>> WELL, GREETINGS AND
SALUITATIONS!
I AM DAN KASTNER, I AM THE
DIRECTOR OF THE NATIONAL HUMAN
GENOME RESEARCH INSTITUTE AND
STILL ACTIVE PHYSICIAN SCIENTIST
IN THE ACTIVE PORTION OF THE NIH
AND IT IS MY ENORMOUS PLEASURE
THIS AFTERNOON TO WELCOME YOU TO
THE 15th INSTALLMENT OF THE
2025 DEMYSTIFYING MEDICINE A
SERIES OF PRESENTATIONS THAT
BRIDGE THE EXCITING DEVELOPMENTS
IN BIOLOGY, ENGINEERING AND
COMPUTER SCIENCE WITH MEDICINE.
AND YOU SEE, UP IN THE UPPER
RIGHT HAND CORNER, THE ICONIC
PHOTO OF THE CONSTRUCTION OF THE
BROOKLYN BRIDGE BACK IN THE LATE
1800S AND IF YOU LOOK CAREFULLY,
YOU CAN SEE ON THE CAT WALK UP
THERE, A NEUROPHYSIOLOGIST FROM
MANHATTAN AND A NEUROLOGIST FROM
BROOKLYN WHO HAVE HAVING A VERY
LIVELY DISCUSSION ABOUT THE
FINDINGS OF SHARCO, ESTABLISHING
THE DIAGNOSIS OF MULTIPLE
SCLEROSIS AND IN FACT, WE WILL
BE TALKING ABOUT MULTIPLE
SCLEROSIS THIS AFTERNOON.
BUT BEFORE WE LAUNCH INTO THAT,
LET ME JUST REMIND YOU THAT THIS
SERIES DEMYSTIFYING MEDICINE
OCCURS ON TUESDAY AFTERNOONS
FROM 3-5 EASTERN TIME FROM
JANUARY-MAY OF 2025.
YOU CAN WATCH IT AT THE VIDEO
LINK SHOWN THERE, GET CME CREDIT
WITH THE CME CODE OF 58794.
THAT'S 58794.
AND IF YOU HAVE QUESTIONS DURING
THE PRESENTATIONS, THERE WILL BE
A COUPLE OF PRESENTATIONS AS
WELL AS A PATIENT PRESENTATION,
CAN YOU USE THE SEND LIVE
FEEDBACK BUTTON TO THE VIDEOCAST
DISPLAY IN ORDER TO ENTER YOUR
QUESTIONS AND THEY WILL BE
RELAYED TO ME FOR THE
INTERROGATION SESSION AT THE
END.
SO IN ANY EVENT, ALL OF THE
PREVIOUS SESSIONS ARE ARCHIVED.
YOU CAN GO IT THAT LINK ON THE
SCREEN TO VIEW THEM AND THERE'S
ADDITIONAL INFORMATION THAT THE
DEMYSTIFYING MEDICINE LINK SHOWN
THERE.
AND OF COURSE, THIS IS A SERIES
THAT BRIDGES SILOS AT THE NIH
AND HAS BEEN DOING SO SINCE
2003.
IN ANY CASE, THE FIRST OF OUR 2
SPEAKERS, IS GOING TO BE
DR. MARIA INES GUYTON AND SHE IS
AN ASSOCIATE RESEARCH PHYSICIAN
AND THE ACTING DIRECTOR OF THE
IMMUNOLOGY CLINIC IN THE
TRANSLATIONAL NEURORADIOLOGY
SECTION OF THE NATIONAL
INSTITUTE FOR NEUROLOGIC
DISEASES AND STROKE.
SHE GOT HER MEDICAL DEGREE WITH
HONORS AT THE BUENOS AIRES
UNIVERSITY SCHOOL OF MEDICINE.
SHE TRAINED IN NEUROLOGY AT THE
INSTITUTE FOR NEUROLOGY
RESEARCH, FLENI, IN BUENOS
AIRES, WAS A POST DOCTORAL
FELLOW IN THE NEUROIMEULOGIOLOGY
BRANCH OF NINDS AND A SENIOR
STAFF CLINICIAN AT FLENI, BEFORE
ASSUMING HER CURRENT POSITION IN
THE NEUROIMMUNOLOGY CLINIC AT
THE NIH.
SHE'S THE RECIPIENT OF A NUMBER
OF AWARDS INCLUDING THE NINDS
CLINICAL DIRECTORS AWARD FOR
CLINICAL EXCELLENCE.
HER RESEARCH GROUP, HER RESEARCH
IS FOCUSED ON DEVELOPING
ADVANCED MRI TECHNIQUES IN
MULTIPLE SCLEROSIS, STUDYING THE
CHRONIC LESIONS IN MS, AND
DEVELOPING IMAGING BIOMARKERS IN
MS.
OUR SECOND SPEAKER IS DR. DANNY
RYKE, WHO IS A SENIOR
INVESTIGATOR AND CHIEF OF THEA
TRANSLATIONAL NEURAL RADIOLOGY
SECTION IN THE DIVISION OF
NEUROIMMUNOLOGY AND
NEUROVIROLOGY IN NINDS, AND HE'S
AN ADJUNCT PROFESSOR IN
RADIOLOGY, AT YALE AND IN
NEUROLOGY, DIAGNOSTIC RADIOLOGY
AT HOPKINS HE GOT HIS MEDICAL
DEGREE AT CORNELL AND Ph.D. AT
PHYSIOLOGY AT THE ROCKEFELLER
UNIVERSITY AND THEN GOT CLINICAL
TRAIN NOTHING NEUROLOGY,
DIAGNOSTIC RADIOLOGY AND
NEURORADIOLOGY AT HOPKINS, AND
NEUROIMMUNOLOGY ALSO AT HOPKIN.
HE IS THE RECIPIENT OF THE
BARANCIK PRIZE FOR MS RESEARCH,
MEMBER OF THE HENRY KUNKEL
ASSOCIATE, ASSOCIATE OF AMERICAN
PHYSICIANS, AAAS FELLOW AND HAS
RECEIVED MULTIPLE OUTSTANDING
MENTOR AND TEACHER AWARDS.
THE GOALS OF HIS RESEARCH GROUP
ARE UNDERSTANDING HOW MS
INJURIES THE BRAIN AND SPINAL
CORD.
HOW TO STOP THAT YOUR AND HOW TO
PROMOTE REPAIR.
ALSO THE DEVELOPMENT OF NEW MRI
TECHNIQUES WITH STATE-OF-THE-ART
EQUIPMENT AT THE NIH CLINICAL
CENTER AND HIS GROUP USES
PATIENT SAMPLES AND ANIMAL
MODELS TO ELUCIDATE CELLULAR AND
MOLECULAR PATHWAYS.
WELL, WITH ALL THAT HAVING KNOW
SAID, I THINK IT'S TIME NOW TO
TURN THINGS OVER TO MARIA WHO IS
GOING TO GET THINGS GOING.
SO MARIA, PLEASE, TAKE IT AWAY.
>> THANK YOU VERY MUCH FOR THE
INVITATION AND IT'S A PLEASURE
TO BE HERE TODAY AND I'M GOING
TO BRUCE OUR PATIENT MR. CARLOS
CHACON, CARLOS IF YOU WANT TO
TURN ON YOUR CAMERA SO YOU CAN
BE PART OF THE CONVERSATION, SO
FIRST I WILL SHARE A COUPLE OF
SLIDES AND THEN I WILL TALK TO
CARLOS AND THEN I WILL ASK HIM
SOME QUESTIONS.
SO TODAY I WILL TALK ABOUT MS,
THROUGH 2 LENSES, THE CLINICAL
INSIGHT AND THE PATIENT
EXPERIENCE SO THE FIRST THING
WE'RE GOING TO DO IS WE'RE GOING
TO TALK WITH MR. CHACON, ABOUT
HIS HISTORY OF PRESENT ILLNESS,
SO I WILL STOP SHARING MY SLIDES
AND I WOULD LIKE TO TALK TO
CARLOS.
SO GOOD AFTERNOON, CAN YOU SEE
ME CARLOS?
YEAH, OKAY.
>> YEAH.
>> THANK YOU SO MUCH FOR COMING.
IT'S A PLEASURE TO HAVE YOU
HERE.
SO I WOULD LIKE TO ASK YOU WHAT
WAS THE FIRST SYMPTOM THAT YOU
EXPERIENCED?
>> THANK YOU FOR INVITING ME.
MY PLEASURE TO BE HERE.
THREE YEARS AGO, BASICALLY MY
EYES, THEY STOPPED COORDINATING.
IT WAS KIND OF CRAZY EYE OR
VETERINARY COMMUNITY GO, WHEN I
WOULD LOOK TO THE RIGHT, THE
RIGHT EYE WOULD GO TO THE RIGHT,
BUT THE LEFT EYE WOULD GO UP OR
IT WOULD BE LOOSE AND WHEN I
WOULD LOOK ON THE LEFT EYE, THE
RIGHT EYE WILL BE IN A CRAZY WAY
AND THAT WAS THE FIRST SYMPTOM I
GOT OFFICIAL DIAGNOSED.
>> HOW OLD WERE YOU AT THE TIM?
>> I WAS 29 YEARS OLD, I THINK,
YEAH.
>> AND HOW MANY DAYS DID IT TAKE
FOR YOUR SYMPTOMS TO REACH THEIR
PEAK OR THEIR WORST?
>> I THINK IT WAS 2 OR 3 DAYS
FROM WHEN I STARTED FEELING BAD.
I ALSO HAD A SUPER HUGE HEADACHE
BEFORE THAT.
A HORRIBLE MIGRAINE AND I THINK
3 DAYS AFTER THAT'S WHEN I WAS
ADMITTED INTO THE HOSPITAL AND I
WAS IN THE HOSPITAL FOR 5 DAYS,
IF I AM NOT MISTAKEN.
>> AND DID YOU FULLY RECOVER.
>> YES.
>> DID YOU RECEIVE ANY TREATMENT
FOR THAT AT THE TIME?
>> YES, I RECEIVED A STEROIDS, I
DON'T REMEMBER THE SPECIFIC NAME
FOR 5 DAYS AND YEAH, AND I WAS
PRETTY FINE AFTER THAT.
AND 2 OR 3 MONTHS AFTER, MY EYES
WERE ALMOST BACK TO NORMAL.
>> OKAY, WONDERFUL.
SO NOW I WILL SHOW MY
PRESENTATION AGAIN AND I WILL
COME BACK TO YOU SHORTLY.
ALL RIGHT, SO WHAT MR. CHACON
HAD AT THE TIME WAS WHAT WE CALL
BILATERAL OPHTHALMIC MALAYSIA,
THIS IS CLINICAL PRESENCE OF
DIVERGENCE OR EYE APPEARANCE IN
THE HORIZONTAL PLANE.
SO BASICALLY WITH WEAK AND SLOW
ADDUCTION OF THE AFFECTED EYE
WHICH MAY BE COMBINED BY THE
INTRA LATERAL EYE, THIS IS THE
EYE THAT WAS AFFECTED AND THIS
IS AN EXAMPLE IN THE LITERATURE
AND THIS EYE WAS MOVING WITH IT
AND LOOKING AT THE FRONT IT WAS
OKAY BUT TRYING TO LOOK TO THE
OPPOSITE SIDE, HE WILL HAVE
EXACTLY THE SAME SYMPTOM.
THIS EYE WAS ABLE NOT ABLE TO DO
ADDUCTION AND THIS WOULD HAVE
TROUBLE MOVING WHEN MOVED TO THE
LEFT.
IT IS 1 OF THE MOST LOCALIZED
BRAIN SYNDROMES RESULTING IN A
LESION FROM THE MEDIA, IN THE
MEDIA BRAIN STEM, OF EITHER THE
POINTS OF THE BRAIN BRAIN, SO
THIS IS CONNECTING THE SIXTH AND
THE THIRD NERVE.
>> DOCTOR, REAL QUICK, YOUR CHAT
BOX IS APPEARING IF YOU WANT TO
GO AHEAD AND MINIMIZE THAT
PLEASE?
>> YEAH, SURE.
APOLOGIZE FOR THAT.
>> OKAY LOOKS GOOD, THANK YOU.
>> SORRY FOR THAT.
SO I WOULD LIKE TO GO BACK TO
YOU AND ASK YOU A COUPLE OF
THINGS, AGAIN, IS HOW WAS
DIAGNOSIS MADE?
>> OKAY, YES, SO I WENT FIRST TO
URJEBT CARE, THE DOCTOR WASN'T
CONVINCED I HAD ANYTHING MORE
THAN VETERINARY COMMUNITY --
VERTIGO, AND SHE GOT SCARED AND
SHE SAID WE NEED TO TRANSFER YOU
IMMEDIATELY TO A HOSPITAL
BECAUSE THIS MAY BE MS, AND THEN
I WAS TRANSFERRED TO A HOSPITAL
AT YORK TOWN AND SEVERAL DOCTORS
DID SEVERAL EXAMINATIONS FOR A
COUPLE HOURS AND THAT NIGHT, 3
AMOR SO I HAD AN MRI AND 2 OR 3
HOURS AFTER THE MRI, I GOT THE
RESULTS.
WELL THE, DOCTOR, THE RESIDENTS
AND THE TREATING DOCTOR CAME AND
THEY TOLD ME THAT THEY FOUND IT
WASN'T THAT I HAVE MS.
IT WAS NOT TO HAVE THE -- THE
THING ON THE BACK, I FORGOT THE
NAME.
>> PUNCTURE?
>> YEAH, IT WAS NOT NECESSARY
BECAUSE THEY FOUND A LESION AND
THATIA HOW I WAS DIAGNOSED.
>> AND HOW DID YOU FEEL AT THE
TIME?
>> WELL, I WAS SCARED OF COURSE,
BECAUSE YOU SEE A LOT OF MOVIES
ON TV, AND I WAS SCARED BUT ALSO
I THINK THE DOCTORS DID A
TERRIFIC JOB EXPLAINING TO ME
HOW MUCH SCIENCE HAS ADVANCED
ESPECIALLY IN THE LAST 20 YEARS
AND THEY WERE REALLY GOOD AT
TEACHING ME THAT A DIAGNOSIS
WELL, OR WELL, 3 YEARS AGO, IS
NOT THE SAME AS IN THE 90S OR
80S OR EVEN A FEW DECADES AGO
AND THOU MUCH MEDICINE
PROGRESSED AND THAT MY PROGNOSIS
WAS VERY POSITIVE ESPECIALLY
BECAUSE THEY FOUND THE LESION
AND EVEN THOUGH I HAD A FEW
SPOTS AND LESIONS IN MY BRAIN
AND MY SPINE, IT WAS VERY EARLY.
SO IT WAS A BITTER SWEET
FEELING, LIKE BITTER THAT I HAVE
A CONDITION BUT ALSO SOME RELIEF
THAT IT WAS CAUGHT ON TIME.
>> OKAY, AND DO YOU HAVE ANY
OTHER MEDICAL CONDITIONS.
>> YES, I HAVE AN AUTOIMMUNE
DISEASE, PSORIASIS, AND IT'S
SKIN CONDITION.
>> DO YOU HAVE IT FROM BEFORE
MS.
>> BEFORE.
I WAS DIAGNOSED AROUND 10 YEARS
AGO, OR O.
>> OKAY.
AND DO YOU HAVE ANY OTHER
MEDICAL CONDITION?
>> NO.
>> DID YOU EVER HAVE -- DID YOU
EVER SMOKE?
>> NO.
>> WERE YOU OVERWEIGHT DURING
ADOLESCENCE?
>> SLIGHTLY, MAYBE.
SOME OVERWEIGHT, NOT OBESITY,
BUT SOME SLIGHT OVERWEIGHT,
YEAH.
NAND DID YOU HAVE MONONUCLEOSIS?
>> MOST LIKELY I HAD IT, YEAH.
I THINK.
>> AND DOES ANYONE IN YOUR
FAMILY HAVE MS OR ANY OTHER
AUTOIMMUNE DISEASE IN.
>> NO, I'M THE ONLY 1 WITH
AUTOIMMUNE DISEASE IN GENERAL IN
MY FAMILY.
AT LEAST THAT HAS BEEN
DIAGNOSED.
MAYBE THERE WAS SOMETHING BUT
THEY WERE NOT DIAGNOSED.
>> I SEE.
ALL RIGHT, SO, NOW I'M GOING
BACK TO MY PRESENTATION, I WILL
BE BACK TO YOU SHORTLY.
THANK YOU.
ALL RIGHT, SO YOU SEE MY SCREEN
I THINK, YES, SO IN BILATERAL,
SO INTERNUCLEAR OPERATING
GLOBALLY THAT WILLETRY, IS
CAUSED BY MS IN ONE-THIRD OF THE
CASES AND MS IS THE MOST COMMON
CAUSE IN YOUNG PERSONS
PARTICULARLY PERSONS THAT ARE
YOUNGER THAN 45 YEARS OLD,
THAT'S THE CASE OF OUR PATIENT
THAT WAS 29.
DEFICIT IN THESE CASES IS
BILATERAL IN MOST MS, AND THE
MOST COMMON EYE MOVEMENT
ABNORMALITY IN MS, AND MOST
PATIENTS HAD LESIONS IN THE
PONTINE MLF REGION.
SO THIS IS 1 SCREEN, THIS IS T-2
AND THIS IS FLARE AND YOU CAN
SEE A SMALL MEDIUM LESION.
SO AS A BRIEF INTRODUCTION MS A
CHRONIC INFLAMMATORY DEBIL
BAITING AND NEURODEGENERATIVE
DISEASE OF THE NERVOUS SYSTEM,
IT'S MOST OFTEN CHRONIC AND
HETEROGENEOUS, MULTIFACTORIAL
AND IMMUNE MEDIATED AND GOES BY
A COMPLEX GENE ENVIRONMENTAL
ENTERACTIONS AND THE MAIN PATH
LODGE CAM HALLMARK IS THE
ACCUMULATION OF LESIONS IN THE
WHITE MATTER AND THE GRAY MATTER
OF THE BRAIN AND SPINAL CORD.
THE CLINICAL MANIFESTATIONS ARE
REALLY HETEROGENEOUS AND MOST
PATIENTS HAVE REVERSE ABLE
EPISODES OF AS THE 1 OUR
PARTICIPANT, OUR PATIENT HAD
THAT USUALLY LASTS FOR A FEW
DAYS, 2 WEEKS AND OVER THE TIME
DEVELOP MAY DEVELOP PERMANENT
DEFICITS THAT IT'S CALLED
PROGRESSION AND IT'S SECONDARY
PROGRESSIVE MS, A MINOR AMOUNT
OF PATIENTS HOW PROGRESS THIS IS
FROM THE ONSET.
