Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
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effort in training today's investigators and discovering
tomorrow's cures.
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OUR SPEAKERS TODAY INCLUDE Dr.
SEHER ANJUM FROM NIAID AND Dr.
DINA HUMUT OF THE CLINICAL
CENTER AND Dr. GARJAN CLINICAL
FELLOW IN NCI AND PETER WILL
JUMP SON, SENIOR INVESTIGATORS
OF THE UNIT AND NIAID AND
THEY'RE GOING TO PRESENT TWO
SIDES OF THE A DEADLY CURVE,
NEUROLOGICAL POST INFLAMMATORY
DISEASE AND WITH THAT, I'LL LET
Dr. ANJUM TAKE THE STAGE.
>>I'M SEHER ANJUM
WITH NIAID AND OUR TOPIC IS TWO
SIDES OF A DEADLY CURVE
REFERRING TO NEUROLOGICAL POST
INFECTIOUS INFLAMMATORY DISEASE
FOLLOWING INFECTION.
YOU I WILL PRESENT THE CASE AND
Dr. HAMMOUD WILL HAVE
RADIOLOGY FINDINGS AND Dr.
RAJAN WILL SHOW US PATHOLOGY AND
Dr. WILLIAMSON WILL BE
WRAPPING UP.
WE, AS A GROUP, DO NOT HAVE ANY
FINANCIAL DISCLOSURES AND THE
LEARNING OBJECTIVES FOR TODAY'S
TALK WILL BE TO GET TO KNOW THE
CLINICAL FEATURE OF MENINGITIS
AND HEALTHY ADULTS TO
DISTINGUISH WE KNOW IMMUNE
DAMAGE AND THE MANAGEMENT OF THE
CRYPTO COCKAL MENINGITIS.
SO START WITH THIS IS SHE
STARTED HAVING A MEMORY LOSS,
LIGHT SENSITIVITY, WORD FINDING
DIFFICULTY AND DIZZINESS.
HE WAS ADMIT TODAY AN OUTSIDE
MEDICAL FACILITIES IN AUGUST OF
2014 WITH ADDITIONAL SYMPTOMS OF
VOMITING, RIGHT-UPPER EXTREMELY
WEAKNESS, RIGHT-SIDED FACIAL
DROOP AND FATIGUE.
A BRAIN MRI SHOWED A LESION WITH
MILD THE LEFT FRONTAL LOBE
MEASURING 2.4 TO 2.3 CENTIMETERS
AND IT WAS D1 HYPO WITH LESIONAL
ADEMA.
AND SINCE THERE WAS A SUSPICION
FOR MALIGNANCY SHE WENT UNDER A
WITH PATHOLOGY SHOWING REACTIVE
CHANGES AND SHE WAS DISCHARGED
FIVE DAYS LATER AND SHE WAS
ORIENTED TIMES TWO AND STILL HAD
DIFFICULTY AMBULATING.
SO S. SHE WAS READMITTED JUST A
DAY LATER FOR AGITATION AND
DECREASED VERBAL RESPONSE THAT
WAS ATTRIBUTED TO SODIUM OF 123
AND HER HEAD CT SHOWED DILATED
VENT RICKAL AND AN LP ON 6-16-14
HAD AN OPENING PRESSURE OF
WATER, GLUCOSE LESS THAN 20 AND
A CYTO SIS AND HER PROTEIN WAS
446.
HER FUNGAL CULTURES AGREED AND
SHE HAD A POSITIVE ANTIGEN WITH
A TIGHTER OF 156.
SHE WAS STARTED WITH -- SHE
UNDERWENT A VP SHUNT PLACEMENT
ON 9-4-14.
MORE FOR POOR MENTAL STATUS.
NOT FOR AN INCREASE INTRACRANIAL
PRESSURE.
AS PART OF HER IMMUNE WORKUP SHE
HAD A HIV TEST WHICH WAS
NEGATIVE AND A LOW COUNT OF 17.
SHE WAS EVENTUALLY DISCHARGED ON
9-12-14 TO REHAB TO COMPLETE A
COURSE.
AND THEN EVENTUALLY TRANSITIONED
TO 9-27-14.
UNFORTUNATELY, WITHIN THE NEXT
FEW DAYS SHE STARTED TO BE MORE
LETHARGIC AND SHE ALSO STARTED
HAVING RIGHT-UPPER EXTREMELY
JERKING MOVEMENTS AND SHE WAS
TRANSFERRED FROM REHAB ON
10-14-14.
THIS TIME HER LP SHOWED 44 WIDE
SHE HAD A DECREASE BUT HER
PROTEIN WAS 500 AND GLUCOSE OF
40 AND CFS ANTIGEN THAT WAS
GREATER THAN 1 OUT OF 256.
A REPEAT MRI SHOWED BOTH
SURGICAL CHANGES OF THE LEFT
FRONT AT MASS AND A SMALLER
RESIDUAL RING ENHANCE LEASH AN
AND THERE WERE CONCERNS FOR
RECURRENCE OF CRYPTOCOCCAL
INFECTION SO SHE WAS RETARDED ON
MEDICINE.
SO, FROM THEN ONWARDS, SHE
REALLY HAD MULTIPLE RECURRENT
HOSPITALIZATIONS AT THE NIH SO
THE NEXT COUPLE OF SLIDES WILL
ALL BE IN TIMELINE FORMAT.
IN OCTOBER 2014, SHE WAS
TRANSFERRED FROM THE OUTSIDE
FACILITY AND ADMITTED TO THE NIH
WITH LETHARGY.
HER SPINAL FLUID THIS TIME
SHOWED A WORSENING CYTO
ADVERTISE AND HER PROTEIN WAS
GREATER THAN 600 AND SHE HAD A
GLUCOSE OF 21.
SHE WAS WORSENING AND HER CSF
WAS CONSISTENT WITH INFLAMMATORY
MARKERS BEING UP.
SHE STARTED ON ONE GRAM DAILY
FOR SEVEN DAYS FOR POST
INFECTIOUS INFLAMMATORY RESPONSE
SYNDROME AND SHE WAS
TRANSITIONED TO PRED NA ZONE 60
AND DISCHARGED ON 11-21-14.
SO THEN IN JANUARY OF 2015, SHE
WAS READMITTED FOR FOLLOW-UP.
THIS TIME SHE WAS DOING FINE.
SHE ACTUALLY BEEN DECREASED PRED
NA ZONE 40 MILL A GRAMS DAILY
AND HER NEUROLOGICAL EXAM
IMPROVED BUT IMAGING SHE HAD A
NEW RIGHT BASAL GANGLIA LESION
WHICH IS CONCERNING FOR HE IS
KEEPIA.
HER BRAIN MRA SHOWED
STINZIANOOSIS OF HER RIGHT AND
LEFT SUGGESTIVE OF AND AS PART
OF A WORKUP SHE -- FOR WHICH SHE
WAS ON ASPIRIN AND THERAPEUTIC
INITIALLY AND THEN TRANSITIONED
TO A DIRECT INHIBITOR.
AND THEN SHE WAS DISCHARGED ON
1-10-2015.
SO THEN IN FEBRUARY OF 2015, SHE
RETURNED FOR JUST TWO DAYS.
SHE HAD DEVELOPED DOR SAL FOOT
ULCERS THAT WERE NOT INFECTED.
SHE WAS GIVEN SOME LACE I CANS
THAT WAS PROBABLY AT TAUGHTED TO
STEROID USE AND SHE WAS
DISCHARGED AND DOING WELL.
IN MARCH 2015, SHE RETURNED AND
WAS INITIALLY ADMITTED TO THE
OUTSIDE MEDICAL FACILITY WITH
RIGHT LOWER EXTREMITY WEAKNESS.
AND SHE ALSO HAD A FACIAL PULSE.
