice. Autopsiile au aratat fibroza sistemului de conductie intracardiac la 33% dintre pacienti datorita descarcarilor repetate de catecolamine, aceasta fiind per se aritmogena.
Carbamazepina creste riscul de alterare a reglarii cardiace marind riscul de SUDEP
Studiile sindromului “QT lung” (genetic) au constatat existenta unei conexiuni (“linkage”) intre epilepsie si disfunctiile cardiace (tendinta la asistolie brusca).
Alicia Golman et al, a raportat, descoperirea unei gene defective care controleaza fluxul transmembranar al potasiului (potassium channel KvLQT ) care are expresie cardiaca dar si cerebrala, iar la liniile de soareci cu aceasta gena s-au constatat modificari EEG asemanatoare celor din epilepsie, crize ca si aritmii. Se preconizeaza dezvoltarea unui test genetic de screening pentru aceasta gena la pacientii cu epilepsie pentru identificarea riscului de SUDEP si tratarea acestuia cu betablocante sau pacemaker
(American Epilepsy Society Congress,2011)

14. Factori de risc pentru SUDEP
Dependenti nde pacienti
Virsta ( ani)
Sex – masculin
Encefalopatie infantila
IQ<70
Rasa afro-american
Alcoolism
Pacient dormind in pozitie anteflectata
Pacient nesupravegheat postcritic
Dependenti de crize
Epilepsie simptomatica (34- 70%)
Tip – generalizata tonico-clonica
Debut precoce
Durata bolii >10 ani
Numar mare de crize (>3/an creste riscul de 8 ori ) Walczak TS, Leppik IE 2001
Crize recente
Scleroza mesiala dreapta
Dependenti de tratament
Subdozare medicamentoasa (noncomlianta, lipsa de control) si variabilitatea dozelor
Politerapia (>3 AED creste riscul >8 ori)
Schimbare recenta sau frecventa a medicatiei
Nivel crescut al carbamazepinei .

15. Profilaxie Educarea pacientilor si a ingrijitorilor acestora
Identificarea pacientilor cu risc inalt
Monoterapia
Evitarea variabilitatii dozelor
Regim de viata si dieta obligatoriu

16. Pornind de la analogia cu sindromul mortii subite a copilului s-a emis ipoteza unei disfunctii a trunchiului cerebral ce produce in final disfunctie respiratorie fatala.
Disfunctia trunchiului cerebral pare a fi determinata de o disfunctie serotoninergica care impiedica raspunsul normal la nivele crescute a CO2

