Management    in    

Status  epilepticus

Dr.  Yotin    Chinvarun    M.D.  Ph.D.  

Comprehensive  Epilepsy  and  Sleep  disorder  Program  

Pramongkutklao  hospital

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Case• F 31 years old with alteration of consciousness and low grade fever 5 day

PTA, the patient was found unconsciousness in her house

• Admitted at nearby hospital, low grade fever, stupor, CT and MRI brain was done

• LP showed no cell, normal protein and sugar, C/S negative

• Dx Acute encephalitis (DDx Herpes encephalitis)

• Rx: Acyclovir and Ampicillin IV

• CT brain and MRI brain were done

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Treatment• Repeated LP was performed, CSF analysis was normal

• Viral study from CSF was negative

• Rx – Valproate 800 mg q 6 hrs – LVT 500 mg q 6 hrs – Then, PB gr I 2-2-2, TPM 100 mg 1-1

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Progression• Autoimmune profile all normal

• U/S whole abdomen was normal

• Methylprednisolone had been given for 7 days

• Anti NMDA, GAD, VGKC: negative

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Why  is  Status  Epilepticus  is  important  ?

• Morbidity/mortality  with  some  types  of  SE  

• Medical  emergency  →  Need  for  rapid  and  accurate  diagnosis  →  Need  for  effective  and  safe  treatment

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Status  epilepticus:  Mortality

DeLorenzo RJ, et al. Neurology. 1996;46:1029-1035.

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15

30

45

60

<1 1-­‐4 5-­‐9 10-­‐15 16-­‐39 40-­‐59 60-­‐79 80+

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1981  ILAE    “Persists  for  a  sufficient  length  of  times  or  is  repeated  

frequently  enough  that  recovery  between  attack  does  not  occur”

Definition7

Status  epilepticus:  Definition  by  Time

• Duration  of  seizures  not  the  sole  cause  of  neuronal  damage,  etiology  is  strong  determinant  of  whether  injury  develops,  seizure  type  and  patient’s  age  also  play  a  role  

• Recent  clinical  trend  define  SE  with  shorter  and  shorter  times  e.g.  20  minutes,  The  Veterans  Affairs  Cooperative  Study  used  10  minutes  for  generalized  SE  

• Lowenstein  et  al  proposed  “operational”  definition  of  SE  as  5  minutes  of  continuous  seizures  or  “two  or  more  discrete  seizures  with  incomplete  recovery  of  consciousness

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Definition  of  Status  Epilepticus• Status  epilepticus  is  present  when  an epileptic  seizure  is  so  frequently  repeated or  is  so  prolonged  as  to  create  a  fixed  and lasting  condition (Gastaut,  1981)  

• “There  can  be  as  many  forms  of  SE  as  there  are  seizure  types…”  (Gastaut,  1983)

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Seizure  type  classification• Generalized  SE  

• Tonic  clonic  SE  • Tonic  SE  • Clonic  SE  • Myoclonic  SE  • Absence  SE  • Atonic  and  akinetic  SE  

• Partial  SE  • Elementary  partial  SE  • Complex  partial  SE  

• Unilateral  SE

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Status  epilepticus:  Epidemiologic  data

• Operational  definition;  a  seizure  lasting  >30  minutes  or  a  series  of  seizures  lasting  >30  min  without  fully  recovery  

• Incidence  of  SE  ranges  between  18.1  and  41  cases  per  100,000  population  per  year  

• Approximately  60,000  to  195,000  cases  /years  in  U.S.A.  40,000  deaths  annually

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Status  epilepticus  and  epilepsy

• 10-­‐12%  of  patients  with  a  first  unprovoked  seizure  or  newly  diagnosed  epilepsy  present  with  SE  

• 25-­‐40%  of  SE  occurs  in  patients  with  epilepsy  

• 15-­‐27%  of  patients  with  epilepsy  will  experience  at  least  one  episode  of  SE  

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Who  is  at  risk  for  SE

• Patients  with  acute  symptomatic  seizures  

• Those  with  pre-­‐existing  neurological  abnormalities  

• The  very  young  

• The  very  old  

• Those  with  a  history  of  prolonged  seizures

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Classification  of  SE

Convulsive Nonconvulsive

Generalized Tonic-clonic Absence

Partial Partial motor (EPC) Complex partial

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Classification  of  SE Primary  Generalized  SE

•Generalized  convulsive  status  epilepticus  (GCSE)       •  Absence  status  epilepticus  (ASE)       •  Atypical  absence  status  epilepticus  (AASE)       •  Generalized  atonic  status  epilepticus  (GASE)       •  Generalized  myoclonic  SE       •  Generalized  clonic  SE       •  Generalized  tonic  SE       •  Electrical  Status  Epilepticus  of  sleep  (ESES)  

