Status Epilepticus Dan Lowenstein, MD The screen versions of these slides have full details of copyright and acknowledgements 1 Status Epilepticus 1 Dan Lowenstein, MD Professor and Vice Chairman, Department of Neurology, University of California, San Francisco (UCSF) Director, UCSF Epilepsy Center Director, Physician-Scientist and Education Training Programs for the UCSF School of Medicine President, American Epilepsy Society Current evidence regarding: 1. The phenomena : a brief discussion about definitions and epidemiology 2. The causes : understanding of basic mechanisms 3. The treatments: emphasis on pre-hospital treatment and refractory status What i will cover: 2 3. The treatments : emphasis on pre hospital treatment and refractory status 1. Non-convulsive status 2. Status in infants and young children 3. Electrophysiology/monitoring What i will not cover: 3 4. Details of standard front-line treatment
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Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 1
Status Epilepticus
1
Dan Lowenstein, MDProfessor and Vice Chairman, Department of Neurology,
University of California, San Francisco (UCSF) Director, UCSF Epilepsy Center
Director, Physician-Scientist and Education Training Programs for the UCSF School of Medicine
President, American Epilepsy Society
Current evidence regarding:
1. The phenomena: a brief discussion about definitions and epidemiology
2. The causes: understanding of basic mechanisms
3. The treatments: emphasis on pre-hospital treatment and refractory status
What i will cover:
2
3. The treatments: emphasis on pre hospital treatment and refractory status
1. Non-convulsive status
2. Status in infants and young children
3. Electrophysiology/monitoring
What i will not cover:
3
4. Details of standard front-line treatment
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 2
Definitions
• “...The repetition, more or less incessant, of seizures that in consequence often become subintrant ”
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that in consequence often become subintrant...Desire Bourneville (1876)
ILAE (1964)
• “A seizure persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring epileptic condition”
Older definitions of status
5
ILAE (1981)
• “A seizure persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur”
• Continuous seizures or repeated seizures without recovery of consciousness lasting at least:
– 30 minutes EFA Working Group on Status (1983) and many others
Evolution of definitions of status
6
g p ( ) y
– 20 minutes Bleck (1991)
– 10 minutes Treiman et al., VA coop trial (1998)
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 3
Duration of generalized tonic-clonic seizure phases
3. Onset4. Pre-tonic/clonic
5. Tonic6. Tremulousness
7. Clonic
(Theodore et al., Neurology 44: 1403, 1994)
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• Phase 3:Mean duration - 9.5 sec
Median duration - 8.0 sec
Range: 0-40 sec
• Phase 4:Mean duration - 8.5 sec
Median duration - 5.8 sec
Range: 2-67 sec
• Phase 5:Mean duration - 18.5 sec
Median duration - 14 sec
Range: 3-63 sec
• Phase 6-7:Mean duration - 43.5 sec
Median duration - 42 sec
Range: 4-107 sec
8Gastaut, 1973
9Epilepsia 47: 1499, 2006
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 4
A proposed OPERATIONAL definitionof generalized T/C status
• Status epilepticus refers to at least five minutes of:
a. Continuous seizures
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or
Lowenstein, Bleck, and Macdonald; Epilepsia 40: 120-122, 1999
b. 2 or more discrete seizures between which there is incomplete recovery of consciousness
• Generalized, convulsive status epilepticus refers to a condition in which there is a failure of the "normal" factors that serve to terminate
A proposed MECHANISTIC definition of generalized T/C status
11
in which there is a failure of the normal factors that serve to terminate a typical, generalized, tonic clonic seizure
