>>> GOOD MORNING AND WELCOME. WE'LL GET STARTED. SO WELCOME TO THE WORKSHOP ON BRIDGING THE KNOWLEDGE GAPS TO UNDERSTAND HOW ZIKA EXPOSURE AND INFECTION AFFECTS CHILD DEVELOPMENT. MY NAME IS NAHIDA CHAKTOURA AND I'M A MEDICAL OFFICER AT THE MATERNAL PEDIATRIC INFECTIOUS DISEASE BRANCH AT NICHD. THIS FIRST SESSION WILL SERVE TO SET THE STAIN FOR THE MEETING TODAY BY PROVIDING AN OVERVIEW OF THE PROBLEM. BEFORE WE GET STARTED, JUST A FEW HOUSEKEEPING THINGS. PLEASE TURN OFF YOUR CELL PHONE OR PLEASE PUT THEM ON SILENT. IS THIS MEETING WILL BE VIDEO CAST SO PEOPLE CAN JOIN US AND WATCH THE MEETING. WHEN YOU DO HAVE A COMMENT OR A QUESTION, PLEASE USE THE MICROPHONES SO EVERYONE CAN HEAR AND INTRODUCE YOURSELF AND YOUR AFFILIATION. PLEASE MAKE YOUR COMMENTS BRIEF BECAUSE WE DO HAVE A TIGHT SCHEDULE. IF YOU FOLLOW US ON TWITTER, THE TWITTER ACCOUNTS ARE UP THERE. AND THERE IS Wi-Fi FOR THE ATTENDEES SO PLEASE SEE THE REGISTRATION DESK FOR MORE INFORMATION AND HOW TO CONNECT. SO TO GET STARTED, IT IS MY FIRST GREAT PLEASURE TO INTRODUCE OUR FIRST SPEAKER, DR. CATHERINE SPONG WHO IS THE ACTING DIRECTOR OF THE EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT. PART OF NIH. IN THIS ROLE SHE OVERSEES INSTITUTE'S RESEARCH ON PEDIATRIC HEALTH AND DEVELOPMENT MA TERM HEALTH, REPRODUCTIVE HEALTH, INTELLECTUAL AND DEVELOPMENT DISABILITIES, AND REHAB MEDICINE AMONG OTHER AREAS. AND SHE HAS BEEN THE FORCE BEHIND WHAT OUR INSTITUTE HAS BEEN ABLE TO ACCOMPLISH TOWARDS THE ZIKA RESEARCH EFFORT. DR. SPONG. [ APPLAUSE ] >> CATHERINE SPONG: THANK YOU VERY MUCH FOR THAT KIND INTRODUCTION AND THANK YOU ALL FOR BEING HERE. ON BEHALF OF NATIONAL INSTITUTES OF HEALTH, I WANT TO THANK YOU FOR COMING TO THIS MEETING AND PARTICIPATING ACTIVELY AS WE REALLY TRY TO TACKLE THIS ISSUE OF UNDERSTANDING THE IMPACT OF ZIKA VIRUS ON PREGNANCY AND CHILD OUTCOMES. THERE HAVE BEEN MANY DIFFERENT CONFERENCES ON ZIKA ITSELF AND WHAT WE REALLY FELT WAS IMPORTANT WAS TO FOCUS ONE ON THE CHILD SO THAT GIVEN ALL THE INFORMATION THAT IS COMING OUT, WE WILL BE BEST PREPARED TO HELP CARE FOR THESE CHILDREN. AND ALTHOUGH, NAHIDA MENTIONED I'M THE FORCE BEHIND ZIKA MA HEATO DESERVES A LOT OF THE KUDOS BECAUSE SHE HAS REALLY IMPLEMENTED EVERYTHING AND I WOULD SAY SHE IS THE FORCE. SO WHY ARE WE HERE TODAY? I'M NOT GOING TO GIVE A LOT OF PRIMER ABOUT ZIKA VIRUS ITSELF BUT WE ARE HERE TODAY BECAUSE IN BRAZIL, SOME OF THE PEOPLE HERE IN THIS AUDIENCE WERE THOSE WHO HELPED US TO UNDERSTAND THE IMPACT OF ZIKA VIRUS ON PREGNANCY AND ON CHILD OUTCOMES. THE FIRST INFECTIONS WERE IN MAY AND BY OCTOBER NOTED TO BE INCREASE IN MIKE SELFIE IN CHILDREN WHOSE MOTHERS WERE INFECTED WITH ZIKA DURING PREGNANCY. -- MICROCEPHALY. THAT INCREASE IN MICROCEPHALY IS STARTLING WHEN YOU LOOK AT RATES OF MICROCEPHALY IN THE PRIOR FIVE YEARS. AND IF IT ISN'T ENOUGH JUST TO HAVE SEEN IT IN BRAZIL, WE SEE THAT THE DISTRIBUTION OF ZIKA VIRUS IS REALLY GONE GLOBAL AND THIS IS SOMETHING THAT HAS WORLDWIDE IMPACT. SOMETHING WE REALLY NEED TO FOCUS ON EVEN IN THE UNITED STATES, BECAUSE ZIKA CASES HAVE BEEN REPORTED IN NEARLY EVERY STATE AND TERRITORY IN THE UNITED STATES. AND WE HAVE SEEN LOCAL TRANSMISSION IN FLORIDA. AND I WILL SAY I SEE PATIENTS HALF DAY A WEEK AND WE SEE PATIENTS IN OUR CLINIC WHO ARE PCR POSITIVE FOR ZIKA. SO EACH WITHOUT LOCAL TRANSMISSION, WE HAVE TRAVEL-RELATED CASES, EVEN IN THE WASHINGTON, D.C. AREA AND ALL ACROSS THE UNITED STATES. AND UNIUNINATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT HAS A SPECIFIC MISSION THAT IS BROAD AND WHAT IS INTERESTING THIS BROAD MISSION ENCOMPASSES SO MUCH OF THE OUTCOMES OF ZIKA VIRUS BECAUSE NOT ONLY ARE WE COVERING THINGS SUCH AS PREGNANCY AND CHILD DEVELOPMENT, BUT WE ALSO DO REHABILITATION AND INTELLECTUAL AND DEVELOPMENTAL DISABILITIES. ALL OF THESE WE WILL SEE AND WE WILL NEED TO HELP US UNDERSTAND HOW TO TAKE CARE OF THESE CHILDREN WITH ZIKA. AND TO BE ABLE TO HELP WITH THE REACH TO UNDERSTAND HOW BEST TO DO THAT. OUR MISSION IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED. THAT WOMEN SUFFER NO HARMFUL AFFECTS FROM REPRODUCTIVE PROCESSES AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY. SO LET'S TALK JUST A LITTLE BIT ABOUT WHAT WE KNOW AND WHAT IS EXCITING IS OVER THE NEXT TWO DAYS, WE'LL LEARN EVEN MORE ABOUT WHAT WE KNOW RELATED TO ZIKA-ASSOCIATED PREGNANCY OUTCOMES. ZIKA HAS BEEN ASSOCIATED WITH FEELS LOSS, MISCARRIAGE, STILL BIRTH, GROWTH ABNORMALITIES, BRAIN ABNORMALITIES AND EYE AND HEARING ABNORMALITIES AS WELL AS NEUROLOGIC COMPLICATIONS AND I WANT TO BRIEFLY HIGHLIGHT SOME OF THESE. WE'LL GET MORE IN-DEPTH OVER THE NEXT SEVERAL LECTURES TODAY AND TOMORROW INTO THESE. BUT IT IS VERY CLEAR THAT ZIKA ITSELF IS ASSOCIATED WITH A NUMBER OF DIFFERENT BRAIN ABNORMALITIES, NOT JUST MICROCEPHALY. AND YOU HEAR SO MUCH IN THE MEDIA BUT IT'S MUCH BROADER THAN MICROCEPHALY, INCLUDING STRUCTURAL CHANGES WITHIN THE BRAIN ITSELF. AS SHOWN BY CT SCANS, OCULAR FINDINGS. WE'LL HEAR MORE ABOUT THIS. HEARING LOSS. NEUROLOGIC ABNORMALITIES INCLUDING HYPERTONIA, HYPOTONIA, ARTHEROGRIO POSEIS, CLUBFOOT, SEIZURES AND NEUROBEHAVIORAL ANOMALIES. AND OF THIS WE HAVE NOT HEARD FROM IN SPECIFIC LITERATURE THAT HAS BEEN PUBLISHED. WE DO SEE IT IN MEDIA REPORTS. OTHER SYSTEMS HAVE BEEN ASSOCIATED TO BE AFFECTED WITH ZIKA INCLUDING CARDIAC, DIGESTIVE AND JEN TI URINARY AND MUCH OF WHAT WE KNOW IS FROM SYMPTOMATIC ZIKA INFECTION. REMEMBER THAT ONLY ABOUT 20% OF PEOPLE HAVE SYMPTOMS WITH ZIKA VIRUS AND THERE WAS A BIG QUESTION OF WHETHER OR NOT IF YOU HAD ASYMPTOMATIC ZIKA, COULD YOU OR WOULD IT IMPACT THE PREGNANCY ITSELF AND YES, CASE REPORTS ARE COMING OUT THAT ASYMPTOMATIC INFECTION IS ALSO ASSOCIATED WITH SOME PREGNANCY COMPLICATIONS. NOW HOW ABOUT FOR THE LONG TERM? LONG TERM FUNCTION, MOTOR AND SENSORY ABNORMALITIES HAVE BEEN REPORTED BUT WE DON'T HAVE REAL LONG TERM INFORMATION BECAUSE THIS IS SOMETHING THAT IS ONLY RECENTLY DESCRIBED. WE WOULD ANTICIPATE BASED ON WHAT WE KNOW FROM OTHER DISEASES AND INFECTIONS THAT THERE WILL BE A SPECTRUM OF OUTCOMES INCLUDING DEVELOPMENTAL DELAY, INTELLECTUAL IMPAIRMENTS AND MENTAL IMPAIRMENTS AND MOTOR ABNORMALITIES. WE NEED TO BE COGNIZANT OF THESE AND TAKE INTO ACCOUNT WHEN WE THINK ABOUT HOW DO WE WANT TO CONTINUE TO MONITOR THESE CHILDRENAT? WHAT POINT IN TIME DO WE FEEL WE NO LONGER NEED TO EVALUATE OR MONITOR. THERE ARE LOTS OF RESEARCH GAPS AND LOTS WE NEED TO HAVE A BETTER HANDLE ON. THE RISK OF INFECTION IN PREGNANCY, THE ZIP STUDY THAT WE ARE WORKING ALONG WITH NIAID AND THE NIEHS AND CREWS IN BRAZIL, IS A STUDY THAT WILL HELP US LOOK AT WHAT THAT RISK OF INFECTION IN PREGNANCY IS AND THE TIMING. THE SEQUELIA ZIKA EXPOSED IN IN FINANCE WHO DON'T HAVE MICROCEPHALY, LONG TERM RESERVOIRS FOR ZIKA AND WHAT WE ARE HERE TODAY TO TALK ABOUT, THE EVALUATION, MANAGEMENT AND TREATMENT FOR CHILDREN WHO ARE EXPOSED TO ZIKA IN UTERO. THE CDC HELD A GREAT WORKSHOP A COUPLE OF MONTHS AGO STARTING THIS PROCESS OFF AND COMING UP WITH SOME ALGORITHMS OF HOW TO EVALUATE AND MANAGE THESE CHILDREN. AND I WANT TO TALK JUST BRIEFLY ABOUT WHAT WE HAVE BEEN DOING TO TRY TO ADDRESS THIS PUBLIC HEALTH EMERGENCY AT THE NATIONAL INSTITUTES OF HEALTH. WE HAVE A RAPID FUNDING ANNOUNCEMENT OUT ON THE STREET THAT WE ENCOURAGE YOU TO APPLY FOR. THIS ANNOUNCEMENT ALLOWS CONTINUOUS REVIEW AND CONTINUOUS FUNDING FOR ZIKA RELATED PROPOSALS. IT'S AN R21. THERE ARE ABOUT EIGHT OTHER INSTITUTES AND CENTERS WHO ARE PARTICIPATING ON THIS AND I ENCOURAGE YOU TO TALK WITH US ABOUT IT IF YOU'RE INTERESTED IN APPLYING. WE ALSO HAVE THE ZIP STUDY. THIS IS A MULTISITE, MULTI-COUNTRY PROSPECTIVE OBSERVATIONAL STUDY THAT WILL HELP US UNDERSTAND THE RISKS OF ZIKA INFECTION DURING PREGNANCY ON MATERNAL AND FETAL OUTCOMES. ENROLLING 10,000 WOMEN AND USING A STANDARDIZED PROTOCOL WITH STANDARDIZED DATA COLLECTION. THERE ARE TWO SITES ALREADY ENROLLING IN PUERTO RICO AND TWO SITES IN BRAZIL WITH OTHER SITES UP-AND-COMING. AND THIS IS A STUDY THAT WILL BEGIN ENROLLMENT THE FIRST TRIMESTER LESS THAN 14 WEEKS. WOMEN WILL BE FOLLOWED THROUGHOUT PREGNANCY AND THUS SOME WOMEN WILL HAVE ASYMPTOMATIC ZIKA INFECTIONS AND SOME WILL HAVE SYMPTOMATIC AND SOME WILL NOT HAVE ANY INFECTION AT ALL AND WE'LL ALSO BE LOOKING AT DIFFERENT COFACTORS TO SEE HOW THEY MIGHT IMPACT THE AFFECT OF ZIKA ITSELF. AND THEN ALL OF THE CHILDREN WILL BE FOLLOWED BOTH THOSE WITH AND WITHOUT ABNORMALITIES. LOTS OF DIFFERENT THINGS WILL BE DONE TO ASSESS THESE CHILDREN AT BIRTH 3 MONTHS, 6 MONTHS AND 12 MONTHS AND OUR HOPE IS THAT WE WILL BE ABLE TO FOLLOW THEM LONGER. SO HOW BEST SHOULD WE EVALUATE CARE FOR AND MANAGE THE CHILDREN? OUR FOCUS FOR TODAY. WE STARTED THIS OFF WITH A BLOG IN THE 'HUFFINGTON POST' TRYING TO SAY, THESE ARE ISSUES THAT WE NEED TO UNDERSTAND THE LONG-TERM EFFECTS OF FEELS EXPOSURE TO ZIKA. BECAUSE THE CURRENT INFORMATION WE HAVE IS LIMITED. AND MOST OF WHAT WE KNOW IS BASED ON OTHER INFECTIONS FROM PREGNANCY AND THEN WHAT WE ARE SEEING IN THE FRONT LINES AND WHAT YOU'LL HEAR ABOUT IN THE NEXT SEVERAL LECTURES. WE NEED TO KNOW THESE HEALTH OUTCOMES AND WE NEED TO HELP GIVEN WHAT WE ARE ABLE TO TAKE FROM INFECTIONS THAT WE ALREADY KNOW ABOUT, AND DESIGN PROTOCOLS ON HOW TO HELP CARE FOR THESE CHILDREN. SO THE STRATEGIES THAT WE HAVE FOR THESE NEXT TWO DAYS ARE TO TAKE WHAT WE KNOW FROM OTHER CONDITIONS THAT ARE NOTED WITH ZIKA TO EVALUATE THOSE SIMILARITIES AND THE DIFFERENCES AND TO DERM THE BEST OPTIONS FOR EVALUATION, MANAGEMENT AND INTERVENTIONS FOR THE CHILDREN. WE HAVE A NUMBER OF WORKSHOP GOALS THAT WE HAVE TRIED TO OUTLINE TO HELP KEEP US ON TARGET TO DEVELOP A RESEARCH STRATEGY TO IMPROVE OUR ASSESSMENT, OUR EVALUATION AND OUR MONITORING. TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE THE EVALUATION FOR NEW AND EMERGING COMPLICATIONS, TO USE THE AVAILABLE INFORMATION FROM OTHER VERTICALLY TRANSMITTED PATHOGENS TO PROVIDE RECOMMENDATIONS FOR ASSESSMENT, EVALUATION AND MANAGEMENT, TO OUTLINE THE RESEARCH NEEDS AND TO EVALUATE AND EXPAND ON TREATMENT OPTIONS THAT ARE CURRENTLY OFFERED. I DO HAVE MANY THANKS THEY WANT TO PROVIDE TO THE NICHD PLANNING COMMITTEE. BILL KAPOGIANNIS, NAHIDA CHAKTOURA, HAZRA AND CHRISTINE ROGERS HAVE DONE A REMARKABLE JOB PULLING THIS TOGETHER. OUR PALLADDIAN PARTNERS, VALENTINE AND CARLIE SULLIVAN AND OUR NICHD MEDIA RELATIONS TEAM, MEREDITH DAILY AND LINDA HUYNH. I WANT TO THANK THE SPEAKERS, MOD SIMILARITIES AND PANELISTS AND THE OFFICE ON THE RESEARCH ON WOMEN'S HEALTH. I'M GOING TO HOLD MY QUESTIONS, I THINK, AND LET DR. FAUCI COME UP TO GIVE HIS PRESENTATION. DR. FAUCI IS A MAN WHO REALLY DOESN'T NEED AN INTRODUCTION. HE IS WELL-KNOWN AS THE DIRECTOR OF NIAID, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE AND THE ONE WHO EVERYONE TURNS TO WHEN THEY HAVE QUESTIONS ABOUT ZIKA. I WANTED TO TAKE A MOMENT THEN STAYED OF GIVING A BROAD INTRODUCTION ABOUT DR. FAUCI, TO THANK HIM PERSONALLY AND TO THANK HIS STAFF FOR ALL OF THEIR COLLEGIAL COLLABORATIONS AS WE HAVE NAVIGATED THIS COURSE WITH THIS INCREDIBLE PUBLIC HEALTH CONCERN. TONY? [ APPLAUSE ] >> ANTHONY FAUCI: THANK YOU VERY MUCH CATHY. THANK YOU, IT'S A PLEASURE TO BE HERE WITH YOU THIS MORNING. I'M GOING TO TAKE MY ALLOCATED TIME TO TALK TO YOU AS YOU SEE ON THIS FIRST TITLE SLIDE OF THE STATE OF SCIENCE ON ZIKA INVOLVING EVERYTHING FROM THERAPEUTICS, DIAGNOSTICS AND VACCINES. SOME OF YOU MAY RECALL THAT A FEW MONTHS AGO IN JANUARY, I WROTE A COMMENTARY IN THE NEW ENGLAND JOURNAL OF MEDICINE AFTER SEEING IN NOVEMBER AND DECEMBER THE EVOLUTION OF ZIKA IN THE AMERICAS. AND I ENTITLED IT YET ANOTHER ASHO VIRUS THREAT. THE REASON I SHOW IT NOW EVEN THOUGH WE ARE SPECIFICALLY TALKING ABOUT ZIKA, IS WHEN WE THINK IN TERMS OF THE CHALLENGES WE HAVE IN INFECTIOUS DISEASES OF THE KNOWNS AND THE UNKNOWNS, THAT THERE HAVE BEEN A NUMBER OF RECENTLY EMERGING HUMAN DISEASES IN THE AMERICAS RANGING FROM DENGUE THAT ACTUALLY STARTED DECADES AGO BUT CAME INTO FORCE JUST IN THE LAST FEW YEARS, WEST NILE HERE IN THE UNITED STATES IN 1999, CHICKEN GUNNIA IN THE CARIBBEAN IN 2013 AND NOW THE PROMPT THREAT THAT WE ARE FACING IN THE SUBJECT OF TODAY'S DISCUSSION IS ZIKA, WHICH WE FIRST BECAME AWARE OF IN TRUE FORM -- OBVIOUSLY THE OUTBREAKS THAT WERE IN THE ISLANDS AND IN THE FRENCH POLNESIA, ANTI-DATED WHAT WE ARE SEEING NOW IN THE AMERICAS BUT RIGHT NOW WE ARE SEEING IT IN FULL FORCE. SO WHAT IS THE NIH'S APPROACH REGARDING THE SCIENCE THAT WOULD BE THE ULTIMATE BASIS FOR DEVELOPING THE KIND OF COUNTERMEASURES WE NEED? I OUTLINE IT ON THIS SCHEMATIC SLIDE. IT REALLY IS FOUNDED IN THE FUNDAMENTAL BASIC RESEARCH TO UNDERSTAND THE VIRUS. IT'S CAPABILITIES AS PATHOGENESIS, THE IMMUNE RESPONSE TO THE VIRUS, AND TO USE THAT AS THE BASIS FOR THE DEVELOPING OF THE KINDS OF COUNTERMEASURES THAT ARE ABSOLUTELY CRITICAL TO ADDRESSING THE PUBLIC HEALTH PROBLEM. SO I WANT TO GO THROUGH A FEW OF THESE VERY QUICKLY FOR YOU. WITH REGARD TO THE BASIC SCIENCE, MOLECULAR VIROLOGY IS SOMETHING THAT CAN BE RAPIDLY ADDRESSED BECAUSE OF THE TECHNIQUES AND CAPABILITIES WE HAVE OF RAPID SEQUENCE AND INFORMATICS TO UNDERSTAND THE DIFFERENCES BETWEEN OUTBREAKS AND THE DIFFERENCES BETWEEN VARIOUS VIRUSES AND THE RELATIONSHIP WITHIN THE CLASS, IN THIS CASE, THE VIRUSES. ALSO UNDERSTANDING THE IMMUNE RESPONSE INNATE AND ADAPTIVE WILL BE VERY IMPORTANT IN GUIDING US TOWARDS A DEVELOPMENT OF VACCINES AND AS ALWAYS IS THE CASE, WHICH WE DID VERY RAPIDLY AS I THINK EVERYBODY IN THE AUDIENCE REALIZES, IS THE ESTABLISHMENT OF ANIMAL MODELS THAT CAN BE USED FOR A VARIETY OF REASONS. HERE ARE SOME OF THE THINGS THAT VERY RAPIDLY CAME OUT AND ONE OF THE WAYS WE DID THAT IS BECAUSE WE HAD A COHORT OF INVESTIGATORS WHO HAD BEEN WORKING WITH NAVY VIRUSES PARTICULARLY DENGUE, IN THE AREAS RIGHT NOW IN THE AMERICAS THAT WERE HAVING ZIKA AND WE IMMEDIATELY SUPPLEMENTED THEIR GRANTS TO ALLOW THEM TO SWITCH THEIR ACTIVITY TO LOOK AT ZIKA AND UNDERSTANDING FOR EXAMPLE BY CRYO-EM, THE STRUCTURE OF THE ZIKA VIRUS, TO BE ABLE TO DETERMINE IF THERE IS ANY CORRELATES WITH PATHOGENESIS. ALSO TO UNDERSTAND THE MOLECULAR SIGNALING EVENTS ASSOCIATED WITH THE INHIBITION OF TYPE I INTERFERON WHICH IS VERY IMPORTANT IN THE HOST DEFENSE AGAINST ZIKA. AND THESE ARE THE THINGS THAT INFORMED ANIMAL MODELS AS WELL AS UNDERSTANDING SOME OF THE PATHOGENIC MECHANISMS. THE ANIMAL MODELS THAT WAS QUICKLY UTILIZED TO SHOW IN A MOUSE MODEL THE MICROCEPHALIC ABNORMALITIES THAT ONE NOW SEES WITH SUCH FORCE IN HUMANS AND THERE HAVE BEEN A NUMBER OF ANIMAL MODELS THAT HAVE EVOLVED FROM THIS. IN ADDITION, RATHER CREATIVE WAY OF STUDYING THE IMPACT OF THE VIRUS UNDER NEUROLOGICAL TISSUES BY USING A CLEVERY-DIVIDES ORGANNOIDS WHICH SOME PEOPLE REFER TO MAYBE A LITTLE BIT OVER EMPHASIZING AS A BRAIN IN A DISH, WHICH IT REALLY ISN'T. IT'S NEUROLOGICAL TISSUE YOU CAN ACTUALLY LOOK AT SOME OF THE AFFECTS IN-VITRO WHICH MAKE IT MUCH MORE EASY TO BE ABLE TO PLAN EXPERIMENTS THAT YOU WOULD ULTIMATELY DO IN-VIVO. NOW, THE SEATTLE SCIENTIST WAS FIRST TO SHOW THE MONKEY MODEEL OF ZIKA DAMAGE AND THESE WERE TAKING A LOOK HERE AT A 9 YEAR-OLD MACAQUE MONKEY WITH ZIKA VIRUS BECAME THE FIRST TO DEMONSTRATE THE AFFECTS IN A NONHUMAN PRIMATE. SO WE WENT FROM A MOUSE MODEL TO A NONHUMAN PRIMATE MODEL AND RIGHT NOW THE NONHUMAN PRIMATE MODEL IS BEING USED AS AN IMPORTANT TOOL IN THE STUDY OF VACCINES. ALSO, UNDERSTANDING IN THE ANIMAL MODEL, WHICH ABSOLUTELY WAS VERY QUICKLY JOINED TO UNDERSTANDING HUMANS IS THE PROLONGED VIREMIA WITH ZIKA INFECTION IN THE STATE OF PREGNANCY, WHICH IS SOMETHING THAT IS ABSOLUTELY CRITICAL TO UNDERSTANDING THE POTENTIAL FOR THE DILLTORIOUS AFFECTS ON THE FETUS. WE OURSELVES AS YOU KNOW RIGHT HERE IN WASHINGTON, HAD EXPERIENCE WITH A WOMAN WHO WAS INFECTED DURING EARLY PREGNANCY WHO DID IN FACT HAVE PROLONGED VIREMIA WITH A POSITIVE SERUM RNA AT 21 WEEKS. SO THE UNDERSTANDING OF THE FACT THAT THAT VERY WELL MAY BE THE BABY INFECTED RECEDING THE MOTHER AS OPPOSED TO THE MOTHER'S INFECTION BEING PERSISTENT. AND THIS IS SOMETHING WE ARE LEARNING MORE AND MORE ABOUT. WHAT ABOUT DIAGNOSTICS? THE GOAL OF THE DIAGNOSIS IS TO DEVELOP RAPID, SPECIFIC, LOW COST DIAGNOSTIC TOOLS. I COULD GO THROUGH EACH AND EVERY ONE OF THINGS ON THIS SLIDE BUT THE REAL CRITICAL ISSUE IS THAT IT IS VERY EASY AS WE ALL KNOW, TO SPECIFICALLY DIAGNOSIS IF YOU ARE INFECTED. PCR TECHNIQUES FOR THE VIRUSES ARE SIMPLE, EASY, REPRODUCIBLE AND WIDELY DISSEMINATED FOR PEOPLE TO USE. WHAT THE REAL CHALLENGE IS TO BE ABLE TO SPECIFICALLY AND IN A HIGH DEGREE OF SENSITIVITY, TO DETERMINE THE SEROLOGICAL DEMONSTRATION, THE QUESTION THAT YOU ALL GET ASKED AND THAT I GET ASKED 5 TIMES A DAY, HOW DO I KNOW IF I WAS INFECTED WITH ZIKA WHEN I WAS IN A ZIKA TRANSMISSION AREA? AND OBVIOUSLY DEPENDING UPON IF YOU'RE LIVING IN A BACKGROUND OF A COUNTRY THAT HAS A LOT OF DENGUE OR THAT HAS A LOT OF YELLOW FEVER VACCINATION, IT MAKES A BIG DIFFERENCE REGARDING THE SENSITIVITY AND THE SPECIFICITY. NOW ONE OF THE WAYS THAT WE ARE TRYING AND IT IS NOT EASY, IT MAY LOOK EASY ON A SLIDE LIKE THIS, IS THAT IF YOU MUTEO JENIZE OUT THE OVERLAPPING