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GOOD AFTERNOON.
I WANT TO CALL YOUR ATTENTION TO
NEXT WEEK'S SESSION OF
DEMYSTIFYING MEDICINE WHICH I
THINK IS REALLY EXTRAORDINARY.
THE SPEAKERS 2 LEADING
SCIENTISTS FROM THE NATIONAL
CENTER, THE NATIONAL GEOGRAPHIC
SURVEY BASED OUT IN MONTANA.
THESE FOLKS DO,A MAZING WORK
WHICH I HEARD OF.
SO 1 SPEAKER JONATHAN SPEEMAN IS
IN CHARGE OF TRACING THE MIG
RATTERY PATTERNS OF EVERYTHING
FROM INSECTS TO ANIMALS AS
INFLUENCED PRIMARILY BY GLOBAL
WARMING AND THE CONSEQUENCES OF
THE VECTORS THAT THEY CARRIED IN
TERMS OF NEW VIRUSES AND OTHER
AGENCIES INCLUDING FUNGI WHICH
APPEAR IN CONNECTION WITH THESE
PATTERNS WHICH ARE TAKING PLACE
AT AN AMAZINGLY DRAMATIC WAY,
NOT ONLY IN THIS COUNTRY BUT
AROUND THE WORLD.
MENT AND MANY OF THESE ARE
VECTORS OF DISEASE.
IT'S GREAT CONCERN FOR EXAMPLE
OF THE I HAVEEROUS OF THE
MOSQUITO ADEC ASCRIPT I, THEY
TRACE THESE PATTERNS AND THE
BIOLOGICAL CONSEQUENCES AT A
MOLECULAR LEVEL AS WELL AS AT A
BROAD EPIDEMIOLOGIC LEVEL AND
SOME OF THE RESEARCH THEY DO IS
JUST AMAZING PARTICULARLY
REGARDING FOR EXAMPLE,
PRION DISEASE IN ANIMALS, SO FAR
NOT YET IN MAN.
BUT WHO KNOWS?
ANYWAY, IT'S EXCITING DIMENSION
AND PARTICULARLY FOR POST DOCS
THERE'S A GREAT OPPORTUNITY
BECAUSE THEY'RE VERY ANXIOUS TO
LINK EXCITING CONTEMPORARY
SCIENCE, PRODUCTION OF SCIENCE
INTO THE WORK THAT THEY DO.
ANYWAY, I HOPE YOU WILL COME AND
FIND IT INTERESTING.
SO, OKAY, TODAY'S TOPIC MULTIPLE
SCLEROSIS IS IN A WAY ANOTHER
EXAMPLE WHICH HAS ALMOST
BEEN--REPEATEDLY COMES UP AS A
THEME WITH DIFFERENT DECEASES,
IT'S SORT OF LIKE THE ICEBERG
PHENOMENA.
MENT DISEASE IS RECOGNIZED IN
THIS CASE, IN 19th CENTURY BY
A FAMOUS FRENCH NEUROLOGIST
JACQUES COLE, THESE WERE FAMOUS
CLINICIANS AND THEY ONLY HAD 2
TOOLS, THE 1 WAS THE BRAIN AND
OBSERVATION AND THE OTHER
AUTOPSIES.
SO WHAT THEY SAW, WHAT HE SAW
SIMILAR TO WHAT OTHER CLINICIANS
HAVE BEEN DESCRIBED HERE BEIS
LIKE THE TOP OF THE ICEBERG, YOU
KNOW PEOPLE SERIOUSLY ILL
INVARIABLILY SOMETIMES AND THEN
YOU SEE THEM IN A NEAR FATAL
TYPE OF CONDITION.
AND THEN AS TIME GOES ON.
SEVERAL THINGS HAPPEN.
THERE'S REALIZE THAT THERE'S A
LIGHT HISTORY OF THE DISEASE AND
PEOPLE HAVE MILDER FORMS AND THE
WHOLE CLINICAL PERSPECTIVE GETS
SPILLED OUT AND IT BECOMES MORE
COMPLICATED, NOT SIMPLER.
AND THEN YOU GET DOWN TO THE
LEVEL OF HOW DO YOU KNOW IF YOU
HAVE IT?
THEN IT REALLY GETS COMPLICATED
BECAUSE THERE, THERE'S A DESIRE
TO USE CONTEMPORARY SCIENCE IN
IMAGING OR CHEMISTRY, MOLECULAR
TO DETECT "EARLY" SIGNS.
AND SOMETIMES IT IS EARLY SIGNS
BUT SOMETIMES IT TURNS OUT THAT
IT'S LIKE AWE SUSCEPTIBILITY
THING.
SO WHAT DO YOU DO IF HAVE YOU A
SUSCEPTIBILITY GENE?
OR AN ANTIBODY OR EACH IMAGE?
HOW DO YOU DEAL WITH IT?
AND THIS IS A HUGE PROBLEM.
IT'S NOT JUST AN ETHICAL
PROBLEM, IT'S A BASIC PROBLEM IN
UNDERSTANDING DISEASE SO
MULTIPLE SCLEROSIS IS AN
EXTRAORDINARY EXAMPLE OF THIS
ICEBERG PHENOMENA AND FOR THOSE
INTERESTED, WE ALSO PUT ON THE
WEB SITE SOME OF THE MORE
HISTORICAL ASPECTS OF THE
DISEASE WHICH ARE AN INTERESTING
THING TO UNDERSTAND HOW PEOPLE
WERE THINKING ABOUT IT AND HOW
IN SOME INSTANCES PREJUDICE GOT
IN THE WAY AND OTHER SCIENCE.
BUT THE KEY IS, YOU NEEDED
AN ANATOMIC DIAGNOSIS AND YOU
CAN'T DO THAT WITH THE BRAIN,
WITH THE SPINAL CORD.
SO IT LEADS TO NONINVASIVE
TECHNIQUE AND THAT'S 1 OF THE
TOPICS WE WILL HEAR ABOUT TODAY.
IN THINKING ABOUT THIS, I--LET
ME GO THROUGH THIS.
[LAUGHTER]
ALL RIGHT, I CAN'T PUSH ANYMORE
BUTTONS.
OKAY, SO ISSUES THESE ARE SOME
OF THE QUESTIONS THAT POPPED
THROUGH MY HEAD AND THROUGH MANY
OF YOURS, OUR PRECENTORS WILL
DISCUSS YOU KNOW, WHAT IS THE
DISEASE?
AND HOW DOES IT ALL HAPPEN?
WHAT ACCOUNTS FOR THE VERY
CLINICAL COURSE, YOU KNOW THE
BOTTOM PART OF THE ICEBERG.
WHY IS THERE A GENDER
DIFFERENCE?
IS IT TRUE THERE'S REALLY A
DIFFERENCE IN GEOGRAPHY IF
THAT'S THE CASE HOW DO YOU
DETECT [INDISCERNIBLE]: OH
YEAH.
SO--SORRY.
THE OH COME ON.
AT ANY RATE.
SO ...
SOME OF THE OTHER QUESTIONS THAT
ALWAYS POP UP IS MS AN
AUTOIMMUNE DISEASE?
SEEMS TO BE BUT WHAT'S THE
AUTOANTIGEN?
AND THEN THE THINGS THAT I
MENTIONED LIKE HOW DO YOU MAKE A
SPECIFIC DIAGNOSIS WHERE YOU
CAN'T TAKE A PIECE OF THE BRAIN
OUT TO BIOPSY AND RELATED TO
THAT IS IN DISEASE HAS MISSIONS
AND EXACERBATIONS AND SOME OF
THESE DEVELOP A CANDIDATE DRUG
FOR 1 REASON OR ANOTHER.
HOW DO YOU EVALUATE TREATMENT IN
A DISEASE THAT FOLLOWS LET'S
CALL IT AN ERRATIC CLINICAL
PATTERN.
IT'S VERY COMPLICATED AND PART
OF THAT COMPLICATION THAT WE'RE
GOING TO HEAR TODAY FROM 2
EXPERTS.
NOW, I GUESS AND WE'RE VERY
GRATEFUL BECAUSE THEY HAVE
BROUGHT 1 OF THEIR PATIENTS WHO
WAS KIND ENOUGH TO TELL YOU A
BIT ABOUT THE DISEASE.
SO I GUESS, DANIEL YOU'RE GOING
TO SPEAK FIRST, IS THAT RIGHT?
SO I WILL INTRODUCE YOU AS A
TRIO, SO IRENE CORTESE IS A
NEUROLOGIST WHO GRADUATE FRIDAY
MEDICAL SCHOOL IN ROME AND HAS
BEEN HERE AND VERY EARLY ON GOT
INTERESTED IN EXPLORING THE
SPECIFICITY OF CERTAIN BANDS AND
GELS OF SPINAL FLUID IN PATIENTS
WITH MULTIPLE SCLEROSIS AND THEN
SHE TRAINED IN NEUROLOGY AND IN
LABORATORY OF SCIENCE, CAME TO
THE NIH AS A RESEARCH FELLOW AND
EVENTUALLY RETURNED IN 2005
WHERE SHE'S NOW A STAFF
CLINICIAN AND SHE HEADS THE
NEURAL IMMUNOLOGY CLINIC WHICH
DIRECTS CLINICAL STUDIES WHICH
YOU'RE GOING TO HEAR ABOUT.
THE AND THIS IS A MAJOR
CHALLENGE IN RESPONSIBILITY.
SO THE OTHER SPEAKER IS DANIEL
REICH WHO GRADUATED FROM CORNELL
MEDICAL SCHOOL, GOT A Ph.D. AT
ROCKEFELLER UNIVERSITY IN
NEUROPHYSIOLOGY AND LATER
TRAINED AT HOPKINS AND
RADIOLOGY, NEURORADIOLOGY AND
NEUROLOGY AND HE'S THE CHIEF OF
THE TRANSLATIONAL NEURAL
RADIOLOGY PLAN AND RADIAL
IMMUNOLOGY BRANCH HERE AT THE
NIH AND IS WIDELY KNOWN FOR HIS
RATHER EXTRAORDINARY EFFORTS
AND,A COMPLISHMENTS IN LINKING
MODERN IMAGING TECHNOLOGY TO
THESE QUESTIONS.
OF DIAGNOSIS, DISEASE,
PROGRESSION, PERHAPS WE WILL
HEAR ABOUT EFFECTS OF THERAPY
AND THE UTILIZATION OF THESE
TECHNIQUE WILL ADVANCE OUR
KNOWLEDGE OF THIS EXTRAORDINARY
IMPORTANT AND CHALLENGING
DISEASE.
SO WE WILL HAVE THE TRIO.
>> GOOD AFTERNOON, EVERYONE, I
AM IRENE CORTESE, AND WE WILL
TAG TEAM THIS A LITTLE BIT.
THIS IS ALAN CALENDAR, A PATIENT
OF OURS FOR THE PAST HOW MANY
YEARS?
SORRY, ALMOST 10 YEARS, 2008.
>> HE WILL SHARE A BIT ABOUT HIS
PERSONAL EXPERIENCE WITH
MULTIPLE SCLEROSIS AND DANIEL.
>> I'LL JOIN IN WHEN IT'S TIME.
>> SO WE THOUGHT WE WOULD START
ABOUT ASKING ALAN HOW THIS
DISEASE FIRST MANIFEST INDEED
HIM AND ABOUT HIS EXPERIENCE?
>> SURE, SO, CAN EVERYBODY HEAR
ME ALL RIGHT?
I THINK SO.
I GET A HANDLE.
I WAS 40 YEARS OLD IN 2008, 39
IN 07.
HIJUST DECIDED TO MOVE IN WITH
MY PARTNER, BUY A HOUSE AND
RETURN TO GRADUATE SCHOOL TO GET
MY MASTERS DEGREE AND IT WAS
THAT FIRST SEMESTER WALKING FROM
THE PARKING LOT TO THE CLASSROOM
WHERE MY RIGHT FOOT STARTED
FEELING LIKE MY SHOE WAS TOO BIG
OR TOO SMALL OR MY FOOT WAS TOO
BIG AND IT WAS JUST AN ANNOYANCE
AT THE TIME.
BUT OVER THE COURSE OF A FEW
WEEKS, MY GAIT STARTED TO BE
IMPACTED AND I STARTED WALKING,
STARTED EXPERIENCING MORE PAIN
AND DIFFICULTY WALKING ON THAT
LEG TO THE POINT WHERE MY
PROGRAM DIRECTOR RECOGNIZED MY
ISSUES AND ACTUAL --ACTUALLY RAISED IT
WITH ME.
AND AT THAT POINT IN TIME I
CALLED AN ON-CALL IN USER WITH
MY INSURANCE COMPANY AND
DESCRIBED WHAT WAS GOING ON.
I HAD SEEN MY PRIMARY CARE
PHYSICIAN AND SAID, LET'S WAIT
AND SEE IF IT GOES AWAY IN A
WEEK OR SO.
IT DIDN'T AND I GOT THIS
FEEDBACK FROM MY PROGRAM
DIRECTOR AND I CALLED THE NURSE
AND WHEN I DESCRIBED WHAT WAS
GOING ON, SHE SAID YOU NEED TO
SEE A NEUROLOGIST RIGHT AWAY.
AND WITHIN A FEW DAYS I HAD MY
FIRST APPOINTMENT.
I HAD MY NEUROLOGIST WITHIN THE
FOLLOWING FEW WEEKS WE WENT
THROUGH A NUMBER OF TESTS TO
CHECK THE NERVOUS SYSTEM AND
ULTIMATELY I DID A LUMBAR
PUNCTURE AND ULTIMATELY AN MRI
AND THE CONCLUSION AT THE END OF
THOSE TESTS WAS THAT IT WAS--IS
DIAGNOSED WITH PROBABLE MULTIPLE
SCLEROSIS.
AND AT THAT TIME WE DID SOME
INITIAL TREATMENTS TO TRY TO
TACH DOWN ON THE EXPERIENCE I
WAS HAVING.
THAT'S HOW I INITIALLY ENDED UP
WITH THE DIAGNOSIS.
>> AND SO THIS IS A PRETTY
TYPICAL INITIAL PRESENTATION.
WHAT I WILL DO NOW IS JUST GIVE
YOU A FACTS ABOUT MS AT THE
BEGINNING OF THE DISCUSSION AS
WELL.
SO MS IS THE MOST COMMON CHRONIC
NEUROLOGICAL DISEASE OF YOUNG
ADULTS.
IT IS UNDERSTOOD TO BE AN IMMUNE
MEDIATED CHRONIC INENEMIATORY
DISEASE WHICH SEEMS TO BE
TRIGGERED BY SOME UNIDENTIFIED
ENVIRONMENTAL FACTORS AND
GENETICALLY SUSCEPTIBLE
INDIVIDUALS.
THE HALLMARK OF MS IS
INFLAMMATORY DEMYELINATING
LESIONS REFERRED TOAC PLAQUES IN
THE CENTRAL NERVOUS SYSTEM WITH
AXONAL LOSS AS WELL AND THE
DISEASE IS CHARACTERIZED BY
REMISSIONS OF THE NEUROLOGICAL
SYMPTOMS AS WELL AS PROGRESSION
AND DISABILITY OVER TIME.
APPROXIMATELY 400,000 CASES OF
MS JUST IN THE UNITED STATES
ALONE AND ABOUT 2.3 MILLION
CASES WORLD WIDE.
IT'S NOT A RARE DISEASE.
THERE'S A HIGHER PREVALENCE IN
CAUCASIANS OF NORTH AND EUROPEAN
ANCESTRY AND HIGHER INCIDENCE OF
WOMEN OF ABOUT 3 TO 1.
