PROBLEM 3

By: Varla Septrinidya G. (405090215)

DEFINITION

The working group on SE of the

Epilepsy Foundationformulated the current
definition: "More than 30 minutes of
continuous seizure activity or two or
more sequential seizures without full
recovery of consciousness between
seizures.

ETIOLOGY

Etiologically, SE can be imperfectly divided

into 3 groups.
SE can represent an exacerbation of a preexisting seizure disorder, the initial
manifestation of a seizure disorder, or an
insult other than a seizure disorder

Other conditions may precipitate SE,

including toxic or metabolic causes and
anything that might produce cortical
structural damage, as follows:

Stroke(remote or acute)
Hypoxic injury
Tumor
Subarachnoid hemorrhage
Head trauma

Drugs (eg, cocaine,theophylline);isoniazid(INH)

may cause seizures and is unique in having a
specific antidote, pyridoxine (vitamin B-6)
Alcohol withdrawal
Electrolyte abnormalities
(eg,hyponatremia,hypernatremia,hypercalcemia,
hepatic encephalopathy)
Neoplasms
CNS infections (eg, meningitis, brain abscess,
encephalitis)
Toxins, notably sympathomimetics

Physiological Changes in GCSECompensation

Cerebral changes

Metabolic changes

Increased blood flow Hyperglycemia

Energy requirements Lactic acidosis
are matched by
increased lactate,
increased glucose

Autonomic changes
Hypertension
Increased CO
Increased CVP
Massive
Catecholamines
Tachycardia
Arrythmias
Hyperpyrexia
Vomiting

Physiological Changes in GCSEDecompensation

Cerebral changes

Metabolic changes

Autonomic changes

Failure of
autoregulation
Hypoxia
Hypoglycemia
Decreased lactate
Increased ICP
Cerebral edema

Hypoglycemia
Hyponatremia
Hypo/Hyperkalemia
Acidosis
Hepatic/Renal
dysfunction
DIC
Rhabdomyolysis
Serum/CSF
leukocytosis

Hypoxia
Decreased blood
pressure
Falling CO
Pulmonary edema
CHF
Arrythmias
Hyperpyrexia

Imaging Evidence of SE Damage

CLASSIFICATION OF STATUS
EPILEPTICUS

Generalized convulsive SE
Subtle SE
Nonconvulsive SE (including absence SE
and complex partial SE)
Simple partial SE

Generalized convulsive status epilepticus

Generalized convulsive SE is the most

frequent and potentially dangerous type of
SE.
Generalizedrefers to the abnormal excessive
cortical electrical activity, while
convulsiverefers to the motor activity of a
seizure.

Subtle status epilepticus

Subtle SE consists of electrical seizure activity

in the brain that endures when the associated
motor responses are fragmentary or even
absent.
Although subtle SE is, by definition,
nonconvulsive, it should be distinguished from
other NCSE.
Subtle SE is considered the most severe
clinical stage of generalized convulsive SE and
patients with subtle SE, in contrast to that of
those with NCSE, have a dismal prognosis.

Nonconvulsive status epilepticus

Nonconvulsive SE is divided into 2 categories:

Absence SE
Complex partial SE.

In one review,NCSE has been further

subdivided according to the age of
occurrence, as follows:

Neonatal and infantile

Only in childhood
In both childhood and adult life
In late adult life

Absence status epilepticus

On clinical presentation, a clear change in the

level of consciousness is observed in patients
with absence SE.
Most patients are not comatose but are
lethargic and confused, with decreased
spontaneity and slow speech.
The ictal electroencephalograph (EEG) during
typical absence SE demonstrates generalized
spike and wave discharges.

Complex partial status epilepticus

Complex partial SE is rare.

Complex partial SE that arises in the limbic
cortex (eg, mesial temporal lobe) causes signs
and symptoms such as staring,
unresponsiveness, automatisms, atypical
anxiety, rising abdominal symptoms, dj vu,
or more profound stupor.