SO THE ONSET IS BETWEEN 20 AND
40 YEARS OF AGE AND IT'S THE
PRIMARY CAUSE OF NONTRAUMATTIC
DISABILITY IN YOUNG ADULTS AND
1 MILLION CASES IN THE U.S., 1
IN 3000 PEOPLE HAS MS AND THE
PREVALENCE BEEN INCREASING SINCE
2013.
SEE THERE ARE MANY FACTORS, NO 1
CAUSE, BUT MANY FACTORS, AND
MOST VARIANTS INVOLVE GENES
REGULATED IMMUNE RESPONSES, HLA
DRB11501 IS THE STRONGEST KNOWN
SUSCEPTIBILITY GENE THAT
INCREASES MS UP TO 3 FOLDS.
SO THE GENETIC RISK IN GENERAL
POPULATION, THE RISK IN
GENTLEMEN POPULATION IS 0.1% AND
THE FIRST DEGREE RELATIVES IS 2
OPINIONED 5 TO 5%.
AND IN IDENTICAL TWINS IT'S UP
TO 30%.
AND THERE ARE OTHER
ASSOCIATIONS, EARLY ADULTHOOD IS
ASSOCIATED WITH THE RISK AND
IT'S ASSOCIATED WITH 32 FOLD
INCREASED RISK, PROTECTED FROM
DEVELOPING MS AND SOME PROTEINS
OF THE VIRUS CAN MIMIC SOME
GLIAL CNS PROTEINS POSSIBLY
LEADING TO AUTOIMMUNITY.
IT'S A HIGHER PREVALENCE IN
CAUSEICATIONIANS AND EUROPEAN
ANCESTRY AND THERE ARE MANY
ENVIRONMENTAL FACTORS SUCH AS
VITAMIN D DEFICIENCY TOBACCO
SMOKING, OBESITY IN ADOLESCENCE
THAT MAY LEAD TO A RISK FACTOR
OF MS.
SO GENETIC AND ENVIRONMENTAL
RISK FACTORS SHIFT IMMUNE
BALANCE TOWARDS MOW PRO
INFLAMMATORY RISK RESPONSES AND
THAT'S PROBABLY THE INTERACTION
OF FACTORS THAT LEAD TO
DEVELOPING MS.
SO THERE ARE -- IT IS CALLED
IMMUNE MEDIATED ATTACK ON THE
MYELIN, THAT IS WHAT OUR PATIENT
HAD, A RELAPSE AND SO THERE IS A
COMBINATION THAT FACTORS BUT
T-CELLS ACTIVATE MOSTLY IN THE
PERIPHERY, ACROSS THE BLOOD
BRAIN BARRIER AND INFLAMMATION
BUT THERE ARE ALSO MANY OTHER
FACTORS THAT PLAY A ROLE LIKE
B-CELLS OR PROINFLAMMATORY AND
THEN THAT SUPPORT IN T-CELL
ACTIVATION, THERE ARE INVOLVING
THE CNS, AND THERE ARE
THERAPEUTIC IMPLICATIONS
ACTUALLY, WE LEARNED A LOT IN
THE LAST YEAR BECAUSE OF THE
HIGH SUCCESS WE SAW OF DEPLETING
THERAPIES HIGHLIGHTING THEIR
CENTRAL ROLE IN THE MASS
PATHOGENESIS.
THESE ARE NICE IMAGES AFTER THE
VENUE AND THEN THE LESIONS
DEVELOPING IN THE BRAIN STEM AS
WELL AS AXONAL DAMAGE DUE TO
LESION INFORMATION.
SO AS I MENTIONED THE HALLMARK
OF FOCAL BRAIN LESIONS AND THIS
IS THE MICROSCOPY OF A FOCAL
MYELIN LESION AND YOU CAN SEE
THAT LESIONS DEVELOP AND HAVE
SOME EDEMA AND THIS IS
INFLAMMATION SURROUNDING THE
BRAIN.
AND SO WE DETECT THEM WITH THE
EYE, IT'S GOOD CORRELATION, THEY
ARE ROUND, THEY DEVELOP IN THE
VENTRICULAR AREA, AND AND WE CAN
ALSO HAVE CORTICALE LESIONS,
THERE ARE MANY TYPES OF
CORTICALE LESIONS AND THEY ARE
VERY DIFFICULT TO DETECT WITH
CURRENT CLINICAL MRIs.
SO EARLY IN THE DISEASE
INFLAMMATION IS COMING MOSTLY
FROM THE PERIPHERY, SO
PERIPHERAL CELLS THAT CROSS THE
BLOOD BRAIN BARRIER, GENERATE
THE LESIONS, THIS IS AN EXAMPLE
OF 1 LESION THAT IS YOU NEW AND
HAS OPENING OF THE BLOOD BRAIN
BARRIER AND WE CAN DETECT IT
BECAUSE IT'S HYPER INTENSITY 1
AND IT'S HYPER INTENSE AFTER WE
PROVIDE CONTRAST TO THE
PATIENTS.
SO THIS IS AN OPEN BLOOD BRAIN
BARRIER AND INFLAMMATORY LESION.
BUT ONLY 1 OR 2 OUT OF THIN
LESIONS ARE SYMPTOMATIC AND
THAT'S WHAT CARLOS IS MENTIONING
THAT HE HAD A LESION, HE HAD AN
EPISODE AND HE HAD A COUPLE OF
OTHER LESIONS IN THE MRI THAT
HOE HAD WHEN HE DEVELOPED THE
FIRST EPISODE.
SO RELAPSE IN PATHOLOGY RECEDES
OVER THE TIME EITHER DUE TO THE
EFFECTS OF THE EMTs OR THROUGH
IMMUNE STAGES.
AT LATER STAGES OF THE DISEASE
AND MORE COMPARTMENTALIZED,
EITHER AS AGGREGATES, FULL OF
B-CELLS, OR CHRONIC ACTIVE
LESIONS OR LESIONS THAT FORM,
THEY DON'T SEAL COMPLETELY,
DON'T REPAIR COMPLETELY AND HAVE
MICROGLIA AND MICROPHAGES
ACTIVATED IN THE BORDER OF THE
LESION OR INNATE IMMUNE
ACTIVATION AND THEN NORMAL WHITE
MATTER DISTRIBUTED ALL AROUND
THE BRAIN.
SO CNS COMPARTMENTALIZE THIS
LESION, AND THIS IS TRIBUTED
THROUGH THE PRODUCTION OF
CHEMOKINES AND OTHER
INFLAMMATORY COMPONENTS.
SO THE FIRST DESCRIPTION OF THIS
WERE MOSTLY FOCUSED ON RELAPSED
PATIENTS, PATIENTS THAT PROGRESS
OVER THE TIME, SECONDARY
PROGRESSIVE BUT THE TRUTH IS
THAT IT'S NOT SO STATIC, IT'S
NOT SO WELL ESTABLISHED.
SO THINGS ARE HAPPENING, SINCE
THE VERY BEGINNING, SO THERE IS
A PRESYMPTOMATIC PHASE WHERE THE
PATIENTS MAY HAVE LESIONS THAT
DO NOT CROSS THE CLINICAL FLESH
HOLD AND THIS IS WHAT WE CALL
REGULARLY ISOLATED SYNDROME AND
THE PATIENT HAS THE FIRST
EPISODE THAT IS THE CLINICAL
ISOLATED SYNDROME AND THEN THE
PATIENT'S ARE -- MAY EVOLVE INTO
RELAPSE AND REMEDIATING MULTIPLE
SCLEROSIS FOR MANY YEARS AND
EVOLVING TO A PROGRESSIVE PHASE
OF THE DEC, -- DISEASE, WHAT IS
CALLED SECONDARY MS, THERE IS
ALSO A FEW PATIENTS THAT MY
DEVELOP PRIMARY MS, PROGRESSION
SINCE THE BEGINNING.
BUT THE TRUTH IS THAT
PROGRESSION IS NOT DICHOTOMOUS,
PATIENTS WITH RELAPSED MS MAY
HAVE REGRESSION FROM RELAPSES SO
BASICALLY MS CLINICAL
PRESENTATIONS REPRESENTS A
CONTINUED SPECTRUM OF MANY
THINGS THAT PLAY TOGETHER LIKE
INFLAMMATION, DEMILENNATION,
AXONAL GENERATION AND THE
CAPACITY OF THE BRAIN,
NEUROPLASTICKITY AND AS WELL AS
AGE AND NEUROBIOLOGICAL AGING.
SO RELAXED PATHOLOGY DOMINATES
IN THE INITIAL PHASES OF MS, AND
RELAPSE ACTIVITY SUBSEQUENTLY
TAKES THE PRIMARY ROAD.
SYMPTOMS MAY BE MANY DIFFERENT
SYMPTOMS, THE MOST IMPORTANT
THING, SO, THE FIRST EPISODE IN
25% OF THE PATIENTS IS OPTIC
NEPHRITIS, AND SEIVET% OF THE
PATIENTS WITH MS DURING THE
COURSE OF THE DEC MAY EXPERIENCE
1.
SO WHAT OUR PARTICIPANT IS
TELLING US IT'S THE PERFECT
DESCRIPTION OF A RELAPSE, IS THE
MODULATION OF SYMPTOMS NEVER
ACUTE THAT LAST MORE THAN 24
HOURS IN THE ABSENCE OF FEVER OR
INFECTION.
SO ACCORDING TO WHERE THE LESION
IS LOCATED, THE SYMPTOM THAT A
PATIENT MAY HAVE AND THESE ARE
ALL POSSIBLE SYMPTOMS THAT MAY
APPEAR IN A REAL LABS.
THERE ARE OTHER SYMPTOMS THAT
ARE NOT TYPICAL FOR RELAPSES BUT
REALLY IMPACT QUALITY OF LIFE.
THE MOST FREQUENT 1 IS FATIGUE,
THAT UP TO 95% OF PARTICIPANT
PATIENTS MAY EXPERIENCE IT,
COGNITIVE IMPAIRMENT, EFFECTIVE
DISTURBANCE, SLEEP DISORDERS AND
PAIN.
SO HOW DO WE DIAGNOSE THAT IS
NOT A SPECIFIC TEST THAT WE CAN
DO SO WE NEED TO SHOW THAT THE
PATIENT HAS DISSEMINATION IN
SPACE AND TIME AND THIS CAN BE
SHOWN WITH MRI, ONCE WE EXCLUDE
OTHER DIAGNOSIS.
SO THE FIRST TIME THAT MRI WAS
INCLUDED IN THE DIAGNOSIS, WAS
IN 2001 WHERE 3 TYPICAL
LOCATION, FRONTAL AND
PERIVENTRICULAR AND WERE
INCLUDED IN THE CRITERIA, LATER
IN 2005, THE SPINAL CORD WAS
INCLUDED AS A PLACE WHERE
LESIONS CAN DEVELOP AND IN 2010,
BOTH LESIONS THAT WERE ENHANCING
AND NONENHANCING COULD COUNT FOR
DISSEMINATION IN TIME.
SO DISSEMINATION AND SPACE TO
AREAS AND DISSEMINATION IN TIME
TO EPISODES OF LESIONS THAT ARE
ENHANCING AND ARE NOT ENHANCING
AND THAT'S WHAT EXACTLY
MR. CHACON HAS AND THAT'S WHY HE
DIDN'T NEED LUMBAR PUNCTURE.
SO WHEN I MENTIONED THE TYPICAL
LESIONS, I'M REFERRING TO THESE
4 AREAS, THE PERIVENTRICULAR, AS
I SHOW YOU, THIS IS I FLIR
SEQUENCE BECAUSE IT INVERTS THE
CONTRAST OF THE CSF, IN THE
LESIONS, WE CAN USE THE SEQUENCE
THAT IS T2.
AND THE FLAIR WHEN IT'S IN 3
DIMENSIONS IS ALSO USEFUL, AND
THE CORTICALE LESIONS THAT
FOLLOW THE U-SHAPE OF THE
FIBERS, AND SPINAL CORD LESIONS,
THE SMALL LESION, LATERAL
LESIONS, SHORT 1S, BUT THE
CORTEX IS ALSO VERY, VERY TOUGH
TO DETECT, SCANNERS WILL DETECT
THEM EASILY AT 17, AND THEY WERE
DEECTOMYOSIN IT INDEED 2017
CRITERIA.
SO LET ME JUST SHOW YOU AN
EXAMPLE OF A BRAIN THAT DOESN'T
SEEM TO HAVE A LOT OF DISEASE
THERE, YOU DON'T SEE WHITE
MATTER LESIONS BUT WHEN YOU LOOK
IN THERE, YOU SEE THERE ARE MANY
LESIONS IN THE BRAIN OF THIS
PARTICIPANT EMPLOY SO THE LUMBAR
PUNCTURE IS SOMETIMES NEEDED FOR
DISDIAGNOSIS, PATIENTS CAN
FULFILL CRITERIA WITHOUT THE
NEED BUT IF THE PARTICIPANT AS A
CLONAL THAT ARE PRESENT, THEY
NEED TO HAVE NEWER LABS OR
ACTIVE LESIONS TO FULFILL THE
CRITERIA IN TIME.
THESE ARE IGG, AND THE
PREVALENCE IS UP TO 90% WITH THE
SENSITIVITY HIGH OF VERY HIGH OF
95%, BUT SPECIFICITY IS NOT AS
HIGH, ON THE ADVANCE, BUT IT'S
ACCELERATE DIAGNOSIS IN PATIENTS
THAT HAVE THE FIRST EPISODE AND
IN PATIENTS THAT HAVE REGULAR
ISOLATED SYNDROME.
SO GOING BACK TO OUR PATIENT,
OUR PATIENT HAD THIS LESION THAT
WAS THE 1 THAT WAS SYMPTOMATIC
IN THE PONTINE AREA, THIS
LESION, SO HE FULFILL THE SPACE
AND HE HAD ENHANCING AND
NONENHANCING LESIONS.
THIS 1 WAS NOT ENHANCING AND
THESE 2 WERE ENHANCING SO HE
FULFILLED CRITERIA FOR
DISSEMINATION IN TIME.
I WILL MENTION A COUPLE OF
THINGS MORE, THERE ARE TYPICAL
FOR MS LESIONS IS THAT A LONG
TIME AGO, DEMONSTRATED THAT
LESIONS DEVELOP SURROUNDING A
VENUE AND THEN THERE IS THE
PERIVASCULAR IMP O SIGHT CALF
AND THEN THE LESION EXTENDS
OUTWARD GENERATING THE
MILENNATION AND MANY, MANY YEARS
AFTER IN 2000, IT WAS ABLE TO BE
DEMONSTRATED AT USING THE STAR
SEQUENCES AND THIS SEQUENCE IS
EXPLORE THE PROPERTIES OF THE
TISSUE AND THE HEMOGLOBIN THAT
IS INSIDE PURTURBING THE
MAGNETIC FIELD AND THE BOXES
THAT ARE WITHIN THAT AREA ARE
SHOWN VERY TARGETS IN THIS
EXAMPLE EMPLOY SO PLAQUES REALLY
FORM AROUND VEINS AND THIS IS
DETECTED AT 70 MRI AS I'M
SHOWING NOW BUT ALSO ONIN
KLF-TWOICAL SCANNERS.
BECAUSE OF THAT THERE ARE INCLUE
CLIEWGZ CRITERIA, SO WE NEED TO
SEE AT LEAST IN 2 PLANES, 1 HAS
TO BE AA LINE, 1 HAS TO BE A
DOT, AND THIS SIDE IS REALLY
VERY IMPORTANT BECAUSE IT HELPS
TO DISCRIMINATE WHITE MATTER
LESIONS AND WHITE MATTER LESIONS
THAT ARE DUE TO MS TO OTHERS
THAT MAY MIMIC MS AND IT'S
REALLY VERY RELIABLE.
SO NOW IN THE NEW CRITERIA THAT
I WILL PROBABLY PUBLISH SHORTLY
ARE THE MITT GAIGDZ OF THE
CRITERIA OF 2024, THEY ARE
PLANNING TO INCLUDE THE OPTIC
NERVE BECAUSE IT'S FREQUENTLY
AFFECTED AS WELL AS A CENTRAL
VEIN SIGN AND OTHER SIGNS THAT
DR. REICH IS PROBABLY GOING TO
DISCUSS LATER.
SO IN OUR PATIENT WE HAVE A FEW
LESIONS.
NOW THEY ARE GETTING VERY SMALL,
BUT THEY WERE ALL CENTRAL VEIN
POSITIVE.
SO WHEN AN MRI HAS MORE THAN 40%
OF THE LESIONS WITH THE CENTRAL
SIGN, WE CAN SAY THAT THAT MRI
IS CENTRAL POSITIVE.
SO IT'S VERY USEFUL BECAUSE
PATIENTS WOULDN'T NEED TO WAIT
FOR ANOTHER MRI TO SHOW
DISSEMINATION AND TIME, AND
WOULDN'T NEED TO HAVE A LUMBAR
PUNCTURE WHEN THEY FULFILL THIS
CRITERIA.
AND IT'S VERY IMPORTANT BECAUSE
IT CAN BE USED ALSO FOR RADIO
LOGICALLY ISOLATED SYNDROME AS I
MENTIONED BEFORE, INCIDENTAL
BRAIN OR SPINAL CORD LESIONS, IN
SYMPTOMATIC PATIENT AND CAN HELP
TO DIAGNOSE THE DISEASE.
SO WITH THAT SAID, I WOULD LIKE
TO GO BACK TO YOU MR. CHACON, I
WILL STOP SHARING.
AND I WILL LIKE TO GO BACK TO
YOU FOR YOUR TREATMENT.
HOW WERE YOU TREATED FOR THIS
DISEASE IN HOW DID YOU MAKE YOUR
DECISION IN, I WOULD LOAMACY
LIKE TO KNOW ABOUT THAT.
>> YES, THANK YOU.
YES, I HAVE BEEN IN TREATMENT
SINCE JANUARY 2022, IF I'M NOT
MISTAKEN.
YEAH.
ONCE I WAS DIAGNOSED, THE
FOLLOWING WEEK I MET WITH A
SPECIALIST, A DOCTOR, AND WE
SPOKE ABOUT THE TREATMENT AND HE
BASICALLY PRESENTED TO ME ALL
THE DIFFERENT OPTIONS FROM
TAKING PILLS TO IMMUNE SUPPRESS
ANTS AND AT THE END WE NARROWED
THE POSSIBILITY TREATMENTS TO 2
OPTIONS.
I CHOSE AN INFUSION THAT'S IT'S
EVERY 6 MONTHS, WELL NOW IT'S
GOING TO BE LIKE WAY EASIER
BECAUSE IT'S GOING TO BE AN
INJECTION INSTEAD OFAIN INFUSION
AND THAT'S THE 1 I'VE BEEN
TAKING SINCE JANUARY 2022 AND
THE REASON I TOOK THAT 1 IS
BECAUSE IT'S EVERY 6 MONTHS
INSTEAD OF AN INJECTION EVERY
MONTH.
>> WONDERFUL SO YOU TOOK PART IN
THE DECISION, RIGHT?
