Nuevos tratamientos en el mal epileptico

Dra. Clarisa Maxit
Sub Jefe Servicio de Neurología Infantil
Hospital Italiano de Buenos Aires
FASES DEL STATUS EPILEPTICUS
SE
INMINENTE
STATUS
SSTAT
SE
REFRACTORIO
ESTABLECIDO
5 MIN
PRE HOSPITALARIO BZD
30 MIN
GUARDIA
AE
UNIDAD DE CUIDADOS INTENSIVOS
ANESTESICOS y otros
y El tratamiento precoz de las crisis previene el efecto kindling
y El tratamiento precoz previene la injuria neuronal
El tto. pre‐hospitalario es importante y 182 chicos con SE convulsivo
por cada minuto de retraso del inicio del tratamiento desde el inicio del SE hay un aumento de riesgo acumulativo del 5% en que el SE dure más de 60 minutos Chin RF, Peckman C et al.
Lancet Neurol 2008
y Los niños que reciben el 3er AE dentro de la hora de tto. regresaron a la línea base en forma significativa más frecuente que aquellos con administración más tardía (81% vs 0%)
Lambrechtsen FA, Buchhalter J
Epilepsia 2008
FASES DEL STATUS EPILEPTICUS
SE
INMINENTE
5 MIN
PRE HOSPITALARIO BZD
SE
ESTABLECIDO
SE
REFRACTORIO
y 30 MIN
GUARDIA
AE
UNIDAD DE CUIDADOS INTENSIVOS
ANESTESICOS
benzodiacepinas
y Son efectivas cuando son utilizadas al inicio de las crisis
y Hay cambios en el receptor GABA que modifican la respuesta subsecuente luego de varios minutos iniciada la crisis
y Diazepam VS lorazepam VS midazolam
Lorazepam
y El lorazepam ev presenta mayor eficacia y disminuye el tiempo de crisis comparado con el diazepam ev
Alldrredge Bk et al. N England J Med 2001
y Requiere refrigeración manejo SE
y Administración IV Hospitalario
midazolam
y Es una imidazobenzodiacepina. A pH 4 es un anillo abierto que es soluble en agua.
y A pH fisiológico el anillo se cierra y se hace muy liposoluble permitiendo una rapida penetrancia cerebral.
y Midazolam bucal /intranasal/IM 0.15 a 0.5 mg/kg
midazolam
y El midazolam por vía NO IV acelera la finalización de las crisis.
y La utilización de midazolam IM o IN vs Diazepam IV presentaban eficacia similar de finalización de crisis pero el midazolam presento una diferencia fija de 3 minutos
RAMPART Trial – Michigan University
Silbergleit R and Lowestein Dan
midazolam
Dan Milikan, Robert Silbergleit
Emerg Med Clin N AM 2009
midazolam
Danie l P Wemwling
Neurotherapeutics A bil 2009
Midazolam IM vs IN vs IV
Danie l P Wemwling
Neurotherapeutics Abril 2009
FASES DEL STATUS EPILEPTICUS
SE
INMINENTE
5 MIN
PRE HOSPITALARIO BZD
SE
ESTABLECIDO
SE
REFRACTORIO
30 MIN
GUARDIA
AE
UNIDAD DE CUIDADOS INTENSIVOS
ANESTESICOS/DC/IG/TPM
Hay que tener un plan
Todas la unidades deben contar con un protocolo escrito del tratamiento farmacológico del SE y este protocolo debe estar claramente estadificado y estructurado por tiempo
Consenso Europeo Tratamiento del Status Epilepticus ‐ Londres 2008
542 pacientes pediátricos, estudio multicéntrico Manejo emergencia del SE convulsivo
En el DE la mediana de tiempo para administrar el 2do fármaco fue de 24 minutos
Acworth J, Lewena S.
Pediatr Emerg Care 2009
Manejo del status epilepticus
30 min
5 min
Pre
Hospitalario
Diazepam
IR
Midazolam
bucal
/IN/IM
Lorazepam IV
VPA IV
Lorazepam IV
Diazepam IV
DFH
Midazolam IV
Diazepam IV
INMINENTE
Unidad de Cuidados intensivos
Departamento emergencia
LEV IV
Midazolam
IV goteo
ketamina
Fenobarbital
20 mg/kg
Dieta
cetogenica
tiopental
IG IV
propofol
ESTABLECIDO
REFRACTARIO
Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in
children.
