Transcript status - McGill University

Status epilepticus
Rashid Alshahoumi
Oct 8th 2008
Outline
• Introduction
• Definition
• pathophysiology
• Etiology
• Classification
• Diagnosis
• Management
• Take home messages
• Discussion/Questions
Introduction
• Status epilepticus (SE) is a medical &
neurologic emergency.
• An under-recognized health problem
associated with substantial morbidity &
mortality.
• Successful therapeutic intervention essential
to efficiently identify & treat patients in SE
Frequency
• An estimated 152,000 cases /yr in the US,
resulting in 42,000 deaths & an inpatient cost
of $3.8 to $7 billion/yr.
• Sex :. ♀ = ♂
• Age :
all age groups but more → extremes of age.
In the neonatal group, SE may be related to
perinatal hypoxic insults or metabolic
disorders.
Elderly persons have an ↑ incidence of SE
secondary to ischemic CNS insults
Epidemiology
• SE of partial onset accounts for the majority of
episodes.
• One study on SE found that 69 % of episodes
in adults & 64 % of episodes in children were
partial onset, followed by secondarily
generalized SE in 43% of adults and 36 % of
children.
• SE occur in 1st yr and after 60 yrs.
• Adults > 60 yrs had the highest risk with an
incidence of 86/100,000/ year.
• Children ≤ 15 yrs, infants < 12 mths had the
highest incidence and frequency of SE.
Mortality/Morbidity

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The mortality rate (defined as death within 30 days) was
22 % in the Richmond study.
The mortality rate among children was only 3% & adults
was 26%.
Elderly population → highest rate of mortality at 38%.

Etiology : damage to CNS caused by acute
insult precipitating the SE.

Systemic stress : alterations from the
persistent seizure activity.

Excitotoxic injury : injury from repetitive
epileptic discharges.

Iatrogenic : injury from treatment

The primary determinants of mortality were
duration of seizures, age at onset & etiology.

Anoxia and stroke : very high mortality rate.

Alcohol withdrawal or low levels of
antiepileptic : relatively low mortality rate.

Nonfatal cases : significant morbidity.
Definitions
• Exact definitions vary.
• It is essentially an acute, prolonged epileptic
crisis.
• The brain is in a state of persistent seizure
• In 1981, the International League against Epilepsy
defined SE as a seizure that “ Persists for a
sufficient length of time or is repeated frequently
enough that recovery between attacks does not
occur". ?? lack of a specific duration → definition
difficult to use.
• In early studies, SE was defined by its duration as
continuous seizures occurring for > 1 hour.
• Clinical & animal experiences later showed that
pathologic changes and prognostic implications
occurred when SE persisted for 30 minutes.→ the
time for the definition was shortened.
• Isolated tonic–clonic seizures in adults rarely
last more than a few minutes
• The need to begin therapy for SE before 30
minutes
• Evidence that 5 minutes is sufficient to
damage neurons & seizures are unlikely to
self-terminate by that time.
An operational definition of
status epilepticus

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Either continuous seizures lasting at least 5
minutes or ≥ 2 discrete seizures between
which there is incomplete recovery of
consciousness
This definition differs from that of serial
seizures.
≥ 2 seizures occurring over a relatively brief
period (minutes to hours), but with the
patient regaining consciousness between the
seizures.
Different in adults and pediatrics?

Shinnar et al. analyzed the duration of
new-onset seizure activity in 407
children → seizures lasting > 5-10
minutes were unlikely to stop
spontaneously & should be treated .
The term status epilepticus may
be used to describe any
continuing type of seizure.
Pathophysiology
In normal brain, excitatory & inhibitory
mechanisms are in balance.
 Glutamate is the main excitatory
neurotransmitter.
 Gamma aminobutyric acid (GABA) is the main
inhibitory neurotransmitter.
 The number and distribution of neurotransmitters
& receptors varies in different areas of the brain,
as does the connectivity of the neurons.e.g.the
temporal& frontal lobes are more epileptogenic
than the parietal or occipital lobes.
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Failure of mechanisms that normally abort an
isolated seizure.
This failure can arise from abnormally persistent,
excessive excitation or ineffective recruitment of
inhibition.
The relative contributions of these factors are
poorly understood?!
Failure of inhibitory processes : the major
mechanism ?
It is likely that numerous mechanisms are
involved, depending on the underlying cause.

