- NOW LET ME WELCOME OUR
SPEAKER FOR TODAY.

DR. CLAUDE WASTERLAIN.

DR. WASTERLAIN, ARE YOU
ON THE LINE?

- MY NAME IS CLAUDE
WASTERLAIN.

I'M IN THE VA AT WEST LOS
ANGELES, AND I WANT TO TALK

TODAY ABOUT ACUTE SEIZURES AND
STATUS EPILEPTICUS AND HOW TO

TREAT THEM.

I WILL START WITH A PERSONAL
ANECDOTE HOW I GOT INTERESTED

IN EPILEPSY.

I WENT TO MEDICAL SCHOOL IN
BELGIUM, AND THEN, PURELY

BECAUSE I WANTED TO SEE THE
WORLD, I CAME TO THE U.S.,

WITH NO INTENTION OF STAYING.

HAD A JOB WAITING FOR
ME AT HOME.

AND I DID MY RESIDENCY WITH AN
EXTRAORDINARY PERSON BY THE

NAME OF FRED PLUM IN NEW YORK
AT CORNELL-NEW YORK HOSPITAL.

AND I DID SOME RESEARCH, BOTH
AS A MEDICAL STUDENT AND AS A

RESIDENT, AND WHEN I FINISHED
MY RESIDENCY, I HAD A JOB

OFFER FROM FRED AND DECIDED TO
GO BACK TO SCHOOL AND DO SOME

SERIOUS TRAINING IN
MOLECULAR BIOLOGY.

IN THAT TIME, THE GENETIC CODE
HAD JUST BEEN DISCOVERED.

IT WAS A VERY EXCITING TIME.

AND I WAS WORKING IN A LAB
WHERE THE FIRST MESSENGER--

EUKARYPTIC MESSENGER
RNA EUKARYOTIC HAD BEEN
ISOLATED,

THE MESSENGER FOR GLOBIN,
THE PROTEIN OF HEMOGLOBIN.

AND I STARTED LOOKING AT
RIBOSOMES AND PUTTING

RIBOSOMES IN THE BRAIN AND
MESSAGE IN THE BRAIN.

AND SINCE MY MAIN INTEREST WAS
REALLY THE PHYSIOLOGY OF

MEMORY, OF WHICH NOTHING WAS
KNOWN AT THE TIME, I USED

SEIZURES TO CAUSE AMNESIA IN
MY RATS, AND THEN I ANALYZED

THE POLYRIBOSOMES, AND THAT'S
HOW I GOT INTO EPILEPSY.

BUT I JUST WANTED TO KILL A
LITTLE TIME SO PEOPLE WOULD

HAVE TIME TO GET IN
ON THE CALL.

SO NOW WE CAN START WITH
THE REAL TALK.

STATUS EPILEPTICUS IS A
RELATIVELY UNCOMMON CONDITION,

AND IF YOU LOOK--FOR THOSE WHO
HAVE ACCESS TO THE SLIDES--AT

THE FIRST SLIDE, YOU WILL SEE
A PAINTING BY MUNCH,

"THE SCREAM," FAMOUS PAINTING.

AND I--IT'S NOT AN EPILEPTIC
SCREAM, BUT I MADE IT INTO AN

EPILEPTIC SCREAM AND PUT A
SEIZURE IN BETWEEN THE

SUBJECT'S EARS.

AND IT REFLECTS GREAT DISTRESS
THAT SEIZURES STILL CAUSE

TODAY, AND PARTICULARLY THAT
STATUS EPILEPTICUS

CAUSES TODAY.

IF YOU SWITCH TO THE SECOND
SLIDE, YOU WILL SEE THE

CURRENT STATE OF AFFAIRS IN
STATUS EPILEPTICUS.

WHAT IS STATUS EPILEPTICUS?

IT'S A BUNCH OF SEIZURES WHICH
GET STARTED AND TEND TO KEEP

GOING ON THEIR OWN, AND IT'S A
VERY DANGEROUS CONDITION.

THERE ARE ONLY ABOUT 150,000
CASES A YEAR IN THE U.S., BUT

MORTALITY IS STILL VERY HIGH--
ON THE AVERAGE, 27%--AND IT'S

VERY AGE-DEPENDENT.

IN THE BEST STUDY DONE IN THE
LAST 10 YEARS, IN RICHMOND,

VIRGINIA, MORTALITY IN
CHILDREN WAS ONLY 3%, BUT IN

THE ELDERLY, IT WAS 38%.

IN THE VA COOPERATIVE STUDY,
WHICH WAS THE BEST STUDY OF

STATUS EPILEPTICUS, BUT WHICH
DEALT LARGELY WITH A QUITE

ELDERLY POPULATION,
MORTALITY WAS 55%.

SO IN SPITE OF THE FACT THAT
WE HAVE MANY MORE DRUGS TO

TREAT EPILEPSY THAN WE HAD 50
YEARS AGO, THERE HAS NOT BEEN

MUCH PROGRESS IN TREATING
STATUS EPILEPTICUS, THAT

CONDITION OF ACUTE REPETITIVE
SEIZURES, WHICH IS

LIFE-THREATENING.

AND WE--ONE OF THE REASONS FOR
THAT IS THAT MANY OF THE DRUGS

WHICH ARE AVAILABLE TO TREAT
EPILEPSY--THE NEWER DRUGS--

MANY OF THEM ARE NOT AVAILABLE
TO TREAT STATUS EPILEPTICUS,

WHICH HAS TO BE TREATED BY THE
INTRAVENOUS ROUTE.

AND AMONG THOSE WHICH ARE
AVAILABLE BY INTRAVENOUS

ROUTE, THE FDA SAYS DON'T USE
THEM FOR STATUS, BECAUSE THERE

HAVE BEEN NO CONTROL STUDIES.

BECAUSE OF THE SIZE OF THE
MARKET, ONLY 150,000 CASES

PER YEAR IN THE WHOLE U.S., IT'S
TOO SMALL TO JUSTIFY CONTROL

TRIALS FINANCED BY INDUSTRY.

THIS IS WHY THE BEST STUDY
EVER DONE WAS DONE IN THE VA.

BUT IT WAS QUITE
A LONG TIME AGO.

IT WAS PUBLISHED IN '88.

SO WE DON'T HAVE ANY
RECENT STUDIES

WHICH CAN COUNT AS TYPE I
EVIDENCE.

SO LET'S SWITCH TO SLIDE NUMBER
3, AND IT SHOWS YOU THAT EVEN

IF YOU SURVIVE STATUS
EPILEPTICUS, YOU MAY END UP

WITH BRAIN DAMAGE.

ON TOP, YOU SEE THE
HIPPOCAMPUS OF A NORMAL BRAIN

OBTAINED AT AUTOPSY.

AND AT THE BOTTOM, YOU SEE THE
BRAIN OF A PATIENT WHO DIED IN

STATUS EPILEPTICUS, AND YOU
CAN SEE THAT THERE'S A WHOLE

RANGE OF CELLS GOING FROM THE
CENTER OF THE SLIDE TOWARD THE

RIGHT AND THE BOTTOM WHICH IS
PRESENT IN THE CONTROL WHICH

IS TOTALLY DESTROYED IN A
PATIENT WHO WENT THROUGH

STATUS EPILEPTICUS.

SO IT KILLS A LOT OF BRAIN
CELLS, OR IT CAN KILL A LOT OF

BRAIN CELLS.

SO EVEN IF YOU SURVIVE IT,
IT'S A VERY DANGEROUS CONDITION.

SO LET'S SWITCH TO SLIDE
NUMBER 4, WHICH SHOWS YOU A

PHENOMENON WHICH HAS BEEN
KNOWN FROM TIMES IMMEMORIAL

BUT ILLUSTRATED BY THE SLIDE
FROM THE V.A. COOPERATIVE

STUDY AND PUBLISHED BY A TEAM
OF COLLABORATORS IN "THE NEW

ENGLAND JOURNAL OF
MEDICINE" IN 1988.

YOU CAN SEE TWO DIFFERENT
TYPES OF STATUS EPILEPTICUS.