HER MRI BRAIN WAS UNI MARKETABLE
BUT THERE WERE CONCERNS FOR A
RECURRENCE OF HER NEURO
INFLAMMATION SO HER PREDNISONE
WAS INCREASED TO 60 MILL A GRAMS
DAILY.
AND THEN, SHE WAS ADMITTED TO
THE NIH A WEEK LATER WITH TWO
NEW FARCS WITH SHE WAS PULSED
AGAIN WITH SOL YOU MED RAL
TRANSITIONED TO PREDNISONE 60
DAILY.
HER HOSPITAL COURSE WAS
COMPLICATED AND SHE CONVERTED TO
NORMAL RHYTHM SPONTANEOUSLY AND
FOUND TO HAVE EXPANSION OF RIGHT
DBT SO FEMALERRAL VEIN AND HER
CHEST SHOT A CLOT IN HER
ARTERIES AND SO IT WAS THOUGHT
THAT THIS WOULD PROBABLY BE
BECAUSE OF FAILURE SO SHE
STARTED ON THERAPEUTIC LOVONOX
AND TRANSITIONED TO WARFRIN.
HER MENTAL STATUS IMPROVED BUT
SINCE SHE WAS ON STEROIDS FOR SO
LONG, IT WAS THOUGHT TO DO A
STEROID SPARING TRIAL AND SHE
WAS DISCHARGED ON 4-7-15 AND
RETURNED MAY 20-15 WITH FOOD
ULCER PAIN AND GIVEN LAY SIX AND
WE ALSO HAD TO MAKE MEDICATION
CHANGES SINCE HER LFTs WERE UP
ALMOST FIVE TIMES AND SHE WAS
TRANSITION FROM DRUGS AND HER
DUMA DIN DOSE WAS TRANSITIONED
FROM TWO TO FIVE ON HER INR AND
SHE WAS FOLLOWING UP AT THE DUMA
DIN CLINIC.
AND THEN IN JUNE OF 2015, SHE
WAS READMITTED AGAIN FOR
WORSENING MEDICATION.
RHEUMATOLOGY WAS CONSULTED AND
THOUGHT IT WAS A POST AND THEY
RECOMMENDED SIGH CO PHOSPHO
MIGHT AND STEROIDS FOLLOWED BY
PREDNISONE.
ON 6-15-15 SHE WAS UNRESPONSIVE
WITH A RAPID RESPONSE BEING
CALLED.
SHE WAS THEN EMERGENCY
TRANSFERRED TO THE ICU AND
INTUBATED AND HYPER VENTILATED
TO A TARGET OF 20 AND GIVEN
MANATOL FOR CEREBRAL ADEMA AND A
HEAD CT SHOWED A MASSIVE LEFT
HEM OR AGE AND HER INR WAS FOUND
TO BE THREE AND QUICKLY
NORMALIZED WITH FFB WITHIN FIVE
HOURS OF THE RAPID RESPONSE
BEING CALLED.
AND THIS WAS A BRISK MASSIVE AR
TERRAL BLEED SO THERE WAS LITTLE
BENEFIT FROM INTERVENTION AND
THE PATIENT EXPIRED ON 6-26 IN
THE AFTERNOON WHICH AFTER AN
AUTOPSY WAS PERFORMED.
THAT'S HER HOSPITAL COURSE AND
Dr. HAMM OUTAOUAIS D WILL BEMOU.
SO MANY OWE LENS.
>> SOME OF THE IMAGE FUNDINGS ON
OUR PATIENT.
THIS IS THE FIRST IMAGING STUDY
WE HAVE ON HER ON FILE WHERE A
PRE OPERATIVE PLANNING STUDY WAS
PERFORMED WITH POST IMAGES ONLY
AND AT WHICH POINT YOU CAN SEE
THAT THERE'S A LEFT FRONTAL RIM
ENHANCING MASS AND SURROUNDED
WITH A BIT OF ADEMA AND
ASSOCIATED WITH MID LINE SHIFT.
WE CAN SEE THERE'S A LITTLE BIT
OF CSF AND VENT RICK ALS AND IF
YOU LOOK CAREFULLY AT THE
RETRUCK YOU CAN SEE THAT THE
ASPECT OF THAT LEASH AN IS
CONTINUOUS WITH MENG ALLEN
HANCEMENT ALONG THE CISTERN ANDE
PATIENT WAS DIAGNOSED ALMOST A
WEEK LATER AND STARTED ON
ANTIFUNGALS AND THIS WAS THE
FIRST POSTOPERATIVE MRI
EXAMINATION AND I CAN NOTICE THE
PATIENT HAD A LOT OF MOTION SO
THIS IS NOT THE BEST EXAM, THIS
IS PERFORMED ON OUTSIDE BASIS.
THE LESION WHICH WE SAW IN THE
LEFT FRONTAL LOBE DECREASED IN
SIZE AND IT STILL SHOWS
ENHANCEMENT OF THE RIM BUT THE
COMPONENT IS SHOWING RESTRICTED
DIFFUSION CONSISTENT WITH EXITED
OR CONTENT AND WHICH WE COMMONLY
SEE IN CRYPTO AND HER
HYDROCEPHALUS HAD WORSENED
SIGNIFICANTLY AND IT HAD BECOME
MORE EVIDENCE AND AS WELL AS
POSTOPERATIVE CHANGES.
SHE WAS SHUNTED FOR
HYDROCEPHALUS AND WHEN SHE
PRESENTED HER FIRST TIME TO NIH,
SHOULD WAS THE FIRST OUR
EXAMINATION WE DID HERE.
ON TOP HERE, YOU HAVE IMAGES AND
THE SECOND ROW IS POST CONTRA
IMAGES SO FLARE IMAGES ARE
IMAGES WHERE WE SUPPRESS THE
SIGNAL OF THE CSF SO IT'S EASIER
TO SEE ABNORMAL SIGNAL
ASSOCIATED WITH ADEMA OR WITH
GLEOSIS LIKE YOU SEE HERE IN THE
BRAIN STEM.
HERE, AT NIH, WE PERFORMED THOSE
STUDIES WITH POST CONTRAST.
THIS IS NOT A STANDARD PROCEDURE
ON THE OUTSIDE BUT WE HAVE FOUND
IT TO BE SENSITIVE FOR DID HE
TECHION OF SUDDEN ABNORMALITIES,
WHEN YOU ARE WORRIED ABOUT MILD
MENINGITIS OR MAYBE CARCINOMA
MATOSIS.
ENOUENOUGHTHE RIGHT HEMISPHERE O
LEFT FRONTAL REGIONS THERE'S A
LOT OF ENHANCEMENT ALONG THE
BASE STEM STRUCTURES AND THE
SISTERS AND ALSO ALONG THE
CIRCLE OF ACAs AS WELL AS
MCAs AND ENHANCEMENT IN THE
INTERNAL AUDITORY CANALS AND THE
POST CONTENT FLARES AS I SAID,
SHOW THE ENHANCEMENT TO A LITTLE
BIT MORE AND THEN YOU CAN
IDENTIFY AREAS OF ADEMA IN THE
ADJACENT STRUCTURES INCLUDING
THE CORTICAL RIBBONS AND MID
BRAIN.
THERE WAS EVIDENCE OF A PENDULUM
ENHANCEMENT WITH THIS.
AN MRI WAS ALSO PERFORMED OF THE
SPINE AND THESE ARE POST
CONTRAST IMAGES AND YOU CAN SEE
THAT THE NERVE ROOTS ARE THICK
END AND ENHANCING AND THERE'S
ENHANCEMENT AND ON THE ACTION I
WILL IMAGES THEY'RE ALL MATTED
AND STRONGLY ENHANCED CONSISTENT
WITH THE SEVERE AND MENINGITIS.
