Status epilepticus

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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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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Types of Seizure Emergencies

• Convulsive status epilepticus (CSE)

• Nonconvulsive status epilepticus (NCSE)

• Acute repetitive seizures or clusters

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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

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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Mortality in Status Epilepticus by Age Group

Among 546 patients with status epilepticus in Richmond, Virginia,

from 1982 to 1989.

% Mortalitiy

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10

20

30

40

50

60

0–1 2–4 5–9 10–19 20–39 40–59 60–79 80+

Age Group

DeLorenzo RJ, e t al. Epilepsia. 1992;33(suppl 4):515-525.

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Length of Seizure

>1 h

<1 h

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 a30-day follow-up period.

Days

DeLorenzo RJ, e t al. Epilepsia. 1992;33(suppl 4):515-525.

% Survival

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0 5 10 15 20 25 30

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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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).

10Claassen J, et al. Neurosurgery 2007 ;61:60-4.

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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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.

12• Vespa PM, et al. Crit Care Med. 2007 Dec;35(12):2830-6.

• 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.13

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Management of Status Epilepticus:

General Principles

n Medical emergency

n Prolonged electrical seizure activity causes neuronaldamage

n EEG monitoring essential

n Systemic factors exacerbate SE-induced neuronal damage

n The longer the duration, the later the EEG stage, andthe more subtle the motor manifestations, the harder SEis to stop

n A predetermined Rx protocol more effective

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Schematic Approach ofStatus Epilepticus

LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.

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1. Assess and control airway2. Monitor vital signs ( including temperature )3. Conduct pulse oximetry and monitor cardiac function4. Perform rapid blood glucose assay

Start intravenous infusionAdminister thiamine ( 100 mg )

and glucose ( 50 ml of 50 percent dextrose )LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.

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

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Start anticonvulsant therapy

Take focused Hx and examine patient

Perform laboratory studies

Known seizure disorder or other

illnesses ?

Trauma ?

Focal neurologic signs ?

Signs of medical illnesses ( e.g.,

infection, hepatic or renal

disease, substance abuse ) ?

Perform laboratory studies

Complete blood count

Serum electrolytes and calcium

Arterial - blood gas

Liver function

Renal function

Toxicology

Serum AEDs concentrations

Undertake further work-up to define cause

Manage other medical problems

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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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Seizures continuing at 5 minPhenytoin (20 mg/kg IV at 50 mg/min) or Fosphenytoin(20 mg/kg IV PE at 150 mg/min)

Seizures continuing at 20 - 25 minPhenytoin or Fosphenytoin

(additional 5 - 10 mg/kg or 5 - 10 mg/kg PE)LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.

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Seizures continuing at 30 - 35 minPhenobarbital( 20 mg/kg IV at 50 - 75 mg/min )Seizures continuing at 50 - 55 minPhenobarbital( additional 5 - 10 mg/kg )

LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.

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Seizures continuing at 60 - 65 min

Anesthesia with IV midazolam ,pentobarbital or propofol

LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.

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]

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]

Evidence based reviewComparison 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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Pharmacology of AED

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DiazepamPeak 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

PhenobarbitalPeak 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

PhenytoinPeak 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

Fosphenytoin

All Fosphenyoin dosing is expressed in phenytoin equivalents (PE)

(1mg PE Fosphenytoin = 1 mg IV phenytoin)

Fosphenytoin

Phenytoin

Phenytoin vs Fosphenytoin

Phenytoin

Water, TRIS

Fosphenytoin

Propylene glycol & ethanolVehicle

8.6 - 9

150 mg PE/min

Saline, dextrose

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50 mg/min

No

pH

Maximum

infusion rate

Admixtures

Fosphenytoin IV administration-events at maximum dose and rate

Perc

enta

ge o

f patients

Nystagmus Dizziness Pruritus Ataxia Somnolence Hypotension Headache

IV Fosphenytoin (n=90)

IV Phenytoin (n=22)

Summary—Fosphenytoin benefits(rapid administration)

• Rapidly and completely converted to phenytoinafter 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

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

Recommended doses and rates

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•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%

• 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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AED Dosage/Rate of Infusion

Phenytoin

(Dilantin®)

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

recommended; Dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not

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

Fosphenytoin

(Cereneu®)

Status epilepticus: Loading Dose: 15-20 mg PE/kg IV

Non-emergent: Loading Dose: 10-20 mg PE/kg IV or IM; MD: 4-6 mg PE/kg/day IV

or IM

Infusion Rate: Should not exceed 150 mg PE/minute

Valproic acid

(Depakine®)

Loading : 15-20/kg

No Loading Dose; 1000-2500 mg/day in 1-3 divided doses

Admin over 60 min (<= 20 mg/min); rapid infusion over 5-10 min as 1.5-3

mg/kg/min

Levetiracetam

(Keppra®)

>16 y/o. No loading dose. 1000 mg/day (500 MG BID). Dose can be increased by

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%

and infuse over 15 minutes

Admixture and Administration of Injectable AEDs

Special group of status epilepticus

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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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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.

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 ???58

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Status epilepticus

Timing is everything

Save the brain!

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