IN THE RED BARS, THE OVERT
STATUS EPILEPTICUS, WHICH IS...

[RUSTLING, STATIC]

...STATUS EPILEPTICUS, WHICH
IS A LATE FORM IN WHICH A

SEIZURE IS--AS THE BRAIN
GETS EXHAUSTED,

THE SEIZURES CAN BE LESS
INTENSE OR INTENSE PHYSICAL.

AND WHAT THESE BARS SHOW IS
HOW MANY PEOPLE HAVE A GOOD

RESULT FROM TREATMENT.

AND YOU CAN APPRECIATE THAT
THE TREATMENTS IN THE RED

BARS, EARLY TREATMENT,
TREATMENT OF THE EARLY FORM OF

STATUS, ARE MUCH BETTER THAN THE
RESULT OF TREATMENT OF THE

LATE FORM OF STATUS.

SO AT THE BOTTOM, YOU CAN SEE
ANOTHER ASPECT OF THE SAME

PHENOMENON.

IF YOU TREAT--IN THAT STUDY,

THE FIRST DRUG USED TO TREAT
HAD A GOOD RESULT IN

53% OF CASES.

SO MORE THAN HALF OF THE
PATIENTS RESPONDED WELL.

THE THIRD DRUG--IF THEY
DIDN'T RESPOND TO THE FIRST

DRUG, THE SECOND
DRUG WAS GIVEN.

IF THEY DID NOT RESPOND TO THE
SECOND DRUG, THE THIRD DRUG

WAS GIVEN.

HOW MANY PEOPLE RESPONDED WELL
TO A THIRD DRUG?

ONLY 2%.

SO YOU MIGHT THINK THAT THIS IS
BECAUSE THESE WERE

DIFFERENT DRUGS.

NOT TRUE.

4 DIFFERENT TREATMENT REGIMENS
WERE RANDOMIZED.

SO WE GOT THE SAME DRUG IN
THE SAME DOSE, JUST GIVEN AT

DIFFERENT TIME.

IF YOU GIVE THEM EARLY IN THE
STATUS, YOU GET A MUCH BETTER

RESULT THAN IF YOU GET THEM
LATE DURING THE SAME SEIZURES.

SO LET'S GO TO SLIDE NUMBER 5
AND TALK ABOUT WHAT IS STATUS

EPILEPTICUS?

STRANGE LATIN NAME.

THAT NAME ACTUALLY WAS
COINED IN 1867.

THE STATUS IS ONE OF THE RARE
CONDITIONS NOT NAMED BY THE

DOCTORS, BUT BY THE PATIENT
WHO SUFFERED FROM IT.

IN PARIS, THERE WERE TWO VERY
LARGE ASYLUMS WITH HOSPITALS,

BICETRE AND SALPETRIERE,

AND THOSE HOSPITALS HAD VERY
LARGE PATIENT POPULATIONS,

MIXING MANY TYPES OF PATIENTS,
INCLUDING THE INSANE AND

INCLUDING THE EPILEPTICS.

AND THERE WAS NO TREATMENT IN
THE EARLY 19th CENTURY.

SO FREQUENTLY PATIENTS WENT
INTO STATUS, REPEATED SEIZURES

THAT COULD NOT BE CONTROLLED,
AND THEY CALLED THESE "STATE

OF ILL..."

ETAT DE MAL IN FRENCH.

AND TROUSSEAU IN 1867 GAVE A
SERIES OF LECTURES IN LONDON,

AND HE WASN'T--HIS ENGLISH WAS
NOT VERY GOOD, SO HE ASKED A

FRIEND OF HIS, BAZIRE, WHO SPOKE
GOOD ENGLISH, TO TRANSLATE

THE LECTURES.

AND BAZIRE DIDN'T KNOW HOW TO
TRANSLATE ETAT DE MAL

IN ENGLISH, SO HE
TRANSLATED INTO LATIN.

STATUS EPILEPTICUS MEANS THE
STATE OF EPILEPSY.

SO WE HAVE VERY EFFECTIVE
NATURAL WAYS OF STOPPING

SEIZURES, AND MOST OF THE
TIME, THEY WORK VERY WELL.

AFTER A SINGLE SEIZURE, PEOPLE
ARE [INDISTINCT]

FOR SEVERAL MINUTES,
FREQUENTLY, AND IT REFLECTS A

VERY LARGE RELEASE OF GABA
THROUGHOUT THE BRAIN.

AND IT WORKS VERY WELL MOST OF
THE TIME, BUT ONCE IN A WHILE,

IT FAILS, AND THEN THE
SEIZURES TEND TO BECOME SELF-

SUSTAINING.

THEY KEEP COMING BACK.

AND THERE'S A DEVELOPMENT OF
PHARMOCORESISTANCE.

I SHOWED YOU A MINUTE AGO THAT
EARLY TREATMENT WORKS MUCH

BETTER THAN LATE TREATMENT FOR
THE SAME DRUGS IN THE

SAME AMOUNT.

SO THAT'S THE TIME-DEPENDENT
PHARMOCORESISTANCE,

WHICH IS A BIG
PROBLEM IN TREATING STATUS.

AND IF YOU LOOK AT THE BRAIN,
YOU SEE BY MRI EARLY

HIPPOCAMPAL SWELLING AND LATE
HIPPOCAMPAL ATROPHY,

SUGGESTING DAMAGE OF THE TYPE
I SHOWED YOU IN THE AUTOPSY

CASE THAT WE LOOKED AT.

SO WHAT'S HAPPENING?

WE CAN HAVE--IMITATE
THE HUMAN

CONDITION IN ANIMAL MODELS,
AND I'M GOING TO SHOW YOU

ONE OF THEM.

SO...WHICH REPRODUCES SOME OF
THE KEY FEATURES OF STATUS

EPILEPTICUS IN PEOPLE--

THAT IS, THE TENDENCY FOR
SEIZURES TO SWITCH TO REPETITIVE

SEIZURES WHICH ARE
SELF-SUSTAINING.

AND THEN THE DEVELOPMENT OF
PHARMOCORESISTANCE,

RESISTANCE TO TREATMENT, WHICH
INCREASES WITH TIME.

SO FOR THOSE WHO SEE SLIDE
NUMBER 7, IT SHOWS YOU THAT

YOU CAN INDUCE THAT STATE OF
REPETITIVE SEIZURES BY PUTTING

AN ELECTRODE IN THE BRAIN AND
STIMULATING

INHIBITORY PATHWAYS.

THE PERFORANT PATH, WHICH GOES
THROUGH HIPPOCAMPUS

FROM ENTHORINAL CORTEX

AND USES GLUTAMATE AS A
TRANSMITTER, WITH

NMDA RECEPTORS.

AND IF YOU STIMULATE THAT
PATHWAY FOR A FEW SECONDS

EVERY MINUTE, THE RESULT IS
SHOWN IN SLIDE NUMBER 8, WHICH

SHOWS THE BRAINWAVES
OF THE RAT.

IF YOU STIMULATE FOR JUST A
FEW MINUTES, WHEN YOU

STIMULATE, YOU GET SEIZURES,
WHICH ARE FAIRLY BRIEF, BUT

WHEN YOU STOP STIMULATING,
THEY ARE IN [INDISTINCT]

SILENCE, AS YOU WOULD EXPECT.

AND NOTHING HAPPENS.

HOWEVER, IF YOU STIMULATE FOR
MORE THAN 15 MINUTES, HALF THE

ANIMALS, AND MORE THAN 30
MINUTES ALL THE ANIMALS,

CONTINUE TO SEIZE WHEN YOU
STOP THE STIMULATION.

YOU HAVE INDUCED A STATE IN
WHICH SEIZURES ARE SELF-

PERPETUATING.

AND THIS IS SHOWN IN
THIS SLIDE.

WE SHOW THE BRAINWAVES.

AFTER 20 MINUTES, YOU SEE,
CONTINUOUS SEIZURES.

AFTER ONE HOUR'S TREATMENT,
CONTINUOUS SEIZURES.

AFTER 3 HOURS,
INTERMITTENT SEIZURES.