SO, THE PATIENT WAS STARTED ON
TREATMENT AND THE FOLLOW-UP
EXAMINATION WAS IN JANUARY OF
2015 AT WHICH POINT YOU CAN SEE
IMAGES THAT THERE WAS COMPLETE
RESOLUTION OF THE ENHANCEMENT ON
FLARE HOWEVER YOU CAN STILL SEE
RESIDUAL MENG ALLEN HANCEMENT
AND THE FISHERS ON THE SOUTH
SIDE AND THE ENHANCEMENT IS
DIFFERENT.
THIS IS BECAUSE OF SHUNTING BUT
THE MEN GEE ALLEN HANCEMENT WAS
THERE AND WE OBTAIN TO WHICH IS
THE HE IS KEEPIA AND ALSO IN
OTHER SITUATIONS YOU CAN SEE
THAT THIS LEASH AN HAD INFUSION
CONSISTENT WITH EARLY SUBACUTE
AND THERE WERE A FIE OTHER
DIFFUSION IN THE AS WELL AS IN
THE PAWNS WHICH SEEM TO BE
SLIGHTLY OLDER.
ALL OF THESE WERE CONSISTENT
WITH THE DISTRIBUTION OF THE
ARTERIES AND THE PER FER
EIGHTING BRANCHES.
AND MRA WAS PERFORMED TWO DAYS
LATER AND AS CAN SEE, THE LEFT
MCA IS MARK HE HADLY ABNORMAL
AND THERE'S MARKED IRREGULAR LAR
TEE AND FOCAL AREA OF STENO SIS
AND A SLIGHTLY LESS APPRECIATION
OF THE BRANCHES AND ON THE RIGHT
SIDE IT SHOWED IRREGULARITIES
AND NOTHING SIMILAR TO THE LEFT
MCA.
I'M SHOWING THE FUSION WEIGHTED
IMAGES FROM MULTIPLE STUDIES,
THIS ONE WE FIRST SAW AND AS
EXPECTED OVER TIME, THESE AREAS
INCREASED SIGNAL WOULD DISAPPEAR
AND ON THIS EXAMINATION YOU
DON'T SEE THEM ANYMORE BUT THEN
IN MAY, SHE PRESENTED WITH
SYMPTOM TOLL GEE WITH BRAIN STEM
INVOLVEMENT AND WE IDENTIFIED
RESTRICTED DIFFUSION IN THE
BRAIN STEM.
AND THE MID BRAIN.
FOLLOWING THAT, SHE PRESENTED IN
JANUARY THERE WAS ALMOST 10 DAYS
BEFORE SHE PASSED AWAY AND THAT
WAS HER LAST MRI EXAMINATION AND
AT THAT POINT THERE WERE NO
SIGNS RESTRICTED DIFFUSION.
YOU CAN SEE THAT THE LAST MRA
SHOWED IMPROVEMENT.
YOU CAN SEE NOW BETTER
ENHANCEMENT AND THERE'S STILL
IRREGULARITY AND STINZIANOOSIS
AND INVOLVEMENT OF THE LEFT MCA
AND
AND THE ARTERY AND THESE ARE
OTHER SEQUENCES ON HER LAST MRI
AND THIS IS THE -- YOU CAN SEE A
MUCH BETTER EXTENT AND YOU CAN
SEE IT ALONG THE FOLIA ALONG THE
FRONTAL CELL SIDE AND THE LEFT
FRONTAL REGION AND YOU CAN STILL
SEE IT ALONG THE LEFT MCA TRACKS
THIS IS MAGNIFIED VIEW COMPARED
TO OF A NORMAL PATIENT WITH THE
SAME EXACT PARAMETERS AND THE
SAME TIME PERIOD.
THIS ENHANCEMENT IS MENGAL AND
IT'S DIFFICULT TO TELL WHETHER
THERE'S INVOLVEMENT OF THE
VESSEL WALL AND THERE'S
ENHANCEMENT ON THE RIGHT SIDE.
IT'S A MASSIVE BLEED.
THE ADEMA SURROUNDING IT IS
CONFORMING TO THE FORM OF THE
SHAPE OF THE HEMATOMA SUGGESTING
IT'S AN ACTUAL THERE WAS A LOT
OF MASS EFFECT, MID LINE SHIFT,
COMPRESSION OF THE VENTRICLES
AND THE BASIL SYSTEMS AND
COMPASSION OF THE FORCED
VENTRICLES SUGGESTING THERE'S
EARLY HERNIATION.
THE PATIENT PASSED AWAY ONE DAY
LATER.
WE DESCRIBED IN PATIENTS WITH
MENINGITIS.
WE HAVE REALLY IDENTIFIED WHAT
WE REFER TO AS CRYPTOCOCCAL
MENINGITIS AND LESIONS, AND THE
LEASHANCE SEEN IN THE BASIL
GANGLIA WITH OR WITHOUT
ENHANCEMENT AND WE SEE THEM
QUITE A BIT IN THE CORTICAL
REGIONS IN CLOSE TO MENINGEAL
ENHANCEMENT.
IF YOU HAVE SICK MENINGEAL
ENHANCEMENT YOU SEE IT VERY
NICELY ON THE IMAGES BUT
SOMETIMES WE ONLY SEE IT OR SEE
IT ON MUCH BETTER EXTENT ON THE
FLARE IMAGES AS YOU CAN SEE HERE
AND TWO SPECIFIC FINDINGS FOR
CRYPCRYPTOCOCCAL MENINGITIS WHIH
EVERY NOW AND THEN IS ASSOCIATED
WITH ADHESIONS AND ENTRAPMENT OF
PORTIONS OF THE VENTRICLES.
THE VAAS LIEU LAR INVOLVEMENT IS
LESS WELL DESCRIBED AND THERE
ARE REPORTS OF PRESENTATIONS
SIMILAR TO OUR PATIENT WHERE
THEY HAVE BEEN DESCRIBED IN THE
BASE SAL GANGLIA AND THOSE ARE
SUPPOSED TO BE DUE TO
INFLAMMATORY CHANGES INVOLVING
ARTERIES AND LIKE THE TRY EIGHT
FOR EXAMPLE AND BECAUSE OF THE
IT'S LESS COMMONLY REPORT AND WE
HAVE TWO CASES AT LEAST NOW AND
WITH THE PRESENTATION AND
HOWEVER IT'S RARE.
WITH THAT I'D LIKE TO CONCLUDE.
THANK YOU AND Dr. RAJAN WILL
SHOW THE PATHOLOGY FINDINGS.
>> THANK YOU Dr. HAMMOUD.
SO WE WILL NOW GO OVER THE NEURO
PATHOLOGICAL FINDINGS FOR THIS
PATIENT.
THE FIRST IS THE LEFT SIDE OF
THE SO THE SCALP HAS BEEN
REFLECTED AND IT'S BEEN OPEN
TRANSVERSANCE AND THE LARGE CLOT
WAS IDENTIFIED OVER THE LEFT
HEMISPHERE AND THIS WAS A LARGE
PRESSURIZED CLOT.
THE BRAIN WAS EXTRACTED AND IT
WEIGHED 1,120 GRAMS FRESH AND
AND IN CROSS EXAM, CONGESTION OF
THE LIP TOE MINUTE VESSELS WERE
AND A LARGE LESION WAS
IDENTIFIED WITH DISTORTION OF
THE A MOVING OVER TO THE VESSELS
OF THE CIRCLE AND HERE WE CAN
IDENTIFY THE BASIL ARTERY AND NO
FINDINGS OF SCLEROSIS WAS NOTED.
HERE ON THE LEFT SIDE WE HAVE A
TRANSVERSE SECTION OF THE SERRE
BELL UM AND THIS IS A FRESH
SECTION AND ON THE RIGHT SIDE
HERE, WE HAVE THESE CAN BE SEENN
THERE'S DOWNWARD MISPLACEMENT
CAUSING TRACTION OF THE
PENETRATING VESSELS RESULTING IN
HEMORRHAGE AND AREAS OF NECK ROW
SIS AND THESE ARE CALLED TO
RIDGES.