>> YES.
>> THAT'S VERY IMPORTANT.
>> YES.
HE PRESENTED OPTIONS TO ME, I
HAVE ANOTHER FRIEND THAT SHE HAS
MS AS WELL, AND SHE'S TAKING
PILLS.
SHE PREFERRED NOT TO BE AS
AGGRESSIVE AS I WAS.
>> OKAY AND DO YOU EXPERIENCE
ANY ADVERSE EEIVET WHEN YOU HAVE
INFUSIONS?
>> NO, SO FAR, NO ADVERSE EVENTS
AND NOW EVERY TIME I GET AN
INFUSION, IT TENDS TO BE FASTER
THAN THE PREVIOUS TIME, THE
FIRST TIME IT WAS LIKE 4 HOURS
AND SOMETHING, NOW IT'S LESS
THAN 4 HOURS, USUALLY.
SO, YEAH, MY BODY RESPONDS WELL.
I EVEN GET A LOT OF ENERGY THAT
DAY SO I USUALLY GO FOR A RUN
THAT SAME DAY.
>> AND DO YOU KNOW IF THE
TREATMENT IS WORKING?
>> I MEAN I HAVEN'T HAD ANY
SYMPTOMS SINCE I WAS DIAGNOSED
THE FIRST TIME.
I THINK I DON'T HAVE NEW LESIONS
OR, WELL, YOU CAN
COROBSESSIVEERATE THAT BECAUSE
YOU HAVE ACCESS TO MY MRIs,
BUT NO NEW LESIONS AND NO
SYMPTOMS AND NO RELAPSES SO FAR
IN 3 AND HALF YEARS AND KNOCK ON
WOOD BY THE WAY NTHAT'S GOOD.
AND DO YOU DO ANY WORK OUT?
DO YOU EXERCISE REGULARLY IN
WHAT DO YOU DO?
DID YOU CHANGE ANYTHING IN YOUR
RECEIVE AFTER DIAGNOSIS?
>> OH YEAH, THAT'S ANOTHER BIG
COMPONENT SINCE I WAS DIAGNOSED,
I'VE BEEN PRIORITIZE A LOT MORE
SLEEP DURING THE FIRST 20
SOMETHING YEARS OF MY LIFE I
DIDN'T PRIORITIZE SLEEP, SO
MAYBE THAT HAD CONSEQUENCE OR
NOT, BUT NOW I DO PRIORITIZE
SLEEP, I TRY TO GET 7 OR 8 HOURS
EVERY NIGHT.
I CHANGED COMPLETELY.
I EAT BETTER, I TAKE BETTER CARE
OF MY DIET, NOT ALWAYS BUT I EAT
BETTER.
>> BETTER DO YOU MEAN HEALTHIER
>> HEALTHIER, YEAH, YEAH.
I PAY A LOT MORE ATTENTION TO
WHAT I EAT.
I BARELY DRINK ALCOHOL, ONLY ON
SPECIAL OCCASIONS AND YEAH, AND
I DO EXERCISE, AND I LIKE TO RUN
AND I ALSO GO TO GYM 1 OR 2
TIMES A WEEK.
>> WONDERFUL, THAT'S GREAT.
AND DO YOU HAVE ANY SYMPTOM, ANY
FATIGUE DO YOU EXPERIENCE DURING
THE DAY?
>> I MEAN YES, AND THE
CHALLENGES,IME NOT SURE IF IT IS
BECAUSE OF MS OR MY RHYTHM OF
LIFE THAT IS VERY INTENSE BUT I
DO FEEL FATIGUE, NOT EVERY DAY
BUT THERE ARE TIMES IN WHICH I
FEEL VERY, VERY TIRED.
I MEAN I FEEL VERY, VERY TIRED.
AND THAT HAPPENS A LOT.
>> AND WHAT TIME OF THE DAY DOES
IT HAPPEN?
>> USUALLY IN THE AFTERNOON, IN
THE AFTERNOON.
IT'S USUALLY NOT HARD FOR ME TO
WAKE UP IN THE MORNING BUT IN
THE AFTERNOON I GET TIRED,
SOMETIMES AND SOMETIMES, IF IT'S
BEING A VERY, VERY LONG DAY LIKE
AT 7 OR 8:00 P.M., I'M DONE.
I MEAN I REALLY WANT TO GO TO
SLEEP.
IT'S NOT THAT COMMON, BUT WHEN
IT HAPPENS, IT'S VERY BAD, YEAH.
>> AND HOW DO YOU MANAGE?
WHAT DO YOU DO WHEN YOU HAVE
FATIGUE IN THE AFTERNOON?
>> WELL, I TRY TO GO FOR A WALK,
GET ACTIVE, I TRY COFFEE BUT IF
IT IS BEFORE 3:00 P.M. OR SO
BECAUSE THEN IT GETS HARDER FOR
ME TO SLEEP, BUT I USUALLY TRY
TO GET ACTIVE AND ENGAGE IN
SOMETHING, MAYBE I GO FOR A
WALK, MAYBE I TRY TO SPEAK WITH
SOMEONE BUT I NEED TO CHANGE THE
COURSE OF THE DAY BECAUSE IF NOT
I JUST WANT TO NAP.
AND I CANNOT TAKE A NAP, NOT IN
THE OFFICE.
BUT IF I AM AT MY PLACE, I AM
CAN REST NDOES IT WORK, DOES IT
HELP WHEN YOU NAP A LITTLE BIT?
>> YEAH THELPS FOR SURE.
>> WONDERFUL AND HOW IS YOUR
MOOD?
>> GOOD.
THANK EMPLOYLY EMPLOY -- THANKI
HAVEN'T BEEN AFFECTED BY
DEPRESSION.
OF COURSE THERE'S ALWAYS A
LINGERING FEAR OF SOMETHING IN
THE FUTURE BUT OVERALL, I -- AND
I THINK MY WIFE CAN CORROBORATE
BUT MY MOOD IS PRETTY STABLE.
>> AND ARE YOU TAKING ANY
SYMPTOMATIC TREATMENT?
>> WHAT DO YOU MEAN?
>> LIKE FOR THE FATIGUE ARE YOU
TAKE ANYTHING MEDICATION THAT
WILL HELP YOU.
>> NO, NO.
>> HAVE YOU DISCUSSED WITH WITH
YOUR NEUROLOGIST.
>> I HAVE DISCUSSED IT BUT WE
DECIDE THAD IT'S NOT NECESSARY
SO FAR.
NSO CAN YOU REVISIT ANY TIME
THAT YOU WANT AND SEE HOW YOU
ARE DOING.
>> OKAY, WONDERFUL THANK YOU SO
NOW I'M GOING TO GO BACK TO MY
PRESENTATION, TALK ABOUT
TREATMENT AND THEN I WILL GO
BACK TO YOU.
THANK YOU.
ALL RIGHT, SO I WILL TRY TO TALK
A LITTLE BIT ABOUT TREATMENT,
IT'S A VERY COMPREHENSIVE TOPIC
BUT I WOULD LIKE TO SAY A COUPLE
OF THINGS, SO THE TREATMENT
EARLY IN THE DISEASE, IT'S
BASICALLY TO PREVENT OR DELAY
DISABILITY IN THE FUTURE BUT
THERE IS NO TREATMENT, THAT IT'S
AVAILABLE IN THE TREATMENT OF
PROGRESSION.
SO WHEN WE GET TO THE TIME OF
PROGRESSION IT'S WORTH TRYING TO
SLOW OR TO STOP THE PROGRESSION
AND IMPROVE THE QUALITY OF LIFE.
SO THE NATURAL HISTORY OF
PATIENTS UNTREATED WHO HAVE A
HUGE, HUGE DATABASES, SHOWING
THAT AFTER AROUND 50 TO 20 YEAR,
30% OF THE PATIENTS ARE
UNTREATED MAY EVOLVE INTO A
SECONDARY PROGRESSIVE PHASE OF
THE DISEASE OR MORE PROGRESSIVE
PHASE OF THE DISEASE.
BUT CURRENTLY WE HAVE ALL THESE
FDA APPROVED THERAPIES FOR
MULTIPLE SCLEROSIS, THAT ARE
HUGE AND IT'S A VERY LONG LIST
OFF ALL THERAPY INFUSION THERAPY
AND INJECTION THERAPY AND THIS
HAS REALLY CHANGED A LOT, THE
EVOLUTION OF THE DISEASE, SO
THESE ARE THE TREATMENTS, THEY
ARE FDA APPROVED AND MOSTLY THEY
ARE CLASSIFIED AS HIGH EFFICACY,
IT MEANS LIKE HAVING MORE
REDUCTION IN RELAPSE RATE,
MODERATE EFFICACY AND LOW
EFFICACY.
I WILL TRY TO GO A LITTLE BIT IN
DETAIL IN EACH OF THEM BUT I'M
NOT SURE I WILL HAVE TIME.
BUT I THINK IT'S VERY IMPORTANT
TO MENTION IS THAT REALLY THIS
IS MODIFYING THERAPY ARE
EFFECTIVE IN IMPROVING
DISABILITY OUTCOME IN RELAPSING
REPEATING MS OVER THE LONG-TERM.
SO IN THIS STUDY OF MS BASE THAT
HAVE 14,700 PEASHT AND SOME OF
THEM WERE FOLLOWED FOR 1000 WERE
FOLLOWED FOR MORE THAN 15 YEARS
AND MOST WERE TREATED FOR
INTERFERON THAT IS LOW EFFICACY
AND CLASSIFIES AS LOW EFFICACY,
THEY SHOW VERY GOOD EFFECT FOR
REDUCING DISABILITY IN THE
FUTURE, THE RISK OF NEED OF
WALKING AID AND FREQUENCY OF
RELAPSES.
HOWEVER, WHENEVER HIGH THERAPY
EFKASP A R SEINTRODUCED EARLY IN
THE ASSIST, THAT RISK OF
PROGRESSION IS LOWER IN THOSE
THAT ARE TREATED EARLY WITH HIGH
AFFECTIVE THERAPY AS OUR PATIENT
WAS TREATED WITH AND THE SAME IN
TERMS OF DISABILITIES SCALE.
SO I WILL VERY BRIEFLY MENTION
THAT THESE ARE INJECTIONS.
INTERFERON, THEY ARE OLD, THESE
ARE VERY SAFE DURING PREGNANCY,
AND NURSING AND THEY MAY
EXPERIENCE INTERFERONS
PARTICULARLY FLU-LIKE SYMPTOMS
AND SOME SITE INJECTIONS AND FOR
THE ACETATE, THEY MAY HAVE
ATROPOMYOSIN TROPHY IN THE FAT,
THEY NEED TO BE CHECKED FOR
HIPOTTIC ENZYMES THAT'S MOST
IMPORTANT BUT SO FAR ARE VERY
SAFE.
ORAL THERAPIES, THERE'S -- THERE
ARE MANY ORAL THERAPIES.
THEY REDUCE THE RISK OF RELAPSES
BETWEEN 30 AND 50% AND THERE IS
INCREASED RISK OF INFECTIONS AND
HEPATIC ENZYMES ALSO CAN BE
AFFECTED AND WHEN THE MOST
FREQUENT OF THIS TYPE, THE MOST
USED OF THIS TYPE IS SINGLE
MODEL THAT MAY HAVE INFECTIONS
AND MAY NEED TO PREVENT FROM
MACULAR EDEMA AND SOME
ARRHYTHMIA, THEN OTHER PEEL THAT
MAY LEAD TO HAIR THINNING AND
ALSO RISK OF INFECTIONS BUT THE
GOOD THING IS THIS DRUG SHOWED
TO REDUCE THE RISK OF RADIO
LOGIC ISOLATED SYMPTOMS THAT
BECOME MS.
THIS IS THERAPY, IT'S SELECTIVE,
SO IT DEPLETES THESE CELLS FOR A
LONG PERIOD OF TIME AND IT HAS
ONLY 2 CYCLES, THE FIRST YEAR, 5
DAYS, THE SECOND YEAR, 5 DAYS.
TWICE DAILY, THEY MAY HAVE A
SIDE EFFECT, GI SYMPTOMS AND
FLASHING, AND THIS MAY LEAD TO
LYMPHPENIA, THESE 3 AND THE
IMPORTANT THING IS THAT THESE
ARE NOT ALLOWED TO HAPPEN DURING
PREGNANCY.
MONOCLONAL ANTIBODIES DECREASE
AROUND 70%, RISK OF NEURAL
RELAPSE AND 45-60 WHEN COMPARED
TO INTERFERONS SO IT'S REALLY
MORE EFFECTIVE.
AND WE HAVE MANY DIFFERENT,
OBVIOUSLY THE THERAPY THAT IS
THE TREATMENT THAT MR. CHACON IS
HAVING, .
THERE ARE MANY APPROVED AND
THERE IS ANOTHER THAT CAN ALSO
BE INFUSIONS EVERY 6 MONTHS, AND
RITUX MAB IS ALSO USED EVERY 6
MONTHS, TOO, SO IN THIS CASE,
THEY NEED TO CHECK FOR
ANTIBODIES AND UPDATE ALL THE
VACCINES BEFORE STARTING THE
TREATMENT AND ONCE THE TREATMENT
IS STARTED, IMMUNOGLOBULIN
LEVELS NEED TO BE CHECKED.
THAT PATIENTS MAY HAVE INFUSION.
MR. CHACON DIDN'T HAVE ANY
INFECTION REACTION, AND THEY ARE
AT HIGHER RISK OF INFECTION SO
IT'S IMPORTANT TO KEEP UP TO
DATE BECAUSE ONCE THE TREATMENT
IS STARTED, THEY -- MOST OF THEM
CANNOT BE APPLIED.
UBLITUXIMAB, IT'S AN INJECTION
EVERY 4 TO 6 WEEKS, 1 CONCERN IS
THE INDEX THAT NEEDS TO BE
CHECKED EVERY 6 MONTHS BECAUSE
OF THE RISK OF PML, THE
INFECTION OF THE CENTRAL NERVOUS
SYSTEM, THAT IS INCREASED IN
PATIENTS THAT HAVE JCV VIRUS
POSITIVE.
AND IT'S A CD52 ANTIBODY AND
ALSO RECONSTITUTION THERAPY AND
IT ALSO HAS 2 COURSES, IT'S THE
FIRST YEAR, 5 DAYS, AND THE
SECOND YEAR 3 DAYS.
BUT IT NEEDS MONTHLY MONITORING,
AND SO IT'S REALLY -- IT'S
CHALLENGING TO DO THE FOLLOW UP.
BUT BASICALLY WE HAVE MANY
OPTIONS AND WHEN WE MAKE THE
DECISION IT HAS TO BE A SHARED
DECISION BETWEEN THE PATIENT
ISSUES THE PROVIDER, BECAUSE
THERE ARE MANY FACTORS THAT 1
HAS TOO KEEP IN MIND, PERSONAL
FACTORS, THE JOB, THE FAMILY
PLAN, AGE, INSURANCE,
CO-MORBIDITIES, I WILL NOT USE A
DRUG IN A PATIENT WITH DIABETES,
ESPECIALLY WHEN INDICATED OR A
PATIENT THAT'S RECEIVING THERAPY
AND ACTIVITIES AND PROJECTS
THAT'S INTERACTING WITH THE DMT.
SO WE ALSO THINK ABOUT DMS, HOW
THE PATIENT WILL TOLERATE THE
SAFETY, OUR PATIENTS ARE MORE
OPEN TO HAVE MORE EFFICACY THAT
LESS SAFETY, AND SOME PATIENTS
WANT TO BE MORE ON THE SECURE
SIDE AND OF COURSE THE
INTERACTIONS AND THIS IS
FACTORS, CLINICAL EVOLUTION,
EARLY NATURAL HISTORY STUDIES,
REPORTED FREQUENTLY RELAPSES IN
THE FIRST 2 YEARS OF ONSET, AND
SHORTER INTERVALS TO BE
ASSOCIATE WIDE SHORTER TIMES TO
LATER DISABILITY.
AND THE MRI ACTIVITY AS WELL.
SO EDUCATION, ANTICIPATING
ADVERSE EVENTS, EASY FOLLOW UP,
AND REALLY IMPROVES COMPLIANCE
THE OTHER ENDS OF THE PATIENT
THAT MOST IMPORTANT BECAUSE ALL
THE RESULTS OF THE TRIALS ARE
WHEN PATIENTS ARE TAKING THE
MEDICATION IN THE RIGHT MANNER.
SO WHAT DO TREATMENTS DO, HOW DO
WE KNOW IF THEY WORK?
THAT'S WHAT I WAS ASKING
MR. CHACON, TREATMENTS MAKE
RELAPSES AND CONTRASTING
ENHANCING LESIONS OR NEW LESIONS
GO AWAY AND WHEN THE TREATMENT
IS THAT, WE KNOW THAT IT'S
WORKING.
SO DMTs, BASICALLY TARGET
INFLAMMATORY MECHANISMS THAT
UNDERLIE RELAPSES AS I MENTIONED
BEFORE AND MINIMIZE FUNCTION BUT
THEY ALL WORK HERE IN THE
PERIPHERY, PREVENTING CELLS TO
GET IN THE BRAIN.
THE UNMET THERAPEUTIC NEEDS
INCLUDE RELAPSING, INDEPENDENT
PROGRESSIVE MECHANISMS AND
REPAIR OF THE CNS INJURY THAT
HAS ALREADY OCCURRED.
THERE ARE OTHER FACTORS THAT
IMPACT INFLAMMATION AND THE
GENERATION THAT INCLUDE VITAMIN
D LEVELS, OBESITY,
CO-MORBIDITIES, SMOKING.
SO THE EFFECT OF SMOKING
CESSATION IN MS WAS SHOWN IN
MANY STUDIES, ACTUALLY, THOSE
THAT QUIT, THEY HAVE THE RISK OF
CONVERGENT TO SPMS, IT
DECREASES.
AND THEN IN PATIENTS WITH CIES,
VITAMIN D, WAS AN EARLY PREDICT
ONER OF MS ACTIVITY AND
PROGRESSION.
AND PATIENTS THAT HAVE VASCULAR
CO-MORBIDITIES FOR EXAMPLE, MAY
EXPERIENCE MORE RAPID DISABILITY
PROGRESSION AND THE NEED OF
UNILATERAL OR BILATERAL
ASSISTANCE, SO TREATING AND
PREVENTING VASCULAR
CO-MORBIDITIES IS VERY
IMPORTANT.
EXERCISE MAY IMPROVE SYMPTOMS,
LIKE PHYSIOLOGICAL FITNESS,
FATIGUE, DEPRESSIVE SYMPTOMS,
PAIN, BUT IT'S NOT CLEARLY
CHANGING THE EVOLUTION OF THE
DISEASE.
WITH THAT I WOULD LIKE TO GO
BACK TO YOU, MR. CHACON AND ASK
YOU A LITTLE BIT -- OOPS -- I
MADE A MISTAKE.