Lowenstein, Bleck, and Macdonald; Epilepsia 40: 120-122, 1999
Epidemiology/outcome
• “The illustrious cardinal Commendoni suffered sixty epileptic paroxysms in the space of 24 hours, under which
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nature being debilitated and oppress’d he at length sank, and died; His skull being immediately taken off, I found his brain affected with a disorder of the hydro-cephalus kind”
Gavassetti, 1586
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 5
30
40
50
60
Etiology/outcome of SE - Richmond, VA 1982-86
n=253
Mor
talit
y
7060 50
2010
4030
0
16-2
0
20-2
9
30-3
9
60-6
9
70-7
9
40-4
9
50-5
9
80-8
9
( )%
Mor
talit
y
13
0
10
20
AE
D-D
C
Ano
xia
Hem
Stro
ke
Tum
or
Met
ab
Infe
ct
Trau
ma
ETO
H
Dru
gs
CN
S In
f
Con
g
Idio
path
% M
Towne et al., Epilepsia 35: 27-34, 1994
Age (yr)
Etiology/Outcome of SE - SFGH/1980s
40
50
60
70
80
or o
utco
me
n=157
14
0
10
20
30
Ano
xia
Stro
ke
Unk
now
n
Met
abol
ic
Tum
or
CN
S In
f
Dru
g to
x
Epi
leps
y
AE
D D
/C
Alc
ohol
Trau
ma
% P
oo
Alldredge and Lowenstein, Neurology 43: 483-488, 1993
Risk factors for mortality - Richmond, VA
Significant risks based on multivariate logistic regression:
FactorSz duration > 1 hr
Odds ratio9.7923
P-value0.0033
95% CI2.13-44.8
15Towne et al., Epilepsia 35: 27, 1994
Etiology: Anoxia
Age
3.6638
1.38940.0051
0.0155
1.47-9.09
1.06-1.81
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 6
Mechanisms
• “In the status epilepticus, when the convulsive condition is almost continuous, something special takes place which requires an explanation ”
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which requires an explanation...Trousseau (1867)
17
Time
Modulation of GABAA receptor function following seizures
18Kapur & Macdonald, J. Neurosci, 17: 7532, 1997
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 7
19Kapur & Macdonald, J. Neurosci, 17: 7532, 1997
1. Enhanced trafficking of GABAA receptor subunits from the synaptic membrane to the cytosol (Brooks-Kayal et al., Nature Med 4: 1166, 1998; Naylor & Wasterlain, J Neurosci 25: 7724, 2005)
Mechanisms of status epilepticus: Modulation of ion channel structure and function
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2. Recruitment of NMDA receptors to the synaptic membrane (Wasterlain et al., Ann Neurol 52: S16, 2002)
3. Changes in sodium channel subunit composition (Ellerkmann et al., Neurosci 119: 323, 2003)
4. Decreased synaptic expression of potassium channels (Lugo et al., J Neurochem 106: 1929, 2008)
1. Single neuron level: ion currents, ion gradients, membrane shunting, energy failure
2. Neuronal network level: glutamate depletion, shifts in extracellular pH,
Mechanisms of status epilepticus: Failure of mechanisms of seizure suppression?
(adapted from Lado & Moshe, Epilepsia 49: 1651, 2008)
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gap junction decoupling, inc. GABAergic inhibition, neuromodulators (endocannabinoids, adenosine, NPY)
The screen versions of these slides have full details of copyright and acknowledgements 8
Treatment
• “After the prolonged attack (use) venesection...d t d i i t th th
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a warm sponge...some mead to drip into the mouth; After the 3rd day...anoint him with warm sweet olive oil.”
Caelius Aurelianus (540)
Initial management of status epilepticus1. Airway2. Vital signs (inc. temp & cardiac monitor
Complete blood countElectrolytes, calciumGlucoseArterial blood gas
Lab studies Start IV
Administer Thiamine (100mg)and glucose (50ml of 50% dextrose)
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Arterial blood gasLiver function testsRenal function testsSerum FTAErythrocyte sedimentation rateTox screen
Quick exam
Trauma (inc. neck injury)PapilledemaFocal neurologic signsEvidence of other medical illnesses (e.g., infection, hepatic or renal disease)Evidence of substance abuse
Anticonvulsant therapy Further workup to define etiology(i.e., CT, LP, etc.)