AND ABOUT 34thS OF CASES
PRESENT IN PATIENTS BETWEEN THE
AGES OF 14 AND 45 WHICH
OBVIOUSLY IMPLY AN IMPORTANT
SOCIOECONOMIC IMPACT OF THIS
ILLNESS THE WE WERE SAYING THE
CAUSE OF MS IS UNKNOWN BUT
VARIOUS RISK FACTORS CAN BE
IDENTIFIED AS GENETIC,
ENVIRONMENTAL AND MORE
SPECIFICALLY INFECTIOUS RISK
FACTORS.
GENOME WIDE ASSOCIATION STUDIES
HAVE IDENTIFIED FROM 2 HELPED
RISK ALLELES.
VAST MAJORITY OF THESE ARE
IMMUNE RESPONSE GENES AND THE
STRONGEST SUSCEPTIBILITY OF
LOCUST IS BY FAR THE H. O. A.,
CLASS 2 REGION WITH THE RB 1,
1601, BEING THE MOST SIGNIFICANT
RISK VARIANCE WHICH ACCOUNTS FOR
ABOUT A 2-6 FOLD INCREASE IN
RISK OF DEVELOPMENT OF MS OVER
THE GENERAL POPULATION.
BUT IN GENERAL THE GENERAL
POPULATION HAS A .1% RISK AND
FIRST DEGREE RELATIVES IS 2.5%.
AND MONOZYGOTIC TWINS HAVE ABOUT
30 PRT.
SO OHM GENETIC SYSTEM PART OF
THE STORY AND THE ENVIRONMENT
HAS AN IMPORTANT INFLUENCE.
PROBABLY THE MOST INTRIGUING
OBSERVATION FROM EPIDEMIOLOGICAL
STUDIES IN MS IS THE GRAPHIC
DISTRIBUTION WHICH FOLLOWS A
NORTH-SOUTH GRADIENT OF RISK
WITH VERY LOW RISK AT THE
EQUATOR AND THEN INCREASING RISK
GOING NORTH AND SOUTH IN
LATITUDE.
AND THIS--THIS DISTRIBUTION IS
SEEN WITHIN THE UNITED STATES
FOR EXAMPLE.
EVEN MORE INTERESTING THOUGH ARE
MIGRATION STUDIES WHICH HAVE
SHOWN THAT IF AN INDIVIDUAL
MIGRATES FROM 1 REGION TO
ANOTHER REGION WITH DIFFERENT
RISK.
IF THEY MOVE BEFORE THE AGE OF
15, THEY WILL TAKE ON THE RISK
OF THEIR ADOPTIVE LOCATION WHILE
IF THEY MOVE AFTER THE AGE OF
15, THEY WILL PRESERVE THAT RISK
OF THE REGION OF ORIGIN.
SO THIS IMPLIES SOME SORT OF
EXPOSURE TO AN ENVIRONMENTAL
FACTOR SPREPUBERTY WHICH THEN,
YOU KNOW IS RISKED LATER.
DIFFERENT IDEAS ARE SUGGESTING
THIS AS EXPANDING THIS, 1 IS SUN
LIGHT AND VITAMIN D LEVELS WHICH
IN FACT HAVE INDEPENDENTLY BEEN
SHOWN TO BE ASSOCIATED WITH RISK
OF MS AND CERTAINLY DEVELOPMENT
OF THE DISEASE AS WELL AS
SEVERITY OF THE DISEASE.
BUT THE EFFECTS OF VITAMIN D IS
AN AREA OF RESEARCH.
ANOTHER ENVIRONMENTAL RISK
FACTOR ASSOCIATED IS SMOKING.
AND MORE SPECIFICALLY IN TERMS
OF RISK FACTORS AS THE ROLE OF
INFECTIOUS AGENTS.
SO COMING FROM EPIDEMIOLOGICAL
STUDIES THAT DESCRIBE MANY
EPIDEMICS OF MS AND IN
PARTICULAR THE MOST STRIKING IS
THE EXPERIENCE IN THE PHARAOH
ISLANDS DURING THE PERIOD IN
POST WORLD WAR II, A REGION
WHERE THERE WAS NO MS PRIOR TO
1943, FOLLOWING BRITISH
OCCUPATION WHICH OCCURRED IN
WAVES, THERE WERE WAVES OF
INCREASE INCIDENCE IN MS, WHICH
APPEARS TO ASSOCIATE WITH
EXPOSURE TO SOMETHING.
REALATEED TO THIS BRITISH
OCCUPATION AND IT SEEMS TO
CORRELATE ACTUALLY WITH PEOPLE
WHO WERE PREPUKEITAL IN THE
PERIOD OF THE OCCUPATION AND SO
THEN AGAIN SUGGESTING POSSIBLY
SOME SORT OF AN INFECTIOUS OR
TRANSPORTABLE EXPOSURE.
AMONG THESE EBV IS DEFINITELY
THE INFECTIOUS AGENT THAT HAS
RECEIVED THE GREATEST DETENTION.
IN FACT MS IS 2 TO 3 TIMES MORE
COMMON IN PEOPLE WHO HAVE A
HISTORY OF INFECTIOUS
MONONUCLEOSIS, INFECTIOUS
MONONUCLEOSIS IS THE CLINICAL
MANIFESTATION OF LATER INFECTION
WITH EBV.
AND SO SUGGESTING MAYBE THAT THE
THEORY OF THE HYGIENE THEORY
WHERE ANTISEPTIC CONDITIONS WE
LIVE IN NOW, REDUCING EXPOSURE
AT AN EARLIER AGE MAY REDUCE IT
LATER IT LIFE.
SO REGARDLESS THIS COMBINATION
OF COMPLEX PREDISPOSITION AND
THEN WELL TIMED ENVIRONMENTAL
TRIGGERS PROBABLY LEADS TO OR IS
BELIEVED TO LEAD TO ACTIVATION
OF SELF-REACTIVE T-CELLS IN THE
PERIPHERY THRU A MECHANISM OF
POETIC LECULAR MIMICKRY.
WHERE A T-CELL IS INITIALLY
PRIMED AGAINST ANOXOG NOWS
ANTIGEN BUT THEN CROSS REACTS
WITH A SELF-EPITOPE, NOT
IDENTIFIED HOWEVER.
THE EBV SUPPORTERS ALSO SUGGEST
THAT POLYCLONAL ACTIVATION BY A
CHRONIC EBV INFECTION MIGHT LEAD
TO BASICALLY RELEASING A LATENT
AUTOIMMUNE RESPONSE WHICH THEN
CAN CULMINATE INTO AN IMMUNE
MEDIATED ATTACK AGAINST MILEIN
WITHIN THE CNS.
PATHOLOGICALLY THIS LEADS TO THE
HALLMARKS THAT WE TALKED ABOUT
EARLIER.
PERIVENOUSLYULAR, INFLAMMATION,
PREDOMINANTLY REPRESENTED BY
LYMPHOCYTIC INFILTRATION RATE
RATE, LEADING TO LESIONS AROUND
THIS INFILTRATE AND ALREADY
EARLY ON IN THE DISEASE,
PROMINENT AXONAL TRANSFECTION
WHICH CAN THEN BE SEEN LATER TO
BE MORE WIDE SPREAD WITH AXONAL
DEGENERATION.
SO WHAT THIS LEADS TO IN
CLINICAL COURSE, WE HAVE
PATIENTS TO COME TO US FOR
MEDICAL ATTENTION BECAUSE OF
DEVELOPMENT OF NEUROLOGICAL
SYMPTOMS WHICH WILL PROGRESS
OVER A FEW DAYS, REACHES A PEEK
AND THEN PERSISTING FOR A FEW
WEEKS AND THEN TYPICALLY
RESOLVING AND THEN ALREADY AT
THIS STAGE AN MRI MIGHT SHOW THE
PRESENCE OF A CONTRASTING LESION
WHICH IS BASICALLY THE IMAGE
CORRELATE OF THAT
PERIVENOUSLYULAR INFLAILATION.
ALL RIGHT AT THAT TIME, VERY
OFTEN PATIENTS WILL ALREADY HAVE
EVIDENCE OF THEIR HAVING BEEN
PREVIOUS EPISODES OF ACTIVE
INFLAMMATION SUGGESTING THAT THE
ONSET OF THE DISEASE IS PROBABLY
EVEN DECADES EARLY EARLY EVEN
THOUGH NEVER MEETING THE
CLINICAL THRESHOLD.
SUBSEQUENT OF THESE OF COURSE
ARE REKERRING EPISODES OF
NEUROLOGICAL SYMPTOMS THAT COME
AND GO AND THIS IS ASSOCIATED
ALSO WITH EVIDENCE BY MRI OF
INFLAMMATORY ACTIVITY.
SYMPTOMS REALLY DEPENDOT
LOCATION OF LESIONS AND CAN BE
VERY VARIABLE RANGING FROM LOSS
OF VISION IN 1 EYE, SENSORY
DEFICITS LIKE ALAN HAD
PRESENTED, BLADDER DYSFUNCTION,
WEAKNESS, LOSS OF BALANCE.
IN TERMS OF DIAGNOSING THIS,
THERE ARE SOME PRINCIPLES.
THERE NO DEFINITIVE LABORATORY
TEST AND WHAT THE CLINICIAN
NEEDS TO DO IS DEMONSTRATE
DISSEM NATION OF LESIONS IN TIME
AND SPACE.
SO A CHRONIC MULTIFOCAL ILLNESS.
AND MUST ALSO EXCLUDE
ALTERNATIVE DIAGNOSIS.
SO THE CLINICIAN WILL RELY ON
MEDICAL HISTORY TO IDENTIFY ANY
EVENTS THAT MIGHT BE SUGGESTED
OF MS SYMPTOMS.
AND OF COURSE CONSIDER
ALTERNATIVE DIAGNOSIS.
THE NEUROLOGICAL EXAM NATION TO
LOOK FOR SUBCLINICAL EVIDENCE
AND THEN PARACLINICAL STUDIES
INCLUDING MRI, CSF ANALYSIS AND
ELECTROPHYSIOLOGICAL STUDIES
THAT AID IN THIS.
SO GOING BACK, ALAN IF YOU THINK
IN RETROSPECT BEFORE THESE FIRST
SYMPTOMS THAT LED TO THE
DIAGNOSIS, IS THERE ANYTHING?
>> YEAH, NO.
I IDENTIFIED BACK IN 2007 WHEN
THIS DIAGNOSIS WAS MADE THAT I
HAD HAD MRIs ABOUT 10 YEARS
EARLIER AND THAT WAS IN RESPONSE
TO A SERIES OF UNEXPLAINED DIZZY
OR VERT GO ATTACKS THAT I WAS
HAVING AND AT THAT TIME THE
PRIMARY CARE PHYSICIAN HAD DONE
A STRESS TEST FOR THE HEART, HAD
CLEANED THE EARS AND CALLED FOR
AN MRI ALSO BECAUSE THE SYMPTOMS
THEY WERE IN RETROSPECT NOW THAT
WE UNDERSTAND--I UNDERSTAND HOW
MS WORKS AND HOW FLARE UPS WORK,
WILL VERY MUCH FOLLOW THAT
PATTERN.
THE DIZZINESS WOULD HIT, IT
WOULD HIT SUDDENLY IT WOULD BE
VERY ALARMING.
I WOULD REGAIN NORMALCY AND THEN
IT WOULD GO AWAY AND I WOULD
WOULD HAVE A SERIES OF THOSE
THAT WOULD PROGRESSIVE LOAMACYY
GET WORSE OVER A FEW WEEKS AND
THEN PROGRESSIVELY BET BETTER
AND THEN GO AWAY ENTIRELY.
THIS HAPPENED OVER A FEW YEARS
IN 1997 WHERE IT HAPPENED AND IT
KEPT GETTING WORSE THAT I
BROUGHT IT TO MY PRIMARY CARE
PHYSICIAN'S ATTENTION.
I FEEL LIKE IN RETROSPECT THAT
FOLLOWED THIS PATTERN THAT
YOU'RE TALKING ABOUT WHERE IT
CAN COME AND GO AND BE HARD TO
IDENTIFY FOR THAT REASON.
I ALSO HAD OTHER SYMPTOMS THAT
WERE UNEXPLAINED THAT WEREN'T AS
DRAMATIC, THINGS LIKE FOR ME,
EVERY TIME I WOULD START TO GET
A COLD, MY BACK WOULD BE VERY
TINNINGLY OR SENSITIVE TO TOUCH
AND I WOULD DESCRIBE THAT TO MY
PRIMARY CARE PHYSICIAN AND SHE
COULDN'T EXPLAIN WHAT THAT WAS
AND ESSENTIALLY I WROTE IT OFF
AS ACHES AND PAINS THAT YOU
WOULD GET WITH A REGULAR COLD
BECAUSE I COULDN'T CALL IT
ANYTHING ELSE AT THAT TIME.
BUT THAT SEEMED LIKE--YOU KNOW
AND THEN I FEEL THAT AND THEN I
GET THE COLD AND IT WOULD ALMOST
ALWAYS PRECEDE GETTING THE COLD
SO MUCH SO THAT LIKE MY IMMUNE
SYSTEM WAS PREDICTING THAT I WAS
GOING TO GET A COLD OR
SOMETHING.
AGAIN IN RETROSPECT, IT FEELS
LIKE THOSE THINGS FOR ME, WERE
NOW, I THINK EARLY AND THEN THE
MRI, THAT I LOOKAD TODAY AND I
THINK I.E., SEE WHAT I KNOW NOW
AS LESIONS.
>> IF YOU GO BACK AS FAR AS HIGH
SCHOOL IS THERE ANYTHING THAT
CAN YOU POINT TOO?
OR MAYBE STARTED IN YOUR 20S?
>> I FEEL LIKE IN HIGH SCHOOL, I
DID BATTLE A LOT OF COLDS, I
DON'T KNOW IF THAT COUNTS.
BUT I HAD SOME BACK ISSUES WHICH
I DON'T KNOW--I DON'T KNOW IF
THOSE WERE--
>> DID YOU EVER HAVE
MONONUCLEOSIS?
>> YES.
>> HOW OLD WERE YOU AT THE TIME.
>> IT MUST HAVE BEEN AT LEAST
ONCE IN HIGH SCHOOL AND TESTED
POSITIVE AGAIN AS A YOUNG ADULT
IN MY 20S BECAUSE I WAS GETTING
THINGS LIKE COLDS OR STREP ONCE
EVERY 3 MONTHS FOR A WHILE.
>> THE EPIDEMIOLOGY OF THAT
VIRUS WAS INTERESTING IN THE
SENSE THAT IT'S THE UBIQUITOUS
VIRUS THAT AS YOU SAID EFFECTS
90% OF PEOPLE HAVE THE, BUT IN
PEOPLE WHO HAVE MULTIPLE
SCLEROSIS, WHO DON'T HAVE
EPSTEIN BAR VIRUS, IS
VANISHINGLY SMALL AND THE NUMBER
WHO MANIFESTED, HAD THE
INFECTION MANIFESTS TO
MONONUCLEOSIS IS FAR HIGHER THAN
IN THE GENERAL POPULATION.
WANT ALTHOUGH FAR AND AWAY, MOST
PEOPLE WHO HAVE EBV AND WHO HAVE
MONONUCLEOISEIS HAVE CLINICAL
MONONUCLEOSIS.
SO IT'S INTERESTING.
>> [INDISCERNIBLE]..
>> RIGHT.