HERE WE GO.
AND I WOULD LIKE TO ASK YOU A
LITTLE BIT ABOUT WHAT YOU THINK
ABOUT THE FUTURE, WHAT ARE YOU
SCARED OF, IF THERE IS ANYTHING
THAT YOU WANT TO SHARE WITH US?
>> YES.
I'M GOING ABOUT THE FUTURE, I
FEEL VERY GRATEFUL BECAUSE FROM
THE MOMENT THAT I WAS DIAGNOSED
AND THEN I BEGAN SEEING MY
NEUROLOGIST AND THEN GOING TO
NIH, MOST PEOPLE THEY HAVE SAID
THAT THEY THINK THAT MY QUALITY
OF LIFE IS GOING TO BE PRETTY
SIMILAR IN THE NEXT 30, 40, 50
YEARS AND SOME DOCTORS HAVE EVEN
SAID THAT THEY THINK THAT I
WOULD LIVE TO SEE THE CURE OF
THE CONDITION, SO THAT'S VERY
HOPEFUL ON 1 HAND.
FEARS, YEAH, THERE ARE FEARS,
THERE ARE 3 MAIN FEARS, 1 IS A
LONG-TERM EFFECTS OF THE
MEDICATION AND I AM ALSO TAKING
MEDICATION FOR MY PSORIASIS, SO
BOTH MEDICATIONS WERE PRETTY NEW
SO THAT'S A FEAR.
I'M NOT THAT CONCERNED ABOUT IT
BUT WE WILL SEE IN A FEW
DECADES.
ALSO, THERE'S A FEAR THAT I CAN
SUFFER FROM DEPRESSION, BUT THE
MOST -- THE FEAR THAT IT'S
ALWAYS LINGERING AROUND US, I
MENTIONED BEFORE IS THAT I CAN
START HAVING SYMPTOMS AGAIN AND
BASICALLY DEVELOP THE
PROGRESSIVE MS, AND WITHOUT
LOOSING COGNITIVE ABILITY OR
OTHER CAPABILITIES IN MY BODY.
I MEAN THAT'S LIKE THE BIGGEST
FEAR THEY DO FEEL AND IT'S
ALWAYS LINGERING AROUND.
I CAN LIVE WITH IT BUT YOU'RE
ALWAYS THINKING ABOUT IT AND AT
THE SAME TIME IT KIND OF HELPS
YOU TO APPRECIATE WHAT YOU HAVE
AND IT ALSO FORCES ME TO -- IF I
SAY THAT I AM NOT EATING WELL,
OR I AM NOT SLEEPING WELL, OR
NOT EXERCISING, IT FORCES ME TO
GOING BACK INTO THAT.
>> AND WHY ARE YOU SCARED ABOUT
DEPRESSION?
DO HAVE YOU ANY LIKE SYMPTOMS?
IS THERE ANYTHING --
>> NO.
I DON'T HAVE SYMPTOMS,
THANKFULLY, BUT I HAVE -- YOU
WHEN GET DIAGNOSED, USUALLY A
LOT OF YOUR FRIENDS AND FAMILY,
THEY KNOW PEOPLE WHO HAVE MS,
AND YOU TALK WITH THEM AND THEY
SAY THAT A LOT OF THEM HAVE
DEVELOPED DEPRESSION EXPRK
THAT'S THE REASON I AM SCARED
BECAUSE I KNOW 6 OR 7 PEOPLE WHO
HAVE MS OR FAMILIES WITH MS AND
THAT'S SOMETHING THEY MENTION
AND I TAKE IT VERY SERIOUSLY IN
CASE IT HAPPENS.
>> IT MAY HAPPEN AND IT COULD BE
DUE TO MS ITSELF, DUE TO THE
DIAGNOSIS, AND YOUR REACTION,
AND IT'S IMPORTANT THAT YOU TALK
TO YOUR PRIMARY NEUROLOGIST AND
WITH US IF YOU HAVE ANY DOUBTS.
SO THAT SAID I WOULD LIKE TO
SHIFT TO DR. REICH, THAT HE'S
GOING TO PROBABLY ANSWER A
COUPLE OF YOUR QUESTIONS AND WE
CAN DISCUSS MORE LATER.
THANK YOU.
>> THANK YOU.
>> THANK YOU DOCTOR, AND THANK
YOU MR. CHACON, FOR SHARING YOUR
STORY WITH US AND YOUR FEARS AND
YOUR HOPES.
I HOPE WE DO SEE THE CURE OF THE
DISEASE AS YOU SAID IN YOUR
LIFETIME AND IN MY LIFETIME.
AND I HOPE THAT WE CAN, THROUGH
RESEARCH, REDUCE THE CHANCE TO
YOU KNOW AS CLOSE TO 0 AS
POSSIBLE THAT PEOPLE IN YOUR
SITUATION WHO ARE DOING SO WELL,
GO ON TO DEVELOP WHAT WE CALL
PROGRESSIVE MS WHICH IS WHERE
DISABILITY JUST CONTINUES TO GET
WORSE AND WORSE.
SO WHAT I WOULD LIKE TO DO
TODAY, IS TO DESCRIBE 1 AREA
WHERE I THINK WE MADE SOME
PROGRESS AGAINST PROGRESSION AND
I'M GOING TO SHARE MY SCREEN.
HOPEFULLY THAT WORKS.
IF YOU CAN GIVE ME A THUMBS UP
IF YOU SEE MY SCREEN.
GREAT.
OKAY, THANK YOU.
OKAY, PERFECT.
SO SOME DISCLOSURES REGARDING
FUNDING BUT MOST OF THE WORK
THAT I'M GOING TO TALK ABOUT HAS
BEEN FUNDED BY THE NATIONAL
INSTITUTES OF HEALTH AND IN
PARTICULAR THE NATIONAL
INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKE, NINDS,
WHERE BOTH OF US WORK AND THE
CLINICAL TRUSTEES WHERE WE SEE
PEOPLE WHO VOLUNTEER FOR OUR
RESEARCH STUDIES LIKE
MR. CHACON.
SO I AM A NEUROLOGIST.
I WAS TRAINED AS A NEUROLOGIST
BUT THESE DAYS I PRACTICE
CLINICAL NEURAL RADIOLOGY SO
INSTEAD OF HAVING THE GOOD
FORTUNE OF TALKING TO PATIENTS
EVERY DAY LIKE MY COLLEAGUE
DOES, I TALK TO COMPUTER SCREENS
AND LOOK AT PICTURES MOSTLY OF
PEOPLE WHO ARE LIVING WITH
MULTIPLE SCLEROSIS AND YOU'VE
ALREADY SEEN A LOT OF MRI SCANS
BUT HERE'S 1 EXAMPLE OF A SCAN
FROM SOMEBODY WHO HAD BEEN
VOLUNTEERING FOR A LONG TIME
ABOUT A QUARTER OF A CENTURY IN
THE CLINICAL PROTOCOLS, THE SAME
PROTOCOL THAT MR. CHACON
VOLUNTEERS FOR AND HAD OVER THAT
TIME ACCUMULATED A LOT OF YOUR
TO THE BRAIN CAUSED BY MULTIPLE
SCLEROSIS AND IN LARGE MEASURE
BECAUSE SHE STARTED
PARTICIPATING AND SHE'S OLDER
AND STARTED BEFORE WE HAD THESE
VERY EFFECTIVE TREATMENTS.
SO THIS IS AFTER ALL THOSE
YEARS, AND WHAT YOU CAN SEE ON
THIS SCAN ARE THESE WHITE SPOTS
IN THE MIDDLE OF THE BRAIN.
THOSE REPRESENT THE PLAQUES OR
LESIONS THAT YOU HEARD ABOUT
BEFORE AND IN THE CENTER HERE,
CAN YOU SEE THESE BLACK SPACES
WHICH ARE THE FLUID FILLED
SPACES OF THE BRAIN.
THEY CONTAIN THE CEREBRAL SPINAL
FLUID AND THEY ARE CALLED THE
LATERAL VENTRICLES AND THEY ARE
LARGER THAN THEY SHOULD BE, SO
THERE ARE THESE WHITE SPOTS,
LESIONS AND FLUID SPILLED SPACES
OF THE LATERAL VENTRICLES THAT
ARE LARGER THAN THEY SHOULD BE
AND THAT'S BECAUSE THEY TAKE UP
SPACE WHERE THERE USED TO BE
BRAIN AND NO LONGER HIS.
AND THIS ACCUMULATED OVER A GOOD
LONG TIME BECAUSE THIS IS
SOMEBODY WHO HAD BEEN COMING FOR
MANY, MANY YEARS TO THE NIH,
GETTING LOTS OF MRI SCANS AND
THIS SHOWS YOU THE CUMULATIVE
EFFECTIVE THAT.
BUT HERE IS A MOVIE THAT IS MORE
THAN A HUNDRED 50 MRI SCANS
TAKEN AT THE SAME LEVEL, THE
SAME PART OF THE BRAIN, THAT ARE
PUT TOGETHER OVER THAT PERIOD SO
YOU SEE IT RUNNING OVER THE
COURSE OF A MINUTE OR SO AND YOU
WILL SEE IT WILL REPEAT AND
EARLY ON, YOU CAN SEE WELL, I
THINK IT WILL REPEAT, I HAVE TO
START IT AGAIN.
AND YOU SEE THESE BRIGHT FLASHES
AND IT REPRESENTS AREA AS YOU
HEARD BEFORE THESE ARE OPENING
IN THE BLOOD VESSEL OF THE
BRAIN, AND THESE ARE AREAS OF
WHAT WE CALL BLOOD BRAIN BARRIER
DAMAGE, IT'S ACTUALLY JUST A
TRANSIENT OPENING OF THE BLOOD
BRAIN BARRIER, THE CONTRAST DIE
THAT WE INJECT WHICH HAS A HEAVY
METAL IN IT CALLED GATTA LYNNIUM
LEAKS OUT THROUGH THAT OPEN
BLOOD VESSEL INTO THE BRAIN JUST
FOR A COUPLE OF WEEKS, 1 OR 2
FRAMES OF THIS MOVIE AND THEN IT
RESOLVES.
SO THE FLASH GOES AWAY, BUT EACH
TIME THAT HAPPENS THERE'S BEEN
DAMAGE THAT OCCURS AND THAT'S
WHAT SHOWS UP AS THE BRIGHT
SPOTS IN THE OTHER IMAGE AND YOU
CAN SEE OVER TIME, THERE ARE
MORE AND MORE OF THESE FLASHES
OCCUR.
THE CENTRAL AREA, THE
VENTRICLES, THE SPACES ARE
GETTING LARGER AND LARGER AND AS
THE PATIENT GETS OLDER, YOU CAN
SEE THE FLASHES LEAVE BEHIND
THESE DARK SPOTS AND THOSE
REPRESENT AREAS OF DAMAGE TO THE
BRAIN THAT REALLY IS
IRREVERSIBLE.
EARLY ON IT TENDS TO REPAIR AND
THEN LATER ON IT BECOMES MORE
IRREVERSIBLE AND THROUGH STUDIES
LIKE THIS, WE HAVE LEARNED A LOT
ABOUT WHAT WE CALL TD NATURAL
HISTORY OF MULTIPLE SCLEROSIS.
WE'VE LEARNED AS WAS MENTIONED
BEFORE THAT THESE NEW LESIONS
OCCUR MUCH MORE FREQUENTLY THAN
THE CLINICAL SYMPTOMS LIKE YOU
HEARD DESCRIBED BEFORE AND SO IT
WAS REALIZED ACTUALLY HERE AT
THE NIH IN THE 1990S THAT IF YOU
USE THE MRI SCANS, YOU COULD
MUCH MORE RAPIDLY SCREEN NEW
MEDICATIONS, ANTIINFLAMMATORY
MEDICATIONS THAT MIGHT BE
EFFECTIVE IN MULTIPLE SCLEROSIS
AND SEE WHETHER THEY STOPPED
THESE NEW LESIONS FROM FORMING
AND AS YOU ALREADY HEARD, WE
HAVE MANY, MANY, MORE THAN 2
DOZEN SUCH ANTIINFLAMMATORY
DISEASE MODIFYING THERAPIES OR
DMTs THAT ARE AVAILABLE FOR
MULTIPLE SCLEROSIS, SOME OF THEM
INFUSIONS, SOME OF THEM PILLS,
AS YOU HEARD, AND SOME OF THEM
EXTREMELY EFFECTIVE, SINCE HIS
SYMPTOMS OCCURRED.
THE PROBLEM IS WHILE WE'VE BEEN
ABLE TO STOP THESE NEW LESIONS
FROM OCCURRING AND THESE NEW
RELAPSES FROM OCCURRING, THESE
CLINICAL EVENTS, WE HAVEN'T
ACTUALLY CURED MULTIPLE
SCLEROSIS BECAUSE WE CAN STILL
SEE, ALBEIT IN A PROPORTION OF
PEOPLE AND STILL A SIZABLE
PROPORTION OF PEOPLE WHO GO TO
DEVELOP THIS DREADED PROGRESSIVE
MULTIPLE SCLEROSIS WHERE PEOPLE
LOSE NEUROLOGICAL FUNCTIONING
AND CAN END UP FOR EXAMPLE
LOSING THE ABILITY TO WALK AND
SO THAT'S WHAT WE REALLY WANT TO
PREVENT AND THE GOAL HERE IS TO
TAKE THIS EARLY INFLAMMATION
THAT WE CAN DETECTOT MRI AND
FIGURE OUT NOT JUST HOW TO
PREVENT THAT BUT HOW TO TREAT
THAT SO THAT WE CAN PREVENT THIS
NEURODEGENERATION MANIFESTED BY
A LOSS OF BRAIN TISSUE AND
ENLARGEMENT OF THE FLUID FILLED
SPACES AND HERE YOU CAN SEE THE
SCHEMATIC, SHOWING THE
INFLAMMATORY INJURY, FOCAL
LESIONS THAT DEVELOP THOSE
FLASHES, BRIGHT FLASHES ON THE
MRI SCAN, BECAUSE IT'S COMING
FROM THE IMMUNE SYSTEM, OF THE
BLOOD, THE BRAIN IS CENTRAL AND
THE BLOOD IS PERIPHERAL IN THIS
CASE, AND WE CAN STOP THOSE BUT
NONETHELESS, THERE STILL
ACCUMULATES WHAT WE CALL CNS, OR
CENTRAL NERVOUS SYSTEM
COMPARTMENTALIZED INFLAMMATORY
INJURY THAT CAN ACCUMULATE.
THERE'S A VARIETY IT MEN FASTS,
1 IS AT THE EDGE OF THOSE FOCAL
LESIONS, 1 IS DIFFUSELY
THROUGHOUT THE BRAIN, AND WE CAN
ALSO SEE INFLAMMATION NOT JUST
IN THE BRAIN, BUT AROUND THE
BRAIN IN THE MENINGS WHICH ARE
THE THING AREAS WHERE THEY COVER
AND PROTECT THE BRAIN WHERE
THERE'S A LOT OF IMMUNE
SURVEILLANCE BUT YET CAN
ACCUMULATE INFLAMMATION IN THE
CONTEXT OF MULTIPLE SCLEROSIS.
THESE ARE THE 3 MAIN WAYS WE
TEND TO HAVE THIS CNS CENTRAL
NERVOUS SYSTEM COMPARTMENTALIZED
INFLAMMATORY INJURY.
AND WHEY WILL FOCUS THE REST OF
THE TIME IN SORT OF DO A DEEP
DIVE ON IS THIS IRON RIM OR
PERIPHERAL PARAMAGNETIC RIM
LESION I WILL EXPLAIN THOSE AND
HOW THEY ARE AND HOW THEY RELATE
TO MS AND UP TILL ABOUT 10 YEARS
AGO THE ONLY WAY WE REALLY KNEW
ABOUT THIS KIND OF INFLAMMATION
AT THE EDGE OF THE LESIONS WAS
THROUGH STUDIES OF BRAIN TISSUE
AFTER DEATH, AFTER AUTOPSIES
WHERE PEOPLE HAD DONATED THEIR
BRAIN TO SCIENCE AND 1 COULD DO
ANALYSIS.
YOU COULDN'T TRACK IT, DURING
THE COURSE OF THE DISEASE, BUT
YOU CAN MAKE INFERENCES AT THE
END BY LOOKING AT MANY, MANY
BRAINS AND SOME OF THEM HAD A
SHORT TIME WITH MS, SOME HAD A
LONG TIME WITH MS, SOME WERE
YOUNG, SOME WERE OLD AND YOU CAN
TRY TO RECONSTRUCT WHAT MAY HAVE
HAPPENED AND HERE IS STILL THE
MOST COMPREHENSIVE STUDY DONE BY
CLAUDIA AT THE MAYO CLINIC, AND
IT'S 120 AUTOPSIES BRAINS,
ALMOST 2500 LESIONS AN LIZED
CAREFULLY UNDER THE MICROSCOPE
AND WHAT WE'RE TALKING ABOUT
HERE ARE THESE LESIONS THAT ARE
IN THIS SORT OF SALMON COLOR AND
YOU CAN SEE THEM IN THE BAR
GRAPHS ON TOP THAT THE
PROPORTION OF LESIONS THAT
ANALYZE THAT HAD THIS FEATURE,
THEY CALL TODAY SMOLDERING, WE
NOW CALL IT CHRONIC ACTIVE
LESIONS, TEND TO INCREASE
ROUGHLY IN PROPORTION AS PEOPLE
LIVE LONGER AND LONGER WITH THE
DISEASE BEFORE THEY CAME TO
AUTOPSIES.
ALTHOUGH INTERESTINGLY THAT MAY
DROP A LITTLE BIT IN THE LONGEST
SPAN PATIENT.
SO THAT'S SORT OF WHAT WE KNEW
BUT PEOPLE WHO HAD VERY EARLY
DISEASE DID NOT TEND TO HAVE
VERY MANY OF THESE AT ALL OR
NONE.
SO TO MAKE A LONG STORY SHORT,
WE'RE FACE WIDE THE TASK OF
TRYING TO UNDERSTAND HOW TO
IDENTIFY WHETHER AN INDIVIDUAL
MAY HAVE HAD THESE -- MAY HAVE
THESE CHRONICALLY INFLAMED
LESIONS AS MUCH AS AFTER THEY
DIE BUT WHILE THEY'RE ALIVE AND
DOING WELL, AND THIS WAS ABOUT
10 YEARS OF WORK IN OUR GROUP
AND ALSO IN OTHER GROUPS TO
FIGURE OUT WHAT THIS WAS AND I
WILL TRY TO SUMMARIZE THAT IN 1
SLIDE, HOW DO WE IDENTIFY THESE
SMOLDERING OR CHRONIC ACTIVE
LESIONS SO WHAT YOU SEE HERE IS
AN IMAGE, OF A BRAIN SECTION, A
SMALL SECTION AND JUST FOR
ORIENTATION, ON THE LEFT SIDE,
IS THE EDGE OF THE BRAIN, YOU
HAVE THE OUTSIDE OF THE BRAIN,
THAT'S THE CEREBRAL CORTEX WHERE
THE CELL BODIES OF THE NERVE
CELLS, THE NEURONS LIVE, AND
THEN THE DARKER BROWN AREA, IS
THE WHITE MATTER, THESE ARE THE
FIBERS THAT CONNECT 1 AREA OF
THE BRAIN TO THE NEXT, 1 CELL TO
THE NEXT.