EPITOPES BETWEEN ZIKA AND DENGUE, YOU SHOULD BE ABLE TO BE LEFT WITH A VIRUS THAT ONLY HAS ZIKA SPECIFIC EPITOPES. THE PROBLEM WITH THAT IS THAT WHEN YOU DO THAT, YOU LOSE A GREAT DEGREE OF SENSITIVITY DESPITE THE FACT THAT YOU HAVE A HIGH DEGREE OF SPECIFICITY. AND THAT IS SOMETHING WE ARE STILL WORKING ON RIGHT NOW. IN ADDITION, A LOT OF SCREENING IS DONE NOW BY A NUMBER OF OUR INVESTIGATORS AND COLLABORATION WITH NCATS, THE NATIONAL CENTER FOR THE ADVANCE AND TRANSLATION SCIENCE LOOKING AT A NUMBER OF COMPOUNDS. I WOULDN'T SAY WARN, BUT GET THE AUDIENCE ALERT TO THE FACT THAT BECAUSE SOMETHING IS A HIT IN-VITRO, DOESN'T MEAN IT IS GOING TO BE A HIT IN-VIVO. AND YOU KNOW, YOU HAVE SEEN A LOT OF DRUGS THAT LOOK LIKE THEY MIGHT BE EFFECTIVE AGAINST ZIKA. WE HAVE BEEN THROUGH THAT WITH A NUMBER OF OTHER DISEASES. I'M NOT SAYING THAT SOME OF THEM ARE NOT GOING TO BE IMPORTANT HITS. BUT THEY ARE NOT ALL GOING TO BE IMPORTANT HITS. ALSO MONOCLONAL ANTIBODIES WHICH WE HAVE A GREAT DEAL OF FACILITY IN DOING, AGAINST ZIKA VIRUS, IS NOW BEING USED IN PRECLINICAL STUDIES. IMPORTANTLY, IS TO IDENTIFY THE PRECISE PROTECTIVE EPITOPE ON THE VIRUS WHICH WILL INFORM VACCINE DEVELOPMENT. AND IT'S VERY INTERESTING THAT BROADLY NEUTRALIZING ACTIVITY OF ZIKA VIRUS IMMUNE SERUM IDENTIFIES A SINGLE VIRAL SEROTYPE SO I DON'T THINK WE WILL HAVE THE PROBLEMS THAT WE HAD OBVIOUSLY WITH DENGUE AND WITH OTHER INFECTIONS THAT HAVE MULTIPLE DIFFERENT TYPES OF SEROTYPES. I WANT TO SPEND THE LAST COUPLE OF MINUTES TALKING ABOUT ZIKA VACCINE, DEVELOPMENT. THE REASON WHY WE ARE OPTIMISTIC BUT NOT OVER CONFIDENT, THERE IS A DIFFERENCE BETWEEN THE TWO. I WANT TO MAKE SURE WE UNDERSTAND THAT. THAT WE WILL HAVE A VACCINE AGAINST ZIKA BECAUSE WE HAVE BEEN ABLE TO SUCCESSFULLY MAKE VACCINES FOR OTHER VIRUS THAT IS ARE NOT THAT DIFFERENT THAN ZIKA. ALTHOUGH ALL OF THESE HAVE SOME DIFFERENCES. NOW, IN THE MONKEY MODDEDEL, THERE HAVE BEEN A NUMBER OF APPROACHES SHOWING SEVERAL THINGS. A, YOU CAN PROTECT THE MONKEY FROM CHALLENGE. B, YOU CAN TAKE SERUM FROM THE MONKEY THAT HAS BEEN INFECTED OR VACCINATED AND PROTECT ANOTHER MONKET BY PASSIVE TRANCES FER. WHY IS THAT IMPORTANT? BECAUSE IT IDENTIFIES THE MODALITY OF PROTECTION. IN THIS CASE, NEUTRALIZING ANTIBODIES. AND THERE WILL BE OTHER PAPERS COMING OUT USING DIFFERENT VACCINES SHOWING THE SAME PHENOMENON. NOW THIS IS A COMPLICATED SLIDE. I DON'T WANT YOU TO TAKE A LOOK AT EVERY SINGLE THING ON IT. I ONLY SHOW IT TO YOU IS THAT WHAT IT IS A TEMPORALLY SEQUEL TIMETABLE FOR VACCINE DEVELOPMENT. I COUPLE OF POINTS TO MAKE AND I'M GOING TO PULL OUT ONE OR TWO OF THESE AND SPEND A HALF MINUTE OF TIME ON THEM. JUST BECAUSE A VACCINE GOES INTO CLINICAL TRIAL FIRST DOESN'T NECESSARILY MEAN IT IS GOING TO BE THE BEST VACCINE T JUST SO HAPPENS THAT TEMPORALLY IT IS IN LINE TO GO IN AND DO THE PRECLINICAL STUDIES T MIGHT TURN OUT TO BE THE BEST T MIGHT TURN OUT TO BE A HOME RUN BUT YOU DON'T KNOW THAT. SO HERE IS A GROUP OF THEM. THE FIRST ONE THAT YOU KNOW IN WHICH THERE ARE TWO IN-HUMAN TRIALS GOING. ONE BY NOVIO AND ONE BY OUR GROUP AT THE VRC. A DNA VACCINE ALONG THE PLATFORM SIMILARITY TO WHAT WAS USED IN THE PAST WITH A WEST NILE VIRUS. AND THAT IS A PLASMID WITH AN INSERT FOR THE PROTEIN, IN THIS CASE, PREM, OF THE ZIKA VIRUS. NOW, I KNOW MOST OF YOU KNOW WHAT THE DNA VACCINE S BUT BARNEY GRAHAM MADE THIS SLIDE. HE IS THE PI IN OUR VRC, TO EXPLAIN IN A VERY SIMPLE WAY WHAT A DNA VACCINE IS. IF YOU LOOK AT THE LEFT-HAND SIDE OF THE SLIDE, IT'S A TYPICAL DNA CIRCULAR PLASMID THAT HAS THE CAPABILITY OF AN INSERT AS YOU SEE IN THE YELLOW. SO YOU STICK THE GENE FOR THE APPROPRIATE ZIKA PROTEIN AND THEN THE NEXT QUESTION IS, WHAT DO YOU DO WITH IT? WHAT YOU DO WITH IT IS THAT YOU STICK IT IN AN E.COLI AND YOU SEE THAT E.COLI THERE WITH A LITTLE SQUIGGLY AROUND IT, AND E.COLI DOES WHAT E.COLI DOES BEST. IT IS A FACTORY FOR WHATEVER GENETIC MATERIAL YOU PUT IN THERE. SO IT MAKES A WHOLE BUNCH OF THESE PLASMIDS. YOU DISRUPT THE E.COLI. YOU SPIN IT DOWN. YOU PURIFY IT. AND LOW AND BEHOLD, THAT IS YOUR DNA VACCINE. YOU THEN STICK IT IN THE ARM OF AN INDIVIDUAL. IT GOES INTO A MUSCLE, GETS INTO THE NUCLEI AND THEN COMMANDS THE GENETIC MATERIAL TO START MAKING VIRUS-LIKE PARTICLES. YOU TAKE THAT, PUT IT IN A VILE, STICK IT INTO SOMEONE'S ARM THE WAY WE DID ON AUGUST 2 AND THE WAY WE ARE DOING IN MULTIPLE MEDICAL CENTERS, AND THEN YOU WIND UP WITH THE END RESULT, HOPEFULLY, SAFETY AND PROTECTIVE IMMUNITY. WHAT WE WILL BE DOING, IF ALL THINGS GO THE WAY WE HOPE THEY WILL, AND THEY ARE GOING WELL. WE HAVE OVER 50 PEOPLE IN THE 80-PERSON PHASE I TRIAL. SO WE ARE ALMOST THERE. SOMEWHERE AROUND NOVEMBER OR EARLY DECEMBER, WE'LL FINISH THAT AND THEN WE WILL, IF WE GET THE RESOURCES, WHICH WE ARE ALL WAITING FOR, WE'LL GO INTO A PHASE II TRIAL IN 20 OR MORE SITES IN AREAS OF OUTBREAK. AND WHAT IT WILL BE, WILL BE A TRIAL THAT WILL HAVE A MINIMUM OF 2400 AND PERHAPS UP TO 5000 PEOPLE. WHY THE DIFFERENCE? IF THERE IS A LOT OF INFECTIONS, YOU'LL KNOW THE ANSWER SOON. SO YOU MAY ONLY NEED 2400 PEOPLE IN THE STUDY. IF THE INFECTIONS GO WAY DOWN, YOU MAY NEED TO HAVE MORE PEOPLE IN THE STUDY. THAT'S WHY YOU CAN GO UP TO 5000. SO I'D LIKE TO SEE THE EPIDEMIC SPONTANEOUSLY DISSOLVE ITSELF BUT I ALSO WOULD LIKE TO HAVE ENOUGH INFECTIONS TO BE ABLE TO PROVE THE VACCINE WORKS. THE NEXT ONE I'M NOT GOING TO EXPLAIN IN DETAIL EXCEPT TO TELL YOU IT'S NEXT IN LINE. IT'S A PARTICLE IN ACTIVATED VACCINE WHICH WILL START A PHASE I TRIAL SOMETIME MID TO LATE OCTOBER. AND THEN THE OTHER ONE IS A LIVE ATTENUATED, WHICH HAS BEEN TRIED-AND-TRUE AMONG MANY INFECTIONS, INCLUDING THE RELATED VIRUS OF DENGUE. AND THAT IS ONE THAT ALSO IS NEXT IN LINE AND LIKELY WILL GO INTO A PHASE I IN 2017. SO I WANT TO END WITH THE SLIDE THAT I ALLUDED TO IN THE BEGINNING WHEN I SHOWED YOU ZIKA IN THE AMERICAS YET ANOTHER VIRUS. EMERGING INFECTIONS: WE ARE ALL FOLK FOCUSED ON THIS WITH ZIKA. IT'S NOT THE FIRST NOR THE LAST ONE THAT WE WILL CHALLENGE WITH IT. LET'S GET THIS RIGHT AS AN EXAMPLE FOR THE NEXT ONE. THANK YOU. [ APPLAUSE ] >> THANK YOU VERY MUCH FOR THE EXCELLENT PRESENTATIONS. DR. FAUCI AND DR. SPONG CAN TAKE A COUPLE OF QUESTIONS IF ANYBODY HAS THEM. THANK YOU VERY MUCH FOR STARTING US OFF WITH THIS EXCELLENT PRESENTATION. I THINK DR. VANESSA VAN der LINDEN WILL BE COMING UP TO SPEAK NEXT. >> WHILE SETTING UP HER SLIDES, LET ME INTRODUCE HER. DR. VANESSA VAN der LINDEN IS A PEDIATRIC NEUROLOGIST WITH THE ASSOCIATION FOR THE ASSISTANCE OF DISABLED CHILDREN, REHAB REFERENCE CENTER IN NORTHEASTERN BRAZIL FOR THE TREATMENT OF CHILDREN WITH PHYSICAL DISABILITIES. VANESSA VAN der LINDEN HAS EXPERTISE IN NEUROMUSCULAR INBORN METABOLISM DISORDERS AND SHE IS ALSO PEDIATRIC NEUROLOGIST AT THE HOSPITAL -- [ INDISCERNIBLE ] AND SINCE 2015, SHE HAS BEEN RESPONSIBLE FOR THE FOLLOW-UP OF CHILDREN WITH CONGENITAL ZIKA SYNDROME AT THE HOSPITAL. AND HER GROUP WAS ONE OF THE FIRST GROUPS IN NORTHEAST BRAZIL TO LINK MICROCEPHALY AND ZIKA VIRUS. >> VANESSA VAN der LINDEN: GOOD MORNING. I'D LIKE TO THANK THE INVITATION TO BE HERE AND TALK ABOUT MY EXPERIENCE DURING THIS LAST YEAR WITH THESE BABIES. ... >> SO WE ARE OBVIOUSLY AS YOU CAN SEE, WE ARE HAVING TECHNICAL DIFFICULT SO WE WILL SWITCH THE ORDER A LITTLE BIT. THE NEXT PRESENTER WILL CARMEN ZORILLA. CARMEN ZORILLA IS A PROFESSOR OF OBGYN AT THE UNIVERSITY PUERTO RICO SCHOOL OF MEDICINE LEADING THE UNIVERSITY PUERTO RICO OBGYN DEPARTMENT SERVICES AND RESEARCH RESPONSE TO ESTABLISH ZIKA EPIDEMIC AMONG PREGNANT WOMEN IN PUERTO RICO. THE RESEARCHERS AT THE UNIVERSITY OF PUERTO RICO ESTABLISHED A MULTIDISCIPLINARY CLINIC FOR PREGNANT WOMEN WITH ZIKA AND SHE IS OUR LEAD INVESTIGATOR AT THE SAN JUAN HOSPITAL FOR THE NIH SPONSORED ZIKA STUDY OR THE ZIP STUDY PRESENTED EARLIER. DR. CARMEN ZORILLA. >> CARMEN ZORILLA: THANK YOU FOR INVITING ME. I'D LIKE TO SAY THAT I AM HUMBLED TO PRESENT VERY SMALL NUMBERS OF PATIENTS THAT WE HAVE FOLLOWED. SO AND I THAN OTHER GROUPS HAVE TREMENDOUS EXPERIENCE WITH ZIKA. WE ARE JUST -- THIS IS AN EPIDEMIC THAT IS EVOLVING. SO THIS IS WHAT THE MOST ACTUAL INFORMATION THAT WE HAVE THAT WE WILL SHARE WITH YOU. BEFORE I START, I LIKE TO QUOTE ONE OF MY FAVORITE AUTHORS. [ READING ] THESE ARE EVERY FRIDAY THE PUERTO RICO HEALTH DEPARTMENT REPORTS CASES OF CONFIRMED ZIKA BY LABORATORY TESTING FOR ADULTS AND ALSO FOR PREGNANT WOMEN. SO EVERY FRIDAY I ADD A BAR TO MY GRAPH AND AS YOU CAN SEE, THE EPIDEMIC IS GROWING. THERE IS NOTHING STOPPING IT RIGHT NOW. IT IS EVOLVING AND GROWING. THAT IS WHAT WE HAVE. RIGHT NOW WE HAVE 1700 PREGNANT WOMEN REPORTED WITH ZIKA. ONE OF THE THINGS THAT THE HEALTH DEPARTMENT IS DOING IS THAT WE ARE TESTING OR THEY ESTABLISHED THIS POLICY OF TESTING PREGNANT WOMEN IN THE FIRST TRIMESTER AND IN THE SECOND TRIMESTER WHETHER THEY ARE SYMPTOMATIC OR NOT. SO WE ARE TESTING ANYBODY WHO IS PREGNANT. FIRST AND SECOND TRIMESTER. AND THEN ANYBODY WHO IS PREGNANT WITH SYMPTOMS THEY ARE ALSO TESTED. THE COLORS IN THAT MAP REPRESENT THE CONCENTRATION OF CASES REPORTED IN THE ISLAND AND AS OF LAST FROM, ALMOST 20,000 CASES, 1700 PREGNANT WOMEN. OF THOSE 67% HAD SYMPTOMS OF ZIKA AND 33% HAD NOT HAD SYMPTOMS AND WE ARE JUST IDENTIFIED BECAUSE OF THE TESTING. 1% OF PEOPLE HAD BEEN HOSPITALIZED THREE DEATHS MOSTLY AMONG VERY OLD INDIVIDUALS AND 48 CASES, 37 RELATED TO ZIKA, 11 TO FLAV I VIRUS, ONE DEATH RELATED TO GPS AND ONE BIRTH DEFECT MICROSELFIE. I'M STARTING WITH THE EXPERIENCE OF THE PEDIATRICIANS REGARDING THE PREVIOUS EP DEMOCRATIC CHING UNIA EPIDEMIC THREE YEARS AGO. THEY WERE VERY CONCERNED ABOUT WHAT HAPPENED HAPPEN TO THE INFANTS BORN TO MOTHERS WHO HAD CHICK UNGUNNIA CLOSE TO DELIVERY. SO THEY HAD AN OPPORTUNITY TO EVALUATE 10 NEWBORNS OF MOTHERS WHO HAD CHICK UNGUNNIA AND OF THOSE, ALL IN PANTS FROM MOTHERS WITH SYMPTOMS OF LESS THAN 5 DAYS FROM DELIVERY, HAD OR SHOWED, THIS WAS JUST 7, SHOWED CONSTITUTIONAL SYMPTOMS AND PHYSICAL AS WELL AS LAB ABNORMALITIES CONSISTENT WITH CHICK UNGUNNIA AND NEONATE INFECTION. AT THE SAME TIME THREE INFANTS WHOSE MOTHERS HAD CHICKEN GUNNIA MORE THAN 5 DAYS FROM DELIVERY AND THESE IN FACTS TWO HAD HYDROSELFIE AND ONE HAD EVIDENCE OF BRAIN INFARC. SO INFECTION FROM WITH CHING UNGUNNIA FURTHER FROM BIRTH WAS ASSOCIATED NOT NECESSARILY THE CAUSE OF BUT WAS RELATED TO SOME BIRTH DEFECTS IN THOSE INFANTS. THE NUMBERS ARE SMALL BUT IT WAS JUST A REASON FOR US TO BE CONCERNED. NOW WE HAVE THESE NEUROTROPIC VIRUS, WHICH IS ZIKA, AND SO PRESENTS WITH US MORE CONCERN. THIS IS THEIR EXPERIENCE UP TO AUGUST. 14 INFANTS EVALUATED IN THE NURSERY. OF THOSE ONE HAD SPONTANEOUS PNEUMOTHORAX. TWO HAD OPTIC DISK HYPOPLASIA BLEEDINGS AND ALL IN PANTS HAD NORMAL SIZE. SO THEY WERE NOT MICROCEPHALY INFANTS. BUT YET THAT HAD, TWO HAD RETINAL ABNORMALITIES, ONE HAD AN ARACHNOID SIFT AND SO 1/3 OF THESE INFANTS HAD ABNORMALITIES NOT RELATED TO MICROCEPHALY AND THEY HAD NORMAL SIZE AT BIRTH OF THE SO THESE ARE WHAT WE ARE SEEING RIGHT NOW WHAT CONCERNS US, WHICH MAKE US ALSO THINK THAT WE NEED TO MAKE SURE THAT IT IS THE MICROCEPHALY IS JUST THE EXTREME BUT WE NEED TO MAKE SURE THAT WE FOLLOW AND EVALUATE ALL THESE INFANTS EXPOSED TO ZIKA INFECTION DURING PREGNANCY. I'M PRESENTING TWO CASES, ONE WAS A PRETERM INFANT EXPOSED TO ZIKA DURING THE SECOND TRIMESTER. THIS MOTHER HAD CORE YON NIGHTIS AND PROLONGED REPATURE OF MEMBRANES. SO SHE DELIVERED AT 29 AND 4 DAYS. 29 WEEKS AND 4 DAYS. THE BABY GIRL WAS 7-8. SO, UPON BIRTH SHE HAD NEUROEVALUATION AND RECOMMENDED BRAIN MRI, ODDOLOGY AND SPEECH PATHOLOGY EVALUATION AND THEY FOLLOWED HER. SO THIS CASE WAS PRESENTED AT ONE OF THESE PEDIATRIC MEETINGS. THE INTERESTING THING WAS THAT THIS GIRL HAD ON HER ULTRASOUND HAD VENTRICAL MEGALY, INTERVEHICULAR HEMORRHAGE, AND NO HYDROSELFIE. BUT THAT WAS AT ONE WEEK. AT ONE MONTH, AGAIN, THERE WAS SOME ABNORMALITIES IN THE BRAIN MRI. SHE HAD DIFFUSED SIMPLIFICATION OF -- THIS IS FROM THE REPORT. WHICH MAY BE SEEN IN PRE-TERM PATIENTS HOWEVER DEGREE OF SELFIE CANNOT BE ENTIRELY EXCLUDED AND THEN WHEN THEY KEPT ON FOLLOWING THIS INFANT, THERE WAS SOME CONCERN THAT SOME MANIFESTATIONS AT FOUR MONTHS OR SO MIGHT NOT HAVE BEEN COMPLETELY EXPLAINED BY THESE BABY GIRL BEING BORN PRETERM. SO THERE IS NOT COMPLETE EVIDENCE THERE IS SOME ABNORMALITY BUT THERE IS SOMETHING POSTNATAL THAT WAS FOUND ON THIS INFANT THAT WAS UNFORTUNATELY PRETERM AND ALSO ZIKA EXPOSED. ANOTHER BABY THAT ACTUALLY I SAW THIS WOMAN ON HER POSTPARTUM VISIT. AND SHE CAME WITH HER BABY GIRL HAD BORN 2720 GRAMS. WHEN I SAW HER THE FIRST IMTOO, THE BABY GIRL WAS 27 DAYS OLD. AND THIS IS A STORY SHE TOLD ME. THE BABY STAYED IN THE NURSERY FOR 5 DAYS BECAUSE THE BABY HAD THIS CONJUNCTIONIVITIS AND THE EYES KEPT CLOSED. SHE COULDN'T OPEN HER EYES EVERY DAY SO THEY NEEDED TO TO USE SOLUTIONS AND GELS. AND AT 27 DAYS OLD THE BABY STILL HAD THAT CONADJOURNINGIVITIS WHICH REALLY CONCERNED ME LIKE MAYBE THIS IS SOME OCULAR MANIFESTATION OF THIS ZIKA EXPOSURE. SO WE MANAGED TO GET HER AN EVALUATION BY THE PEDIATRIC OP THYMOL GEE WHO SHOWED NORMAL FINDINGS SO FAR. I SAW AGAIN THIS MOTHER AND HER BABY LAST WEEK. THE BABY IS NOW ALMOST 3 MONTHS OLD AND IT RESOLVED. SO, BUT AGAIN, I CANNOT SAY FOR SURE THAT THIS WAS RELATED OR NOT. BUT THIS IS THE FIRST BABY THAT I SEE WITH CONJUNCTIVITIS THAT LAST FOR A MONTH. IN ADDITION TO THOSE CASES REPORTED BY THE PEDIATRICIANS, WE HAD 21 LIVE BIRTHS OF MOTHERS, ONE PREGNANCY TERMINATION THAT THAT IS THE CASE OF MICROCEPHALY REPORTED BY THE HEALTH DEPARTMENT. TWO MISCARRIAGES, AND I HAVE JUST WANT TO SHOW THIS GRAPH WHICH JUST SHOWS THE PATTERN OF BIRTH SO THAT MEANING WE ARE GOING TO SEE THESE BABIES BORN NOW DURING THESE MONTHS BECAUSE THIS IS A BUSY SEASON FOR US OBSTETRICIANS. AFTER AUGUST AND SEPTEMBER, THESE ARE THE PEAK OF BIRTHS IN PUERTO RICO. SO VERY LIKELY WE WILL SEE NOT JUST BABIES THAT ARE BORN EXPOSED BUT ALSO THAT WILL PRESENT SOME ABNORMALITIES. AND OF ALL OF THESE 1700 INFANTS REPORTED IN THE ISLAND, WITH ZIKA, MEANING PREGNANT WOMEN, SORRY. WE ARE NOT SEEING ALL THESE WOMEN IN OUR HOSPITALS. SO THEY HAVE BEEN FOLLOWED ALL OVER. SO I CANNOT SAY WHAT INFORMATION DO WE HAVE ON THESE WOMEN, WHAT FINDINGS DO WE HAVE ON THEIR ULTRASOUNDS OR WHAT OUTCOMES THEY MIGHT HAVE. I CAN ONLY REFER TO THE EXPERIENCE IN OUR HOSPITAL. SO I TOOK UPON MYSELF AND REVIEWED 39 PREGNANT WOMEN, CURRENTLY PREGNANT FROM OUR CLINIC. MOST OF THEM YOUNG WOMEN, 23 YEARS OLD. MOST OF THEM -- ABOUT 51% AND ALMOST 60% HAD NOT HAD ANY CHILD. SO MOST OF THEM FOR MOST OF THEM WHO HAD BEEN EXPOSED TO ZIKA, THIS PREGNANCY IS REALLY VERY IMPORTANT BECAUSE IT IS THE FIRST PREGNANCY THAT MIGHT HAVE -- THEY MIGHT CARRY TO TERM. 42% WERE DIAGNOSED DURING THE FIRST TRIMESTER. THERE IS ONE PATIENT OUT OF THESE 39 THAT I COULDN'T FIND IN THE CHART. WHEN WAS THE EXPOSURE? I BELIEVE IT WAS IN THE FIRST TRIMESTER BECAUSE THAT PARTICULAR PATIENT, THE FETUS HAS ZIKA FOR INSTANCE IN THE FIFTH PERCENTILE. SO I'M PRESUMED SHE WAS EXPOSED IN THE FIRST TRIMESTER BUT I CAN'T NOT SAY SO. SECOND TRIMESTER 42%. THIRD TRIMESTER ALMOST 16%. SO AGAIN, MEANING THAT WE CANNOT JUST STOP TESTING WOMEN IN FIRST AND SECOND TRIMESTER. WE NEED TO CONTINUE TESTING THIRD TRIMESTER AND MAYBE EVEN DURING LABOR AND DELIVERY IF THEY HAVE NOT BEEN TESTED. THE PURPOSE OF TESTING IS NOT TO -- ONE OF THE PURPOSES OF TESTING, MIGHT BE TO OFFER PREGNANCY OPTIONS BUT THE PURPOSE OF TESTING IS TO IDENTIFY EXPOSED FETUSES AND INFANTS AND TO BE ABLE TO HAVE PROPER CARE AND FOLLOW-UPS FOR THESE INFANTS. SO CANNOT STOP AT THE SECOND TRIMESTER. HALF HAD SYMPTOMS OF ZIKA AND HALF OF THEM WERE A LITTLE BIT WERE DIAGNOSED WITH THE IGM SO THE REPORTS SAY PRESUMPTIVE DIAGNOSED AND HALF HAD BRC POSITIVE AND OF THOSE 39, WE HAVE TWO RIGHT NOW THAT HAVE OR FALL INTO THE CATEGORY OF HAVING A CHC BELOW THE THIRD PERCENTILE AND WE ALSO HAVE 4 MORE THAT HAVE SMALLER HEADS, ONE IN THE FOURTH PERCENTILE AND TWO IN THE 5th PERCENTILE AND ONE IN THE 9th PERCENTILE. SO DEFINING MICROCEPHALY BECAUSE IT'S SO EXTREME THIRD PERCENTILE, WE MIGHT MISS AFFECTED IN FACTS WHO MIGHT BE ON THAT GRAY ZONE BELOW THE 10 PERCENTILE FOR HEAD CIRCUMFERENCE. I'M GOING TO PRESENT THIS INFORMATION SHARED WITH ME BY DR. De La VEGA, THE PERSON WHO IS DOING MOST OF THE LEVEL TWO RESULTRA SOUND ON THE WOMEN WITH ZIKA DIAGNOSE AT THE UNIVERSITY OF PUERTO RICO. HE REVIEWED HIS EXPERIENCE FOR THE PAST YEAR AND HE ALSO -- SO IN THIS SERIES OF SLIDES YOU'RE GOING TO SEE, HE HAS ABOUT 247 PATIENTS DIAGNOSED WITH ZIKA WHO HAD SYMPTOMS SO HE COULD KNOW EXACTLY WHEN WAS THE EXPOSE NUR TERMS OF GESTATIONAL AGE. AND HE ALSO HAD ALL THE NORMAL PREGNANCIES PLOTTED IN A GRAPH FOR US TO KNOW WHETHER OUR HEAD CIRCUMFERENCES CIRCUMFERENCES AND OUR FEELS PARAMETERS REPRESENT OR ARE SIMILAR TO THE ONES IN THE TABLES FOR THE U.S. -- FETAL. SO THAT WAS FIRST QUESTION. ARE OUR BABIES SMALLER? OR ARE THEY SIMILAR TO THE U.S.? SO THIS IS WHAT HE FOUND. 