Simple partial status epilepticus

By definition, simple partial SE consists of

seizures that are localized to a discrete area
of cerebral cortex and produce no alteration in
consciousness.
When motor cortex is affected, the condition
is termedepilepsia partialis continua(EPC),
which characteristically involves repetitive,
often rhythmic, unilateral focal twitching of
the limbs and/or face, usually with
preservation of consciousness.

PATOPHYSIOLOGY

Pathophysiology - SE

numerous mechanisms - poorly understood

failure of mechanisms that usu abort isolated sz

excess excitation or ineffective inhibition
there are excitatory and inhibitory receptors
in the brain - activity is usually in balance

Pathophysiology - SE contd

GLUTAMATE = the major excitatory AA

neurotransmitter in brain

any factor which increases Glutamate activity can

lead to seizures
e.g. 1987- mussels contaminated with Domoic
acid, a glutamate analog --> profound SE / deaths

Pathophysiology - SE continued

GABA = main inhibitory neurotransmitter

GABA antagonists can cause SE, eg Penicillins,

other antibiotics
prolonged sz can desensitize GABA receptors

Pathophysiology - SE continued

CNS damage can occur - mechanism:

uncontrolled neuronal firing -> excess

glutamate -> this sustained high influx
of calcium ions into
neurons leads to
cell death (excitotoxicity)
GABA released to counteract this, but GABA
receptors eventually desensitize
these effects worsened if hyperthermia,
hypoxia, or hypotension

Pathophysiology - SE continued

PHASE 1 (0-30 min) -- compensatory

mechanisms remain intact

adrenaline or noradrenaline release ++

increased CBF & metabolism
hypertension, hyperpyrexia
hyperventilation, tachycardia
lactic acidosis

Pathophysiology - SE continued

PHASE 2 (>30 min) -- compensatory

mechanisms failing

cerebral autoregulation fails / cerebral edema

respiration depressed
cardiac arrhythmias
hypotension
hypoglycemia, hyponatremia
renal failure, rhabdomyolysis, hyperthermia
DIC

Clinical - Generalized SE

at onset - usu obvious tonic / clonic

as continues often subtle - slight twitch of
face / extremities, nystagmoid eye
movements
may be NO observable motor sz ***still
risk for CNS injury - assume still seizing if
SE pt not waking
need

EEG to definitely dx - not

uncommon in comatose hospital
inpatients

DIAGNOSIS

Nonmotor simple partial status

epilepticus

Focal or unilateral paresthesias or numbness

Focal visual changes, usually characterized by
flashing lights
Focal visual obscuration or focal colorful
hallucinations
Olfactory or gustatory hallucinations
Atypical rising abdominal sensations

Epilepsy partialis continua

Some authors subdivide epilepsy partialis

continua into type I (nonprogressive) and type
II (progressive).
Type I epilepsy partialis continua features
intermittent, semirhythmic, and involuntary
twitching involving a discrete subset of
muscles. Although any group of muscles may
exhibit these features, it is observed most
commonly in the face and ipsilateral distal
hand musculature. Myoclonus of this variety
may evolve into a partial or generalized
convulsion.

Type II epilepsy partialis continua, the

progressive form, is usually linked with
Rasmussen encephalitis, a unique and rare
epilepsy syndrome that predominantly affects
children.
Children with Rasmussen encephalitis
historically had a variety of seizures, including
simple and complex partial seizures with
occasional secondary generalization; epilepsy
partialis continua is yet another seizure type
these patients have.

Complex partial status epilepticus

Complex partial SE often begins with a history

of recurrent or prolonged simple partial
seizures, or it may follow or precede a
generalized convulsive seizure.
Patients are often confused and have variable
responsiveness.
Memory of the event is usually impaired.
Behavior may fluctuate or be bizarre.

Type I complex partial SE refers to recurrent,

recognizable complex partial seizures without
recovery between seizures.
Type II represents continuous, ongoing
complex partial seizure activity.

Physical Examination

Generalized convulsive status epilepticus

often is recognizable to the clinician at the
bedside when typical rhythmic tonic-clonic
activity is present.
Consciousness is impaired.
Needle track marks might suggest SE
secondary to the use of illicit, or street, drugs.
Papilledema, a sign of increased intracranial
pressure, suggests a possible mass lesion or
brain infection.