Appleton R, Macleod S, Martland T.Roald Dahl
EEG Unit, Alder Hey Children's Hospital, Eaton Road, Liverpool
OBJECTIVES: To review the evidence comparing the efficacy and safety of midazolam, diazepam, lorazepam,
phenobarbitone, phenytoin and paraldehyde in treating acute tonic-clonic convulsions and convulsive status
epilepticus in children treated in hospital.
SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialized Register (1st July 2007), the
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007), and
MEDLINE (1966 to July 2007). SELECTION CRITERIA: Randomized and quasi-randomized controlled trials
comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including
convulsive status epilepticus in children. DATA COLLECTION AND ANALYSIS: Two review authors
independently assessed trials for inclusion and extracted data. MAIN RESULTS: Four trials involving 383
participants were included.(1) Intravenous lorazepam is as effective as intravenous diazepam in the treatment
of acute tonic clonic convulsions, 19/27 (70%) versus 22/34 (65%), RR 1.09 (95% CI 0.77 to 1.54), has fewer
adverse events and rectal lorazepam may be more effective than rectal diazepam, 6/6 versus 6/19 (31%), RR
3.17 (95% CI 1.63 to 6.14)(2) Buccal midazolam controlled seizures in 61/109 (56%) compared with 30/110
(27%) of rectal diazepam treated episodes with acute tonic-clonic convulsions, RR 2.05 ( 95% CI 1.45 to
2.91)(3) Intranasal midazolam is as effective as intravenous diazepam in the treatment of prolonged febrile
convulsions, 23/26 (88%) versus 24/26 (92%), RR 0.96 (95% CI 0.8 to 1.14)(4)
AUTHORS' CONCLUSIONS: The conclusions of this update have changed to suggest that intravenous
lorazepam is at least as effective as intravenous diazepam and is associated with fewer adverse events in the
treatment of acute tonic-clonic convulsions. Where intravenous access is unavailable there is evidence from
one trial that buccal midazolam is the treatment of choice
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD001905.
Acido Valproico (VPA) Levetiracetam (LEV)
y
y
y
y
Baja unión a proteínas
Cinética lineal
LVT: bajo metabolismo hepático y pocas interacciones VPA: metabolismo microsomal y muchas interacciones
Acido valproico
y 20 estudios publicados: 533 adultos y niños
Todos mostraron efectividad similar a la DFH en pacientes que NO respondieron a las benzodiacepinas o como primea línea de tto
y Dosis usual 15 a 45 mg /kg en bolo (6mg/kg/min) seguido de infusión 1 a 5mg/kg/hora
y Efectos adversos: menos del 10% hipotensión, plaquetopenia, mareo
Levetiracetam
y Antiepileptico de amplio espectro:
‐ Inhibe canales de calcio voltaje dependiente
‐ facilita la inhibición gabaergica al desplazar moduladores negativos
‐ Reduce las corrientes tardías de potasio ‐ Presenta unión a proteínas sinápticas que modulan la liberación de neurotransmisores
Levetiracetam (LEV)
y
y
y
y
y
y
Disponible IV en forma reciente. Dosis de carga 20 mg/Kg IV
Biodisponibilidad y bioequivalencia probadas
No hay estudios controlados
Control referido del 31 al 100% de pacientes
Efectos adversos: somnolencia, agresividad, plaquetopenia
y SE debe ajustar la dosis en la falla renal
J Child Neurol. 2010 May;25(5):551-5.
Intravenous levetiracetam in children with seizures: a prospective safety
study.
Ng YT, Hastriter EV, Cardenas JF, Khoury EM, Chapman KE.
Department of Pediatric Neurology, Barrow Neurological Institute, Phoenix,
Arizona 85013, USA.
Abstract
In 2006, intravenous levetiracetam received US Food and Drug Administration
(FDA) approval for adjunctive treatment of partial onset seizures in adults with
epilepsy, 16 years or older. We have established the safety, tolerability, and
dosage of intravenous levetiracetam in children. This prospective study included
30 children (6 months to <15 years of age). Patients were administered a single
dose of intravenous levetiracetam (50 mg/kg, maximal dose 2500 mg) over 15
minutes. A blood level of levetiracetam was performed 10 minutes after the
infusion. The treated children's average age was 6.3 years (range 0.5-14.8
years). The mean levetiracetam level was 83.3 microg/mL (range 47-128
microg/mL). There were no serious adverse reactions. Minor reactions included
sleepiness, fatigue, and restlessness. An apparent decrease in seizure
frequency across all seizure types was noted. The dose of 50 mg/kg was well
tolerated by the patients and is a safe, appropriate loading dose.