THIS IS THE SPINAL CORD.
HEMORRHAGE WAS SEEN AND BOTH AT
THE CERVICAL AS WELL AS THORACIC
LEVELS.
AND NEXT WE MOVE ONTO THE IMAGES
THAT THE FIRST SECTION THAT WE
HAVE IS THAT OF THE LEFT
KAWARTHA TECORTEX ANDTHIS IS THE
MATTER AND THE RIGHT SIDE THIS
IS A LARGE AREA OF INTRA CRANIAL
HEMORRHAGE.
THIS IS ANOTHER SECTION OF THE
LEFT CORTEX AND VASCULAR
CONGESTION AS WELL AS HEMORRHAGE
IS BEING HIGHLIGHTED HERE.
THIS IS A SECTION OF THE THIN
WALL VESSEL WITH SER UNDERRING
AREAS OF NECROSIS WITHIN THE
POINTS.
ON THE LEFT SIDE HERE, WE HAVE A
CROSS SECTION OF THE ARTERY AND
ON THE RIGHT WE HAVE THE VESSELS
AND IF WE FOCUS CLOSELY ON THE
BASSLAR ARTERY WE CAN SEE THE
INTERNAL ELASTIC SO IT'S THE
MEDICINE YAN AND THE
ADVANTAGEOUS AND THE ARTERY
APPEARS THICK END AND EVEN ON
LOW POWER WE CAN SEE
INFLAMMATORY CELLS SURROUNDING
BOTH THE BASILAR ARTERY AS WELL
AS THE HELP TOE VESSEL SO WE
HAVE INFLAMMATORY CELL
SURROUNDING IT AND THEY ARE
HIGHLIGHTED WITH THE CD68 AND B
AND T CELLS HIGHLIGHTED ON CD20
AND CD3 IMMUNO SO IT'S A MIXED
INFLAMMATORY THAT WAS IDENTIFIED
SURROUNDING THE VESSELS.
HERE WE HAVE AN H AND E SECTION
OF THE THESE ARE BUDDING FORMS
OF VARIOUSES CRISIS WITH THICK
CAPSULE AND THIS IS CRYPTOCOCCAL
ORGANISMS AND THEY WERE SEEN
SURROUNDING THE VESSELS.
THIS IS A SECTION OF THE AGAIN
WE CAN SEE SEVERAL CRYPTICAL
ORGANISMS AND FOCAL AREAS OF THE
NECROSIS AND THIS IS WITHIN THE
PROSECUTE' AND THIS IS A RGMS
AND AGAIN THIS IS A CROSS
SECTION OF THE VESSEL AND IT
HIGH LIGHTS THE BUDDING YEAST
FORMS IN THESE DARK BROWNISH
BLACK COLOR AND AS WELL AS THE
VESSEL WALL THIS IS A HIGHER
POWER IMAGE AGAIN HIGHLIGHTING
THE ORGANISMS ON SILVER STAIN
AND AND OWN HISTOLOGY AS WELL
THESE ARE THE PLOTS WITH AN AREA
OF HEMORRHAGE AND UPON DOING A
STAIN, CRYPTOCOCCAL ORGANISMS
WERE IDENTIFIED WITHIN THE BLOCK
AS WELL SO MOVING FORWARD TO THE
SUMMARY OF THE FINDINGS, THIS
PATIENT HAD A INFRACTION AND AND
HEMORRHAGE AND HEMORRHAGE IN THE
BONDS AND AND THANK YOU VERY
MUCH AND Dr. WILLIAMSON WILL
TAKE OVER FROM NOW.
>>ALL RIGHT, THANK YOU, VERY
MUCH.
THOSE ARE TERRIFIC
PRESENTATIONS.
IT'S VERY COMPLICATED CASE, LET
ME SEE IF I COULD PROVIDE OF A
CONTEXT AND SUMMARY OF THE WORK
THAT'S BEEN DONE ON THIS DISEASE
AT NIH.
SO, THIS IS SUMMARIZED QUICKLY,
THIS IS A 64-YEAR-OLD PREVIOUSLY
HEALTHY FEMALE DEVELOPS
CRYPTOCOCCAL MENINGITIS AND THEN
WITH CLINICAL WORSENING THE
TERMINAL EVENT OF A HEMORRHAGE,
SO THE NUMBER OF COM REFLECTING
COMPLICATING FACTORS HERE AND
THIS WAS SEVEN OR EIGHT YEARS
AGO AND SOME OF THE CASES THAT
COMPLICATE THIS IS WE HAVE
INFECTIOUS ORGANISMS, AND WE
HAVE A POST INFECTIOUS
INFLAMMATORY RESPONSE SYNDROME
AND THIS IS THE DEADLY CURVE
THAT OUR TITLE CAME FROM.
AND BASICALLY I'M GOING TO TALK
ABOUT THIS A LITTLE BIT MORE IN
DETAIL.
WHEN YOU HAVE AN INFECTION, A
NEUROLOGICAL INFECTION, EARLY
ON, YOU HAVE INCREASED FUNGAL
CULTURES AND YOU HAVE A LOT OF
DAMAGE FROM THE ORGANISMS ITSELF
PRODUCING PRODUCTS, DIGESTING
AND THEN AS YOU KILL THE FUNGUS,
IN CRYPTOCOCCAL, YOU HAVE
RELEASE OF ALL THESE FUNG ALAN
TEE AGAINS THAT CULTURES ARE
NEGATIVE BUT YOU HAVE AN
INFLAMMATORY RESPONSE THAT COMES
IN INTO THE BRAIN AND CAUSES
IMMUNE DAMAGE FROM THAT AND THE
QUESTION IS, AT ANY GIVEN TIME,
IS WHERE ARE YOU ON THIS CURVE.
WE ALSO HAVE AN ADDITIONAL
EFFECT OF THE VAAS CUE ON AGENT'
AND COULD DEAL WITH BOTH AND YOU
HAVE NEURO VASCULAR DISEASE AND
WE HAVE COMPLICATIONS OF THOM
BOW SIS AND ANTI COAGULATION.
IF YOU THINK ON THAT AUTOPSY, I
SEE ALL THOSE ORGANISMS AND IT
MUST HAVE BEEN THE FUNGUS WAS
GROWING AND IT WASN'T BEING
CONTROLLED AND THE FUNGUS IS NOT
LIKE A BACTERIA THAT JUST
DISAPPEARS OR PROTOZONE WHEN IT
SKILLS IT DISAPPEARS, THE FUNGAL
FORMS STAY IN THE BRAIN FOR A
LONG TIME.
JUST TO ILLUSTRATE THAT FACT,
HERE IS ANOTHER PATIENT WHO DIED
10 YEARS AFTER THEIR
CRYPTOCOCCAL INFECTION OF
UNRELATED CAUSES AFTER ANTI FUNG
ALS AND STABLE BUT YOU CAN SEE
THESE ALONG THE CHANNEL IN THE
BRAIN.
IT LOOKS LIKE AN ACTIVE
INFECTION THAT WAS JUST
HAPPENING YESTERDAY.
IT CAN BE DIFFICULT.
AND THE CREATION OF BIOMARKERS
IS REALLY CRITICAL.
SO LET'S PULL BACK A LITTLE BIT
AND JUST A LITTLE REVIEW OF WHAT
CRYPTOCOCCAL IS.
IT'S SOIL OF BIRDS WE ACQUIRE
THIS WHEN WE WERE FIVE-YEARS-OLD
DRAWING AROUND ON THE DIRT AND
IT'S A REACTIVATION DISEASE IN
MANY OF THESE CASES, PROBABLY
10% OF US HAVE A LIVE FUNGUS IN
OUR LUNG.