(Treiman,  1995)

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Classification  of  SE Partial  SE

• Simple  partial  status  epilepticus  (SPSE)  •  Epilepsia  partialis  continua  (EPC)  •  Rolandic  status  epilepticus  (RSE)  

• Complex  partial  status  epilepticus  (CPSE)  

• Secondarily  generalized  convulsive  status  epilepticus  (GCSE)

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Clinical  features:  Convulsive  SE

• Generalized  tonic-­‐clonic  seizures    – Unconsciousness  – Firstly,  tonic,  clonic,  or  tonic-­‐clonic  – With  time,  subtle  motor  involvement  – Tonic  status  commonly  in  children  e.g.  LGS  

• Clonic  status:  commonly  in  neonate    

• Myoclonic  status  e.g.  JME,  Mitochondrial  diseases,  anoxic  encephalopathy

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Clinical features: Convulsive SE

• Simple  partial  status  epilepticus  

• Epilepsia  partialis  continua  

• Commonly  in  the  Rasmussen’s  encephalitis  

• Others  causes  e.  q.  focal  motor  seizure  (due  to  localized  cerebral  lesions),  metabolic  disturbances  (nonketotic  hyperglycemia)

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Non-­‐convulsive  SE

• NCSE  is  a  term  used  to  denote  a  range  of  conditions  in  which  electrographic  seizure  activity  is  prolonged  and  results  in  non-­‐convulsive  clinical  symptoms  

• Note  –  no  time  limit  set  -­‐ Emphasis  on  EEG  patterns  for  diagnosis  

-­‐ NCSE  is  best  viewed  as  a  form  of  cerebral  response  dependent  on:  age,  cerebral  development/integrity,  anatomical  location,  epilepsy  syndrome  

-­‐ Diagnostic  difficulties  –  ‘boundaries  of  SE’ -­‐ EEG  changes  in  acute  cerebral  damage  (Coma  with  PLEDs)  

-­‐ Epileptic  encephalopathies  –  differentiation  of  ictal  vs  interictal  state  

-­‐ Epileptic  behavioral  changes  with  limbic  but  no  scalp  EEG  change  

-­‐ EEG  change  in  metabolic/drug  induced  encephalopathies

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Determination  of  NCSE• Altered  consciousness  or  behavior  from  baseline  for  >  30  

minutes  without  convulsive  movements  AND:  

– Repetitive  focal  or  generalized  epileptiform  activity  (spikes,  sharp  waves,  spike-­‐and-­‐wave,  sharp-­‐and-­‐slow  wave  complexes)  or  rhythmic  theta/delta  activity  at  >2/sec  

– Above  EEG  patterns  at  <  1/sec  with  improvement  or  resolution  of  epileptic  activity  and  clinical  state  following  injection  of  rapid  onset  AED  (e.g.BZP)  

– Temporal  EEG  evolution  of  epileptiform  or  rhythmic  activity  >  1/sec  with  change  in  location  or  frequency  of  rhythmic/epileptiform  activity.

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NCSE:  complex  partial  SE• Clinical  pattern  

– Usually  recurrent,  attacks  can  be  prolonged  

– EEG  features-­‐  variable,  can  be  slight  

– Anatomy-­‐  often  frontal  (65%)  rather  than  temporal  (35%)  

– Clinical  features  • Confusion  or  altered  consciousness,  range  in  severity  (video),  video  2,  video  3  

• Often  fluctuates  (cycling/discontinuous,  vs  continuous  forms)  

• Motor  features  (jerking,  automatism)  

• Behavioural/psychic  changes  –  agitation,  excitation,  questing,  sluggish,  restless,  retardation,  questing  

• Amnesia  common  

• EEG  variable  and  inconsistent  patterns  

• Treatment  with  IV  BZD  only  sometimes  helpful.  Response  often  incomplete.  Other  oral  or  IV  AEDs  may  be  effective.  Anaesthesia  seldom  indicated

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The  umlity  of  intravenous  benzodiazepine

• Clear  clinical  improvement  of  following  BZD:  likely  indicator  of  NCSE  • Lack  of  clinical  improvement  following  BZD  

– Does  not  rule  out  NCSE  – 15%  of  NCSE:-­‐  resistant  to  BZD  treatment  

• Lagging  clinical  improvement  in  28%  of  54  NCSE  paments  (Shneker  and  Fountain  2003)  – Delayed  or  masked  by  Rx  itself  – Prolonged  posmctal  state  (especially  in  elderly)  – Concurrent  nonepilepmc  encephalopathy,  associated  acute  brain  injury  