ON THE FAR RIGHT AT THE BOTTOM,
IS THAT THE FLUID SPILLED SPACE,
IT'S BLACK HERE BECAUSE THE
FLUID IS GONE WHEN WE PREPARE
THE TISSUE AND THEN YOU HAVE
THESE AREAS WHERE THERE IS NO
STAINING -- LET ME SEE IF I CAN
GET A LACER POINTER, SO THESE
AREAS OVER HERE WHERE THERE'S NO
BROWN AT ALL, THE BROWN IN THIS
CASE IS A STAIN FOR MELYN, THAT
IS THE FATTY SUBSTANCE THAT HAS
PROTEINS IN IT THAT ENSUEALATES
THE NERVE FIBERS AND WIRES.
AND THE MILEIN IS ACTUALLY THE
TARGET OF THE IMMUNE ATACT IN
MS, SO THESE ARE LESIONS AND
THERE'S NO MYELIN, THIS SHOULD
ALL BE BROWN.
SO THESE HAVE BEEN HERE FOR
QUITE A LONG TIME IN THIS
INDIVIDUAL.
AND IF YOU LOOK IN DETAIL AT THE
EDGE OF 1 OF THESE NOW WE'RE
STAINING FOR A PROTEIN CALLED
CD68.
CD68 IS A PROTEIN THAT IS
PRESENT IN CELLS THAT ARE EATING
DEBRIS FOR EXAMPLE, AND YOU CAN
SEE THAT AT THE EDGE OF THIS
LESION, ARE FULL OF THESE SMALL
CELLS THAT ARE PRESENT AND THESE
ARE CELLS OF THE IMMUNE SYSTEM,
SO EVEN THOUGH IT LOOKS SORT OF
BENIGN HERE ON THE LEFT OR
QUIET, YOU CAN ACTUALLY SEE
THERE'S LOTS OF IMMUNE CELLS
PRESENT AROUND THE EDGE OF THIS
LESION AND IF YOU LOOK IN MORE
DETAIL, THIS IS NOW A STAIN FOR
LIPID, AND PROTEIN LIPID FATTY
SUBSTANCE THAT'S IN THE MYELIN,
YOU CAN SEE THAT THAT SUBSTANCE
IN BLUE AND PURPLE IS INSIDE
THESE CELLS AT THE EDGE OF THE
LESION AND THAT MEANS THAT
THERE'S ACTIVE EATING OF MYELIN
GOING ON.
BUT THAT'S QUITE -- SORRY SO
SOME FRACTION OF THOSE CELLS
ACTUALLY HAVE IRON IN THEM, AND
WE CAN TALK ABOUT THE IRON A
LITTLE BIT LATER, WE WILL
ACTUALLY TALK ABOUT A LITTLE
MORE.
AND THAT'S REMARKABLE BECAUSE WE
CAN SEE IRON ON THE MRI SCAN, ON
A SPECIFIC KIND OF MRI SCAN,
CALLED A SUSCEPTIBILITY
SENSITIVE MRI, AND THIS IS AN
IMAGE OF THAT SAME LESION, RIGHT
OVER HERE EMPLOY THIS LESION
OVER HERE THAT I'M OUTLINING AND
YOU CAN SEE A DARK LINE AT THE
EDGE OF THAT LESION, THAT
REPRESENTS THE AREA WHERE
THERE'S IRON.
THIS HAPPENS TO BE AN IMAGE OF
THE BRAIN BEFORE YOU CUT IT TO
PUT IT UNDER A MICROSCOPE BUT WE
CAN ACTUALLY SEE THIS IN LIVING
PEOPLE AS WELL, WITH RELATIVE
EASE.
AND IN THIS INDIVIDUAL, CAN YOU
ACTUALLY SEE THAT OVER THE 7
YEARS, THAT WE FOLLOWED THEM,
BEFORE THEY DIED, THE SIZE OF
THESE LESIONS RIGHT UP AGAINST
THE VENTRICLE, THESE ARE SCANS
TAKEN WHILE HE WAS ALIVE, CAN
YOU SEE THERE'S BEEN SUBSTANTIAL
ENLARGEMENT OF THOSE SCANS AND
THAT MAKES A LOT OF SENSE WHEN
YOU THINK ABOUT THE FACT THAT
THERE'S ACTIVE EATING BREAK DOWN
OF THE MILEN THAT'S OCCURRING.
SO THE LESIONS WOULD ENLARGE.
SO HOW DO WE IDENTIFY THESE
SMOLDERING LESIONS, WE LOOK FOR
THIS PARAMAGNETIC OR IRON OR
DARK RIM, AND WHEN WE SEE THAT,
ON THE MRI, WE CAN INFER THAT
THERE'S CHRONIC INFLAMMATION,
MYELIN DESTRUCTION AND LESION
EXPANSION.
SO WITH THIS TOOL IN HAND WE
WERE ABLE TO GO BACK AND SAY,
OKAY, WE CAN NOW IDENTIFY IT,
HOW DO THESE KINDS OF LESIONS OR
PLAQUES ARISE IN AND THIS
ACTUALLY GOES BACK TO WORK THAT
THE DOCTOR DID WHEN HE WAS A
TRAINEE IN OUR LAB.
SHE DID EXPERIMENTS AND STUDIES
LOOKING AT THE EARLIEST STAGES
OF LESION DEVELOPMENT WHERE SHE
INJECTED THE GATTA LYNNIUM
CONTRAST MATERIAL AND VERY EARLY
ON WHEN A LESION DEVELOPS, CAN
YOU SEE THAT THE BRIGHT SPOT
HERE, SO THIS A MOVIE OVER ABOUT
AN HOUR OR SO, MAYBE SHORTER
THAN THAT, CAN YOU SEE THERE'S
LEAKAGE FROM THE DYE FROM THE
CENTER OF THE DARK AREA HERE AND
IT SPREADS OUT OVER TIME.
ABOUT HALF OF THE TIME IF YOU
WAIT A FEW DAYS, BRING THE
PERSON BACK AND SCAN THEM AGAIN,
WHAT YOU CAN SEE IS ABOUT HALF
OF THOSE LESIONS HAVE A
DIFFERENT BEHAVIOR.
LET ME SEE.
I LOST THE VIDEO.
LET ME TRY IT AGAIN.
YES, CAN YOU SEE THAT THE
CONTRAST IS NOW LEAKING FROM THE
EDGE AND FILLING OUT THE CENTER
AS THIS LESION EXPANDS.
AND THOSE WERE ABOUT 50% OF THE
LESIONS THAT WE TRACKED AND THEY
TENDED TO BE THE LARGER 1S.
AND SO WHAT WE DID WAS WE
INVITED THESE PEOPLE BACK TO GET
REALLY HIGH RESOLUTION DEDICATED
MRI SCANS, OF THE SAME AREA
USING OUR ADVANCE 7 TESLA
SCANNER, THESE ARE AMONG THE
STRONGEST SCANNERS AVAILABLE,
FORTUNATELY WE HAVE 3 OF THEM
HERE AT THE NIH CLINICAL CENTER,
WHERE WE CAN DO THESE KINDS OF
STUDIES AND HERE YOU CAN SEE THE
LEAKAGE OF THE CONTRAST
MATERIAL, THE OPEN BLOOD BRAIN
BARRIER AT THE EDGE OF THE
LESION AND WHEN WE DO THAT, IRON
SENSITIVE SCAN, YOU CAN SEE A
DARK RIM AROUND THE EDGE OVER
HERE YOU CAN ALSO SEE THE
CENTRAL VEIN THAT THE DOCTOR
TALKED ABOUT AND YOU CAN SEE HOW
THE LESION IS FORMING AROUND
THIS CENTRAL VEIN.
SO WE WENT ON TO SHOW THAT ABOUT
A QUARTER OF THE NEW LESIONS
THAT DEVELOPED HAD THIS REALLY
INTERESTING FEATURE.
THEY WERE START SMALL, ABOUT A
MONTH LATER YOU CAN SEE THIS
OPEN BLOOD BRAIN BARRIER, A RIM
IS BEGINNING TO FORM AND THEN IT
PERSISTS OVER TIME EVEN AS THE
BLOOD BRAIN BARRIER REPAIRS, SO
THERE'S THIS CHRONIC
INFLAMMATION THAT WE CAN DETECT
AND INFER BY THE PRESENCE OF
IRON IS REALLY SET UP OVER THE
FIRST FEW MONTHS AFTER A NEW
LESION FORMS AND THAT REALLY
WASN'T UNDERSTOOD AT THE TIME.
ARE THESE -- WE COULD ALSO ASK
QUESTIONS ABOUT, YOU KNOW WHY
AND HOW THESE KINDS OF LESIONS
MAY BE MORE DESTRUCTIVE THAN
OTHER SORTS OF LESIONS, SO
HERE'S AN EXAMPLE, THIS IS JUST
A ZOOMED IN MRI, SO I'M SORRY IT
DOESN'T ACTUALLY SHOW SORT OF
THE CONTEXT OF WHERE IT IS IN
THE BRAIN BUT HERE YOU CAN SEE,
IN THIS KIND OF MRI, THE LESION
IS DARK, AND HERE, I THINK IT
PROBABLY DOESN'T PROJECT VERY
WELL, BUT THERE IS A DARK RIM AT
THE EDGE OF THAT LESION.
THIS IS A LESION THAT ACTUALLY
CAUSED THE SYMPTOM AND THAT
SYMPTOM WAS A LOSS OF ABILITY TO
SEE PART OF THE WORLD BECAUSE
THIS LESION AFFECTED A PATHWAY
IN THE BRAIN CALLED THE OPTIC
RADIATION TOWARD THE BACK OF THE
BRAIN WHICH IS WHERE THE VISUAL
PROCESSING HAPPENS AND EVEN
THOUGH IT'S A REALLY TINY LITTLE
LESION BECAUSE IT WAS SUCH A
DAMAGING LESION, THE INVOLVEMENT
OF THAT FUNCTIONAL PATHWAY WAS
QUITE SIGNIFICANT AND HERE'S 1
WAY OF LOOKING AT THAT.
THIS IS WHAT WE DID HERE IS WE
TOOK 2 SCANS, 1 BEFORE THE
OCCURRED BECAUSE THIS IS
SOMEBODY WE WERE FOLLOWING OVER
TIME AND 1 AFTER AND WE JUST
OVERLAID THEM AND SUBTRACTED
THEM AND YOU CAN SEE, THE VERY
BRIGHT SPOT WHICH IS WHERE THE
LESION IS, BUT YOU CAN SEE A
MUCH MORE SUBTLE, WE DIDN'T --
YOU CAN'T SEE IT ON THE ORIGINAL
SCANS BUT ON THE SUBTRACTION,
CAN YOU ACTUALLY SEE THE WHOLE
PATHWAY OF THE OPTIC RADIATION
IS LIEDING UP HERE TELLING US
THIS LITTLE LESION HERE WHICH
WAS DESTRUCTIVE AND HAD THIS
CHRONIC INFLAMMATION ATTRIBUTE
COULD ACTUALLY AFFECT UPTREME
AND DOWN STREAM THROUGHOUT THE
PATHWAY AND CAUSINGED REALLY
SIGNIFICANT SYMPTOMS.
WE HAVE LOOKED NOW AT 500
PEOPLE, THE SCAN, THIS SLIDE IS
A FEW YEARS OLD, SO WE'RE CLOSER
TO A THOUSAND PEOPLE NOW, AND WE
ARE ABLE TO SHOW THAT THESE
PRLs, THESE PARAMAGNETIC RIM
LESIONS, THESE LESIONS WE CAN
DETECT ON MRI, ARE OCCURRING IN
ROUGHLY 50-60% OF INDIVIDUALS
WITH MS, THEY ARE A BIT MORE
FREQUENT IN PEOPLE WITH
PROGRESSIVE MS.
BUT WHEN YOU SEE THEM, THEY TEND
WHEN THERE ARE POWER OR MORE IN
THE BRAIN THEY TEND TO PREDICT A
WORSE DISEASE COURSE BECAUSE
THERE'S ALL THIS INFLAMMATION
GOING ON IN THE BRAIN AND ACTIVE
DAMAGE TO TISSUE.
AND THESE LESIONS OCCUR VERY,
VERY RARELY IN PEOPLE WHO DO NOT
HAVE MULTIPLE SCLEROSIS, EVEN IF
CLINICALLY, THEY MIGHT APPEAR TO
POSSIBLY HAVE MULTIPLE
SCLEROSIS, IT'S VERY RARE TO SEE
1 OF THESE AND AS SUCH THE
PRESENCE OF PARAMAGNETIC RIM
LESIONS IF THEY OCCUR IN 50 OR
60% OF PEOPLE OVERALL ARE HIGHLY
SPECIFIC FOR MS AND WILL ENTER
THE DIAGNOSTIC CRITERIA VERY
SHORTLY.
THIS IS A SECOND STUDY FROM
COLLEAGUES IN SWITZERLAND WHO
ALSO LOOKED AT PARAMAGNETIC RIM
LESIONS USING TECHNOLOGY WE
BUILT HERE AT THE NIH AND
REPLICATE FINDING SHOWING THAT
PEOPLE WHO HAD SUCH LESIONS OR
PLAQUES IN THE BRAIN WERE MORE
LIKELY TO HAVE PROGRESSIVE
MULTIPLE SCLEROSIS AND
PROGRESSION, WORSENING OF
DISABILITY EVEN IN THE ABSENCE
OF RELAPSES, THAT'S WHAT WE CALL
PROGRESSION INDEPENDENT RELAPSE
ACTIVITY.
PIRA.
I SHOWED YOU AT THE EDGE OF THE
LESIONS 1 CAN SEE MYELIN, THE
INSULATION OF NERVES INSIDE
CELLS THAT ARE EATING THEM AND
CLEANING IT UP.
YOU CAN ALSO SEE THE AXONS,
THESE ARE THE NERVE FIBERS
THEMSELVES, ARE BEING CUT AT THE
EDGES OF HE'S LESIONS WHERE THE
INFLAMMATION IS OCCURRING, AND
THAT'S SHOWN HERE ON THE TOP
LEFT IN BROWN AT THE EDGE OF A
CHRONIC ACTIVE LESION, CAN YOU
SEE THESE BROWN SPOTS WHICH
REPRESENT RECENT CUTTING OF
AXONS.
AXONS ARE THE HIGHWAYS OF THE
BRAIN.
THIS IS WHERE THE COMMUNICATION
IS OCCURRING, WHEREAS IN A
CHRONIC INACTIVE LESION, WE
STILL HAVE A LESION WITH NO
MYELIN, WITHOUT STANDING HERE IN
THE BOTTOM, WITHOUT THE BLUE
STAINING BUT YOU DON'T HAVE THE
BROWN DOTS PRESENT.
AND SO THIS IS REALLY OLD DAMAGE
WHEREAS THIS IS REALLY ONGOING
AND INTERESTINGLY WE CAN NOW
DETECT 1 OF THE PROTEINS INSIDE
AXONS CALLED NEUROFILAMENT, NOT
JUST IN THE SPINAL FLUID BUT
ALSO IN THE BLOOD.
AND WHAT WE WERE ABLE TO SHOW IN
COLLABORATION WITH OUR
COLLEAGUES, IN EUROPE, IS THAT
PEOPLE WHO HAD 1 TO 3 OF THESE
PARAMAGNETIC RIM LESIONS
COMPARED TO 0 HAD A 15%ILE
INCREASE IN THE LEVELS OF THIS
BLOOD PROTEIN, THAT DETECTS AXON
NEURON NERVE FIBER DAMAGE AND
THOSE WHO HAD 4 OR MORE SUCH
LESIONS HAD A 30 PERCENTILE
INCREASE, SO GOING ALONG WITH
THE IDEA THAT AS THE BRAIN IS
BEING DAMAGED BY THIS CHRONIC
INFLAMMATION ACCIDENT WE MAY
ACCUMULATE A DISABILITY AND WE
ARE ALSO ABLE TO SHOW THAT IF
YOU LOOK OVER TIME, THAT THESE
KINDS OF LESIONS ISSUE THESE
PRLs, CAN ACTUALLY EXPAND
SLOWLY AS I SHOWED YOU EARLIER
WITH THE PATIENT WHOSE BRAIN WE
LOOKED AT AND HERE YOU CAN SEE 1
CLEEGZ JUST GRADUALLY EXPANDING
OVER TIME IN THE FRAMES OF THIS
MOVIE.
THIS IS SOMEBODY WHO HAD MS FOR
ALMOST 30 YEARS AND IT'S 118
SCANS THAT GO INTO THIS MOVIE
AND HERE YOU SEE A FEW
SNAPSHOTS, AGE 35, 40, 45, 55
ISSUEs AS THIS LESION IS
EXPANDING OVER TIME.
YOU CAN SEE IT'S RIM AT THE
EDGE.
THIS IS NOW A SCAN.
AND THIS PATIENT IS VERY MUCH
STILL ALIVE.
THIS JUST QUANTIFIES WHAT I JUST
SHOWED YOU ACROSS 54 LESIONS
THAT TEND TO HAVE THIS RIM GET
LARGER BY 2 PERCENT PER YEAR ON
AVERAGE WHEREAS THOSE THAT DO
NOT TEND TO GET SMALLER OVER
TIME, NOT SO MUCH BECAUSE
THEY'RE REPAIRING BUT BECAUSE
THERE'S SORT OF SLOW CLEAN UP
THAT OCCURS AND 2% PER YEAR MAY
NOT SEEM LIKE A LOT BUT IF YOU
ADD THAT YEAR AFTER YEAR, IT
BECOMES QUITE SUBSTANTIAL AND
THE WAY THE BRAIN IS WIRED UP,
THAT KIND OF EXPANSION CAN HAVE
REALLY IMPORTANT DOWN STREAM
CONSEQUENCES.
SO THIS IS NOT THE ONLY REASON
WHY SOMEBODY MAY DEVELOP MS
PROGRESSION BUT IT MAKES SENSE,
STANDS TO REASON THAT IT MIGHT.
SO ARE WE ABLE TO TREAT THESE
WITH OUR CURRENT DISEASE
MODIFYING THERAPIES, THE 2 DOZEN
THERAPIES THAT WE HAVE?