An exogenous toxin : e.g. the ingestion in 1987 of
mussels contaminated with domoic acid, an
analogue of glutamate → Some patients had
prolonged & profound SE.

This occurrence suggests that excessive
activation of excitatory amino acid receptors can
cause prolonged seizures and excitatory amino
acids have a causative role in SE.

SE can also be caused by penicillin & related
compounds that antagonize the effects of GABA.
 Recent studies suggest that the failure of inhibition may
be due in some cases to a shift in the functional
properties of the GABA receptor that occurs as seizures
become prolonged.
 This damage is partly a consequence of glutamatemediated excitotoxicity & does not appear to be due
primarily to an excessive metabolic demand imposed by
repetitive neuronal firing.
 The superimposition of systemic stresses e.g.
hyperthermia, hypoxia, or hypotension ↑↑↑ degree of
neuronal injury .
 The most vulnerable areas include the limbic system,
cerebellum, middle cortical area & thalamus.
 Many of the systemic responses e.g. hypertension,
tachycardia, cardiac arrhythmias, and hyperglycemia are
thought to result from the catecholamine surge that
accompanies the seizures.
 Body temp may ↑ following the vigorous muscle activity
that accompanies GCSE .
 Lactic acidosis is common after a single generalized motor
seizure & resolves with termination of the seizure.
 Cerebral metabolic demand increases greatly with GCSE;
however, cerebral blood flow & oxygenation are thought to
be preserved or even ↑ early in the course of GCSE.
Etiology : damage to CNS caused by acute
insult precipitating the SE.
Systemic stress :alterations from the
persistent seizure activity
Excitotoxic injury : injury from repetitive
epileptic discharges
Iatrogenic : injury from treatment
Lungs

Due to both metabolic and respiratory acidosis,
the pH of ABG is often found to be below normal
in SE.
Heart

The sympathetic overdrive can cause
tachycardia.
Muscle :

As a result of continued
seizure activity,
conversion to anaerobic
metabolism contributes to
lactic acidosis .
Blood chemistries:

De-margination of
neutrophils occurs with
the stress of seizing
Vital signs
BP
TEMP
RR
The initial phase of SE
results in ↑ BP with ↑
in peripheral vascular
resistance .
As the seizure progresses, the
body's core temp↑
The patient in
SE often has a
transient
change in RR &
tidal volume
As the status becomes
prolonged, the BP will
normalize or even
begin to fall with
resultant hypotension.

2 distinct phases with specific neurophysiological
changes occur during the progression of GCSE.

In phase I :
The increased metabolic requirements of
abnormally discharging neurons are adequately
met.
The increased cerebral activity results in a
coupled ↑ in CBF & ↑ in autonomic activity. The
later results in tachycardia, hypertension and an
increase in blood glucose levels.

After about 30 minutes of seizure activity, the
compensatory mechanisms that have
maintained adequate cerebral perfusion
begin to fail.

This stage (phase II) is characterized by a
failure of cerebral autoregulation, ↑ICP
systemic hypotension, hypoglycaemia,
↑ systemic & IC lactate levels. When this
occurs, cerebral O2 requirements exceed
supply & electromechanical dissociation
occurs in which cerebral seizure activity may
be accompanied by minimal visible muscular
twitching.

The degree of brain damage increases
markedly as decompensation occurs. General
tonic–clonic convulsions predominate initially,
changing to myoclonus, then complete
cessation of clinical seizure activity
(electromechanical dissociation).