6 HOURS, THE SAME, AND THEN THEY
BECOME LESS INTENSE BECAUSE

THE BRAIN GETS EXHAUSTED.

BUT YOU CAN SEE THAT AFTER 12
HOURS, THERE IS STILL SEIZURE

ACTIVITY GOING ON.

AND ON THE NEXT SLIDE, WHICH
IS SLIDE NUMBER 9, SHOWS THE

PHENOMENON OF PHARMOCORESISTANCE
IN WHICH WE

STIMULATED THE PERFORANT PATH OF
30 MINUTES IN THE RED BAR.

AND THEN WE RECORDED
BRAINWAVES AND COUNTED THE

NUMBER OF SPIKES.

AND THE SPIKES ARE A
MANIFESTATION OF THE SEIZURES.

SO THEY ARE VERY LOW IN NUMBER
IN A NORMAL BRAIN, VERY RARE.

THEY'RE VERY FREQUENT
DURING SEIZURES.

AND THIS WAS DONE FOR 24 HOURS
CONSECUTIVELY.

AND IF THE ANIMAL WAS NOT
TREATED, YOU CAN SEE, A LARGE

NUMBER OF SPIKES.

DECLINING PROGRESSIVELY BUT
STILL VERY HIGH AFTER 24

HOURS, SHOWING THAT SEIZURES
WERE GONE FOR ESSENTIALLY THE

WHOLE DAY.

IF THE ANIMAL WAS TREATED WITH
VALIUM, DIAZEPAM,

12 MILLIGRAMS PER KILOGRAM,

EARLY IN THE SEIZURES,
EVERYTHING STOPPED.

THE TREATMENT WAS
VERY EFFECTIVE.

BUT IF THE TREATMENT WAS GIVEN
HALF AN HOUR LATER, THERE WAS

A TRANSIENT DEPRESSION OF THE
SEIZURES, BUT THEN THEY

CAME BACK.

AND IF THE TREATMENT WAS GIVEN
AN HOUR LATER, THERE WAS

BARELY ANY EFFECT.

SO THE SAME TREATMENT IF GIVEN
EARLY WAS VERY EFFECTIVE AND

GIVEN LATE WAS QUITE
INEFFECTIVE IN A SIMILAR

SITUATION THAT WE SAW

IN THE--I'LL SHOW YOU FROM THE
VA COOPERATIVE STUDY.

SO WHAT'S GOING ON IS SHOWN IN
THE NEXT FEW SLIDES.

THE NEXT SLIDE, SLIDE NUMBER
10, DESCRIBES THE ROLE OF

GABA IN SEIZURES.

WE KNOW THAT GABA IS A MAIN
INHIBITORY TRANSMITTER IN

THE BRAIN, AND THAT MANY DRUGS
THAT TREAT SEIZURES INCREASE

GABA EFFECTS, AND MANY DRUGS
THAT CAUSE SEIZURES BLOCK

GABA EFFECTS.

SO GABA IS A MAIN INHIBITORY
TRANSMITTER AND ALSO THE MAIN

INHIBITOR OF SEIZURES.

SO WHAT HAPPENS IF WE
RECODE CURRENTS

INDUCED BY GABA IN A CONTROL
RAT, IN A HIPPOCAMPUS SLICE

COMING FROM A CONTROL RAT;
AND A HIPPOCAMPUS SLICE COMING

FROM A RAT IN STATUS
EPILEPTICUS?

WELL, RETURNS IN THE ANIMAL THAT
WAS IN STATUS ARE MUCH LOWER

THAN IN THE CONTROL ANIMAL.

ABOUT HALF IN THIS
PARTICULAR EXPERIMENT.

AND UNDER THE CONDITIONS OF
THE EXPERIMENT, THE CURRENT

REPRESENTATIVE RESPONSE OF THE
POSTSYNAPTIC MEMBRANE OF

A NERVE CELL

TO A SINGLE [INDISTINCT]

RELEASING TRANSMITTER IN THE
SYNAPSE TENDS TO [INDISTINCT]

TRANSMITTER.

SO THIS IS A MEASURE OF HOW
THE NERVE CELL

WILL RESPOND TO A FIXED
AMOUNT OF STIMULATION.

SO THE STIMULATION BY GABA
HAS MUCH LESS EFFECT IN THE

ANIMAL IN STATUS, AND THAT'S
BAD BECAUSE IF YOU ARE IN THE

MIDDLE OF SEIZURES, YOU WANT
MORE INHIBITION.

YOU DON'T WANT LESS
INHIBITION.

BUT HERE, WE OBSERVE LESS
INHIBITION IN

RESPONSE TO GABA.

SO WHAT'S HAPPENING IS SHOWN,
FOR THOSE WHO CAN SEE IT,

SLIDE NUMBER 12, IN THIS SLIDE
IN WHICH WE DON'T EVEN

ASSIGN THE CHEMISTRY IN
THE SAME CELLS, THE GRANULE

CELLS, OF THE HIPPOCAMPUS FROM
WHICH THE CURRENTS WERE

RECODED IN A PREVIOUS SLIDE.

AND ON THE LEFT, YOU CAN SEE
CONTROL GRANULE CELLS, AND IN

THE RIGHT, YOU SEE THE
ANTIBODIES TO--

THE BETA-2, BETA-3 SUBUNITS,

THE MOST COMMON SUBUNITS OF GABA
RECEPTORS, THE GABA-A

RECEPTOR.

IN THE GREEN IS THE SYNAPTIC
MARKERS, AND UP TO 5.

AND IN THE CONTROL BRAIN ON
THE LEFT, YOU CAN SEE THAT THE

TWO ARE ON THE OUTSIDE OF THE
NEURON PRETTY MUCH IN THE

SAME LOCATION.

IN MANY OF THE LOCATIONS, THE
RED AND THE GREEN COLOCALIZE

SO YOU HAVE A YELLOW SPOT.

BUT IN THE ANIMAL IN STATUS,
THE RED DOT IS MOVED INSIDE

THE GREEN DOT.

THE GREEN DOT, A SYNAPTIC
MARKER WHICH DOES NOT MOVE.

SO THE RECEPTOR FOR GABA-A IS
MOVED FROM THE MEMBRANE, THE

SYNAPSE, TO INSIDE THE CELL.

AND WHEN THE RECEPTOR IS
INSIDE THE CELL, IT CAN NO

LONGER BE REACHED BY
THE TRANSMITTER.

SO--AS PARTICULAR TEMPORARY
LAWS OF A TRANSMITTER.

SO IF YOU LOOK AT SLIDE NUMBER
13, IT EXPLAINS WHAT'S

HAPPENING.

WE HAVE ALWAYS KNOWN THAT IF
WE ARE TALKING ABOUT CHANGES

IN BRAIN EXCITABILITY,

IN SYNAPTIC EXCITABILITY,

WHICH HAPPEN IN
MILLISECONDS, THEY REPRESENT

CHANGES IN SHAPE OF ENZYMES
OR...WHICH ARE DUE TO PHYSICAL

CHEMICAL CHANGES OR TO
[INDISTINCT] OF ENZYMES.

IF WE TALK ABOUT LONG-TERM
CHANGES, WEEKS,

WE ARE TALKING ABOUT
GENE EXPRESSION.

BUT RECENTLY WE HAVE REALIZED
THAT IN BETWEEN THE CELL AND

THE NEURON IS A VERY NICE WAY
TO INACTIVATE MOLECULES FOR A

FEW MINUTES, AND THEN WE USE
THEM UNDAMAGED.

AND THAT'S TRAFFICKING, IN
WHICH THE RECEPTOR IN THIS

CASE, OR THE ENZYME IN OTHER
CASES, IS STAKING FOR A PLACE

WHERE IT'S ACTIVE, SUCH AS A
SYNAPTIC NERVE RIGHT HERE, AND

THEN PUT IN A PLACE WHERE IT'S
NOT ACTIVE, LIKE

INSIDE THE CELL.