WELL OUR EARLY CLUE IS THAT WE
ACTUALLY SAW SUCH LESIONS ON
BASIC -- PEOPLE WHO WERE TAKING
ALL THE DIFFERENT KINDS OF
DISEASE MODIFYING THERAPIES THAT
ARE AVAILABLE FOR US.
SO IT DIDN'T REALLY SEEM, EVEN
THOUGH THESE WERE NOT TRIALS
WHERE WE FOLLOWED PEOPLE OVER
TIME TO SEE WHETHER THE LESIONS
WOULD RESULT, NONE THE LESS, WE
CAN INFER FROM THIS LOOK, THAT
EVEN IF THERE IS SOME EFFICACY
OF OUR MEDICATIONS, IT'S NOT
PERFECTLY EFFECTIVE BECAUSE WE
CAN SEE IRON RIM, THE
PARAMAGNETIC RIM LESIONS ON
PATIENT WHO IS ARE TAKING ALL
THE DIFFERENT THERAPIES THAT WE
HAVE.
SO OVERTIME WE HAVE OTHER VS
STARTED TO LOOK AT WHETHER OR
NOT THE THERAPIES CHANGE THE
APPEARANCE OF THESE IRON RIM
LESIONS OVER TIME, THIS IS 1 OF
THE MOST EFFECTIVE THERAPIES,
THE 1 THAT MR. CHACON IS TAKING,
WHERE IT REMOVES THE B-CELLS
FROM THE CIRCULATION, WE WERE
ABLE TO TRACK 70 PATIENTS OVER
TIME, ABOUT 350 LESIONS OVER THE
COURSE OF 2 YEARS IN PATIENT WHO
IS ARE TAKING THIS THERAPY WHERE
PEOPLE HAVE OFTEN NO NEW
LESIONS, NO SYMPTOMS AND YET WE
SAW NO CHANGE IN THE APPEARANCE
OF THESE LESIONS WHEN WE TRACK
THEM BY MRI OVER TIME.
SO WE REALIZE WE WILL NEED TO
LOOK FOR OTHER MEDICATIONS THAT
TREAT THIS.
AND SO HOW DO WE DO THAT?
SO WE'VE BEEN FOCUSING ON AND
OTHERS ARE FOCUSING ON AS WELL
IS THE CELLS THAT ARE PRESENT AT
THESE LESIONS.
THE MAIN CELL WE'VE BEEN
FOCUSING ON ARE MICROGLIA.
MICROGLIA ARE A BRAIN CELL
THAT'S PRESENT IN EVERYBODY,
THEY HAVE LOTS AND LOTS MUCH
ROLES.
THEY HAVE ROLES IN NORMAL
DEVELOPMENT OF THE BRAIN.
THEY'RE INVOLVED IN MAKING AND
MATURING SYNAPSES WHICH ARE HOW
NERVE CELLS ARE CONNECTED TO 1
ANOTHER, AND THEY'RE INVOLVED IN
SURVEILLANCE OF THE BRAIN AND
PROTECTING FROM INFECTION, EVEN
WHEN THERE'S NOTHING WRONG AT
ALL.
AND THEY ARE ALSO INVOLVED IN
LOTS AND LOTS OF DIFFERENT DECS,
THEY'RE INVOLVED IN MULTIPLE
SCLEROSIS AND THE WAY THEY'RE
DRIEBED ARE INVOLVED IN STROKE
AND ALZHEIMER'S DISEASE, IN
PSYCHIATRIC DISORDERS, LIKE
SCETS FRENNIA AND AUTISM AND
THEY ARE REALLY 1 OF THE KEY
CELLS INVOLVE CELL TYPES OF THE
BRAIN INVOLVED IN INFLAMMATION,
AND SO, YOU KNOW THEY CAN HAVE 2
FACES, THEY CAN BE VERY HELPFUL,
BUT THEY CAN ALSO BE DAMAGING
AND SO WE NEED TO UNDERSTAND HOW
THAT OCCURS IN ORDER TO TREAT T
WHEN THINGS ARE NOT GOING WELL
AND 1 OF THE WAYS WE'VE DONE
THAT IS TO ANALYZE TISSUE IN A
WAY THAT WAS INFORMED BY THE MRI
SCANS THAT WE DO SO WE WERE ABLE
TO USE THE MRI KAN--KANAS TO GO
RIGHT TO THE EDGE OF THESE
LESIONS IN THE BRAIN WHERE THE
IRON WAS PRESENT TO TAKE.
THIS IS LOOKING AT POST
AUTOPSIES BRAINS BUT WE'RE ABLE
TO TAKE BIOPSIES OF THOSE POST
AUTOPSIES BRAINS, REALLY
DIRECTED BYOPSYS AND SUBJECT THE
CELLS ACTUALLY THE NUCLEI OF
THOSE CELLS TO A TECHNIQUE
CALLED SINGLE NUCLEUS, RNA
SEQUENCING, THIS TELLS US ALL OF
THE GENES THAT HAVE BEEN TURNED
ON IN THAT CELL, AND THAT GIVES
US THE SIGNATURE OF NOT ONLY
WHAT CELL TYPE IT IS SO WE CAN
RECOGNIZE READILY, MICROGLIA AND
OTHER TYPES OF IMMUNE CELLS AND
NERVE CELLS AND OTHER TYPES OF
CELLS IN THE BRAIN AND BLOOD
VESSEL CELLS, ET CETERA, OR TO
SOME EXTENT WHO THOSE CELLS ARE
DOING BECAUSE IF THEY'RE
INVOLVED IN INFLAMMATION FOR
EXAMPLE, THEY MAY BE MAKING
PROTEINS THAT ARE INVOLVED IN
THE INFLAMMA ARE TOY REINTONS,
SO THIS IS A LANDSCAPE THIS, IS
A SORT OF MAP HERE, IN THE
MIDDLE OF THE DIFFERENT, EACH
DOT IN THIS MAP REPRESENTS A
SINGLE CELL.
AND THESE ARE THE DIFFERENT CELL
TYPES OF THE BRAIN, THESE ARE
THE -- BECAUSE WE WERE IN THE
WHITE MATTER WHERE THE NERVE
FIBERS ARE CONNECTED WE HAD VERY
FEW NERVE CELLS ISSUES THE
NEURONS, NEU BUT LOTS AND LOTS
OF OLIGO DENDRITES WHICH ARE
CELLS AND WE HAD THE IMMUNE
CELLS, BLOOD VESSEL CELLS, ASTRO
SIGHTS WHICH ARE ALSO VERY
INTERESTING CELL TYPE AND
VARIOUS OTHER CELL TYPES.
WE DID A DEEP DIVE INTO THE
MICROGLIA COMPARING MICROGLIA IN
CONTROL WHITE MATTER, SO PEOPLE
WITHOUT MULTIPLE SCLEROSIS WHO
ARE NEUROLOGICALLY HEALTHY AND
THOSE WITH MS AND YOU CAN SEE
MANY MORE MICROGLIA PRESENT
WHICH IS NOT SURPRISING, THIS
WAS ALREADY KNOWN FROM THE
HISTOLOGY THAT WAS DONE FROM A
CONVENTIONAL HISTOLOGY BUT NOW
WE CAN GET MUCH MORE INFORMATION
ABOUT WHAT THOSE CELL TYPES ARE
DOING THAT WE WERE ABLE TO SHOW
THAT THEY PROBABLY ARE
MICROGLIA, THAT'S ON THE RIGHT.
WE CAN SHOW THAT THEY'RE
PROBABLY MICROGLIA, THAT IS THEY
ARE MOSTLY THE CELLS THAT WERE
INVOLVED IN THIS DAMAGE THAT ARE
OCCURRING ARE CELLS THAT
ORIGINATED IN THE BRAIN, WERE
CARRYING OUT THEIR NORMAL DUTIES
BUT GOT INVOLVED IN THE MULTIPLE
SCLEROSIS ATTACK, BUT IN
ADDITION THERE WERE ALSO CELL
TYPES CALLED MACROPHAGE AND
MONOCYTES THAT WERE ACTUALLY
COMING FROM THE BLOOD STREAM AS
WELL.
BUT WE DON'T THINK THAT THOSE
WERE ACTUALLY AFFECTING DAMAGE
FOR A VARIETY OF REASONS.
AND WHAT WE IDENTIFIED AFTER A
LOT OF ANALYSIS, ARE 2 TYPES OF
MICROGLIA THAT WERE PRESENT
PRETTY SPECIFICALLY AT THE EDGE
OF THESE CHRONIC ACTIVE OR
SMOLDERING LESIONS 1 OF WHICH
CONTAINED THE MACHINERY OF
INFLAMMATION AS WELL AS PROTEINS
THAT BIND TO IRON AND THIS MAKES
A LOT OF SENSE BECAUSE ON THE
MRI, WE CAN SEE THE EFFECTS OF
THAT IRON DIRECTLY, THAT'S THAT
DARK RIM AND ANOTHER TYPE OF
CELL THAT WE CALLED FOAMY
BECAUSE THEY CONTAINED MATERIAL
PROTEINS THAT ARE INVOLVED IN
CLEAN UP OF DEBRIS AND IN THIS
CASE THE DEBRIS IS MILEN, MILEN
IS A FATTY SUBSTANCE AS I
MENTIONED AND THAT GIVES IT THIS
FOAMY APPEARANCE SO WE HAVE
THESE 2 TYPES.
WE CAN NOW GO BACK INTO THE
TISSUE AND LOOK AT WHAT'S THERE
AND 1 OF THE INTERESTING THINGS
WE FOUND IS THAT THERE WAS
INCREASE OF PROTEINS RELATED TO
THE COMPLEMENT SYSTEM.
THIS IS AN EVOLUTIONARY ANCIENT
SYSTEM, PART OF THE IMMUNE
SYSTEM, WHERE PROTEINS ARE
INVOLVED IN INFECTIONS BUT IN
THIS CASE, IT'S NOT INVOLVED IN
AN INFECTION, IT'S AN
INFLAMMATORY DEC OF THE BRAIN
AND WE CAN SEE HERE IN YELLOW
THE INCREASE OF PROTEIN OF A
COMPLEMENT SYSTEM CALLED C1 Q
RIGHT AT THE EDGE OF THE LESION
BUT NOT SO MUCH AT THE CENTER OF
THE LESION OR IN THE WHITE
MATTER OUTSIDE.
SO THEN WE WENT BACK INTO MICE
AND WE BLOCK THAD PROTEIN, THE
C1 Q PROTEIN, THE COMPLEMENT
PROTEIN USING A DRUG AND
ANTIBODY AGAINST IT.
AND WE COULD SHOW THAT IN THIS
CASE, EVEN THOUGH WE DIDN'T
EFFECT OVER HERE ON THE TOP
RIGHT THE SEVERITY OF THE
MULTIPLE SCLEROSIS, ANIMAL MODEL
THAT WE USED CALL EAE
EXPERIMENTAL AUTOIMMUNE INSEVERE
MITRAL LOW MILITEIS, WE WERE
ABLE TO DECREASE THE LEVEL OF
INFLAMMATION IN MICROGLIA WITH
THE STRATEGY.
WE ALSO COLLABORATED WITH DORI
SHAVER AT THE UNIVERSITY OF
MASSACHUSETTS TO SHOW THIS IN A
DIFFERENT WAY, NOT WITH A DRUG
ANTIBODY BUT RATHER HERE BY
USING A GENETIC TRANSGENIC
STRATEGY IN MICE AND SHOWED VERY
MUCH THE SAME THING.
SO HERE WE LEARNED A LOT MORE
WHERE 1 MECHANISM IS PROPAGATED
AT THE EDGE OF THESE LESIONS AND
CAN WE SEE THAT IN PEOPLE, AND
SO WHAT WE'VE DONE NOW IS WE
HAVE BEEN COLLECTING FROM OUR
RESEARCH VOLUNTEERS, SPINAL
FLUID, THROUGH A LUMBAR PUNCTURE
AND SUBJECTING IT TO THE CELLS
THAT WE GET OUT OF THE SPINAL
FLUID TO THE VERY SAME
TECHNOLOGY, THE SINGLE CELL RNA
SEQUENCING, AND HERE YOU CAN SEE
A SIMILAR MAP OF THE CELL TYPES
IN THE SPINAL FLUID FROM 33
PEOPLE LIVING WITH MULTIPLE
SCLEROSIS AND COMPARISON TO 5
HEALTHY CONTROLS, AND AGAIN, YOU
SEE LOTS AND LOTS OF CELL TYPE
-- DIFFERENT CELL TYPES WHICH WE
CAN RECOGNIZE BY THE GENES THAT
ARE TURNED ON, INCLUDING T-CELLS
AND B-CELLS, THESE ARE CELLS OF
THE SO CALLED ADAPTIVE IMMUNE
SYSTEM AS WELL AS MYELOID CELLS
OF WHICH MICROGLUE MARIOUSA ARE
1 ALTHOUGH WE DON'T ACTUALLY SEE
MICROGLIA IN THE BRAIN, BUT WE
STILL SEE SIMILAR THINGS IN THE
SPINAL FLUID AND THAT'S WHAT WE
WANT TO KNOW.
SO WHAT WE DID WAS WE LOOKED AT
THE SUBSET OF PEOPLE WHO WERE
UNTREATED BECAUSE YOU CAN -- YOU
DON'T WANT TO AFFECT THIS
ANALYSIS BY THE REALLY PROFOUND
IMMUNE EFFECTS OF THE TREATMENTS
THAT PEOPLE ARE TAKING.
THEY HAD OR THEY DID NOT HAVE
PARAMAGNETIC RIM LESIONS ON
THEIR MRI, THEY HAD NOT
DEVELOPED NEW LESIONS AND HAD
NOT HAD NEW FOCAL SYMPTOMS, NEW
RELAPSES IN A FEW YEARS, SO THIS
IS REALLY TRYING TO COMPARE WHAT
THE SPINAL FLUID LOOKS LIKE IN
THESE 2 GROUPS OF PEOPLE.
SO, WE FOUND SOME INTERESTING
THINGS, WE FOUND AN INCREASED
PROPORTION OF DENDRITIC CELLS,
SO THESE ARE CELLS THAT PRESENT
PROTEINS RELATED TO THE
AUTOIMMUNE ATTACK IN PEOPLE
WITHOUT THE PARAMETTIC RIM
LESIONS AS WELL AS INCREASES OF
OTHER KINDS OF CELLS IN PEOPLE
WHO DO HAVE THE PARAMAGNETIC RIM
LESIONS SUGGESTING THE IMMUNE
MILIEU IN THE SPINAL FLUID IS
QUITE DIFFERENT BETWEEN THE 2.
WHEN WE DO A DEEPER DIVE AND
LOOK AT THESE MYELOID CELLS THAT
ARE SIMILAR IN SOME WAYS TO
MICROGLIA, WE CAN SUBSET THEM
INTO DIFFERENT TYPES.
WE CAN LOOK THEA THE GENES THAT
ARE PRESENT AND AMONG THESE
GENES ARE GENES OF THE
COMPLEMENT SYSTEM WHICH ARE THE
SAME, THE SAME SYSTEM THAT I
DESCRIBED AT THE EDGE OF THE
LESIONS IN THE PATHOLOGY, AND IF
YOU LOOK AT PEOPLE WHO HAVE
PARAMAGNETIC RIM LESIONS IN THIS
SPECIFIC M5 GROUP OF CELLS, YOU
CAN SEE THAT MANY OF THE GENES
THAT ARE MOST STRONGLY INCREASED
RELATE TO THAT SAME COMPLEMENT
SYSTEM.
WE THEN WERE ABLE TO TAKE THE
MAP AND RELATE IT TO THE BRAIN
CELL MAP AND DIFFERENT PEOPLE,
-- CELLS FROM DIFFERENT PEOPLE
BUT NONETHELESS WE CAN MATCH
THEM UP BY THE GENES THAT ARE
TURNED ON AND WE FOUND THAT
THERE REALLY IS AN OVERLAP
BETWEEN THESE M3 AND M5 CLUSTERS
AND THE CELL TYPES WE KNEW WERE
PRESENT AT THE EDGE OF THE
LESIONS, AGAIN, THESE ARE NOT
EXACTLY THE SAME CELLS BECAUSE 1
IS LOOKING IN SPINAL FLUID, 1
LOOKING IN BRAIN, BUT
NONETHELESS, THEY SHARE A LOT OF
FEATURES.
SO WE NOW HAVE A WAY POTENTIALLY
OF LOOKING AT THE SPINAL FLUID
AND ASSESSING WHETHER
MEDICATIONS THAT WE MIGHT TRY
MIGHT INFLUENCE THESE CELL TYPES
AND MAYBE THEY ARE ALSO
INFLUENCING THE BRAIN AS WELL,
SO CAN WE DO THESE KINDS OF
TRIALS?
WELL IF WE LOOK OVER TIME AT
PARAMAGNETIC RIM LESIONS, THE
IRON RIM LESIONS I DRIEBED
EARLIER, INITIALLY WE THOUGHT
THEY WOULD STICK AROUND FOR A
LONG TIME, BUT WHAT WE ACTUALLY
FOUND AFTER WE STARTED FOLLOWING
PEOPLE UP FOR 10 YEARS OR SO, IS
THAT MANY OF THEM ACTUALLY, THE
RIM STARTS TO RESOLVE THAT IRON
SIGNATURE WHICH IS PRESENT
INSIDE OF INFLAMMATORY CELLS.
SO THIS GIVES US HOPE AND
ACTUALLY A VERY POWERFUL METHOD
OF POTENTIALLY TESTING NEW
MEDICATIONS ON CHRONIC
INFLAMMATION AND NOT JUST ACUTE
INFLAMMATION AND IF YOU REMEMBER
THE VIDEO I SHOWED AT THE
BEGINNING WITH ALL THE FLASHES,
NEW LESIONS DEVELOPING, IT WAS
STOPPING THOSE FLASHES THAT LED
TO THE DEVELOPMENT OF THE 25 OR
SO TREATMENTS THAT WE HAVE
AVAILABLE INCLUDING OCULIZUMAB
COULD WE USE NEW MEDICATIONS TO
BLOCK THIS IMPORTANT PART FOR MS
PROGRESSION.
SO IF WE DO THAT HOW WOULD WE DO
THAT?
WELL IF WE TAKEAUR MASSIVE
COLLECTION OF INFORMATION WE GET
FROM THESE HIGH THROUGH PUT
TECHNIQUES LIKE SINGLE CELL
SEQUENCING AND DO SOME ANALYSIS,
MAKE SOME HYPOTHESIS GENERATION,
WHAT IF WE DELETE A CERTAIN CELL
TYPE OR CERTAIN GENE FROM THE
CELL TYPES.