524 ULTRASOUNDS EVALUATIONS ON 220 PREGNANT WOMEN CONFIRM WITH INFECTION. HE FOUND INTRACRANIAL CALCIFICATIONS AND SIZE OF DEFICIENT BRAIN GROWTH AMONG FOUR. AND 4% OF THESE FETUSES HAD BEEN AFFECTED BETWEEN 8-14 WEEKS AND HE MAKES A POINT OF CHOOSING THE 8 WEEKS GESTATIONAL AGE BECAUSE IT SEEMS THAT THE FETUSES OF WOMEN EXPOSED BEFORE 8 WEEKS WHERE YOU DON'T HAVE A PLACENTA MIGHT SOMEHOW BE SPARED. BUT FETUSES EXPOSED AFTER 8 WEEKS MIGHT HAVE MORE IMPACT ON THE INFECTION BECAUSE YOU HAVE NO PLACENTA WHICH COULD BE A CULTURE MEDIUM FOR THIS VIRUS. I FOUND VENTRICAL MEGALY IN FIVE. HEAD CIRCUMFERENCE BETWEEN TWO STANDARD DEVIATIONS THREE AND HEAD CIRCUMFERENCE BETWEEN THREE STANDARD DEVIATIONS MEAN ZERO. ONE MICROCEPHALY THAT WAS INTERUTERINE REPORTED BY THE HEALTH DEPARTMENT HE FOUND PLACENTA CALCIFICATIONS, AND IUFD AMONG THREE OF THEM. SO THIS IS THE COMPARISON OF THE HEAD CIRCUMFERENCES AMONG THE NORMAL FETUSES AT THE UNIT EVALUATED BEFORE THE ZIKA EPIDEMIC, MEANING BEFORE THIS YEAR, COMPARED TO THE MEAN STANDARD DEVIATIONS FOR THE U.S. NORMAL POPULATION. AS YOU CAN SEE -- DO I HAVE A POINTER? SO THIS IS THE NORMAL CURVE FOR THE MEAN FOR THE U.S. AND THE MEAN FOR PUERTO RICO. THEY ARE MATCHED. THEY ARE MATCHED. AND ALSO NOTE THAT YOU HAVE DOTS ABOVE AND BELOW THE LINES. MY MESSAGE HERE WOULD BE LOOK FOR THE DOTS ABOVE AND BELOW THE LINE. SO THESE ARE HEAD CIRCUMFERENCES AMONG NORMAL FETUSES SEEP AT THE UNIVERSITY HOSPITAL AND THE ONES WHO HAD ZIKA PRIOR TO 8 WEEKS. AS YOU SEE, YOU SEE THE NORMAL MEAN BUT YOU SEE THESE FETUSES MOST OF THEM BELOW. STILL WITHIN THE NORMAL RANGE BUT BOW LOW THE CURVE. FETUSES EXPOSED IN THE SECOND TRIMESTER AGAIN SOMEHOW SPREADING BELOW, STILL NORMAL BUT BELOW THE NORMAL CURVE. THIRD TRIMESTER, SAME THING. THE LINE IS SOMEWHAT LOWER. AND THEN IN CONTRAST, WHEN -- THESE ARE SORRY, THESE ARE THE FETUSES WITH EXPOSED TO ZIKA AFTER 8 WEEKS GESTATIONAL AGE. AND THESE ARE THE LINKS. SO WE ARE SEEING HEAD CIRCUMFERENCES A LITTLE BIT SMALLER BUT STILL WITHIN THE NORMAL OF TWO STANDARD DEVIATIONS OF THE GROWTH CURVE. BUT NOW WHEN WE SEE THE PEOPLEAL LENGTH, THEY FAMILIAR THE GRAPH. SO -- THE PEOPLEAL LENGTH. THERE COULD BE SOME DISCREP' BETWEEN HEAD CIRCUMFERENCE AND THE REST OF THE BODY. WHEN WE LOOK AT THE ABDOMINAL CIRCUMFERENCES THE LINES ALSO MATCH. SO THESE FETUSES, IT SEEMS THEY HAVE NORMAL GROWTH PARAMETERS FOR ABDOMINAL CIRCUMFERENCES, FOR MEMORIAL LEAPT BUT NOT NECESSARILY FOR FEELS HEAD. -- FEMORAL LENGTH -- SO FAR WE BELIEVE THAT MOST ZIKA EXPOSED FETUSES SEEM TO HAVE SMALLER HEAD CIRCUMVENT FRANCES THAN THE NORMAL POPULATIONS OF FETUSES BUT STILL WITHIN THE NORMAL LIMITS. THERE IS HIGH FREQUENCY OF RETINAL ABNORMALITIES ON NORMAL-SIZED INFANTS SUGGESTS THAT WE NEED TO PERFORM MORE DETAILED ASSESSMENTS OF THE EYES AND PARTICULARLY THE RETINA. MOST OF OUR PATIENTS WERE IDENTIFIED IN THE FIRST AND SECOND TRIMESTER BUT STILL A GROUP OF THEM WERE IDENTIFIED IN THE THIRD TRIMESTER. SO, TESTING NEEDS TO BE EXPANDED THROUGHOUT PREGNANCY. AND ONLY HALF OF THE WOMEN WHO WITH CONFIRMED DIAGNOSIS HAD SYMPTOMS. HAD WE NOT TESTED THEM WE WOULDN'T HAVE FOUND THEM. THEREOF TESTING IS ESSENTIAL IN EXPOSED -- AREAS THAT ARE PREVALENT FOR ALL PREGNANT WOMEN AND THROUGHOUT THEIR PREGNANCY AND SUMMERY MAYBE TESTING OF INFANTS AS WELL BECAUSE THE MOTHER DIDN'T HAVE IT DOESN'T MEAN THE INFANT MIGHT NOT GET IT LATER ON. SO I WANT TO END WITH THIS QUOTE AGAIN FROM PAULO. AND HE WROTE, NONE OF US KNOWS WHAT MIGHT HAPPEN EVEN THE NEXT MINUTE YET WE STILL GO FORWARD BUZZ WE TRUST. BECAUSE WE HAVE FAITH. THANK YOU VERY MUCH. [ APPLAUSE ] >> NAHIDA CHAKTOURA SO, WE WILL GO AHEAD AND TAKE QUESTIONS FOR CARMEN BUT WE WILL ALSO ASK HER TO COME BACK AFTER BREAK TO BE ON THE PANEL WITH DR. VANESSA VAN der LINDEN HOPEFULLY WE WILL BE ABLE TO LOAD YOUR SLIDES. SO IF THERE IS ANY QUESTIONS FOR CARMEN? INTRODUCE YOURSELF AND YOUR AFFILIATION, PLEASE. >> I'M CAMILLA FROM BRAZIL. I'M AN OPHTHALMOLOGIST AND MY QUESTION IS REGARDING THE FIRST CASE YOU PRESENTED. THE BABY -- WAS THE BABY EXAMINED THE FIRST BABY. NOT THE SECOND. I REALIZE THE SECOND BABY HAD THE OCULAR EXAMINATION. WHAT ABOUT THE FIRST? >> I DON'T HAVE THAT INFORMATION BUT MOST PRETERM BABIES ARE EXAMINED BY THE PEDIATRIC OPHTHALMOLOGIST AS WELL. THAT'S PART OF THE PROTOCOL FOR PRETERM BIRTH. THEY MIGHT NOT HAVE FOUND ANYTHING. IT WAS NOT THERE. >> HIGH NAME IS -- WITH THE SCIENTIST MAGAZINE. I WANT TO CLARIFY SOMETHING YOU SAID IN THE VERY END OF YOUR TALK AND I MIGHT HAVE MISUNDERSTAND. BUT EVEN IF THE MOTHER DOESN'T HAVE IT THE INFANT COULD GET TO THE LATER ON. ARE YOU TALKING ABOUT BABIES BEING INFECTED WITH ZIKA DIRECTLY? >> NO. REFERRING IN A AREA WHERE ZIKA IS ENDEMIC OR EPIDEMIC, THE FETUS -- THE INFANTS ARE NOT OUT OF THE OR AWAY FROM THE PROBLEM BECAUSE NAY CAN STILL HAVE INFECTION LATER ON. THAT IS MY POINT. >> AFTER BIRTH. >> YES. >> YES. I THOUGHT THAT WAS VERY INTERESTING. IS THAT SOMETHING YOU'RE MONITORING INFANTS EVEN IF THEIR MOTHERS NEVER TESTED POSITIVE FOR ZIKA? >> RIGHT NOW WHAT I'M SEEING AND THIS IS ANECDOTALLY. THERE IS STILL RESISTANCE FOR PEOPLE TO BE TESTED EVEN IF THEY HAVE SYMPTOMS AND SO WE ARE ENCOURAGING CLINICIANS AS WELL AS PATIENTS IF THEY HAVE SYMPTOMS THEY SHOULD BE TESTED SO IT SO HAPPENS THAT I SEE MANY PLACES THEY SAY, WELL, RESULTS WILL TAKE TWO MONTHS. YOU HAVE IT ALREADY. SO BUT WE NEED A DIAGNOSIS. THAT'S THE IMPORTANT THING. PEOPLE NEED TO BE TESTED. >> RIGHT. AND IN GENERAL FUTURE RESEARCH ON INFANTS WHO CONTRACT ZIKA AFTER BIRTH. NOT ENOUGH TIME FOR THAT TO KNOW. >> NOBODY KNOWS. REMEMBER THE ZIKA ASIMPLE MAT NIKKEI LOT OF PEOPLE. SAME THING HAPPEN WITH PREGNANT WOMEN. IF WE DON'T TEST INFANTS, WE WOULDN'T KNOW THEY WERE EXPOSED. >> OKAY. THANK YOU. >> GOOD MORNING, DANA THOMAS FROM THE PUERTO RICO DEPARTMENT OF HEALTH. I HAD A QUESTION REGARDING THE 14 INFANTS IN THE STUDY. DO WE HAVE HAVE THEM AS CONCORDANT OR DISCORDANT WITH THEIR MOMS. >> WE DON'T HAVE ANY RESULTS FROM THESE INFANTS BECAUSE THE HEALTH DEPARTMENT HAS NOT REPORTED ON THOSE RESULTS THAT WERE SENT. >> SO THOSE ARE PENDING? I'M WONDERING IF THERE IS A CONCERN IF THEY WERE TRULY ZIKA INFECTED INFANTS OR NOT. >> THE MOTHERS WERE. YES, WE DON'T HAVE ANY INFORMATION ON ANY INFANTS THAT HAVE BEEN DELIVERED ON THEIR TESTING EITHER CORE BLOODS OR NURSERY SAMPLES. >> VERTELEFROM FDA. SO YOU HAVE IDENTIFIED SOME 1SOMETHING -- 1700 PREGNANT WOMEN WHO HAVE TESTED POSITIVE FOR ZIKA. ARE THERE ANY PLANS TO FOLLOW THESE KIDS IN TERMS OF DEVELOPMENT FOR THE FIRST YEAR OR TWO OF LIFE TO SEE IF THEY DEVELOP NORMALLY? >> I WAS PART OF A MEETING WITH THE HEALTH DEPARTMENT HAD THIS MEETING WITH PEDIATRICIANS AND CERTAINLY THEY ARE TRYING TO DEVELOP A PLAN FOR FOLLOWING THESE INFANTS. THEY HAVE A SYSTEM OF CLINICS FOR IDENTIFYING CHILDREN WITH NEURODEVELOPMENTAL PROBLEMS AND DELAYS AND THAT PROGRAM WAS SORT OF DISMANTLED SOMEHOW OR SHORTENED BECAUSE OF LACK OF FUNDS AND SO I BELIEVE -- GIVEN RESOURCES, THAT PROGRAM SHOULD BE IMPLEMENTED. ANYWAY, IN OUR HOSPITAL WE ARE ACTUALLY HAVING CONVERSATIONS SO AS TO HAVE A COMPREHENSIVE CLINIC FOR ALL THE INFANTS BORN IN OUR HOSPITAL. FT. INDEPENDENT OF THE PUERTO RICO HEALTH DEPARTMENT. >> AND JUST AS AN FYI, WITH THE STUDY THAT YOU'RE PARTICIPATING IN, WE ARE FOLLOWING THE INFANTS FOR AT LEAST A YEAR POST-BIRTH AND WE ARE HOPING TO EXTEND THE FOLLOW-UP OF THE INFANTS FOR LONGER. >> HI. GOOD MORNING. DR. VALENCIA DIRECTOR OF THE SPECIAL HEALTH CLINIC IN PUERTO RICO. I WANT TO FOLLOW ON THAT QUESTION. YES, WE HAVE A PROGRAM IN PLACE. WE HAVE OVER 100 BEING FOLLOWED THAT HAVE BEEN BORN TO PREGNANT WOMEN POSITIVE. IT HAS DEVELOPMENTAL SURVEILLANCE SCHEDULE FOR UP TO THREE YEARS OLD. SO THEY ARE CURRENTLY BEING FOLLOWED. THEY HAVE A SPECIAL COORDINATORS THAT THOSE FAMILIES JUST TO MAKE SURE THEY COME TO THEIR APPOINTMENTS AND THEY CAN HAVE ACCESS TO THE DIFFERENT EVALUATION SPECIALISTS THANK YOU. >> THANK YOU FOR SHARING THAT. I KNOW THAT YOU HAVE BEEN VERY ACTIVE IN ACTUALLY IMPLEMENTING THAT PROGRAM. >> SANCHEZ COLUMBUS, VALENCIA. ANY INDICATION OF ANY BREAST MILK TRANSMISSION IN FOLLOWING OF THESE BABIES? ANY TESTED NEGATIVE IN MOTHERS THAT ARE BREAST-FED? >> I DO NOT HAVE THAT INFORMATION. I DO KNOW I HAVE SEEN PATIENTS WHO ARE BREASTFEEDING WHO DEVELOP ACUTE ZIKA AND ACTUALLY -- >> THE MOTHER. >> YES, THE MOTHER WHO DEVELOP ACUTE ZIKA SO I RECOMMENDED THEM TO STOP BREASTFEEDING AND USE THE REPOSITORY OF MILK THEY HAD STORED. BUT I ASSUME FROM THE CASES REPORTED FROM THE FRENCH POLYNESIA EPIDEMIC, THEY WERE PCR POSITIVE AMONG WOMEN IN BREAST MILK SAMPLES. IT'S A MATTER OF TIME THAT WE DOCUMENT TRANSMISSION BY BREASTFEEDING. >> SO HOW LONG DO YOU TELL THEM TO DO YOU STOP BREASTFEEDING? >> THAT PATIENT WAS ACUTE ZIKA. SO THAT PATIENT I TOLD HER UNTIL YOU FEEL BETTER AND IT'S OVER, SHOULD YOU STOP THE BREASTFEEDING. BUT THEIR RECOMMENDATION RIGHT NOW IS FOR REST FEEDING TO CONTINUE BECAUSE WE DON'T KNOW. >> THANK YOU. >> HERNANDO, ACADEMY OF PEDIATRICS IN PUERTO RICO. I'M ADDRESSING THE ISSUE OF THE BABIES WHO ARE BORN AFTER BEING BORN IN THE NEONATAL PERIOD OR AFTERWARDS THAT DO TEST POSITIVE. THOSE THAT WERE CAUGHT PRIOR TO, BEING BORN, WILL HAVE THE SCREENING AND WILL GO TO THOSE CLINICS BUT IF A BABY IS NOW TESTED POSITIVE AND DOES NOT SHOW OVERT SYMPTOMS, WE WILL NOT DO THE EYE SCANS OR THE MRIs. THE SONOGRAM. SO, A LOT OF THINGS MUST COME TO REINFORCE THE BRAIN DOES CONTINUE GROWING AFTER BIRTH. SO THAT IS MY POINT. >> CITIZEN TORONTO THANK YOU FOR A WONDERFUL PRESENTATION. IN THE OBSTETRIC ULTRASOUNDS, ANY PLACENTAL ABNORMALITIES DETECTED IN THE AFFECTED BABIES? >> JUST ABNORMAL CALCIFICATIONS AND SMALLER BREAST -- WHO HAD IUGRs BUT NOT SPECIFIC LIKE IF YOU'RE LOOKING FOR LIKE CYSTS OR STUFF LIKE THAT, NONE THAT WERE REPORTED OR SEEN. >> THANK YOU. NICHD. YOU REPORTED OVER 50% OF THE EXPOSED CONFIRMED WOMEN HAD SYMPTOMS AND THAT'S HIGHER THAN WHAT IS TRADITIONALLY REPORTED. CAN YOU COMMENT ON THOSE SYMPTOMS? ASCERTAINMENT BECAUSE OF HEIGHTENED AWARENESS OR DO YOU THINK THERE ARE DIFFERENCES IN PREGNANT WOMEN AND THEIR SYMPTOMATOLOGY? >> THE WOMEN MOST OF THE WOMEN WHO HAD SYMPTOMS REPORTED RASH AND THE RASH IS VERY TYPICAL LIKE IF YOU PRESS YOU CAN BLANCH THE AREA WHEN YOU PRESS THE RASH. THE CONJUNCTIVITIS WAS NOT VERY COMMON, MUSCLE ACHES. BUT THE MOST COMMON SYMPTOM THEY REPORTED WAS RASH. REMEMBER THESE WOMEN WERE TESTED BECAUSE THEY WERE PREGNANT. AND SOME OF THEM WERE TESTED BECAUSE THEY HAD SYMPTOMS OR THEY DEVELOPED SYMPTOMS AFTERWARDS. BUT OTHERWISE THEY WOULDN'T HAVE NOT BEEN IDENTIFIED. MOST OF THEM, I CAN TELL YOU IN THE EARLY MONTHS OF THE EPIDEMIC, MAYBE FROM FEBRUARY TO MAY, MAYBE JUNE, MOST OF THE WOMEN OR ALMOST 100% WENT TO AN EMERGENCY ROOM WITH THE RASH AND THEY WERE TOLD THEY HAD AN ALLERGIC REACTION AND GIVEN BENADRYL. >> FROM NICHD. YOU MADE A VERY INTERESTING POINT THAT BEFORE 8 WEEKS OF PREGNANCY THERE SEEMS TO BE SOME PROTECTION AND WHEREAS EARLIER PLACENTA SEEMS TO LET THE VIRUS GO IN AND LATER PLACENTA DOESN'T SEEM TO BE DOING THAT MUCH IN TERMS OF -- SEEMS TO PROTECT. ARE THERE ANY MECHANISTIC EXPLANATIONS AS TO HOW THIS IS DONE? WHY DOES EARLY PLACENTA LET IT GO AND EVEN BEFORE NO PLACENTA THERE SEEMS TO BE SOME SORT OF PROTECTION? >> PLACENTA, MY UNDERSTANDING IS PLACENTA FORMS AFTER 5-6 WEEKS AND SO BEFORE THAT, YOU HAVE -UE MIGHT HAVE FEELS NUTRITION AND CIRCULATION BUT NOT A STRUCTURE PLACENTA WITH ALL THE. [ INDISCERNIBLE ] ALL THESE CELL LAYIERS THAT ARE VULNERABLE TO THE ZIKA INFECTION. SO MAYBE THIS IS WHY THERE IS SOME RELATIVE -- WE DON'T KNOW. THAT IS MY -- IT'S BEEN SUGGESTED BY THE CLINICAL FINDINGS. SO, MAYBE THERE IS SOME SORT OF PROTECTION BECAUSE THERE IS NOT ENOUGH CELLS OR LAYERS OR TISSUES THAT ARE PLACENTAL TISSUES THAT ARE TARGET FOR THE INFECTION. THANK YOU. >> ROBERTA FROM CHILDREN'S NATIONAL. JUST TO FOLLOW-UP ON THAT POINT. IT COULD ALSO BE THAT IT IS NOT PLACENTA RELATED BUT RELATED TO THE SUSCEPTIBILITY OF THE PARTICULAR NEUROCELLS AT DIFFERENT STAGES OF DEVELOPMENT. SO THE CASE WE REPORTED IN THE JOURNAL WE ARE LOOKING AT THAT CAREFULLY AND THERE IS SOME SUGGESTION OF CERTAIN STAGES OF DIFFERENTIATION ARE AFFECTED AND OTHERS ARE NOT. SO THAT MAY ALSO BE AN EXPLANATION. >> THAT IS A GREAT POINT. THANK YOU. >> HACK HACK ANY OTHER NAHIDA CHAKTOURA: THANK YOU. WE'LL TAKE OUR BREAK NOW AND WE'LL LOAD UP DR. MANUEL VINHATIERO'S SLIDES. >>> WE ARE GOING TO GET STARTED FOR THIS SESSION. WOB MORE HOUSEKEEPING ITEM. SO FOR THE PEOPLE WHO CAME AND PARKED, PLEASE TAKE YOUR PARKING TICKET TO THE REGISTRATION DESK AND THEY'LL BE ABLE TO VALIDATE FOR YOU. DR. VANESSA VAN der LINDEN. >> A LIPPED LIND: I'D LIKE TO THANK AGAIN THE INVITATION TO BE HERE AND TALK A LITTLE ABOUT MY -- >> VANESSA VAN der LINDEN I WORK IN TWO DIFFERENT HOSPITALS, THE REHABILITATION CENTER AND HOSPITAL WITH MATERNITY WHERE THE FIRST PATIENTS. AND I AM PRESENT MAIN FIND IS IN NEUROLOGICAL PART OF THE DISEASE. AND THIS IS IMPORTANT TO SAY MICROSELFY IS ONLY TOP OF THE ICEBERG. IT'S ONLY THE THING WE SEE WHEN THE BABY IS BIRTH OF THE BUT WE HAVE MUCH MORE THAN MICROCEPHALY INCLUDING PATIENTS -- [ INDISCERNIBLE ] IN MY CITY, WAS THE FIRST CITY THAT NOT TRY TO UNDERSTAND THIS DISEASE. WE HAVE DIFFERENT CUT OFF OF TO THE GOVERNMENT, THE PATIENTS WITH MICROCEPHALY. THE FIRST CUT OFF IS 3 SEPTEMBER MINORITIES. BECAUSE OF THAT WE HAVE -- [ INDISCERNIBLE ] AND THEN WE HAVE DIFFERENT SENSITIVITY IN SPECIFIC -- WHEN WE -- THE CUT OFF. NOW WE ARE USING THIS CUT OFF PUBLISH ASSESSMENT IN PATIENTS WITH ZIKA VIRUS AND IT IS IMPORTANT TO SAY THAT THEY PUT ALSO OUT OF PROPORTION BECAUSE WE HAVE SOME PATIENTS WITHOUT MICROCEPHALY -- [ INDISCERNIBLE ] AT BIRTH. THIS IS MY CITY. MY STATE AND NOW WE HAVE ONE89 PATIENTS WITH ZIKA, CONGENITAL ZIKA SYNDROME. THIS PHOTO OF PATIENTS WE HAVE THREE PATIENTS WITH YMV AND SOME PATIENTS -- CMZ, BECAUSE WE NEED TO EXCLUDE THE OTHER INFECTIONS AND ALSO DID PCR IN IGM FOR ZIKA IN CSF SO WE HAVE 106 PATIENTS POSITIVE FOR ZIKA VIRUS AND ALL THE PATIENTS HAVE PICTURES OF CONGENITAL INFECTIONS BRAIN MRI OR CT SCAN ABNORMAL CALCIFICATION OR ABNORMAL BRAIN DEVELOPMENT BUT ONLY 106 PATIENTS WITH IGM POSITIVE. THIS PATIENTS WITH IGM POSITIVE, ALSO TWO THAT ARE POSITIVE FOR ZIKA VIRUS AND PCR-CMV. WE HAVE THIS NUMBER OF PATIENTS THAT WAS DIAGNOSED BEFORE THE BIRTH DURING THE PREGNANCY BUT TWO PATIENTS WITH ULTRASOUND BUT ONLY 11 BEFORE TWO WEEKS OF PREGNANCY. MOST BETWEEN 7 AND 8 MONTHS OR 18 MONTHS OF PREGNANCY. THIS NUMBER OF PATIENTS MOTHER REPORTED SOME RASH DURING PREGNANCY SO IT IS IMPORTANT BECAUSE OF THAT WE THINK IN THE VALUES IN THE BEGINNING. AND MOST OF THE PATIENTS ARE APPROPRIATE FOR GESTATIONAL AGE. WE HAVE PATIENTS WITH NORMAL HEAD CIRCUMFERENCE AT BIRTH BETWEEN 2-3 STANDARD DEVIATION AND BELOW 3 STANDARD DEVIATION MORE FREQUENT. SO I WILL TALK ABOUT THIS IS THE FIND IN PATIENTS WITH CONGENITAL ZIKA VIRUS. I'M TALKING ABOUT THIS FIND. THE FIRST SIGN, THE FIRST THING THAT WE SEE DIFFERENT IN PATIENTS IS BECAUSE PRESENT SPECIAL SIGNS LIKE DISPROPORTION BUT YOU SEE CONGENITAL INFECTIONS AND ALSO THE PRESENT HEAD AND SCALP SKIN LIKE THIS. SOMETIMES IT LOOKS LIKE A. [ INDISCERNIBLE ] BUT THEN THEY ARE GROWN AND IT DISAPPEAR AND THEY HAVE ALSO. [ INDISCERNIBLE ] THIS PART OF SIGNS WAS DESCRIBED IN 1984 AND THIS HAPPENED PROBABLY BECAUSE OF DESTRUCTION OF THE BRAIN DURING SECOND TRIMESTER OF THE PREGNANCY. AND THERE IS. [ INDISCERNIBLE ] IN THE COLLAPSE OF THE SKULL. AND HAVE YOU THIS PAPER THAT SHOW A PATIENT WITH CONGENITAL INFECTIONS SIMILAR WITH PATIENTS WITH CONGENITAL ZIKA SYNDROME. IN THE BEGINNING, THE FIRST THING THAT WE SEE IN THESE PATIENTS IS THEY ARE VERY DATED -- HYPEREXCITABILITY LIKE STARTLED OR SPASMS. DIFFICULT TO DIFFERENTIATE BETWEEN SEIZURES AND ONLY SPASMS AND THEY ARE VERY IRRITATED. MOST OR HALF OF PATIENTS HAVE SOME KIND OF IRRITABILITY IN THE FIRST MONTHS OF AGE. THIS IS THE FIRST DAYS OF LIFE AND FIRST WEEK. DIFFICULT TO DIFFERENTIATE BETWEEN SEIZURES AND HYPEREXCITABILITY. AND SOME PATIENTS EVEN JUST AFTER BIRTH, SOME KIND OF HYPEREXCITE BUILTY AND THEY CRY A LOT. SOMETIMES THEY CRY MORE THAN 24-HOURS A DAY. IT'S DIFFICULT BECAUSE THE MOTHER CAN'T SUPPORT THIS. THE OTHER THING THAT YOU SEE IN DIFFERENT FOR OTHER CONGENITAL INFECTIONS OR OTHER SEVERE ENCEPHALOPATHY, THEY HAVE HYPER-- THEY ARE VERY HYPERTONIC DURING THE FIRST WEEK OR FIRST MONTHS OF AGE. USUALLY PATIENTS WITH SEVERE ENCEPHALOPATHY IN THE BEGINNING THEY ARE MORE HYPERTONIC THAN HYPERTONIC BUT THE PATIENTS HAVE ONLY 10 DAYS OF LIFE AND YOU SEE WE. [ INDISCERNIBLE ] SIGNS LIKE HISTONIA BUT VERY EARLY THAN USUAL. THIS PATIENT ONLY HAS TWO MONTHS OF AGE AND DID NOT USUAL TO SEE THIS IN PATIENTS WITH SEVERE IN SELF OPY THAT. WE HAVE ALSO PATIENTS WITH -- SIGNS AND PATIENTS AT BIRTH -- HYPEREXTENSION OF THE LIMBS. SO IN THE BEGINNING WE DON'T UNDERSTAND WHY THIS BABY CRY A LOT AND AFTER SOME MONTHS WITH TREATMENT WE UNDERSTAND THAT PROBABLY THERE IS A COMBINATION OF THESE THREE FACTORS, REFLUX, EPILEPSY, HYPEREXCITABILITY THESE BABIES DON'T SUPPORT THIS POSITION WHEN YOU PUT THIS PATIENT IN SUPINE POSITION THEY START WITH START TO CRY AND BUT SOME PATIENTS TREAT AND NO IMPROVE AND SOME PATIENTS ONLY IMPROVE AFTER TREATED