>> YEAH, THERE'S SOME REASONABLE
MECHANISTIC DATA SUPPORTING
THERE COULD BE A LINK BUT OF
COURSE IF YOU LOOK AT A LIST OF
THE VIRUSES THAT HAVE BEEN
IMPLICATED AS A CAUSE OF
MULTIPLE SCLEROSIS GOING BACK
150 YEARS OR SO, I MEAN THE LIST
PICKS UP SEVERAL COLUMNS OF FINE
PRINT IN A TEXTBOOK AND YOU KNOW
MEASLES, VIRUS AND *** AT 1
POINT.
BUT THAT'S THE VIRUS OF THE DAY.
AND THE LINK HAS PROBABLY
SURVIVED FOR A DECADE OR SO NOW,
WHERE VACCINES [INDISCERNIBLE].
>> SO I'LL BRIEFLY MENTION THE
AUTOCLONAL BANDS.
AL AN UNDER WENT THE LUMBAR
PUNCTURE.
TYPICALLY THE ANTIBODIES IN THE
SPINAL FLUID THAT ARE NOT
PRESENT IN THE SERUM AND THESE
AREN'T PRESENT IN A NORMAL
INDIVIDUAL.
AND THIS IS TAKEN TO INDICATE
INFLAMMATION.
THE SPECIFICITY OF THE BANDS IS
UNKNOWN AND THE PATTERNS ARE
INDIVIDUAL AND NOT SHARED ACROSS
PATIENTS WHICH AGAIN SORT OF
SUPPORTS THIS POLYCLONAL
ACTIVATION IDEA.
BANDS THAT ARE PRESINENT ABOUT
98% OF PEOPLE WITH MS, SO IT'S
CONSIDERED A VERY SPECIFIC OR
SENSITIVE FINDING.
BUT THERE'S CERTAINLY NOT
EXCLUSIVE TO MS, ANY INFECTION
OR ANY PROCESS EFFECTS THE CNS
MIGHT BE ASSOCIATED WITH THESE
BANDS.
>> SO AT 1 POINT WE HAD THAT IN
THE CONTEXT, THAT IF YOU LOOK,
YOU CAN FIND SOME SOMEWHERE
AROUND 30-40% OF PATIENTS BANS
FOR THE EPSTEIN BAR VIRUS
[INDISCERNIBLE].
>> HOPEFULLY TO--
>> *** VIRUSES BUT ANYWAY, WE
PUBLISHED ON THAT A LITTLE BIT.
>> OKAY.
>> YEAH, WE CAN PAUSE NOW FOR
SOME QUESTIONS.
THE I THINK WE'LL GET BACK TO
ALAN A BIT LATER BUT NO PROBLEM
STOPPING NOW.
>> [INDISCERNIBLE].
>> I HAVE NOT, I HAVE NOT.
LET NO.
>> [INDISCERNIBLE].
[INAUDIBLE RESPONSE FROM
AUDIENCE ]
>> YES, I WAS IN ART SCHOOL.
I WAS IN ART SCHOOL AND IT WAS
MY ART PROGRAM
[INAUDIBLE RESPONSE FROM
DIRECTOR IN ART
SCHOOL:
[INAUDIBLE RESPONSE FROM
AUDIENCE ]
>> HE
JUST SAID YOU AREN'T WALKING
RIGHT.
YOU LOOK LIKE YOU'RE HAVING
DIFFICULTY WALKING.
YOU SHOULD TALK TO SOMEBODY.
AND THAT'S WHEN I CALLED THE
NURSE, THE INSURANCE NURSE ON
CALL, I WAS WALKING FROM THE
PARKING LOT TO CLASS AND I
CALLED AND SHE SAID AFTER I
DESCRIBED--AFTER I DESCRIBED THE
SITUATION, I'D SEEN MY DOCTOR,
BEEN HAVING THIS FOR A WHILE, IT
SEEMS TO BE GETTING WORSE, SHE
SAID YOU NEED TO SEE A
SPECIALIST.
SO I GIVE HER A LOT OF CREDIT
FOR MAKING THE CALL.
>> THE WAY INSURANCE IS SUPPOSED
TO WORK.
>> REALLY
[INAUDIBLE RESPONSE FROM
TRULY SURPRISES ME.
>> [INDISCERNIBLE].
[INAUDIBLE RESPONSE FROM
AUDIENCE ]
>> HE IS NOT MY GP RIGHT NOW.
I CHANGED MY GP.
I WENT BACK TO THE 1 I HAD WHO
ORIGINALLY IN 97 DID EVERYTHING
RIGHT IN RETROSPECT.
>> I SWITCHED.
>> LET'S POINT OUT THAT THE
DIAGNOSIS OF MS CAN ACTUALLY BE
QUITE TOUGH AND ORDERING--WE'LL
TALK ABOUT MRI IN A MINUTE BUT
ORDERING THE RIGHT STUFF, IT
TAKES SOMETIME TO GET TO THAT
POINT AND WE ARE MAKING
DIAGNOSIS RARELY BUT
OCCASIONALLY SOME PEOPLE
[INDISCERNIBLE].
>> I WILL SAY JUST IN HIS
DEFENSE, THE NEXT TEST WAS THE 1
THAT WOULD BE VERY PAINFUL AND
HE WAS TRYING TO SPARE ME FROM
HAVING TO TAKE THAT TEST: IN
RETROSPECT, I WOULD HAVE
PREFERRED THE PAINFUL TEST, THE
EMG TEST.
>> RIGHT.
>> RIGHT WHICH WOULD NOT HAVE
REALLY HELPED IN THIS CASE.
>> OKAY.
[INAUDIBLE RESPONSE FROM
>> ANY OTHER?
>> [INDISCERNIBLE]
[INAUDIBLE RESPONSE FROM
>> SORRY.
WE'LL GO
ON AND THERE WILL BE OTHER
OPPORTUNITIES, I'M SURE.
>> SO I'M JUST GOING TO TALK A
LITTLE BIT ABOUT MRI AND HOW WE
MAKE THE DIAGNOSIS OF MS.
HERE'S AN MRI MRI SCANNER, AND JUST
TO BE SURE, THERE ARE SOME WHO
KNOW HOW THESE WORK IN ROOM AND
OTHERS WHO DON'T.
I WILL TALK ABOUT HOW WHEY MAKE
IMAGE IT IS AND WHAT IT IS IS A
MAGNET, AND THE MAGNET IS WHEN
YOU PUT SOMEBODY INSIDE THE
SCANNER, THE MAGNETIC FIELD, THE
PROTONS WHICH MAKE UP MOST OF
OUR BODIES WHICH ARE ALWAYS
SPINNING AROUND AT A RAPID RATE
WILL ALIGN IN THE DIRECTION OF A
MAGNETIC FIELD INSIDE THIS
MAGNET.
AND THAT HAPPENS VERY, VERY
QUICKLY AND THEN, THEY'RE ALL
ESSENTIALLY OOH LIENED IN THE
SAME DIRECTION AND WHAT WE CAN
DO IS TO DELIVER A PULSE OF
RADIO FREQUENCY ENERGY, INTO THE
MAGNET, INTO THE PERSON WHO'S
INSIDE THE MAGNET AND THAT WILL
PERTURB THE NAG NETTIZATION OF
THE THIN OF THE PROTONS THAT ARE
INSIDE THE PERSON.
AND THEN WE CAN JUST WATCH USING
INTENTIONALLY AN ANTENNA WE CAN
WATCH THESE PROTONS RELAX BACK
INTO ALIGNMENT INSIDE THE
MAGNETIC FIELD.
THE AND THERE'S A LOT OF PHYSICS
BEHIND THAT AND THE REASON IT'S
USEFULFUL MEDICALLY IS BECAUSE
DEPENDING ON WHICH TISSUE THE
PROTONS ARE IN THIS, THE RATE OF
RELAXATION WILL DIFFER: AND
THERE ARE A NUMBER OF TIME
CONSTANT OR RATE CONSTANTS THAT
ARE REALLY CHARACTERISTIC AND WE
CAN MEASURE IN THE MRI SCANNER
AND WE CAN USE THOSE TO MAKE
IMAGES OF ANY PART OF THE BODY
BUT WE'RE INTERESTED HERE IN THE
CENTRAL NERVOUS SYSTEM, IN
PARTICULAR IN THE BRAIN AND
SPINAL CORD.
SO WHEN WE MAKE PICTURES OR MAKE
IMAGES THAT ARE--THAT ARE
WEIGHTED TO TELLING US ABOUT THE
DIFFERENT RATE CONSTANTS, THE
LACTATION RATE CONSTANTS, YOU
GET THESE 2 TYPINGS OF IMAGES
WHICH ARE P1 IMAGES AND P2
IMAGES.
AND YOU CAN SEE THAT STRUCTURES
IN THE BRAIN APPEAR DIFFERENT
DEPENDING ON WHAT STRUCTURE THEY
ARE.
FOR EXAMPLE, IN THE P1 WEIGHTED
IMAGE YOU CAN SEE THAT THE FLUID
IN THE BRAIN, THE SPINAL FLUID
INSIDE THE VENTRICULAR SYSTEM OF
THE BRAIN IS DARK OVER HERE.
THAT MEANS IT HAS A VERY LONG
TIME OF RELAXATION.
THE GRAY MATTER, THE CORTEX WITH
THE CELL BODIES OF THE NEURONS
ARE IS DARK AND THE WHITE MATTER
WHERE THE MILENNATED NERVE
FIBERS ARE IS RIGHT, AND THAT'S
BECAUSE OF THE MILEIN WHICH IS
MOSTLY A FATTY SUBSTANCE WHICH
IS A RAPID RELAXATION AND THAT
SHOWS UP AS BRIGHT ON THIS IMAGE
AND THEN ON THE C2 IMAGE, THE
CEREBRAL SPINAL FLUID SHOWS UP
AS BRIGHT.
SO WE CAN SEE THE VENTRICLES
VERY NICELY THROUGH THE SPINAL
FLUID SURROUNDING THE BRAIN VERY
FIES NICELY AS WELL AND THAT
OUTLINES STRUCTURES SUCH AS
[INDISCERNIBLE].
LET AND WE DON'T GET VERY GOOD
CONTRAST WITHIN THE BRAIN
BETWEEN THE GRAY MATTER AND
WHITE MATTER ON THIS TYPE OF
IMAGING, THOSE, THE C2 TIMINGS
OF GRAY AND WHITE MATTER ARE
QUITE SIMILAR BUT AS A
RADIOLOGYST I USE THESE 2 TYPES
OF IMAGES AND A FEW OTHERS EVERY
DAY TO TRY TO FIGURE OUT WHAT IS
WRONG, WHERE THERE ARE
OBLIGATIONS NORMALITYS IN THE
BRAIN AND THEN I HAVE TO KIND OF
USE MY KNOWLEDGE OF HOW THEY'LL
SHOW UP ON THESE 2 TYPES OF
IMAGES AND A FEW OTHERS IN ORDER
TO FIGURE OUT WHAT THE DIAGNOSIS
IS.
AND WITH RESPECT TO MS, THERE'S
IN ADDITION TO THESE IMAGES THAT
WE CAN TAKE JUST IMMEDIATELY
AFTER WE PUT SOMEBODY INSIDE THE
SCANNER, WE CAN ALSO GET
FUNCTIONAL INFORMATION USING
CONTRAST AGENTS.
AND IN MRI MOST OF THESE
CONTRAST AGENTS ARE BASED ON
GADDA LYNNIUM, IT'S A HEAVY
METAL THAT HAS THE EFFECT OF
SHORTENING THE C1 TIME OF KIND
OF PROTONS THAT ARE IN THE
VICINITY.
SO KEYALATES ARE MADE WHICH ARE
SAFE WHEN USED APPROPRIATELY.
AND AND NORMALLY THE BRAIN THAT
THE PLOD VESSELS IN THE BRAIN
ARE NOT LEAKY SO THAT THESE
INJECTED INTRANSLATIONAL
RESEARCH VENOUSLY WILL TRAVEL UP
TO THE BRAIN AND THEY WON'T GET
INTO THE BRAIN P A
RENKMA ITSELF.
BUT IN GENERAL, THE BRAIN DOES
NOT REALLY CHANGE VERY MUCH
AFTER WE INDADOLINIUM.
BUT THAT'S NOT THE CASE IN
MULTIPLE SCLEROSIS, AS IRENE
MENTIONED THERE IS OFTEN
INFLAMMATION AROUND BLOOD
VESSELS AND ACUTELY THAT CAN BE
ASSOCIATE WIDE LEAKINESS OF THE
BLOOD VESSELS AND ABNORMALITIES
OF THE PLOD BRAIN BARRIER AND
IT'S BLOCKING THE GADO LYNNIUM
IN THE BRAIN.
THIS IS 2 IMAGES, 1 IS BEFORE
AND 1 IS AFTER THE GADDA LYNNIUM
IS INJECTED AND YOU CAN SEE HERE
THE IMAGE ON THIS SIDE IS
SIMILAR TO WHAT I SHOWED YOU,
THOUGH WHITE MATTER IS BRAT.
THERE ARE A FEW DARK SPOTS HERE
WHICH ACTUALLY REPRESENT
THE--OUR AREAS WHERE THERE ARE
REGIONS DUE TO MULTIPLE
SCLEROSIS WHICH WE'LL GET BACK
YOU IN A BIT BUT IN THE POST
IMAGE, CAN YOU SEE OF COURSE THE
STRUCTURES THAT ENHANCE
NORMALLY, INCLUDING THE
COREY-PLEXUS AND THE SUBVESSELS
AND INCLUDING THE DURA MATTER
WHICH IS THE THICK MEMBRANE
WHICH COVERS THE BRAIN SO WE CAN
SEE THAT NICELY OVERHERE BUT OF
COURSE YOUR EYE IS PICKED UP,
THIS SPOT HERE WHICH REPRESENTS
AN AREA WHERE THE GADDA LYNNIUM
IS OUT IN THE BRAIN AND IF YOU
LOOK CLOSELY YOU CAN SEE THERE'S
A DARK SPOT OVER THERE.
AND SO THIS IS--THIS TELLS US A
LOT.
IT TELLS US THERE'S ACTIVE
INFLAMMATION IN MS, THERE IT
TELLS A BIT ABOUT THE AGE OF
THAT AREA, OF ACTIVE
INFLAMMATION AND I'LL GET BACK
TO THAT IN A BIT AS WELL.
AND AGAIN FEEL FREE TO STOP FEE
IF THERE'S ANYTHING I CAN EXPAND
ON.
MENT.
>> [INDISCERNIBLE]
>> NO, THERE ARE VARIOUS
KEYLATES THAT ARE USED, LINEAR
KEYLATES AND THEY HOLD ON TO THE
GADDA LYNNIUM MORE OR LESS
TIGHTLY.
MENT THERE ARE SOME THAT--THAT
THE KEYLATE BINDS TO THE
ALBUMIN, SO IN THIS CASE, THAT
WOULD NOT SHOW US ANYTHING ON
THIS IMAGE BUT IT WOULD BE WITH
THE 1S WE USE, THAT SHOW SOME
DEGREE AND THEN WILL GET OUT.
BUT THE IMPORTANT POINT FROM AN
MRI POINT OF VIEW IS THAT WE'RE
NOT ACTUALLY IMAGING THE GAD
GADDA LYNNIUM, BUT THE PROTONS
THAT ARE NEAR WHOSE RELAXATION
PROPERTIES ARE CHANGED BY THE
GADDA LYNNIUM.
SO IT'S EXTREMELY CRITICAL
CLINICALLY.