Lateralized neurologic features, such as

increased tone, asymmetric reflexes, or
lateralized features of the movement
during SE itself, are suggestive of the
seizures beginning in a localized region of the
brain, and they may suggest a structural brain
abnormality.
Repetitive myoclonus in a comatose
patient following diffuse hypoxic brain injury
may simulate generalized seizures.

Laboratory Studies

Electrolytes
Calcium
Magnesium
Glucose
Complete blood count
Renal function tests
Toxicologic screening
Anticonvulsant levels
Liver function tests

Arterial Blood Gases

Arterial blood gas (ABG)measurement may be

useful to monitor oxygenation and ventilation
efficacy and to discover any unexpected acidbase abnormalities.
An episode of generalized seizures will
typically result in a metabolic acidosis, but this
should correct rapidly following seizure
cessation as the lactate generated by vigorous
muscle contractions is metabolized.
Profound metabolic acidosis and continuing
seizures might raise the possibility of isoniazid
poisoning

Electroencephalography

EEG is the criterion standard for diagnosing

EEG, and some authors believe that EEG
should be a routine part of management of
SE.
Nevertheless, EEG is rarely available in the
acute-care setting; normally, it is obtained
through neurologic consultation.
When EEG is unavailable for the acute
workup, presumptive treatment strategies
must occasionally be started before EEG
confirmation becomes available.

Computed Tomography

CT scanning of the brain is often helpful in

evaluating for a structural lesion (eg, brain
tumor, infarction, abscess, hemorrhage) that
may underlie SE.
Noncontrast CT is the imaging procedure of
choice for emergency department patients
with SE.

Chest Radiography

Chest radiography may be used to assess for

aspiration or endotracheal tube positioning.
If clinically indicated, other plain radiographs
may be useful to assess fractures or
dislocations.

Lumbar Puncture

If CNS infection is in the differential diagnosis,

consider alumbar puncture(after appropriate
head imaging to ensure safety).
Initiate antibiotic therapy if CNS or systemic
infection is strongly suspected.

DIFFERENTIAL DIAGNOSES

Encephalitis
Heatstroke
Hypernatremia in Emergency Medicine
Hyperosmolar Hyperglycemic Nonketotic Coma
Hypocalcemia in Emergency Medicine
Hypoglycemia
Hyponatremia
Medication-Induced Dystonic Reactions
Neuroleptic Malignant Syndrome
Uremic Encephalopathy
Withdrawal Syndromes

TREATMENT

Emergency Department Care

Establish intravenous access, ideally in a large

vein.
Intravenous administration is the preferred
route for anticonvulsant administration
because it allows therapeutic levels to be
attained more rapidly.
Begin cardiac and other hemodynamic
monitoring.
Administer a 50-mL bolus of 50% dextrose IV
and 100 mg of thiamine.

If seizure activity does not terminate

within 4-5 minutes, start anticonvulsant
medication.
If EMS history has already defined SE, treatment
should begin immediately.
In some settings where drug intoxication
might be likely, consider also adding
naloxone at 0.4-2.0 mg IV to the dextrose
bag
Administer diazepam (0.15 mg/kg) or
lorazepam (0.1 mg/kg) IV over 5 minutes,
followed by fosphenytoin or phenytoin.

Ensure airway control.

Nasopharyngeal airway placement is sufficient
for some patients, particularly if the seizures are
stopped and the patient is awakening.
For other patients, endotracheal intubation is
necessary.
In neuromuscular paralysis,rapid sequence
inductionis necessary at times.
Use short-acting paralytics to ensure that
ongoing seizure activity is not masked.
Use EEG monitoring if long-acting paralytics
are used and if a question exists about seizure
cessation.

Correct any metabolic imbalances.

Control hyperthermia.
If seizures continue after 20 minutes,
give additional fosphenytoin (10 mg PE/kg
IV) or phenytoin (10 mg/kg IV).
Aim for a total serum phenytoin level of about
22-25 g/mL.