AND WHEN IT'S READY TO BE RE-
USED, WHEN THE CELL IS READY

TO USE IT AGAIN, IT'S RECYCLED
INTO THE MEMBRANE, INTO THE

SYNAPSE, AND IT CAN WORK
WITHOUT HAVING TO GO THROUGH

THE EXPENSE OF DESTROYING A
MOLECULE AND THEN MAKING IT

AGAIN, WHICH IS
VERY EXPENSIVE.

SO THIS SEEMS TO BE WHAT WE ARE
OBSERVING HERE; THE GABA-A

RECEPTOR IS BEING MOVED FROM
THE SYNAPTIC MEMBRANE TO

INSIDE THE CELL AND READY TO
BE RECYCLED WHEN NEEDED.

SO THE NEXT SLIDE, SLIDE 14,
SHOWS A CARTOON OF THIS.

AS YOU CAN SEE, IN THE CARTOON
OF THE SYNAPSE, THE LITTLE

BLUE DOTS ARE GABA BEING
RELEASED BY THE SEIZURES IN

ENOUGH TIME TO STOP
THE SEIZURES.

BUT IT ACTS ON THE RECEPTORS,
AND IT INTERNALIZES, IT

CREATES
CLATHRIN-ENCODED PITS

WHICH INCLUDE
THE RECEPTOR WHICH GO INSIDE

THE CELL AND GO TO ENDOPLASMIC
RETICULUM, AND THEN CAN EITHER

BE TRANSPORTED TO LYTOZOMES
AND DESTROYED OR CAN BE

TRANSPORTED BACK AS A MEMBRANE
RECYCLED, AS WE SAID A

MINUTE AGO.

SO WHAT HAPPENS IS THAT THE
RECEPTORS WHICH ARE

INTERNALIZED ARE NOT
FUNCTIONAL ANYMORE.

HAVING FEWER GABA RECEPTORS
FOR THE BRAIN MEANS LOSS OF

GABA INHIBITION, WHICH IS A
MAIN MECHANISM OF INHIBITION

FOR THE BRAIN IN GENERAL AND
FOR SEIZURES IN PARTICULAR.

SO THE DRUGS THAT WE USE TO
STOP SEIZURES, SUCH AS

BENZODIAZEPINE, WHICH IS USED
FOR TREATING ACUTE SEIZURES

AND STATUS EPILEPTICUS,

ACT ON THOSE GABA RECEPTORS.

IF THERE ARE FEWER
RECEPTORS TO ACT ON, THEY WILL

HAVE LESS EFFECT, AND THAT
EXPLAINS THE DEVELOPMENT OF

PHARMOCORESISTANCE.

THE MORE MOST SEIZURES
YOU HAVE, THE MORE YOU

INTERNALIZE THE RECEPTORS; AS
MORE PHARMOCORESISTANCE

DEVELOPS, THE LESS EFFECT YOU
HAVE WITH THE AMOUNT OF DRUG.

SO THERE IS LESS
DEFENSE AGAINST

SEIZURES, THEY TEND TO BE
SELF-SUSTAINING,

AND THERE IS LESS

EFFECT OF THE DRUGS--
PHARMOCORESISTANCE

AT THE SAME TIME, THE SAME
MALADAPTIVE PHENOMENON OCCURS

TO GLUTAMATE RECEPTORS,
[INDISTINCT] RECEPTORS.

INSTEAD OF MOVING INSIDE THE
CELLS, THEY MOVE TO THE

MEMBRANE, WHICH IS ALSO
WHAT YOU DON'T WANT

DURING SEIZURES.

YOU DON'T WANT [INDISTINCT]

RECEPTORS, BUT THAT'S
WHAT YOU GET.

AND THAT'S WHAT THE
SLIDE 15 SHOWS.

I'M SORRY, SLIDE 16.

SO SLIDE 17 DRAWS THE
CONCLUSIONS OF RECEPTIVE

TRAFFICKING FOR THE DOCTOR.

SINCE YOU HAVE A SITUATION
WHICH GETS WORSE WITH TIME,

IT'S VERY IMPORTANT TO
TREAT EARLY.

TIME IS OF THE ESSENCE.

AT THE SAME TIME, WE HAVE SEEN
EARLIER THAT STATUS CAN

PRODUCE BRAIN DAMAGE.

SO TIME IS VERY--IN STATUS,
THE EARLIER YOU TREAT, THE

BETTER YOUR RESULTS, THE MORE
BRAIN YOU CAN SAVE.

AND THEREFORE, WE SHOULD TREAT
IT IDEALLY BEFORE THE PATIENT

REACHES THE HOSPITAL TO AVOID
THE DEVELOPMENT

OF PHARMOCORESISTANCE.

WE SHOULD NOT START WITH SMALL
AMOUNTS OF DRUGS.

WE SHOULD START WITH HIGH DOSE
TO STOP THE SEIZURES AS SOON

AS WE CAN.

AND WE SHOULD IDEALLY COMBINE
A DRUG WHICH ACTS IN GABA,

WHICH IS A STANDARD DRUG
FOR USE,

LIKE BENZODIAZEPINE, LIKE
VALIUM AND ATIVAN.

WE SHOULD COMBINE THEM WITH A
DRUG WHICH ACTS AT

THE SITE WHICH IS
NOT GABA DEPENDENT SUCH AS

PHENYTOIN OR FOSPHENYTOIN.

ALL RIGHT?

SO, AS DOCTORS, HOW DO WE APPLY
THAT IN PRACTICE?

UNFORTUNATELY, THE PRE-
HOSPITAL TREATMENT HAS BEEN

PROVEN EFFECTIVE, BUT IT'S
STILL NOT IN GENERAL USE.

THERE ARE SEVERAL
WAYS TO DO IT.

RECTAL VALIUM, RECTAL
DIAZEPAM, IS AVAILABLE AND IS

VERY EFFECTIVE.

IT'S OFTEN USED BY PARENTS FOR
THEIR CHILDREN WHO TEND TO GO

INTO STATUS REPEATEDLY.

BUT IT'S RARELY USED IN ADULTS
FOR VARIOUS REASONS.

PEOPLE DON'T LIKE TO USE
SUPPOSITORIES IN ADULTS, AND I

SUSPECT THAT PARAMEDICS ARE
AFRAID TO BE SUED FOR SEXUAL

HARASSMENT IF THEY USE
SUPPOSITORIES IN ADULTS.

BUT WHATEVER THE REASON, IT'S
NOT BECOME A GENERAL PRACTICE,

EVEN THOUGH THE MEDICINES ARE
THERE TO TREAT.

OTHER STUDIES HAVE SHOWN THAT
INTRAVENOUS INJECTION OF

EITHER LORAZEPAM--ATIVAN IS A
BRAND NAME--OR DIAZEPAM--VALIUM

IS A BRAND NAME--ARE
VERY EFFECTIVE.

ALLDREDGE AND LOWENSTEIN IN SAN
FRANCISCO DID A VERY NICE

STUDY PUBLISHED IN "THE NEW
ENGLAND JOURNAL" 9 YEARS AGO

AND SHOWED THAT THIS REALLY
REDUCES THE INCIDENCE OF

STATUS AND THE COMPLICATIONS
OF STATUS AND THAT THE PATIENT

IS IN BETTER SHAPE WHEN THE
PATIENT GETS TO THE HOSPITAL.

HOWEVER, IT HAS NOT
BEEN IN GENERAL USE,

PROBABLY BECAUSE
THE PARAMEDICS ARE AFRAID TO

INJECT INTRAVENOUS DRUGS IN
THE ABSENCE OF A DOCTOR.

SO WE...THERE IS A TRIAL
UNDERWAY TO USE VERSED,

MIDAZOLAM,

INTRAVASCULARLY, AND THAT
TRIAL WILL--I THINK

RECRUITMENT HAS ENDED AND THE
STUDY RESULT WILL BE KNOWN

NEXT YEAR.

AND HOPEFULLY, THAT CAN BECOME
AN EFFECTIVE AGENT FOR PRE-

HOSPITAL TREATMENT WHICH WILL
BE BOTH ACCEPTABLE TO THE

PEOPLE WHO HAVE TO GIVE IT--
THE PARAMEDICS--AND SAFE.