EPILEPSY. SO WE DON'T HAVE -- IN MY CITY BUT PROBABLY IF WE PROCEED -- [ INDISCERNIBLE ] WE WILL SEE MOST PATIENTS HAVE MAYBE HAVE SEIZE YOURS EARLY. BUT MOST OF THEM INCLUDING PATIENTS IN WE HAVE NO SUCCESS WITH THE TREATMENT IN THE BEGINNING, THEY IMPROVE EXCITABILITY AFTER 3-5 MONTHS OF AGE. PROBABLY HYPEREXCITABILITY IS VERY IMPORTANT TO THIS -- SOMETIMES WHEN WE START THE MEDICATION FOR REFLUX THIS BABY HE START WITH ADEANA NO RESULT AND THEN WE START REFLUX -- [ INDISCERNIBLE ] AND HE IMPROVE A LOT AFTER OM EPRA ZOL. SO SEE VERY HAPPY WITH THIS RESULT. AND A LOT THINK THAT IS VERY IMPORTANT THEY HAVE VERY PRIMITIVE REFLEX. THIS BABY IS ONLY FEW DAYS OF LIFE IN THE MATERNITY AND WHEN WE HOLD HER LEGS HE IS ABLE TO SIT WITHOUT SUPPORT. ONLY USING THE PRIMITIVE REFLEX AND IT'S NOT NORMAL. SOMETIMES THE MOTHER THINK THAT IS IT GOOD BECAUSE MY BABY IS ABLE TO SIT BUT IT'S NOT GOOD. AND THEY HAVE THIS KIND OF -- WITH NECK REFLEX. AND SOME BABIES IS ABLE TO CRAWL ONLY USING PRIMITIVE REFLEX. IT'S NOT SO -- SOME PARENTS ASK IF THE BABY IS VERY GOOD BECAUSE HE HAS ONLY TWO MONTHS OF AGE AND HE IS ABLE TO CRAWL. BUT IT'S NOT GOOD. ANOTHER FACTOR IS A LOT OF MAIN FIND IS WE FIND IN THESE PATIENTS EPILEPSY. MOST OF THE PATIENTS STARTING IN THE BEGINNING BUT NOW AFTER THE BABY HAS NO EPILEPSY IN THE BEGINNING. AFTER 4-5 MONTHS OF AGE THEY START WITH THIS KIND OF SEIZURES. THEY CRY A LOT IN BETWEEN CRYING THEY PRESENT SOME KIND OF SEIZURES. SO IT IS DIFFICULT TO FIND SOMETIMES THESE KIND OF SEIZURES. HE MAKE THIS KIND OF MOVEMENT LIKE REFLEX, THIS IS THE PATTERN OF THE EGF PATIENTS SHOWING UP MULTIPLE DISCHARGE BUT MOST OF THE PATIENTS PRESENT SPATMS AND THEY CRY A LOT. SO THERE IS SOME PATIENTS THAT DIDN'T CRY IN THE BEGINNING BUT WHEN THEY START WITH SEIZURES RESORT TO CRYING A LOT AND MOST OF THE PATIENTS THE MOTHER DURING SLEEPING THEY WAKE UP, MAKE SOME KIND OF SPASMS AND THEN CRY A LOT. AFTER WE TREAT THIS KIND OF -- WE STARTED MEDICATION ON SOME PATIENTS, THIS DISAPPEAR THIS PATTERN OF SPASM IN CLUSTERS AND YOU CAN SEE THAT THE SEIZURES. SOMETIMES DIFFICULT TO UNDERSTAND SEIZURES OR ONLY HYPEREXCITABILITY LIKE THIS BABY. THIS ABNORMAL MOVEMENT. BUT WHEN WE HOLD HER LIMBINGS SHE STOP THE MOVEMENT. SO PROBABLY NOT SEIZURES BUT DIFFICULT AND SOMETIMES I THINK THAT IT IS BETTER TO UNDERSTAND THESE SYMPTOMS. WE PROCEEDED EEG IN SOME PATIENTS I BRING HERE 67 PATIENTS. IN THE GIPPING WE HAVE ONLY 95 PATIENTS WITH IGM POSITIVE SO ALL OF THESE PATIENTS IGM POSITIVE FOR ZIKA VIRUS AND YOU SEE ONLY ONE CHILD -- SO THEY LOOK LIKE SYNDROME, THE SAME SIGN LIKE SPASMS IN CLUSTERS BUT EEG, I DON'T KNOW IF YOU GO AND EVALUATE -- BUT MOST PRESENT WITH -- DISCHARGE OR FOCAL DISCHARGE ESPECIALLY IN FRONTAL LOBE. WE HAVE MANY PATIENTS ONLY WITH LOW ACTIVITY, LOW BACKGROUND ACTIVITY. ANOTHER PROBLEM WITH THIS BABY IS DISPHASIA ESPECIALLY NOW. IN THE BEGINNING WE SOMETIMES DON'T USE THE BRAIN TO COORDINATE IN THE BEGINNING ONLY REFLECTS SO IN THE GIPPING NOT SO BIG PROBLEMS ONLY MOST SEVERE PATIENTS BUT NOW AFTER 4-5 MONTHS OF AGE, THEY START WITH THIS PROBLEM AND NOW I THINK THAT IS MEMBERSHIP PROBLEM IN MY PATIENTS. MORE THAN -- THAT IS MAIN PROBLEM IN PATIENTS. SOME SIGN OF DISPHASIA AND 21 PATIENTS SEIZ DISPHASIA WITH RESPIRATORY PROBLEMS AND HAVE MANY PATIENTS IN HOSPITAL THAT GO WITH DIAGNOSIS OF OTHER RESPIRATORY PROBLEMS -- [ INDISCERNIBLE ] WE HAVE SOME EXAMS TO PROCEED ESPECIALLY ENDOSCOPY OF SWALLOW AND WE HAVE MANY PROBLEMS WITH ZOO END SCOPEY IN THIS PATIENT BUT THEY CRY A LOT AND IT'S NOT SO EASY TO UNDERSTAND AND INTERPRET THE RESULTS SO WE PREFER TO USE A GROUP OF GASTROINTERPEDIATRICS THAT TRY TO ANALYZE THIS DATA. WE ANALYZE PATIENTS WE FIND POSITIVE WITH THIS ANALYSIS AND WE TRY TO UNDERSTAND THE BETTER WAY TO EVOLUTION THESE PATIENTS. ANOTHER GASTROTESTINAL DISORDERS, MOST OF THE PATIENTS PRESENT CONSTIPATION AND ALSO THEY HAVE DELAY OR IMPAIRED GASTROEMPACY. WE HAVE PATIENTS WE DID GASTRIC EMPTY AND SEE VERY LOW EMPTY OF THE GASTRIC. WE TRY TO UNDERSTAND BETTER THIS. THEY IMPROVE A LITTLE WITH AGENT BUT WE DON'T KNOW IF WE HAVE SOME PATIENTS ESPECIALLY PATIENTS WITH -- THAT MAYBE CAN HAVE SOME KIND OF AUTONOMY. WE TRY TO UNDERSTAND THIS. WE ARE PRO SEED SPECTRUM ANALYSIS OF THE HEART VIABILITY BUT WE ARE ANALYZING YET THIS DATA TO UNDERSTAND THE AUTONOMY COULD CAUSE THIS KIND OF SYMPTOM BECAUSE IT'S VERY FREQUENT. PATIENTS SOMETIMES IS ABLE TO EAT ONLY 30 MILLIMETERS OF MILK, VERY SMALL TO EAT. AND I THINK THAT IN THE BEGINNING THE MOST PREVALENT SIGNS IN PATIENTS IS THE BRAIN AGE. WE HAVE SOME PAPER THAT PUT MAIN FIND IN THE PATIENTS WITH MICROCEPHALY SO SPECIAL -- MAIN FIND IS IN THESE PATIENTS IS CALCIFICATIONS IN CORTICAL OR SUB-CORTICAL, ESPECIALLY IN TRANSITION BETWEEN LIKE MATTER. SOMETIMES THEY DELINEATE ALL THIS AREA. SOME PATIENTS MORE SEVERE AND OTHER LESS. BUT WE HAVE ALSO MANY PATIENTS CORTICAL DEVELOP AND SOMETIMES THE PATIENT HAVE ONLY A FEW CALCIFICATIONS BUT VERY SEVERE MALFORMATION OF CORTICAL DEVELOPMENT. THIS IS NORMAL SO WE CAN COMPARE. WE HAVE NOT ALL PATIENTS BUT WE HAVE SOME PATIENTS WITH ABNORMALLY BRAINSTEM INCLUDING CALCIFICATION IN BRAINSTEM. WE HAVE SOME PATIENTS WITH CEREBELLUM AND BRAINSTEM -- INCLUDING TWO PATIENTS WITH MALFORMATION. THE BRAIN MRI WE CAN SEE MORE DETAIL THE ABNORMAL BRAIN DEVELOPMENT INCLUDING THE CEREBELLUM -- AND ABNORMAL PATTERN -- IS MOST BRAIN FIND IN THESE PATIENT. WE HAVE ONE PATIENT, ONLY ONE PATIENT WITH PATTERN SIMILAR TO IN SELFIE. WE HAVE TWO PATIENTS WITH NO CALCIFICATIONS. I THINK TO PROVE THAT IT IS WITH IGM POSITIVE, I THINK MAYBE IT WILL BE NECESSARY TO PROCEED WITH EXAMS TO FIND GENES THAT CAUSALS POLYMICROGEIA. BUT WE HAVE TWO PATIENTS W. WITHOUT CLAMSIFICATION WITH MICROCEPHALY, AND IGM POSITIVE AND ABNORMAL PATTERN OF BRAIN DEVELOPMENT. ONLY ONE PATIENT WITH CALCIFICATION WITH ABNORMAL BRAIN DEVELOPMENT. MRI IS NORMAL ONLY WITH CALCIFICATION IN HIGH -- [ INDISCERNIBLE ] CHARACTERISTIC AREAS LIKE WE SEE IN CMV -- CYSTIC -- NOT USUALLY IN PATIENTS WITH ZIKA VIRUS, INTERFERE MORE WITH THE DEVELOPMENT OF THE BRAIN AND NOT WITH THE BRAIN TISSUE. BUT WE HAVE SOME PATIENTS THAT PRESENT THIS AREA WITH IGM POSITIVE. BUT WE HAVE ALSO MILD CASES, CASES THAT SIMILAR PATTERN OF BRAIN AGE BUT SIMILAR BUT DIFFERENT, LESS SEVERE. WE HAVE 12 PATIENTS WITH IGM POSITIVE AND HEAD CIRCUMFERENCE NORMAL AT BIRTHDAY. ONE OF THESE PATIENTS IS POSITIVE ALSO FOR CMV, PCR. SO THIS IS FOUR PATIENTS AND SO WE CAN SEE THAT SOME OF THESE PATIENTS HAVE DISPROPORTION EVEN WITH NORMAL HEAD CIRCUMFERENCE BUT WE HAVE ANOTHER PATIENTS WITHOUT DISPROPORTION. THIS FOUR PATIENTS THEY PRESENT MICROCEPHALY. AT BIRTH THEY ARE NORMAL. HEAD CIRCUMFERENCE WERE NORMAL BUT NOW THEY HAVE MICROCEPHALY. WE HAVE ONLY -- THESE PATIENTS WITH NORMAL HEAD CIRCUMFERENCE AT BIRTH, WE HAVE ONLY ONE WITH SEVERE FINDS. WE DON'T HAVE THE MRI FOR THESE PATIENTS. 9 OTHER PATIENTS THAT IS THE SAME PATTERN MALFORMATION OF CORTICAL DEVELOPMENT, ESPECIALLY IN FRONTAL AREA. WITH CALCIFICATIONS AND ESPECIALLY IN CONJUNCTION WITH THE TWAINSITION BETWEEN WHITE MATTER. ESPECIALLY IN HIGH CORTICAL -- BUT THERE ARE SOME PATIENTS THAT THEY BORN WITH NORMAL -- THEY HAVE NORMAL HEAD CIRCUMFERENCE AT BIRTH BUT THEY DROP IN PERCENTILE. IN SOME PATIENTS WE DIAGNOSIS BECAUSE THEY ARE NOT IN OUR CUT OFF IN THE BEGINNING. WE HAVE SOME PATIENTS BETWEEN 32-33 BUT WE HAVE 5 PATIENTS THAT WERE IN OUR CENTER -- REFERRED TO OUR CENTER THAT THEY WERE NOT NOTIFIED BY THE PROTOCOL GOVERNMENT BUT THE PEDE TRISHIAN NOTES THE PATIENTS PRESENTED NEAR DEVELOPMENT LATE AND THEN PEDE TRISHIAN WE DID THE BRAIN ANAL, SAME PATTERN OF THE OTHER PATIENTS. WE HAVE ONLY ONE WE TESTED FOR ZIKA. THE OTHER LAST WEEK BECAUSE IT HAPPENED IN TWO WEEKS THIS MONTH. AND WE ARE WAITING FOR THE RESULT FOR IGM FOR ZIKA. BUT THIS PATIENT EXCLUDED OTHER CONGENITAL INFECTIONS. THIS IS ONE OF THE PATIENTS. THIS PATIENT WAS REFERRED BY GOVERNMENT PROTOCOL AND HAD CIRCUMFERENCE BETWEEN 32-33. AND MOST OF THE PATIENTS THEY HAVE LIKE CEREBRAL -- NO SIGNS. THEY HAVE MOTOR DISABILITY THAN A COGNITIVE DISABILITY BUT THEY HAVE ONLY -- THEY ARE VERY YOUNG AND DIFFICULT TO NAME THAT STABLING. WE ANALYZE THE COGNITIVE AND THIS OTHER PATIENT THE SAME. HE HAS ONLY LEFT PARALYSIS. THIS BABY WAS BORN WITH 32 HEAD CIRCUMFERENCE. AND THIS OTHER PATIENTS THEY WERE REFERRED TO US AFTER 5 MONTHS OF AGE BECAUSE THEY DEVELOP DELAY IN THEIR DEVELOPMENT. AND THEY WERE BORN WITH NORMAL HEAD CIRCUMFERENCE AND THEN -- [ INDISCERNIBLE ] THIS PATIENT IS POSITIVE FOR IGM, BUT WITH 5 MONTHS OF AGE BUT WE EXCLUDED ALL OTHER INFECTIONS. THE PATTERN IS SIMILAR WITH MALFORMATION OF BRAIN DEVELOPMENT, CORTICAL MICRO-- ESPECIALLY IN FRONTAL AND WILL. [ INDISCERNIBLE ] AND THIS OTHER PATIENT HE HAS DIFFICULT ONLY WITH THIS HAND AND A LITTLE HYPERTONIC IN THE LOWER LIMBS. BUT SHE IS ABLE TO CRAWL AND TO SIT DOWN AND IS ABLE TO USE IT WELL THE LEFT HAND BUT NOT THE RIGHT HAND. I DON'T HAVE THE MRI BECAUSE THIS PATIENT I SAW TWO WEEK AGO BUT THE CT SCAN IS SIMILAR WITH THE OTHER PATIENTS. WE ARE WAITING FOR IGM. WE HAVE ALSO A PATIENTS THAT I WORK TOGETHER WITH NEUROAUDIOLOGIST AND THE SHE RECEIVE PATIENTS ANALYZE TO MRI AND WHEN SHE ANALYZE THE MRI, SHE SAW THIS CALCIFICATION WITH THIS PATTERN OF BRAIN DEVELOPMENT. AND NOW THIS BABY HAS ALMOST ONE YEAR. THE MOTHER HAD RASH IN THE FIRST -- IN THE SECOND MONTHS OF PREGNANCY. WE ARE WAITING FOR -- SHE COLLECTED CSF WAS NEGATIVE FOR OTHER CONGENITAL INFECTIONS AND DURING PREGNANCY DID ALL THE EXAMS FOR CONGENNATIVE INFECTIONS AND IT WAS NORMAL. BUT WE ARE WAITING FOR IGM. SO WE NEEDED TO PAY ATTENTION AND TO THINK THAT SOME PATIENTS IN EP DICKIC AREAS WITH NO DEVELOPMENT DELAY -- EPIDEMIC AREAS. WE NEED TO THINK ABOUT ZIKA AND FIND THIS KIND OF PATTERN IN MRI. SO THIS PATIENT THAT IS IS LESS SEVERE WE SEE MORE. [ INDISCERNIBLE ] YOU SEE PATTERN OF MOUTH. TYPICAL WITH PATIENTS WITH. [ INDISCERNIBLE ] AND WE TRY TO USE BOT LUMTOXIN FOR TYPE A. WE HAVE A LITTLE USING TOXIN IN BABY BUT WE HAVE THIS PAPER THAT HE USE IT IN THE FIRST YEARS OF LIFE AND YOU HAVE A GOOD RESULT. WE DID IT I THINK AROUND MORE THAN 10 PATIENTS WITH A GOOD RESULT BECAUSE THEY HAVE HYPERTONIA OF THE LEGS AND THEY SOME PATIENTS DEVELOP HIP DYSPLASIA AND WE NEED TO TREAT THIS BECAUSE IN THE FUTURE, IT IS NOT GOOD FOR THE BABY. SO THIS BABY -- HE IS DISTONIC. HE IS NOT ABLE TO SIT. AND THIS IS -- [ INDISCERNIBLE ] AND HE WORK WITH BOT YOU LIN YUM. SO BEFORE THE TOX IN. AND AFTER TOXIN, THIS IS THE -- HE IS THE PHYSICAL THERAPIST. SHE SAID THAT HE IMPROVE A LOT. EXDEVELOP OTHER PROBLEMS. THEN AFTER THE TOXIN HE IS ABLE TO SIT AND THEN HIS PHYSICAL THERAPIST COULD IMPROVE HIS TREATMENT IN PHYSICAL THERAPY INCLUDING TO STAND MORE. AND ANOTHER FIND IS HYDROSELFIE. WE HAD TWO PATIENTS NOW 3. BUT TWO THAT DEVELOP HYDROSELFIE AFTER TREE-4 MONTHS OF AGE. THEY INCREASE THEIR HEAD CIRCUMFERENCE AND THIS IS THE CT SCAN OF ONE OF THESE PATIENTS. WE NOTE THEY HAVE HIGH. [ INDISCERNIBLE ] AND IT'S NOT POSSIBLE TO SEE HERE BUT VERY THICK. AND THIS IS THE BRAIN AGE AFTER VENTRICAL SHUNT. BOTH PATIENTS WERE DEVELOP IGM WITH 4 MONTHS OF AGE. WE COLLECTED SAMPLE. BUT WE HAVE ALSO MORE 5 PATIENTS IN STARTED WITH INCREASE HEAD CIRCUMFERENCE WITHOUT SYMPTOMS BUT THEY APPEAR THE HEAD FINE. THE MOTHER SAID THE DOCTOR I THINK THAT IS DIFFERENT BECAUSE MY CHILD LOOKS LIKE MICROCEPHALY BEFORE SO IT'S NOT GOOD WHEN WE DID THE MRI. YOU SEE IN THE FIRST MONTHS OF LIFE WITH 7 MONTHS OF LIFE. BUT THEN WE DECIDED TO ONLY OBSERVE AND AFTER ONE MONTH WE REPEAT THE MRI AND SHE IS STABLE. THE HEAD CIRCUMFERENCE IS STABLE. THEN SHE IS OKAY WITHOUT SYMPTOMS. THE SAME WITH THESE PATIENTS. NOTICE THE APPEARANCE OF THIS SKULL IS DIFFERENT. THE HEAD IS DIFFERENT. NOT LIKE THE PATIENT WITH MICROCEPHALY. SO SHE WAS BORN WITH HEAD CIRCUMFERENCE -- THIS IS CT SCAN IN THE FIRST MONTHS OF LIFE HERE WITH 8 MOTION OF LIFE. AND SHE IS A STABLE TOO. -- 8 MONTHS OF LIFE. IT'S LIKE THEY INCREASE AND THEN STABLE. AND THIS IS ANOTHER PATIENTS. THE MOTHER, THIS PATIENT I SAW IN THE ACUTE PHASE. HYPERTONIC. SHE STAY VERY -- CRY A LOT AND WHEN WE DID MRI, WE DIAGNOSIS HYDROSELFIE BUT AFTER ONE WEEK, SHE IS WELL. SO WE ARE CONTINUING TO EVALUATE THESE PATIENTS AND SHE DIDN'T DWELVE HYDROSEF ELLIE MORE THAN THAT. IQM POSITIVE FOR ZIKA MICROCEPHALY AND HIS CT SCAN HAS ALSO HIP DYSPLASIA. AND LAST MONDAY I SAW THIS PATIENT AND THE FRONTAL INCREASE, BECAUSE IT WAS CLOSED BEFORE AND THERE IS LACK BETWEEN THE BONES, AND THE HEAD CIRCUMFERENCE INCREASED 2 1/2 CENTER METERS IN ONLY TWO WEEKS. AND WE DID -- I DON'T HAVE THE EXAM. SOMEONE SEND ME A ZOO. -- A VIDEO. NOW HE IS 10 MONTHS OF AGE. I RECEIVE THE NEUROSURGERY HE UNDERWENT A SHUNT THIS MORNING TWO HOURS AGO AND NOW HE IS WELL. IF YOU COMPARE WITH THE EXAM, HE IS NOT SO SEVERE LIKE THE OTHER PATIENTS IN DEVELOP HYDROCEPHALY. SO IT IS IMPORTANT TO FOLLOW-UP THE HEAD CIRCUMFERENCE LINE AND IF THE HEAD CIRCUMFERENCE IS INCREASED, WE NEED TO CARE. SO WE HAVE THREE PATIENTS THAT WITH SHUNT INDICATION. ALL IGM POSITIVE. WE COLLECT THE SAMPLE, I HOPE THAT THEY COLLECT THE SAMPLE BECAUSE THE SURGERY WAS TODAY. THIS MORNING. AND TO TRY TO -- BECAUSE IN THE FIRST TWO PATIENTS WE ANALYZE ONLY IGM BECAUSE THE NEUROSURGEON PUT THE SAMPLE OF CSF IN THE FREEZER AND WE COULDN'T ANALYZE THE PCR BUT THESE PATIENTS WE ARE GOING TO TRY TO ANALYZE PCR AND IGM NOW AT 10 MONTHS AGE. WE HAVE ALSO TWIN PREGNANCY. IN MY CENTER WE HAVE THREE TWIN -- ONLY ONE AFFECTED AND ANOTHER ONE NORMAL. TWO OF THEM HAVE THE AFFECTED BABY HAVE IGM POSITIVE AND THE NORMAL HAVE IGM NEGATIVE. THE OTHER ONE, THE DIAGNOSIS WAS AFTER 7 MONTHS OF AGE. SO WE DON'T HAVE THE CSF FROM THE BEGINNING. AND YOU CAN SEE THE DIFFERENCE BETWEEN THEM. I ANALYZE THESE PATIENTS WITH ONE YEARS OF AGE AND SHE TOTALLY NORMAL. HE HAS ALSO HIP DYSPLASIA AND HE UNDERWENT A SURGERY AND NOW HE IS OKAY. FROM IS HIS CT SCAN AND HE HAS ALSO HEARING LOSS AND GLAUCOMA. HE IS A SURGERY OF GLAUCOMA AT 3 MONTHS OF AGE. EPILEPSY CONTROL. HIP DYSPLASIA AND CLUBFOOT. HE UNDERWENT SURGERY FOR HIP DYSPLASIA AND CLUBFOOT. SO WE NEEDED TO WAIT A LITTLE ESPECIALLY FOR THE NEW CASES THAT ARE ARRIVING NOW WITH THE PATIENTS THAT WAS NOT DIAGNOSED WITH MICROCEPHALY AT BIRTH BUT EVEN THE PATIENTS WITH MICROCEPHALY AT BIRTH DIFFICULT TO ANALYZE THE NEUROLOGICAL FINDS BECAUSE WE NEED THE CENTRAL NERVOUS SYSTEM TO UNDERSTAND BETTER HOW THEY ARE GOING TO EVALUATE. WE HAVE A GROUP -- WE ONLY HAVE ONE CENTER WE CAN DO EVERYTHING AND THEN WE HAVE A BIG GROUP WITH DIFFERENT PLACE THAT ARE HELPING TO UNDERSTAND BETTER THIS DISEASE INCLUDING CAMILLA THAT SHE IS HERE. AND THANK YOU. [ APPLAUSE ] >> SO DR. VAN DERLYNDEN IS OPEN FOR QUESTIONS. AS EVERYBODY IS COMING UP, HOW DO YOU KNOW THAT SOME OF THE INFANTS THAT WERE DIAGNOSED WITH PROBLEMS LIKE AT 5 MONTHS, 10 MONTHS AND 11 MONTHS, THAT THESE WERE NOT INFECTED POSTNATALLY AS OPPOSED TO IN UTERO? YOU DON'T HAVE THE INFORMATION ON THE MOTHERS, CORRECT? >> YES, BUT THE PATTERN OF MRI WHEN WE SEE DISORDER OF CORTICAL DEVELOPMENT YOU KNOW THE PROBLEM WAS BEFORE. MOST OF THE PATIENT -- I HAVE ONLY ONE PATIENT THAT WAS DIAGNOSED AT BIRTH WITHOUT A NORMAL PATTERN OF BRAIN DEVELOPMENT. SO ALSO EVEN THE PATIENT WE HAVE -- PRESEN T HAVE NORMAL CORTICAL DEVELOP SO WE KNOW THE PROBLEM WAS BEFORE DEVELOPMENT, AFTER BIRTH. >> THANK YOU. >> SO VERY NICE JOB VANESSA AND YOU'RE SITTING IN THE WRONG SEAT. YOU'RE CARMEN. SO, MY QUESTION RELATES TO THE INFANTS THAT YOU IDENTIFIED WITH THIS MOTILITY, GASTROINTESTINAL MOTILITY AND I AM WANDERING IF ANYBODY CONSIDERED A BOPS TOW LOOK AT THE PATHOLOGY AND WHAT MIGHT BE THERE IN TERMS OF THE NERVOUS SYSTEM AUTONOMICS AS YOU WERE ALLUDING TO AND WHAT THESE EFFECTS ARE. LIKELY THEY ARE SYSTEMIC AS WE PROBABLY ARE DEALING WITH THE VIRUS DOING THE SAME THINGS HERE AS IN THE CENTRAL NERVOUS SYSTEM. WONDERED IF THAT HAD HAPPENED? >> YES, WE TRIED TO ANALYZE THE FINDS BECAUSE ESPECIALLY THE PATIENTS THAT WE KNOW THAT WE ARE TALKING TOMORROW ABOUT ADD I POSE? BUT THE PATIENTS ARE ABNORMALLY IN SPINE. SO WE FIND ANOTHER ABNORMAL BUT I'LL TALK ONLY TOMORROW ABOUT THIS. AND WE HAVE OTHER NEUROLOGICAL DISEASE. GASTROPROBLEMS AND KNOW THAT IS IT BECAUSE OF THE -- IS SO FIRST WE TRY TO ANALYZE THE OUGHT NO NOMIC SYSTEM AND TRY TO UNDERSTAND THIS BUT PROBABLY I THINK THAT IS CORRELATED, CASTRO INTESTINAL PROBLEMS ARE CORRELATED WITH NEUROLOGIC PROBLEMS. >> THANK YOU VERY MUCH FOR A WONDERFUL PRESENTATION. I HAVE A BUNCH OF QUESTIONS BUT I'M GOING TO JUST START WITH ONE ON TWINS. YOU MENTIONED IF I HEARD CORRECTLY, THAT IN THE THREE SET OF TWINS, ONLY ONE WAS AFFECTED. HAVE YOU THOUGHT ABOUT WHY WHEN YOU HAVE AN ENVIRONMENT THAT IS BASICALLY EVEN IF THEY ARE DIZYGOTIC, WHY ONE WOULD BE AFFECTED AND THE OTHER NOT AND ONE WOULD HAVE SYMPTOMS AND THE OTHER NOT? THOUGHTS ON WHY THAT IS HAPPENING? >> I THINK THAT IT IS VERY IMPORTANT TO APP LIES THE PLACENTA BECAUSE WE DON'T KNOW IF THERE IS A PROBLEM -- WE HAVE TWO PLACENTAS FOR TWO BABIES. WE DON'T KNOW IF THE TWO PLACENTAS WAS INFECTED AND THEN THE BABIES ONE REACTED