SO WE CAN LOOK IN FACT OF WHAT
HAPPENS IF YOU DEPLETE B-CELLS
WHICH ARE THE TARGET OF
OCULIZUMAB, AND I CHOSE THIS
BECAUSE FOR A VARIETY OF REASONS
IT IS 1 OF THE THERAPYINGS
TESTED HEAVILY IN MS NOW AND YOU
CAN SEE THERE'S MANY, MANY MORE
ABOUT 6 TIMES MORE GENES THAT
ARE BEING AFFECTED EVEN THOUGH
BTK AND CD20 ARE GENES THAT ARE
PRESENT IN SOME OF THE SAME CELL
TYPES AND MANY OF THOSE GENES
THAT WE WOULD EXPECT TO BE
CHANGED BY INHIBITING THIS BTK,
ARE ACTUALLY GENES OF THE
COMPLEMENT SYSTEM, THIS C1 Q, C1
QC, C3, ET CETERA.
SO POTENTIALLY COULD BE AN
INTERESTING WAY TO GO.
NOW BTK IS AN ENZYME THAT'S
PRESENT, IT'S A SIGNALING
MOLECULE THAT'S PRESENT INSIDE
B-CELLS AND WE KNOW THAT
BLOCKING B-CELLS IS EFFECTIVE IN
BLOCKING MS RELAPSE BUT IT'S
ALSO PRESENT IN THESE MYELOID
CELLS INCLUDING MICROGLIA AND IT
HAS MANY, MANY FUNCTIONS THAT WE
DON'T HAVE TIME TO TALK ABOUT SO
IT'S PLAWSIBLE THIS MIGHT
ACTUALLY WORK.
AND IN FACT WE WERE ABLE TO SHOW
WITH STAINING HERE IN BROWN,
THAT BTK IS PRESENT AT THE EDGE
OF THESE CHRONIC ACTIVE LESIONS
THAT HAVE IRON RIMS AS WELL.
THERE'S PRECLINICAL WORK THAT
WAS DONE IN CELL CULTURE BY OUR
COLLEAGUES AT SENOFI, WHICH IS A
COMPANY THAT'S DEVELOPING
INHIBITORS PER DTK FOR MS,
THERE'S 4 MAJOR COMPANIES IN
THAT ARE DOING THIS CURRENTLY
AND YOU CAN SEE THAT IN THEIR
CELL CULTURES, THEY CAN
PROFOUNDLY DECREASE THE LEVELS
OF MANY OF THESE MOLECULES WHICH
ARE IMPORTANT INFLAMMATORY
MEDIATORS USING THE INHIBITOR
THAT THEY HAVE DEVELOPED AND
OTHER INHIBITORS WORK SIMILARLY.
AND SO HERE YOU CAN SEE IN A
TABLE, ALL THE DIFFERENT TRIALS,
ALL THE DIFFERENT PHASE 3
CLINICAL TRIALS, THESE ARE THE
MASSIVE TRIALS THAT CAN GENERATE
DATA THAT MAY BE USEABLE FOR THE
FDA TO, PROVE OR DISAPPROVE A
MEDICATION FOR A PARTICULAR
DISEASE LIKE MULTIPLE SCLEROSIS
AND YOU CAN SEE THAT THESE
DIFFERENT MOLECULES ARE BEING
TEST INDEED A VARIETY OF MS
TYPES, THEY'RE RELAPSING TYPE,
THAT MR. CHACON PRESENTED WITH
OR OTHER TYPES.
AND THESE ARE IN VARIOUS TAIJS
OF PROGRESS AT THIS TIME AND 3
OF THEM SPECIFICALLY ARE BEING
USED IN PROGRESSIVE MS.
THIS IS THE DATA FROM THE FIRST
RELEASE LAST YEAR, THIS IS A
MODEL CALLED EVOBRUTINIB, THIS
WAS ONLY TESTED IN RELAPSES MS
AND IT HAD NO EFFICACY
WHATSOEVER COMPARED TO THE
COMITITTOR DRUG, WHICH IS A
MEDICATION THAT IS APPROVED FOR
MS.
IT TURNED OUT TO BE NO BETTER AT
ALL.
HOWEVER WHAT DISTINGUISHES THESE
FROM OTHERS IS THE ABILITY TO
GET INSIDE THE BRAIN WHERE
MICROGLIA LIVE, AND FENEBRUTINIB
IS NOT ABLE TO GET IN THE BRAIN
AND THIS IS SHOWN ON THE LEFT
LOOKING AT THE CONS TRAITIONZ OF
THE DRUG RELATIVE TO THE
CONCENTRATION THAT IS NEEDED TO
ACHIEVE EFFECT FOR TOLEBRUTINIB,
AND EVOBRUTINIB, AND
FENEBRUTINIB, AND SO, AS PART OF
MY CORRELATED FICIAL DUTY HERE
AT NIESH H I HAVE BEEN WORKING
WITH SENOFI IN THEIR TESTING OF
THE THIS DRUG BECAUSE IT WILL
TEACH US ABOUT MS, I DON'T GET
PAID FOR THIS WORK, THIS IS PART
OF MY GOVERNMENT WORK.
JUST BECAUSE AGAIN, I THINK WE
CAN LEARN ABOUT HOW TO MOVE
FORWARD WITH MULTIPLE SCLEROSIS
TREATMENT AND WE RECENTLY IN
COLLABORATION WITH THEM REPORTED
RESULTS AT 3 OF THESE TRIALS AND
2 TRIALS IN RELAXING MS AND
THERE WERE 2 TRIALS IN
NONRELAPSING MS WHERE
TOLEBRUTINIB WAS COMPARED TO
PLACEBO.
AND I WILL SKIP OVER THIS IN THE
INTEREST OF TIME TO SHOW YOU THE
END RESULTS.
THIS WAS IN THE HERCULES TRIA,
WHERE THE PEASHT HAD A WORSENING
OF DISABILITY COMPARED TO
PLACEBO AND YOU CAN SEE THAT 37%
OF THE PEOPLE TAKING PLACEBO HAD
SUCH AN EVENT WHEREAS 27% STILL
A SUBSTANTIAL NUMBER BUT 30%
ROUGHLY 30% LOWER NUMBER WHO ARE
TAKING THE DRUG HAD A
PROGRESSIVE -- HAD AN EVENT OF
PROGRESSIVE MS, THAT IS THEIR
DISABILITY WORSENED OVER TIME.
THIS IS NOW PUBLISHED DATA AND
IT'S THE FIRST LARGE PHASE 3
TRIAL TO SHOW REAL EFFICACY,
EVEN IF ALBEIT SMALL OR ALBETIT
A FIRST STEP STILL GOOD IN MS.
AND INTERESTINGLY EVEN THOUGH IN
THE RELAPSING TRIALS THE GEMIN I
TRIALS, THERE WAS NO DIFFERENCE
IN RELAPSE PROTECTION, THERE WAS
STILL A SMALL BUT SIGNIFICANT
REDUCTION IN THE RISK OF PEOPLE
WITH RELAPSING MULTIPLE
SCLEROSIS, PROGRESSING AND
GETTING WORSE.
SO WHAT IS THE BASIS FOR THIS,
IS IT BECAUSE BTK INHIBITORS,
CROSS INTO BRAIN AND AFFECT
MICROGLIA, WELL, 1 THING WE CAN
DO IS TO LOOK AT THOSE
PARAMAGNETIC RIM LESIONS THAT'S
WHAT WE DID, ABOUT A THIRD OF
PATIENTS IN THIS TRIAL HAD MRI
SCANS THAT ALLOWED US TO DO THAT
SO ABOUT A THOUSAND TOTAL OUT OF
THE 3000 PATIENTS HAD THAT.
YOU CAN SEE HERE, IN THE 2
TRIALS, GEMIN I 1 AND 2, THIS IS
2 TRIALS MERGED TOGETHER AND THE
HERCULES PROGRESSIVE TRIAL,
DISDISTRIBUTION OF PATIENTS IN
THESE TRIALS, YOU WILL RECALL IN
THE DATA I SHOWED YOU BEFORE
THAT PEOPLE WITH MORE THAN 4
PRLs ARE LIKELY TO HAVE A
WORSE COURSE OF THE DISEASE AND
THIS RECAPITULATES WHAT WE FOUND
IN OUR STUDIES IN TERMS OF
PROPORTIONS.
IN THE RELAPSES MS TRIAL,
COMPARING PEOPLE WITH 0-1-3 AND
MORE THAN 4 PRLs IN TERMS OF
LIKELIHOOD OF GETTING WORSE AND
THEIR DISABILITY BY PERCENTAGE,
IN TOLEBRUTINIB, AND VERSUS THE
COMPARATOR, EVEN WITH THOSE WITH
LESIONS 4 OR MORE THE CHANCE OF
GETTING THAT DISABILITY
WORSENING WAS REALLY NOT
DIFFERENT WHEREAS IT WAS WORSE
AS EXPECTED IN THE TERIFLUNOMIDE
STUDY.
PEOPLE WERE ALREADY PROGRESSING
SO THERE WAS A HIGHER CHANCE OF
HAVING A WORSENING OF DISABILITY
TO THE TRIAL, WE SAW VERY MUCH
THE SAME EFFECT.
ABOUT A 50% REDUCTION IN THE
RISK OF HAVING WORSENING IF YOU
HAVE THIS EVIDENCE OF CHRONIC
INFLAMMATION IN THE BRAIN.
AND I WILL JUST VERY QUIEKLY
BECAUSE I KNOW YEAR RUNNING
SHORT ON TIME TELL YOU ABOUT A
TRAIL WE DID, THE DOCTOR AND I
AND OUR TEAM HERE AT THE NIH TO
TRY TO GET AT THIS DEEPER.
AND THIS IS THE NIH CLINICAL
CENTER WHERE WE WORK BUT WE
STUDY A FEW PEOPLE IN A DEEP WAY
SO WE CAN UNDERSTAND WHAT'S
GOING ON, WE TOOK A SMALLER
TRIAL AND WE STUDY THEM WITH A
POWERFUL MRI SCAN, THEY HAD HAD
THIS PARAMAGNETIC RIM LESION,
THEY HAD ALL BEEN TAKING B-CELL
DEPLETION AND ALL WITH THE SAME
MEDICATION AND WE WILL CONTINUE
TO FOLLOW SEVERAL OF THESE
PEOPLE WHO ARE TAKING THE
MEDICATION AND WE DID IT WITH
LUMBAR PUNCTURE AND MRI, SO WE
TRACKED HOW THEIR B-CELLS HAD
BEEN DEPLETED WITH THE THIS
BEGAN TO REPOPULATE BUT VERY
SLOWLY OVER TIME AND SO WHAT DO
WE FIND.
WE FOUND I GUESS SOMEWHAT
DISAPPOINTINGLY AT THE END OF 48
WEEKS, THAT EVEN WITH THIS
MEDICATION WE WERE NOT ACTUALLY
REALLY ABLE TO AFFECT THE
PARAMAGNETIC RIM LESIONS THAT
WERE PRESENT AT BASE LINE AND
THIS WAS DONE BEFORE WE HAD THE
RESULTS OF THE PHASE 3 AND WHERE
I SHOWED YOU BEFORE WHERE THERE
WAS A DISABILITY AFFECT BUT I
COULD BT SEE IT IN THIS GROUP OF
7.
HOWEVER, AND WE LOOKED DEEPER
AND THAT'S WHAT WE CAN DO HERE
AT THE NIH AND WE DID THAT SAME
SEQUENCING OF THE CELLS IN THE
SPINAL FLUID, AND HERE YOU CAN
SEE BTK, THE PURPLE DOTS SHOWING
YOU THE CELLS IN THE B-CELL
LINEAGE AND THE MYELOID CELLS
THAT CONTAIN BRUTON'S TYROTEEN
KINASE, WE FOCUSED ON THE
MYELOID CELLS WHICH ARE
MICROGLIA LIKE, SOME OF THEM AND
WE LOOKED AT HOW THEY MIGHT
CHANGE EAEVER 48 WEEKS OF
TOLEBRUTINIB, AND WE LOOKED AT
EACH CASE BUT THIS M2 CLUSTER
HAS GENES THAT ARE SIMILAR TO
THE 1 I SHOWED BEFORE INCLUDING
COMPLEMENT YEERNS AND AFTER 48
WEEKS, OF TREATMENT, SHOWS GENES
WERE SUBSTANTIALLY REDUCED BY
TREATMENT AND HERE IS JUST
ANOTHER VERSION OF THAT WITH
ADDITIONAL MOLECULES FROM THE
COMPLEMENT SYSTEM AS WELL AS
OTHER MOLECULES, FOR EXAMPLE,
APOLIPIE PROTEIN E WHICH IS AN
IMPORTANT MOLECULE FOR
MICROGLIAL INFLAMMATION, SO I
WILL SUMMARIZE, AND JUST TELL
YOU WHAT I ALREADY TOLD YOU THAT
CHRONIC ACTIVE WHITE MATTER
LESIONS ARE DETECTABLE, IN VIVO,
IN LIVING PEOPLE AS PARAMAGNETIC
RIM LESIONS AND THEY ARE
IMPORTANT FOR THE DEVELOPMENT OF
THESE CHRONIC ACTIVE LESIONS,
WE'RE STILL WORKING OUT MANY OF
THE PATHWAYS, MOLECULAR AND
CELLULAR PATHWAYS THAT ARE
INVOLVED IN THOSE LESIONS, WE'RE
DOING THAT USING HIGH THROUGH
PUT OIMMUNE DYSFUNCTION MICS
TECHNIQUES TO IDENTIFY GENES OF
INTEREST OR TARGETS FOR NEW
DRUGS AND TO TEST OUTCOMES IN
THE CONTEXT OF THOSE TRIALS,
THIS IS THE BTK INHIBITOR WHICH
DID NOT RESOLVE THE RIM LESIONS
BUT DID STILL HAVE ANTIINFLAMMA
ARE TOY PROPERTIES AND WE KNOW
FROM THE LARGE TRIALS HAVE SOME
INFLUENCE ON DISABILITY AND I
WOULD SAY WE'RE STILL SEARCHING
FOR OPTIMIZED PROOF OF CONCEPT
TRIAL DESIGNS FOR PROGRESSIVE
MS, BUT I THINK WE'VE HOPEFULLY
TAKEN THE NEW STEPS.
MANY, MANY PEOPLE INVOLVED IN
WORK, MANY OTHER GROUPS AND OUR
COLLABORATORS, AND HERE'S JUST
SOME PICTURES OF THE GROUPS
WONDERFUL PEOPLE I WORK WITH
HERE AT TD NIH WHO ARE DOING
THIS WORK.
>> WHERE WE ARE IN TERMS OF
CHALLENGES AND OPPORTUNITIES IN
TERMS OF MULTIPLE SCLEROSIS, CAN
YOU HEAR ME?
OR NOT?
>> I DON'T KNOW WHY MY SPEAKER
STOPPED.
>> I CAN HEAR YOU NI CAN HEAR
YOU?
I CAN HEAR YOU, TOO NIT WOULD BE
NICE IF DANNY CAN HEAR ME TOO SO
THAT I CAN MODERATE A LITTLE BIT
OF A DISCUSSION AMONGST US.
>> YES, HE MIGHT BE SIGNING OUT
AND SIGNING BACK IN, THAT'S MY
SENSE.
>> YEAH, YEAH, PERHAPS.
>> WHILE HERE DOING THAT PERHAPS
I CAN ASK THE DOCTOR SINCE WE
HAVE QUITE A FEW QUESTIONS FROM
THE AUDIENCE AND A FEW THAT HAVE
OCCURRED TO ME AS WELL, SO 1 OF
THE INTERESTING QUESTIONS IS
JUST THIS 1 THAT HAS BEEN RAISED
BEFORE OF THE EPITEEMIOLOGY OF
MS AND THE DISTRIBUTION OF
CASES, COULD YOU POSSIBLY SAY A
LITTLE BIT MORE DOCTOR ABOUT
THAT?
I UNDERSTAND AT LEAST THERE'S
SOME ASSOCIATION WITH FREQUENCY
AND INCIDENCE OF MS AND MORE
NORTHERN LATITUDES.
IS THAT SO?
AND IF SO, WHAT MIGHT BE THE
MECHANISM OF THAT?
>> YES, IT IS ACTUALLY RIGHT AND
IT MAY BE SOCKED LESS EXPOSURE
FOR EXAMPLE AND GENETIC VALID
AND RELIABLUATION SOPHISTICATED
OOTH BEEN SHOWN, WHICH IS CLEAR
AND PROBABLY SOME EXPOSURE, LESS
EXPOSURE PLUS GENERATEDETEC
FACTORS ARE RESPONSIBLE FOR
THAT.
I SEE, I SEE AND THEN YOU HAD
MENTIONED VITAMIN D AS BEING
ANOTHER FACTOR THERE, SO I TAKE
THAT VITAMIN D AND PROTECTIVE
FOR MS IS THAT CORRECT?
>> YEAH, SO THE EFFICIENT OF
VITAMIN D AND LOW SUN LIGHT
EXPOSURE ARE BOTH IMPORTANT IN
MS AND THERE WERE ASSOCIATION
SO, PATIENTS WITH HIGHER LEVEL
OF VITAMIN D FOR EXAMPLE AT THE
TIME OF THE FIRST CLINIC EPISODE
HAVE LESS RISK OF RELAPSING, SO
HIGHER LEVELS OF VITAMIN D AT
THE TIME OF EPISODE ARE
ASSOCIATE WIDE LESS RISK FOR
EVOLUTION OF LESS RELAPSE IN MS,
AS WELL THERE WERE OTHER STUDIES
THAT SHOW LOWER LEVELS OF
VITAMIN D WERE ASSOCIATE WIDE
NEUROLESIONS OR ENHANCED LESIONS
HOWEVER, THE REPLACEMENT WITH
VITAMIN D IS NOT SHOWING ANY
BENEFIT, SO TAKING RL IS NOT
SHOWING A CHANGE IN THE
EVOLUTION OR IN THE MRI.
>> YES, I WAS ABOUT TO ASK YOU
THAT QUESTION GIVEN WHAT YOU HAD
SAID AND WHAT YOU SAID ABOUT SUN
LIGHT AND SO FORTH IS WOULD
THERE BE SOME SORT OF SUPPLEMENT
THAT MIGHT BE BENEFICIAL.
ARE THERE ANY SUPPLEMENTS THAT
MIGHT BE BENEFICIAL.
>> YEAH, WE SUGGEST PATIENTS TO
HAVE LEVELS OF VITAMIN D ABOVE
14 NANO GRAMS, SO IT'S VERY
THERE AT THE COUNTER, SO IT'S
VERY STRAIGHT FORWARD TO GET THE
VITAMIN D REPLACEMENT.
MAYBE I SHOULD REPEAT THE CME
CODE NOW THAT WE'RE ENGAINLING
IN THIS DISCUSSION FOR THOSE WHO
WANT TO GET CONTINUING MEDICAL
EDUCATION CREDIT, IT IS 58794.
AGAIN THAT'S 58794.
LET ME SEE IF I CAN FIND A
COUPLE MORE QUESTIONS.
