Status epilepticus o nomanejo da crise nica

1
Status epilepticus (o não-manejo da crise única)

• Prof. Paulo R M de Bittencourt, MD, PhD
• www. unineuro.com.br

2
Treiman DM. New Brunswick, NJ Convulsive Status
EpilepticusCurr Treat Options Neurol 1999
Sep1(4)359-369

• Generalized convulsive status epilepticus (GCSE)
  is a medical emergency that must be treated
  rapidly and aggressively to prevent neuronal
  damage.
• Treatment should be initiated with iV lorazepam,
  0.1 mg/kg, no more than 2 mg/min.
• If convulsions persist for more than 10 min or
  recur more than 20 minutes after lorazepam
  therapy is started
• fosphenytoin (20 mg of phenytoin equivalents per
  kilogram) should be infused at a rate of no more
  than 50 mg/min.

3
Treiman 1999 cont

• If convulsions still continue, IV general
  anesthesia with pentobarbital, benzodiazepine
  drip, or propofol should be initiated after
  respiratory support has been established
• All patients with GCSE who do not recover
  consciousness should be monitored with EEG
• any residual epileptiform activity including
  periodic epileptiform discharges (PEDs) should be
  considered evidence of continuing GCSE and
  treated aggressively

4
Treiman DM. Status epilepticus. Baillieres Clin
Neurol 1996 Dec5(4)821-39 UCLA

• Status epilepticus is a condition in which
  multiple epileptic seizures occur without
  complete recovery from the physiological effects
  of one seizure before another seizure occurs.
• There are as many types of SE as there are kinds
  of epileptic seizures.
• Generalized convulsive status epilepticus
  initially presents with repeated generalized
  convulsions without full recovery of
  consciousness between seizures.
• If untreated or undertreated, the convulsive
  activity becomes progressively subtle and is
  accompanied by a predictable series of
  progressive EEG changes

5
Treiman 1996 cont

• Non-convulsive SE refers to complex partial SE or
  absence SE, both of which exhibit an epileptic
  twilight state of altered contact with the
  environment.
• In simple partial SE there is no impairment of
  consciousness, and the behavioural changes
  reflect focal ictal discharges confined to one
  area of the cortex.
• There are between 65,000 and 150,000 cases of SE
  in the US each year. Both acute and remote
  cerebral insults can cause SE, as can severe
  systemic disease that causes SE secondary to a
  toxic-metabolic encephalopathy.
• Mortality is high, but is largely a reflection of
  underlying aetiology when SE is treated
  appropriately and aggressively.

6
Treiman 1996 cont

• Treatment is focused on terminating ongoing
  seizure activity as quickly as possible, both
  because the longer SE persists the more likely
  permanent neuronal damage will ensure and also
  because of strong evidence that the longer SE
  persists the more refractory to treatment it will
  be.
• Currently the most commonly accepted treatment
  protocol involves rapid initiation of therapy
  with IV lorazepam (0.1 mg/kg), followed, if
  necessary, by 20 mg/kg of phenytoin, followed, if
  necessary, by 20 mg/kg of phenobarbital. However,
  some neurologists still use intravenous diazepam
  (because of its more rapid antistatus effect)
  followed by phenytoin. New experimental data in
  the rat suggest that phenytoin followed by
  diazepam may be more effective, but this order of
  administration still has to tested in properly
  designed clinical trials.

7
Uncle Sam once again

• Phenobarbitone, USA, 1912
• Phenytoin, USA 1939
• Lorazepam, Wyeth, USA
• Phosphenytoin, USA 1990s

8
Rational management of epilepsy in developing
countries requirements and resources

• Prof. Paulo R M de Bittencourt, MD, PhD
• Co-chairman, Subcommission on Therapeutic Needs
  in Emerging Countries
• ILAE Commission on Therapeutic Strategies

