1. Status Epilepticus
Time is brain!
Kongkiat Kulkantrakorn, M.D.
Associate Professor
Neurology division, Department of Internal Medicine
Faculty of Medicine , Thammasat University
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2. Status Epilepticus: Operational
Definition
• Generalized, convulsive status
epilepticus in adults and older children
(>5 years old) refers to at least 5 min of
– (a) continuous seizures or
– (b) two or discrete seizures between which there
is incomplete recovery of consciousness
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3. Types of Seizure Emergencies
• Convulsive status epilepticus (CSE)
• Nonconvulsive status epilepticus (NCSE)
• Acute repetitive seizures or clusters
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4. Generalized Convulsive Status
Epilepticus (GCSE): Characteristics
• Broad spectrum of clinical presentations
– Tonic-clonic motor activity
– Impaired consciousness
– Ictal discharges
• Subtle GSCE
– Continuous subtle motor phenomena
– Generalized ictal discharges
– Profound coma
• Other types
– Myoclonic
– Focal 4

5. Status epilepticus
• Incidence:
– 27/100,000 in young adult
» with 14% mortality rate
– 86/100,000 in elderly
» with 38% mortality rate
• Number of cases:
– 65,000- 150,000 cases per year in USA
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6. Mortality in Status Epilepticus by Age Group
Among 546 patients with status epilepticus in Richmond, Virginia,
from 1982 to 1989.
% Mortalitiy
60
50
40
30
20
10
0
0–1 2–4 5–9 10–19 20–39 40–59 60–79 80+
Age Group
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DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.

7. Survival in Status Epilepticus by
Duration of Seizure
Survival curves for prolonged (solid line) and nonprolonged (dashed line)
seizure duration. The data are presented as percent survival based on a
30-day follow-up period.
% Survival
100
90 Length of Seizure
>1 h
80 <1 h
70
60
0 5 10 15 20 25 30
Days
7
DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.

8. Main causes of status epilepticus
• Low AED level patients with epilepsy (34%)
• Remote symptomatic causes (24%)
• Cerebrovascular accidents (22%)
• Anoxia or hypoxia (~10%)
• Metabolic causes (~10%)
• Alcohol and drug withdrawal (~10%)
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10. Generalized convulsive status epilepticus after
nontraumatic subarachnoid hemorrhage: the
nationwide inpatient sample.
• Nationwide Inpatient Sample, a database of admissions to
nonfederal United States hospitals between 1994 and 2002
• Among the 29,998 patients hospitalized with nontraumatic
SAH, GCSE was reported to occur in 0.2% of patients (N = 73
patients).
• GCSE risks: the youngest tertiale 49 years old or younger;
OR ( 2.0-5.1), those with renal disease OR 4.8 ( 2.6-8.8),
and those who did not undergo a neurosurgical procedure
involving a craniotomy ; OR 2.2 (1.3-3.8).
Claassen J, et al. Neurosurgery 2007 ;61:60-4. 10

11. Generalized convulsive status epilepticus after
nontraumatic subarachnoid hemorrhage: the
nationwide inpatient sample.
• GCSE : higher in-hospital mortality (48% versus 33% of
patients; OR 2.1 (1.3-3.4; P = 0.002) and longer (9 versus 7
days; P = 0.016) and more expensive (US $39,677 versus
US $26,686; P = 0.007) hospitalizations.
• CONCLUSION: GCSE rarely complicates SAH; however, it
is associated with increased patient mortality, length of
hospital stay, and cost. GCSE occurs more frequently in
young patients, those with a history of renal disease, and
patients who do not undergo a craniotomy
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12. Nonconvulsive electrographic seizures after
traumatic brain injury result in a delayed,
prolonged increase in intracranial pressure
and metabolic crisis.
• 20 moderate to severe TBI (Glasgow Coma Score 3-
13) : continuous EEG and cerebral microdiablysis for 7
days after injury.
• Ten patients had seizures , matched with control TBI.
SE in 7 patients
• Using a within-subject design, post-traumatic seizures
resulted in episodic increases in intracranial pressure
(22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an
episodic increase in lactate/pyruvate ratio (49.4 +/- 16
vs. 23.8 +/- 7.6; p < .001) in the seizure group.
• .
Vespa PM, et al. Crit Care Med. 2007 Dec;35(12):2830-6 12

13. • Using a between-subjects comparison, the seizure group demonstrated a
higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p
< .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p <
.001) compared with nonseizure patients.
• The intracranial pressure and lactate/pyruvate ratio remained elevated
beyond postinjury hour 100 in the seizure group but not the nonseizure
group (p < .02).
• CONCLUSION: Post-traumatic seizures result in episodic as well as
long-lasting increases in intracranial pressure and microdialysis
lactate/pyruvate ratio. These data suggest that post-traumatic seizures
represent a therapeutic target for patients with traumatic brain injury.
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18. Management of Status Epilepticus:
General Principles
n Medical emergency
n Prolonged electrical seizure activity causes neuronal
damage
n EEG monitoring essential
n Systemic factors exacerbate SE-induced neuronal damage
n The longer the duration, the later the EEG stage, and
the more subtle the motor manifestations, the harder SE
is to stop
n A predetermined Rx protocol more effective
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19. Schematic Approach of
Status Epilepticus
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976. 19