SOMEONE IS CATEGORY GO THE
DEVELOPMENT OF BI-SPECIFIC
ANTIBODIES FOR THE THERAPY OF
MS.
IN OTHER WORDS ANTIBODIES WHERE
1 ARM OF THE ANTIBODY MOLECULE
MIGHT BE DIRECTED AGAINST
B-CELLS AND THE OTHER HARM MIGHT
BE DIRECTED AT LEAST BASED ON
DR. REICH'S PRESENTATION MAYBE
TOWARDS MICROGLIAL CELLS OR
WHATEVER?
>> YEAH, SO THESE, THESE,
ANTIBODIES ARE IN DEVELOPMENT
FOR MANY CONDITIONS AND MS IS NO
EXCEPTION TO THAT.
THEY ARE IN VERY EARLY STAGES OF
TREATMENT -- SORRY OF TESTING.
ONE OF THE -- SO 1 OF THE
TREATMENTS IN QUESTION IN
PARTICULAR IS WHETHER IT WILL
GET INTO THE BRAIN IN SUFFICIENT
AMOUNTS TO BE EFFECTIVE BECAUSE
ANTIBODIES ARE LARGE PROTEINS
AND THEY DON'T READILY ACROSS
THE BLOOD BRAIN BARRIER,
PROBABLY 1 PART IN A THOUSAND OR
SO, GETS ACROSS OF NORMAL ASPECT
BODIES, THERE ARE NORMAL
TECHNOLOGIES TWEPPED TO TRY TO
INCREASE THAT USING SHUTTLE
SYSTEMS FOR EXAMPLE, REALLY SORT
OF CLEVER, MOLECULAR TRICKS TO
GET INTO THE BRAIN OR TO NOT GET
SHUTTLED OUT OF THE BRAIN BUT
THAT ALSO IS AN EARLY STAGES
MUCH SO IDEALLY I THINK FOR MUCH
OF WHAT IS BEING DONE IN THE
BRAIN, SMALL MOLECULES WHICH CAN
GET ACROSS THE BLOOD BRAIN
BARRIER OR EVEN CELL THERAPY
BECAUSE CELLS CAN GET INTO THE
BRAIN, THROUGH VARIOUS
MECHANISMS, MAY PROVE MORE
PROMISING BUT NONETHELESS, IT'S
BEEN SURPRISING THAT ANTIBODIES,
EVEN IF THEY DON'T GET IN MUCH
CAN SOMETIMES HAVE EFFICACY AND
I THINK WE ARE GOING TO LEARN A
LOT MORE ABOUT THAT AS THESE NEW
BI-SPECIFIC ANTIBODIES ARE BEING
DEVELOPED.
>> AND MAYBE JUST TO FOLLOW UP A
LITTLE BIT ON THIS THOUGHT WITH
REGARD TO POSSIBLE CONNECTIONS
BETWEEN B-CELL TARGETING AND
MICROGLIAL OR MYELOID TARGETING,
WHAT EXACTLY FOR PLASMA CELLS,
WHAT ARE THE B-CELLS DOING WHY
ARE THEY THE BAD GUYS IN THIS
AND THERE'S BENEFIT IN KNOCKING
THEM OFF?
>> YEAH, I MEAN B-CELLS HAVE
MANY FUNCTIONS.
THE ANTIBODY PRODUCTION FUNCTION
EVEN THOUGH YOU KNOW WE DO SEE
ANTIBODIES IN THE SPINAL FLUID
WHEN WE TEST THIS, 1 OF THE
TESTS WE USE FOR MULTIPLE
SCLEROSIS, IT'S PROBABLY NOT THE
ANTIBODIES, THERE'S SOME DEBATE
BUT IT'S PROBABLY NOT THE
ANTIBODIES THAT ARE THE MAJOR
CAUSE OF THE MS DISEASE, BUT
B-CELLS HAVE OTHER FUNCTIONS.
THEY CAN FUNCTION FOR EXAMPLE,
AS ANTIGEN PRESENTING CELLS
WHERE THEY CAN TAKE PROTEINS AND
SHOW THEM TO OTHER CELLS OF THE
IMMUNE SYSTEM THAT MAY CAUSE
DAMAGE, THEY CAN FUNCTION IN
WORKING WITH OTHER IMMUNE CELLS
INCLUDING T-CELLS WHICH FOR MANY
YEARS, PEOPLE HAVE OCCURRED THE
MAJOR CELL TYPE INVOLVED IN
MULTIPLE SCLEROSIS, SO B-CELLS
CAN GIVE HELP TO T-CELLS IN
CARRYING OUT THE AUTOIMMUNE
ATTACK AND B-CELLS
INTERESTINGLY, AND IMPORTANTLY
ARE, YOU KNOW THE TARGET
EPI-BLAST STEIN BARRE VIRUS
WHICH IS A VERY COMMON, IT WAS
MENTIONED IN THE DOCTOR'S
PRESENTATION, A VERY COMMON
VIRUS TYPE OF HERPES VIRUS THAT
IS THE CAUSE OF MONONUCLEOSIS
AND EVEN THOUGH IT AFFECTS --
INFECTS 90% OR MORE OF PEOPLE,
IT VERY, VERY FEW PEOPLE IF ANY
WHO HAVE MULTIPLE SCLEROSIS HAVE
BEEN UNINFECTED BY IT SO THERE'S
A STRONG EPIDEMIOLOGICAL
ASSOCIATION BETWEEN THE 2
MR. CHACON MENTIONED THAT HE
THINKS HE HAD MONONUCLEOSEIS AND
WE GET THAT HISTORY MOST OF THE
TIME AND IT MAY BE THAT THE
B-CELL INFECTION BY THE VIRUS IS
1 OF THE REASONS WHY B-CELL
THERAPY IS EFFECTIVE IN THIS
DISEASE NYES AND ACTUALLY ALONG
THE LINE OF THE EBV, 1 OF OUR
MEMBERS OF THE AUDIENCE ASKS THE
QUESTION WHETHER IT COULD BE
THAT MONONUCLEOSIS VIRAL
INFECTION WHICH MIMICS GLIAL
CELLS AND CAUSES AN AUTOIMMUNE
RESPONSE AGAINST THE MYELIN
SHEATH COULD BE HIDING IN THE
IMMUNE RESPONSE AND EVEN THOUGH
THE SYMPTOMS OF THE VIRUS ARE
GONE, THE VIRUS COULD PERSIST IN
THE BRAIN AND BE THE TARGET OF
IMMUNE ACTIVITY.
>> WELL THIS IS 1 OF THE RAGING
DEBATES AND I WOULD SAY EVERY
CONFERENCE WE GO TO THIS IS 1 OF
THE -- 1 OF THE QUESTIONS THAT
PEOPLE SEPARATE INTO THEIR CAMPS
ABOUT WHETHER THAT'S THE CASE OR
NOT, THERE ARE PEOPLE WHO HAVE
REPORTED EPSTEIN BARRE VIRUS
WHEN THEY LOOK IN THE BRAIN, NO
MATTER HOW HARD THEY LOOK, THERE
ARE PEOPLE WHO DESCRIBED NORMAL
PROEN TEES OF THE BRAIN THAT
LOOK LIKE OR MIMIC EPSTEIN BARRE
VIRUS PROTEINS AND THAT'S AN
EASY TO UNDERSTAND WAY IN WHICH
THE IMMUNE SYSTEM MAY BE TRICKED
INTO ATTACKING THE BRAIN BUT
WHILE THESE FINDINGS -- YOU YOU
CAN COME UP WITH THEM IN A
HANDFUL OR 1 OR ANOTHER, THEY
DON'T REALLY TWHAI HAVEN'T BEEN
CONVINCING IN THAT IS THAT A
SORT OF EXPLAIN ALL OF THE
SCREKS OF SYMPTOMS AND ALL THE
EPIDEMIOLOGY OF THE DISEASE AND
EVERYTHING YOU WILL LIKE TO SEE
FOR EXAMPLE, YOU KNOW THAT STORY
IS TANTALIZING, YOU KNOW THERE'S
A LOT OF PEOPLE WHO BELIEVE THAT
PREVENTING EPSTEEN BARRE VIRUS
WITH A VACCINE MAY PREVENT MS
FROM OCCURRING IN THE FIRST
PLACE, YOU WOULD HAVE TO
VACCINATE CHILDREN IN ORDER TO
DO THAT AND SO, SPECIAL THAT
RAISES ALL SORTS OF QUESTIONS OF
COURSE AND ALSO THE EPSTEIN
BARRE VIRUS IS 1 WE'VE LIVED
WITH AS A SPECIES FOR SUCH A
LONG TIME AND YOU NEVER KNOW
WHEN YOU ELIMINATE A VIRUS WHAT
THE UNXEBTED, UNTOURED EFFECTS
MIGHT BE.
SO THIS A RAGING DEBATE IN THE
FIELD.
I DON'T KNOW WHETHER THE DOCTOR
HAS SOMETHING TO ADD TO THAT?
>> I AGREE WITH THAT, I VACCINE
COULD POTENTIALLY PREVENT OTHER
DISEE DISEASES THAT MAY BE
ASSOCIATE WIDE EPSTEIN BARRE,
NOT ONLY MS.
>> OKAY, SO, NOW, ANOTHER OF OUR
AUDIENCE IS ASKING THE QUESTION
OZ TO WHETHER ARTERIES ARE ALSO
INVOLVED IN THE MS BRAIN OR IS
THE PRIMARY LOCUST THE VEINS?
>> SO LESIONS DEVELOP
SURROUNDING VEINS IN THE
PERIVASCULAR SPACE, WHEREAS THE
ACCUMULATION OF CELLS AND IN THE
BLOOD BRAIN BARRIER AND THE
MELINNATION OCCURS AND CYTOKINES
AND CHEMOKINES ARE GENERATED AND
THERE'S OPENING OF THE
CAPILLARIES WITHIN THE LESION SO
OF COURSE THERE IS A OPENING OF
THE BLOOD BRAIN BIRRIER
SURFACESSIER THAT IMPAIRS
CAPILLARIES BUT THE MAIN
STRUCTURE THAT IS IMPAIRED IS
THE VEIN SO IT'S A CENTRAL VEIN.
YOU NOT ONLY SEE THAT IN WHITE
MATTER LESIONS BUT WE ARE ALSO
FINDING THE SAME THING IN
CORTICALE LESIONS AND WE HAVE
SOME MODELS SHOWING THIS LESION
DEVELOPMENT, MAYBE I CAN ADD 1
PIECE TO THAT, YOU KNOW THE
BRAIN HAS EVOLVED WAYS OF
PROTECTING ITSELF IS THAT'S CALL
IMMUNE SURVEILLANCE BECAUSE THE
IMMUNE SYSTEM HAS TO KNOW NOT TO
COME INTO THE BRAIN AND THAT
HAPPENS IN THE MENNEGES AND
SURROUNDING SPACES OF THE BRAIN
AND AROUND SMALL VEINS AND
THAT'S WHERE THE CELLS OF THE
IMMUNE SYSTEM HAD THE ABILITY TO
TRAFFIC AND IN AND OUT OF THE
BLOOD VESSELS AND SAMPLE THE
BRAIN AND IN NORMAL
CIRCUMSTANCES, HEALTHY
CIRCUMSTANCES TO GET USED TO
THEM SO THAT THEY DON'T ARK TACK
THE BRAIN AND THAT'S WHERE IT
HAPPENS AROUND VEINS BUT IT'S
VERY UNUSUAL AND YOU KNOW YOU'RE
A RHEUMATOLOGIST SO YOU CAN --
YOU CAN TALK ABOUT THIS AS WELL
BUT I THINK IT'S RELATIVELY
UNUSUAL AMONG BLOOD VESSEL
DISEASES TO HAVE THIS PHENOMENON
OF THE VEIN BEING THE MAIN
PLACE.
MOST OF THE TIME WE ARE TALKING
AROUND SMALL ARTERIES,
INFLAMMATION AROUND SMALL
ARTERIES VASCULITIS, ET CETERA,
AND WE DO SEE THAT IN THE BRAIN
AND CLINICALLY IT LOOKS
DIFFERENT AND CLINICALLY IT
LOOKS DIFFERENT AS WELL.
SO MS DOESN'T APPEAR TO DIRECTLY
AFFECT THE ARTERIES ALTHOUGH WE
DO KNOW -- WE DO KNOW THAT
PEOPLE WHO HAVE OTHER DISEASES
FOR EXAMPLE, HYPERTENSION, HIGH
BLOOD PRESSURE, DIABETES THAT DO
AFFECT THE ARTERIES WHEN YOU
HAVE THAT IN THE SAME PERSON
WITH MS, THINGS GOT A LOT WORSE.
AND WE CAN SOMETIMES SEE WHEN WE
LOOK AT THE MRI SCANS, SPACES
AROUND THE ARTERIES WHICH ARE
NORMALLY SPACES FOR FLUID FLOW
AND WITHIN THE BRAIN CAN GET
QUITE BIG.
THOSE ARE CALLED PERIVASCULAR
SPACES AND WE AND OTHERS ARE
INVESTIGATING THE ROLE OF THAT
BECAUSE IT DOES SEEM TO BE
SOMETHING GOING ON AROUND THE
ARTERIES, TOO BUT THE PRIMARY
IMMUNE ATTACK IS CLEARLY AROUND
VEINS.
>> ALL RIGHT, SO MAYBE JUST
FOLLOWING A LITTLE BIT ON THIS
CONCEPT OF CELLS GETTING INTO
THE BRAIN, SO OF COURSE, 1 OF
THE TOPICS THAT'S OF GREAT
INTEREST IN THE WORLD OF
RHEUMATOLOGY BUT NOW, EVEN IN
THE -- I THINK THE WORLD OF MS,
IS THE WHOLE IDEA OF CAR T-CELLS
AS A POSSIBLE TREATMENT.
WOULD YOU WANT TO COMMENT AT ALL
ON CAR T-CELLS AND AT LEAST
RIGHT NOW WHAT'S THE REPORT CARD
ON CAR T-CELLS?
>> WELL, VERY EXCITING BECAUSE
YOU CAN MAKE CAR T-CELLS AND
DIRECT THEM FOR EXAMPLE AGAINST
B-CELLS THIS THAT'S THE MOST
COMMON THING THAT'S BEING DONE
NOW AND TESTED IN AUTOIMMUNE
DISEASE.
YOU KNOW WE TALKED ABOUT OCREVIA
AS AN ANTIBODY TARGETING CD20
WHICH IS A PROTEINOT SURFACE OF
THE B-CELLS, THERE'S ANOTHER
PROTEIN CALLED CD19 WHICH IS ON
A WIDER SPECTRUM OF B-CELLS IN
CD20 AND THERE ARE LOTS AND LOTS
OF COMPANIES, ARE DEVELOPING CAR
T-CELLS ENGINEERED T-CELLS THAT
CAN ATTACK THE CELLS THAT HAVE
CD19 ON THEM AND HOPEFULLY, THE
IDEA IS THAT THEY WOULD BE ABLE
TO HAVE THE IMPACT NOT JUST IN
THE PERIPHERY, IN THE BLOOD
STREAM AND THE PERIPHERAL IMMUNE
SYSTEM BUT ALSO TO GET INTO THE
BRAIN BECAUSE T-CELLS CAN GET
INTO THE BRAIN AND ATTACK
WHATEVER B-CELLS MAY STILL BE
PRESENT AROUND THE EDGES OF
THESE CHRONIC ACTIVE LESIONS
WHICH WE DO SEE, OR IN THE
MENENG ES, IN THE SURROUNDING
AND TO PROPAGATE INFLAMMATION SO
I THINK VERY LITTLE HAS BEEN
DONE.
THERE ARE A FEW CASE REPORTS
HERE AND THERE, THERE ARE SAFETY
CONCERNS WITH T-CELLS, YOU KNOW
CAR T-CELLS HAVE MOSTLY BEEN
USED IN CANCER WHERE THE
TOLERANCE FOR AN ADVERSE EVENT
MAY BE DIFFERENT THAN IN
MULTIPLE SCLEROSIS WHERE PEOPLE,
FOR EXAMPLE, MR. CHACON WHO ARE
FORTUNATELY DOING REALLY WELL
WITH THE DISEASE, YOU DON'T WANT
TO PUT THEM AT RISK.
SO WE'RE AT VERY EARLY STEAJS. .
THERE ARE OTHERS THAT ARE
DEVELOPED, SPECIALIZED T-CELLS
THAT CAN QUELL INFLAMMATION AND
MAYBE CONTRIBUTE TO REPAIR.
AND THERE ARE ALSO COMPANIES
THAT ACADEMIC INSTITUTIONS THAT
ARE DEVELOPING THOSE KINDS OF
APPROACHES AS WELL AND WE DON'T
KNOW WHAT WILL BE BETTER BUT
IT'S VERY EXCITING.
>> YES, INDEED, IT APPEARS WE
ARE GETTING CLOSE TO THE END OF
OUR TIME.
WE'RE JUST 2 MINUTES AWAY FROM
OUR TIME LIMIT.
SO AT THIS POINT I THINK I WOULD
LIKE TO JUST THANK THE BOTH OF
YOU FOR A REALLY WONDERFUL
PRESENTATIONS AND TO OUR PATIENT
WHO REALLY HAS PUT TOTALLY
IMPORTANT HUMAN FACE ON WHAT'S
GOING ON HERE AND CERTAINLY
GIVES AUSA LOT TO THINK ABOUT.
CERTAINLY WE'RE IN A SITUATION
IN WHICH AN ENORMOUS AMOUNT HAS
BEEN DONE AND CERTAINLY A LOT OF
IT OWING TO STUDIES THAT WERE
DONE IN THE NIH CLINICAL CENTER
AND CLEARLY THERE'S A WHOLE NEW
CHAPTER YET TO BE WRITTEN WHICH
AGAIN IS BASED ON A LOT OF TOOLS
THAT HAVE BEEN DEVELOPED IN THE
NIH CLINICAL CENTER AND STUDIES
THAT ARE ONGOING.
AND SO, WE'RE REALLY EXCITED BY
ALL THIS AND LOOKING FORWARD TO
THE NEXT ADVANCES IN THE STUDY
OF AND TREATMENT OF MS.
SO ANYWAY, THANK YOU BOTH VERY
MUCH AND THANK OUR PATIENT AS
WELL.
>> THANK YOU FOR INVITING US AND
HOPEFULLY WE CAN COME BACK
SOMETIME AND REPORT ON MORE
PROGRESS IN THE FUTURE.
>> BRAVO.
>> YES INDEED.
>> THANK YOU AND WE WILL CALL IT
TO A CLOSE THEN AND WE WILL LOOK
FORWARD TO SEEING EVERYONE TO
TALK ABOUT NUTRIFILL NETS NEXT
WEEK.
SO IN ANY CASE, THANK YOU AGAIN
AND HAVE A GOOD AFTERNOON TO
EVERYONE.