9
What is irrational in Latin America and the
Caribbean

• Widespread use of drugs to which tolerance
  develops
• Phenobarbitone, clonazepam and clobazam are cheap
  and tremendously easy to start
• Slow development of knowledge in clinical
  pharmacology
• Generics versus similars
• Kinetics of phenytoin, carbamazepine
• Dynamics of valproate

10
Resultado prático

• Grande quantidade de pseudo-status
• Síndromes de retirada de fenobarbital, clobazam,
  clonazepam, diazepam
• Interrupção abrupta de carbamazepina

11
Health Management Organizations

• Low pay, large numbers
• No time for history or orientation, one visit per
  month, useless EEGs
• No diagnosis of age related idiopathic epilepsies
• Potential failures
• Diagnosis of partial seizure
• kinetics
• Action
• Phenobarbitone in simple cases
• Benzos in complex, spike-wave/ absence cases

12
What is irrational

• Barbiturates and benzos
• Tonic clonic seizures
• Frequent status
• Somnolonce
• Low IQ
• Depression

• New drugs
• Polytherapy
• Compliance

13
Resultado prático

• Mariela entre 6/2000 e 6/2001, 4 vezes, recebeu
  Hidantal EV em hospitais de Curitiba e Caiobá
• 15 anos, VIP, portadora de epilepsia generalizada
  idiopática familiar desde 5 anos de idade
• Pai, irmão também
• Causa das crises night-clubs

14
Status em 2000/2001

• Ronalda, epilepsia mioclônica infantil familiar ?
• Irmão e ela com crises neonatais? Intratáveis
• Exigência familiar de contrôle absoluto de
  qualquer crise
• queima neurônios

• Nenhum outro caso admitido a hospital

15
Onde estamos

• Status convulsivo, ou generalizado tônico-clônico
  é a única real emergência, tratável em UTI
• Status não convulsivo nunca é emergência, nem
  indicação absoluta de UTI
• Problema em status não convulsivo é diagnóstico
• Conduta depende de diagnóstico
• Prognóstico depende de patologia básica

16
PRM Bittencourt and A Richens Epilepsia
22129-134, 1981Anticonvulsant induced status
epilepticus in Lennox-Gastaut syndrome

• Janet Rickets, Chalfont Centre for Epilepsy,
  carbamazepina, fenitoína e primidona
• Status de ausência, 4 h depois tônico-clônico
• UTI por 26 dias, status tônico com apnéias,
  induzido por clormetiazole, clonazepam, diazepam,
  tiopental
• Retirada toda medicação, inclusive fenitoína e
  carbamazepina após diagnóstico de Lennox-Gastaut
• Melhora e alta com primidona 1500mg ao dia

17
5 years, English, review, human found 150
references

• Neurophysiol Clin 2000 Dec30 (6)377-82
• No, some types of nonconvulsive status
  epilepticus cause little permanent neurologic
  sequelae (or "the cure may be worse than the
  disease").
• Kaplan PW. Johns Hopkins Bayview Medical Center,
  Baltimore.

18
NeurointensivismoKG Jordan. Continuous
monitoring in the neurosciences intensive care
unit and emergency care. J Clin Neurophysiol 16
(1) 14-40

• Enfermeiras/ médicos controlam pentobarbital,
  midazolam ou propofol por EEG contínuo em HIC,
  SAH, Status
• EEG decisivo em 54, contribui em 32, não em
  14 de 200 pacientes
• 20 de TCE tem status não ou convulsivo
• de alfa é medida quantitativa
• Stroke, SAH, trauma, hypoxia, doença

19
PW Kaplan. Assessing the outcomes in
nonconvulsive status epilepticus underdiagnosed,
potentially overtreated and confounded by
comorbidity. J Clin Neurophysiol 16 (4) 341-352,
1999

• Alteração comportamental ou cognitiva com EEG
  ictal durante 30 minutos
• Parcial complexo ou generalizado
• Confundido com coma, estados pós-ictais e
  psiquiátricos
• Diagnóstico por EEG
• hidantalização formalmente contra-indicado
• Prognóstico dependente de etiologia

20
Pediatr Neurol 1999 Jul21(1)511Midazolam and
pentobarbital for refractory status epilepticus.
Holmes GL, Riviello JJ Jr.