SO WHAT DO WE SEE WHEN WE IMAGE
MULTIPLE SCLEROSIS, SO HERE
AGAIN ARE 2 IMAGES, THIS IS A
TYPE OF IMAGE I HAVEN'T SHOWN
YOU BEFORE, IT'S A FLAIR IMAGE,
WHERE WE'VE DONE SOMETHING TO
SUPPRESS THE SIGNAL INSIDE THE
WATER AND IN THE SPINAL FLUID
THAT'S DARK, BUT WE SEE THE
AREAS THAT ARE RATHER WATERY
WHICH ARE ACTUALLY THE LESIONS
OF MS, AND SO, CAN YOU SEE IN
THIS PERSON THERE ARE DISCREET
FOCI, RIGHT UP AGAINST THE
VENTRICULAR SYSTEM OR SOMETIMES
DEEP IN THE WHITE MATTER OR
RIGHT UP AGAINST THE CORTICAL
SURFACEOT BOTTOM: THAT ARE
AGAIN REPRESENTING SOME TISSUE
DAMAGE DONE.
THIS IS A SIMILAR PICTURE, MAYBE
THE SAME PERSON WHO HAS A LESION
HERE IS THE SAME AS THAT 1 OVER
HERE BUT OF COURSE WE'RE NOW
SLICING THE BRAIN SAGEITALLY AND
YOU CAN SEE THESE CAN OCCUR
ANYWHERE IN THE BRAIN.
THERE ARE MANY OF THEM.
NOT ALL OF THEM BUT MANY OF THEM
ARE LEAKING GADDA LYNNIUM AS YOU
CAN SEE HERE SO ON THE SCAN
AFTER CONTRAST, ADMINISTRATION,
CAN YOU SEE THAT MANY OF THESE
LESIONS ARE LIGHTING UP AND
THEY'RE LIGHTING UP IN A
CHARACTERISTIC WAY AND LOOK AT
THAT AND SAY, YES FOR SURE THIS
IS MULTIPLE SCLEROSIS.
SO MS WAS FIRST STUDIED VERY
SOON AFTER MRI SCANNERS WERE
FIRST MADE.
MRI, THE EARLY 1S, WERE MIDOR
LATE 70S.
THE FIRST PAPER DESCRIBING AN
IMAGE OF SOMEBODY WHERE MS CAME
OUT IN 1981.
THE FIRST USE OF GADDA LYNN NUM
WAS IN 86 OR 87 OR SO.
AND IN THE LATE 80S AND EARLY
90S ACTUALLY THE FIRST TIME MS
WAS STUDIED HERE AT NIH WITH MRI
WAS IN 1989 AND WE HAVE SOME OF
THOSE IMAGES STILL IN OURIGEITAL
ARE ARCHIVES FOR PEOPLE WHO ARE
COMING BACK TO THIS DAY.
SO A LOT OF EXPERIENCE WAS
GATHERED IN THOSE EARLY DAYS AND
EVENTUALLY BASED ON THAT PEOPLE
GOT TOGETHER AND SAID, WELL,
WHAT ARE THE TYPICAL
CHARACTERISTICS THAT DISTINGUISH
MS FROM OTHER DISEASES?
SO 1 OF THE FIRST PAPERS
DESCRIBING THAT IS WHAT ARE THE
CHARACTERISTIC FEATURES OF
LESIONS FOR MS IN PEOPLE?
SO I'LL SHOW YOU SOME OF THOSE
LESIONS THAT ARE IN THE
PERIVENTRICULAR REGION, THESE
ARE HERE IN THE AXIAL CRANE AND
HERE IN THE SAGEITAL PLANE.
THEY STICK UP LIKE THUMBS OUT OF
THE VENTRICLE AND I'LL GET BACK
TO THAT LATER.
SO THAT'S 1 OF THE VERY
CHARACTERISTIC FEATURES OF THE
DISEASE.
JUXTAKEN--THEY CORTICAL LESIONS
WHICH ARE RIGHT UP AGAINST THE
CORTICAL SURFACE SO CAN YOU SEE
NICE EXAMPLES OF THAT IN THIS
PATIENT OVER HERE, THIS LESION
HERE IS FOCUSED RIGHT UP AGAINST
THE CORTEX.
HE WERE'S ANOTHER 1.
AND WE KNOW NOW THAT MOST OF
THESE LESIONS ACTUALLY INVOLVE
NOT JUST THE WHITE MATTER WHERE
THE MILEIN, BUT ALSO THE DEEPER
LAYERS OF THE CEREBRAL CORTEX AS
WELL.
THE BUT HERE CAN YOU SEE THAT
THAT PARTICULAR LESION ENHANCES
FOLLOWING GADDA LYNNIUM ALTHOUGH
THE 1 BELOW IT DOES NOT.
ALSO, THE PRESENCE OF LESIONS IN
THE BRAIN STEM AND CEREBELLUM AS
SHOWN HERE ON THIS SCAN, SO
HERE, IN THE MIDDLE CEREBELLAR,
REPEAT UP AGAINST THE FOURTH
VENTRICLE IN THE MONITORED.
AND DIETS TINNINGISHING IT FROM
THE MANY THINGS CAN CAUSE WHITE
SPOTS ON THE BRAIN IN AN MRI,
NOTABLY AND DISEASE OFTEN COMES
FROM HYPERTENSION OR SMOKING,
HYPER LIP DEEMIA, BUT DOESN'T
CAUTION LESIONS IN LIKE WHAT I'M
SHOWING YOU HERE AND THEN VERY
IMPORTANTLY, NOT JUST THE
DIAGNOSIS, BUT ALSO PROBABLY FOR
THE DISABILITY THAT THE
[INDISCERNIBLE] DECEASE HERE IN
THE SPINAL CORD, HERE CAN YOU
SEE THE IMAGE OF THE SPINAL
CORD, HERE'S THE VERTEBRAL
COLUMN, IT SHOULD BE BLACK, WITH
THE IMAGE, WHITE MATTER, IS
BLACK, AND I DON'T KNOW IF YOU
CAN SEE THESE BUT THESE FOCI
DOTS THAT REPRESENT WHITE AREAS
THAT ARE AGAIN, THE VERY SAME
THING THAT HAPPENS IN THE BRAIN
IS HAPPENING HERE IN THE SPINAL
CORD AND IN THE AXIAL IMAGE, CAN
YOU SEE THAT THE CORD ALSO HAS
BRIGHT SIGNALS SO THESE ARE
AREAS WHERE THERE'S A LOT OF
WATER AND CAUSING PROLONGATION
OF THE ACTIVATION RATE.
AND I MENTIONED ALREADY, THE
GADA LYNNIUM ENHANCEMENTS WE SEE
AND THE CHARACTERISTIC THAT
WE'VE BEEN STUDYING IN THE LAB
OVER THE LAST 6 YEARS OR SO AND
UNDERSTANDING WHAT IS THIS WING
PATTERN HERE WHERE IN THIS CASE,
CAN YOU SEE IN THE OPEN WING
WITH THE OPENING OF THAT, RIGHT
UP GABS THE CEREBRAL CORTEX AND
WHY IS THAT NEAR THE OPEN RINGS
UP AGAINST THE VENT REICLES.
SO, BASED ON THOSE EARLY STUDIES
AND KIND OF THE STIMULATION OF
EXPERIENCE ABOUT HOW MS APPEARS
ON MRI.
MRI ACTUALLY BECAME THE CENTRAL
TEST FOR MAKING THE DIAGNOSIS OF
MS AND YOU CAN SEE HENRY
Mc FAR LAN'S NAME - THIS LIST,
HENRY WAS THE HEAD OF THE
NEUROLOGY BRANCH HERE FOR
SEVERAL DECADES AND CONTRIBUTED
GREATRY TO THE UNDERSTANDING OF
THE DISEASE THROUGH MRI.
LET AND SO MRI BECAME CRITICAL
ASPECT OF THE DIAGNOSIS OF MS,
HERE IN 2001 AND SET OF CRITERIA
UNDERGONE MULTIPLE REVISIONS IN
THE LAST 15 YEARS OR SO.
MOST RECENTLY, IN THIS PAPER,
JUST PUBLISHED THIS YEAR, WHERE
THESE CRITERIA HAVE BEEN
ENUMERATED THAT WAS MENTIONED
DISSEMINATION IN SPACE AND TIME
AND WE DEMONSTRATE BOTH OF THOSE
BY MRI AND MS IN SPACE BY
SHOWING 3 OR MORE
PERIVENTRICULAR LESIONS AND 1 OR
MORE INFRANCIS COLLINS
TENTERRIAL LESIONS, 1 OR MORE
SPINAL CORD LESION, 1 OR MORE
OPTIC NERVE LESION, 1 OR MORE
CORTICAL OR JUXTACORTICAL
LESION.
AND THAT GIVES YOU EXTRA
PESFISCHERRITY FOR MAKING THE
DIAGNOSIS AND AGAIN,
DISSEMINATION AND TIME WHICH IS
SHOWING THAT LESIONS HAPPEN, NOT
ALL AT SAME TIME BUT AT
DIFFERENT TIMES.
CAN ALSO BE DEMONSTRATE SAID AS
MRI BECAUSE IT CAN BE WITH THE
LAST 4 TO 6 WEEKS OR SO, BUT
LESIONS AS I SHOWED YOU ARE
PRESENT BUT DON'T HAVE LEAKAGE,
THAT WAS JUST REFERRED TO
EARLIER SO WE KNOW THAT THE
DISSEMINATION CAN CONSIDER.
SO, WHAT ARE SOME OTHER FEATURES
THAT ARE IMPORTANT FOR US TO
NOTE WHEN WE--WHEN WE LOOK AT
MRI SCANS FOR PEOPLE WITH MS, 1
IS AS I MENTIONED BEFORE, THAT
THE LESIONS ARE BRIGHT ON THE
WEIGHTED SCANS.
THEY CAN BE DARK ON THE 2-1
WEIGHTED SCANS AND THAT'S MORE
DESTRECTIVE PATHOLOGY IN THE
LESIONS AND TRANSSECTIONS OF
AXONS AND LOSS OF BRAIN TISSUE
AND SO YOU CAN SEE SOME OF THAT
HERE.
THE VISUAL SYSTEM WAS MENTIONED
SO OPTIC NEURITEIS IS A COMMON
PRESENTING SYNDROME OF MULTIPLE
SCLEROSIS, ABOUT A THIRD OR SO
OF PATIENTS THEIR FIRST SYMPTOM
OF MS IS A TRANSIENT LOSS OF
VISION IN 1 EYE AND ABOUT YOU
CAN SEE HERE, THAT THESE ARE THE
OPTIC NERVE IS THE LEFT OPTIC
NERVE IT'S DARK, BLACK, WHY?
BECAUSE THE OPTIC NERVE IS A
MILENNATED STRUCTURE AND
ACTUALLY OF THE BRAIN ITS, IT'S
JUST LIKE THE MATTER OF THE
BRAIN, IT HAS CEREBRAL SPINAL
FLUID HERE, THE OPTIC NERVE IS
NOT LIT DARKED.
IT'S BRIGHTER THAN THE PART OF
ON THE OTHER AND ACTUALLY THE
GADDA LYNNIUM, IT'S NOT NORMALLY
ENHANCED AND AS YOU SEE IN THE
LEFT EYE, THEY'RE ENHANCED
NICELY BUT THE NORMAL FINDINGS
ON THE RIGHT SIDE, THE MUSCLES
ARE ENHANCING BUT THE OPTIC
NERVE IS BETTER AND JUST LIKE IN
THE BRAIN WHEN WE HAVE ACTIVE
AND ACUTE INFLAMMATION, IN THE
OPTIC NERVE THAT'S EXACTLY THE
SAME, AND THEN AGAIN, IN THE
SPINAL CORD, THIS IS ANOTHER
CASE SHOWING YOU ON 2 DIFFERENT
TYPES OF IMAGES.
THE 2 WEIGHTED IMAGE AND HERE
THE PROTONS RELATED IMAGE IN THE
SIGNAL AND THE SPINAL CORD.
I MENTIONED CORDICLE LESIONS
THIS IS AN AREA OF INTENSE
INTEREST IN THE LAST 10 YEARS OR
SO BECAUSE IT TURNS OUT THAT IF
YOU DO IMMUNO HISTOCHEMICAL
STAINS FOR MILEN PROTEINS SUCH
AS PROTEIN COMPLEXIO LITHIC
PROTEIN OR MILEN-BASIC PROTEINS
YOU CAN SEE A TREMENDOUS LOSS IN
AGAIN A FOCAL LOSS OF THOSE
PROTEINS WITHIN THE CORTEX THAT
DOES NOT SHOW UP NEARLY SO WELL
ON MILEN STAINS SUCH AS THE BLUE
STAIN WHICH IS SENSITIVE ACROSS
THE LIPIDS BUT IF YOU LOOK FOR
THE PROTEINS YOU SEE THESE ARE
NORMAL IN THE CORTEX AND WE'VE
HAD A REALLY HARD TIME FINDING
THOSE ON MRIS.
SO, YOU KNOW THE EARLY MRI SCANS
EVEN THOUGH THEY WERE DONE WITH
MAGNET STRENGTH, YOU KNOW IN
ORDER TO ORDER THOSE WEAKER THAN
WHAT WE HAVE TODAY, THE LESIONS
WERE VERY, VERY OBVIOUS, BUT IN
THE CORTEX WE'RE STILL HAVING
TROUBLE SEEING THEM DESPITE
INCREASES IN TECHNOLOGY SO THERE
ARE VARIOUS WAYS THAT 1 CAN LOOK
AT THIS, 1 OF THE WORLD EXPERTS
ON THIS IS ACTUALLY A POST DOC
IN THE LAB.
CURRENTLY AND SO HERE'S AN
EXAMPLE OF 1 SUCH LESION IN THE
CORTEX OF SOMEBODY WITH MULTIPLE
SCLEROSIS.
SOMETHING ELSE THAT HAS BEEN
RECOGNIZED IS THE TISSUE
ABNORMALITY.
SO FROM THE PATHOLOGY POINT OF
VIEW, AND THE WAY WE'VE BEEN
DESCRIBING IT, MS IS REAL A
DISEASE THAT IS MULTIFOCAL AND
THE LESION THAT'S WHAT WE SEE ON
THE MRI, HERE'S AN EXAMPLE OF A
LESION BUT IT TURNS OUT THAT
THERE ARE STILL AREAS OF WHITE
MATTER THAT REALLY ARE SUDDENLY
ABNORMAL AND THAT'S BEEN
DESCRIBED IN DIRT WHITE MATTER
AND AREAS OF NORMAL WHITE MATTER
AND WHAT IS THE BASIS OF THIS
SUBTLE ABNORMAL SIGNAL IS HAS TO
DO WITH DROWN STREAM EFFECTS OF
THE LOCAL REGIONS AND IF IT'S
NOT QUITE CLEAR.
I MENTIONED THE FINGER LIKE
PROFUSIONS OUT LIKE FINGERS, LET
ME FINISH THIS SLIDE AND I'LL
ANSWER IT.
DALTON WAS A NEUROPATHOLOGIST
WHO WORKED ABOUT A HUNDRED YEARS
AGO AND DESCRIBED THE APPEARANCE
OF THE LESIONS THAT COME OUT OF
THE VENTRICLES AND HE DEFINED
THE REASON FOR THAT AND THE
REASON FOR THAT SIMPLY HAS TO DO
WITH THE NORMAL VENUS *** A--ANATOMY
IN THE BRAIN.
BECAUSE THIS ACTUALLY FLOW INTO
THE VENTRICLES OR FLOW OUT INTO
THE CORTEX.
AND IT TURNS OUT THAT THE
INFLAMMATION IN MS, FORMS AROUND
THOSE LESIONS.