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21. 1. Assess and control airway
2. Monitor vital signs ( including temperature )
3. Conduct pulse oximetry and monitor
cardiac function
4. Perform rapid blood glucose assay
Start intravenous infusion
Administer thiamine ( 100 mg )
and glucose ( 50 ml of 50 percent dextrose )
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976. 21

22. Investigation
•Antiepileptic drug level
•Septic work up
•CBC, UA
•Blood sugar
•BUN, Cr
•Liver function test
•Electrolyte
•Calcium, Magnesium,
Phosphorous
•Toxicology
•Lumbar puncture
•CT brain
•MRI brain 22

23. Start anticonvulsant therapy
Take focused Hx and examine patient Perform laboratory studies
Perform laboratory studies Complete blood count
Known seizure disorder or other Serum electrolytes and calcium
illnesses ? Arterial - blood gas
Trauma ? Liver function
Focal neurologic signs ? Renal function
Signs of medical illnesses ( e.g., Toxicology
infection, hepatic or renal Serum AEDs concentrations
disease, substance abuse ) ?
Undertake further work-up to define cause
Manage other medical problems 23

24. Schematic Approach of Status Epilepticus
Antiepileptic Drug Therapy
• Begin with Lorazepam 4mg
• (0.1 mg/kg ) at 2 mg/min i.v.
• or Diazepam 10-20 mg
• (0.3 mg/kg ) at 2 mg/min i.v.
LowensteinD, Alldredge B. NEJM.1998; 338:970-976.
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25. Seizures continuing at 5 min
Phenytoin (20 mg/kg IV at 50 mg/min) or
Fosphenytoin(20 mg/kg IV PE at 150 mg/min)
Seizures continuing at 20 - 25 min
Phenytoin or Fosphenytoin
(additional 5 - 10 mg/kg or 5 - 10 mg/kg PE)
LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 25

26. Seizures continuing at 30 - 35 min
Phenobarbital
( 20 mg/kg IV at 50 - 75 mg/min )
Seizures continuing at 50 - 55 min
Phenobarbital
( additional 5 - 10 mg/kg )
LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 26

27. Seizures continuing at 60 - 65 min
Anesthesia with IV midazolam ,
pentobarbital or propofol
LowensteinD, Alldredge B. NEJM.1998; 338:970-976.
27

28. EFNS guideline on the 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.
Eur J Neurol. 2009 Dec 30. [Epub ahead of print]

29. EFNS guideline on the management of
status epilepticus in adults.
• 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.
• In subtle SE, in refractory GCSE is treated by anaesthetic
doses of barbiturates, midazolam or propofol; the
anaesthetics are titrated against an electroencephalogram
burst suppression pattern for at least 24 h. Most patients,
i.v. anaesthesia is required.
Eur J Neurol. 2009 Dec 30. [Epub ahead of print]

30. Evidence based review
Comparison of 2 drugs
• Benzodiazepine:
– no difference among lorazepam, diazepam, midazolam
• Hydantoin:
– Fosphenytoin: less pain and phlebitis at injection side
– Faster infusion rate in fos-PHT with 10-15 min
dephosphorylation
» Save 19 min on 150mg/kg vs 50 mg/kg in 70 kg patient
» Advantage: displace PHT form albumin binding site in
chronic PHT treatment, rapidly increase free PHT
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37. Pharmacology of AED
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38. Diazepam
Peak brain levels in 5 minutes by IV
Dosage : I.V. : 0.15-0.25 mg/kg.
IV rate : No faster than 5 mg/min
Effective level : more than 0.2-0.8 mcg/dl
Time to stop Sz : 1 - 3 minutes
Effective duration : 15-30 minutes
Half-life : 30 hr, rapid redistribution to fat/muscle
Volume of distribution : 1-2 L/kg
Advantage : rapid action, can be given rectally
Disadvantages : hypotension, respiratory depression

39. Phenobarbital
Peak brain levels in 20-60 minutes by IV
Dosage : I.V. : 20 mg/kg.
IV rate : No faster than 100 mg/min
Effective level : more than 20 mcg/dl
Time to stop Sz : 20 - 30 minutes, 60-70% effective
Effective duration : > 24 hours
Half-life : 4-6 days
Volume of distribution : 0.7 L/kg
Advantage : Long lasting therapeutic effort
Disadvantages : Hypotension, Respiration depression
Sensorial depression, Consider intubation when used
after diazepam administration

40. Phenytoin
Peak brain levels in 15 minutes by IV
Dosage : I.V. : 20 mg/kg.
IV rate : No faster than 50 mg/min
Effective level : more than 25-35 mcg/dl
Time to stop Sz : 10 - 30 min
Effective duration : > 24 hr, 50% effective after failing BDZ
Half-life : varies, around 24 hours
Volume of distribution : 0.5-0.8 L/kg
Advantage : No sedation, less respiratory depression
Disadvantages : hypotension, cardiac arrhythmia
need ECG monitoring, purple glove syndrome, cannot mix
with glucose