FASES DEL STATUS EPILEPTICUS
SE
INMINENTE
5 MIN
PRE HOSPITALARIO BZD
SE
ESTABLECIDO
SE
REFRACTORIO
y 30 MIN
GUARDIA
AE
UNIDAD DE CUIDADOS INTENSIVOS
ANESTESICOS
Manejo del status epilepticus
5 min
Pre
Hospitalario
Diazepam
IR
Midazolam
bucal /IN/IM
Diazepam IV
30 min
Unidad de Cuidados intensivos
Departamento emergencia
VPA IV
Lorazepam IV
Diazepam IV
DFH
Midazolam IV
LEV IV
Midazolam
IV goteo
ketamina
Fenobarbital
20 mg/kg
Dieta
cetogenica
tiopental
IG IV
propofol
Lorazepam iv
Lorazepam IV
TOPIRAMA
TO
INMINENTE
ESTABLECIDO
REFRACTARIO
midazolam
y Metanalisis 111 niños SER fue efectiva como otras drogas inductoras de coma con menor mortalidad.
Gilbert DL, Glauser TA. Jchild Neurol 1999
y 40 niños midazolam vs diazepam IV eficacia similar , midazolam recurrencia mayor (57% vs 16%)
Singhi S et al. J Child Neurol 2002
y EA: desaturaciones transitorias, hipotensión arterial
y Midazolam: bolo inicial 0.1 mg/kg con infusión posterior 1 a 2 Microgramo/kg/mi hasta 30microgramos/kg/min
Rev Neurol (Paris). 2010 Jun-Jul;166(6-7):648-52.
[Use of midazolam for refractory status epilepticus in children].
Lampin ME, Dorkenoo A, Lamblin MD, Botte A, Leclerc F, Auvin S.
Service de réanimation pédiatrique, CHRU de Lille, Lille cedex, France.
METHODS:
This was a retrospective analysis of 29 children admitted to the Lille University Hospital
pediatric intensive care unit (PICU) for RSE between May 2006 and July 2008. The
onset of the study corresponded with a new therapeutic protocol applied in the PICU
for RSE where midazolam was proposed as the first-line treatment (bolus ten
continuous infusion until control) to be replaced by thiopenthal in case of failure.
RESULTS:
We recorded 29 patients with RSE during the study period: 26 were treated with
midazolam, including two where midazolam replaced thiopenthal because of
hypotension. Midazolam successfully controlled RSE in 58% of patients. Mean delay to
cessation of RSE was 48+/-65 minutes. Hypotension was observed in 8% of
midazolam-treated patients and 71% of thiopenthal-treated patients. Overall mortality
was 15% (4/26). Two deaths occurred long after the cessation of RSE. None of the
deaths occurred in midazolam-treated patients.
CONCLUSION:
Midazolam is an efficient treatment for RSE in children. Morbidity and mortality appear
to be lower with midazolam compared with other antiepileptic drugs used for the
treatment of RSE
FENOBARBITAL
y El fenobarbital a altas dosis hasta máximo de 120 mg/kg es una opción en el manejo del SER
y Menos inestabilidad hemodinámica, íleo e infecciones
y Dosis repetidas de bolos de 10 mg/kg cada 30 minutos sin máximo nivel predeterminado
y El efecto sedante y depresor respiratorio se van tolerando no así el efecto anticonvulsivante
Crawford TO et al Neurology 1988
Lee WK Pediatr Neurol 2006
Drogas nuevas
y Topiramato
y Lacosamida
Topiramato
y Mecanismo de acción: aumento de la función inhibitoria del receptor GABA a, inhibición de los receptores excitatorios AMPA, bloqueo de los canales de Ca y Na e inhibición de la anhidrasa carbónica
y Varios casos reportados en SE Refractario de buena tolerancia y efectividad administrado por SNG (3 a 10 mg/kg/dia)
y Inicio de efecto luego de 12 a 48hs
y Papel tardío en el SE en la salida del coma farmacológico
Lacosamida
y Aumenta la inactivación lenta de los canales de sodio
y Formula vía oral e IV.
anestésicos
Dieta cetogénica
Teatment of malignant refractory status epilepticus with ketogenic diet: 5 case reports.