GO TO THE NEXT SLIDE, SLIDE 19.

WE HAVE SAID THAT TIME IS OF
THE ESSENCE.

HOW CAN WE SAVE TIME?

THE SLIDE 19 SHOWS A STUDY
DONE IN SAN BERNARDINO BY

DR. JORDAN AND COLLABORATORS
SHOWING HOW MUCH TIME IT TAKES

TO TREAT A PATIENT WHO GOES
INTO REPEATED SEIZURES AND

STATUS EPILEPTICUS.

THEY HAD A PRETTY GOOD TIME
BETWEEN THE ONSET OF SEIZURES

AND THE ARRIVAL OF THE
AMBULANCE--ONLY 30 MINUTES.

THAT'S PRETTY GOOD.

FROM THE TIME THAT THE
AMBULANCE ARRIVED TO THE TIME

THAT THE PATIENT WAS DELIVERED
TO THE EMERGENCY ROOM WAS 20

MINUTES, WHICH IS ALSO
PRETTY GOOD.

BUT THEY FOUND THAT BETWEEN
THE TIME THAT THE PATIENT

ARRIVED IN THE EMERGENCY ROOM
AND THE BEGINNING OF TREATMENT

WAS 35 MINUTES.

THAT'S FAR TOO LONG.

THAT SHOULD BE 5 MINUTES.

SO THAT IS WHERE WE CAN SAVE
TIME AND HAVE MORE EFFECTIVE

TREATMENT.

WE CAN PROBABLY SAVE A HALF-
HOUR BY TREATING VERY QUICKLY

AND VERY VIGOROUSLY.

SO THIS IS WHERE WE CAN
IMPROVE TREATMENT.

SO...WHO SHOULD WE TREAT?

AND HOW DO WE DEFINE STATUS
EPILEPTICUS ONCE A PATIENT

GETS TO THE EMERGENCY ROOM?

WELL, IF WE LOOK AT HOW LONG
SEIZURES, TONIC-CLONIC

SEIZURES, LAST, THEY ALMOST
NEVER LAST MORE THAN

TWO MINUTES.

AND WE HAVE VERY GOOD STATISTICS
OF STUDIES DONE ON PATIENTS WHO

WERE IN HOSPITAL AND BEING
RECORDED IN EEG AND VIDEOTAPE

AT THE TIME OF THE SEIZURE.

SO WE HAVE VERY GOOD DATA
SHOWING THAT ALMOST NONE OF

THEM LAST TWO MINUTES.

AND THAT MEANS THAT 5 MINUTES
OF CONTINUOUS SEIZURES IS A

VERY RARE PHENOMENON.

AND ALSO, WE HAVE SEEN--OUR
ANIMAL STUDIES SHOW THAT 15

MINUTES IS THE TIME WHEN HALF
OF THE ANIMALS ARE IN STATUS.

WE DON'T KNOW WHAT THE
EQUIVALENT TIME IN HUMANS IS,

BUT WE KNOW

THAT SOMEWHERE IN THE FIRST 15
MINUTES, SOME CHANGE HAPPENS

IN THE BRAIN.

AS TROUSSEAU SAID ALREADY IN
THE 19th CENTURY, WHAT CHANGES

BRAIN EXCITABILITY

CAN TEND TO MAKE SEIZURES
HARD TO STOP.

SO WE ALSO KNOW THAT SEIZURES
LASTING MORE THAN A HALF-HOUR

CAN CAUSE LOSS OF NEURONS AND
THAT SEIZURES LASTING OVER 15

MINUTES TEND TO BECOME
PHARMOCORESISTANT.

SO WE SHOULD PROBABLY TREAT
STATUS EPILEPTICUS WITH

INTRAVENOUS DRUGS AFTER 5
MINUTES OF CONTINUOUS OR

REPEATED PATIENT MOTOR
SEIZURES WITHOUT RECOVERY OF

CONSCIOUSNESS BETWEEN SEIZURES.

IF WE DO THAT, WE KNOW THAT
NOT ALL PATIENTS ARE IN

STATUS, BUT THE RISK OF THE
PATIENT DEVELOPING STATUS OR

BEING IN STATUS IS HIGH ENOUGH
THAT IT JUSTIFIES THE RISK OF

INTRAVENOUS TREATMENT.

WE SHOULD NEVER TREAT A
SINGLE SEIZURE WITH

INTRAVENOUS DRUGS.

THEY HAVE DANGERS.

AND FOR A SINGLE SEIZURE, EVEN
THOUGH THE SEIZURE IS SCARY AND

SPECTACULAR, WE SHOULD NEVER
TREAT IT WITH INTRAVENOUS

DRUGS, BECAUSE WE DON'T NEED TO
RUN THAT RISK OF THE

COMPLICATIONS OF
INTRAVENOUS TREATMENT.

BUT IF YOU SEE 5 MINUTES OF
CONTINUOUS SEIZURES OR

REPEATED SEIZURES WITHOUT
RECOVERY OF CONSCIOUSNESS

BETWEEN THE SEIZURES, THAT MEANS
THAT STATUS EPILEPTICUS IS

IMPENDING, IN THE WORDS COINED
BY JAMES CHEN, AND THAT THE RISK

OF STATUS BEING THERE OR
DEVELOPING IS HIGH ENOUGH TO

JUSTIFY THE RISK OF
INTRAVENOUS TREATMENT.

SO THAT MEANS WE KNOW PRETTY
WELL WHO TO TREAT.

UH...HOW DO WE TREAT?

NOW THAT WE HAVE DECIDED THE
PATIENT HAS BEEN SEIZING FOR 5

MINUTES, WE NEED TO TREAT,
HOW DO WE TREAT?

WELL, THE FIRST THING TO DO IS
NOT TO GIVE INTRAVENOUS DRUGS.

SINCE STATUS EPILEPTICUS IS A
CONDITION THAT STOPS BREATHING

DURING THE TONIC SEIZURES AND
CAN CAUSE A DECREASE IN BLOOD

PRESSURE--IT CAUSES AN
INCREASE INITIALLY BUT LATER A

DECREASE--AND CAN CAUSE A LOT
OF MEDICAL COMPLICATION, WE

HAVE TO FIRST MAKE SURE THAT
THE AIRWAY IS MAINTAINED.

IT'S VERY COMMON FOR PEOPLE TO
VOMIT AND ASPIRATE DURING

SEIZURES OR TO BE ON THEIR
BACK AND ASPIRATE.

AND IT IS VERY COMMON FOR THE
BLOOD PRESSURE TO BE TOO HIGH

OR TOO LOW.

SO FIRST WE HAVE TO MAKE SURE
THAT THEY CAN BREATHE AND THAT

THEIR BLOOD PRESSURE IS OK.

AND WE HAVE TO START AN
INTRAVENOUS LINE SO THAT WE

CAN GIVE DRUGS AND DRAW BLOOD.

IN THE HOSPITAL, WHERE WE DEAL
WITH A HIGH PERCENTAGE OF

PEOPLE WITH ALCOHOL ABUSE AND A
HIGH PERCENTAGE OF DIABETICS,

WE SHOULD PROBABLY TREAT
PATIENTS FIRST BY INJECTING

GLUCOSE AND VITAMINS AS WELL
SO THAT WE PROTECT THEM FROM

HYPOGLYCEMIA AND FROM THE
COMPLICATION OF GLUCOSE

TREATMENT IN SOMEONE AS
DEFICIENT IN VITAMIN B1 AS

MANY ALCOHOLICS ARE.

AND THEN WE INJECT INTRAVENOUS
ANTICONVULSANTS.

WE RECOMMEND MANY TREATMENTS,
AND WE WILL SEE IN A MINUTE

SEVERAL TREATMENTS WHICH
ARE ACCEPTABLE.

THE ADVANCED TREATMENTS WHICH

HAVE BEEN VALIDATED ARE...
[INDISTINCT] ALONE, LORAZEPAM,

PHENOBARBITAL ALONE--WHICH I
PERSONALLY DON'T LIKE--VALIUM,

FOSPHENYTOIN,

DIAZEPAM/FOSPHENYTOIN,

AND PHENYTOIN

ALONE WAS SHOWN IN THE VA
COOPERATIVE TRIALS TO BE

INFERIOR TO THOSE 3 TREATMENTS.