I'LL SHOW YOU IN A SECOND.
SORRY.
FELT.
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> RIGHT.
SO THAT'S A GREAT QUESTION.
IT TURNS OUT THAT MOST OF WHAT
PEOPLE HAVE DESCRIBED AS FAR AS
THE DIRTY OR DIFFUSELY WHITE
ABNORMAL MATTER IS SHOWING UP
LATER IN THE DISEASE AND 1 THING
I THINK WE KNOW IS WE WILL GET
BACK TO THIS IS THAT THE LESIONS
IF GENERAL STOP FORMING AFTER 10
OR 15 YEARS OF THE DISEASE WHICH
IS A REALLY INTERESTING QUESTION
SO I THINK THAT MOST OF US HAVE
TO DO WITH LONG-TERM DOWN STREAM
EFFECTS OF HIGHER INFORMATION
BUT IT'S STILL A GREAT QUESTION
BECAUSE THERE HAVE BEEN STUDIES
THAT HAVE DONE SERIAL SCANNING
OF PEOPLE WITH THE DISEASE
MONTHLY.
IN HERE IN THE 90S THERE WERE A
COHORT OF PEOPLE THAT CAME IN
EVERY MONTH FOR YEARS AND THEY
DID THAT.
IF YOU GO BACK AND YOU LOOK AT
AREAS THAT LATER FORMED LESIONS
IN THOSE LOCATIONS, YOU'RE ABLE
TO PICK OUT SPECIFIC
ABNORMALITIES.
WE'VE TRIED TO REVISIT THAT
RECENTLY USING HIGH FIELD HIGH
RESOLUTION IMAGING AND HAD SHOWN
AT LEAST IN SOME CASES THAT THAT
PROCESS IS NOT A DIFFUSION ISSUE
FOR PRECONDITIONING BUT RATHER
SOMETHING FOCAL GOING ON AROUND
THESE BLOOD VESSELS.
AND THE REASON WE CAN DO THAT IS
BECAUSE WE NOW HAVE WAYS OF
MAKING MRI SENSITIVE TO THE
PRESENCE OF BLOOD VESSELS AND
THAT HAS TO DO WITH
THE--ACTUALLY WITH GENERALLY AN
ENDOGENOUS MECHANISM.
SO THE HEMOGLOBIN IS IN A
DEOXIDIZED FORM AND
DEOXYHEMOGLOBIN HAS THE PROPERTY
OF BEING ABLE TO CAUSE VERY
SUBTLE SHIFTS IN THE MAGNETIC
FIELD LOCALLY AND IT'S THAT
PROPERTY THAT'S ACTUALLY THE
BASIS FOR FUNCTIONAL MRI HERE
BUT THAT'S WHY FUNCTIONAL MRI
WORKED AND IN THIS CASE WHAT
WE'RE DOING IS TAKING HIGH
RESOLUTION PICTURES OF THE BRAIN
WHICH WE CAN DO RAPIDLY, THESE
ARE IMAGES THAT HAVE A
RESOLUTION OF ABOUT HALF A
MILLIMETEROT EDGE OF EACH PIXEL
AND WHAT CAN YOU SEE WHEN DO YOU
THAT IS THAT THE LESIONS WHICH
ARE BRIGHT SPOTS AS I SHOWED YOU
BEFORE HAVE THESE DOTS IN THE
CENTER OF THEM.
SO HERE FOR EXAMPLE ARE DOTS IN
THE CENTER OF ALL OF THESE
LESIONS AND IF YOU--IF YOU
CUT--IF YOU LOOK IN A DIFFERENT
PLANE THAT THAT MAY ACTUALLY BE
A LINE.
SO THIS REPRESENTS A BLOOD
VESSEL AROUND WHICH THAT LESION
HAS FORMED AND IF YOU LOOK AT IT
THIS WAY, CAN YOU SEE HOW SORT
OF BEAUTIFULLY SYMMETRIC, THAT
THE LESIONS ARE.
SUGGESTING THAT THE LESION IS IN
THE CENTER OF THE BLOOD VESSEL
THAT'S INFLAMED.
AND WE'RE TRYING TO NOW, IN OUR
LAB WORK ON THE PATHOLOGY OF
THIS AND WHY IS THIS BLOOD
VESSEL SO PROMINENT.
THIS MAY TURN OUT TO BE
DIAGNOSTICALLY VERY, VERY
HELPFUL DOWN THE ROAD.
SOY THAT'S 1 FEATURE THAT HAS
BEEN REALLY INTERESTING TO US.
ANOTHER FEATURE THAT WE PICKED
UP ON USING HIGH FIELD SCANNERS
HERE WE HAVE A 7 TESLA MRI
SYSTEM THAT'S PROBABLY ABOUT 5
DOZEN OR SO OF THOSE IN THE
WORLD AND THEY'RE VERY--THEY'RE
VERY ABLE TO TAKE PICTURES AT
HIGHER RESOLUTION AND ALSO TO
GIVE CONTRAST WHERE YOU HAVE
THESE SUBSTANCES LIKE THE
HEMOGLOBIN AND THAT CAN SHIFT A
LITTLE BIT AND IT TURNS OUT THAT
IN SOME FRACTION OF MS LESIONS
THERE IS AN ACCUMULATION OF DARK
SUBSTANCE THAT CAN OCCUR AROUND
THESE LESIONS.
SO I'M SHOWING YOU HERE ON THE
BOTTOM WITH THESE ARROWS, A DARK
LINE THAT CAN YOU SEE AT THE
EDGE OF THIS LESION AND WE
BELIEVE AND WE HAVE EVIDENCE FOR
THIS NOW IN SEVERAL GROUPS, ALSO
HAVE CORROBORATING EVIDENCE THAT
THIS REPRESENTS AN ACCUMULATION
OF IRON AT THE EDGE OF THESE
LESIONS WITHIN MACROPHAGE.
FELT AND THAT'S REALLY
INTERESTING.
I WILL SHOW YOU SOME MORE GENES.
SO NOW WE'RE LESS THAN A HUNDRED
YEARS AFTER DAWSON SHOWED
PICTURES OR DRAWINGS LIKE THIS
OR IMAGES LIKE THIS, THIS IS
FROM DAWSON'S ORIGINAL MONOGRAPH
AS WHEN MENTIONED AT THE TIME
WHERE THE TOOLS AND THE BRAIN
AND THE AUTOPSIES AND THIS CASE,
THE AUTOPSIES OF THE BRAIN AND
THE IMAGES THAT YOU SEE IN
DAWSON'S WORK ARE REALLY NOW
ABLE TO BE RECAPITULATED,
NONINVASIVELY IN THE MRI.
I MENTIONED PATHOLOGY.
WE'RE STILL VERY, VERY
INTERESTED IN THE PATHOLOGY AND
WE'VE HAD PATIENTS WHO HAD VERY
GENEROUSLY DONATED OR MADE
ARRANGEMENTS TO DONATE THEIR
BRAIN AND SO THIS WAS 1 EXAMPLE
OF A PATIENT WHO WE FIRST
STARTED SCANNING IN 2006,
ACTUALLY, I STUDIED THIS PATIENT
WHEN I WAS IN MY FELLOWSHIP AT
HOPKINS AND THEN HE CAME HERE,
LATER AND PASSED AWAY FROM
CAUSES UNRELATED TO MS IN 2013.
BUT WE DID HAVE THE OPPORTUNITY
IN THIS PERSON TO EXAMINE WHAT
WAS THE BASIS OF SOME OF THE
THINGS WE SAWOT MRI SCAN.
SO HERE YOU CAN SEE, 2 SCANS
SHOWING INITIALLY IN 2063
LESIONS SRIGHT AROUND THE
VENTRICLE BY 2013 AT LEAST 1 OF
THESE HAD THE QUITE
SUBSTANTIALLY, ON THE SCAN THAT
WE DID OF THE BRAIN, WE TOOK THE
BRAIN AND WE FIXED THE WHOLE AND
YOU CAN SEE THIS LINE AROUND THE
LESION, I SHOWED YOU THAT BEFORE
THAT, AND THE CORRESPONDING
PICTURES SOING ABSENCE OF MILEN
AND MILEN PROTEINS ON THE LIPID
PROTEIN STAINS AND THEN
DISRUPTION OF THE AXONS HERE IN
THE EFFECTIVE STAINS AT THE EDGE
OF THAT LESION THERE IS A DENSE
COLLECTION OF POSITIVE 8
T-CELLS, AND AND AND ALSO I
AND THAT MACROPHAGE RIGHT AT THE
CONTACT THAT YOU SEE.
AND AREA PERSISTENT INFORMATION
AT THE EDGE OF LESIONS AND THE
ENLARGEMENT OF THAT FROM 2013 IS
SOMETHING WE'RE INTERESTED IN
THIS.
SO I WOULD WOULD LIKE TO COME
BACK TO ALAN AND SHOW YOU SOME
OF HIS SCANS.
SO NOW YOU KNOW ALL ABOUT WHAT
DISTINGUISHES THE MRI OF
SOMEBODY WHO HAS MULTIPLE
SCLEROSE AND I GUESS ALL OF
THOSE FEATURES I DESCRIBED WERE
IN THE FIRST SCAN THAT WE DID
THAT WORKED ON ALAN FROM THE
NIH.
SO YOU CAN SEE DAWSON'S FINGERS
IN THE PERIVENTRICULAR REGION
AND ALSO ON THE AXIAL SCAN.
YOU CAN SEE IN THE EDITORIAL
LESIONOT IMAGE HERE IN THE
MIDDLE, AND AT THAT TIME, HERE'S
THE LESION THAT'S ENHANCING WITH
THE GADDA LYNNIUM RIGHT UP
AGAINST THE CORTEX SO IT HAS
THAT CHARACTERISTIC OPEN RING
PATTERN WHERE IT DOESN'T LEAK
DIRECTLY INTO THE CORTEX.
SO, YOU CAN--IN THIS INSTANCE
MADLY MAKE THE DIAGNOSIS OF
MULTIPLE SCLEROSIS ALONE BECAUSE
IT DEMONSTRATES MEETING MULTIPLE
DISSEM NATION OF SPACE AND TIME.
AND ALAN MENTIONED HE HAD A
PRIOR MRI AND WHICH IS IN THAT
AND AND THEN ACTUALLY ON SCAN,
SADLY THIS WAS MISSED BY THE
INTERPRETING DOCTOR AT THE TIME
BUT CLEARLY THERE IS A FOCAL
LESION HERE RIGHT UP AGAINST THE
CORTEX AND WE CAN SEE THAT
SPECIFIC LESION TODAY WHEN WE DO
SCAN A BALANCE.
ALSO WHEN WE LOOK AT IT, WE
FOUND A COUPLE OF GADDA LYNNIUM
AND HAD SEEN IT ON THAT INITIAL
SCAN IN 97.
ALAN'S SPINAL CORD IS SHOWN
HERE.
YOU CAN SEE SEVERAL LESIONS IN
THE CERVICAL REGION, ANOTHER
HERE, ANOTHER HERE, ANOTHER HERE
AND HERE'S 1 IN THE THORACIC
REGION.
THIS IS APPEARANCE OF THE LESION
AND AXIAL SECTION IN THE LATERAL
COLUMN WHERE THE CORTICO SPINAL
MOTOR FIBERS THAT ARE PASSING
DOWN TO THE ARMS AND LEGS WILL
TRAVERSE.
YOU ASKED ABOUT VISUAL SYMPTOMS
HE HAS BT HAD VISUAL SYMPTOMS
BUT THE MRI SHOWS THAT THERE IS
AN ABNORMALITYOT OPTIC NERVE, 1
IS CLEARLY BRIGHTER THAN THE
COUNTERPARTOT OTHER SIDE
SUGGESTING THERE WAS SUBCLINICAL
INFLAMMATION WHICH IS REMARKABLE
BECAUSE WE TOLD YOU THERE ARE
MANY LESIONS THAT ARE
ASYMPTOMATIC THAT CAN OCCUR IN
THE DISEASE BUT FOR A LESION IN
A STRUCTURE AS NEUROLOGICALLY IS
ENTIRELY ASYMPTOMATIC NOT CAUSE
PROBLEMS ON THIS SORT OF THIS
FOR ALAN IS REMARKABLE AND THEN
WE CAN DO THE STAIN IMAGING AS
WELL, AND HERE'S AN EXAMPLE OF
HOW 1 OF THE LESIONS, SEVERAL OF
THE LESIONS THAT ALAN HAS ARE
AGAIN CENTERED AROUND THAT DOT
OR BLOOD VESSEL AND HAS THAT
DARK RING AROUND IT THAT I
DESCRIBED AS WELL.
ALL RIGHT, I'VE TALKED ENOUGH
FOR NOW.
ANY QUESTIONS BEFORE WE GET BACK
TO MOVE ON TO TREATMENT?
>> [INAUDIBLE QUESTION FROM
AUDIENCE ]
>> A LARGE PART OF THE EFFORT
GOING ON RIGHT NOW.
IT'S NOT A SIMPLE QUESTION TO
ANSWER.
WHEN WE GIVE MEDIDATIONS ALL THE
MEDICATIONS THAT ARE CURRENTLY
APPROVED FOR MS, THEY DON'T MAKE
THE LESIONS THAT EXIST GO AWAY,
THEY SIMPLY REDUCE THE CHANCE
THAT A NEW LESION WILL FORM.
YEAH, WE STILL SEE THAT.
THEY'RE STILL THERE.
WE SEE THERE HAS BEEN A
MILENNATION, THERE'S BEEN
SCARRING AND AXONAL LOSS AND
THAT WILL PERSIST FOREVER IN
THAT PERSON.
SO THE GOAL OF THE THERAPY THAT
WE HAVE, THE TREATMENTS WE HAVE
IS LARGELY TO STOP LESIONS FROM
FORMING AT THIS POINT AND I
THINK WE WILL GET A BIT INTO HOW
WE CAN MONITOR THAT.
RIGHT?
>> RIGHT.
>> ARE THERE ANY OTHER
QUESTIONS?
AT THIS POINT.
>> OKAY, MAY I ASK 1?
>> YEAH.
>> SO IN THE OLD EXPERIMENTS, I
THINK OF THOMAS RIVER WHO I
RECALL INJECTED MILEN AND
ANTIBODIES AND CREATED ALLERGIC
MILEIN DEMYELINATING DISEASE, IS
THAT A USEFUL MODEL IF BOTH FOR
THE STUDY OF THE DISEASE AT THE
CELLULAR LEVEL BECAUSE THERE CAN
YOU GET TISSUE AND FROM THE
IMAGING STANDPOINT OF--
>> I THINK THAT E. A. E. WHICH
IS WHAT YOU'RE REFERRING TO AS
BEEN A USEFUL MODEL FOR
UNDERSTANDING THE BASIC
MECHANISMS UNDER LYING MS, BUT
IT'S DEFINITELY NOT THE SAME AS
MS.
SO IN THE E. A. E. MODEL, YOU
KNOW THE ANTIGEN THAT YOU'RE
ADMINISTERING AND THE BACKGROUND
IS USUALLY HOMOGENIUS AND
THERE'S PREDICTABLE COURSE SO
THERE'S MANY PREDICTIONS CAN
ACTUAL MS BUT IT'S BEEN USEFUL
IN TEASING OUT BASIC MECHANISMS.
INTERESTINGLY ENOUGH, A LOT OF
THESE THERAPIES THAT WORKED WELL
IN E. A. E.
WE CAN CURE VERY, VERY WELL,
DON'T WORK IN MS AND VICE VERSA.