DIFFERENT FROM THE OTHER. WE DON'T KNOW BECAUSE WE DON'T HAVE ANALYZE PLACENTA. WHEN WE THINK ABOUT THAT, WE DON'T HAVE THOSE TWINS YET. BUT WE TRIED TO ANALYZE THIS AND YOU HAVE A GROUP IN SAN POW, SHE PROCEED WITH ANALYSIS. WE DON'T HAVE THE RESULTS YET. WE HAVE SOME FINDS BUT SHE WILL PUBLISH THIS. SO WE TRY TO UNDERSTAND IF THERE IS SOME GENET CALL CAUSE FOR DIFFERENT REACTIONS TO THE VIRUS. WE DON'T KNOW YET. BUT WE ARE STUDYING ABOUT THAT. BUT I THINK IT WOULD BE VERY IMPORTANT IF WE CAN ANALYZE BECAUSE WE HAD ONE ZYGOTIC TWINS AND BOTH WERE COMMITTED. SO -- CONNECTED. SO I DON'T KNOW IF THERE IS ANY MONOZYGOTIC TWINS THAT ONLY ONE WAS -- I DON'T KNOW. BUT THE ONLY TWINS SYMBOLS THAT WAS BOTH ACCOMMODATED, THEY WERE MONOZYGOTIC SNIPES SO FOR THE ZIP STUDY MAY BE VERY IMPORTANT TO HAVE VERY DETAILED STUDIES AND ESPECIALLY IN TWINS THAT WE MAY ENCOUNTER. THANK YOU. >> THANK YOU. NICHD. FROM THE KIND OF CRY THESE BABIES ARE HAVING IT SEEMS TO ME THEY MAY BE HAVING HEADACHE AND PAIN BECAUSE WELL-KNOWN THAT BABIES WHO HAVE ENCEPHALITIS AND MENINGITIS HAVE A VERY SEVERE HEADACHE AND CHILDREN COMPLAIN THAT WHEN THEY CAN TALK BUT YOUNG BABIES CONTINUOUSLY CRY AND AS A PEDE TRISHIAN HAVING TAKEN MENINGITIS BABIES, I KNOW THAT IT IS A FACIALLY COMMON THING. SO MY QUESTION IS, HAS ANY ATTEMPT BEEN MADE TO REDUCE THE PAIN WITH AN ELOGESSICS AND THAT STOP THEIR CRYING? >> WE HAVE -- THE PATIENT REACT DIFFERENT FROM THE TREATMENT. IN PATIENTS WITH NEUROLOGIC PROBLEMS IT IS USUALLY THE PEDE TRISHIAN SAYING -- SOMETIMES PATIENTS CRY A LOT AND EVERYBODY THINK FIRST IT'S NEUROLOGIC PROBLEMS. MAY FIND IS IN PATIENTS THAT CRY A LOT BECAUSE THEY HAVE PAIN AND THE ONLY WAY TO SAY FOR US IS TO CRY. THEY CRY TO SAY THAT SOMETHING IS WRONG WITH THEM. BUT THIS PATIENTS WE TRY TO -- THEY DON'T RESPOND BECAUSE THE MOTHER GIVES PARASET MEDICAL OR OTHER KIND OF MEDICATION FOR PAIN BUT THEY DIDN'T IMPROVE IN BEGINNING WE HAVE SUCCESS WITH SOME PATIENTS LIKE THE PATIENTS IN THE VIDEO. AND THEY DIDN'T IMPROVE A LOT IN THE BEGINNING THEY ONLY IMPROVE WITH. [ INDISCERNIBLE ] FOR BABIES BUT NOT ALL PATIENTS IMPROVED AND THEN WE TRY TO USE MEDICATIONS FOR IRRITABILITY TO DECREASE IRRITABILITY OF THIS BABY SOME PATIENTS IMPROVE A LOT BUT AFTER SOME PATIENTS THEY WORSE THIS PATIENT BECAUSE OF THESE MEDICATIONS AND THEN SOMETIMES THEY BECOME IRRITATED AGAIN. I THINK THAT MOST OF THE PATIENTS IMPROVE WITH THE TREATMENT OF EPILEPSY. I THINK THAT MOST OF THIS KIND OF ABNORMAL MOVEMENT IN THE BEGINNING PROBABLY IS NOT ONLY [ INDISCERNIBLE ] BUT SOME PATIENTS THE EEG HAVE NORMAL PATTERN AND WHEN WE START TO MEDICATION TO DECREASE HYPEREXCITABILITY, EVEN THE LESS PATIENTS THAT THEY SHOW THAT THEY ARE LESS SEVERE, SOME PATIENTS LIKE MILD [ INDISCERNIBLE ] THEY HAVE LIKE A IRRITABILITY WHEN WE PUT THEM IN SUPINE POSITION LIKE STARTLED WITH -- ANY STIMULUS LIKE WIND, LIKE SOUND, AND THEY PREFER WHEN THEY STAY HOLD IN THE ARMS OF THE MOTHER OR IN ANOTHER -- IN -- POSITION. SO SOMETIMES WHEN THESE MEDICATIONS FOR THIS, THEY IMPROVE A LOT. SO, SOME PATIENTS IMPROVE MEDICATION FOR HYPEREXCITABILITY SOME OTHER FOR EPILEPSY. >> THANK YOU. >> IRENEA BIRD, JOHNS HOPKINS UNIVERSITY. MATERNAL FETAL MEDICINE SPECIALIST AND I WANT TO THANK YOU FOR A WONDERFUL AND THOUGHT PROVOKING TALK. BECAUSE WHAT I HEARD FROM THIS IS THAT IT MAY NOT BE ONLY NECESSARILY ZIKA THAT IS OCCURRING BUT A NEUROLOGICAL LOAD ON THE MOTHER. THAT IS WHAT WE SEE IN PRETERM BIRTH AND UTERINE INFLAMMATION. SO POTENTIALLY INFLAMMATION BY ITSELF MAY BE PLAYING A ROLE IN THIS BECAUSE YOU SEE MOTOR DEFICITS AND THAT'S WE SEE WITH BABIES BORN PRETERM. MAYBE WE SHOULD BE PAYING ATTENTION WHAT IS INFLAMMATORY LOAD OF THE MOTHER GOING FURTHER AND HOW THAT IMPACTS FETAL BRAIN DEVELOPMENT. SO, YOU MAY NOT SEE PARTICULAR FINDINGS IN THE BRAIN BUT IT MAY BE AFFECTED BY IMMUNE ACTIVATION IN THE MOTHER AND PASSING CYTOKINES ET CETERA TO THE FETUS. SO TO ME, IT JUST PROVOKES SOME THOUGHTS IN THAT REALM. WHAT ARE YOUR THOUGHTS ABOUT THIS? >> TO ANALYZE THE IMMUNE REACTION OF THE BABY OR THE MOTHER? >> MOTHER AND TO CORRELATE WITH THE FINDINGS. BECAUSE -- >> WE DIDN'T THINK ABOUT THAT. SO MAYBE NOW I CAN THINK ABOUT THAT. BUT WE DID NOT THINK ABOUT THAT. >> THANK YOU. >> WE HAVE TIME FOR ONE MORE QUESTION AND THEN WE NEED TO MOVE ON. >> I'M ADAM FROM NIPPED A PEDIATRIC NEUROLOGIST. -- NINDS. ONE GRATES ON IA WONDERFUL PRESENTATION AND YOU HAVE A VERY HARD JOB SEEING A LOT OF THESE BABIES. MY QUESTION IS, LOOKING AT YOUR FINDINGS IT SEEMS LIKE WHAT YOU'RE SEEING CLINICALLY AND RAID LOGICALLY ARE PRETTY COMPARABLE AND BABIES WITH OTHER TYPES OF PATHOLOGY LIKE NEONATAL IN SEF LOPPY THAT COULD HAVE SIMILAR LOOKING IMAGING WITH THE EXCEPTION OF THE CALCIFICATIONS SO THINKING ABOUT DISTINGUISHING THIS FROM OTHER CONGENITAL INFECTIONS AND THIS IS MORE OF AN IN TUITION TYPE OF A QUESTION I'M ASKING AND YOU SEEN MORE OF THESE PATIENTS THAN MOST. IS THERE ANYTHING THAT CLINICALLY DISTINGUISHES THEM FROM OTHER CONGENITAL INFECTIONS OR OTHER TYPES OF PATHEDDOLOGY? >> THE MOST SEVERE PATIENTS, THE CLINICAL PICTURE IS SIMILAR BECAUSE THEY ARE VERY SEVERE AND WE HAVE 106 PATIENTS. ONLY 22 PATIENTS ARE ABLE TO MAKE SOME EYE CONTACT. THE REST OF THE PATIENTS HAVE NO EYE CONTACT. NO CONTROL OF THE HEAD. SO MOST OF THE PATIENTS ARE SEVERE. AND THE PATIENTS THAT ARE VERY SEVERE HAVE VERY SEVERE -- SOMETIMES NOT SO DIFFERENT BUT THIS PATTERN OF HYPEREXCITABILITY THAT THEY HAVE, WE CAN SEE IN A LOT OF INFECTION BUT NOT SO FREQUENT LIKE THESE PATIENTS. AND BUT IN THE MILDER CASES, THEY HAVE OR ARE DIFFERENT FOR PATIENTS WITH CMV. I SEE MANY PATIENTS WITH CMV. THE PATIENTS WE SEE MORE COGNITIVE PROBLEMS THAN MOTOR PROBLEMS. THESE PATIENTS THEY LOOK LIKE CEREBRAL PALSEY. LESS SEVERE. PATIENTS WITH MILD CASE PROBABLY BECAUSE THE PROBLEM IS MORE CORTICAL AND MORE PROBABLY DEVELOPMENT OF THE BRAIN NOT THE INJURY LIKE WE SEE DAMAGE IN THE BRAIN CAUSED BY IN FLORIDAITIONIMATION. THESE PATIENTS I THINK THAT IS DIFFERENT. THEY ARE MORE ABNORMAL -- INFLAMMATION -- MORE ABNORMAL BRAIN DEPARTMENT THAN DAMAGE. THE BRAIN MEASURE IS SOMETHING LIKE THIS. SO IN CLINICAL PICTURES THEY DEFER FROM THE MILD CASE DEFER FROM PATIENTS WITH CMV BECAUSE THEY HAVE MORE MOTOR PROBLEMS THAN THE OTHER DISEASE. BUT I THINK THAT THE SPECIAL SIGN THAT IS YOU CAN SEE THAT IS DIFFERENT FROM OTHER CONGENNATIVE IS THE BRAIN AGE. CALCIFICATION BETWEEN CORTICAL AND SUB-CORTICAL AREA AND WE CAN SEE IN OTHER CONGENNATIVE AFFECTS THE DIFFERENCE. IN THE BEGINNING WE HAD SOME TIMES THREE PATIENTS PER DAY. AND THERE IS A PEDIATRICS THAT WORK WITH ME AND WHEN WE SEE THE BRAIN IMAGE SAYING THIS IS NOT ZIKA. THIS IS CMV. THIS IS KNOCKSO -- AND WHEN WE DID THE EXAMS, WE ARE RIGHT. SOMETIMES WE ARE NOT SO RIGHT BUT THE BRAIN AGE I THINK IT IS VERY IMPORTANT TO TRY TO UNDERSTAND THIS. INCLUDING THE PATIENTS THAT WE PRESENT SOME NEURODEVELOPMENT DELAY IN THE FUTURE AND WE ARE -- DON'T FINISH WE ARE ABLE TO LYINGINOSIS ZIKA BECAUSE CONGENITAL INFECTION WE NEED TIME. WE NEED TO MAKE THE EXAMS IN THE BEGINNING. SO I SAW THE MOST SEVERE PATIENTS AND MOST OF THEM HAVE SOME ABNORMAL CORTICAL DEVELOPMENT SO I KNOW THAT THIS IS HAPPENED BEFORE THE DELIVERY. BUT I THINK THAT BRAIN AGE IS THE MOST IMPORTANT THING THAT WE NEED TO LOOK IN THE FUTURE, ESPECIALLY FOR THE ONES NOT FINDING AT BIRTH. >> THANK YOU. >> THANK YOU VERY MUCH FOR AN AMAZING PRESENTATION. SO I KNOW THAT YOU'LL BE PRESENTING TOMORROW SO MORE TO COME. SO THANK YOU VERY MUCH. [ APPLAUSE ] >> I'D LIKE TO ADD MY WELCOME TO THE WORKSHOP AND THE NEXT SESSION ON IMPACT ON THE CHILD. I'M BILL KAPOGIANNIS, AN INFECTIOUS DISEASE SPECIALIST AND I WORK WITH NAHIDA IN THE NICHD AND I'LL HELP FACILITATE THIS SESSION AND LEAD YOU THROUGH THE REST OF THE AFTERNOON AND ALSO TOMORROW. SO, A LITTLE BIT ABOUT THE SESSION AND THE STRUCTURE. SO FIRST ACTUALLY I REALLY WOULD LIKE TO BEGIN BY THANKING ALL OF THE SPEAKERS AND PANELISTS AS WELL AS THE MODERATORS AND ALL OF OUR SUPPORT STAFF FOR THEIR HARD WORK IN PUTTING ALL OF THIS TOGETHER, PARTICULARLY ON THIS NEXT SESSION ON THE IMPACT ON THE CHILD. IT'S GOING TO BE INFORMATION PACKED AS YOU HAVE SEEN ALREADY BY THE OTHERS. DRIVEN BY IN THIS SESSION SEVERAL OVER ARCHING QUESTIONS YOU HAVE ON YOUR AGENDA AND THESE WILL STRADDLE BOTH DAYS. SO THE QUESTIONS ARE -- [ READING ] SO WE'LL HAVE TWO SETS OF TWO PRESENTATIONS AND A PANEL DISCUSSION AND HOPE TO CLOSE BY 5 P.M. TODAY AND FOR THIS SESSION, AS WE HAVE DONE PREVIOUSLY FOR THE SPEAKERS, I'D LIKE TO ASK IF YOU HOLD YOUR QUESTIONS UNTIL AFTER THE 30 MINUTE PRESENTATION FOR THE 15 MINUTE DISCUSSION IN CLARIFYING Q&A SESSION. I ALSO WOULD ASK DURING THAT SESSION IF YOU COULD KINDLY DO WHAT I DID NOT DO WHEN I WENT AND ASKED MY QUESTION, IS TO STATE YOUR NAME AND AFFILIATION. SO, LAST HOUSEKEEPING NOTE HERE IS AROUND THE TIMING OF THE LUNCH. SO, WE'LL HAVE THE FIRST PRESENTATION AND THEN WE WILL BREAK FOR LUNCH, WHICH WILL BE AT 12:15, I HOPE TO STAY ON TIME BEING OPTIMISTIC. AND THEN WE'LL COME BACK PROMPTLY AT 1:15 WHERE WE BEGIN THE SECOND PRESENTATION FOLLOWED BY THAT PANEL. SO, THERE ARE SEVERAL OPTIONS WHERE MEALS CAN BE PURCHASED ALONG WITH SNACKS HERE. THERE IS A RESTAURANT AND A GIFT SHOP LOCATED IN THE HOTEL, HOT AND COLD BEVERAGES AND GRAB AND GO SANDWICHES IN THE GIFT SHOP, THERE IS A COMPLEX NOT FAR DOWN THE STREET LOCATED ACROSS THE STREET FROM THIS HOTEL. MAPS ARE AVAILABLE OUTSIDE IN REGISTRATION AREA. AND THEN I'LL REMIND FOLKS THAT TO VALIDATE THEIR PARKING STICKERS FOR PARKING. SO, WITH THAT, I'LL ASK DR. BRITT TO COME ONBOARD AND JOIN US. SO IT'S MY PLEASURE TO INTRODUCE DR. WILLIAM BRITT WHO IS THE CHARLES A ALFRED PROFESSOR OF NEUROBIOLOGY AND MICROBIOLOGY AT THE UNIVERSITY OF ALABAMA BIRMINGHAM AND FOCUSED RESEARCH ON STUDIES OF VIRUSES FROM CREDIT ROW VIRUSES TO HERPES VIRUSES, HE HAS MAINTAINED A SIGNIFICANT REACH EFFORT IN THE STUDIES OF CONGENITAL CMV INFECTION, THE MOST COMMON VIRUS ASSOCIATED CAUSE OF HEARING LOSS IN NEURODEVELOPMENTAL ABNORMALITIES WORLDWIDE. MORE RECENTLY HIS STUDIES FOCUSED ON NEUROPATHOGENESIS OF HUMAN CMV INFECTIONS INCLUDING THE USE OF PATIENT COHORTS AND I THINK FORMATIVE ANIMAL MODELS TO TRANSLATE BASIC IMMUNOLOGICAL AND VIRAL LOGICAL FINDINGS INTO THE MODELS INTO NEW THERAPIES. HE CURRENTLY LEADS NIH SUPPORTED MULTIINVESTIGATOR STUDIES WITH SCIENTISTS FROM BRAZIL, GERMANY, CROATIA AND SEVERAL OTHERS FROM THE UNITED STATES. I WELCOME YOU AND HIS TALK IS ENTITLED OTHER CONGENITAL INFECTIONS WITH NEURODEVELOPMENTAL CONSEQUENCES. >> WILLIAM BRITT: THANK YOU FOR THAT INTRODUCTION. PROBABLY THE BEST ONE I EVER HAD. I WISH IT WAS COMING FROM A REVIEWER BY MIGRANTS. [ LAUGHS ] SO, THIS WAS THE TITLE THAT I SORT OF BUILT THE TALK AROUND, THE ADVERSE NEURODEVELOPMENT OUTCOMES ASSOCIATED WITH ZIKA. AND AS A ROADMAP PROVIDED BY CONGENITAL CMV AND RUBELLA VIRUS. I APOLOGIZE TO MANY IN THE AUDIENCE THAT IT PROBABLY HAVE BEEN THROUGH PROBABLY KNOWS MUCH ABOUT THESE TWO INFECTIONS AS I DO. I'M ASSUMING THERE ARE PEOPLE IN THE AUDIENCE THAT DON'T KNOW SO THERE WILL BE SOME REVIEW IN THIS BEFORE WE GET TO THE END THIS. SO, THIS IS THE RATIONAL FOR A WELL DESIGNED COMPREHENSIVE NATURAL HISTIE STUDY OF ZIKA AND THIS QUOTE CAME FROM NOT A LITERARY GIANT BUT FROM A BASEBALL PLAYER WHO PEOPLE IN MY EN JUDGEERATION WAS A HERO. AND HE LIKES TO HAVE LOTS OF SAYINGS. AND HE SAYS MANY, MANY THINGS I THINK ARE PRETTY PROFOUND. AND THIS IS WHAT HE SAID, YOU'VE GOT TO BE CAREFUL IF YOU DON'T KNOW WHERE YOU'RE GOING BECAUSE YOU YOU MIGHT NOT GET THERE. THAT'S PRETTY OBVIOUS BUT THAT'S SOMETHING WE MIGHT KEEP IN MIND ABOUT ZIKA VIRUS. THIS TALK IS GOING TO BE FOCUSED ON CONGENITAL INFECTIONS. THOSE ARE THAT ARE ACQUIRED IN ROUTE UTROW AND NOT SO MUCH PERINAILS IN AFFECTIONS ACQUIRED DURING BIRTH OR AFTER. I'M GOING TO TALK ABOUT CONGENITAL INFECTIONS. SO THESE ARE CONGENITAL INFECTIONS AND THESE ARE INCIDENTS HERE FOR BRAZIL BECAUSE OF THE SLIDE I USED FOR ANOTHER TALK BUT TO SHOW YOU THAT CONGENITAL CMV OCCURS IN ONE PER 100 LIVE BIRTHS IN BRAZIL. RUBELLA IS REPORTED NOT TO OCCUR IN BRAZIL BY THE DATA I GOT FROM THE BRAZILIAN PUBLIC HEALTH AUTHORITIES. SYPHILIS IS SURPRISING, SEVERAL US US IN THE AUDIENCE SEE THIS AND BE SHOCKED. THESE ARE SOME OF THE OTHER AGENTS ALSO THAT HAVE BEEN ASSOCIATED WITH CONGENITAL INFECTION LCMV, HIV AND CHICK AND HSV AND HPV. AND THESE ARE THE PERINATAL INFECTIONS. I'M ONLY GOING TO TALK ABOUT THESE. SO HOW COMMON ARE CONGENITAL INFECTIONS IN WE DON'T KNOW WHAT THAT IS FOR ZIKA BUT WE HAVE DATA FOR CONGENITAL CMV. IN THE UNITED STATES IT'S SOMEWHERE BETWEEN.2 TO.7%. IN LATIN AMERICA, MOST OF THE REST OF THE WORLD ABOUT 1-200. I JUST SAW DATA MY COLLEAGUE SHOWED ME FROM SOUTH AFRICA WHICH WAS REALLY FRIGHTENING IN TERMS OF THE INCIDENTS. WHAT IS THE PUBLIC HEALTH IMPORTANCE OF THIS? THIS JUST SHOWS YOU THE NUMBER OF CHILDREN IN THE UNITED STATES WITH LONG TERM SEQUELAE FROM CONGENITAL CMV. THESE NUMBERS ARE GENEROUS. TING GIVES YOU SOME IDEA IN COMPARISON TO DOWN SIM DREAM, FETAL ALCOHOL SYNDROME, SPINAL BIFIDA, PEDIATRIC AIDS AND WE DON'T HAVE CONGENITAL RUBELLA SYNDROME IN THE UNITED STATES. SO A PRETTY COMMON CAUSE OF DISEASE IN CHILDHOOD. WHAT IS IMPORTANT? THIS IS IMPORTANT BECAUSE PEOPLE FROM PROGRAM HERE WHEN THEY GO TO ARGUE THEIR BUDGETS, WHAT SILENT ECONOMIC BURDEN? RUBELLA PANDEMIC. >> OCCURRED IN THE U.S. BETWEEN 1963 AND 1965 WAS ESTIMATED TO COST ABOUT TWO BILLION DOLLARS BECAUSE THE BABIES WERE BORN. THOSE WERE TWO BILLION 1963 DOLLARS. IN THE CONGENITAL CMV, NUMBERS ARE NOT REALLY READILY AVAILABLE BUT IF WE THINK THERE IS 15-20,000 INFANTS IN THE UNITED STATES WITH CONGENITAL CMV, 10% WILL HAVE HEARING LOSSES AND IT'S BEEN ESTIMATED A CHILD WITH HEARING LOSS OVER A LIFETIME WILL COST ABOUT 300,000 DOLLARS. SO DO SOME MATH AND FIGURE OUT THAT THIS IS QUITE A BURDEN TO THE HEALTH CARE SYSTEM. AND SOCIETAL BURDEN. THIS IS SOMETHING THAT IS NOT WELL APPRECIATED. THE ECONOMIC AND RACIAL DISPARITIES IN THE PREVALENCE OF CONGENITAL CMV ARE VERY APPARENT IN THE UNITED STATES. IT MIGHT HELP US TO DISTINGUISH AND PREDICT OUTCOMES OF ZIKA VIRUS INFECTIONS. CLINICAL FINDINGS ARE OFTEN CENTRAL NERVOUS SYSTEM WITH MICROCEPHALY, MICRODEFICITS IN VISION AND HEARING AND SOMETIMES WE SEE PERIPHERAL ABNORMALITIES SUCH AS RASHES AND DEPENDING ON WHEN THESE AGENT INFECT THE FETUS AND WE OFTEN SEE INTERUTERINE GROWTH RESTRICTION. IT'S IMPORTANT TO NOTE THAT WE ALSO SEE VERY SIMILAR FINDINGS FROM PARACYTIC INFECTIONS. AGAIN DEPENDING ON WHEN THE FEET SUSINFECTED AND WHAT THE SPECTRUM OF INFECTION WILL BE. WHAT ARE THE LABORATORY IMAGING FINDINGS? CENTRAL NERVOUS SYSTEM FINDINGS WE HEARD ABOUT THOSE IN THE PREVIOUS TALK. HEMATOLOGIC ABNORMALITIES. THROMBOCYTOPENIA AND LIVER INVOLVEMENT. THESE FINDINGS ARE RELATIVELY NONSPECIFIC AND CERTAINLY NONSPECIFIC FOR INFECTIOUS AGENCY AND MAY NOT BE PREDICTIVE OF LONG TERM OUTCOMES WITH THE EXCEPTION OF THE OBVIOUS ABNORMALITIES IN THE CENTRAL NERVOUS SYSTEM. SO, THE ADVERSE OUTCOMES WITH CONGENITAL INFECTIONS WE FOCUS ON AND MOST PEOPLE FOCUS ON ARE CENTRAL NERVOUS SYSTEM DAMAGE INCLUDING HEARING LOSS, NEUROMUSCULAR OR NEURODEVELOPMENTAL ABNORMALITIES. THAT'S WHAT WE ARE FOCUSED ON. THE FIRST MODEL IS CONGENITAL RUBELLA SYNDROME. AND I CAN LOOK IN THE AUDIENCE AND THERE ARE GRAY HAIRS AND LIKE ME THAT HAVE SEEN CONGENT GENITAL RUBELLA SYNDROME BUT THERE PROBABLY ISN'T MANY IN THE AUDIENCE WHO HAVE TAKEN CARE OF A CHILD WITH THIS. THESE ARE SOME OF THE THINGS WE SEE. OCULAR DEFECTS, CENTRAL NERVOUS SYSTEM DAMAGE, DEAFNESS AND GROWTH RETARDATION AND CARDIOVASCULAR DEFECTS. RUBELLA SYNDROME OBSERVED IN THE FIRST TRIMESTER IN PREGNANCY AND THAT WAS REALLY HOW IT WAS FIRST REPORTED AND DESCRIBED. THE RISK IS VERY HIGH DURING THE FIRST TRIMESTER FOR THESE ABNORMALITIES. IT DROPS IN THE SECOND TRIMESTER WITH MORE OF THE DEAFNESS IN THE CENTRAL NERVOUS SYSTEM ABNORMALITIES YET STILL SOME ABNORMALITIES NOTED IN THE THIRD TRIMESTER. SO IT WAS REALLY VERY IMPORTANT FOR THE MATERNAL TIMING OF THIS INFECTION. VERY EASY TO DISTINGUISH BECAUSE RUBELLA PRESENTED WITH CLINICAL SYMPTOMATOLOGY THAT OBSTETRICIANS COULD DIAGNOSE LIKE HAS BEEN DONE SO FAR IN SOUTH AMERICA WITH ZIKA. HEARING LOSS AGAIN IS A VERY IMPORTANT PART OF CONGENITAL RUBELLA AND THIS SHOWS THE INSTANCE OF HEARING LOSS ACCORDING TO THE TRIMESTER OF MATERNAL INFECTION. IT'S HIGHER IN THE FIRST TRIMESTER BUT NOT INCONSEQUENTIAL IN THE SECOND AND THIRD AS THESE MAKE UP A SIGNIFICANT NUMBER OF PATIENTS HERE WITH HEARING LOSS. IMPORTANT AND THIS IS IMPORTANT FOR FOLLOW-UP WITH ZIKA AND I'LL TALK ABOUT THIS MORE WITH CMV, 25% OF THESE INFANTS THAT HAVE HEARING LOSS HAVE PROGRESSION OF HEARING LOSS. HEARING LOSS GOT WORSE OVER TIME AND THAT IS SOMETHING THAT WE NEED TO KEEP IN MIND WHEN WE FOLLOW ANY INFANTS WITH CONGENITAL INFECTIONS. THE OCULAR MANIFESTATION OF CONGENITAL RUBELLA SYNDROME PERHAPS THE MOST RECOGNIZED IS CATARACTS. ABOUT 16%. THIS WAS A INFECTION OR DEFECT THAT WAS ASSOCIATED WITH INFECTIONS EARLY IN GESTATION BECAUSE OF THE DEVELOPMENT OF THE LIMBS. MICROTHAT WILL MIA AND RETINOPATHIES