• Resolumon  of  periodic  discharges  with  BZD  – Can  occur  in  metabolic  cause  of  periodic  discharge  (such  as  Triphasic  wave)

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Myoclonic  SE  and  Subtle  SE

• Myoclonic  SE  in  coma  – Acute  onset  –  in  context  of  severe  brain  injury  –  usually  anoxic  (e.g.  post  cardiac  arrest)  

– Deep  coma  

– Myoclonic  jerking,  ocular  movements  

– EEG  shows  PLED/BiPLEDs/other  spikes  

– Rx  controversial  –  anaesthetic  AEDs  vs  none  

– Poor  prognosis  >80%  death  rate    

– Not  clear  to  what  extent  this  is  a  form  of  SE  or  whether  the  EEG  changes  simply  are  a  reflection  of  severe  brain  damage  

• Subtle  SE  clinical  features  – Deep  coma  in  the  aftermath  of  a  GTCS  or  SE  

– Myiclonic  jerking,  ocular  movement  

– EEG  shows  PLEDs  BiPLEDs/other  spikes  

– Rx  anaesthetic  AEDs  or  BZD  

– Prognosis  good

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NCSE-­‐ABI  Brain  Damage:The  Clock  is  Ticking

• Seizure  duration  and  delay  to  Dx  are  major  determinants  of  mortality,  independent  of  etiology  (Young  et  al,  1996;  DeLorenzo  et  al,  Neurology  1998)  

• 36%  if  <  30  min  vs  75%  if  >24  hrs  delay  

• 10%  if  <  10  hrs  vs  85%  if  >20  hrs  duration

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Survival  in  Status  Epilepticus  by  Duration  of  Seizure  Survival  

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NCSE  causes  neurological  morbidity  and  mortality,  related  to

• Adverse  systemic  metabolic  and  physiologic  effects  

• Brain  injury  caused  by  an  acute  insult  that  may  induce  NCSE  

• Direct  neuronal  damage  from  the  abnormal  electrical  activities

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NCSE-­‐ABI  Increases  Brain Damage:  Biochemical  Evidence

• Increased  excitotoxic  cell  injury  metabolites:  

– Brain  glutamate:  exceeds  the  concentration  for  excitotoxic  cell  death  and  swelling  (Vespa  et  al.  J  Neurosurg  1998)  

– Excitotoxic  cell  membrane  peroxidation  products;  e.g.,  glycerol  (Vespa  et  al.  Acta  Neurochir  Suppl  2002)  

– Lactate/pyruvate  ratio  suggesting  ischemic  cascade  activation  (Vespa  et  al.  JCN  2005)  

– Serum  neuronal  enolase:  highest  levels  in  combined  SE  and  ABI  (DeGiorgio  et  al.  Neurology  1999)

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NCSE-­‐Acute  Brain  Injury  (ABI)  Increases  Mortality

•Clinical  Evidence  

– 57%  vs  9%  NCS  alone  (Young  et  al,  Neurology,  1996)  

– 46%  vs  16%  remote  brain  injury  (Young  et  al,  ibid)  

– In  Acute  Ischemic  Stroke  39%  vs  14%  AIS  alone.  AIS  +  SE  mortality  is  synergistic  and  not  merely  additive  (Waterhouse  et  al.  Epilepsia  1998.)  

– Preventing  NCSE  in  experimental  AIS:  70%  lower  mortality  (Williams,  et  al.  J.  Pharmacol  Exp  Ther  2004)  

– In  ICH,  assoc  with  cerebral  edema  and  midline  shift,  independently  predicts  mortality  (Vespa  et  al.  Neurology  2003)

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Status Epilepticus NMDA receptor activation

Seizure-induced neuronal loss

Reduced GABAA

receptor function

Neuronal Dysfunction Sustaining SE

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Neuronal  injury  and  network  reorganization

• Recently,  evidence  that  prolonged  febrile  seizures  and  episode  of  SE  produce  hippocampal  cell  loss  and  shrinkage  

• Seizure-­‐induced  presumably  excitotoxic  pathology  includes    – neuronal  loss    – reactive  gliosis    – aberrant  synaptic  reorganization

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The pathology of status epilepticus (SE)31

Treatment

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Treatment  of  SE

• Assessment  and  control  airway  • Monitor  vital  signs  • Conduct  pulse  oximetry  and  monitor  cardiac  function  • IV  fluid  replacement  • Administer  glucose  if  suspect  hypoglycemia  • Start  anticonvulsant

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Treatment• Goal  to  prompt  cessation  of  seizure  activity  

• Should  be  easy  to  administer  

• Have  immediate  and  long-­‐lasting  antiseizure  activity  

• Least  effect  particularly  to  cardiovascular  and  pulmonary  function  and  level  of  consciousness