SO THERE ARE CLEARLY BIG
DIFFERENCES BETWEEN THE MODELS.
FROM AN IMAGING PERSPECTIVE,
IT'S BEEN VERY, VERY USEFUL.
>> YEAH, SO THE MOUSE MODEL OF
MS E. A. E. IS INDEED DONE BY
INJECTING MILEN IN THE
[INDISCERNIBLE] AND THIS STARTS
BY INJECTING IN THE TAIL AND
MOVES UP THE FORELIMBS AND IT'S
A CONFLUENT SPINAL CORD LESION
THAT OCCURS IN PATHOLOGY.
GENTLEMENLY IN THE LOWER SORT OF
LUMBAR CORD.
MS A MULTIFOCAL DISEASE THAT CAN
INVOLVE ANY PART OF THE CENTRAL
NERVOUS SYSTEM, BRAIN, SPINAL
CORD AND TENDS TO CAUSE FOCAL
LESIONS RATHER THAN THESE AGENTS
THAT ARE [INDISCERNIBLE].
SO THERE IS QUITE A DIFFERENCE
PATHOLOGICALLY.
SO WE HAVE BEEN USING ABOUT 6
YEARS AGO, WE REVISED A MODEL
HERE 6 YEARS AGO OF MS IN THE
MONO[INDISCERNIBLE] IS A SMALL
NEW WORLD MONKEY THAT HAS A MUCH
PATHOLOGICALLY MUCH GREATER
SIMILARITY THAN HUMANS.
AND PART OF THE--SO WHEN YOU
INDUCE E. A. E. IN THE
MONOSETUTESSING AGAIN THE SAME
WAY IN THE ADJUVANT, THEY WILL
GET MULTIFOLK AT LESIONS IN THE
BRAIN IN THE SPINAL CORD THAT
UNDER THE MICROSCOPE ARE
INDISTINGUISHABLE FROM THE
LESION.
SO THAT HAS BEEN IMMENSELY
USEFUL TO US IN TERMS OF
UNDERSTANDING THE RADIOLOGICAL
PATHOLOGICAL CORRELATE OF THE
DISEASE.
AND SOME OF THOSE WERE AROUND
THE LESION WAS TRYING TO CHASE
THAT DOWN IN THE MODEL NOW.
BUT CERTAINLY WE CAN SEE THE
THINGS AT THE CENTER OF THE
LESION.
>> WOULD YOU LIKE TO TELL US A
LITTLE BIT ABOUT WHAT HAPPENED
AFTER YOUR DIAGNOSIS?
>> SURE.
SO, IN 2008 RIGHT AFTER THE
DIAGNOSIS TO KIND OF HALT THE
MORE EXTREME SYMPTOMS, WHICH
WERE THE FOOT AND ALSO A VERY
UNCOMFORTABLE TINGLING AND
STRANGE SENSATION THAT ROSE UP
THE LEG, UP THE BACK TO THE NECK
WAS VERY DISTRACTING.
TO ADDRESS THAT WE DID--I WAS
GIVEN STEROID TREATMENTS LIKE 3,
5 OR 10 DAY IV, WHATEVER YOU
CALL THAT, TREATMENTS THAT YOU
KNOW PRESUMABLY THEN STOPS,
HALTED MAYBE REVERSE THE
PRESENCE OF THE SYMPTOMS.
FELT AND THOSE SEEMED TO WORK.
THEN I THINK IN A YEAR OR SO, I
WAS FINALLY, FROM THAT, SO 2009,
ASHTSZ ROUND, I WAS FINALLY BUT
ON AN INTERFERON DRUG THAT WAS
ON THE MARKET APPROVED, 1 OF THE
3.
I WAS STILL HAVING THE THESE
FLAIR UPS PERIODICALLY, MAYBE
ONCE EVERY 3 MONTHS, ONCE EVERY
6 MONTHS.
THEY WERE GETTING WORSE WHEN
THEY HAPPENED.
SO AFTER A FEW YEARS IT WAS
DECIDED THAT THE INTERFERONS
WERE UNLIKELY TO BE SUFFICIENT
FOR CONTROLLING THE PROGRESSION
OF MS IN ME.
AND BY THIS TIME, HIAN ONGOING
RELATIONSHIP WITH NIH.
I HAD BEEN PARTICIPATING IN THIS
THE LIFE--NATURAL HISTORY STUDY.
I MEAN GETTING MY BRAIN SCANNED
PERIODICALLY AND THERE WAS A
DRUG THAT WAS AVAILABLE FOR
CONSIDERATION WHEN INTERFERONS
WERE NOT DOING WHAT THEY WERE
DOING AND WAS SUPPOSED TO DO,
AND THE DISEASE PROGRESSION AND
THE DISEASE WAS PROGRESSING.
AND THAT WAS DECLUES MACK AND
THAT'S WHAT I'M ON NOW.
THOUGH IT TOOK A LITTLE WHILE TO
STOP THE FLARE UPS IT HAS NOW
BEEN A FEW YEARS, 3 YEARS MORE
WHERE I HAVE NOT HAD ANY FLARE
UPS, ANY--YEAH, I MEAN
CONTRASTING ENHANCING LESIONS ON
MRIS.
I GET MRIS EVERY 3 MONTHS.
SO FOR 3 OR SO YEARS NOW, BOTH
SYMPTOMS AND MRI INDICATIONS
SUGGEST THAT THINGS ARE WORKING
WELL.
THAT'S WHY I AM.
I TAKE OTHER DRUGS FOR SYMPTOM
MANAGEMENT BUT THOSE ARE THE
MAIN 1S FOR THE DISEASE.
>> SO JOHN HAS PARTICIPATED IN A
CLINICAL TRIAL HERE AT NIH,
USING AN EXPERIMENTAL DRUG
CALLED DECLUES MACK AND IT WAS
DEVELOPED WITH THE IDEA THAT IT
MIGHT SUPPRESS TEFFECTOR CELLS.
LET IN REALITY SUBSEQUENT
STUDIES HAVE SHOWN THAT PROBABLY
THIS DRUG WHICH IS VERY
EFFECTIVE AT SUPPRESSING
INFLAMMATORY ACTIVITY IN MS AND
INHIBITING RELANCES FROM
DEVELOPING AND ALSO NEW LESIONS
BY MRI, IT APPEARS THAT THE
MECHANISM AND PROBABLY MORE
COMPLEX AND MORE PREDICTED BY
THE IMOAP TARGET OF THIS
MONOCLONAL ANTIBODY.
AND JUST TO VERY QUICKLY SAY HOW
IT'S ACTED, BY BLOCKING
COMSUMPTION OF IL2 BY EFFECTOR
T-CELLS THIS LEADS TO THEIR
BEING AN EXCESS OF IL2 AVAILABLE
WHICH IS THEN USED BY NK-CELLS
WHICH DO HAVE IL2 RECEPTORS AND
APPEAR TO EXPAND DRAMATICALLY IN
RESPONSE TO THE AVAILABLE IL2
AND THEN HAVE A REGULATORY
EFFECT BASICALLY IN SUPPRESSING
THE ACTIVE IMMUNE RESPONSE SO IN
THIS DIRECT WAY WHICH WAS BT
PREDICTED, IT WOULD END UP
HAVING A VERY FAVORABLE OUTCOME
IN CONTROLLING MS AND THIS DRUG
IS A SUCCESS STORY AT NIH
BECAUSE RIGHT NOW IT'S UNDER
REVIEW AT FDA, AND EXPECT IT TO
BE APPROVED PROBABLY THIS
SUMMER, PREVIEW.
SO JUST TO TALK A LITTLE BIT
ABOUT TREATMENTS AND MS.
THE OPTIONS HAVE REALLY
DRAMATICALLY CHANGED OVER THE
LAST DECADES WITH THE VERY FIRST
FD APPROVED DISEASE MODIFYING
DRUG WHICH WAS BETA FERON IN 97
AND THEN SINCE THEN WE'VE HAD AN
EXPLOSION OF MEDICATIONS THAT
ARE AVAILABLE FOR TREATING
RELAPSING REMITTING EMS AND
THESE ARE PREVENTIVE MEDICATIONS
THAT SUPPRESS THESE AND ACCESS
DISEASE BY MRI.
THEY'RE NOW 13 DIFFERENT
FORMULATIONS THAT ARE FDA
APPROVED AND ALAN MENTIONED
THOUGH THAT OFTEN THE LIST OF
MEDICATION THAT IS A PATIENT
WITH MS WILL BE ON WILL BE MUCH
LONGER THAN JUST A DISEASE
MODIFYING TREATMENT AND WILL
INCLUDE SYMPTOMATIC THERAPIES
FOR EXAMPLE, DEALING WITH
SENSORY SYMPTOMS OR SPECIFICITY
OR TO IMPROVE BLADDER FUNCTION.
AND IN ADDITION IN THE STUDYING
OF AN ACUTE RELAPSE, WE WILL
VERY OFTEN USE IV STEROIDS IN
ORDER TO DAMPEN THAT ACTIVE
IMMUNE RESPONSE IMMEDIATELY: SO
ALL OF THESE MEDICATIONS THAT
ARE APPROVED DO TARGET IMMUNE
MECHANISMS IN DIFFERENT WAYS.
SO FOR EXAMPLE, THEY MIGHT TRAP
IMMUNE CELLS IN THIS LYMPHNODES
LIKE SINGLE [INDISCERNIBLE].
THE SO LIKE DECLUES MACK DOES,
IT BLOCKS CD25 RECEPTOR ALLOWING
NK CELL EXPANSION OR MIGHT BLOCK
PENETRATION OF IMMUNE CELLS INTO
THE CENTRAL NERVOUS SYSTEM.
AND SO THEY ALL HAVE A VERY
SIMILAR SORT OF MECHANISM IN
TRYING TO DAMPEN THE IMMUNE
RESPONSE.
ALL OF THESE DRUGS HAVE SIDE
EFFECTS AS ANY DRUG DOES.
AND WE'VE BEEN TALKING ABOUT
DECLUES MACK WHICH
PROBABLY--WELL, NOT PROBABLY THE
MOST COMMON SIDE EFFECTS OF THE
TREATMENT IS RASH, HERE YOU SEE
PHOTOGRAPHS OF EXAMPLES OF THE
TYPES OF RASH THAT CAN DEVELOP
IN PATIENTS WITH--IN TREATMENT
WITH DECLUES MACK, FOR THE MOST
PART THESE REACTIONS AREN'T
TREATMENT LIMITING.
ABOUT 10% OF PATIENT WHO IS ARE
ENROLL INDEED OUR STUDY ENDED UP
DROPPING OUT BECAUSE OF SEVERE
RASH.
AND ALAN 1 OF THESE PHOTOS IS
YOURS, I'M NOT GOING TO SAY
WHICH.
ALAN DID EXPERIENCE RASH AS WELL
DURING THE COURSE OF HIS
TREATMENT.
I DON'T THINK THAT'S BEEN AS
MUCH OF AN ISSUE RECENTLY.
>> IT'S LARMINGLY IT FEELS LIKE
IT'S LARGELY DECREASED OVER TIME
AND IT IS ALSO SOMETHING I
TOPICALLY TREAT.
WHEN IT DOES START TO SHOW UP.
>> SO MOST OF THE PARENT
PATIENTS WHO WERE ENROLL IN OUR
STUDY EXPERIENCE SIMILAR TYPES
OF RASH THAT CAME UP PROBABLY IN
THE FIRST YEAR OF TREATMENT AND
THEN GETTING OVER THAT HUMP WAS
ENOUGH TO BE ABLE TO CONTINUE
EVEN PREVIOUS.
WE HAVE PATIENT WHO IS HAVE BEEN
ON THE TREATMENT NOW GOING
ON--LET ME THINK 10 YEARS AT
LEAST.
AND SO SOPHISTICATED SEEMS TO BE
THE CASE.
BUT IN SOME CASES, YOU CAN SEE
HERE, THERE CAN BE PRETTY
DRAMATIC LASHES, SO THIS IS--A
PLOT THAT IS TRYING TO DEPICT
THE RELATIONSHIP BETWEEN
EFFICACY WHICH ESSENTIALLY IS
RELATED TO THE DEGREE OF IMMUNE
SUPPRESSION THAT IS APOREDDED BY
AN AGENT EITHER BECAUSE IT IS A
BROAD--BROADLY IMMUNO
SUPPRESSIVE AGENT AND TARGETED
BUT ROBUST IMUME O SUPPRESSIVE
EFFECT AND THIS IS TYPICALLY
DRUGS THAT ARE MORE EFFECTIVE
ARE ASSOCIATED WITH GREATER RISK
FOR EVEN THREATENING LIFE
COMPLICATIONS SO THE RASH
WORRIES US LESS BUT
OPPORTUNISTIC INFECTIONS ARE
NEARLY THE 1S THAT WE FEAR THE
MOST AND THAT ARE A PROBLEM WITH
SOME OF THE DRUGS THAT ARE USED
FOR TREATING MS.
SO WE HAVE 13 DIFFERENT
FORMULATIONS APPROVED BUT THE
EFFICACY IS VARIABLE AND THERE'S
ALWAYS THAT CONCERN IN THE
BACKGROUND OF THE SIDE EFFECT.
SO OUR GOALS IN CARING FOR
PEOPLE WITH MS ARE TOO REDUCE
ACCUMULATION OF DISABILITY OVER
THE LONG-TERM TO IMPROVE QUALITY
OF LIFE, SO WE DO 3 LAPSES, MIN
MIDSING CONVENIENCE, MANY OF
THESE DRUGS ARE INJECTABLE
AGENTS, MANY OF THEM DAILY AND
THEN DIFFERENT COSTS.
DIFFERENT ALGORITHMS FOR
TREATING MS BUT FOR THE MOST
PART OUR APPROACH IS TO TREAT
EARLY DISEASE OR MILD DISEASE
WITH FIRST LINE AGENTS NAHAVE
MINIMAL SIDE EFFECTS AND ONLY IF
THE TREATMENT FAILURES DO WE
THEN ESCALATE TO THE
MORE--STRONGER MEDICATIONS THAT
HAVE A GREATER RISK PROFILE AND
AT ANY TIME POINT EITHER HERE OR
ELSEWHERE, CLINICAL TRIALS ARE
AN OPTION AS ALAN TOOK ADVANTAGE
OF AS HE WAS BEING FOLLOWED.
AND YOU WERE GOING TO TALK A
LITTLE BIT ABOUT MRI AND
TREATMENT.
>> [INDISCERNIBLE]--
>> SO THAT'S A GREAT QUESTION.
>> SO SYMPTOMS IN THE ACUTE
SETTING OF A RELAPSE, SYMPTOMS
ARE PROBABLY DUE A BIT TO
FUNCTIONAL IMPAIRMENT DUE TO
ACTIVE INFLAMMATION.
AS THAT ACTIVE INFLAMMATION
SUBSIDES, THE SYMPTOMS WILL
LARGELY RESULT, ESPECIALLY EARLY
IN DISEASE.
AND SO, IT SEEMS THAT THERE IS
MORE OF A--CONDUCTION BLOCK THAT
IS RELATED TO ACTIVE
INFLAMMATION THAT IS
CONTRIBUTING TO THE SORT OF
DRAMATIC ONSET OF SIM TOMS WHICH
THEN REMAIN AT THEIR PEAK FOR
PROBABLY A FEW WEEKS AND THEN
COME DOWN MORE SLOWLY AND BACK
TO BASELINE.
WITH STEROIDS CAN YOU ACCELERATE
THAT IMPROVEMENT AND MOSTLY
BECAUSE YOU'RE RESOLVING THAT
ACUTE INFLAMMATION.