AND OTHER OCULAR FINDINGS INCLUDING GLAUCOMA. THESE ARE THE THINGS AMONG SPECIFIC HOWEVER. NOW IF WE SWITCH TO CONGENITAL CMV, THIS IS DIFFERENT BECAUSE IN ALMOST NO INSTANCES ARE THE WOMEN INFECTED WITH CMV AS THEY KNOW THEY ARE INFECTED DURING PREGNANCY. THIS IS A SILENT INFECTION IN ALMOST ALL WOMEN. WE DON'T REALLY HAVE A PREDICTER OF WHEN A CMV INFECTION MAY BE MORE DAMAGING TO THE DEVELOPING FETUS. AND INSTEAD, ONE OF THE FIRST STUDIES THESE WERE DONE, WE LOOKED AT LONG TERM OUTCOMES SUGGESTED BY THE CLINICAL PRESENTATION OF INFANT. WE LOOKED AT THOSE WITH SYMPTOMATIC INFECTIONS VERSUS THOSE THAT HAD NO SYMPTOMS IN THE NURSERY YOU WOULDN'T HAVE DETECTED AS HAVING CONGENITAL CMV UNLESS YOU WERE LOOKING. WE FOUND WITH THE INFANTS WITH CENTRAL NERVOUS SYSTEM ABNORMALITIES OR EVIDENCE OF INVOLVEMENT OF THE LIVER OR THE SPLEEN, THAT 40-60% OF THEM HAD PERMANENT SEQUELAE INCLUDING HEARING LOSS, COGNITIVE IMPAIRMENT, RETT NIGHTIS AND NEUROMUSCULAR DISORDERS. AND THE ASYMPTOMATIC GROUP WHICH REPRESENTED THE VAST MAJORITY OF INFANTS, 10-15% HAVE SEQUELAE. HEARING LOSS MOST COMMON OCCASIONALLY COGNITIVE IMPAIRMENT AND SOMETIMES HIGH INVOLVEMENT. THESE WERE STUDIES DONE BY LARGE NATURAL HISTORY STUDIES, MOST OF THEM I'M NOT GOING TO TAKE CREDIT FOR BUT WAS STARTED IN BIRMINGHAM IN THE LATE 70s AND EARLY 70s RATHER BY CHARLES AND CERTAINLYIO AND COLLECTED LARGE NUMBERS OF INFANTS THAT ARE REALLY MAKING UP WHAT I THINK WHAT WE BEEN THE NATURAL HISTORY OF THE INFECTION. MORE RECENTLY, WHEN MY COLLEAGUES AND I AT BIRMINGHAM WENT BACK AND LOOKED AT SOME OF THESE SERIES, WE NOTICED SOMETHING INTERESTING AND I THINK IT IS SOMETHING WE HAVE TO BE VERY CAREFUL ABOUT IN EVALUATION OF THE DATA OF ZIKA VIRUS. AND THAT IS THAT THE CLINICAL FINDINGS IN THESE WERE CONTAMINATED BY REFERRED PATIENTS. PATIENTS WITH SYMPTOMS. SO IN OTHER WORDS THE ORIGINAL SERIES WE HAD REFERRED PATIENTS AND SCREEN APPEARS LUMPED TOGETHER TO GENERATE THE INSTANCE OF THESE SEQUELAE AND DISEASE. AND I'M JUST GOING TO SHOW YOU SOME EXAMPLES HERE. IF WE LOOKED AT JAUNDICE, 56% OF THEM VERSUS 43% AND 49% OBVIOUS BECAUSE PEDIATRICIANS COULD RECOGNIZE THESE ABNORMALITIES AND THEY WERE FLIPPED INTO OUR CLINIC. THIS GOES DOWN INTO THE SEQUELAE IF WE LOOK AT HEARING LOSS, HIGHER IN REFERRED POPULATION THAN THOSE SCREENED AND ALSO WITH THE NEUROCOGNITIVE DISORDERS. SO AGAIN, SOMETHING I WOULD BE VERY CAREFUL AS WE START TO EVALUATE THE CLINICAL SPECTRUM OF DISEASE ASSOCIATED WITH CONGENITAL ZIKA VIRUS INFECTION THAT IT IS DONE IN A VERY CAREFUL NATURAL HISTORY STUDY WHERE THE PATIENTS ARE SCREENED AND WE TAKE ALL COMMERCE AND DEFINE THE SPECTRUM OF DISEASE. AND NOT JUST THE OBVIOUS CLINICAL ABNORMALITIES. SOHOERING IS A VERY IMPORTANT PART OF CONGENITAL CMV AND THESE ARE DATA THAT ARE GENERATED FROM NIDCD CHIME STUDY WHICH LOOKED AT A LARGE NUMBER LIKE 100,000 BABIES, AND WE CAN SEE THAT AT BIRTH 8% OF BABIES WITH CONGENITAL CMV WILL HAVE HEARING IMPAIRMENT BY 4 YEARS OF AGE BECAUSE OF THE PROGRESSION AND DELAYED ONSET AND 12% OF IN FANS WILL HAVE VARYING ABNORMALITIES. THESE ARE OLDER DATA GENERATED FROM BIRMINGHAM JUST FROM THE GROUP IN BIRMINGHAM. THIS HAS A POPULATION OF 800 BABIES. IF YOU LOOK AT THOSE WHO HAD NO SYMPTOMS AT BIRTH AGAINST THOSE THAT HAD SYMPTOMS AT BIRTH -- NEXT IF YOU LOOK AT THE ONSET DELAYED ONSET AND PROGRESSIVE LOSS, THESE ARE HEARING IMPAIRMENTS THAT DEVELOP AFTER NEWBORN SCREENING FOR INSTANCE NEWBORN HEARING SCREENING. THESE IN THIS GROUP THE MEDIAN AGE WAS ABOUT 44 MONTHS AND HEARING LOSS DEVELOPED AT LEAST DETECTABLE BY AUDIOLOGISTS. AND YOU CAN SEE IN BOTH GROUPS WE DID HAVE DELAYED ONSET AND WE HAD PROGRESSION OF HEARING LOSS. SO THAT SUGGESTS WE NEED TO FOLLOW THESE INFANTS MORE MORE THAN JUST A TIME THAT WE HAVE DIAGNOSED THE ABNORMALITY. FINALLY THIS HEARING LOSS IS NOT TRIVIAL. IF WE LOOK AT INFANTS WITH ASYMPTOMATIC INFECTION OR SYMPTOMATIC, WE SEE WITH ASYMPTOMATIC INFECTION, PATIENTS HAVE HEARING LOSS, 50% HAD MODERATE TO PROFOUND LOSS AND ABOUT 75% SYMPTOMATIC PATIENTS HAVE MODERATE TO PROFOUND OF SO THESE ARE NOT MINOR HEARING ABNORMALITIES. OCULAR MANIFESTATIONS ARE SOMEWHAT DIFFERENT PROBABLY BECAUSE THE VIRUS IS DIFFERENT AND IT BEHAVES IN A DIFFERENT MANNER. AND PRIMARILY THE MOST COMMON ONE WAS RETINAL SCARS AND CORIORETINITIS. THESE WERE TWO DIFFERENT SERIES. THE COGNITIVE AND NEUROCOGNITIVE INTELLECTUAL OUTCOME HAS BEEN DONE ROLE NETWO STUDIES AND I'M NOT GOING TO SHOW YOU THE DATA ON RUBELLA BECAUSE I COULDN'T FIND GOOD DATA IN A FORMAT I COULD PUT IN THE A SLIDE. THIS WAS A STUDY AGAIN DONE FROM BIRMINGHAM WITH 32 INFANTS WITH CONGENITAL CMV AND REALLY BIMODAL. YOU CAN SEE THAT ABOUT HALF OF THE BABIES HAD IQs GREATER THAN 70. VERSUS ABOUT 40% HERE YOU SIGH WITH LESS THAN 70. IMPORTANTLY, AND I THINK THIS IS IMPORTANT FOR REMAINDER OF THE TALK, THE ASSOCIATIONS WITH LOWER INTELLECTUAL DEVELOPMENT WAS MICROCEPHALY AND NOT SURPRISING STRUCTURAL ABNORMALITIES IN THE BRAIN. NEUROLOGIC ABNORMALITIES AND CORIORETINITIS SIGNIFYING THE CENTRAL NERVOUS SYSTEM HAD BEEN INVOLVED IN THIS INFECTION. SIMILAR STUDY DONE IN HOUSTON REALLY HAD ABOUT THE SAME RESULTS BELOW 70B44% OR SO AND ABOUT 55% ABOVE 70. AGAIN THEIR ASSOCIATIONS SIMILARLY MICROCEPHALY DAMAGE TO THE NERVOUS SYSTEM AND NEUROLOGIC ABNORMALITIES ON THE EXAM. EYE ABNORMALITIES AND IN THEIR CASE THEY DID IMAGING AND FOUND CENTRAL NERVOUS SYSTEM ABNORMALITIES WERE ASSOCIATED WITH LOWER INTELLECTUAL DEVELOPMENT. SO, CAN THE ADVERSE OUTCOMES OF CONGENITAL OUTCOMES BE PREDICTED FROM CHARACTERISTICS OF MA TERNITY INFECTION DURING PREGNANCY? THIS IS VERY IMPORTANT BECAUSE IF THEY CAN BE, PERHAPS IT WOULD HELP IN TERMS OF TAILORING FOLLOW-UP. I SAW VERY BEAUTIFUL STUDIES FROM BRAZIL AND PUERTO RICO. BUT IF THIS OUTBREAK IS AS LARGE AS IT IS, AND I'M NOT SURE WE ARE GOING TO DO AN MRI AND CT SCAN ON EVERY BABY THAT IS PORN. SO IF WE CAN FIND THINGS IN MATERNAL HISTORY TO HELP US IDENTIFY BABIES THAT MIGHT BE CANDIDATES FOR MORE INTENSIVE FOLLOW-UP, THAT WOULD HELP. WITH RUE BELLAL THAT WAS THOUGHT TO BE THE CASE. THIS IS THE TRANSMISSION RATE. MUCH HIGHER IN FIRST TRIMESTER AND DROPS IN THE SECOND TRIMESTER. INCREASES AGAIN IN THE THIRD. AND INTERESTING ENOUGH THIS IS ALSO THE GESTATIONAL AGE ASSOCIATED WITH MOST OF THE ABNORMALITIES. AND AGAIN THIS IS JUST A SORT OF GRAPH FOLLOWING FROM THAT SHOWING THAT DEAFNESS, HEART DISEASE, AND SOME OF THE OTHER FINDINGS WERE MORE COMMON IN THE FIRST TRIMESTER. SO THIS REALLY I THINK POINTED TO FOLLOWING INFANTS BORN FOLLOWING THE FIRST TRIMESTER RUBELLA INFECTION. HOWEVER, AGAIN THOSE WERE CLINICAL DIAGNOSIS. SO STUDY DONE IN 1973 WHICH I FOUND WAS INTERESTING DONE AT JOHNS HOPKINS WHERE THEY ENROLLED ALL WOMEN IN A STUDY PROECT SUSPECTIVELY AND DOCUMENTED RUBELLA INFECTION BY LABORATORY METHODS NOT BY CLINICAL FINDINGS IN THE MOTHER. ABOUT 50% WERE CLINICALLY APPARENT. ABOUT 50% WERE SUB CLINICAL. SO THESE WOULD HAVE BEEN MISSED DURING THE INFECTION. AND THE OFFSPRING PRESENTED OFTEN WITH ONE OR TWO COMPONENTS SO CONGENITAL RUBELLA SYNDROME. MAYBE JUST HEARING DEFICITS OR PERHAPS EYE FINDINGS AND SECOND TRIRESTER INFECTIONS WERE SORT ASSOCIATED WITH CATARACTS, DEAFNESS AND COGNITIVE DYSFUNCTION SUGGESTING THAT FOLLOWING THE CLINICAL APPEARANCE OF MOTHER MAY NOT -- CLINICAL SIGNS OF MOTHER MAY NOT BE PREDICTIVE. THAT IS THE CASE WITH CMV. I TOLD THAT YOU VERY RARELY ARE PREGNANT WOMEN INFECTED WITH CMV CLINICALLY SYMPTOMATIC. TRANSMISSION DOES OCCUR IN ALL TRIMESTERS DURING MATERNAL INFECTION WITH CMV. SOMEWHAT HIGHER IN THE SECOND AND THIRD TRIMESTER. OUS COMES SEEM TO BE WORSE IF THE WOMEN ARE AFFECTED EARLIER IN PREGNANCY WHICH IS NOT SURPRISING SINCE WE ARE FOCUSED ON CENTRAL NERVOUS SYSTEM DEVELOPMENT WHICH IS PIVOTAL DURING EARLY TRIMESTER. AND SO THIS IS NOT SURPRISING THAT IF WE HAD A WAY TO REALLY PERHAPS FIND EARLY INFECTIONS IN WOMEN WITH CMV,ING THIS PERHAPS IDENTIFY THOSE UP INFANTS AS CANDIDATES FOR MORE INTENSE FOLLOW-UP. HOWEVER, I HAVE TO GIVE YOU A CAVEAT ON THIS. EVEN IF A WOMAN IS INFECTED WITH CMV, 5, 10, 15 YEARS PRIOR TO THIS TIME, THEY CAN READILY TRANSMIT TO THEIR FETUS. SO WE DON'T EVEN KNOW WHEN THE VIRUS GOES ACROSS IN MOST CASES. WE DON'T KNOW EVEN IF THE MOTHER IS INFECTED IN THE FIRST TRIMESTER THE VIRUS MAY NOT CROSS UNTIL THE THIRD TRIMESTER. VERY DIFFICULT. SO I DON'T THINK THIS WILL WORK WITH CMV. SO WHAT ARE THE PREDICTORS OF ADVERSE OUTCOMES AND WHAT CAN WE LEARN FROM CMV THAT MIGHT HELP US WITH ZIKA? THESE ARE REPORTED PREDICTERS OF ADVERSE OUTCOMES FROM CONGENITAL CMV. FIRST I TOLD THAT YOU INTRAUTERINE TRANSMISSION IN PREGNANCY, THAT IS A VERY IMPORTANT PREDICTER AND I THINK IT WILL BE IMPORTANT TO ZIKA. IF THE VIRUS CROSS SYSTEM EARLY IN GESTATION, THIS IS GOING TO BE IMPORTANT FOR THE ADVERSE OUTCOMES. SYMPTOMATIC CONGENITAL CMV, THIS IS A USEFUL PREDICTOR. IT'S NOT ABSOLUTE BUT IT IS USEFUL AND I THINK CLEARLY THAT IS THE CASE FOR ZIKA. IF YOU HAVE A BABY THAT IS TERRIBLY MICROCEPHALIC WITH OBVIOUS CENTRAL NERVOUS DISEASE OR DAMAGE, CERTAINLY THOSE PATIENTS NEED TO BE FOLLOWED FOR THEIR OUTCOME. HOW ABOUT PRIMARY MATERNAL INFECTION? I HEARD DR. FAUCI MENTION THAT TODAY THAT WE ARE PROBABLY SAFE BECAUSE THERE IS ONLY ONE ZIKA SEROTYPE. HE MAY COME BACK IN A FEW YEARS AND SAY THAT MIGHT NOT BE TRUE. WE USED TO THINK THERE WAS ONLY ONE UNIVERSAL CMV AND REINFECTIONS DIDN'T HAPPEN. THEY DO HAPPEN AND THEY HAPPEN NOT INFREQUENTLY. SO IS PRIMARY MATERNAL INFECTION A PREDICTER? THE THOUGHT WAS IF YOU HAVE A PRIMARY INFECTION, YOU HAVE NO IMMUNITY SO YOU'RE MUCH MORE LIKELY TO END UP WITH A BABY WITH SEQUELAE. THIS IS A STUDY WE DID IN 1992. IT FORMED THE BASIS FOR PROPOSING DEVELOPMENT OF A CMV VACCINE. AND SOME PEOPLE STILL USE IT. I PERSONALLY DON'T BECAUSE I KNOW THAT A LOT OF THESE PATIENTS WERE ACTUALLY PROBABLY NOT NON-PRIMARIES. THEY WERE -- THESE PRIMARIES WERE NON-PRIMARIES. SO IF WE LOOK AT THAT AND AGAIN MORE RECENT RE-EVALUATION OF THE DATA, IF WE LOOK AT NON-PRIMARY INFECTIONS AND PRIMARY, THESE ARE WHEN IT WAS ESTABLISHED COMMUNITY AND DEVELOPED OR HAD A BABY WITH CONGENITAL CMV, WE FIND ABOUT 11% HAD THESE INFANTS BORN TO THESE WOMEN WITH SYMPTOMATIC INFECTION VERSUS 11% WITH PRIMARY INFECTION. SAME THING WAS FOUND MANY YEARS AGO IN SWEDEN. IN THE EARLY 80s AND FINALLY PUBLISHES IN A LARGER SERIES BY KARIN IN 1999 AND AGAIN LOOKING AT SYMPTOMATIC AT BIRTH FOLLOWING PRIMARY INFECTION ABOUT THE SAME NUMBER NEUROLOGIC SEQUELAE ABOUT THE SAME NUMBER. SO, NOT CLEAR THAT NON-PRIMARY INFECTION IS A PREDICTER THAT WILL HAVE A GOOD UTCOME. THIS IS WORK DONE SHOWING THE SAME THING WITH PRIMARY AND NON-PRIMARY AND I WANT YOU TO LOOK AT ANY SEQUELAE ABOUT THE SAME IN BOTH GROUPS. AND FINALLY, JUST TO PUT IN FOR MY COLLABORATORS IN BRAZIL. THIS IS A STUDY WE ARE DOING IN BRAZIL MATERNAL SEROPREVALENCE IS 96% AND THAT IS BY A LICENSE SO MY VIEW PROBABLY ALMOST ALL THOSE WOMEN HAVE BEEN INFECTED WITH CMV PROBABLY BY THE TIME THEY ARE 12 OR 15 YEARS OF AGE. RATES OF CONGENITAL CMV ARE 1% AND SYMPTOMATIC RATES ARE 8% WHICH IS WHAT WE SEE IN THE UNITED STATES AND LONG TERM SEQUELAE ALL OF THEM CAME FROM THE BABIES WITH NON-PRIMARY FINN FECKS. THAT'S NOT A GOOD PREDICTER. MAYBE FOR ZIKA BUT I THINK THAT'S STILL SOMETHING WE HAVE TO FIGURE OUT. NEXT WHAT ABOUT VIRAL BURDEN? AND THAT IS CAN WE PICK UP BABIES EARLY ON IF THEY HAVE LOTS OF VIRUS IN THEIR BLOOD? IS THAT A PREDICTER THERE WILL BE A BAD OUTIN? SNOW. THESIS ARE BABIES WITH HEARING OR WITH ABNORMAL HEARING AND NORMAL HEARING AND ABNORMAL HEARING AND NORMAL HEARING. THE MEDIANS LOOK DIFFERENT BUT IF YOU SEE THE OVERLAP IS ENORMOUS HERE. NOT A GOOD PREDICTER FROM BLOOD VIRAL LOAD. WHAT ABOUT CENTRAL NERVOUS SYSTEM ABNORMALITIES? THESE ARE AUTOPSY FINDINGS SO THAT IS CLEARLY AN ADVERSE OUTCOME IF YOU'RE A PATIENT F YOU'RE AN AUTOPSY FINDING. BUT THIS IS TO SHOW THAT THERE IS LOTS OF INVOLVEMENT OF THE BRAIN. MANY DIFFERENT AREAS OF THE BRAIN ASSOCIATED WITH WHY. MORE. V AND CALCIF CAITION AND SO IT GOES ON AND ON. SO THERE IS REALLY THE WHOLE SPECTRUM OF ABNORMALITIES IN THE BRAIN. AND IMAGING, SIMILARLY WE SEE THE SAME THINGS IN PATIENTS THAT WERE IMAGED. ABNORMALITIES IS CLEARLY A PREDICTER OF ADVERSE OUTCOME AND I THINK WE SEE THAT ALSO WITH THE ZIKA PATIENTS. INTERESTINGLY ENOUGH, AND THIS IS AN INTERESTING -- THIS IS A VERY NORMAL STUDY DONE BY A COMPULSIVE TO APOLOGIST IN NEW ZEALAND. HE AUTOPSIED 90% OF ALL THE PERINATAL DEATHS IN HIS HOSPITAL, PERSONALLY AUTOPSYIED ALL OF THIS THEM AND LOOKED FOR A NUMBER OF DIFFERENT ABNORMALITIES. ONE OF THE THINGS HE LOOKED FOR WAS CONGENITAL CMVN THOSE DAY HE DIDN'T HAVE PCR. HE HAD VIRAL CULTURE BUT DIAGNOSIS THEM BY PATHOLOGIC FINDINGS AND OTHERS THAT YOU SEE. HE FOUND 16 BABIES WITH CONGENITAL CMV. 9 OF THEM WERE LIVE BIRTHS. 8 HAD THESE TOTAL PATIENTS HAD CNS LESIONS. INTERESTING ENOUGH, 4 OF THESE HAD NO OTHER FINDINGS WHATSOEVER. THESE WERE COMPLETELY ASYMPTOMATIC BABIES BUT THEY HAD CENTRAL NERVOUS SYSTEM -- AGAIN SUGGESTING THAT SEEING A BABY WITHOUT ANY SYMPTOMS AT BIRTH DOESN'T SUGGEST THAT THE CENTRAL NERVOUS SYSTEM IS NOT INVOLVED. WE ROOKED AT THIS MORE RECENTLY LOOKING AS THIS AS A PREDICTEDDER OVHEARING LOSS. WE TOOK OUT THE OTHER FINDINGS SUCH AS -- THAT RESOLVED AND JUST CENTRAL NERVOUS SYSTEM INVOLVEMENT AND YOU CAN SEE IT'S A GRATED PREDICTEDDER OF HEARING LOSS IN THESE INFANTS. SO AGAIN, SEEING THE CENTRAL NERVOUS SYSTEM INVOLVED IS PROBABLY SOMETHING WE OUGHT TO REALLY FOCUS ON IN TERMS OF FOLLOWING THESE BABIES FOR ADVERSE OUTCOMES ANY WAY WE CAN COME UP WITH TO DO A EVALUATION OF THE CENTRAL NEW YORK SYSTEM. MICROCEPHALY, ABNORMAL CNS IMAGING AND ABNORMAL EYE EXAMS POINT TO THE CENTRAL NERVOUS SYSTEM, SOMETHING WE SHOULD FOLLOW. AND WITH THAT OKAYS - THIS IS THE SLIDE I BUILT FROM THAT. THESE ARE THE OLD DAYS WHERE WE TRIED TO DIE COT MYSELF THE OUTCOMES OF CMV. -- MORE SEQUELAE IF YOU HAD SYMPTOMATIC INFECTION OR PRIMARY INTERNAL INFECTION OR A NON-PRIMARY INFECTION. DIDN'T REALLY WORK THAT WELL. OY WE OUGHT TO LOOK AT THE SEVERITY OF THE CENTRAL NERVOUS SYSTEM INVOLVEMENT AND LOOK AT TO THE AS A CONTINUUM AND NOT A BINARY, EITHER HAVE YOU IT OR YOU DON'T. AND LAST SLIDE OF ALL, AGAIN FOR THE PEOPLE IN THE AUDIENCE THAT DON'T CARE OR DON'T KNOW ABOUT CMV. I SHOULDN'T SAY YOU DON'T CARE ABOUT IT. IF YOU LOOK AT CLINICALLY APPARENT SYMPTOMATIC INFECTIONS 90% OF THE CASES BUT SEQUELAE ABOUT 3 PER 100 BABIES INFECTED WITH CMV RESULT ARE CLINICALLY IMPAIRED OR SYMPTOMATIC INFECTIONS. 9 PER 100 ARE FOUND IN THE BABIES THAT WOULD NOT BE DETECTED IN A NURSERY UNLESS YOU SCREENED. I THINK THIS IS WHERE WE PROBABLY PUT OUR MONEY ON WITH ZIKA ALSO. I'LL STOP THERE. THANK YOU. [ APPLAUSE ] >> THANK YOU FOR A TERRIFIC PRESENTATION. I'LL KICK THIS OFF. THE QUESTIONS OFF. SOMETHING THAT RELATES BACK TO YOUR COMMENT ON POTENTIAL FOR REINFECTION AND I GUESS THE ISSUE AROUND PRE-EXISTING IMMUNITY. WHAT DO YOU THINK ABOUT THE REPORTS THAT WE HAVE BEEN HEARING SPREADING BACK TO ASIAN COUNTRIES AND SHOULD WE BE REALLY NOT SO COMPLACENT ABOUT POTENTIALLY SEEING CASE THERES EVEN THOUGH THEY HAVE -- IT'S THE SAME STRAIN? >> SO I THINK THAT IS A VERY GOOD POINT AND I SEE -- LOOKING AT ME AND I KNOW SHE HAS BEEN ON A LOT OF TELEPHONE CALLS WITH ME AND WE SPEND A LOT OF TIME TRYING TO FIGURE OUT HOW TO DIAGNOSIS ZIKA VIRUS INFECTIONS SEAR LOGICALLY. A LOT OF MONEY IS RIDING ON THE IDEA THAT AREN'T BODIES PROTECT YOU FROM THIS VIRUS BUT A LOT OF THE PROBLEMS WITH DIAGNOSTICS IS THE PEOPLE WHO DON'T HAVE ZIKA THAT HAVE DENGUE AND EVERYTHING ELSE HAVE A LOT OF ANTIBODIES THAT RECOGNIZE ZIKA. AND ALL THE TESTS THAT WE DO FOR ZIKA, NONE OF THEM ARE QUALITATIVE. THEY ARE ALL QUANTITATIVE. IN OTHER WORDS THERE IS INCREASE ABOVE THE DENGUE SEROLOGIY. SO I'M NOT COMPLETELY CONVINCED THAT WE ARE NOT GOING TO SEE PERHAPS NEW ZIKAS OR OLD ZIKAS OR THE NEW ZIKA VISITING OLD POPULATIONS LET'S SAY. SO I DON'T KNOW. I THINK THAT IS SOMETHING FOR THE ZIKA VIROLOGISTS TO DEAL WITH. >> PHILIP LINEY FROM DUKE. COULD YOU COMMENT ON YOUR BACKING THE ARGUMENT ABOUT PRIMARY VERSUS NON-PRAMY. COULD YOU TALK ABOUT REACTIVATION VERSUS INFECTION. >> I'D LOVE TO. EVERYBODY CAN GO TO LUNCH AND WE CAN JUST TALK. [ LAUGHS ] SO THE WHOLE REACTIVATION THING IS BASED ON ANCIENT RESTRICTION MAPPING. OKAY? ANCIENT. PUBLISHING IN THE NEW ENGLAND JOURNAL IN 1976 OR SOMETHING. CLARK WONG FROM U IN. C. YOU LOOK AT THOSE GELS AND NOT COMPLETELY CONVINCING THOSE WERE REACTIVATION. YOU COULD EVEN ARGUE THERE IS A NEW VIRUS. RIGHT OFF TO YOUR LEFT IS SIRESH AND WE SPENT A LONG TIME LOOKING AT REINFECTION AND IT TURNS OUT THAT IT IS QUITE EASILY TO DEMONSTRATE IN THE BRAZILIAN POPULATION, REINFECTION RATE IS 20% DURING PREGNANCY. YOU CAN RECOVER THE NEW VIRUS THEY WERE REINFECTED WITH FROM THE BABY. NOW, ARE YOU GOING TO TELL ME THAT IS NOT ENDOGENOUS REACTIVATION THAT APPEARS AS AIDS NEW INFECTION? CAN'T ARGUE THAT. ALL I CAN TELL YOU IS WOMEN HAD NO SEROLOGIC RECOGNITION OF THAT VIRUS UNTIL THAT PREGNANCY. SO IN OTHER WORDS IF IT WAS IN THEM, IT WAS QUIET. AND THEN IT CAME OUT. SO I CAN'T -- UNTIL I CAN DO A