IT'S THAT COMMON.
AND IT SITS THERE AND IT'S LIKE
TB BUT NOT AS VIRULENT AND WE
GET SUPPRESSED FOR WHATEVER
REASON, GENETICALLY, WITH AGE OR
WITH HIV, OR WITH STEROIDS, THEN
YOU CAN REACTIVATE.
IF THE PULMONARY PRESENTATION
CAN COMPOSE OF INFRILL TRAITS
THE NODULES AND INSEV LIGHT US
IS A BAD THING AND THE NEURO
TROPPISM OF THIS ORGANISM IS
REALLY IMPRESSIVE AND IT'S
RELATED TO A NUMBER OF THINGS
INCLUDING THE ABILITY TO INVADE
THE NEURO VASCULAR AND HERE IS
WORK FROM Dr. FUNG CHUNG'S LAB
IN LCIM WHERE SHE CHOSE THE
FUNGUS BEING TAKEN OUT AND OVER
HERE ON THE RIGHT WE HAVE A
FRESH SAMPLE OF BRAIN AND YOU
CAN SEE THIS HAZINESS IS NOT
BECAUSE OF FIXATION OR BECAUSE
OF ANY ARTIFACTS, BUT THIS IS
THE ORGANISM AND THE
INFLAMMATION THAT CAN OBSTRUCT
IN THE SEVERE ASPECT OF THE A
RACK NODE VILLY SO THIS IS
REALLY -- NOW, YOU THINK THIS
CRYPTOCOCCAL IS SO RARE BUT NOW
BECAUSE OF THE CRYPTO COCK US
BECAUSE OF THE VACCINES OF THE
PATHOGENS, CRYPTOCOCCUS AS
STAYED THE GAME AND IT'S THE
MOST COMMON NON VIRAL MENINGITIS
IN THE UNITED STATES.
SO LET'S COME BACK TO THIS
DEADLY CURVE A LITTLE BIT.
WHAT WE'VE BEEN ABLE TO DO
BECAUSE OF THE REALLY THE
SPECIALIST OF THE NIH CLINICAL
CENTER, IS WE'RE ABLE TO SEE
PATIENTS AT THE BEDSIDE AND
WE'RE ABLE TO DO PRETTY
EXTENSIVE IMMUNO PHENOTYPING OF
THE PATIENT WITHIN AN HOUR AND
CSF DOES NOT LAST VERY LONG SO
IT'S REALLY IMPORTANT.
WE DID THIS IN COLLABORATION
WITH OUR LARGER LABORATORY AND
DEVELOPED A LOT OF THESE
PROTOCOLS FOR MULTIPLE
SCLEROSIS.
WE WERE ABLE TO FIND A NEW
SYNDROME OF POST INFECTIOUS
INFLAMMATORY RESPONSE SYNDROME
AND WE DEFINED AS FOUR WEEKS IN
THE EFFECTIVE ANTI FUNGALS AND
CSF FUNGAL CULTURES NEGATIVE,
DECLINING MENTAL STATUS AND WE
USED A MOCA SCORE MONTREAL
COGNITIVE AND I WOULDN'T SUGGEST
IT FOR PRESIDENTS BUT YOU DRAW
CLOCKS AND YOU HAVE TO MEMORIZE
THINGS AND DO SERIAL AND IT
GIVES YOU A NICE NUMEROUS I
CANAL ASSESSMENT OF HOW
COGNITIVE AWARE YOU ARE.
ALSO, IN ADDITION TO DECLINING
MENTAL STAGE AND PROGRESSIVE
HEARING DEFICITS, AFTER THESE
CULTURES ARE BECOMING NEGATIVE
AND THE REASON WHY THE MO CA22
IS SO IMPORTANT IS IN A
COLLECTION OF 25 CENTERS WE DID
WITH KAREN AND JOHN HOPKINS THE
LOW MOCA SCORE OF 22 YOU CAN SEE
MANY OF THEM DO NOT ACHIEVE A
NORMAL MOCA SCORE AT END
WHEREAS, PEOPLE ABOVE 22 DO
FINE.
IT'S A NICE MARKATOR OF THE
DISEASE.
AND OF COURSE, WE WERE ABLE TO
CHARACTERIZE THE IMMUNE SYSTEM
BY CLOSE CYTOMETRY AND I REALLY
IMPORTANT BECAUSE OUR FIRST
PATIENT WHO REALLY DID BADLY WE
GAVE HIM STEROIDS AND HE
IMPROVED AND WE DID ALL SORTS OF
CRAZY THINGS AND THE IMPORTANCE
OF BEING ABLE TOLL DO
PHENOTYPING IS IT ALLOWED US TO
BE PERSISTENT AND PUSH THE
AMOUNT OF IMMUNO SUPPRESSION AND
STEROID TREATMENT.
THIS PARTICULAR PATIENT WAS
DIFFICULT BECAUSE WE HAD AN WE
COULDN'T ACCESS THE LB AND WE
HAD TO USE MRI THAT WE'RE STILL
LEARNING HOW TO USE.
TO DESCRIBE THIS CASE, WE
HAVE -- WE COMPARED IT TO THE
HIV RELATED IRIS AND IN THIS
CASE THE CRYPTOCOCCUS KILLED
WHEN YOU GET WE HAVE A
RECONSTITUTION OF THE IMMUNE
SYSTEM IT COMES BACK AND OVER
ANYWHERE FROM THREE TO SIX
MONTHS LATER, ALL THE ANTIGENS
FROM THE CRYPTOCOCCUS STIMULATE
THE CELLS AND ACTIVATE T CELLS
AND YOU HAVE ACTIVATION.
THEY'RE HEALTHY PREVIOUSLY AND
WE DON'T GIVE THEM ANYTHING TO
RECONSTITUTE THEM.
WHEN YOU LICE THOSE
CRYPTOCOCCUS, IT'S COVERED BY
THIS CAPSULE THAT IS SORT OF
INSULATING IT FROM THE IMMUNE
SYSTEM BUT WHEN YOU BREAK IT
OPEN AND RELEASE IT'S LIKE
INJECTING PROTEIN INTO YOU AND
YOU HAVE A IMMUNE RESPONSE AND
FOLLOWED BY T-CELL ACTIVATION.
ONE THING TO NOTE HERE, THIS IS
ONE OF THE SOL YOU BULL MARKERS
AND YOU NOTICE IN THE CNC
PATIENTS HAZEL RATE ISED, 10 TO
100 FOLD.
IT'S IMPORTANT BECAUSE THE
CURRENT IBSA RECOMMENDATIONS ARE
IN THESE PATIENTS IS THAT ARE
REFLECTORRING THE DISEASE AND
NON IS TO GIVE THEM AND KNOWING
THE PATHOGENESIS OF THE DISEASE,
THIS IS LIKE PUTTING GASOLINE ON
THE FIRE.
YOU CAN SEE WHY IT MAY NOT BE A
GOOD IDEA AND WE GIVE IT TO A
FIRST PATIENT AND THEY
DETERIORATED AND THEY FLIPPED
OVER AND GAVE THEM STEROIDS AND
THEY IMPROVED.
