Stato di male epilettico refrattario e super-refrattario Chiara Pizzanelli

1. Stato di male epilettico refrattario e super-refrattario Chiara Pizzanelli Centro di RiferimentoRegionaleEpilessia • U.O. Neurologia - AOUP

2. Historical background 1970 Status Epilepticus (SE) was defined as “a seizure that persists for a sufficient lenght of time or is repeated frequently enough to produce a fixed and enduring condition” 1981 ILAE Classification of Seizure: SE partial/ generalized/epilepsiapartialis continua

3. Historical background 1970 Status Epilepticus (SE) was defined as “a seizure that persists for a sufficient lenght of time or is repeated frequently enough to produce a fixed and enduring condition” 1981 ILAE Classification of Seizure: SE partial/ generalized/epilepsiapartialis continua Concetti validi, ma imprecisi «Sufficientlenght of time», «repeatedfrequentlyenough», «fixed and enduring» che cosa significano? Non c’è nessuna definizione operativa Non una descrizione clinica semeiologica

4. Convulsive status epilepticus: time limit 1962 Gastaut 60 min 1993 Guidelines ILAE 30 min 1993 Epilepsy Foundation USA 20 min 1998 Treiman 10 min 1999 Lowenstein 5 min

5. Status epilepticus Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus, Trinka et al., 2015

6. Status epilepticus Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Defizioneconcettuale Definizioneoperativa A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus, Trinka et al., 2015

7. Time is brain! Trinka and Kalvainen, 2017

8. Status epilepticus Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Defizioneconcettuale Definizioneoperativa Classificazione semeiologica (asse 1) A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus, Trinka et al., 2015

9. Axis 1: Semiology Trinka et al., 2015

10. Clinicalcourse of convulsive status epilepticus Trinka and Kalvainen, 2017

11. Staged treatment protocol for status epilepticus Trinka and Kalvainen, 2017

12. Refractory status epilepticus SE that continues despite treatment with BDZ and one AED 31-43% of patients in established SE are not controlled with AEDs Anesthetic drugs have been used and still are commonly used in this phase MIDAZOLAM (59%) PROPOFOL (32%) BARBITURATES (8%) Ferlisi et al., 2015

14. MIDAZOLAM Mechanism of action: BDZ, modulation of GABA-A receptor Short half-life after a single bolus Tachyphylaxis No problems inherent to its pharmacodynamic or pharmacokinetic properties The safest drug with the lowest rate of cardiovascular and metabolic complications Availability of an antidote (Flumazenil) Rossetti and Lowenstein, 2011

15. PROPOFOL Mechanism of action: modulation of GABA-A receptor, action on Na and Ca channels and NMDA receptor Short half-life PRIS (Propofol Infusion Syndrome) cardiocirculatory collapse lactic acidosis hypertriglyceridaemia rhabdomyolysis Incidence of PRIS in RSE: 45% (7% fatal, 38% non-fatal), but in other studies 0-7% Prolonged perfusions (more than 48 hours over 5 mg/kg/h) should be avoided Rossetti and Lowenstein, 2011

16. THIOPENTAL and itsmetabolite PENTOBARBITAL Mechanism of action: modulation of GABA-A receptor, NMDA antagonist Long half-life, with accumulation in adipose tissue Often associated with cardiovascular complications, immunosuppression and infections Rossetti and Lowenstein, 2011

17. EEG target Once a coma has been induced, cEEG monitoring helps to manage the level of sedation. It is unclear whether complete suppression of cerebral electrogenesis, simple seizure suppression, or burst-suppression pattern are more effective. It is also not established how long coma should be maintained and when to gradually withdraw anesthetic medications. Proposal: MDZ anesthesia targeting burst-suppression with interburst interval of about 10 sec for 24 hours, followed by progressive tapering over 6-12 hours under EEG monitoring Rossetti et al., 2011

18. EEG all’arrivo in TI, dopo terapia ev di prima linea

19. EEG dopo inizio di infusione TPS a dosaggi crescenti

20. EEG in corso di TPS a 4.5 g/die Altre terapie in corso: VPA 2000 mg/die, PHT 300 mg/die, PB 200 mg/die, LEV 2000 mg/die

21. Alterazioni RM reversibili: iperacutadellosplenio, subacute del claustro e cortecciainsulo-parietalebilaterale RM a 3 settimane RM a 1 settimana RM in urgenza DWI FLAIR

22. Involuzioneatroficabiemisferica/ipometabolicafronto-insularebilateraleInvoluzioneatroficabiemisferica/ipometabolicafronto-insularebilaterale RM a 8 mesi PET a 9 mesi

23. Anaestetic agents used in refractory SE

24. Otherpharmacological and nutritionaltreatments for refractory SE

25. Non-pharmacologicaloptions for refractory SE

27. Bozza PDTA Epilessia Regione Toscana, 2019

28. Fig.2 Dispositivo: sede di impianto e connessione con il nervo vago Grazie per l’attenzione