SO ANY OF THOSE 3 ARE
QUITE ACCEPTABLE.

OUR PERSONAL RECOMMENDATION IN
PRACTICE IS TO COMBINE A

BENZODIAZEPINE--CAN BE EITHER
VALIUM, ATIVAN, OR VERSED--

IN THIS CASE, WE SAY VERSED--

AND COMBINE IT WITH
FOSPHENYTOIN,

WHICH IS A PRODUCT WHICH
GENERATES PHENYTOIN.

BUT THERE ARE
LOCAL COMPLICATIONS.

SO IF YOU SWITCH TO SLIDE 22,
IT WILL SHOW YOU THE LIST OF

MEDICAL COMPLICATIONS AND THE
TESTS YOU SHOULD RUN TO AVOID

THEM ON THE INITIAL
EVALUATION.

AND NEXT SLIDE, NUMBER 23,
SHOWS YOU HOW WE DECIDE TO

TREAT WITH ONE DRUG
VERSUS TWO DRUGS.

BOTH ARE ACCEPTABLE,
WE ARE SAYING.

THE VA COOPERATIVE STUDY
SHOWED NO DIFFERENCE BETWEEN

LORAZEPAM AND DIAZEPAM
COMBINED WITH PHENYTOIN

OR BETWEEN THOSE AND
PHENOBARBITAL.

SO WHAT'S BEST?

WE DON'T REALLY HAVE TYPE
I EVIDENCE

TO TELL US WHAT'S BEST.

THIS TREATMENT WASN'T
SPECIFICALLY EQUIVALENT

IN THE VA COOPERATIVE STUDY.

HOWEVER, PERSONALLY, I DID NOT
GIVE DIAZEPAM IN COMBINATION.

AND THERE HAVE BEEN SEVERAL
STUDIES SHOWING A COMPARISON

BETWEEN LORAZEPAM AND
DIAZEPAM, AND THEY SHOW THEM

TO BE EQUALLY GOOD.

SO BASICALLY WE HAVE A CHOICE.

MANY DRUGS, AS SHOWN IN THE
NEXT SLIDE, SLIDE 24, ARE

CURRENTLY AVAILABLE IN
INTRAVENOUS FORM, BUT MANY OF

THEM ARE NOT ACCEPTED BY THE
FDA AS INDICATED FOR STATUS

EPILEPTICUS.

NEXT SLIDE, WHICH IS SLIDE 25.

IF WE COMPARE DIAZEPAM,
LORAZEPAM, AND MIDAZOLAM

AND ASK WHICH IS THE BETTER
DRUG FOR INITIAL TREATMENT OF

ACUTE SEIZURES AND STATUS,
DIAZEPAM IS THE FASTEST-

ACTING, BUT IT GETS INTO BRAIN

VERY, VERY QUICKLY AND THEN
REDISTRIBUTES BECAUSE IT'S SO

SOLUBLE IN FAT, [INDISTINCT]
TO GENERAL BODY FAT.

SO YOU COULD SEE HOW THE
INITIAL PEAK IN BRAIN IS AN

ASSET, BUT IN PRACTICE, THE
SEIZURES STOP, AND THEN THEY

TEND TO RECUR WHEN THE BRAIN
LEVEL GOES DOWN AFTER 15 TO

30 MINUTES.

SO MANY DOCTORS
DON'T LIKE THAT.

THEY THINK THEY HAVE CONTROL
OF THE SEIZURES, AND THEN THEY

HAVE ANOTHER SEIZURE
COMING BACK.

SO MANY NEUROLOGISTS PREFER
LORAZEPAM, WHICH IS A VERY

GOOD DRUG, VERY EFFECTIVE IN
THE VA COOPERATIVE STUDY.

IT'S NOT QUITE AS FAST AS
DIAZEPAM, WHICH IS A

DISADVANTAGE, BUT IT'S OK, AND
FROM A KINETIC VIEWPOINT, IT'S

QUITE ACCEPTABLE.

MY PERSONAL PREFERENCE IS FOR
MIDAZOLAM, WHICH IS VERSED,

BECAUSE IT GETS IN VERY
QUICKLY, LIKE VALIUM--NOT

QUITE AS FAST AS VALIUM.

BUT IT HAS A SHORTER
HALF-LIFE.

SO IF YOU SUCCEED, IT DOESN'T
MATTER WHICH ONE YOU USE.

IF YOU CONTROL THE SEIZURES,
EVERYTHING IS DANDY.

BUT IF YOU DON'T CONTROL THE
SEIZURES, THOSE DRUGS HAVE A

DEPRESSIVE EFFECT ON
RESPIRATION AND CIRCULATION.

SO DEPRESSING RESPIRATION IS
NOT VERY IMPORTANT BECAUSE YOU

HAVE TO INTUBATE THE PATIENT
AFTER THE FIRST TWO DRUGS

FAILED ANYWAY.

BUT DEPRESSING BLOOD PRESSURE
IS CERTAINLY NOT DESIRABLE

BECAUSE YOU WANT TO
PROFUSE THE BRAIN.

SO FROM THAT VIEWPOINT,
MIDAZOLAM,

WHICH HAS A
SHORTER EFFECT, SHORTER HALF-

LIFE, IS BETTER THAN
LORAZEPAM OR DIAZEPAM.

SO LET'S SWITCH TO THE SECOND
DRUG THAT WE INJECT TOGETHER

WITH A BENZODIAZEPINE.

IS PHENYTOIN BETTER THAN
FOSPHENYTOIN?

PHENYTOIN IS MUCH CHEAPER, BUT
THE COST OF ONE DAY IN THE ICU

IS SO HIGH THAT IT IS NOT
PROBABLY A SIGNIFICANT

DIFFERENCE.

FOSPHENYTOIN CAUSES FEWER LOCAL
COMPLICATIONS AND POSSIBLY

FEWER CARDIAC COMPLICATIONS,
ALTHOUGH THAT IS NOT PROVEN.

SO I PERSONALLY FAVOR
FOSPHENYTOIN.

PHENYTOIN, IT DISSOLVES
IN ANTIPHASE.

SO IF THE NEEDLE STAYS IN THE
VEIN, NO PROBLEM, BUT IF IT

GETS OUT OF THE VEIN AND IT'S--
I STARTED TO SAY INTO THE

TISSUES--YOU CAN HAVE
[INDISTINCT]

SYNDROME, AND
THAT'S A PROBLEM.

SO THESE ARE MY
PERSONAL PREFERENCES.

THOSE ARE ACCEPTABLE DRUGS FOR
CONTROLLING SEIZURES.

SO ARE THERE TIMES WHEN YOU
DON'T WANT TO INJECT

THOSE DRUGS?

THE NEXT SLIDE, WHICH IS SLIDE
NUMBER 27, SHOWS YOU SEVERAL

CONDITIONS IN WHICH THE
TREATMENT I JUST RECOMMENDED

SHOULD NOT BE USED.

FIRST, ONE THING YOU HAVE TO
TRY TO DO AS BEST YOU CAN IF A

PATIENT COMES IN IN STATUS IS
GET A HISTORY OF DRUG ALLERGY.

USUALLY YOU DON'T HAVE TIME
FOR A COMPLETE HISTORY OR

FOR A COMPLETE
NEUROLOGICAL EXAMINATION.

YOU WANT TO TREAT QUICKLY, AND
YOU'LL EXAMINE THE PATIENT

LATER, AFTER THE
TREATMENT HAS STARTED.

BUT YOU WANT IDEALLY TO SEE
WHETHER THE PATIENT,

ESPECIALLY IF KNOWN TO HAVE
EPILEPSY, IS ALLERGIC TO ANY

OF THE DRUGS, BECAUSE IF YOU
INJECT INTRAVENOUSLY DRUGS TO

WHICH A PATIENT IS ALLERGIC,
YOU CAN CAUSE FATAL

ANAPHYLACTIC SHOCK.

