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:

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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

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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

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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

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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)

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Time

Modulation of GABAA receptor function following seizures

18Kapur & Macdonald, J. Neurosci, 17: 7532, 1997

Status Epilepticus

Dan Lowenstein, MD

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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)

3. Diffuse/remote systems: neuroadrenergic outflow (locus coeruleus), subcortical structures (subthalamic nucleus, substantia nigra reticulata)

Status Epilepticus

Dan Lowenstein, MD

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)

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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

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• 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

• No patients had cardiovascular side effects

• Mortality 17% (responders 4%, non-responders 45%)

N.B. More recent report by Eue et al., (Epilepsy Behav 15: 467, 2009) showed response in 19/43 patients…

Seizures continuing

Seizures continuing

Phenobarbital

Midazolam, Propofol or PB anesthesia

Consider IV Valproate, Levetiracetam

Refractory Status Epilepticus

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Seizures continuing

IV Valproate, LevetiracetamNG Topiramate

Seizures continuing

Consider Ketamine or inhalational anesthesia

Seizures continuing

Consider ECT or surgery

Status Epilepticus

Dan Lowenstein, MD

The screen versions of these slides have full details of copyright and acknowledgements 13

Endpoint for treatment of RSE?

• Depth of EEG suppression and outcome in Barbiturate anesthetic treatment for refractory status epilepticus

Krishnamurthy & Drislane, Epilepsia 40: 759, 1999

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Pre-hospital therapy

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Pre-hospital therapy

The prehospital treatment of status epilepticus study

• PHTSE - study design

– Objective: to evaluate the safety and efficacy of paramedic-administered prehospital Benzodiazepine therapy for SE in adults

39Alldredge et al., NEJM 345: 631-637, 2001

– Design: randomized, prospective, placebo-controlled, double-blind clinical trial

– 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?

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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

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than IV therapy

• Design: Randomized, prospective double-blind clinical trial

• 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

The screen versions of these slides have full details of copyright and acknowledgements 16

• IM Midazolam autoinjector vs. IV Lorazepam

• Double dummy blinded design

• Exception to consent for emergency research

RAMPART - study design

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• 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

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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

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