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Current  medications35

The ideal IV AED in Status Epilepticus

• Easy to administer

• Quick onset of action

• Long duration of action

• Good safety & tolerability profile

• No drug interactions

• Smooth transition to oral treatment

Currently available IV AEDs

•Benzodiazepines• Diazepam• Lorazepam• Midazolam• Clonazepam

•Phenytoin, FPHT

•Valproate

•Levetiracetam

•Lacosamide

•Barbiturates• Thiopental, Pentobarbital

•Propofol

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Treatment

▪ Prehospital  treatment  with  IV  benzodiazepine  improves  outcome  and  reduces  morbidity1

1. Alldredge BK, et al. N Engl J Med. 2001;345:631-637. Erratum in: N Engl J Med. 2001;345:1860.

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Initial  Therapy

▪ Outpatient  therapy  – Rectal  diazepam  gel  –  0.2  mg/kg  – Intranasal/buccal  midazolam  –  10  mg  

▪ Inpatient/emergency  department  therapy  – IV  lorazepam  2  mg  q  5-­‐10  minutes,  maximum  10  mg  – IV  fosphenytoin  (18  mg/kg  load,  level  >20  μg/mL)  

▪ Maximize  phenytoin  – Additional  load  of  10  mg/kg  – Desired  serum  level  of  25  to  30  μg/mL

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• Should  be  prompt  administer  after  diagnosed  as  SE  

• Choice  of  AED  based  on  the  rapid  onset  and  half-­‐life  of  AED  

• Prospective  blinded  studied,  comparing  Lorazepam,  Phenytoin,  Diazepam  with  Phenytoin,  and  Phenobarbital;-­‐  all  were  equally  effective  

• Except  the  Lorazepam  was  superior  to  PHT  when  seizures  were  assessed  20  min  after  drugs  administration

Treatment42

• Benzodiazepines;  diazepam,  lorazepam,  or  clonazepam  

• Phenytoin;  20-­‐25  minutes  used  for  the  drug  to  attain  its  maximal  effect  

• Hypotension  occur  30-­‐50%,  cardiac  arrhythmias  2%  

• Fosphenytoin  a  water-­‐soluble  form  of  PHT  (half  life  15  min)  can  be  administered  at  phenytoin-­‐equivalent,  rate  can  be  up  to  150  mg/min,  less  side  effects  of  infusion-­‐site  reaction  

Treatment43

• Phenobarbital;  using  when  benzodiazepine  or  PHT  failed,  dosage  20mg/kg  (at  a  rate  50-­‐75  mg/min)  

• Be  careful  about  depression  of  respiratory  function  

• BP  and  level  of  consciousness  

• Can  be  use  as  3rd  line  with  high  dosage  to  induced  “Barbiturate  coma”

Treatment44

• Valproate  used  intravenously  treatment  of  SE    

• Case  series  suggest  useful  for  variety  of  seizure  types  

• Loading  dose  15  mg/kg  and  maintenance  of  1  mg/kg/h,  stopped  seizures  within  30  minute  in  80%  of  cases    

• Valproate  IV  also  been  successful  in  children    

• Well  tolerated  and  causes  less  cardiovascular  instability  than  does  IV  phenytoin,  non-­‐sedative

Treatment45

When  does  SE  become  refractory

• No  standard  definition  

• Most  authors  have  considered  SE  refractory  when  adequate  does  of  a  benzodiazepine  and  phenytoin  fail  to  terminate  SE  – Others  required  Phenobarbital  as  well  

• Duration  of  SE  prior  treatment  

• Effects  of  treatment  sequence

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Agents  commonly  recommended  for  refractory  SE  treatment

• High  dose  Barbiturates  (“Barbiturate  coma”)  • Thiopental  • Phenobarbital  

• High  dose  benzodiazepines  • Midazolam  • Lorazepam  • Diazepam  

• Propofol

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Drug  treatment

• Midazolam    • (0.2mg  /kg  slowly  administer  followed  by  0.75-­‐10  microgram/min  

• Propofol    • (1-­‐2  mg/kg  /hour),  maintain  infusion  of  these  drugs  for  12-­‐24  hours      

• Thiopental  and  pentobarbital  • 10-­‐15  mg/kg  IV  administer  over  a  period  of  one  hour  followed  by  0.5-­‐1  mg/kg/hour

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Carbamazepine,  Oxcarbazepine,  Topiramate,  and  Levetiracetam

• These  antiseizure  medications  often  added  to  the  acute  AED  regimen  with  the  intention  of  providing  adequate  maintenance  AED  coverage  to  pre-­‐  vent  SE  recurrence  when  infusion  therapy  is  withdrawn  

• In  the  setting  of  SE,  these  medications  generally  titrated  quickly  up