SO IF THE PATIENT IS ALLERGIC
TO A DRUG, DON'T USE IT.

GET A SUBSTITUTE, AS WE SEE IN
A MINUTE WHICH SUBSTITUTES

ARE ACCEPTABLE.

IF THE PATIENT HAS MYOCLONIC
EPILEPSY--JUVENILE MYOCLONIC

EPILEPSY, WHICH IS RELATIVELY
COMMON; PROGRESSIVE MYOCLONIC

EPILEPSY IS VERY RARE.

BUT PHENYTOIN
OF FOSPHENYTOIN

MAKE THE SEIZURES WORSE, SO
THEY SHOULD NOT BE USED, AND

SHOULD PROBABLY BE REPLACED BY
INTRAVENOUS VALPROATE OR

INTRAVENOUS LEVETIRACETAM.

IF THE PATIENT HAS VERY SEVERE
LIVER DISEASE, YOU CAN STILL

INJECT PHENYTOIN,
FOSPHENYTOIN, AND

BENZODIAZEPINES, BUT THE
BENZODIAZEPINES, EVEN THOUGH

THEY ARE ACCEPTABLE, ARE NOT
IDEAL, BECAUSE [INDISTINCT]

HEPATIC COMA.

SO IT'S PROBABLY BETTER TO USE
LEVETIRACETAM IN THAT

CONDITION INSTEAD OF A
BENZODIAZEPINE, EVEN THOUGH

LEVETIRACETAM IS NOT AN FDA-
APPROVED INDICATION FOR STATUS

EPILEPTICUS.

IN THE RARE--VERY RARE
PATIENTS WITH ACUTE

[INDISTINCT],

YOU MUST USE LEVETIRACETAM
BECAUSE PHENYTOIN ESPECIALLY

IS METABOLIZED BY THE LIVER
AND WILL CAUSE AN ACUTE CRISIS.

BUT THAT'S A VERY
RARE CONDITION.

SO LET'S KEEP GOING.

AND SLIDE NUMBER 28 SUMMARIZES
WHAT I HAVE SAID SO FAR.

IF YOU IMPENDING
STATUS EPILEPTICUS,

JUST 5 TO 15 MINUTES OF
RECURRENT SEIZURES WITHOUT

FULL RECOVERY BETWEEN
SEIZURES, YOU WANT TO TREAT AS

SOON AS YOU CAN, IDEALLY
BEFORE REACHING THE HOSPITAL;

IF NOT, AT LEAST AS SOON AS
YOU CAN IN THE EMERGENCY ROOM.

AND YOU WANT TO TRY WITH A
BENZODIAZEPINE THE 3 DRUGS,

AND THE WAY TO GIVE THEM IS
LISTED IN THAT SLIDE.

AND I.V. FOSPHENYTOIN COMBINED
WITH A BENZODIAZEPINE.

AND THAT IS ESTABLISHED FOR
STATUS EPILEPTICUS.

SO... NOW, WHAT HAPPENS IF
THOSE TWO DRUGS FAIL?

IF YOU FINISH INTRAVENOUS
INJECTION AND THE PATIENT IS

STILL SEIZING, WELL, WE DEFINE
THAT AS REFRACTORY STATUS

EPILEPTICUS, AND THAT IS A
VERY DIFFICULT

CONDITION TO TREAT.

WE SAW AN EARLIER STATISTIC
THAT THE VA COOPERATIVE STUDY

SHOWED THE THIRD DRUG TO BE
EFFECTIVE IN ONLY 2% OF

THE PATIENTS.

SO THAT'S A TOUGH
CONDITION TO TREAT.

BUT...[COUGHS]

WE HAVE MORE DRUGS AVAILABLE
NOW, AND ALSO, GENERAL

ANESTHESIA.

ANESTHESIA WORKED BETTER THAN
A THIRD DRUG IN THE

COOPERATIVE STUDY.

SO WE DEFINE REFRACTORY STATUS
AS A FAILURE OF SEIZURES TO

STOP AFTER INJECTION OF
ADEQUATE AMOUNTS OF TWO

APPROPRIATE ANTICONVULSANTS.

WHAT DO I MEAN BY APPROPRIATE?

IF YOU ARE TREATING SOMEONE
WITH JUVENILE MYOCLONIC

EPILEPSY AND YOU INJECT
PHENYTOIN, THAT'S NOT AN

APPROPRIATE DRUG.

IT DOESN'T COUNT.

IF YOU ARE TREATING WITH,
LET'S SAY, PHENYTOIN, AND YOU

ARE INJECTING ONE GRAM IN A
200-POUND MAN, THAT MOST

LIKELY WILL NOT GET YOU AN
ADEQUATE BLOOD LEVEL.

IN STATUS, WE WANT TO GET A
HIGH BLOOD LEVEL IN A HIGH

THERAPEUTIC RANGE, LOW
TOXIC RANGE.

IT DOESN'T MATTER IF YOU MAKE
THE PATIENT A LITTLE BIT

DROWSY OR [INDISTINCT].

WHAT YOU WANT IS TO STOP THE
SEIZURES AND THE LIFE-

THREATENING CONDITION.

SO YOU WANT TO HAVE
HIGH THERAPEUTIC SERUM

LEVELS OF ANTICONVULSANTS.

SO...AND THAT'S WHAT I MEAN BY
ADEQUATE AMOUNTS.

IF YOUR BLOOD LEVELS OF THE
ANTICONVULSANT YOU USE ARE

AVAILABLE, USE THEM, BUT YOU
SHOULD NOT WAIT FOR BLOOD

LEVELS TO COME BACK BEFORE
CONTINUING THE TREATMENT.

IF TREATMENT STARTS, IS NOT
STOPPED, AND INTRAVENOUS

INFUSION IS COMPLETE, GO
IMMEDIATELY TO THE NEXT

TREATMENT.

AND WE WILL SEE IN A MINUTE
THAT YOU HAVE SEVERAL CHOICES.

SO BY THAT TIME, USUALLY, THE
PATIENT IS HAVING SOME

DIFFICULTY BREATHING, AND
YOU'D BETTER INTUBATE OR AT

LEAST HAVE ANESTHESIA READY TO
INTERVENE IF YOUR NEXT

TREATMENT STOPS BREATHING.

AND YOU SHOULD NOT HESITATE TO
COMPROMISE RESPIRATION.

INTUBATION IS SIMPLE, AND
MAINTAINING A PATIENT ON A

RESPIRATOR FOR A FEW HOURS IS
NO PROBLEM IN THE E.R.

OR THE ICU.

YOU WANT TO MAINTAIN BLOOD
PRESSURE, HOWEVER, IN A NORMAL

RANGE, AND AT WORST ABOVE 90
SYSTOLIC, BECAUSE YOU WANT TO

MAINTAIN BLOOD FLOW TO THE
BRAIN, WHICH IS

BLOOD-PRESSURE-INDEPENDENT
DURING SEIZURES.

SO THE FIRST THING YOU DO IS
MAKE SURE YOU HAVE INJECTED

ENOUGH ANTICONVULSANT.

FOR FOSPHENYTOIN,
FOR EXAMPLE,

YOU DON'T STOP AT 20 MILLIGRAM
PER KILOGRAM OF

PHENYTOIN EQUIVALENT.

YOU GO TO 30 MILLIGRAM PER
KILOGRAM OF PHENYTOIN

EQUIVALENT, WHICH WILL USUALLY
GIVE YOU A BLOOD LEVEL NOT

BETWEEN 10 AND 20, LIKE WE
THINK OF THE USUAL THERAPEUTIC

BLOOD LEVEL, BUT A BLOOD LEVEL
BETWEEN 20 AND 30, WHICH IS

HIGH THERAPEUTIC LOW TOXIC
RANGE.

YOU DON'T WANT TO GO
OVER 30, HOWEVER.

YOU HAVE HAD TIME NOW TO
COMPLETE THE DIAGNOSTIC WORK.

IT IS VERY IMPORTANT TO KNOW
WHAT IS CAUSING THE SEIZURES.