OUTLINE - Management of SE

General approach
Anti - Epileptic Drugs:

Benzodiazepines
Phenytoin / Fosphenytoin
Barbiturates
Propofol

Management of SE

ABCs (+ monitor / O2 / large IVs)

START PHARMACOTHERAPY ASAP
Metabolic acidosis common - if severe, give
Bicarb
if intubating / ventilating - avoid long-acting
n-m blockers - masks sz activity
beware hyperthermia 2 sz - in 30-80% -->
passive cooling

Management of SE continued

consider underlying causes:

infection (systemic / CNS)

structural: trauma, CVA, IC bleed
CNS malformations
metabolic - hypoxia, abn electrolytes,
hypoglycemia
toxic - alcohol, other drugs
drug withdrawal - AEDs, benzos
congenital - inborn errors of metabolism

Management of SE continued

History & Physical - do once Rx initiated

Hx: events, trauma, meds, sz hx, ETOH,

infx

P/E: Neuro - look for focal signs vs.

generalized

tonic-clonic

look for signs of underlying causes - trauma,

infection, etc

LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg,

Phos, LFTs, AED levels, ETOH / toxicology,

PTT / INR
-ABG

Management of SE continued

consider....
Thiamine
Glucose
Pyridoxine
reverses

5 gm IV (70 mg/kg kids)

INH action inhibiting GABA

synthesis
now recommended routinely by NYC
Poison Control in REFRACTORY SE d/t
frequency of INH OD

Status Epilepticus Treatment

Time post
onset
Treatment
Onset

Ensure adequate ventilation/O2

2-3 min.

IV line with NS, rapid assessment, blood

4-5 min.
Lorazepam 4 mg (0.1 mg/kg) or diazepam
(0.2 mg/kg) over 2 minutes via
second IV line or rectal diazepam

draw
10 mg

7-8 min.
Thiamine 100 mg, 50% glucose 25 mg IV Phenytoin or
fosphenytoin 20 mg/kg IV (phenytoin PE) at 50 mg/per
minute phenytoin or 150 mg per minute fosphenytoin ( 0.75
mg/kg/min)
Pyridoxine 100-200 mg IV in children under
18 mo.

Status Epilepticus Treatment

(cont.)
Time post
onset Treatment
10 min.

Can repeat lorazepam or diazepam if

seizures ongoing

30-60 min. EEG monitoring unless status ended

and patient waking up
40 min.

Phenobarbital 20 mg/kg at 5 mg per

minute (0.75 mg/kg per minute)
continued

Reference: Lowenstein DH, Alldredge BK, Status Epilepticus. NEJM 1998; 338: 970-976.

Status Epilepticus Treatment (cont.)

Time post
onset

Treatment

70 min.
Pentobarbital 3-5 mg/kg load, 1 mg/kg per
hour infusion, increase to burstsuppression
OR
Propofol 3-5 mg/kg load, 5-10 mg/kg/hr
infusion then 103 mg/kg/hr

initial

OR
Midazolam 0.2 mg/kg load, .25-2 mg/kg

infusion

Reference: Lowenstein DH, Alldredge BK, Status Epilepticus. NEJM 1998; 338: 970-976.

Drug Rx of SE

Starting Rx ASAP has been correlated with

a better response rate to drug Rx, and
lower morbidity

Lowenstein DH, Alldredge BK

Neurology 1993 (43): 483-8

< 30 min - 80% stopped

> 120 min - < 40% stopped
but - retrospective review; ?
groups
comparable

Drug Rx of SE

Ideal agent characteristics:

easy to administer
prompt onset, long-acting
100% effective vs seizures
no depression of cardio-resp function or mental
status
no other adverse effects

Drug Rx of SE

Existing agents - adverse effects:

Benzos / Bbts - decrease LOC / respiration

Dilantin / (Fosphenytoin) - infusion rate-related
hypotension / dysrhythmias
Dilantin / Bbts / (Fosphen) - slow onset d/t limited
rate of administration