• initial therapies with diazepam, phenytoin, or
  phenobarbital terminate seizure activity in 30-60
  minutes
• pentobarbital has been the most commonly
  prescribed agent for the management of RSE in
  children however, midazolam is a new treatment
  option.

21
Holmes GL, Riviello JJ Jr. cont

• Both drugs effectively terminated refractory
  seizure activity, although pentobarbital use was
  complicated by hypotension, delayed recovery,
  pneumonia, and other adverse effects.
• Midazolam use was effective and well tolerated,
  affirming its value in pediatric RSE management.

22
J Emerg Med 1999 Mar-Apr17(2)323-8Use of
intramuscular midazolam for status
epilepticus.Towne AR, DeLorenzo RJ.

• rectal administration as challenging as iv in
  convulsing patient, im easier, less invasive
• diazepam and lorazepam may be administered i.m.,
  but are absorbed slowly
• Midazolam is rapidly absorbed and
  pharmacodynamic effects can be seen within
  seconds, seizure arrest within 5 to 10 min
• J Child Neurol 1998 Dec13(12)581-7 Use of
  midazolam for refractory status epilepticus in
  pediatric patients.Pellock JM.

23
J Child Neurol 1998 Oct 13 Suppl
1S23-6Additional modalities for treating acute
seizures in children overview. Bebin EM.

• The recently approved intravenous formulation of
  valproate may be of use in children receiving
  oral valproate who develop breakthrough seizures
  caused by subtherapeutic plasma levels secondary
  to missed doses or an inability to tolerate oral
  valproate.

24
Status epilepticus. Current concepts and
management. Starreveld E, Starreveld AA. Can Fam
Physician 2000, 461817-23

• inform primary care physicians about GCSE
  emphasizing definition, pathophysiology,
  treatment, and prognosis
• MEDLINE (1994 to 1999 479 references MeSH
  "status epilepticus" and "treatment
• selected 30 English-language articles. Key source
  documents from previous years and information
  from modern textbooks and recent symposia also
  included.

25
MAIN MESSAGE

• Generalized convulsive status epilepticus
  continues to be a medical emergency, high
  morbidity and mortality. It must be managed
  promptly and effectively. The operational
  definition of GCSE is a seizure that lasts longer
  than 5 minutes or two or more seizures between
  which patients do not recover. Main differential
  diagnosis is nonepileptic status.

26
Status convulsivo na América do Norte

• Intravenous therapy with combined lorazepam and
  phenytoin is the initial treatment of choice.
  Other preferred medications are diazepam,
  midazolam, and propofol. Some should be
  considered before arrival at hospital. Prognosis
  determined by cause, delay in adequate treatment,
  and comorbidity. GCSE lasting longer than 30
  minutes require intensive care and EEG
  monitoring.

27
Current Concepts Status epilepticus. DH
Lowenstein and BK Alldredge. NEJM 338 (14)
970-976, 1998

• Cuidados gerais, monitorização do EEG, tiamina,
  glicose
• Lorazepam 0.1mg/kg 2mg/min, EV
• Fenitoína 20mg/kg 50mg/min, EV ou fosfenitoína
  20mg/kg 150ug/min
• Fenobarbital 20mg/kg 50-75mg/min ou anestesia
  com midazolam ou propofol

28
Lowenstein and Alldredge 1998, cont

• Midazolam
• 0.2mg/kg IV lento 0.75-10uG/kg/min
• Propofo1
• 2mg/kg 2-10mg/kg/h

29
Nervenarzt 2000 71(2)65-77 Therapy of
generalized tonic-clonic status epilepticus in
adulthood.  Beyenburg S, Bauer J, Elger CE.
Klinik fur Epileptologie der Universitat Bonn.