Autores: Vaccarezza, M; Aberastury, M.; Silva, W; Maxit, C; Marchione, D.; Agosta, G.
Child Neurology Autores: Department. Hospital Italiano de Buenos Aires
Introduction: Refractory status epilepticus (RSE) is a life-threatening
condition defined as ongoing intermittent or continuous status epilepticus
despite the administration of adequate doses of two standard intravenous
anticonvulsant drugs. It can last days, weeks regardless of an adequate
treatment with numerous antiepileptic drugs includi. This condition is
called malignant status epilepticus (MSE). Many therapeutic approaches
have been documented for these patients, such as intravenous valproic
acid, pentobarbital induced coma, high dose phenobarbital, midazolam
and propofol
Ketogenic diet is a safe and effective alternative treatment for patients with
refractory epilepsy, when epilepsy surgery is not an option. There are no
studies of the use of ketogenic diet in refractory status epilepticus and we
found isolated case reports in the literature.
In this study we report five consecutive patients, in a 4 year period, with a
malignant status epilepticus, that lasted more than 5 days, and receive
ketogenic diet as treatment after failure with other more conventional
treatment options.
DISCUSION
We present a series of 5 patients with malignant status epilépticus. In 4 patients the KD
was effective in aborting the MSE, where other antiepileptic drugs had failed, including
burst suppression coma.
The etiology of the SE differed between the patients. The main cause was encephalitis
(acute symptomatic), in three patients and 2 patients had chronic epilepsy (remote
symptomatic). The 3 patients with encephalitis had a better outcome.
As ketosis can easily be achieved with fasting and that it was effective in aborting MSE in
a high percentage of our patients, we recommend to include the ketogenic diet in the
treatment protocol for MSE. It is relatively easy and safe to fast patients in the ICU after
the patient has a diagnosis of MSE.
One of the patients with encephalitis, became seizure free 24 hs. after introducing KD.
The other three patients have a refractory epilepsy and one patient with a a previous
chronic epilepsy died.
CONCLUSION
KD can be easily introduced in patients in the ICU, with an initial fasting phase followed
by a 4:1 ratio. These results support the potential efficacy and safety of KD for children
with MSE, where many other antiepileptic have failed.
Tratamiento inmunológico
y Hay casos de status epilepticus refractario que son inmunomediados
y Se debe considerar la terapia inmune en pacientes con status epilepticus refractario de origen incierto o asociado a anticuerpos
y Se utiliza gamaglobulina, metilprednisolona, plasmaferesis
Protocolo acelerado del Manejo del SE
5 min
Pre
Hospitalario
Diazepam
IR
30 min
Unidad de Cuidados intensivos
Departamento emergencia
Lorazepam IV
Midazolam
bucal
/IN/IM
DFH
VPA IV
LEV IV
Midazolam
IV goteo
ketamina
Fenobarbital
20 mg/kg
Dieta
cetogenica
tiopental
IG IV
propofol
TOPIRAMA
TO
INMINENTE
ESTABLECIDO
REFRACTARIO
conclusiones
y El tto de las crisis DEBE comenzar a los 5 minutos de iniciada
y La 1ra línea de tto prehospitalaria incluye al DZP (IR), Midazolam (IM, IN, Bucal)
y La 1ra línea de tto en el DE es el DZP /LZP EV. Se sugiere dosis de carga de DFH si se utiliza DZP.
y Se diagnostica status epilepticus refractario luego del fracaso a la primera línea de tto: la elección de la medicación dependerá de la disponibilidad, capacidad del centro y el estado hemodinámico.
conclusiones
y El acido valproico sería una opción de tratamiento en el SE Establecido.
y El fenobarbital a altas dosis es una alternativa al tiopental en el SER.
y La dieta cetogénica es una medida terapéutica no farmacológica efectiva ante la recurrencia luego del coma farmacológico.
y Considerar tratamiento inmunológico en el SER sin etiología clara
Acad Emerg Med. 2010 Jun;17(6):575-82.