Drug Rx of SE

1st - Benzodiazepines
*

Lorazepam, Diazepam

2nd - Phenytoin, Fosphenytoin

3rd - Phenobarbital

Drug Rx - Refractory SE

Anesthetic doses of:

Midazolam (0.2 mg/kg slow IV bolus) ->continuous IV infusion @ .4 - 6.0 mcg/kg/min

OR .1 - 2.0 mg/kg/hr
Propofol (1-2 mg/kg)
Barbiturates (Thiopental, Phenobarbital,
Pentobarbital)
Inhalational anesthetics (Isoflurane)

GA can suppress immune system -->infection

Non - IV Rx of SE

e.g. out of hospital -- often in children

Midazolam IM (or Intranasal) .15-.3 mg/kg

Diazepam Rectally .5 mg/kg (to 20 mg)
Lorazepam SL
(Paraldehyde rectally)

Lorazepam

1st agent to use

Dose: Adults 4 -10 mg (.1 mg/kg) IV. Peds .05
- .1 mg/kg (to 4 mg) IV
less lipid soluble than Diazepam --> smaller
volume of distribution / longer T1/2
effects

last 12 - 24 hr

S/E: resp depression, hypotension, confusion,

sedation (but less than diazepam)

Diazepam

Dose: Peds .1-1.0 (.2-.5) mg/kg IV

Adults 10 - 20 mg (.2 mg/kg) IV

Duration of action: < 1 hr

Lorazepam vs. Diazepam

Durationof
action
Onsetof
action
Sedation

Lorazepam

Diazepam

*1224hr

*<1hr

23min

13min

++

Midazolam

Dose: 2 mg/kg IV, 5-10 mg IM, 0.2 mg/kg

Intranasal
Dose for refractory SE - continuous IV
infusion @ .1 - 2.0 mg/kg/hr - titrated
Onset: IV 2 - 3 min / other routes 15 min
Duration: 1 - 4 hr

Phenytoin (Dilantin)

still the standard 2nd IV Rx after

Benzo
dose: 18 - 20 mg/kg (better than 1 gram)
IV solution is highly alkaline - dissolved in
propylene glycol, alcohol, and NaOH

pH is 12
give in large vein, dilute N/S, flush

rate: 50 mg / min (Peds: 1 mg/kg/min)

onset of action: 10 - 30 min
duration of action: 12 - 24 hr

Phenytoin continued

S/E - (most avoided if slower administration)

hypotension
arrhythmias

- (must monitor)
respiratory depression
venous irritation
extravasation -->tissue injury /
necrosis
purple glove syndrome: progressive limb
edema, discoloration and pain 2-12 hr post IV admin

Fosphenytoin

Advantages over Phenytoin:

pH 8 (vs Phenytoin pH 12)

does not require solvent (Phenytoin is dissolved in
propylene glycol)
can

give IM when no IV access

IV: - less potential for irritation - can give
faster
- no risk of
tissue necrosis if goes interstitial
- does not precipitate in IV solutions

lower risk of hypotension and dysrhythmias

Fosphenytoin

minor S/E similar to Phenytoin (since is

converted to Phenytoin):

nystagmus, dizziness, headache, somnolence,

ataxia;
MORE pruritus & paraesthesias, esp in groin area responds to Benadryl

Despite giving more rapidly, not shown to

have more rapid onset of action

Barbiturates

in use since 1912

general CNS depressant activity

raise threshold of most neuronal pathways to

direct and indirect stimulation
at high levels, slows EEG --> burst suppression
and ultimately electrocortical silence
mechanism of action not clearly defined

S/E: resp depression, hypotension

Phenobarbital

Dose: 20 mg/kg IV (range 10-40 mg/kg) -usu

maximum 1 gm
Maximum rate: 100 mg/min
onset of action: 10 - 20 min
duration of action: 1 - 3 days

Phenobarbital

IV Phenobarb in Refractory SE:

as effective as Diazepam plus Phenytoin, but S/E

more pronounced
because of profound hypotension & respiratory
depression, patient will likely need intubation &
ventilation at this point; (and will need ICU
admission and continuous EEG monitoring if SE
persists)