OVER TIME AS WE SAW EARLY EARLY
THOUGH, WHAT CAN HAPPEN IS THAT,
ISN'T A COMPLETE RETURN TO
BASELINE AND THERE CAN BE SOME
DEGREE OF RESIDUAL SYMPTOM THAT
REMAINS AFTER RELAPSE AND THIS
CAN STEADILY INCREASE OVER TIME
AND I DON'T KNOW IF APPROXIMATE
YOU WOULD LIKE TO COMMENT ON
THAT AT ALL.
>> I'M NOT SURE, I MEAN, FOR ME
THE WHOLE DIAGNOSING EVENT WAS
IN MY RIGHT FOOT AND TINGLING
SENSATIONS LIKE SOMEONE WAS
SQUEEZING MY FOOT OR THE SHOE
WAS 2 TYPE.
DURING THE FLARE UPS THAT
SENSORY DISTORTION WOULD GET
REALLY BAD, UP MY LEG, UP MY
BACK AND THEN GO BACK DOWN.
SOMETIMES EARLY ON, THEY FELT
LIKE THEY WOULD GO AWAY
ENTIRELY.
BUT OVER TIME, THEY WENT AWAY
LESS.
SO, ONCE I WAS ON DECLUESA MACK,
I DIDN'T HAVE ANY OF THESE
REALLY--HAVEN'T HAD ANY OF THESE
CRAZY INTENSE ACUTE WEIRD
SENSATIONS GOING UP THE BACK TO
THE NECK.
BUT THE SENSATIONS THAT MY SHOE
IS TOO TIGHT OR SOMEBODY'S
SQUEEZING MY FOOT TOO TIGHT HAVE
SLOWLY GOTTEN WORSE.
IS ACTUALLY MY LEFT FOOT AS WELL
NOW.
THE AND I CAN--I CAN TRY TO WORK
WITH THAT THROUGH PHYSICAL
THERAPY AND STRENGTH TRAINING
AND YOU KNOW, WHAT OTHER THINGS
I CAN DO, SOME GABBA PENTINE
REGIMENIN DRUG THERAPY BUT
IT'S--I CAN TELL IT'S STILL
THERE, I CAN STILL TELL AND I
THINK IT'S SLOWLY OVER THE
YEARS, GETTING A LITTLE BIT
WORSE.
LET.
>> BUT INITIALLY THE
DEMILENNATION CERTAINLY PREDOM
NATIVE AMERICANS IN THE
NORTHERNS OVER ARCSONNAL INJURY
AND WHAT CAN HAPPEN VERY
COMMONLY IS THAT PATIENTS MAY
RETURN TO THE BASELINE BUT THEN
UNDER STRESS OR WHEN EXPOSED TO
HEAT WERE TO INFECTION, THEN OLD
SYMPTOMS CAN REEMERGE AND THIS
PROBABLY HAS TO DO WITH LESS
EFFECTIVE CONDUCTIONIST SIGNAL
IN REGIONS THAT HAVE BEEN
DEMILENNATED AND WHERE YOU HAVE
DISPERSION OF SIGNAL CONDUCTION
BECAUSE OF THE LOSS OF THAT
INFILTRATION WHICH IS NORMALLY
PRESENT.
OVER TIME THIS CHRONIC
MILENNATION IS GOING TO LEAD
TOSOME SUFFERING OF THIS, AND
THIS IS THOUGHT TO BE HAPPENING
FROM THE EARLY STAGES OF MS BUT
BECOMING MORE PROMINENT OVER
TIME AND THAT MIGHT BE IN PART
THE EXPLANATION FOR THE CLINICAL
COURSE WITH THIS FULL
ACCUMULATION AND REEMERGENCE IN
CERTAIN SERIES OF THICISM THOMS.
>> YOU JUST REMIND ME, I WILL
SAY THAT HEAT, LIKE WASHINGTON
SUMMER HEAT, HUMIDITY IS
VERY--IS VERY DIFFICULT.
AND FEVER, LIKE WHEN I GET A
FEVER, THOSE SYMPTOMS LIKE
CRAZY, CRAZY COME IN.
WHEN THE FEVER BREAKS, IT
BREAKS, IT'S NOT--IT DOESN'T
LAST LIKE THE FLARE UP DID OR
DOESN'T LAST LIKE THAT.
BUT YEAH.
LET SO.
>> YEAH, SOME PATIENTS WILL WEAR
A COOLING VEST IN ORDERED TO
HELP TOLERATE EFFECTIVE HEAT.
BECAUSE THE HEAT EFFECT WHICH IS
CALLED [INDISCERNIBLE]
PHENOMENON IS QUITE PROMINENT IN
MS PATIENTS.
>> SO WE TALK ABOUT THE
DRUGGINGS.
I MENTIONED THAT THE MEDICINE WE
HAVE ARE EFFECTIVE BY REDUCING
THE INCIDENCE, THE GADDA LYNNIUM
LESIONS.
SO HERE--THERE YOU GO, GADDA
LYNNIUM ENHANCED LESIONS AND
GIVE THE DRUGS AND THEY'RE NOT
THERE ANYMORE AND WE CAN
QUANTIFY THIS ON MRI BY USING
FANCY IMAGE *** SILLS TOOLS TO
BREAK DOWN THE SEGMENT OUT OF
THE NORMAL STRUCTURES OF 9 THE
BRAIN.
THERE ARE VARIOUS APPROACHES TO
DO THIS.
JUST SHOWING EXAMPLES HERE, THE
C1 FLARED IMAGE, HERE THE
COMPUTER TOLD US WHERE THE
CORTEX IS, WHERE THE WHITE
MATTER IS, WHERE THE THALAMUS,
DEEP BRAIN MATTER, NUCLEI, AND
THEN IN RED WHERE THE LESIONS
ARE, THE FOCAL LESIONS AND THAT
WORKS OUT PREY WELL WHEN YOU
COMPARE IT TO WHAT WE CAN SEE OR
PICK UP BY OUR OWN EYES AND THEN
HERE RENDERED IN 3D THE COMPUTER
THOUGHT THE LESIONS ARE SO IN
CLINICAL TRIALS, IT'S VERY
HELPFUL TO BE ABLE TO DO
SOMETHING LIKE THIS PARTICULARLY
IN TRIALS THAT ARE DONE ACROSS
MULTIPLE SITES.
WHERE YOU CAN QUANTIFY THE
NUMBER OF LESIONS, WHERE THEY
ARE AND DETECT WHETHER ANYTHING
NEW IS CONSIDERING ON THE DRUG.
ON THE DRUG THAT'S BEING TESTED
AND IT TURNS OUT THAT THERE IS A
TREMENDOUSLY TIGHT CORRELATION
BETWEEN THE EFFECTS OF DRUGSOT
INDENSE OF NEW LESIONS AND THE
PRESENCE OF CLINICAL RELAPSES.
SO THAT'S SHOWN HERE IN A
META-ANALYSIS BY SORMANI, WHO
LOOKED AT THE EFFECTS OF THE
DRUG ON THE Y-AXIS AND THEN HERE
ON THE X-AXIS FOR THE FLARES
THAT OCCUR: AND YOU CAN SEE THE
CORRELATION IS EXTREMELY TIGHT
ACROSS MULTIPLE, MULTIPLE
STUDIES SO THAT YOU REALLY ON
SOME LEVEL FOR DRUGS LIKE THIS.
WE HAVE A MARKER ON MRI THAT IS
SO GOOD THAT IT CAN ACTUALLY
TELL US WHAT THE PATIENT WILL
EXPERIENCE ON THE CLINICAL SIDE
WHICH IS WHAT'S IMPORTANT TO THE
FDA FOR GETTING A DRUG
REGISTERED.
BUT IT'S ACTUALLY BETTER AND
MORE VALUABLE THAN THAT!
THIS IS THE CORRELATION AT THE
MRI AND CLINICAL OUTCOMES IN THE
SAME TRIALS, BUT IF YOU THEN
TAKE EARLY PHASE TRIALS, SO
NORMALLY WHEN A DRUG IS TESTED,
IT WILL GO THROUGH A SMALL PROOF
OF CONCEPT STUDY WHERE YOU'RE
TRYING TO GET ENOUGH DATA TO
SAY, IS THIS LIKELY AND WORTH
TESTING IN A VERY EXPENSIVE
MULTIMILLION DOLLAR PHASE 3
STUDY AND YOU KNOW HUNDREDS IF
NOT THOUSANDS OF PATIENTS AND
USING THIS MRI OUTCOME, WE CAN
DO THIS PROOF OF CONCEPT FOR THE
PHASE 2 STUDIES VERY RAPIDLY, ON
THE ORDER OF 4-6 MONTHS OR SO IN
ROUGHLY 10 OR 12 PATIENTS.
AND IF YOU LOOK AT THE EFFECT ON
THE MRI IN THOSE PHASE 2 EARLY
PROOF OF CONCEPT STUDIES, AGAIN
HERE ON THE X-AXIS AND LOOK AT
HOW THAT CORRELATES WITH THE
PHASE 3 CLINICAL OUTCOME, THE
RELAPSE OUTCOME, AGAIN, THE
CORRELATION IS VERY, VERY
INSTRUCT.
SO IF YOU'RE A DRUG COMPANY AND
YOU HAVE A COMPOUND THAT YOU
WANT TO SEE, WHETHER IT'S GOING
TO BE EFFECTIVE IN MS FOR
PREDUCING NEW LESIONS AND
INFLAMMATION, IF WE DO THESE
EARLY, SMALL, QUICK TRIALS, YOU
KNOW YOU HAVE A PRETTY GOOD BET
FOR GOING AHEAD.
THE SO YOU KNOW, THEN YOU JUST
WORRY ABOUT THE SAFETY PROFILE
PRIMARILY ABOUT YOU FOR EFFICACY
POINT OF VIEW, YOU COULD DO THAT
XREAMLY WELL.
THE AND THE WAY TO DO THAT WAS
WORKED OUT HERE AT THE NIH IN
THE 90S BASED ON THOSE MONTHLY
MRI SCANS I TOLD YOU ABOUT.
AND WHY DOES THAT WORK?
IT WORKS BECAUSE THE GADDA
LYNNIUM ENHANCING LESIONS
CORRELATE WITH THE PRESENCE OF
NEW INFLAMMATION IN THE BRAIN.
THAT WAS SHOWN IN THIS PAPER
AGAIN FROM THE NIH WHERE
SOMEBODY IN THE VERY EARLY DAYS
OF THOSE 1991 OR 1992 PRESENTED
WITH A AGGRESSIVE CASE OF MS,
HAD MULTIPLE GADDA LYNNIUM IN
THE BRAIN, OLD MRI SCAN AND
SUCCUMBED TO THE DISEASE AND YOU
CAN SEE VERY INTENSE
INFLAMMATION IN THE AREA WHERE
THE GADDA LYNNIUM WAS LEAKING
INTO THE BRAIN AND AGAIN BY THE
MONTHLY CEREAL STUDIES IT WAS
DETERMINE THAD THE INCIDENCE OF
THE NEW LESION IS ROUGHLY 10
TIMES AS GREAT AS THE INCIDENCE
OF FLARE OF THE CLINICAL
REBOUND.
SO THE IN, RI BECOMING THAT MUCH
MORE SENSITIVE THAN THE CLINICAL
OUTCOME AND THAT'S WHY THE TRIAL
CANS BE SHRUNK DOWN INTO THE
SHORT 4 OF 6 MONTH BLOCKS IN
SMALL NUMBERS OF PATIENTS.
AND JUST TO GIVE YOU A VISUAL
IDEA OF WHY THAT'S THE CASE.
SO THESE--THESE ARE DATA FROM
HARVARD, WHERE THEY DID ACTUALLY
WEEKLY MRI SCANS OF PATIENTS
WITH ACTIVE MS, THIS IS BACK IN
THIS THE EARLY 90S BEFORE ANY
DRUGS WERE APPROVED.
YOU CAN SEE THE PLAQUE, THE
IMAGES AND THEN AS I PLAY THIS
IMAGE, IT'S REALLY DRAMATIC.
YOU WOULDN'T SEE THIS, THESE
DAYS BUT--SORRY.
THE SEE IF I CAN GET IT GOING.
CAN YOU SEE THAT THESE BLACKS
THESE LESIONS THEY APPEAR, GROW
RAPIDLY OVER THE COURSE OF
SEVERAL WEEKS AND THEN THEY
SHRINK DOWN AS THEY BEGIN TO
REPAIR AND THEY ARE POPPING UP
ALL OVER THE PLACE.
LET ME PLAY IT 1 MORE TIME.
BECAUSE IT'S SORT OF DRAMATIC.
SO YOU CAN SEE THIS IN THE
REGION BUT THE DRUGS WE HAVE AND
PARTICULARLY THE LATEST
GENERATION ARE EFFECTIVE IN
SUPPRESSING THAT FROM OCCURRING.
BUT THE QUESTION COMES UP IF IF
YOU TAKE SOMEBODY WITH EARLY
ACTIVE MS AND YOU REALLY
SUPPRESS THE LESIONS FROM
OCCURRING WHAT'S GOING TO HAPPEN
TO THEM DOWN THE ROAD?
THAT'S HUGE.
THAT SEGUE'S INTO THE LAST THING
YOU WANT TO TALK ABOUT.
>> ALAN YOU TOLD US A BIT ABOUT
HOW IN MORE RECENT YEARS DESPITE
NOT HAVING THESE RELAPSES WHAT
YOU'VE BEEN NOTICING IS
ACCUMULATION OF SIM TOMS OVER
TIME AND THIS IS REALLY VERY
TYPICAL OF THE LATER CLINICAL
COURSE IN MS, ALAN'S SYMPTOM VS
BEEN RELATIVELY MODEST BUT WHAT
TYPICALLY ENSUES AFTER 10 OR 15
YEARS OF RELAPSE IS UNTREATED MS
IS THAT IN 70% OF UNTREATED MS,
THE RELAPSES WILL DECREASE IN
FREQUENCY AND WILL BEGIN TO SEE
THIS VERY SLOW ACCUMULATION OF
DISABILITY OVER TIME.
THIS IS USUALLY ASSOCIATED ALSO
WITH THE DISAPPEARANCE OF THESE
FLEW CONTRAST ENHANCING LESIONS
AND ALSO EVEN NOT VERY MANY NEW
LESIONS BEING NOTICED BY MRI
EITHER.
WHILE--WHILE WHAT WE WILL SEE IS
A DECREASE IN BRAIN VOLUME AND
OVER TIME WE WILL HAVE SEEN AN
INCREASE IN LESION LOAD.
AND THIS IS THOUGHT TO BE THAT
IN THE YEARS OF EARLIER MS,
THERE PREDOMINANT INFLAMMATORY
MECHANISM AND LATER IN THE
COURSE, WE HAVE PREDOMINANTS OF
NEURODEPRIVATION GENRATIVE
MECHANISMS UNDERLYING THE
SUBSEQUENT--SUBSEQUENT COURSE.
ABOUT 10% OF PATIENTS ACTUALLY
PRECEPT WITH THE
NEURODEGENERATIVE CLINICAL
COURSE FROM THE GET GO, WITH
VERY SLOW PROGRESSIVE
ACCUMULATION OF DISABILITY AND
VERTUALLY NO RELAPSES AND THESE
ARE CALLED PRIMARY PROGRESSIVE
PATIENTS WHILE PRIMARY
PROGRESSIVE DENOTES A TYPICAL
COURSE.
IT'S ANYONE MORE RECENTLY
SUGGEST THAD THIS MAY NOT BE
THAT THERE'S NO MORE
INFLAMMATION.