• If continuous seizure activity lasts longer than
  5 minutes generalized tonic-clonic seizures
  require prompt treatment, if significant
  morbidity and mortality are to be avoided.
• The mortality varies (mean 20) depending on
  patient age and etiology.

30
Status convulsivo na Alemanha

• Control is achieved by benzodiazepines in about
  80 of cases Lorazepam is longer-acting
  phenytoin is used for maintenance
• Fosphenytoin can be given three times more
  rapidly and produces fewer side effects.
• IV valproic acid seems promising, but needs
  further evaluation.

31
Status na Alemanha

• There is no accepted treatment protocol for the
  therapy of persistent seizure activity lasting
  more than 60 minutes (i.e.,refractory status
  epilepticus).
• phenobarbital or general anesthesia with
  thiopental or pentobarbital are treatment
  recommendations.
• In recent reports, midazolam or propofol proved
  to be effective and well-tolerated

32
Drug Saf 2000 Jun22(6)459-66 Fosphenytoin and
phenytoin in patients with status epilepticus
improvedtolerability versus increased
costs. DeToledo JC, Ramsay RE.

• intravenous phenytoin has largely replaced
  phenobarbital as the second agent of choice
  (following the administration of a
  benzodiazepine) in the treatment of TCSE.
• Intravenous phenytoin has been associated with
  fatal haemodynamic complications and serious
  reactions at the injection site including skin
  necrosis and amputation of extremities

33
Fosphenytoin, prodrug,same pharmacological
properties, none of the site and cardiac
complications

• fosphenytoin better tolerated, delivered faster
• The tolerability of intramuscular fosphenytoin
  also extends its use to situations where prompt
  administration of a non depressing anticonvulsant
  is indicated but secure intravenous access and
  cardiac monitoringare not available, such as by
  rescue squads in the field and serial seizures in
  the institutionalised and elderly.

34
MM Stecker et al. Treatment of refractory status
epilepticus with propofol clinical and
pharmacokinetic findings. Epilepsia 3918-26, 1998

• 8 casos com barbitúricos em dose alta, 8 com
  propofol
• Após lorazepam e fenitoína em todos midazolam
  (3) ou fenobarbital (12)
• 82 (9 de 11 tratamentos) versus 63 ( 5 de 8
  casos) controlados
• Alta mortalidade ambos grupos pelo mau
  prognóstico
• Suspender propofol lentamente senão crises voltam
• Dose de propofol por surto-supressão no EEG

35
Pediatr Rev 1998 Sep19(9)306-9 Management of
status epilepticus in children.Sabo-Graham T,
Seayve T.

• Initially lorazepam 0.1 mg/kg or diazepam 0.5
  mg/kg
• Seizures longer than 10 minutes phenobarbital
  20mg/kg
• Further seizure activity lorazepam or diazepam.
  Seizure longer than 10 minutes, a second
  long-acting anticonvulsant should be
  administered, followed by induction of general
  anesthesia.

36
Ideal adultos e criançasBoa avaliação clínica e
EEGstatus convulsivo

• Status generalizado
• Diazepam infusão direta sem diluição até parar
• Repetir em 3-4h
• Valproato VSNG depois

• Status localizado
• Diazepam infusão direta até parar, sem diluição
• Repetir em 3-4h
• Oxcarbazepina VSNG depois

37
Ideal adultos e criançasBoa avaliação clínica e
EEGstatus não-convulsivo

• Status generalizado
• ? Diazepam infusão direta sem diluição até parar
• Pequena dose
• Valproato VSNG depois

• Status localizado
• Diazepam infusão direta até parar, sem diluição
• Pequena dose
• Oxcarbazepina VSNG depois

38
Diferencial do atendimento de ponta

• Não usar cronicamente drogas que levam a
  tolerância
• Não utilizar drogas que induzem enzimas hepáticas
  em pacientes dependentes de politerapia
• Portanto afastar barbitúricos, benzos,
  fenitoína, carbamazepina
• Portanto valproato, oxcarbazepina