Lowenstein DH. Seizures and epilepsy; Harrison’s Principles of Internal Medicine, 17th Edition (Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson LJ, Loscalzo J, eds) McGraw-Hill, Inc. 2008
Diazepam0.15 mg/kg IV @ 2 mg/min
Proceed immediately to:
Seizures continuing
Seizures continuingmed
icat
ions
Phenytoin20mg/kg IV @ 50 mg/min
Phenytoin 7-10mg/kg IV @ 50 mg/min
Treatment of status epilepticus circa 1990…
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Phenobarbital20mg/kg IV @ 50 -75mg/min
Phenobarbital5-10 mg/kg IV @ 50-75 mg/min
Admit to ICU and startPentobarbital anesthesia
Seizures continuing
Seizures continuing
Seizures continuing
Sequ
ence
of m
10 80706050403020Time (minutes)
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 9
LorazepamAdditional emergent drug therapy may not be required if seizures stop and the etiology of status epilepticus is rapidly corrected
Fosphenytoin 20mg/kg IV @ 150mg/minPhenytoin 20mg/kg IV @ 50 mg/min
Treatment of status epilepticus circa 2010…
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Seizures continuing
Fosphenytoin 7-10mg/kg IV @ 150mg/minPhenytoin 7-10mg/kg IV @ 50 mg/min
Phenytoin 20mg/kg IV @ 50 mg/min
Consider IV Valproate, Levetiracetam
Seizures continuing
Refractory status epilepticus
VA cooperative trial: Treatment of generalized convulsive status epilepticus:
Multicenter comparison of four drug regimens
• Comparison of 4 treatments:
– Phenytoin, 18 mg/kg
Di 0 1 /k f ll d b Ph i 18 /k
26Treiman et al., NEJM 339: 792, 1998
– Diazepam, 0.15 mg/kg followed by Phenytoin, 18 mg/kg
– Phenobarbital, 15 mg/kg
– Lorazepam, 0.1 mg/kg
• Main endpoint: success of Rx – no clinical or electrical seizure activity from 20-60 min post start of infusion
VA cooperative trialTreiman et al., 1998
Main results
64.9*58.2 55.8
43 6*
60
70
80
OvertSubtlee
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*P = 0.002
17.924.2
8.3
43.6*
7.7
0
10
20
30
40
50
LZ PB DZP/PHT PHT
Subtle
% R
espo
nse
97 39 91 33 95 36 101 26
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 10
VA cooperative trial –sequential responses to treatment
Treiman et al., (unpublished data)
ding
100
90
80
70
60
50%
12%
1st agent23%
7%2nd agent
28Overt SE
n=384Subtle SE
n=134
% R
espo
nd 60
50
40
30
20
10
0
3rd agent
Rx failure55%
15%
Any other agent
7%
28%
3%5%
• Status epilepticus in ICU
Seizures continuing
* Phenobarbital
Consider IV Valproate, Levetiracetam
Refractory status epilepticus
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Seizures continuing
Seizures continuing
• Status epilepticus in ICU • Severe systemic disturbances
(e.g., extreme hyperthermia)• Seizures continued for >60 min
Phenobarbital
Midazolam, Propofol or PB anesthesia
Meta-analysis of treatment response and outcome in refractory status epilepticus
(Claassen et al., Epilepsia 43: 146, 2002)
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Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 11
Midazolam (n=55) Propofol (n=35) Pentobarb (n=106) Total (n=196)
%
Acute treatment failure
20 2713
%
Breakthrough seizures
51
2415
Meta-analysis of treatment response and outcome in RSE
(Claassen et al., 2002)
31
813 12
15
%
Withdrawal seizures
63
4346 47 %
Ultimate Rx failure
10320
21
Midazolam (n=55) Propofol (n=35) Pentobarb (n=106) Total (n=196)
Hypotension requiring pressors
77
Mortality
Meta-analysis of treatment response and outcome in RSE (2)
(Claassen et al., 2002)
32
%
3042
77
54 %46 4852 48
• Premised on multiple actions of TPM:
– Use-dependent blockade of Na+ channels
– Potentiation of GABA inhibition
– Blockade of glutamate receptors
The use of Topiramate in refractory status epilepticus
Towne et al., Neurology 60: 332, 2003
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– Inhibition of Ca++ channels
– Inhibition of carbonic anhydrase activity
• 6 patients in RSE following LZP, PHT, and aggressive 2nd/3rd line therapy (PB, MDZ, PRO)
• Max TPM doses ranged from 300-1,600 mg/d via NG tube
• All 6 patients appeared to have resolution of RSE following TPM (within “several hours” to 48 hours)
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 12