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Carbamazepine,  Oxcarbazepine,  Topiramate,  and  Levetiracetam

• The  use  of  carbamazepine  in  SE  primarily  as  maintenance  antiseizure  medication  

• A  parenteral  formulation  is  not  yet  available.  Typical  daily  doses  in  the  setting  of  SE  are  up  to  1600  mg/d  

• Oxcarbazepine  is  used  in  the  same  way  as  carbamazepine

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Carbamazepine,  Oxcarbazepine,  Topiramate,  and  Levetiracetam

• Topiramate  has  been  reported  to  be  effective  when  administered  enterally  in  the  setting  of  SE    

• Topiramate  can  be  administered  by  nasogastric  tube  or  rectally,  is  generally  well  tolerated  except  for  mild  sedation,  and  can  be  quickly  titrated  to  dose  ranges  of  up  to  1600  mg/d  

• Levetiracetam  can  now  be  administered  parenterally  as  well  as  by  nasogastric  tube    – Typical  daily  doses  of  levetiracetam  in  the  setting  of  SE  are  up  to  5000  mg/d.  

– Main  advantage  of  levetiracetam  in  the  setting  of  acute  seizures  and  SE  is  ease  of  administration,  rapid  titration,  easy  transition  to  use  as  a  maintenance  AED,  and  few  drug−drug  interactions  

– However,  limited  data  on  its  efficacy  in  SE  in  humans

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Other  AEDs• Other  maintenance  AEDs  is  growing  and  includes  lamotrigine,  gabapentin,  

zonisamide,  pre-­‐  gabalin,  felbamate,  methsuximide,  ethosuximide,  acetazolamide,  primidone,  tiagabine,  and  vigabatrin.    

• Although  used  in  chronic  epilepsy,  these  agents  are  rarely  used  in  SE  owing  to  slow  titration  or  lack  of  evidence  for  clinical  efficacy  in  the  setting  of  SE

52

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EFNS  guideline:  Management  of  status  epilepticus  in  adults

• The preferred treatment pathway for generalised convulsive status epilepticus (GCSE) is

• Intravenous (i.v.) administration of 4-8 mg lorazepam or 10 mg diazepam directly followed by 18 mg/kg phenytoin.

• If seizures continue more than 10 min after first injection, another 4 mg lorazepam or 10 mg diazepam is recommended.

• The initial therapy of non-convulsive SE depends on type and cause.

Complex partial SE is initially treated in the same manner as GCSE.

• However, if it turns out to be refractory, further non-anaesthetising i.v. substances such levetiracetam, phenobarbital or valproic acid should be given instead of anaesthetics.

H. Meierkord, et. al. Eur J Neurol. 2010, 17: 348–355

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EFNS  guideline:  Management  of  status  epilepticus  in  adults

• Pharmacological  treatment  for  refractory  GCSE  and  subtle  status  epilepticus  – In  generalized  convulsive  and  subtle  SE,  proceed  immediately  to  the  infusion  of  anesthetic  

doses  of  midazolam,  propofol  or  barbiturates    

– Because  of  poor  evidence,  cannot  recommend  which  anaesthetic  substances  should  be  the  drug  of  choice.  

– Recommends  titration  against  EEG  burst  suppression  pattern  with  propofol  and  barbiturates.  If  midazolam  is  given,  seizure  suppression  is  recommended,  maintained  for  at  least  24  hours.  Simultaneously,  initiation  of  the  chronic  medication  (GPP)

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EFNS  guideline:  Management  of  status  epilepticus  in  adults

• Pharmacological  treatment  for  refractory  NCSE  – In  complex  partial  SE,  the  time  that  has  elapsed  until  termination  of  status  is  less  

critical  compared  to  GCSE    

– Thus,  general  anesthesia  due  to  its  possible  severe  complications  should  be  postponed  and  non-­‐anaesthetizing  anticonvulsants  may  be  tried  initially  (GPP)  

• Phenobarbital:   20  mg/kg  i.v.,  administration  of  additional  boluses  requires  intensive  care  conditions  

• Valproic  acid:  i.v.  bolus  of  25–45  mg/kg  is  administered  followed  by  maximum  rates  up  to  6  mg/kg/min

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Case:  Bursts  suppression  by  using  Barbiturate

Using  too  much  barbiturate  may  casing  fatal  complication

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Novel  Therapeutic  Approaches  in  Highly  Refractory  Status  Epilepticus

• Most  effective  way  to  terminate  RSE  is  to  successfully  treat  the  underlying  cause  

• it  is  important  to  treat  any  active  underlying  disease  processes  in  conjunction  with  treatment  of  the  SE  

• However,  many  causes  of  SE  are  actually  static  or  remote  from  the  active  episode  of  SE,  such  as  an  old  stroke

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What  does  a  clinician  do  when  patient  remains  in  SE  despite  pharmacologic  suppression  of  seizures  by  coma-­‐

inducing  agents?• Re-­‐evaluate  identified  underlying  cause  particularly  metabolic,  

inflammatory,  infectious,  or  iatrogenic  causes  

• Ensure  that  imaging  studies,  using  MRI,  positron  emission  tomography  (PET),  and  single-­‐photon  emission  computed  tomography  (SPECT),  if  available  

• Be  certain  that  the  electrographic  seizure  activity  is  abolished  while  the  patient  is  receiving  infusion  therapy.  