Pentobarbital

Dose: 5 - 12 mg/kg
Rate: 5 - 20 mg/min

once SE resolved -maintenance: 1-10 mg/kg/hr

Thiopental

Dose: 2-5 mg/kg IV

rapid onset: 30 - 60 sec
short duration: 20 - 30 min
S/E:

CV depression, hypotension, arrhythmias

resp depression, apnea

Thiopental

Thiopental - negative aspects:

accumulates in fatty tissues

an active metabolite - Pentobarbital
long recovery time after infusion
hemodynamic instability

Propofol

Dose: 1-2 (3-5) mg/kg

Rate: 5-10 mg/min (1-15 mg/kg/hr)
Onset: 2-4 min
Half-life: 30-60 min
does not accumulate --> rapid recovery
Mechanism:

stimulates GABA receptors (like Benzos/Bbts)

suppresses CNS metabolism

Propofol

Advantages over Barbiturates

less

hypotension
more rapid onset of action
rapid elimination

Pro-convulsant effect - is now thought

to be myoclonus, unlikely a significant
problem

Paraldehyde

an old agent, but has uses:

when no IV - rapid IM or PR absorption

effective vs ETOH withdrawal seizures / SE

Dose: .1 - .15 ml/kg

has fallen out of favor because:

smells very bad - an aromatic aldehyde

degrades easily, which increases toxicity
decomposes plastic syringes & tubing < 2 min
significant toxicity - other agents safer

Possible new drugs for Status

Lidocaine - some positive trials

Valproate - IV form available
15-20

mg/kg IV.
Not studied yet in SE

Gabapentin / Vigabatrin / Lamotrigine

Felbamate - blocks NMDA receptors
Ketamine - blocks NMDA receptors

Ketamine in SE

blocks NMDA receptors - this may

protect brain from effects of excitatory NTs

may be neuroprotective as well as antiepileptic

some animal studies have demonstrated

control of refractory SE with Ketamine:

Ketamine Controls Prolonged SE

- DJBorris
Epilepsy Research 42
(2000): 117-22

more efffective than Phenobarb in LATE

SE
(>60 min); not as effective in EARLY
SE

Consensus Guidelines:
if IV Access

1. Lorazepam 0.1 mg/kg (over 30-60

sec)
2. Lorazepam - repeat
3. Phenytoin 18 mg/kg (over 20 min)
OR

Phenobarbital 20 mg/kg
(over 10 min) if already on
Phenytoin
AND Paraldehyde rectally 0.4
ml/kg in same volume olive oil

4. RSI - Thiopental induction 4 mg/kg

Consensus Guidelines:
if NO IV Access

1. Diazepam 0.5 mg/kg rectally

2. Paraldehyde 0.4 ml/kg rectally
start intraosseous if still no IV
then follow IV algorithm
4.

RSI using Thiopental

3. Phenytoin / Phenobarb; plus
Paraldehyde rectally

Consensus Guidelines

Suggestions for future:

compare rectal with buccal midazolam

compare IV Fosphenytoin with IV Phenytoin
for refractory SE, after algorithm, consider
midazolam

infusion
inhalational anesthetic e.g. Isoflurane

Take-Home points - Status

better outcome if sz stopped earlier

Lorazepam - best 1st line Rx
Fosphenytoin - surpasses Phenytoin for SE,
and for any patient with altered mental status
who would otherwise need IV Phenytoin hopefully more available soon
Propofol - advantages over barbiturates for
resistant SE

COMPLICATIONS

Hyperthermia
Acidosis
Hypotension
Respiratory failure
Rhabdomyolysis
Aspiration

PROGNOSIS

Prognosis is related most strongly to the

underlying process causing SE.
For example, if meningitis is the etiology, the
course of that disease dictates outcome.
Patients with SE from anticonvulsant
irregularity or those with alcohol-related
seizures generally have a favorable prognosis
if treatment is commenced rapidly and
complications are prevented.