41. Fosphenytoin
Fosphenytoin
Phenytoin
All Fosphenyoin dosing is expressed in phenytoin
equivalents (PE)
(1mg PE Fosphenytoin = 1 mg IV phenytoin)

42. Phenytoin vs Fosphenytoin
Phenytoin Fosphenytoin
Vehicle Propylene glycol & ethanol Water, TRIS
pH 12 8.6 - 9
Maximum
infusion rate 50 mg/min 150 mg PE/min
Admixtures No Saline, dextrose

43. Fosphenytoin IV administration-events at maximum
dose and rate
IV Fosphenytoin (n=90)
IV Phenytoin (n=22)
Percentage of patients
Nystagmus Dizziness Pruritus Ataxia Somnolence Hypotension Headache

44. Summary—Fosphenytoin benefits
(rapid administration)
• Rapidly and completely converted to phenytoin
after IV and IM dosing
• Completely converted regardless of dose, rate, or
route
• Bioequivalent to phenytoin when infused at 150
mg PE/min
• Therapeutic phenytoin levels rapidly achieved
— Within 7 minutes with IV infusion at 150 mg PE/min
— Within 30 minutes with IM injection

45. Summary—Fosphenytoin benefits
(tolerability)
• Better tolerated at injection site than IV phenytoin
• Improved flexibility of IM administration
• CNS adverse events similar to phenytoin
• Transient paresthesia and pruritus with IV infusion
• Fewer reductions in IV rates and site changes than IV
phenytoin
• IV loading dose-special populations

46. Recommended doses and rates

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48. •32 cases diagnosed as SE with VPAiv treatment; 12 and 20 patients
received VPAiv as the first- and second-line therapy, (15-20 mg/kg).
•SE ceased in 7/12 patients (75%) and in 7/20 (35%) patients
•Hypotension and leucocytosis associated with death
•Mortality 54.8%
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51. • Thirty-two patients (15 female) were treated with i.v. LEV for SE
(median age 71 years).
• SE was generalized convulsive in five, nonconvulsive in 20, and
simple focal in seven patients.
• Etiology was acute 13 times and remote symptomatic 16 times;
three SE were of unknown etiology.
• Therapy was initiated within a median time of 3 h and
• LEV i.v. was applied within a median time of 6 h. Median LEV
bolus was 2,000 mg; median total dose on day 1 was 3500 mg
• Benzodiazepines plus i.v. LEV terminated SE in 23 patients without
application of additional anticonvulsants, 10 within 30 min.
• LEV could not terminate SE in seven patients.

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54. Admixture and Administration of
Injectable AEDs
AED Dosage/Rate of Infusion
Loading Dose: 15-20 mg/kg; up to 25 mg/kg has been used clinically.
Maintenance Dose: 300 mg/day or 5-6 mg/kg/day in 3 divided doses,IM not
Phenytoin recommended; Dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not
(Dilantin®) refrigerate, use within 4 hrs. Use inline 0.22-5 micron filter
Infusion Rate: Should not exceed 50 mg/min; elderly/debilitated should not exceed
20 mg/min
Status epilepticus: Loading Dose: 15-20 mg PE/kg IV
Fosphenytoin Non-emergent: Loading Dose: 10-20 mg PE/kg IV or IM; MD: 4-6 mg PE/kg/day IV
(Cereneu®) or IM
Infusion Rate: Should not exceed 150 mg PE/minute
Loading : 15-20/kg
Valproic acid No Loading Dose; 1000-2500 mg/day in 1-3 divided doses
(Depakine®) Admin over 60 min (<= 20 mg/min); rapid infusion over 5-10 min as 1.5-3
mg/kg/min
>16 y/o. No loading dose. 1000 mg/day (500 MG BID). Dose can be increased by
Levetiracetam 1000 mg/day ever 2 weeks up to a maximum dose of 3000 mg/day
Rate: Dilute in 100ml of normal saline (NS), lactated ringers (LR) or dextrose 5%
(Keppra®)
and infuse over 15 minutes

55. Special group of status epilepticus
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56. SE in children
• Young children: More febrile seizures and acute
causes, infection in etiology than older children
• Generalized SE, less NCSE
• Similar treatment protocol as in adult
• May use IV or rectal diazepam or buccal
/intranasal midazolam as initial treatment
• Should not use valproate if below 2 years old or
propofol
• Midazolam IV infusion in refractory cases
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57. Relationship between depth of coma (x-axis), prognosis (x-axis),
degree of structural brain damage (red y-axis) and epileptic brain dysfunction (blue y-axis) due to status epilepticus.

58. Refractory Status epilepticus
• Definition: failure to stop after 2 drugs
• Slow taper of continuous infusion at least over 24 hours
after seizure control
• Possible benefit of more intensity of burst suppression
• Recurrence: 25% in acute or remote symptomatic and
idiopathic cases
• Role of neuroprotection ???
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63. Status epilepticus
Timing is everything
Save the brain!
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