Ongoing EEG seizures are replaced by periodic
epileptic discharges (PEDs), and then generally
slowed background activity .
Causes of SE
 Many patients who present in convulsive
SE do not have a history of seizures.
 In people with known epilepsy, the most
common cause is a change in
medication; noncompliance or
discontinuation.
Some of the more common
predisposing factors include:
 Withdrawal syndromes
 Acute structural injury
 Remote or longstanding structural injury
 Metabolic abnormalities
 Use of, or overdose with drugs that lower
the seizure threshold
 Chronic epilepsy; SE may represent part
of a patient's underlying epileptic
syndrome
Age significantly affects etiology of
SE
 In patients < 16 years, the most common cause was
fever and/or infection (36%); in contrast, this accounted
for only 5% in adults (DeLorenzo, 1995).
 The same study revealed that the most common
precipitant in adults was cerebrovascular disease (25%),
whereas this factor caused only 3% of pediatric cases.
 In a more refined study that focused on children, Shinnar
et al (1997) found that more than 80% of children < 2
years had SE of febrile or acute symptomatic origin,
whereas cryptogenic &remote symptomatic causes were
more common in older children.
Clinical manifestations & Classification

The classification systems used for SE
are discrepant throughout the literature.

Many schemes have been generated
that rely on both clinical and
electrographic findings.

Rona and Luders (2005) have suggested a
detailed semiologic classification along 3
axes:
(1) The type of brain function predominantly
compromised
(2) The body part involved
(3) The evolution over time.
 Celesia (1976) & Treiman (1994) proposed
simpler schemes.
Various approaches to classifying SE have been suggested
Classification 1
Classification 2
• Generalized
(tonic-clonic,
myoclonic,
absence, atonic,
akinetic)
• Generalized SE Classifying SE by
(overt or subtle) life stage :
• Partial (simple
or complex) SE.
• Nonconvulsive
SE (simple
partial, complex
partial, absence).
Classification 3
•Neonatal period
• Infancy and
childhood
• Childhood and
adulthood
•Adulthood only
• It is important to note that almost all seizure
types may become prolonged, fulfilling the
definition of SE
• So as there are many types of epileptic
seizures, there are many forms of SE.
• The simplest classification is convulsive versus
nonconvulsive, but a description of syndromes
based on generalized or partial (focal) onset of
seizures provides more insight into
pathophysiology and clinical management.
Generalized
• Generalized tonic-clonic "Grand mal" :may be
secondarily generalized from a focus
• Absence : "Petit mal"
• Myoclonic : primary or secondary
• Tonic : Pediatric, often with Lennox-Gastaut
syndrome
• Atonic/akinetic : Pediatric; often with LennoxGastaut syndrome
• Clonic : Infants
Partial (focal) onset
 Simple partial :
• Motor : epilepsia partialis continua
• Sensory : rare or rarely diagnosed
• Autonomic : rare or rarely diagnosed
• Psychic : fear, emotional content
• Aphasic
 Complex partial :
• Includes impairment of consciousness
Special types
• Neonatal/pediatric: Includes electrographic SE of sleep,
infantile spasms
• "Subtle" status
Stages of Status Epilepticus
• Premonitory (Prodromal) Stage: Increasing
seizure frequency, myoclonus, confusion
Early stage: Continuous Seizures
• Late or established stage: > 30 minutes
• Refractory Stage: > 60 to 90 minutes, with
Persistence despite adequate AED therapy
Diagnosis
Convulsive SE is rarely a
diagnostic difficulty, but
nonconvulsive forms may be
difficult to recognize or missed
Differential diagnosis of SE :
With prominent motor abnormalities
• Movement disorders (myoclonus, tremors,
chorea, tics, dystonic reactions)
• Structural disease (decerebrate, decorticate
posturing)
• Psychiatric disorders
(pseudoseizure/conversion, acute psychosis)
 Usually "nonconvulsive"
• Epilepsy-related disorders (postictal state, periodic
lateralized epileptiform discharges with acute structural
lesions)
• Acute encephalopathies (toxic, metabolic e.g,
hypoglycemia, organ failure, delirium related to drugs,
alcohol, or infection)
• Psychiatric disorders (catatonia, acute psychosis)
• Sleep disorders (narcolepsy, cataplexy, parasomnias)
• Syncope (cardiac, vagal, hypovolemic; medication
toxicity)
• Vascular disease (strokes, transient ischemic attacks)
• Head injury (stupor, coma, amnesia)
• Transient global amnesia (usually clears quickly; rare
recurrence)
Nonepileptic seizures :
"pseudoseizures" or "pseudo status“ :
troublesome.