• 7 patients (17 - 71 yo) received an average of 10 AEDs before starting inhalational anesthetics
• All patients received Isoflurane, 1 had Desflurane added
Treatment of refractory status with inhalational anesthetic agents
Isoflurane and DesfluraneMirsattari, et al., Arch Neurology 61: 1254, 2004
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• Sustained burst-suppression attained in all 7 pts –“…dose dependent, easy to achieve, and rapidly reversible.” (3 pts had RSE controlled with Thiopental, but changed to IAs due to concern for toxicity)
• All patients required additional pressure support
• 5/7 pts had seizure recurrence following d/c of IA
• Outcomes: excellent (n=2), good (n=2), death (n=3)
Intravenous Levetiracetam: a new treatment alternative for refractory status epilepticus
Moddel et al., JNNP 80: 689, 2008
• Retrospective review of 36 patients who received LVT after failing at least one AED
• LVT administered as either bolus (n=30) or pump infusion (n=6)
• SE terminated in 69%
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• Factors associated with non-response included dose escalation over 3,000 mg/day, lack of bolus loading, treatment latency over 48h, age > 80y, subtle SE, PLEDS
– Setting: prehospital emergency medical system of San Francisco
– Patients: adults in generalized convulsive status epilepticus
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 14
Intervention
Placebo
Diazepam (5 or 10 mg)
Lorazepam (2 or 4 mg)
PHTSE - study design
40
(NS w/20% prop. glycol)100
75
50
25
%
82%
54%
LZP (4mg) DZP (10mg)
Andermann et al., 1994
Alldredge et al., NEJM 345: 631-637, 2001
PHTSE - final resultsPrimary outcome: status epilepticus at ED arrival
Chi-Square = 0.001
41
q
* P < 0.5
Alldredge et al., NEJM 345: 631-637, 2001
patie
nts
7%
30%19%
38%
ED discharge
Ward admit
ICU admit
N=151 N=107
PHTSE – patient disposition
80
60
100
42
% o
f p
Status at ED arrivalYES NO
38%
73%
32%
Chi-Square = 0.001
Alldredge et al., NEJM 345: 631-637, 2001
40
20
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 15
Prehospital treatment of status epilepticus
• Questions:
1. Is intravenous administration of Benzodiazepines by paramedics an effective and safe means of treating SE in the prehospital setting?
2. Is Lorazepam superior to Diazepam for the treatment of SE in the prehospital setting?
43
in the prehospital setting?
3. Does the control of SE prior to arrival to the emergency department influence patient disposition?
4. Does treatment of SE with Lorazepam or Diazepam in the prehospital setting affect patient outcome?
IM Midazolam vs. IV Lorazepam in pre-hospital Rx of SE:
Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART)
• Objective: to improve prehospital care of patients with status epilepticus by determining if IM Midazolam is effective and more rapid than IV therapy
• Setting: Prehospital emergency medical system throughout the U.S. (NETT)
• Patients: Adults and children in generalized convulsive status epilepticus
NETT network
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Coordinating CentersHub Sites
Status Epilepticus
Dan Lowenstein, MD
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• IM Midazolam autoinjector vs. IV Lorazepam
• Double dummy blinded design
• Exception to consent for emergency research
RAMPART - study design
46
• Primary outcome: termination of SE at time of ED arrival
• Sample 800 patients (400 per group)
• Intention to treat, non-inferiority analysis
1 ml dosepurple cap/label
2 ml dosewhite cap/label
47
Take home messages…
1. Operationally, SE refers to either 5 min. of continuous seizures, or 2 or more discrete seizures between which there is incomplete recovery of consciousness
2. SE has a wide range of etiologies that remain a primary determinant f t
48
of outcome
3. The neurobiological substrate of SE remains poorly understood –there is evidence to support the concept of seizure-induced changes in receptor function; Also, further insight into the mechanisms that cause “normal” seizures to stop should provide new therapeutic targets for SE
Status Epilepticus
Dan Lowenstein, MD
The screen versions of these slides have full details of copyright and acknowledgements 17