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What  does  a  clinician  do  when  patient  remains  in  SE  despite  pharmacologic  suppression  of  seizures  by  coma-­‐

inducing  agents?• Ensure  that  adequate  levels  of  maintenance  AEDs    

• If  an  infusion  therapy  does  not  work,  then  another  should  be  tried  – If  infusion  therapy  regimen  does  not  terminate  SE  after  initial  12-­‐  to  24-­‐

hour,  then  it  is  unlikely  to  be  successful  after  a  48-­‐  or  72-­‐hour  period.    – The  regimen  should  be  changed,  and  the  underlying  etiology  should  be  

identified  and  treated.

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Surgical  Intervention• Although  rarely  undertaken,  surgery  plausible  option  where  electrographic  

SE  remains  focal,  particularly  if  there  is  evidence  causal  structural  lesion  

• The  same  criteria  can  be  extended  to  acute  setting  of  refractory  focal  SE.,  however,  consideration  of  postoperative  deficits  and  prospect  of  long-­‐term  seizure  freedom  should  be  weighed  against  the  risks  associated  with  ongoing  focal  SE  

• Identification  of  a  structural  lesion  or  functional  region  requires  correlation  of  EEG  with  MRI  and  functional  (usually  PET  or  SPECT)  imaging  

• Reports  of  successful  treatment  of  refractory  focal  SE  by  surgical  removal  of  an  underlying  structural  lesion,  particularly  in  the  pediatric    – Surgery  generally  lesionectomy,  partial  or  complete  lobectomy

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Case

• Girl  4  year  old  

• Presenting  with  seizures,  spastic  quadriparesis,  right  facial  palsy

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Progression

• Patient  developed  status  epilepticus  

• Rx:  VPA  IV,  FosPHT    • Current  med:  VPA,  LTG,  PHT,  TPM,  Rivotril

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Case

• F    88  years  old  

• Presenting  with  dizziness,  headache  and  ataxia  

• Later  on,  had  alteration  of  consciousness

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Case

• Surgical  partial  tumor  removal  

• Pathological  finding:  CNS  lymphoma  

• cEEG  was  done  

• Rx  as  NCSE  – Fosphenytoin  IV  100  mg  q  8  hrs  

– LVT  IV  2,000  mg  per  day  

– PGB  600  mg/day  

• Rx  with  XRT

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Case

• Patient  was  diagnosed  as  Highly  Refractory  NCSE  

• Patient  on  come  state,  pupil  2  mm,  no  reflex  was  noted,  on  respirator    

• Rx  with  XRT

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Multiple  Continuous  Infusion  Therapy

• if  a  single-­‐agent  infusion  therapy  is  not  effective  on  the  first  trial,  it  generally  remains  ineffective  thereafter.    

• It  is  not  known  whether  combinations  of  these  infusions  are  more  effective  or  safer.  If  hypotension  is  a  major  problem,  then  infusion  rate  of  pentobarbital  can  be  lessened  if  midazolam  is  commenced  

• Different  modes  of  action  may  enhance  the  chance  of  terminating  SE

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Ketamine

• Potent  NMDA  antagonist  has  been  used  in  some  institutions  in  RSE  

• Loading  dose  of  2  mg/kg,  followed  by  an  infusion  of  10  to  50  μg/kg/min.    

• Limited  data  are  available  

• Evidence  that  excessive  NMDA  excitatory  receptor-­‐mediated  transmission  is  an  important  mechanism  of  persistent  neuronal  firing,  may  explain  ineffectiveness  of  GABA  agonists

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Ketamine

• Adverse  effects  relate  to  its  use  as  an  analgesic,  such  as  – Hallucinations  and  other  transient  psychotic  sequelae    

– Associated  with  cardiovascular  stimulation  and  a  rise  in  arterial  pressure  and  heart  rate  and  should  be  used  with  caution  in  patients  with  systemic  or  intracranial  hypertension.    