CHALLENGE TEST IN A PREGNANT WOMAN WHICH I DON'T THINK I WANT TO DO TO LOOK FOR REINFECTION, I DON'T THINK I CAN ANSWER THAT QUESTION. BUT FINALLY, I'M SORRY. HE HIT A REAL SWEET SPOT WITH ME. LEWIS PICKER AT THE OREGON PRIMATE CENTER HAS TONSE OF MONEY FROM AID, FROM GATES, AND HE IS DEVELOPING A CMV VECTOR VACCINE FOR HIV. AND THE BASIS OF THAT IS THAT HE CAN TAKE RHESUS MACAQUES THAT ARE RHESUS CMV CLOSELY RELATED TO HUMAN AND READILY REINFECT THEM WITH A VARIETY OF ANTIGENS FROM TB, FROM HIV, FROM PROBABLY ZIKA BY NOW AND REPEATEDLY REINFECT. IMMUNITY IS SOFT WITH CMV. >> THANK YOU. >> ONE MORE QUESTION. >> LAURA RILEY, MASS GENERAL. I TOO AM A MA TERNITY FETAL MEDICINE SPECIALIST. SO ON THAT LAST SLIDE YOU SHOWED WITH THE THREE PER 1000 VERSUS 9 PER THOUSAND, IS ANY OF THAT INFLUENCED BY PREGNANCY TERMINATION AT ALL? THAT WE SEE NOW? IT WOULDN'T BE, RIGHT? >> I'M SORRY? >> SO I'M WONDERING BECAUSE I WOULD SAY IN THE US ANYWAY, MOST WOMEN WHO HAVE PRIMARY CMV IN WHOM WE MAKE THE DIAGNOSIS, THEY ARE COUNCIL ABOUT NOTHING THAT CAN BE DONE AND LOTS WILL TERMINATE THEIR PREGNANCY. SO YOU DON'T SEE THOSE BABIES ANYMORE. >> THERE ARE TWO EASY ANSWERS. MOST OF THAT DATA WAS GENERATED PROBABLY 20 YEARS AGO AND SECONDLY, THAT DATA COMES FROM ALABAMA. TERMINATION IS A WORD THAT IS NOT ROUTINELY USED IN ALABAMA. >> OKAY. >> I'LL LET IT GO AT THAT. >> GREAT. CAN I ASK ANOTHER QUESTION. >> YOU MAY. >> AND SO THINKING OF USING CMV AND THE -- I'M ASSUMING THIS IS THE ANALOGY THAT IS BEING USED FOR ZIKA, MOST OF OUR CONCEPTION COUNSELING PERICONCEPTION INFECTION AND OUTCOME FOR THE BABY, CAN YOU COMMENT ON THAT? BECAUSE I FEEL LIKE THAT MUST BE WHAT WE ARE EXTRAPOLATING WHEN WE ARE SORT OF GIVING COUNSELINGS TO ZIKA. >> YES. I THINK THAT IS A REALLY EXTRAORDINARILY TOUGH QUESTION. I MEAN, I DON'T HAVE AN ANSWER BECAUSE I THINK WHAT YOU'RE ASKING IS, AND I THINK IT'S A GREAT QUESTION. DO WE HAVE A MARKER, BIOMARKER OR SOME PREDICTER THAT SAYS LIKELIHOOD OF YOUR FETUS BEING DAMAGED BY THIS INFECTION IS SIGNIFICANT. AND WE REALLY DON'T HAVE THAT OF THE WE HAVE THAT -- I MEAN, I HAVE GONE THROUGH THIS LOTS OF TIMES WITH WOMEN WITH CMV INFECTIONS OR THE OB STRA TRICIAN DRAWS A SEROLOGY. I HAVE ONE IN MY E-MAIL FROM GERMANY ASKING THESE QUESTIONS. WE DON'T HAVE ANY WAY EXCEPT TO GIVE PEOPLE NUMBERS. YOU'RE A PHYSICIAN. MEDICINE IS BINARY, EITHER YOU GOT IT OR YOU DON'T. SO, I DON'T HAVE AN ANSWER. >> OTHER QUESTIONS? WE HAVE TIME STILL. >> STANFORD. SO, WE KNOW FROM STUDYING CMV AND HAVING EXPERIENCE WITH CMV THAT POSSIBLY PERINATAL INFECTIONS WOULD NOT LEAD TO ADVERSE NEUROLOGICAL OUTCOME. NOW I KNOW WE WON'T KNOW THAT UNTIL WE HAVE SOME CLINICAL DATA WITH ZIKA VIRUS, BUT DO YOU THINK THAT FROM THE PATHOGENESIS STANDPOINT WE CAN EXTRAPOLATE? >> ABSOLUTELY NOT. I MADE THAT STATEMENT NOT TO BE FLIPPABILITY. I JUST MADE THE STATEMENT -- FLIPPANT -- I'M NOT AWARE OF DATA THAT STRONGLY SUGGESTS THAT PERINATAL ACQUISITION OF ZIKA IN A WELL-CONTROLLED STUDY LED TO ADVERSE OUTCOMES. BUT I HAVE NO INFORMATION FOR THAT. AND I AGREE WITH YOU. IT'S PROBABLY THESE ARE DIFFERENT VIRUSES. >> SO, ACTUALLY I HAVE ONE MORE QUESTION, BILL. WHEN YOU MADE THE EXCEPT ABOUT VIRAL LOAD, QUANTIFICATION AND -- THE COMMENT -- IT'S YOUR CMV SO WHEN I LOOK AT THE OVERARCHING QUESTION ABOUT WHAT WE CAN TAKE FROM LEARNING ABOUT OTHER CONGENITAL INFECTIONS IS THE SUGGESTION HERE YET OR DO WE NOT HAVE ENOUGH DATA YET THAT VIROLOGIC QUANTIFICATION WILL OR WILL NOT BE HELPFUL AT LOOKING AT OUTCOMES EVENTUALLY IN ZIKA? >> AGAIN, I DON'T HAVE AN ANSWER BUT I WOULD PROPOSE THAT VIROLOGIC MONITORING WOULD PROBABLY BE VERY USEFUL DURING THE INITIAL PHASE OF THE ZIKA VIRUS INFECTION BUT FOR INSTANCE IF YOU COULD MONITOR THE VIRAL LOAD IN A FETUS AT 12 WEEKS, THAT WOULD PROBABLY BE VERY INFORMATIVE. BUT, A FEET US THAT IS INFECTED IN 12 WEEKS AND MONITORING VIRAL LOAD AT 36 WEEKS, I'M NOT SURE THAT IS GOING TO REFLECT WHAT YOU'RE LOOKING FOR. YOU'RE PROBABLY GOING TO BE MUCH MORE THAN FROM MONITORING THE TISSUE THAT WAS AFFECTED THAN THE VIRUS AT THAT POINT. >> THANK YOU. I THINK IF THERE ARE NO MORE QUESTIONS, WE CAN CLOSE THIS SESSION AND MOVE ON TO OR CLOSE THIS TALK AND MOVE ON TO LUNCH AND COME BACK PROMPTLY. [ APPLAUSE ] COME BACK AT 1:15. >> I HAVE 1:20 ON MY WATCH SO WE'LL BEGIN THE AFTERNOON SESSION. WELCOME AGAIN, EVERYBODY. I HOPE YOU ENJOYED YOUR LUNCHES. WE'LL BEGIN WITH THE AFTERNOON SESSION. IT IS MY PLEASURE TO INTRODUCE OUR SECOND SPEAKER OF THIS SESSION, FOCUSING ON THE IMPACT OF CHILD, DR. SONJA RASMUSSEN, DR.S ARE ACCEPT IS EDITOR IN CHIEF OF -- DR. RASMUSSEN, CHIEF OF MMWR SERIES AND DIRECTOR OF PUBLIC HEALTH INFORMATION DISSEMINATION. SHE'S ALSO BOARD CERTIFIED PEDIATRICIAN AND CLINICAL GENETICIST AND AUTHORED MORE THAN 200 PEER REVIEWED PAPERS. SHE PLAYED A LEADERSHIP ROLE IN SEVERAL CDC EMERGENCY RESPONSES TO INFECTIOUS DISEASES INCLUDING THE 2009 A 1N 1 INFLUENZA, CORONA VIRUS, EBOLA VIRUS AND NOW ZIKA VIRUS. SO SHE BRINGS A WEALTH OF EXPERTISE TO THE TABLE, SHE WILL TALK TO US TODAY ABOUT MICROCEPHALY AND OTHER BRAIN ABNORMALITIES. WE'LL GIVE US A BIT OF A BIRDS EYE VIEW OF THE UPDATED CDC INTERIM GUIDANCE. WELCOME. >> THANK YOU, BILL, PLEASURE TO BE HERE THIS AFTERNOON TO TALK ABOUT MICROCEPHALY AND BRAIN ABNORMALITIES. AND THEN I WILL ALSO AS HE MENTIONED BE TALKING TO YOU ABOUT THE MOST UPDATED INFANT GUIDANCE -- INTERIM INFANT GUIDANCE WE PUT TOGETHER FROM CDC. SO I'M GOING TO BEGIN WITH LOOKING AT WHAT WE KNOW ABOUT THE PATHOGENUSES OF CONGENITAL ZIKA SYNDROME, WHAT WE KNOW ABOUT ZIKA VIRUS INFECTION. WE BELIEVE THE INITIATING FACTOR OF THIS IS DESTRUCTION OF CNF TISSUE AND DECONSTRUCTION OF NEURODEVELOPMENTAL PROCESSES BUT THE INFECTION OF ZIKA VIRUS IN CELLS IN THE BRAIN. WE KNOW THAT ZIKA VIRUS HAS FROM BASIC SCIENCE STUDIES ZIKA PRICERRER VIRUS HAS A PREDILECTION TOWARDS NEUROPROGENERALTOR CELL BUT OTHER TYPES OF CELLS AS WELL SO THAT'S THE FIRST STEP, AFFECTING THE BRAIN CELLS. AND THAT RESULTS IN LOSS OF BRAIN VOLUME AND NEUROLOGIC DYSFUNCTION. LOSS OF BRAIN VOLUME IS WHY WE SEE THE SEVERE MICROCEPHALY AND YOU HAVE HEARD THIS MORNING ALREADY ABOUT THIS, YOU HAVE HER ABOUT FETAL BRAIN DISRUPTION SEQUENCE, I WILL TALK MORE ABOUT THAT. WE BELIEVE THE DESTRUCTION OF THE BRAIN CELLS ARE LEADING TO COLLAPSE OF SKULL. I WILL SHOW YOU 3-D CT THAT GIVE VISUAL EMPHASIS HOW THAT'S OCCURRING. SO THAT RESULTS IN OVERLAPPING SUTURES APPROXIMATE REDUNDANCY OF THE SCALP, OVERLAPPING SCALP -- THE -- YOU SEE IS BECAUSE THE SCALP IS GROWING WITH THAT SKULL, WHEN THE SKULL COLLAPSES DOWN YOU SEE THAT OVERFOLDING OF THE SCALP TISSUE. THEN THE NEUROLOGIC DYSFUNCTION WHEN THERE'S DECONSTRUCTION OF BRAIN TISSUE THERE'S NEUROLOGIC DYSFUNCTION AS YOU EXPECT. WE SEE HEARING VISION SWALLOWING PROBLEMS GLOBAL DEVELOPMENTAL IMPAIRMENT, LIMB CONTRACTURE SO THAT'S CLUB FOOT AND ARTHEROHYPERTONIA, HYPOTONE Y EPILEPSY, YOU SEE EXTREME IRRITABILITY AND THE PROGRAM TALL AND EXTRA PROGRAM TALL SIGNS SHE SHOWED IN PICTURES TODAY. THOSE WHAT WHAT WE'RE SEEK WHAT WE THINK OF NOW SAYING CONGENITAL ZIKA SYNDROME. THAT'S RECOGNIZABLE PATTERN OF ABNORMALITIES THAT HAS BEEN SEEN IN THESE KIDS. AND IT IS SIMILAR TO WHAT HAS BEEN SEEN, SIMILAR RECOGNIZABLE PATTERN WHAT WAS SEEN IN OTHER TERATOGENS EARLY ON. CONGENITAL RUBELLA SYNDROME, I WANT TO EMPHASIZE WHEN WE SEEN PREVIOUS TERATOGENS WE SEE THE TIP OF THE ICEBERG AS WE HEARD EARLIER TODAY, FIRST. AND LIKELY THIS IS THE TIP OF THE ICE BESTING AND THERE WILL BE CHILDREN WITHOUT THE FULL CONGENITAL STUDY SYNDROME BUT HAVE CONGENITAL AFFECTS OF ZIKA. SO I WANT TO SHOW AGAIN, YOU SAW PICTURES FROM DR. MOORE'S PAPER TODAY EARLIER, THE FATAL BRAIN DISRUPTION SEQUENCE, THE PHENOTYPE GAVE US THE SENSE THAT THIS WAS A REAL TERATOGEN, BEFORE THE EPIDATA, BEFORE THE EPIDEMIOLOGIC DATA WAS CONVINCING WE FELT THIS PHENOTYPE WAS CONVINCING. THE PHENOTYPE WAS FIRST DESCRIBE BY RUSSELL AND COLLEAGUES IN 1984 THOUGH IT HAD BEEN PICTURES HAD BEEN DESCRIBED IN FRENCH ANATOMY BOOK AS FAR AS BACK AS 1836. IT IS A BRAIN DISRUPTION, MICROCEPHALY, AND NEUROLOGIC IMPAIRMENT. THERE'S A REVIEW BY RIVERA DONE IN 2001, ALL THE CASES EVER REPORTED IN THE LITERATURE AT THAT TIME WERE INCLUDED IN THAT PAPER AND THERE WERE ONLY 20 CASES IN 2001. SO THIS IS A RARE PHENOTYPE BEFORE ZIKA. NOW THERE ARE A LOT OF KIDS WITH THIS BUT BEFORE ZIKA THIS WAS RARE. AND THOSE CASES THAT CORONA RIVERA REPORTED HAD INFECTION, ONE CASE APPEARED TO BE POSSIBLY A CMV INFECTION, ONE CASE HAD A PREVIOUS FEVER, THERE WAS CASE WITH A VASCULAR DISRUPTION THAT APPEARED A STROKE LIKE EVENT SO THE DIFFERENT THINGS THAT CAUSE THAT INITIAL CNS DESTRUCTION LEADS TO IN SEQUENCE, THAT'S WHY IT'S CALLED DISRUPTION SEQUENCE THAT LEADS THE OTHER ABNORMALITIES. THESE ARE PICTURES FROM THE 1990 SERIES THAT DR. MOORE PUBLISHED BACK THEN. SO I WILL TALK A LITTLE BIT ABOUT THE CRANIAL MORPHOLOGY AND SOME OF THIS YOU ALREADY HEARD BUT HOPE REVIEW IS GOOD. THESE OFTENTIMES NOT ALWAYS BUT OFTEN TIMES HAVE SEVERE MICROCEPHALY MOST HAVE BEEN GREATER THAN THREE STANDARD DEVIATIONS BELOW THE MEAN, KIDS WITH CONGENITAL ZIKA SYNDROME, AS PART OF THAT FETAL BRAIN DISRUPTION THERE'S COLLAPSE OF THE SKULL WITH OVERLAPPING SUE CHUS. YOU HEARD DR. VAN DER LINDEN OCCIPITAL BONE PROMINENCE. THAT'S OFTENTIMES A SMALL OR ABSENT FONTANEL, WE HEARD FROM BRAZIL IT'S DIFFICULT IN SOME CASES TO DO HEAD ULTRASOUND. ALL THOSE FINDINGS ARE CONSISTENT WITH THE FETAL BRAIN DISRUPTION SEQUENCE REPORTED BACK IN 1984. IT'S IMPORTANT NOTE NOT ALL KIDS WITH ZIKA INFECTION HAVE FETAL BRAIN DISRUPTION SEQUENCE AND NOT ALL BRAIN DISRUPTION SEQUENCE IS ZIKA. SO YOU HAVE TO THINK ABOUT OTHER POSSIBLE CAUSES OF BRAIN DISRUPTION SEQUENCE, THERE ARE GENETICS CAUSES AND OTHER CAUSES. SO JUST SEEING THIS PHENOTYPE IS NOT ENOUGH FOR THE DIAGNOSIS IN AND OF ITSELF. SO THIS IS A PICTURE OF THE CRANIAL MORPHOLOGY, HERE YOU CAN SEE OVERLAPPING FEATURES. THE FRONTAL BONES HAVE UNDERLYING THE PARIETAL BONE AND THE OCCIPITAL STAYS PRETTY MUCH IN ITS PLACE, THAT'S WHY IT'S PROMINENT, YOU CAN SEE ON THE LEFT THE SKULL X-RAY THE PROMINENCE OUT THE BACK OF THE HEAD AND ON THE RIGHT THE OTHER WAY THE OCCIPITAL PROMINENCE ON CT. SO HOPE THAT'S CLEAR. YOU CAN SEE HOW DISTINCTIVE IT IS FROM NORMAL SKULL. SO WHAT ARE THE BRAIN ANOLLIES? THIS WAS DISCUSS -- ANOMALIES? THIS WAS A REVIEW. THIN CEREBRAL CORTEX, YOU SAW PICTURES PRESENTED THIS MORNING. INTRACRANIAL CALCIFICATIONS, SUBCORTICAL IN LOCATION SEEN IN OTHER CONGENITAL VIRAL INFECTION. THERE'S HYDROCEPHALUS AND HYDROCEPHALUS HYDROENCEPHALY, THERE'S GYRE ABNORMALITIES AND FROM THE EXPERTS IN NEUROIMAGING WHICH I'M NOT ONE OF THOSE, THAT IT'S POLYMICROEYE RA, NOT IN SENLY. THERE'S ALSO OFTENTIMES ABSENT OR HYPOPLASTIC CORPUS CASH FLOW SUM AND HYPERPLASIA OF THE CEREBELLUM. AND HERE YOU CAN SEE THE CALCIFICATIONS, SUBCORTICAL CALCIFICATIONS IN THESE PICTURES HERE, YOU CAN SEE THE FLATTENING THE SKULL COLLAPSED, LITTLE BIT OF THE OCCIPITAL PROMINENCE. YOU CAN SEE A NORMAL CEREBELLUM BUT THIS -- OBESE CEREBELLUM IS ALMOST COMPLETELY GONE. YOU CAN SEE LARGE AREAS OF FLUID, BOTH IN THE VENTRICLES AND EXTRA AXIAL, SO THAT'S HYDROCEPHALUS. A LOT OF THIS STARTED TO BE NOTED BECAUSE OF MICROCEPHALY. I WANT TO BE SURE WE TALK ABOUT MICROCEPHALY, BUT NOT MAKE TOO BIG A DEAL ABOUT THE MICROCEPHALY. IT'S NOT THE MICROCEPHALY, IT'S THE UNDERLYING BRAIN DEFECT THAT RESULTS IN MICROCEPHALY THAT HELPED US TO IDENTIFY THIS IN THE FIRST PLACE. SO THIS IS A PICTURE THAT HAD BEEN DONE BY BIRTH EFFECTS GROUP AT CDC A CHILD WITH TYPICAL HEAD SIZE AND A CHILD WITH SEVERE MICROCEPHALY, SHOWING SOME OF THOSE CALCIFICATIONS AND LARGE VENTRICLES. WITH FLUID. WE HAVE PUT TOGETHER CASE DEFINITION OF MICROCEPHALY. SO AS PEOPLE THINK ABOUT RESEARCH STUDY YOU HAVE TO CHOOSE WHAT YOUR CASE DEFINITION IS GOING TO BE BUT I WANT TO MENTION THAT AT THE START OF THIS OUTBREAK, THIS IS ONE OF THE NICHES THAT'S COMPLICATED THINGS THAT MICROCEPHALYS THROUGH THE YEARS HASN'T HAD A STANDARD CASE DEFINITION. SOME SAY LESS THAN THIRD PERCENTILE, SOME LESS THAN 5TH PERCENTILE, TWO STANDARD DEVIATIONS BELOW THE MEAN, THREE STANDARD DEVIATIONS BELOW THE MEAN. EVEN IF PEOPLE MEASURE EVERY KID THEY MAY HAVE DIFFERENT DEFINITIONS AND DIFFERENT RATES OF MICROCEPHALY, EVEN THE BIRTH SYSTEMS IN THE U.S. THE RATE OF MICROCEPHALY, THE BIRTH PREVALENCE VARIES WIDELY IN THE PAST. SO WHAT HAS BEEN SELECTED BY CDC FOR OUR STUDIES IS HEAD CIRCUMFERENCE, CENTER FOR GESTATIONAL AGE AND SEX SO THINK ABOUT GESTATIONAL AGE AND BABY SEX. AND THAT WAS REALLY BECAUSE THAT'S WHAT MOST PEDIATRICIANS WITH HAVE IN THEIR OFFICE. IT ISN'T THAT'S SOMETHING MAGIC WE THOUGHT THIS WAS BETTER THAN OTHERS. WE ALSO MADE A SPECIFIC DEFINITION OF POSSIBLE CONGENITAL MICROCEPHALY. AND THAT WOULD BE IF FOR SOME REASON BABY HEAD WASN'T MEASURED UNTIL AFTER SIX WEEKS OF LIFE, HARD TO KNOW IF IT WAS CONGENITAL NORTH BUT IF HEAD CIRCUMFERENCE IS LESS THAN 3RD PERCENTILE IT'S CONSIDERED POSSIBLE CONGENITAL MICROCEPHALY. ALSO IMPORTANT HEAD CIRCUMFERENCE IS MEASURED RIGHT, IT IS EASY TO MEASURE, NOT THAT EASY, I HAVE SEEN A LOT OF INCORRECT HEAD CIRCUMFERENCE MEASUREMENTS EVEN IN KIDS WITH NORMAL HEAD CIRCUMFERENCE BUT EASIER WITH A KID WITH NORMAL HEAD SIZE, IT'S THE BROADEST THE HEAD IS BROADEST PLACE IN THE FOREHEAD AND THEN THE BROADEST PLACE IN THE BACK OF THE HEAD, ABOVE THE EARS, BUT YOU CAN IMAGINE ESPECIALLY IF YOU THINK ABOUT SOME OF THE BABIES THAT YOU SAY PICTURES OF, WHERE THERE'S NOT A FOREHEAD, IT IS CHALLENGING IN THESE CHILDREN WITH FETAL BRAIN DISRUPTION SEQUENCE. ANOTHER ISSUE THAT YOU NEED TO ADDRESS IS WHETHER THE HEADS CIRCUMFERENCE IS MEASURED THE FIRST 24 HOURS OF LIFE, MOST OF YOU KNOW WHEN BABIES HAVE -- VAGINAL DELIVERY OCCURS OFTEN TIME THERE'S SIGNIFICANT MOLDING. SO THE HEAD CIRCUMFERENCE MIGHT NOT BE EVIDENT UNTIL 24 TO 36 HOURS. SOME SAID WAIT UNTIL THEN, MOA MOST MEASUREMENTS HAVE BEEN DONE THE GROWTH CURVES ARE DONE EARLIER ON. SO WHEN YOU THINK ABOUT DOING A STUDY TO GET CAREFUL MEASUREMENTS AND HAVE IT CONSISTN'T ACROSS YOUR STUDY, YOU NEED TO THINK ABOUT THOSE SORTS OF ISSUES AS WELL. YOU NEED TO THINK OF WHAT GROWTH CURVES AND THIS IS HARD FOR PEOPLE TO SEE BUT I WANT TO EMPHASIZE YOU HAVE TO PICK SOME GROWTH CURVE, THERE'S PROBABLY NOT ONE BETTER THAN THE OTHER BUT YOU NEED TO PICK ONE WHEN -- FOR MEASUREMENTS THAT INCLUDES GESTATIONAL AGE AND SEX MEASUREMENTS. SO NOW I'LL SWITCH GEARS AND TALK ABOUT OUR INTERIM GUIDANCE FOR EVALUATION AND MANAGEMENT OF INFANTS WITH CONGENITAL ZIKA VIRUS INFECTION. I WANT TO EMPHASIZE AT THE START THIS IS INTERIM GUIDANCE AND WE HAD PUBLISHED GUIDANCE EARLIER THIS YEAR AND WE KNOW IF WE WAIT FOR ALL THE INFORMATION TO COME IN IT WOULD BE TOO LATE TO GUIDE RIGHT NOW SO WE HAVE COME UP WITH GUIDANCE, WE WILL CHANGE THAT GUIDANCE WHEN WE GET NEW INFORMATION. I EXPECT, I WOULD GIVE YOU ABOUT 100% CHANCE THIS GUIDANCE WILL GET CHANGED IN THE NEURO. THIS WAS THE BEST ADVICE WE CAN GIVE TO PEDIATRICIANS RIGHT NOW. ONE OTHER THING THAT I WANTED TO MENTION IS THIS IS FOR CLINICAL CARE, THIS IS NOT FOR RESEARCH. I THINK LOTS OF TIMES YOU MIGHT THINK I LIKE TO KNOW THIS OR THAT. LIKE TO KNOW THAT TOO, WE'RE TRYING TO THINK ABOUT WHAT SHOULD WE RECOMMEND TO A PEDIATRICIAN IN AN OFFICE IN PUERTO RICO OR SOME OTHER PLACE IN THE UNITE SEEING A BABY. THIRDLY WE WERE WEIGHING A LOT OF THE TIME AND IN THE MEETING THAT WE HAD WITH AAP, WE WERE WEIGHING NOT WANTING TO PANIC PARENTS, NOT TRYING TO CREATE A VULNERABLE CHILD WHEN THERE HAVEN'T EVIDENCE SOMETHING COULD CAUSE PROBLEMS. SO YOU LESSEE SOMETIMES YOU MIGHT THINK WHY WOULDN'T YOU WANT TO CONTINUE TO FOLLOW THAT KID? WE WILL CONTINUE TO FOLLOW THAT CHILD, THE CHILD WILL BE FOLLOWED IN THE ZIKA REGISTRY IN U.S. OR AMERICAN SAMOA OR U.S. VIRGIN ISLANDS OR DIFFERENT ZIKA ACTIVE SURVEILLANCE PREGNANCY SURVEILLANCE SYSTEM IN PUERTO RICO SO THE KIDS WILL CONTINUE TO BE FOLLOWED. THROUGH THE FIRST YEAR OF LIFE TRY TO GET ADDITIONAL INFORMATION. SO WE'LL BE CONTINUING TO ACCUMULATE INFORMATION AS WE GO ON, THIS IS OUR BEST GUIDANCE AT THIS TIME. SO BECAUSE WE KNEW THAT THERE REALLY WASN'T A LOT OF DATA, THERE WEREN'T A LOT OF DATA OUT THERE, THERE'S A LOT OF CASE REPORTS AND A FEW CASE SERIES OF KIDS WITH ZIKA INFECTION, WE COULDN'T COUNT ON COMPLETELY ON DATA WHEN WE PUT TOGETHER THIS GUIDANCE. SO WE WANT TO WORK WITH THE SMARTEST PEOPLE WE COULD FIND AND COLLABORATED WITH THE AMERICAN ACADEMY OF PEDIATRICS AND OUR AAP COLLEAGUES ARE HERE AND I'M GRATEFUL TO SAM AND LAURA, ERIC FOR ALL THE HELP THEY GAVE ON THIS MEETING. SO E WE CO-SPONSOR AD MEETING JULY 21 AND # 2ND, CLINICAL EVALUATION MANAGEMENT AND CONGENITAL ZIKA VIRUS INFECTION. THERE WERE 27 CLINICS FROM AAP THAT CAME INTO THE MEETING, ON VERY SHORT NOTICE, WE'RE GRATEFUL TO THEM TO REPRESENTING A LARGE NUMBER OF SPECIALTIES, ALSO A NUMBER OF PARTNERS, IN ADDITION TO ARCAP, THERE'S AMERICAN COLLEGE OF OBGYN, FAMILY PRACTICE, FAMILY VOICES MARCH OF DIMES SO ON. THERE WERE ALSO COLLEAGUES ARE OTHER FEDERAL AGENCIES INCLUDING NICHD AND OTHERS. SO WE HAD THREE AREAS OF FOCUS, AT OUR MEETING. THE FIRST WAS THE INITIAL