Midazolam versus diazepam for the treatment of status epilepticus in
children and young adults: a meta-analysis.
McMullan J, Sasson C, Pancioli A, Silbergleit R.
Source
Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH,
USA. mcmulljWe performed a search of PubMed, Web of Knowledge,
Embase, Cochrane Database of Systematic Reviews, Database of Abstracts
of Reviews of Effects,for studies published January 1, 1950, through July 4,
2009. English language quasi-experimental or randomized controlled trials
comparing midazolam and diazepam as first-line treatment for SE, and
meeting the Consolidated Standards of Reporting Trials (CONSORT)-based
quality measures, were eligible. Two reviewers independently screened
studies for inclusion and extracted outcomes data. Administration routes were
stratified as non-IV (buccal, intranasal, intramuscular, rectal) or IV. Fixedeffects models generated pooled statistics.
OBJECTIVES:
The objective was to determine by systematic review if nonintravenous (nonIV) midazolam is as effective as diazepam, by any route, in terminating SE
seizures in children and adults. Time to seizure cessation and respiratory
complications was examined.
RESULTS:
Six studies with 774 subjects were included. For seizure cessation, midazolam,
by any route, was superior to diazepam, by any route (relative risk [RR] = 1.52;
95% confidence interval [CI] = 1.27 to 1.82). Non-IV midazolam is as effective
as IV diazepam (RR = 0.79; 95% CI = 0.19 to 3.36), and buccal midazolam is
superior to rectal diazepam in achieving seizure control (RR = 1.54; 95% CI =
1.29 to 1.85). Midazolam was administered faster than diazepam (mean
difference = 2.46 minutes; 95% CI = 1.52 to 3.39 minutes) and had similar times
between drug administration and seizure cessation. Respiratory complications
requiring intervention were similar, regardless of administration route (RR =
1.49; 95% CI = 0.25 to 8.72).
CONCLUSIONS:
Non-IV midazolam, compared to non-IV or IV diazepam, is safe and effective in
treating SE. Comparison to lorazepam, evaluation in adults, and prospective
confirmation of safety and efficacy is needed
Eur J Paediatr Neurol. 2010 Mar;14(2):162-8
Lorazepam versus diazepam-phenytoin combination in the treatment of
convulsive status epilepticus in children: a randomized controlled trial.
Sreenath TG, Gupta P, Sharma KK, Krishnamurthy S.
Source
Department of Pediatrics, University College of Medical Sciences and Guru
Tegh Bahadur Hospital, India.
Abstract
OBJECTIVE:
To determine whether intravenous lorazepam is as efficacious as diazepamphenytoin combination in the treatment of convulsive status epilepticus in
children.
STUDY DESIGN:
Randomized controlled trial.
METHODS:
A total of 178 children were enrolled in the study; 90 in the lorazepam group
and 88 in the diazepam-phenytoin combination group. Enrolled subjects were
between 1 and 12 years with a clinical diagnosis of convulsive status
epilepticus, presenting in pediatric emergency of a tertiary care hospital.
They were randomized to receive either intravenous lorazepam (0.1 mg/kg)
or intravenous diazepam (0.2 mg/kg)-phenytoin (18 mg/kg) combination at
admission and were followed up for subsequent 18 h.
RESULTS:
The overall success rate of therapy was 100% in both the groups. There was
no statistically significant difference in the two groups (lorazepam versus
diazepam-phenytoin combination) in the median time taken to stop the seizure
[20s in both groups], the number of subjects requiring more than one dose of
the study drug to stop the presenting seizure [lorazepam 6(6.7%) versus
diazepam-phenytoin combination: 14 (15.9%); adjusted RR (95% CI)=0.377
(0.377, 1.046); P=0.061] and the number (%) of patients having respiratory
depression [lorazepam 4(4.4%) versus diazepam-phenytoin combination 5
(5.6%)]. None of the patients in the two groups required additional
anticonvulsant drug to stop the presenting seizure. No patient required
mechanical ventilation and none of the patients in the two groups required
cross-over to the alternative regimen.
CONCLUSION:
Lorazepam is as efficacious and safe as diazepam-phenytoin combination. We
recommend use of lorazepam as a single drug to replace the two drug
combination of diazepam-phenytoin combination to control the initial seizure in
pediatric convulsive status epilepticus