– Cerebellar  damage  has  been  reported  after  longer-­‐term  use

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Lidocaine  Infusion

• A  number  of  reports  of  successful  use  of  lidocaine  in  the  setting  of  RSE  

• Should  not  be  used  in  patients  with  coexisting  sinoatrial  disorders

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Inhalation  Anesthetics

• There  have  been  several  case  reports  of  successful  use  of  inhalation  anesthetics  in  the  setting  of  RSE  including  isoflurane  and  desflurane

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Paraldehyde

• Important  therapy  in  the  past  but  is  now  rarely  used  because  of  difficulties  in  administration    

• Associated  unwanted  adverse  effects.

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Allopregnanolone  (SAGE  547)• Allopregnanolone  (SAGE  547):  Intravenous  allosteric  modulator    

of  both  synaptic  and  extra  synaptic  GABAA  receptors  

• Effective  AEDs  when  prolonged  seizure  activity  has  become  resistant  to  benzodiazepine  treatment.  

• A  novel  agent  designed  to  treat  super-­‐refractory  status  epilepticus  (SRSE)  proving  successful  in  71%  of  patients  (20  patients  2>2  years  of  age  diagnosed  with  SRSE)

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Direct  Brain  Stimulation

• Surface  and  deep  brain  stimulation  devices  are  being  developed  for  use  in  focal  and  generalized  epilepsies,    

• Their  use  has  not  been  reported  in  humans  in  the  setting  of  SE

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Transcranial  Magnetic  Stimulation

• Transcranial  magnetic  stimulation  has  similarly  been  evaluated  in  animal  models  of  focal  SE    

• However,  has  not  yet  been  reported  to  be  helpful  in  human  SE

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Electroconvulsive  Therapy• Owing  to  its  potent  anticonvulsant  actions,  electro-­‐  convulsive  therapy  has  

been  proposed  as  an  intervention  for  SE    

• It  may  seem  illogical  to  administer  a  proconvulsive  stimulus  in  SE,  but  after  coming  inhibitory  state  after  a  convulsion  induced  by  electroconvulsive  therapy  may,  in  theory,  be  beneficial  to  patients  in  SE.    

• Has  not  been  evaluated  in  a  rigorous  fashion  by  clinical  trial.  

• However,  it  seem  to  be  not  helpful  in  the  management  of  refractory  SE

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Diagnostic  Tools  in  Refractory  Status  Epilepticus

• Advances  in  diagnostic  techniques  in  the  setting  of  difficult-­‐to-­‐control  SE  have  been  digital  EEG  recording  and  novel  imaging  approaches  – Continuous  digital  EEG  monitoring  allows  for  easier  data  acquisition,  

reformatting,  storage,  and  application  of  seizure-­‐screening  software  tools  such  as  event  detection  and  spectral  analysis.    

– Continuous  video  recording  in  conjunction  with  EEG  facilitates  interpretation,  principally  by  facilitating  artifact  rejection  and  assessing  the  clinical  correlation  of  paroxysmal  EEG  activity  or  events.  

– Imaging  plays  a  role  in  the  management  of  SE  such  as    • MRI  brain  

– Exclude  neurosurgical  causes  for  seizures  – Peri-­‐ictal  structural  changes  

• Both  ictal  SPECT,  FDG-­‐PET,  can  provide  valuable  data  in  focal  seizures

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Peri-­‐ictal  structural  changes

• Remote  – Occurrence  of  migratory  T2  and  lesions  on  diffusion-­‐weighted  imaging,  appearing  in  remote  cortical  areas  

– Often  reversible

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Peri-­‐ictal  structural  changes

• Categorized  as  local  or  remote    

• Local  – Include  a  swollen  cortical  ribbon  with  loss  of  grey−  white  matter  

differentiation.    – Increased  T2  signal  intensity  due  to  edema  occurs  in  areas  of  cortex  and  

adjacent  subcortical  white  matter.    – The  local  T2-­‐  weighted  changes  may  be  associated  with  MRI  evidence  of  

restricted  diffusion,  which  are  bright  on  diffusion-­‐weighted  imaging  and  dark  on  apparent  diffusion  coefficient  maps

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Outcome

• Factors  contribute  to  the  morbidity  and  mortality  associated  with  SE  are    – Underlying  etiology,    – Age    – Duration  of  the  SE.    

• Secondary  factors  that  likely  contribute  to  the  outcome  from  SE  include    – sepsis,  anoxia,  duration  of  infusion  therapy,  and  comorbid  ICU-­‐  related  

medical  complications

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Outcome• Inpatient  mortality  linked  to    

– potentially  fatal  etiologies,    

– increasing  age,    

– severely  impaired  consciousness  when  first  evaluated  

• Patients  with  underlying  anoxic  brain  injury,  vascular  lesions,  tumors,  and  infections  fare  worse  than  patients  whose  SE  was  provoked  by  alcohol,  drug  withdrawal,  or  noncompliance  with  AED  therapy  

• Numerous  reports  of  survival  even  after  very  prolonged  hospital  courses  for  SE,  particularly  in  children.    