THE INTERESTING THING IS MANY
CASES THEY ARE REALLY WHERE THE
DEFECT IS RATHER THAN T CELLS
AND ON AUTOPSY AND BRAIN BIOPSY,
THIS IS A BRAIN BIOPSY SPECIMEN,
MARKERS SUCH AS INOS WHICH MARK
AN ACTIVATED N1 POLARIZED TISSUE
AND YOU CAN TAKE UP CYTO SIS AND
KILL IT IT'S NOT PRESENT AND TWO
MARKERS ARE ACTIVATED SUGGESTING
AN ALTERNATIVELY ACTIVATED MACRO
PAGE WHICH DOESN'T DO A GO AHEAB
IN CLEARING THE FUNGUS SO IT'S
NOT ENOUGH TO DESCRIBE A
SYNDROME, YOU KNOW, IT'S NICE IF
YOU HAVE A THERAPY FOR IT, MUCH
BETTER FOR PATIENTS AND SO, OVER
A PERIOD OF TIME WE DEVELOPED
THIS IDEA OF DOING THIS PULSE
TAPER THERAPY, AND THEN WHEN WE
HAD ALL THE SORT OF END POINTS
WE WANTED DO WE DID A
PERSPECTIVE FOLLOWING OF THESE
USING A UNIFORM TREATMENT AND
FOLLOW-UP AND THIS IS REPORT OF
15 PREVIOUSLY HEALTHY PATIENTS
ADMITTED OVER A FIVE-YEAR PERIOD
ALL TREATED UNIFORMLY AND
RETROSPECTIVE LEANNE ALLIES AND
THEY ALL GOT 5FC FOR WOULD YOU
WEEKS AND CULT TURES NEGATIVE.
THEY HAD A PULSE FOR SEVEN DAYS
AND REALLY IS NEEDED AND THEN WE
FOLLOW IT WITH A MILL A GRAM OR
KILOGRAM OF PREDNISONE AND IT
TAKES ABOUT A YEAR TO GET
PATIENTS OFF IT AND OF COURSE WE
DO PROPHYLACTIC BACK DROWN AND
VIRUSES AT THIS POINT AND WE
TAPER THEM OVER SLOWLY WATCHING
THEM CLINICALLY AND GETTING A
LOT OF MRI, WHICH CAN BE USEFUL.
SO, WHAT ARE THE RESULTS ON
THIS?
THEY HAD A TREMENDOUS RESPONSE,
IT'S LIKE SOMETHING OUT OF A
MOVIE ACTUALLY.
THEY ALL RESPONDED SEM PRESS I
HAVELY.
THERE'S ANOTHER MEASURE OF
NEUROLOGICAL PERFORMANCE ALL
IMPROVED AND THE PRESSURE CAME
DOWN AND WE WERE ABLE TO AVOID
SHUNTING IN HALF THE PATIENTS.
VISUAL FEELS ARE A MEASURE BY
DIS A BELL AND THEY DO IT WITH
HEARING AND ALSO WITH VISION.
YOU CAN SEE ON THE BOTTOM A
CARTOON, ZERO DECIBELS IS A
NORMAL FIELDS WHEN YOU COME DOWN
AND LOSE YOUR VISUAL FIELDS HERE
IS AN EXAMPLE OF -20.
YOU CAN SEE THEY ALL IMPROVE AS
WELL SO EVERYBODY IMPROVES WITH
THIS THERAPY.
LOOKING AT THE CSF PARAMETERS,
THE CSF GLUCOSE RISES TOWARDS
NORMAL AND THIS IS AFTER JUST
SEVEN DA OF A FULLS AND IT IMPRS
LATER ON THE THE CELL COUNTS
COME DOWN AND ELEVATED PROTEINS
COME DOWN, AND HERE WE GO WITH
SOME OF O'ER FLOW CYTOMETRY AND
THE MARKER OF T-CELL ACTIVATION
AND T CELLS CAN PRESENT ANTIGENS
IT'S NOT THE QUESTION.
IT'S BEEN USED AS A T-CELL
MARKER AND YOU CAN SEE HERE THE
CD4, THE PURPLE CELLS HERE, ARE
THE ACTIVATED CELLS AND WITH
SEVEN DAYS OF PULSE, THEY COME.
ABOUT 10-FOLD FOR EACH PATIENT
AND THE INFLAMMATORY MONEY
SIMONOCYTESARE AND TH CYTOKINESD
CD25 THE IL2 RECEPTORS WHICH IS
ALSO A MARKER IN OTHER
ACTIVATION SYNDROMES LIKE HLH
AND MACRO FAGE ACTIVATION COMES
DOWN 10 FOLD.
AFTER ABOUT THREE DAYS THE
PATIENT BEGINS TO WAKE UP AND
PROGRESSES FROM THERE AND SO
Dr. HAMM OUTAOUAIS OUD AND AND D
IMPROVEMENT IN EVERYTHING
PATIENT.
IN ADDITION MARKER A LITTLE
DAMAGE AND YOU CREDIT SEE IN THE
CSF AND SHOWED BY YOU CAN SEE IT
OVER TIME THERE'S NOT A REBOUND
BUT THERE'S A PROGRESSIVE
DECREASE AS YOU REDUCE DAMAGE TO
THE NEUROLOGICAL TISSUE AND THEY
IMPROVE ALL THE WAY OUT TO A
YEAR VERY SLOWLY.
SO, LET ME GIVE YOU SOME
ANECDOTES BECAUSE YOU SEE
NUMBERS AND YOU ARE LIKE A
COUPLE NUMBERS HERE.
THIS IS ACTUALLY A VERY TYPICAL
RESPONSE THAT WE SEE.
WHIFF 15 PATIENTS THAT HAVE
TAPERED DOWN.
IT TOOK A AVERAGE OF 1 POINT A
YEARS TO GET THEM OFF ST STEROI.
WE HAD ONE DEATH FROM A
PULMONARY AM BOLISM.
THE COMPLICATIONS WE DIDN'T SEE
ANY INFECTIONS AND WE GET THEM
OFF STEROIDS FAIRLY QUICKLY AND
THEY TAPER DOWN FREQUENTLY SO
COMPARED TO OTHER DISEASES WHERE
THEY'RE ON LIFELONG STEROIDS AND
WE DID HAVE TO USE THIS
PHOSPHATES AND WE DID SEE SOME
CAT A RACKS AND MOST OF THESE
PATIENTS ARE OLDER AND NOT TOO
BAD CONSIDERING THE DOWNSIDE OF
THE DISEASE.
HERE ARE SOME TYPICAL ANECDOTE
STORIES.
YOU SEE THE NUMBERS BUT YOU WANT
TO SEE AN AVERAGE PATIENT.
SO THIS IS WITHIN TWO MONTHS OF
DIAGNOSIS, THEY GO TOO FAR THE
DAMAGE IS ALREADY BEEN DONE AND
YOU CAN SEE IN THIS PATIENT HOW
THAT CHRONIC CRYPTO AND CHRONIC
INFLAMMATION CAN CAUSE A LOT OF
DAMAGE.
THIS IS A PATIENT, A 59-YEAR-OLD
PREVIOUSLY HEALTHY PATIENT SHE
WAS CULTURE NEGATIVE IN TWO
WEEKS AND DETERIORATING MENTAL
STATUS AND DISCUSSION TO
REFERRAL OF THE HOSPITAL AND
THEY PUT HIM ON A JET AND FLEW
HIM HERE AND THIS IS WHERE THE
NIGHT HE ARRIVED HERE AND THIS
IS HIS WIFE TRYING TO GET HIM TO
RESPOND A LITTLE BIT.
>> CAN YOU TALK TO ME?
>> YOU CAN SEE NOT TERRIBLY
RESPONSIVE AND AFTER 10 DAYS OF
THERAPY, HERE HE IS STANDING UP
AND HE IS FACIAL DROOP BUT HE IS
OR' ENTERTAINMENTED TIMES THREE
AT THIS POINT AND WALKING AROUND
THE HALL WITH A WALKER.
IN THREE MONTHS ACTUALLY HE WON
THE BASS FISHING CONTEST.
HE WAS A BASS FISHER AND HE HAD
BEEN FISHING IN A YEAR AND HE
WENT OUT AND WON THE CONTEST.
THE HAT ON HIS HEAD IS BECAUSE
OF THE SUN AND HE WAS VERY HAPPY
AT THAT POINT AND THEN A PATIENT
CAN RESPOND.