17. Prevention
We do not know how to prevent sudden, unexpected death in epilepsy. No prospective or controlled studies have evaluated interventions to reduce its incidence. Since a tonic–clonic seizure precedes most sudden deaths in patients with epilepsy, seizure control — and the appropriate use of medication as well as counseling on lifestyle — is the focus of prevention (Table 3Table 3Prevention of Sudden, Unexpected Death in Epilepsy.). The lack of therapeutic levels of antiepileptic drugs, nonadherence to treatment regimens, and frequent changes in regimens are all risk factors for sudden death.9,11,12,19,20,25 For patients who have never been treated with antiepileptic drugs, the risk of sudden death may be more than 20 times as high as that for treated patients.20 A discussion of sudden, unexpected death in epilepsy may be worthwhile for patients with tonic–clonic seizures who are beginning an antiepileptic-drug regimen and for patients at high risk for recurrent tonic–clonic seizures who are discontinuing such a regimen.
Thirty percent of patients with epilepsy have treatment-resistant epilepsy, and these patients — who are at high risk for sudden death — present the greatest challenge. Frequent changes in multidrug regimens are commonly undertaken to reduce the frequency of seizure or the side effects of medication, but the potential effects of regimen changes on the risk of sudden death are rarely considered and remain unknown. Patients who are free of seizures after surgery for epilepsy have reduced rates of sudden death,8,10,62 with mortality approaching that in the general population. In contrast, patients with postoperative seizures have very high rates of sudden death.62
Patients should be informed about the fundamentals of seizure prevention: observance of a healthful lifestyle (e.g., avoiding sleep deprivation and excessive consumption of alcohol), adherence to their antiepileptic-drug regimen (e.g., avoiding and identifying missed doses with the use of weekly pill boxes and watch alarms), knowledge of how to make up for missed doses and of factors influencing drug levels, and avoidance of drugs that lower the threshold for seizure. Patients should also be asked whether they have symptoms of nocturnal tonic–clonic seizure. For patients who do have nocturnal tonic–clonic seizure, bedtime medication doses can be increased and seizure-detection devices (discussed below) considered.
Educating persons who live with patients with epilepsy may also help to prevent sudden death. Knowledge of how to perform the appropriate first-aid responses to seizure (repositioning the patient and protecting the airway after a tonic–clonic seizure) may prevent death. A case–control study of adults showed that as compared with unmonitored controls, patients who were monitored while they slept had a reduced risk of sudden death by a factor of 2.5 if another person older than 10 years of age was in the room and by a factor of 10 if there were frequent nighttime checks or if a sound-monitoring device was used.20 In a study of 14 residents at a special-needs school who had severe epilepsy and died suddenly, all 14 died at home, and most of them were not being monitored.7 None died at school, where they were monitored during sleep by four attendants and an on-call nurse and a sound-monitoring device was used. The manufacturers of several commercial devices state that their products can detect tonic–clonic seizure, but very limited data are available on the sensitivity and specificity of these devices for the detection of tonic–clonic seizure,63 and there is no evidence that their use prevents sudden death. Patients with nocturnal tonic–clonic seizure may want to consider the use of motion-detection devices (e.g., the Emfit monitor [Emfit]) that have a configurable sensing unit that is placed under the mattress and a receiver located in another room with audiovisual alarms. Pulse oximeters and heart-rate monitors may detect seizure-induced hypoxemia and tachycardia. Nonetheless, sudden death occurs in hospitals and other medical environments, despite prompt attempts at resuscitation.11
The effectiveness of strategies intended to prevent sudden death by improving respiration or oxygenation remain unproven. Since many patients are found prone, some practitioners advocate the use of antisuffocation pillows (e.g., see for the prevention of sudden death in epilepsy, but data on their clinical value are lacking. The potential role of oxygen administration during and after a tonic–clonic seizure — a common practice in hospitals but not in patients' homes — deserves study.
Routine ECG screening of all patients with epilepsy is of uncertain value. Patients with tonic–clonic seizure or episodic loss of consciousness who have normal or nonspecific findings on magnetic resonance imaging of the brain and EEG should undergo ECG to rule out the long-QT syndrome, a lethal disorder that mimics epilepsy64; these patients may also benefit from Holter ECG monitoring to rule out arrhythmia. Misdiagnosis of the long-QT syndrome as epilepsy precludes the use of effective therapy, and the inappropriate administration of antiepileptic drugs can induce arrhythmias.51
One additional preventive step is to discuss sudden, unexpected death in epilepsy with patients — a step few physicians initiate because it may cause stress about an uncommon problem for which there is no proven means of prevention. However, most patients with epilepsy and their families want information about sudden death.65,66 Although national guidelines in the United Kingdom recommend that all patients with epilepsy and their families be provided with information about sudden, unexpected death in epilepsy,66 most neurologists cited in the study discuss it only with high-risk patients or when specifically asked.65,66 Guidelines and tools are needed to assist physicians and patients and their families in becoming educated about sudden, unexpected death in epilepsy, and outcome measures are needed to assess the effectiveness of this education. Patients with risk factors that can be modified — such as nonadherence to antiepileptic-drug regimen, tonic–clonic seizure, nocturnal seizure, and treatment-resistant epilepsy — may benefit most from counseling. When patients ask whether seizures can injure their brain or kill them, a simple “no” is insufficient. Epilepsy is associated with significant risks of morbidity and death.
Future Directions
Reductions in sudden deaths among patients with epilepsy may be achieved by increasing awareness on the part of the general public and the medical community, improving the prevention and treatment of epilepsy, further developing and encouraging the use of devices that detect seizure and can alert caretakers, improving our understanding of the mechanisms of sudden, unexpected death in epilepsy, and conducting interventional trials to prevent the p rogression of life-threatening seizure to sudden death. If patients are aware that seizure can be deadly, they may be more motivated to adhere to antiepileptic-drug regimens and to avoid lifestyle choices that increase the likelihood of seizure. Patients with seizures that remain uncontrolled after the administration of two different drug regimens should be referred to an epilepsy center for evaluation. Preventing seizures can be lifesaving.