• However,  many  patients  will  have  persistent  refractory  epilepsy  and  functional  deficits

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Outcome

Holtkamp  M  et  al,  2005,  Rossetti  AO  et  al.  2005

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Problem  Areas  in  Intensive  Care  Unit  Management  of  Status  Epilepticus

• Management  of  SE  is  frequently  difficult.  “Status  epilepticus”  is  not  a  single  entity  but  is  a  heterogenous  collection  of  electroclinical  syndromes  with  wide  ranging  etiologies,  some  benign  and  some  malignant,  and  with  varied  clinical  outcomes  

• SE  is  often  treated  by  the  same  management  algorithm  within  the  same  institution

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Post-­‐anoxic  Status  Epilepticus

• A  specific  electroclinical  state  resulting  from  diffuse  cortical  damage  

• Postanoxic  state  varies  in  severity  from  electro-­‐  cerebral  silence  to  diffuse  nonreactive  alpha  and  theta-­‐range  activity  (“alpha  coma”  and  “theta  coma”)  to  burst−suppression  pattern  or  frequent  generalized  epileptiform  discharges  

• EEG  findings  may  reflect  activity  of  the  residual  islands  of  viable  cerebral  cortex

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Postanoxic  Status  Epilepticus

• Patient  may  or  may  not  exhibit  myoclonus.    

• Such  myoclonic  status  that  arises  in  patients  after  an  anoxic  insult  is  usually  transient  (evolving  into  motionless  coma)  and  invariably  has  a  dismal  outcome    

• Presence  of  myoclonus  may  confer  a  worse  prognosis  than  electrographic  SE  without  clinical  manifestations

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Post-­‐anoxic  Status  Epilepticus

• Reasonable  course  of  action  is  to  institute  a  clearly  defined  course  (24-­‐48  hours)  of  IV  propofol  or  midazolam  sufficient  to  abolish  the  myoclonus  and  to  suppress  EEG  

• This  can  be  performed  in  conjunction  with  other  interventions  such  as  head-­‐  cooling  and  administering  neuroprotective  agents

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Potential  Mistakes  in  the  Management  of  Status  Epilepticus

• Relate  to  the  early  recognition  and  prompt  use  of  appropriate  doses  of  appropriate  first-­‐  and  second-­‐line  AEDs  

• Potential  mistakes  include    – Assuming  seizure  activity  has  terminated  when  overt  convulsive  activity  

has  stopped  but  the  patient  remains  obtunded  – Failure  to  administer  appropriate  loading  doses  of  AEDs  in  proportion  to  

the  patient’s  weight  – Failure  to  recognize  nonepileptic  seizures  or  pseudostatus

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Potential  Mistakes  in  the  Management  of  Status  Epilepticus

• Potential  errors  in  an  ICU  setting  include    – Mis-­‐  labeling  of  paroxysmal  clinical  behaviors  as  seizures  – Underutilization  or  overutilization  of  diagnostic  EEG  monitoring  – Lack  of  recognition  of  NCSE  or  metabolic  encephalopathy  – Failure  to  initiate  adequate  amounts  of  maintenance  AED  therapy  – Inappropriate  delay  in  switching  from  an  ineffective  treatment  regimen  

(manifesting  as  ongoing  seizure  activity  on  EEG  monitoring)  to  another  regimen  

– Use  anaesthetic  agents  too  much  casing  fatal  complication

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Conclusion• Initial  management  of  SE  is  now  well  established,  but  the  management  of  

advanced  or  refractory  SE  remains  difficult  proposition  

• However,  advances  in  our  understanding  of  SE  as  well  as  both  diagnostic  and  monitoring  tools  offer  the  prospect  of  better  clinical  outcomes  in  the  future  

• Early  recognition  and  intervention  in  SE  is  far  more  likely  to  succeed  than  any  delayed  intervention.    

• Ensuring  an  appropriate  dose  of  a  first-­‐  and  second-­‐line  AEDs

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Conclusion• All  ED,  neurology,  and  ICU  personnel  should  be  well  versed  in  the  initial  

management  of  SE  

• Neurologists  are  ideally  placed  to  manage  SE,  particularly  those  with  a  knowledge  of  EEG,  and  should  be  consulted  early  

• Because  of  high  morbidity  and  mortality  associated  with  SE,  physicians  and  staff  must  be  aggressive  in  the  management  of  SE.  

• Finally,  surgery  should  be  considered  a  potential  therapeutic  option  in  refractory  focal  SE.

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