HERE IS ANOTHER 25-YEAR-OLD WITH
HEADACHES FOR TWO MONTHS
TESTICULAR PAIN, BLURRY VISION
AND PRETTY SUPER US AT THAT
POINT AND WE GAVE HIM AND AFTER
TWO DAYS, HE WAS OFF ALL HIS
NARCOTICS AND HE SAID CAN THEY
GO TO THE GYM?
AND THEN WITH THE PULSE DECLINED
AND NORMALIZED GOING FORWARD
FROM THAT SO THE RESULTS ARE
PRETTY MUCH LIKE THIS AND THIS
IS THE EXPERIENCE WITH PATIENTS
WITH A NEUROLOGICAL SCORED
LOOKING AT THE LOWER MOTOR
NEURON FUNCTION AND THAT WILL
IMPROVE WITH TIME.
DESPITE REALLY SMALL AND IT'S
BECAUSE OF THE EFFECT SIZE AND
SO LARGE.
WE HAVE AN OUTRAGEOUS GOAL, WE
MAKE NON HIV THIS IS A HISTORY
OF OUTCOME AND SO IN THE 50s,
BEFORE THE ADVENT, WE HAD 100%
MORTALITY AND WE WERE ABLE TO
GET IT DOWN TO 30% AND STAYED
THE SAME FOR 30 YEARS.
AND THIS IS KIND OF A 60 YEARS
SO IT'S EMBARRASSING BECAUSE
I'VE BEEN WORKING ON
CRYPTOCOCCUS AND TRYING TO KILL
THE FUNGUS AND IT WAS
INFLAMMATORY RESPONSE KILLING
ABOUT A THIRD OF THESE PATIENTS
AND WHEN HE TREATED THEM WITH
STEROIDS WE GOT THE MORTALITY
DOWN TO 1% TO 2%ER AEVERYTHINGS
WELL AND GO BACK AND FUNCTION.
THE HARDEST QUESTION WAS BY THE
FORMER CLINICAL DIRECTOR JOHN
GOUGHEN SAID WHY DID IT TAKE YOU
60 YEARS TO FIGURE THIS OUT.
WITH THE KNOWLEDGE OF
PATHOGENESIS WE WERE ABLE TO
GAIN WITH THE INTIMATE
ASSOCIATION OF OUR LABORATORY
FACILITIES AND GOING TO THE
BEDSIDE AND BACK AND FOURTH AND
BACK AND FOURTH AND NO NEW
THERAPY JUST UNDERSTANDING THE
PATH OF PHYSIOLOGY OF THIS
DISEASE SO SOME OF OUR FUTURE
STUDIES WE'RE LOOKING AT
STEROIDS SPARING AGENTS AND WAYS
WE TRY BUT IT WASN'T IMPRESSIVE
AND WE FOUND THAT REXOLINDEN
SEEMS TO BE MORE IMPRESSIVE AND
IT'S PROXIMAL AND YOU CAN SEE
THIS MULTIFACETED AND IMMUNE
RESPONSE WITH T-CELL ACTIVATION
AND RECRUITMENT AND REALLY TAKES
A SLEDGEHAMMER TO DO THAT AND IN
HUMANS WE'VE HAD A COUPLE
PATIENTS, FOUR COURSES WHERE WE
KEEP PREDNISONE THE SAME AND TH-
WE GO TO A MOUSE MODEL WHERE WE
HAD TO DEVELOP A NEW MODEL
BECAUSE WE DIDN'T HAVE ONE AND
THAT ALLOWS US 20 LOOK AT IT
ALLOW WITHOUT STEROIDS SO IT'S
NOT SURPRISING WE CAN REDUCE CD4
CELLS IN THE BRAIN OR REDUCE
ACTIVATED T CELLS IN THE BRAIN
OR MYELOID OR MONOCYTES IN THE
BRAIN THE IMPORTANT THING IS WE
CAN REDUCE BRAIN EDEMA.
WE WERE GIVING STEROIDS AND IT
HAD NOTHING TO DO WITH THE
INFLAMMATION BUT TREATING THE
INFLAMMATION ALONE CAN HAVE SOME
IMPACT AND WE MIGHT USE THIS
GOING FORWARD AND NOW THIS AS
ANNAN SIL ARY TREATMENT WE'LL
HAVE TO DO A RANDOMIZED TRIAL
BECAUSE WE HAVE SIGNIFICANT
POSSIBILITY FOR TOXICITY FROM
THIS.
THE FIRST STUDY WAS DONE BECAUSE
THEY DIDN'T KNOW THESE RESPONDED
NORMALLY WITHOUT THERAPY AND SO
THEY KNEW THEY HAD TO HAVE A
RANDOMIZED STUDY BUT THE
PRECEDING THAT WAS TB MENINGITIS
WHERE THEY ALL DIE SO IF YOU
TREAT ANYBODY AND THEY GET
BETTER THEY'RE HAPPY AND THEY
DIDN'T FEEL LIKE THEY NEEDED A
RANDOM SIZED STUDY.
SO EVERYBODY ALWAYS ASKS ME, WHY
DO THESE PREVIOUSLY HEALTHY
PATIENTS GET CRYPTO CAUCUS?
WE'VE SEQUENCES THIS STUDY 86
PATIENTS AND WE TOOK THE STOP
700 GENES THAT SHOWED MUTANT
ALLELES AND WE USED THE MUTANT
FREQUENCY AND VERY RARE BECAUSE
THE DISEASE IS RARE AND WE USED
A CAD SCORE OF 25 WHICH IS A
MEASURE OF PROBABLE DYSFUNCTION
OF THE INDIVIDUAL MUTATION AND
WE USED PATHWAY ANALYSIS FOR THE
INGENUITY AND PATHWAY TOOL.
WE DO THAT AND WE FIND ONE A
PREDOMINANT PATHWAY INVOLVED IS
KINASE AKT TOUR PATHWAY AND WE
HAVE PATIENTS THAT WE'RE
EXAMINING NOW LOOKING AT
MUTATIONS, RARE MUTATIONS IN
THESE.
INCLUDING RAPTOR AND WE HAVE
FOUR PATIENTS WITH M.T.O. R
MUTATIONS.
IF YOU KNOW ANYTHING ABOUT
M.T.O. R IT'S A KINASE AND IT IS
INVOLVED IN METABOLISM AND IN
T-CELL ACTIVATION AS WELL AND
YOU CAN MEASURE IT BY S6 FOSS
FILLATION SO MOST OF THESE CASES
ACTUALLY HAVE BEEN REPORTED SO
FAR AND THEY HAVE BEEN GAIN OF
FUNCTION AND THE CLASSIC ONE IS
THE SMITH KINGS MORE SYNDROME
AND GAIN OF FUNCTION AND MUTANT
PATIENTS AND IT'S EXHIBITING THE
MOW SAY CIVIL AS YOU CAN IMAGINE
IT'S NOT IN BLOOD BUT ONLY IN
BRAIN AND THEN FOCAL CORTICAL
DYSPLASIA TYPE TWO AND INTENSE
ACTIVATION OF THIS S6K AND AS A
LOW FRACTION IN BRAIN, AND IT'S
NOT IN BLOOD.