WE KNOW THERE IS INFLAMMATION BY
PATHOLOGY BUT MAYBE THERE'S BEEN
A CHANGE IN THE TYPE OF
INFLAMMATION, IN IT PARTICULAR
COMPARTMENTALIZATION OF
INFLAMMATION HAS BEEN IDENTIFIED
AND IS NOT UNIQUE TO MS, IN
OTHER CHRONIC INFLAMMATORY AND
ILLNESS SUCH AS RHEUMATOID
ARTHRITIS OR [INDISCERNIBLE]
SYNDROME WE SEE LESIONS WHERE
THERE'S CHRONIC INFLAMMATION AND
SIMILAR SIM TOM VS BEEN
SUGGESTED IN MS AS WELL AND
POSSIBLY PLAYING A ROLE IN THE
PROGRESSIVE PHASE OF THE
ILLNESS.
AS THE TRIANGLESOT BOTTOM
SUGGEST THOUGH, WE SEE REDUCTION
IN THE CONTRIBUTION OF
INFLAMMATORY MECHANISMS.
THIS STAGE OF THE DISEASE IS
ALSO LESS RESPECTFUL TO
TREATMENT BY THE APPROVED
MEDICATIONS WHICH IN FACT HAVE
ALMOST NO IMPACT ON THE
PROGRESSIVE ACCUMULATION OF
DISABILITY OR LEADING COURSE.
WHAT WE DO IS SEE IS THAT
BEGINNING TREATMENT EARLY SEEMS
TO DELAY AND IN MANY PEOPLE MUCH
IMPROVED THE ULTIMATE OUTCOME
BUT ONCE THAT PHASE HAS BEGUN
THERE'S ALMOST NO IMPACT BY THE
AGENTS THAT ARE AVAILABLE TODAY.
>> SO JUST TO SHOW WHAT THAT
LOOKED LIKE ON MRI, WE TALK THE
NEURODEGENERATION AND LOSS OF
BRAIN VOLUME THAT CAN OCCUR IN
PROGRESSIVE STAGES OF THE
DISEASE.
SO THIS IS THE PATIENT WHO WE'VE
SEEN AT NIH TRACKED OVER 19
YEARS AND JUST PUT TOGETHER
DOZENS OF MRI SCANS TO SHOW YOU
WHAT HAPPENS OVER THAT LONG
PERIOD OF TIME.
SO THIS IS NOT WEEKLY SCANS.
THESE ARE MOSTLY ANNUAL SCANS OR
MORE FREQUENT THAN THAT.
OF THE AND YOU CAN SEE THE AGE
ON THE BOTTOM, 53, POSITIONAL
CLONING AND AS CAN YOU THROUGH
THIS YOU SEE THE EXPAPGZ OF THE
VENTRICLES WITH THE SPINAL FLUID
AT THE EXPENSE OF THE BRAIN
TISSUE BUT THERE ARE NO NEW
LESIONS POPPING UP, BUT THERE
ARE VERY, VERY FEW THAT ARE
POPPING UP OVER A PERIOD OF
TIME, BUT THEY'RE REALLY
DIFFERENT FROM THE EARLY ACCESS
POINT THAT I SHOWED YOUMENT AND
BY AGE 69 IN THIS PERSON HAS
BEEN TREMENDOUS LOSS OF BRAIN
TISSUE THAT OCCURS.
SO LET ME RUN THAT 1 MORE TIME
AGAIN.
IT'S VERY, VERY DIFFICULT.
THE RATE AT WHICH THAT OCCURS IS
ON AVERAGE HALF A% OF BRAIN
VOLUME PER YEAR.
SO HALF A PERCENT, HALF AIAN
PERCENT, HALF A PERCENT IS
ACCUMULATES AND COMPOUNDS OVER
TIME.
THE TYPICAL RATE OF BRAIN VOLUME
LOSS IS .2% OR SO IN THE GENERAL
POPULATION SO IT'S REALLY--IT'S
SUBSTANTIALLY DIFFERENT AND IT
GETS GREATER OVER THE YEAR.
SO BY 59 WHICH IS VERY, VERY
LARGE THROUGH THE SPINAL FLUID
WHICH IS THE BRAIN ATTRIBUTE
OCCURRED SO AGAIN ABOUT HALF A
PERCENT A YEAR AND IT TURNS OUT
IF YOU DO THAT SAME ANALYSIS I
SHOWED YOU BEFORE ASKING WHETHER
THE EFFECT ON MRI OF THE
DISAPPEARANCE OF LESIONS IS
PREDICTIVE OF THE CLINICAL
OUTCOMES, THAT'S THOAN SHOULD
THE MIDDLE HERE, THE ATROPHY
EFFECT IS LESS STRONG BUT STILL
PRESENT AND SINNER GESTIC WITH
THE LESION OUT COMES.
SO UNDERSTANDING THE EFFECT ON
DISABILITY CASE WHICH IS NOT
RELAPSES, DISABILITIES REALLY
HELPS TO KNOW WHAT IS THE
NEURODEGENERATIVE COMPONENT IN
THE DISEASE.
IN THIS THE LAB AS I MENTION
SAID WE CAN SEGMENT THE BRAIN
INTO THE COMPONENT STRUCTURES,
AGAIN ON T-1 RATED IMAGE.
I HAVEN'T SHOWN YOU YET A
CORONAL IMAGE OF THE BRAIN.
BUT THIS IS 1.
WE CAN SEPARATE OUT THE
DIFFERENT PARTS OF THE BRAIN ON
HIGH RESOLUTION SEQUENCE LIKE
THIS AND MEASURE THE VOLUME OVER
TIME AND THIS IS AN EXAMPLE,
THIS IS THE PAPER WE PUBLISHED A
COUPLE OF YEARS AGO, ACTUALLY
LOOKING AT 2 LARGE COHORTS, SEEN
AT THE NIH.
ONE OF WHOM--1 OF THOSE COHORTS
WAS ACTUALLY A PATIENT WHO HAD
BEEN STUDIED WHO HAD BEEN IN THE
CLINICAL TRIALS OF DECLUES MACK
SHOWING THE WEIGHT OF THE BRAIN
*** CHANGE OVER TIME IN.
AND THE GRAY MATTER HERE IS YOU
SEE A LOT OF NOISE AND
MEASUREMENTS BUT A STEADY
DECLINE AND MOST PEOPLE
REGARDLESS OF THE AGE AT WHICH
IT OCCURS, IT DOESN'T DOESN'T
ACCELERATE WITH AGE.
AT LEAST IN THIS AGE RANGE OF
20-60.
IT MAY GOT MORE AFTER THAT.
BUT IN THE WHITE MATTER IT'S
STABLE OVER TIME AND THAT'S
INTERESTING BECAUSE YOU THINK OF
MS AS A WHITE MATTER DISEASE
WHERE THE LESIONS ARE
DEMYELINATING LESIONS IN THE
WHITE MATTER BUT IT TURNS OUT
THAT IN THE WHITE MATTER, THE
TISSUE IS GENERALLY NOT LOST BUT
RATHER REPLACED BY FAR THE
TISSUE WHERE THE GRAY MATTER IS.
BECAUSE THE BRAIN IS MADE UP
LARGELY OF GRAY MATTER, WHITE
MATTER AND SEEREBERAL SPINAL
FLUID WE CAN SEE THIS COMPOUNDED
IF WE MEASURE THE VOLUME OF THE
SPINAL FLUID AS YOU SLEEP APNEA
AND OBESITYY HERE.
SO THIS IS PROBABLY OUR MOST
EFFECTIVE WAY OF TESTING WHETHER
MEDICINES THAT MIGHT INFLUENCE
THE DEGENERATIVE ASPECTS OF THE
DISEASE THAT MIGHT PROTECT THE
NEURONS OR REPAIR THEM MAY BE
EFFECTIVE.
AND MY FINAL SLIDE WAS JUST TO
MENTION THAT INFLAMMATION OCCURS
NOT ONLY IN THE BRAIN BUT IN THE
MENNEN GEES AROUND THE BRAIN.
IT'S DETECTABLE AT AUTOPSIES BUT
IT MAY BE ASSOCIATE WIDE
DEGENERATIVE COMPONENTS OF THE
DISEASE AND WE HAVE BEEN ABLE TO
OBSERVE THAT IN VIVO USING A
PARTICULAR KIND OF CONTRAST POST
GADDA LYNNIUM THAT I DIDN'T HAVE
TIME TO TALK ABOUT BUT TO SHOW
YOU EXAMPLES IN A CASE THAT
LATER CAME TO AUTOPSIES HERE,
WHERE YOU CAN SEE, THE FOCAL
AREA OF GADDA LYNNIUM LEAKAGE
INSIDE THE MENINGIES, IT'S NOT
ACIN THE BRAIN, IT'S AROUND THE
BRAIN.
IT'S IN THE CORTEX AS WELL AS
ADJACENT WHITE MATTER AND THIS
IS WITHIN THE MININGIES ITSELF
AND WE FOUND THIS FINDING WAS
ALMOST TWICE AS FREQUENT IN
PEOPLE WHO HAD PROGRESSIVE
MULTIPLE SCLEROSIS AND IT
ACCUMULATES OVER TIME.
SO WE HAVE SOME HOPE THAT WE
WILL BE ABLE TO DEVELOP BRAIN
AND MARKERS, NONINVASIVE OR
MINIMALLY INVASIVE MARKERS THAT
TELL US ABOUT THE CHRONIC
INFLAMMATORY ASPECT OF THE
DISEASE AND THE GOAL ULTIMATE
GOAL MAYLY FROM OUR POINT OF
VIEW IS SORT OF ADDRESS THESE
BIG UNSOLVED QUESTIONS AT MS, 1
OF WHICH IS HOW THE DISEASE
STARTS.
SO, IT MIGHT BE EBD, IT MIGHT BE
MANY, MANY THINGS, IT MIGHT BE
DIFFERENT IN DIFFERENT PEOPLE.
HOW IS TISSUE DAMAGED WITHIN
THESE FOCAL LESIONS, HOW IS IT
REPAIRED?
IS THAT CAME UP BEFORE BUT WE
DIDN'T TALK ABOUT MUCH?
AUMING QUESTION FROM THE PATIENT
POINT EVER VIEW IS WHERE CHRONIC
LOAMACYY DAMAGED TISSUE, SCAR
TISSUE CAN BE REPAIRED, CAN BE
REMILENNATED?
THAT IS AN OPEN QUESTION.
THAT IS A VERY HARD THING TO
ACHIEVE.
THE AND THEN OF COURSE WHAT
CAUSES CLINICAL PROGRESSION?
WHAT DO SOME PEOPLE PROGRESS AND
NOT OTHERS AND CAN WE STOP THAT?
I THINK THAT SHOULD BE STUDIED.
I THINK THAT'S IT.
>> THAT'S IT.
>> WE'RE DONE.
TOKAY.
>> WELL, THANK YOU VERY, VERY
MUCH WE DO HAVE A FEW MINUTES IF
YOU HAVE SOME QUESTIONS.
I'M GOING TO ASK THAT YOU PLEASE
USE THIS MICROPHONE BECAUSE
THERE ARE PEOPLE WHO ARE
LISTENING AND THEY LIKE TO HEAR
THE QUESTIONS AS WELL AS THE
ANSWERS.
>> THAT WAS A GREAT
PRESENTATION, I'M CURIOUS WHAT
GOES ON WITH THE BANDS WITH THE
TREATMENT, DOT BANDS PERSIST?
AND THEN FOLLOWING ON THAT IS
DAMAGE MEDIATED BY THE
ANTIBODIESS OR B-CELLS OR IS IT
KNOWN THAT DAMAGE IS MEDIATED BY
THE T-CELLS?
>> I CAN START.
SO HISTORICALLY, NO TREATMENTS
HAVE EFFECTED ALL THE CLONAL
BANDS AND THE PATTERN REMAINS
EXTREMELY STABLE OVER TIME.
MORE RECENTLY WITH SOME OF THE
MORE ROBUST IMMUNO SUPPRESSIVE
AGENTS THERE HAVE BEEN REPORTS
OF BANDS DISAPPEARING I'M NOT
SURE YET WHETHER THAT WILL BE
CONFIRMED AND WHETHER THAT WILL
REMAIN A FINDING OR HOW EXACTLY
THAT WILL EFFECT PROGNOSIS
AND/OR DISEASE COURSE.
>> OR PARTICULARLY STEM CELL
TRANSPLANTS.
THE IT'S THE 1 WHERE PEOPLE WILL
SAY MAYBE IT WILL OCCUR.
>> MAYBE BUT IT HASN'T BEEN BUT
IT HASN'T SEEN IT--YEAH.
YEAH.
NOT IN THE--YEAH, NOT IN THE
STUDIES THAT HAVE BEEN RECORDED.
THE--WHAT IS THE ROLE OF
ANTIBODIES IN THE DISEASE
ITSELF, I THINK?
IS STILL A QUESTION.
YOU KNOW CERTAINLY THE DISEASE
SEEMS TO BE LARGELY DRIVEN BY
T-CELLS AND THAT'S SORT OF THE
DOGMA, WE KNOW FROM PATHOLOGY
THAT THERE IS A ROLE OF
COMPLEMENT AND ANTIBODIES AS
WELL BUT HOW MUCH IS DRIB BY
THAT IS UNCLEAR.
MORE RECENTLY ANTIB-CELL THERAPY
SPECIFICALLY HAVE BEEN SHOWN TO
BE EXTREMELY EFFECTIVE BUT
EXACTLY BY WHAT MECHANISM THAT'S
WORK SUGGEST UNCLEAR AND IT'S
MOSTLY THOUGHT THAT IT'S
PROBABLY INDIRECTLY EFFECTING
T-CELL FUNCTION AND THAT THAT'S
ACTUALLY THE WAY THAT THEY ARE
SO EFFECTIVE.
AND THAT'S ALSO BECAUSE AGAIN
CLONAL BANDS DON'T APPEAR WITH
THAT TYPE OF TREATMENT AND MOST
OF THOSE STRATEGIES WHICH ARE
TREATMENTS DON'T ACTUALLY EFFECT
PLASMA CELLS.
>> DO INSURANCE COMPANIES COVER
THE COST?
>> OF TREATMENT.
>> IT'S APPROVED BY THE FDA?
>> SO WHEN IT'S APPROVED BY FDA,
THEN YES.
I THINK THAT THAT'S GENTLEMENLY
THE CASE.
I THINK THAT SOME PATIENTS MAY
HAVE RESTRICTIONS ON WHAT
TREATMENTS THEY'RE ALLOWED TO
INITIATE TREATMENT WITH AND
SOMEHOW A NEUROLOGIST WROTE THAT
YOU HAVE PRIMARY PROGRESSIVE MS
THAT CAN BECOME PROBLEMATIC BUT
I THINK FOR THE MOST PART
PATIENTS HAVE ACCESS.
THE AND THERE ARE ALSO
ASSISTANCE PROGRAMS BY PHARMA
COMPANIES FOR INTERNAL AUDIT
SURED PATIENTS OR PATIENT WHO
CAN'T AFFORD TREATMENT.
AND SO WE HAVEN'T USUALLY FOUND
IT TO BE A PROBLEM WITH GETS
PATIENTS ON TREATMENT EVEN
THOUGH POSSIBLY THERE MIGHT NEED
TO BE A BIT OF BACK AND FORTH
AMONG THE TREATMENT THAT YOU
WANT TO INITIATE.
WE'VE ALSO FURTHER HAD
EXPERIENCE WITH OFF-LABEL
TREATMENT.
PATIENTS COMING