These episodes often occur in patients who
also have epileptic seizures.
Features that suggest nonepileptic spells include:
• Out-of-phase limb movements
• Complicated vocalizations
• Forced eye closure during the event with resistance to
eye opening, eyes are usually open during both partial
and tonic clonic seizures
• Tearfulness or sobbing during or after the seizures
• Absence of epileptiform features on the EEG during
spells and quick return of normal background following
termination of the spells. (Epileptic seizures cannot be
totally excluded because the surface EEG may be
unaffected by some epileptic seizures, especially in the
frontal lobe
History and physical
• The patient's history often reveals the cause
of a patient's SE.
• Factors such as trauma, drug overdose,
alcohol use, medical illness, stroke, or
epilepsy may be uncovered through
discussions with the patient's family
members and companions or the patient's
medical bracelet and personal possessions.
• Physical examination focuses on the
ascertaining the underlying cause of SE,
localizing the neurologic abnormality &
determining whether complications have
occurred.
• Vital signs are crucial given the cardiovascular
complications.
• Signs of infection ( fever, nuchal rigidity, or skin
lesions) or systemic illness, such as kidney or
liver disease.
• Signs of head injury or coagulopathy are also
important.
• The neurologic examination also assesses
whether seizures are actually continuing in
subtle ways.
Laboratory Studies

Search for metabolic
abnormalities, particularly of
Na, Cal, Mg, and glucose

Kidney, liver, and coagulation
assays
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Pregnancy test for women of
childbearing age (partially for
purposes of counseling about
effects and implications)

Assessment for eclampsia in
pregnancy

Urgent CT scans in cases with
asymmetric neurologic exam,
seizures with a focal origin, or
head injury

LP, if there is any suggestion of
CNS infection or when SE is of
unknown cause or difficult to
control
Toxicology screening
Anticonvulsant levels & arterial
oxygen tension (but treatment
must begin before these levels
are known)
Blood gas and prolactin levels
(to check for the possibility of
pseudoseizures)
EEG
• Generalized convulsive SE is diagnosed
without an EEG & treatment begins without
it.
• An EEG is necessary for the diagnosis of
nonconvulsive SE, although treatment may
begin based on clinical suspicion.
• EEGs are mandatory when a patient does
not respond to initial treatment
Tonic-clonic seizures
Generalised spike-wave activity,
paroxysmal fast activity
Tonic-Clonic Status
Myoclonic seizures
Generalised polyspikes or
polyspike and wave activity
Myoclonic Status
Simple Partial SE
Periodic Epileptic Discharges in Anoxic
Brain Injury
OUTLINE/Management
of SE
• General approach
• Anti - Epileptic Drugs:
– Benzodiazepines
– Phenytoin / Fosphenytoin
– Barbiturates
– Propofol
– others / new possibilities
Management of SE
ABC’s
(+ monitor / O2 / large IV’s)
START
PHARMACOTHERAPY ASAP
Metabolic
acidosis common - if severe, give
Bicarb
Beware hyperthermia 2º sz - in 30-80% →
passive cooling