BUT AS I SAID, YOU CAN SEE THAT
MTOR AND WE'RE FINDING IN THESE
PATIENTS, LOSS OF FUNCTION AND
IT WOULD GO ALONG WITH THE
T-CELL DEFECTS THAT YOU MIGHT
SEE IN EXPECTED IN ADAPTIVE
IMMUNITY ORGANISM HERE AND THE
SECOND ONE I'M GOING TO TALK
ABOUT, I THINK I'M GOING TO GET
TIME TO DO THIS IS A NEWLY
DEVELOPED MODEL OF POOR
DEPENDENT RNA DEGRADATION WHICH
IS DIFFERENT FROM RNA INDUCED
SILENCING AND WHAT THAT INVOLVES
IS POOR PHOSPHORYLATION OF THIS
MOLECULE AND WE GET RECRUITMENT
OF MRNA AND A MICRO MRNA AND
CAPPING AND WE'VE BEEN ABLE TO
DESCRIBE BOTH DEFECTS IN INNATE
AND ADAPT OF IMMUNITY AND MOST
RECENTLY I'M GOING TO TROY TO
WHIP THROUGH THIS IT WAS THE PI3
AND WE WERE ABLE TO SHOW THE
EFFECT ON INNATE IMMUNITY BUT
THE INTERESTING ONE 20 THIS TALK
IS A 2-YEAR-OLD THAT INVOLVED TO
VANCOUVER ISLAND WHICH IS FULL
OF CRYPTOCOCCUS HAD MULTIPLE
NODULES AND INTEGRATED 14
MUTATION NOVEL AND INTEGRATED
COMPLEX IS INVOLVED IN THE
PRODUCTION OF NON MICRO RNAs
AND MR12-46 THE CO FINDER AND
DEGRADED BY THIS PATHWAY AND SO
IN THIS PARTICULAR CASE, IN THIS
PATIENT, THE 12-46 IS REDUCED
WAS OF THE MUTATION RESULTING IN
A HUGE INCREASE IN FOX P3 WHICH
ALSO RESULTED IN AN INCREASE IN
P CELL SUPPRESSER CELLS AND
AGAIN IS OPPOSITE TO A DISEASE
ON THE LEFT WHERE YOU HAVE
ACTIVATION OF TOR AND HERE YOU
HAVE INSTEAD OF INFLAMMATORY YOU
HAVE IMMUNE SUPPRESSION AND
T-CELL POSSESSORS PREVENT THE T
CELLS FROM GETTING INTO THE LUNG
AND CONTROLLING IT.
WITH THAT, I'D LIKE TO THANK MY
COLLABORATORS AND A LOT OF THIS
WORK WAS DONE BY Dr. UNJUM AND
THE REST OF OUR LAB AND OUR
NEUROLOGICAL CONSULT AND A
NUMBER OF OUTSIDE INVESTIGATORS
AND AS WELL SO THANK YOU VERY
MUCH AND IF THERE ARE ANY
QUESTIONS?
>> THANK YOU, EVERYONE FOR THAT
FANTASTIC PRESENTATION.
I'LL REMIND THE AUDIENCE IF YOU
HAVE QUESTIONS, YOU CAN SUBMIT
THEM BY USING THE LIVE FEEDBACK
BUTTON ON YOUR SCREENS.
IN THE MEANTIME, Dr.
WILLIAMSON, I DO HAVE A QUESTION
FOR YOU.
SO, I MAY HAVE MISSED THIS BUT
DOES EVERY PERSON WHO GET
CRYPTOCOCCAL MENINGITIS DEVELOP
THIS INFLAMMATORY RESPONSE
SYNDROME AND IF NOT, ARE THERE
BIOMARKERS TO PREDICT WHO MIGHT
DEVELOP IT SO YOU CAN THEN FLAG
THEM FOR TREATMENT WITH STEROIDS
OR OTHER IMMUNOSUPPRESS ANTS?
>> THE PATIENTS WE HAVE A
REFERRAL SO WE HAVE TO GO AND
DIG INTO OUR MULTI CENTER
TRAVELS TO DO THAT AND WHEN WE
FIND THAT WE FIND THAT SOME OF E
MARKERS WILL BE ELEVATED IN THE
PATIENTS WHO GET THE DISEASE AND
WHEN YOU COMPARE, IL6 IS HERE
AND I L6 IS LIKE HERE IN THE
ONES THAT DON'T SO THE CLINICAL
MARKER IS STILL THE BEST THING
AND IT'S LIKE NEW ASSISTANCE WHO
IS GOING TO GET THE DISEASE AND
REQUIRE A STEROIDS THERE?
THEY GIVE YOU P VALUES AND
GRANTS IF YOU ARE EXTRAMURAL BUT
FOR THE CLINICIAN THEY'RE NOT
POWERFUL ENOUGH MARKERS TO
PREDICT THINGS.
I THINK WHAT IS MORE USEFUL IS,
YOU ARE CONFRONTED WITH A
PATIENT WHO IS DOING BADLY, WHY
IS THAT AND WHAT CAN YOU DO?
AND THAT IS WHERE WE REALLY PUT
OUR ENERGY IN.
THAT'S VERY STRONG.
SO WHAT WE HAVE FOUND IS THAT
SOME OF THESE BIOMARKERS, LIKE
IL6, LIKE THE 25, THE ACTIVATED
T CELLS, THEY HAVE THRESHOLDS SO
IF WE GET A PATIENT THE
ACTIVATED T CELLS DOWN TO 200,
WE CAN TELL THEY'RE GOING TO
RESPOND AND WHEN THEY DON'T GET
BELOW 200 THEY DON'T SEEM TO
RESPOND AND WE HAVE THIS ONE
POOR GUY THAT'S GONE A YEAR AND
HE STILL HAS ACTIVATED T CELLS
WAY BEYOND THAT AND WE HAD THE
FIRST ONE TO USE AND WE GET THEM
BACK DOWN AND THEN THEY DO FINE,
OR WE HAVE SOMEONE THAT COMES IN
AND DOES A RESPOND TO THEIR
PULSE AND WE CAN MEASURE THEM
AND THEY HAVE A LOT OF
INFLAMMATION AND WE HIT THEM
WITH ANOTHER PULSE THEY COME
DOWN AND WAKE UP.
THE TREATMENT EFFECT IS
DIFFICULT.
USUALLY PROGNOSTIC MARKERS ARE
EASY TO FIND AND TREATMENT
MODIFIERS ARE DIFFICULT AND IN
THIS CASE THE TREATMENT
MODIFIERS HAVE BEEN EASIER TO
FIND AND THE PROGNOSTIC MARKERS
AREN'T QUITE AS STRONG.
>> GREAT.
THERE'S A QUESTION THROUGH THE
LIVE FEEDBACK BUTTON.
THIS IS FROM JUAN.
IS THE AN TO BE PATHWAY GAIN OF
FUNCTION MUTATION DOES THAT
SUGGEST THE PATHOGENESIS IS
SIMILAR TO PK DELTA SYNDROME.
>> WE SEE THE REVERSE.
WE SEE DEFECTS IN THAT WHICH
ACTUALLY HAVEN'T BEEN REPORTED
BUT WE THINK IT'S GOT TO BE A
MOW A SIS SYSTEM AS WELL BUT WE
SEE DEFECTS AND THAT'S MORE
EXPECTED.
SO WE HAVE THE YING AND THE YANG
HERE CONTINUALLY AND A LOT OF
OUR -- A NUMBER OF QUEEN'SING ON
WE HAVE DEFECTS AND YOU SEE
Dr. GOLD BACK WILL HAVE UP
REGULATED THE SAME QUEEN AND
SHE'LL HAVE INFLAM ON AGENT' AND
WHERE THEY GET ALL SORTS OF
INFLAMMATORY DISEASES SO IT JUST
DEPENDS ON WHICH DIRECTION YOU
ARE GOING AND OURS ARE LOSS OF
FUNCTION.
>> OK.
GREAT.
THANK YOU, AGAIN, TO ALL OUR
WONDERFUL PRESENTERS FOR REALLY
INTERESTING TALK TODAY.
IF ANYBODY HAS QUESTIONS, FEEL
FREE TO E-MAIL THEM TO OUR
PRESENTERS AFTER THE DISCUSSION.
I THINK WE'RE COMING CLOSE TO
TIME HERE AND I I DON'T SEE ANY
OTHER QUESTIONS COMING THROUGH
THE LIVE FEEDBACK.
I'LL SAY THANK YOU AGAIN AND
HAVE A GREAT REST OF THE DAY.