THE MAJORITY OF PATIENTS HAVE
STATUS AS A PHENOMENON AS A

SIGN OF ACTIVE BRAIN DISEASE,
AND YOU WANT TO DIAGNOSE AN

ACTIVE BRAIN DISEASE
AND TREAT IT.

AND THEN YOU HAVE TO DECIDE TO
USE ONE OF THE NEWER

ANTICONVULSANTS WHICH ARE NOW
AVAILABLE I.V. OR TO USE

GENERAL ANESTHESIA AFTER THE
FIRST TWO DRUGS HAVE FAILED.

AND THE NEXT SLIDE, WHICH IS
NUMBER 31, SHOWS YOU THE TESTS

YOU WANT TO ORDER AND THE
THINGS YOU WANT TO DO DURING

THE INTRAVENOUS INJECTION AND
THE EARLY PHASE OF STATUS.

YOU WANT TO GET A DETAILED
HISTORY FROM THE CHARTS OR

FROM THE FAMILY.

THE PATIENT IS USUALLY NOT
ABLE TO GIVE IT.

YOU WANT TO DO A
PHYSICAL EXAMINATION.

YOU WANT TO GET
ANTICONVULSANT BLOOD LEVELS.

YOU WANT TO GET [INDISTINCT]
TO A COMPLETE BLOOD COUNT,

VARIOUS CHEMISTRY, INCLUDING
THE NEUROCHEMISTRY.

YOU WANT TO MONITOR THE HEART.

IF AVAILABLE, YOU WANT TO
MONITOR THE EEG, THE

BRAINWAVES.

THAT'S REALLY...NECESSARY BUT
ALSO IT'S A GREAT COMFORT FOR

THE PHYSICIAN TO HAVE THAT
READY AND KNOW EXACTLY WHAT'S

HAPPENING.

YOU WANT TO MONITOR OXYGEN
SATURATION BY PULSE OXIMETRY,

AND IF NECESSARY,
ARTERIAL BLOOD GASES.

GET A CHEST X-RAY TO SEE IF
ASPIRATION IN THE BODY HAS

OCCURRED, AND GET A TOX SCREEN
BECAUSE, AT LEAST IN MY

HOSPITAL, WE HAVE A LOT OF
DRUG-INDUCED SEIZURES,

PARTICULARLY COCAINE INDUCED,

AND THAT'S ALWAYS A
CONSIDERATION.

SO...WHAT ARE THE OPTIONS?

THE FIRST ONE, IN SLIDE 32, IS
LEVETIRACETAM --BRAND NAME IS

KEPPRA--AND THAT HAS NOW BEEN
USED QUITE A BIT TO TREAT

STATUS, BUT IT DOES NOT HAVE
AN FDA-APPROVED INDICATION.

AND MY USUAL PRACTICE IS TO
INJECT 4 GRAMS.

IT HAS BEEN INJECTED IN NORMAL
HUMAN CASES IN AS LITTLE AS

15 MINUTES.

USUAL PRACTICE IS NO MORE THAN
50 MILLIGRAM PER...MINUTE.

AND THE ADVANTAGE OF THAT
DRUG, IT DOES NOT METABOLIZE

IN THE LIVER AND HAS NO DRUG-
DRUG INTERACTIONS AND DOES NOT

HAVE TOO MUCH EFFECT ON
CONSCIOUSNESS OR

BLOOD PRESSURE.

IT ALSO HAS BEEN SHOWN, NOT IN
HUMANS, BUT IN ANIMALS, TO BE

SYNERGISTIC WITH
BENZODIAZEPINE, WHICH YOU HAVE

ALREADY INJECTED.

SO... THERE HAVE BEEN A NUMBER
OF STUDIES, AND THE RESULTS

REPORTED ARE VERY FAVORABLE
WITH VERY FEW COMPLICATIONS.

WE HAVE ALREADY SAID THAT IT'S
PARTICULARLY GOOD FOR TREATING

MYOCLONIC SEIZURES AND FOR
TREATING PEOPLE WITH

LIVER DISEASE.

SO--AND THIS IS SHOWN
IN SLIDE 33.

SO AN ALTERNATIVE WHICH IS
ALSO VERY GOOD, EXCEPT FOR

PEOPLE WITH LIVER DISEASE, IS
VALPROATE, WHICH IS SHOWN

IN SLIDE 34.

YOU INJECT ALSO ABOUT 40 TO 60
MILLIGRAM PER KILOGRAM, AND IT

CAN BE GIVEN UP TO 50 MILLIGRAM
PER MINUTE.

SO YOU ALSO HAVE THE ADVANTAGE
THAT IT'S PRETTY EFFECTIVE FOR

STOPPING THE SEIZURES.

NOT MUCH EFFECT ON BLOOD
PRESSURE OR CONSCIOUSNESS, BUT

EVEN THOUGH THERE ARE FEW
COMPLICATIONS--PROBABLY THERE

ARE SOME--IT IS DANGEROUS IN
PEOPLE WITH LIVER DISEASE, AND

IT'S DANGEROUS IN THE RARE
PEOPLE WITH MITOCHONDRIAL

MYOPATHIES SUCH AS MERRF, WHO
CAN GO INTO STATUS AND WILL

HAVE [INDISTINCT]

AND USE [INDISTINCT]

FREQUENTLY IF THAT
DRUG IS USED.

SO THERE HAVE BEEN MORE
STUDIES OF VALPROATE THAN

THERE HAVE BEEN STUDIES OF
LEVETIRACETAM, AND THEY ARE

SHOWN IN SLIDE 35.

I WILL SKIP THEM
BECAUSE MANY OF THEM

ARE NOT VERY GOOD, BUT THEY
ALL REPORT VARIABLE RESULTS.

SO... IF YOU DECIDE NOT TO USE
THOSE DRUGS, EITHER BECAUSE

THEY ARE NOT APPROVED BY THE
FDA FOR THAT INDICATION OR

BECAUSE YOU PREFER GENERAL
ANESTHESIA, YOU HAVE THE

CHOICE OF SEVERAL ANESTHETICS.

PROPOFOL IS VERY GOOD.

MIDAZOLAM IS VERY GOOD.

AND THEY ARE SHOWN
IN SLIDE 36.

AND SLIDE 37 SHOWS
PHENOBARBITAL AND

PHENYLBARBITAL, WHICH I PREFER
TO PHENOBARBITAL...WHICH I

ALSO WOULD USE TO INDUCE
GENERAL ANESTHESIA.

AND WHAT YOU DO THEN IS--
UNLESS IT'S OUT OF THE PATIENT

FOR 24 HOURS, STOP THE NEXT
MORNING AND RECODE THE EEG IF

POSSIBLE TO SEE IF THE
SEIZURES RECUR.

I THINK I AM OUT OF TIME, AND
I'D BETTER STOP HERE.

THOSE WHO WANT TO SEE HOW TO
TREAT OTHER FORMS OF STATUS

EPILEPTICUS BESIDES THE MAJOR
MOTOR STATUS WHICH I DETAILED

CAN USE THE REST OF THE SLIDE
PRESENTATION AT LEISURE.

SO THANK YOU FOR YOUR
ATTENTION, AND I DON'T KNOW IF

YOU HAVE ANY TIME
LEFT FOR QUESTIONS.

I THINK I WENT OVER TIME
A LITTLE BIT.

BUT THANK YOU.

- ALL RIGHT.

IF THERE'S NO QUESTIONS,
WE'LL WRAP THIS UP.

I WANT TO THANK YOU, DOCTOR,
FOR DOING THIS.

- THANK YOU.

- AND I'D LIKE TO LET
EVERYBODY ELSE KNOW THAT

YOU'LL SEE SOME INFORMATION
COMING OUT SOON FROM THE

EPILEPSY CENTER FOR
EXCELLENCE TALKING ABOUT THE

NEXT AUDIO CALL COMING UP.

ONCE AGAIN, THANKS, EVERYONE,
FOR JOINING US, AND MAKE SURE

YOU FILL OUT YOUR SURVEY.

THANK YOU.