Management of SE
Consider
 Infection
continued
underlying causes:
(systemic / CNS)
 Structural: trauma, CVA, IC bleed
 CNS malformations
 Metabolic - hypoxia, abn electrolytes,
hypoglycemia
 Toxic - alcohol, other drugs
 Drug withdrawal - AED’s, benzos
 Congenital - inborn errors of metabolism
Management of SE
 History
continued
& Physical - do once treatment initiated
 Hx: events, trauma, meds, sz hx, ETOH, infection
 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, LFT’s, AED
levels, ETOH / toxicology, PTT / INR - ABG
 Consider....
 Thiamine
 Glucose
 Pyridoxine 5 gm IV (70 mg/kg kids)
– Reverses INH action inhibiting GABA synthesis
Anti - Epileptic Drugs:
– Benzodiazepines
– Phenytoin / Fosphenytoin
– Barbiturates
– Propofol
– others / new possibilities
Drug Rx of SE
Starting Rx ASAP has been correlated
with a better response rate to drug Rx &
lower morbidity

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
– DREAM TICKET !
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 due to
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
If NO IV line
( out of hospital -- often in children) →
– Midazolam IM (or Intranasal) 0.15-0.3 mg/kg
– Diazepam Rectally 0.5 mg/kg (to 20 mg)
– Lorazepam SL 0 .1 mg /kg
Lorazepam
 1st agent to use
 Dose: Adults 4 -10 mg (.1 mg/kg) IV
Peds .05 - .1 mg/kg (to 4 mg) IV
 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
Lorazepam vs. Diazepam
Duration of
action
Onset of
action
Sedation
Lorazepam
Diazepam
*12-24 hr
*< 1 hr
2-3 min
1-3 min
+
++
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: 20 mg/kg
 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 :
 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
A prodrug of Phenytoin
It has no anticonvulsant action itself, but
is rapidly converted to Phenytoin
Dosage: in “Phenytoin Equivalents” to
attempt to avoid confusion
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
 Lower risk of hypotension and dysrhythmias
 No risk of tissue necrosis
 Does not precipitate in IV solutions

Fosphenytoin
Negative considerations:
COST Approx 20x that of Phenytoin
 CONFUSION of ordering in “Phenytoin
equivalents”
can give IV at rate of 150 PE/min, which
delivers 100 mg/min of Phenytoin
750 mg Fosphen = 500 mg PE

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
- 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:
 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
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

Other possible drugs for
Status
 Lidocaine
-
 Valproate
 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 NT’s
 May
be neuroprotective as well as
antiepileptic
Take home Messages

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There is a better outcome if sz stopped earlier
Several medications are widely used for the
treatment of SE. no medication is generally accepted
as best in all circumstances.
There are many possible approaches to the
treatment of SE.
Remember 1st line anticonvulsants : Lorazepam
diazepam, Phenytoin
SE that is refractory to first line anticonvulsants
indicates a grave prognosis and requires
management in an intensive care setting
The primary drugs used for refractory SE are
phenobarbital, pentobarbital, midazolam & propofol.
References
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Practice parameter: diagnostic assessment of the child with status
epilepticus (an evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology and the Practice
Committee of the Child Neurology Society.
Neurology. 2006 Nov 14;67(9):1542-50. Review
Status epilepticus: pathophysiology and management in adults
Lancet Neurol. 2006 Mar;5(3):246-56
Advances in the management of seizures and status epilepticus in critically
ill patients
Crit Care Clin. 2006 Oct;22(4):637-59
Intensive Care Med 2002; 17; 174
Simon J. Parsons, Katarina Tomas and Peter Cox
Outcome of Pediatric Status Epilepticus Admitted to Intensive Care
Shinnar S, Pellock JM, Moshe SL, et al. In whom does status epilepticus
occur: age-related differences in children. Epilepsia. Aug 1997;38(8):90714
Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al.
A comparison of four treatments for generalized convulsive status
epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N
Engl J Med. Sep 17 1998;339(12):792-