EVALUATION AND TESTING OF INFANTS BORN TO MOTHERS WITH LABORATORY EVIDENCE OF POSSIBLE ZIKA VIRUS INFECTION DURING PREGNANCY. SO WE KNEW AT FIRST YOU NEED TO DO SOME EVALUATION AND PROBABLY THAT THE POINT YOU AREN'T GOING TO HAVE LAB TESTS BACK BECAUSE WE KNOW THE LAB TESTS TAKE TIME. SO THAT'S WHAT IS THE INITIAL EVALUATION YOU DO FOR THESE KIDS. THEN THE OUTPATIENT MANAGEMENT WE DIVIDED INTO TWO GROUPS, ONE KIDS THAT HAVE FINDINGS CONSISTENT WITH CONGENITAL ZIKA SYNDROME AND KIDS THAT LOOK NORMAL AT BIRTH BUT WE KNOW THAT'S A POTENTIAL, YOU HEARD BEFORE, THIS IS -- CONGENITAL ZIKA SYNDROME IS THE TIP OF THE ICEBERG, WE WAN TO BE ABLE -- WANT TO BE ABLE TO FOLLOW KIDS THAT ARE LAB TESTING AND POSITIVE BUT THEY DON'T HAVE ANY FINDINGS OF CONGENITAL ZIKA INFECTION YOU CAN SEE AT BIRTH. SO WE DIVIDED THOSE TWO GROUPS. FIRST I'M GOING TO TALK LABORATORY TESTING AND THE LABORATORY TESTING HAS REALLY BEEN A CHALLENGE THROUGHOUT THIS WHOLE RESPONSE. THERE ARE -- IF YOU HEARD EARLIER TODAY THERE'S A LOT OF WORK GOING ON ABOUT THIS, DR. FAUCI TALKED ABOUT THIS THIS THIS MORNING. PARTICULARLY THE PCR IS SLAM DUNK, IT'S THERE, IT'S POSITIVE, POSITIVE, IT'S NEGATIVE, NEGATIVE. MOST LIKELY NEGATIVE. BUT THE IDM TESTING HAD BEEN CHALLENGING. AND THAT IS EVEN MORE SO TRUE FOR KIDS. SO WE ARE RECOMMENDING TESTING FOR INFANTS WHO ARE BORN TO MOMS WHO HAD LABORATORY EVIDENCE OF ZIKA VIRUS INFECTION. AND THAT LAB EVIDENCE IS THEY EITHER HAVE PCR POSITIVE, SO ZIKA RNA DETECTED BY PCR OR A POSITIVE ZIKA VIRUS IGM. AND THE CONFIRMATORY NEUTRALIZING ANTIBODY TITER. THE REASON FOR THE CONFIRMATORY NEUTRALIZING ANTIBODY TITER IS BECAUSE THERE IS CROSS ACTIVITY WITH OTHER FLAVA VIRUSES AS YOU HEARD THIS MORNING WITH PEOPLE WHO HAVE BEEN RECEIVED YELLOW FEVER VACCINE OR DEN GAY GIVE IN THE PAST. THE OTHER REASON WHY A BABY MIGHT BE TESTED EVEN IF THE MOTHER DIDN'T HAVE POSITIVE TESTING RESULTS IS IF THE BABY HAS ABNORMAL CLINICAL OR NEURAL IMAGING FINDINGS SUGGESTIVE OF CONGENITAL ZIKA SYNDROME AND EPIDEMIOLOGIC LINK SO TRAVEL ALREADY -- SIDED IN AN AREA WITH ACTIVE ZIKA TRANSMISSION OR SEX WITH A PARTNER WHO TRAVELS TO OR RESIDED IN SUCH AN AREA. THE REASON WE INCLUDED THIS GROUP IS WE REALIZE A LOT OF CALLS THAT WE HAVE GOTTEN AT CDC HAVE BEEN MOMS THAT WEREN'T TESTED BECAUSE THEY WERE IN A ANOTHER COUNTRY AT THE TIME, THEY COME TO THE U.S. DELIVER THEIR BABY AND THE BABY HAS FINDINGS, THE MOM WAS NEVER TESTED SO WE ARE RECOMMENDING TESTING FOR THOSE BABIES. THE LABORATORY TESTING THAT IS RECOMMENDED CURRENTLY IS RTPCR ON INFANT SERUM AND URINE, AND WE WERE JUST RECOMMENDING THAT ON SERUM, SERUM AND EUROPE BECAUSE IT APPEARS TO HAVE HIGHER SENSITIVITY IN URINE. IGM ANTIBODY SHOULD BE PERFORMED ON INFANT SERUM, THE CEREBRAL SPINAL FLUID IF LUMBAR PUNCTURE IS DONE FOR ANOTHER REASON, TESTING SHOULD BE DONE ON CSF FOR PCR AND IDM. PREVIOUSLY WE HAD TALKED ABOUT HAVING CORED BLOOD SPECIMEN TESTED AND WE NO LONGER ARE ASKING PEOPLE TO DEPEND ON THAT. WE BELIEVE THE BABY NEEDS TO HAVE BLOOD DRAWN AND WE HAVE SEEN FALSE POSITIVES AND NEGATIVES WITH CORED BLOOD TESTING WE'RE RECOMMENDING TESTING SHOULD BE PERFORMED WITHIN TWO DAYS AFTER BIRTH, IF TESTING PERFORM LATER IT'S TOUGH TO DECIDE ESPECIALLY IN AN AREA WITH AFTER ZIKA TRANSMISSION WHETHER POSTNATAL INFECTION OR -- AND WE BELIEVE THOSE WOULD HAVE DIFFERENT EFFECTS. SO THIS IS WHAT WE ARE RECOMMENDING FOR INTERPRETATION OF INFANT ZIKA VIRUS TESTING IF RTPRC IS POSITIVE, THE IGM IS POSITIVE OR NEGATIVE WE KNOW IT CAN WANE BUT IF PCR IS POSITIVE, CONFIRMS INFECTION. IF PCR IS POSITIVE BUT IGM IS NEGATIVE WE KNOW THERE'S PROBLEMS WITH TICKERGM TEST, WE SAY PROBABLE ZIKA INFECTION. BOTH GROUPS PROBABLE ALL END UP TREATED THE SAME IN OUR ALGORITHMS FOR TESTING RECOMMENDED. IF PCR IS NEGATIVE AND IDM, RIGHT NOW THAT'S THE BEST WE HAVE, WE'RE BELIEVING THE BABY IS NEGATIVE FOR CONGENITAL ZIKA VIRUS INFECTION. THIS IS THE OVERALL ALGORITHM, NO DETAILS BECAUSE I WILL GO PIECE BY PIECE BUT WANT TO SHOW THIS IS A MOM REQUEST LAB EVIDENCE, THIS IS THE INITIAL EXAMINE TO A BABY WITH CONGENITAL ZIKA OR BABY WHO DOESN'T HAVE FINDINGS CONSISTENT WITH CONGENITAL ZIKA. WE EXPECT THE LAB TEST WILL BE BACK AND THAT GUYS OUTPATIENT MANAGEMENT. NOW MOVING TO THE INITIAL EVALUATION, YOU HAVE THIS MOM WITH LAB EVIDENCE ZIKA VIRUS INFECTION, WE WANT PEDIATRICIANS OR HEALTHCARE PROVIDERS PERFORM A COMPREHENSIVE PHYSICAL EXAM ON THE INFANT AND TO HAVE A HEAD ULTRASOUND, THIS IS ALSO DIFFERENT FROM OUR PROVEIOUS GUIDELINES WE WANT THE BABIES TO HAVE HEAD ULTRASOUND, THERE WAS A PRENATAL ULTRASOUND LATE IN PREGNANCY THAT LOOKED FORMAL, YOU DIDN'T NEED HEAD ULTRASOUND. WE FEEL EVERY BYE-BYE SHOULD HAVE A HEAD ULTRASOUND, THOSE LATER ARE NOT SENSITIVE. THE NEWBORN HEARING SCREENING IN THE UNITED STATES, AND INFANT STUDY VIRUS LABORATORY TESTING, THAT WILL DIVIDE TO TWO CATEGORY, FINDINGS CONSISTENT WITH CONGENITAL ZIKA OR FININGS WITHOUT FINDINGS CONSISTENT WITH CONGENITAL STUDY. HERE IS THE EVALUATION INITIAL EVALUATION FOR INFANTS WITH FINDINGS CONSISTENT WITH CONGENITAL ZIKA SYNDROME, YOU CAN SEE THIS IS EXTENSIVE EVALUATION, KIDS GET A BIG EVALUATION AND WE DID TALK ABOUT THE POSSIBILITY THAT SOME BABIES, SOMETIMES YOU MAY WANT TO TRANSFER A CHILD TO HIGHER LEVELS FACILITY IF AT A FACILITY ALL THESE ARE NOT AVAILABLE BUT THAT NEEDS TO WEIGH THE THOUGHTS AND YOU WILL TAKE THE MOM AND BABY, SEPARATING THE MOM AND BABY. SO WE'RE RECOMMENDING NEUROLOGY, INFECTIOUS DISEASE FOR CONSIDERATION OF ZIKA AND OTHER POSSIBLE CAUSES OF CONGENITAL INFECTION. OPHTHALMOLOGIST, ENDOCRINOLOGIST, BABIES WITH SEVERE BRAIN PROBLEMS SOMETIMES HAVE HYPOPITUITARISM AND WE DON'T WANT TO MISS SOMETHING LIKE HYPOTHYROIDISM, A CLINICAL GENETICIST AND DEPENDING THE FINDINGS YOU SEE WE'RE RECOMMENDING CONSIDERING CONSULTATION WITH ORTHOPEDIST, THAT WOULD BE IF A CHILD HAS CLUB FOOT, WITH PULMONOLOGIST AND OR OTOLAIRN GOLGI, IF YOU BELIEVE THE CHILD IS AT RISK OF ASPIRATION. THERE'S A CHILD WITH SIGNIFICANT FEEDING ISSUES, LACTATION SPECIALIST, NUTRITIONISTS, GASTROENTEROLOGISTS OR SPEECH THERAPIST. WE'RE RECOMMENDING A HIGHER LEVEL OF HEARING SCREENING ABR TO ASSESS HEARING COMPLETE CDC COMPLETE BLOOD COUNT METABOLIC PANEL INCLUDING LIVER FUNCTION TEST AND THROUGHOUT THIS WHOLE THING WE RECOGNIZE THAT ALL THIS IS GOING TO BE VERY STRESSFUL TO FOR FAMILIES, SO THROUGHOUT THE PROCESS WE'RE RECOMMENDING FAMILY SUPPORTED SERVICES. SO NOW WE'RE GOING TO HAVE THE LAB TESTING WE'RE HOPING THE LAB TESTING IS GOING TO BE BACK, THAT'S GOING TO DIVIDE INTO BABIES THAT HAVE CONFIRMED OR PROBABLE CONGENITAL ZIKA VIRUS INFECTION, THAT WILL TAKE US TO THE OUTPATIENT MANAGEMENT FOLLOW UP VERSUS BABIES THAT ARE NEGATIVE FOR CONGENITAL ZIKA, BUT WE KNOW THEY HAVE PROBLEMS, WE ARE GOING TO NEED ADDITIONAL EVALUATION TO FIGURE WHY THEY HAVE HAVE THESE PROBLEMS WHETHER MICROCEPHALY OR CALCIFICATION THERE NEEDS TO BE ADDITIONAL EVALUATION WHAT CAUSES CONGENITAL ANOMALY. WHAT ABOUT INFANTS WITHOUT FINDINGS CONSISTENT WITH CONGENITAL ZIKA SYNDROME? THESE ARE BABIES BORN TO MOMS WITH ZIKA INFECTION, THEY TEST POSITIVE FOR ZIKA INFECTION BUT THEY LOOK REALLY NORMAL BY EVERYTHING THAT WE CAN SEE BUT ALL THE TESTS DONE. WHAT WE RECOMMEND FOR THOSE BABIES IS ROUTINE NEWBORN CARE, AND PERFORMING ARCVR, AUDITORY BRAIN STEM RESPONSE HEARING TEST AND OPHTHALMOLOGY EXAM WITHIN A MONTH OF LIFE. THAT WAS SOME FROM WHAT KNOW FROM ZIKA BUT OTHER INFECTIONS LIKE CMV, WE KNOW SOMETIMES HEARING AND EYE PROBLEMS CAN BE SEEN. LATER ON. WE'LL GO INTO OUTPATIENT MANAGEMENT FOR BABY THAT TESTS NEGATIVE, SO NO FINDING, BABY LOOKS NORMAL AND TESTS NEGATIVE FOR CONGENITAL ZIKA VIRUS INFECTION, WE'RE RECOMMENDING ROUTINE CARE, THAT BABY WILL CONTINUE TO FOLLOW REGISTRY SO IF SOMETHING COMES UP LATER WE WOULD BE ABLE TO HEAR ABOUT IT AND THEN OF COURSE WE WOULD NEED TO ADAPT OUR RECOMMENDATION. KNEW MOVING TO THE OUTPATIENT MANAGEMENT, SO THIS IS INFANTS WITH LABORATORY EVIDENCE OF CONGENITAL S SYNDROME AND WITH FINDINGS, SO THESE ARE BABIES THAT HAVE CONGENITAL ZIKA SYNDROME AND THEY HAVE LAB EVIDENCE OR LAB TESTING WITH POSITIVE OR EITHER CONFIRMED OR PROBABLE. ONE OF THE FIRST THINGS THAT WE TALKED ABOUT WAS THESE ARE BABIES THAT MORE THAN -- ALL CHILDREN NEED A MEDICAL HOME BUT THESE REALLY NEED ONE. THEY ARE GOING TO NEED PEDIATRIC HEALTHCARE PROVIDER THAT IS GOING TO BE WILLING TO HELP TO BE SURE THEY -- HELP FAMILIES TO GET THEM TO THESE SUBSPECIALTIES, THAT PERSON SEES THEM MONTHLY THE FIRST SIX MONTHS OF LIFE FOLLOWING GROWTH PARAMETER, MONITORING DEVELOPMENT, PROVIDING ROUTINE IMMUNIZATIONS, WE DON'T WANT TO FORGET THAT THEY ARE A BABY THAT NEEDS IMMUNIZATION AND ANTICIPATORY GUIDANCE AND PSYCHOSOCIAL SUPPORT AND ENSURING THE BABIES RECEIVE TESTING AND CONSULTS. RECOMMENDATION FOR NEUROLOGIC EXAM AGE 1 AND 2 MONTHS AND AS NEEDED AND CERTAINLY WE SAW FROM THE TALK EARLIER TODAY, THE NEED FOR THAT NEUROLOGIC EXAM. REFER TO IT AS DEVELOPMENTAL SPECIALISTS AND TO EARLY INTERVENTION SERVICES. REPEATING AN OPHTHALMOLOGY EXAM AT WITH RETINAL ASSESSMENT AT THREE MONTHS. AVR HEARING ASSESSMENT AT 4 TO 6 MONTHS. REPEAT TESTING SO BABY SHOULD HAVE GOTTEN NEWBORN SCREEN FOR THYROID AT BIRTH BUT WE RECOMMEND REPEAT TESTING FOR HYPOTHYROIDISM AT TWO WEEKS AND THREE MONTH. AGAIN, PROVIDING THE FAMILY SUPPORT. NOW FOR BABIES WITHOUT ABNORMALITIES CONSISTENT CAN ZIKA SYNDROME, WE RECOMMEND MEDICAL HOME SHOULD BE ESTABLISHED FOR BABIES BORN, FOLLOW GROWTH PARAMETERS, PERFORM DEVELOPMENTAL SCREENING AT EACH CHILD VISIT, EMPHASIZE ANTICIPATORY GUIDANCE, DEVELOPMENTAL MILESTONES, SLEEP ABNORMALITY AND MOVEMENT. WE WANT TO BE SURE WE DON'T WANT TO MAKE FAMILIES TOO SCARED, AND I THINK PEDIATRICIAN IS GOING TO BE TOUGH TO FIND THAT LINE BUT WE DID DO RECOGNIZE THE POSSIBILITY OF LATER ONSET SEIZURE, DEVELOP MENTAL DELAY OR OTHER SORTS OF PROBLEMS ARE A POSSIBILITY AND WE WANT TO BE SURE THOSE ARE BROUGHT TO THE ATTENTION OF THE PEDIATRICIAN AND AS THE PARENT SEES THEM. WE RECOMMEND USING A STANDARDIZED VALIDATED DEVELOPMENTAL SCREENING TOOL AT NINE MONTHS. PERFORMING VISION SCREENING AN ASSESS VISUAL REGARD AT EVERY WELL CHILD VISIT. IF THAT'S ANY CONCERN THE CHILD IS REFERRED TO OPHTHALMOLOGIST AGAIN. WE TALKED ABOUT ABR TESTING AT FOUR TO SIX MONTHS. THERE WAS SOME CONCERNS IN OUR GROUP ABOUT THAT. AND SO WE GAVE OR POSSIBILITY HERE, DOING THE ARCBREST THING AT FOUR TO SIX MONTHS WHICH IS GOING TO NEED SEDATION OR POSSIBLY WAITING FOR BEHAVIORAL DIAGNOSTIC TESTING AT NINE MONTHS THAT WOULDN'T REQUIRE SEDATION. P FAMILY SUPPORT. YOU HEARD THROUGHOUT THIS WHOLE THING, EMPHASIS ON FAMILY AND PSYCHOSOCIAL SUPPORT AND I'M JUST GOING TO BRING ISSUES RAISED AT OUR MEETING. WE FEEL ALL FAMILIES WHO HAVE BABIES WITH ZIKA VIRUS INFECTION, EVEN BABIES THAT LOOK FINE REQUIRE ONGOING PSYCHOSOCIAL SUPPORT, THEY ARE SCARED WORRIED ABOUT WHAT THEIR CHILD IS GOING TO BE. THE FAMILY SHOULD BE PARTICIPANTS IN CHILD MONITORING AN CARE AND THE HEALTHCARE PROVIDERS SHOULD WORK CLOSELY WITH PARENTS TO ENSURE THAT THE CARE PLAN IS CONSISTENT WITH THE INFANT NEEDS AND WITH FAMILIES WISHES. WE NOTED IT'S POSSIBLE THERE MAYBE A DISPROPORTIONATE BURDEN OF ZIKA VIRUS INFECTION ON FLAMES THAT HAVE LIMITED ACCESS TO MEDICAL CARE WHICH IS GOING TO COME MR. KATE THINGS FOR THE HEALTHCARE PROVIDER EVEN MORE. AND BARRIERS TO CARE FOR ALL INFECTED INFANTS AND FAMILIES SHOULD BE ADDRESSED THROUGH MAKE SURING THEY'RE LINKED TO NATIONAL STATE AND LOCAL HEALTH PROGRAMS. WE DO HAVE A WEBSITE WITH ADDITIONAL RESOURCES FOR FAMILIES. I WANT TO EMPHASIZE THERE IS -- AS I SAID BEFORE SWEAR RIM GUIDANCE AND THERE'S QUESTIONS THAT REMAIN SO THERE'S A LOT OF WORK LEFT TO DO, LOTS OF RESEARCH GAPS. ONE OF THE ISSUES REALLY RELATED TO LABORATORY TESTING AND DR. FAUCI TALKED ABOUT THAT THIS MORNING. THIS HAD BEEN A TOUGH SITUATION BECAUSE OF THE PROBLEMS OF THE LABORATORY TESTING. ONE QUESTION PARTICULARLY RELATED TO KIDS, IF YOU GET ZIKA VIRUS INFECTION EARLY IN PREGNANCY, MIGHT YOUR IBM BE NEGATIVE BY THE TIME YOU'RE BORN. THAT'S A POSSIBILITY AND THAT COULD MISLEAD US, THE KIDS WE ARE CURRENTLY SAYING DON'T HAVE ZIKA VIRUS INFECTION COULD POSSIBLY HAVE IT. SO THAT'S ONE OF THE QUESTIONS WE THINK IS REALLY IMPORTANT TO BE ANSWERED. WHAT IS THE LEVEL OF RISK FROM ZIKA VIRUS INFECTION DURING PREGNANCY, YOU SAW THIS MORNING I THINK IN DR. SWAN'S TALK 1 TO 13% STUDY BY JOE HANSON FOR FIRST TRIMESTER EXPOSURE AND 1 TO 13% IS RATE OF MICROCEPHALY AND 1 TO 13% IS A WIDE RANGE. SO WE NEED TO DO BETTER ABOUT THAT. BUT WE ALSO KNOW IT'S NOT JUST MICROCEPHALY. WE KNOW THERE ARE LIKELY TO BE OTHER PROBLEMS TOO, WE NEED TO BE ABLE TO UNDERSTAND WHAT THE RISK IS FOR THAT FULL RANGE OF PROBLEMS. WE ALSO NEED TO UNDERSTAND WHAT HAPPENS WHEN YOU'RE INFECTED AT DIFFERENT TIMES DID YOU RECOLLECT PREGNANCY. WHAT WE KNOW FROM BABIES THAT HAVE HAD FETAL BRAIN DISRUPTION SEQUENCE, CONGENITAL ZIKA SYNDROME THAT WE HAVE SEEN, MOST OF THEM THEIR MOMS HAVE REPORTED EXPOSURE OR INFECTION IN THE FIRST TRIMESTER, EARLY SECOND TRIMESTER BUT WE DON'T KNOW FROM'S TIME DURING PREGNANCY THAT'S SAFE TO BE ABLE TO GET ZIKA VIRUS INFECTION, CERTAINLY THERE'S RECENT PAPERS SHOWING EFFECTS IN THE THIRD TRIMESTER. WHAT IS THE FULL RANGE OF POTENTIAL HEALTH PROBLEMS, I WILL SAY AGAIN, THE TIP. OF THE ICEBERG, IT'S LIKELY THE KINDS OF FINDINGS SEEING RIGHT NOW ARE THE TIP OF THE ICEBERG AND I SAW SOMEBODY MAY HAVE BEEN DR. SWAN'S SLIDE THIS MORNING THE POSSIBILITY OF AUTISM SCHIZOPHRENIA, OTHER THINGS THAT WE COULD SEE MUCH LATER ON. WHAT IS RISK FOR LATER HEALTH PROBLEMS IN INFANT THAT DOESN'T HAVE ABNORMALITIES AT BIRTH AND WHAT ARE THE OTHER FACTOR, CO-OCCURRING FACTOR, OTHER INFECTIONS, NUTRITIONAL FACTORS, SO ON THAT MIGHT AFFECT THE RISK FOR BIRTH DEFECTS. SO CDC IS WORKING WITH OUR COLLABORATORS IN THE U.S., OUR STATE AND LOCAL STATE DEPARTMENT PARTNERS, WE WERE WORKING WITH PUERTO RICO AND PARTNERS THERE AND WORKING WITH PARTNERS IN COLUMBIA TO COLLECT DATA IN A PROSPECTIVE WAY, EACH OF THESE ARE PROSPECTIVE STUDIES TO HELP ANSWER SOME OF THESE QUESTIONS AND I LOOK FORWARD TO ANSWERS FROM THESE STUDIES AS WELL AS FROM SOME OF THE NIH AND OTHER STUDIES ONGOING. I THINK THAT'S GOING TO HELP US TO BETTER DEFINE INTERIM GUIDANCE THAT WE HAVE PUT TOGETHER SO FAR. I JUST WANTED TO END BY THANKING OUR MANY COLLABORATORS AND PARTNERS AND IN PARTICULAR, I WANT TOK ACKNOWLEDGE DR. CINDY MOORE WHO I SNITCHED SOME OF HER SLIDE AND SHE HELP ME IN PUTTING THE TALK TOGETHER. THANK YOU SO UP MANY. [APPLAUSE] >> >> THANK YOU FOR THAT TERRIFIC PRESENTATION, I'LL OPEN UP FOR SOME QUESTIONS IN ABOUT FIVE MINUTES ORSOR BEFORE THE PANEL. >> HI FOR THE TAKER, (INAUDIBLE) PEDIATRICIAN. IS THERE ANYTHING TO THINK ABOUT FOR IMMEDIATE DELIVERY MANAGEMENT, PARTICULARLY IF THERE'S PREFATAL FINDINGS ON ULTRASOUND, AIRWAY MANAGEMENT OR SEIZURE MANAGEMENT OR ANYTHING THE FOLKS IN THE DELIVERY ROOM OR EARLY NEONATAL CARE SHOULD BE THINKING ABOUT OR KIDS TYPICALLY GOING TO NORMAL INFANT NURSERY, NICU, WHAT IS THE IMMEDIATE MANAGEABILITY? THE SECOND PIECE IS THINKING ABOUT DR. SANDER LYNN DEN'S TALK THIS MORNING. I DIDN'T SEE RECOMMENDATIONS ABOUT REFLUX MANAGEMENT OR EVEN A TRIAL OF ANTI-EPILEPTICS, IS THERE ANYTHING ELSE THAT'S A GENERAL PEDIATRICIAN SHOULD CONSIDER THESE KIDS IN EARLY DAYS? >> I WILL ANSWER THE SECOND FIRST, WE RECOMMENDED WIDE EARLY TO SPECIALISTS AND SO NEUROLOGIES WERE RATHER THAN SAYING WHO NEEDS WHAT YOU NEED CT OR MR, WE LEFT THOSE DECISIONS TO THE SPECIAL iS TO THE NEUROLOGISTS AND HE THOUGHT THERE WAS CONCERNS ABOUT FEEDING ISSUES AND REFLUX RECOMMENDATIONS FOR REFERRALS TO GASTROENTEROLOGIST, SO ON. FOR THE FIRST QUESTION ABOUT IMMEDIATE MANAGEMENT, I KNOW I READ SOME CHILDREN ARE GOING TO INTENSIVE CARE UNITS, I DON'T KNOW THAT I CAN ANSWER THAT QUESTION, MAYBE OUR COLLEAGUES FROM BRAZIL HAVE BETTER INFORMATION ON WHETHER THERE SHOULD BE RECOMMENDATIONS, WE DIDN'T FOCUS ON THAT IMMEDIATE MANAGEMENT AND MAYBE WE SHOULD HAVE. >> WE HAD SOME -- ESPECIALLY PATIENTS WITH (INAUDIBLE) IN THE CEREBELLUM, NEED INTENSIVE CARE FIRST DAY OF LIFE SO I HAD AT THAT MOMENT I HAD THREE PATIENT, (INDISCERNIBLE) BUT THEY IMPROVE A LITTLE. ONE OF THESE PATIENTS NOW HAS (INAUDIBLE) BUT IS ABLE TO STAY A LITTLE OUT OF VENTILATION. WE HAD ONE PATIENT THAT DIED LAST MONTH. I DON'T KNOW THERE -- (INAUDIBLE) PROBLEM. HE HAS ALSO (INAUDIBLE) BUT NOW THE MAIN PROBLEM IS PATIENT WITH DISFASCIA AND (INDISCERNIBLE) SO THIS PATIENT HAS DIAGNOSE LIKE IN OTHER DISEASE, THEY HAVE A COUGH, SPASTIC COUGH PATIENTS WITH A(INAUDIBLE) AND DON'T HAVE SO MANY INTENSIVE CARE FOR THESE PATIENT. AND WE HAD ONLY A FEW PLACES FOR THESE PATIENTS. AND SOMETIMES THEY DON'T LIKE TO (INAUDIBLE) INTENSIVE CARE BECAUSE YOU KNOW MAYBE THEY CAN SPEND A LOT OF TIME -- THEY NEVER (INAUDIBLE). WE DON'T HAVE IT YET SOMETHING FOLLOWING ABOUT THIS. WE TREAT PATIENTS LIKE WE TREAT THE OTHER PATIENTS, WITH THE SAME DISEASE, I THINK THE DIFFERENCE OF THESE PATIENTS, (INDISCERNIBLE) NEUROLOGIC DISEASE OR OTHER CONDITIONS. BUT I THINK THAT THE PROBLEM IS THE NUMBER OF PATIENTS SO WE HAVE SO MANY SEVERE PATIENTS AT THE SAME TIME, THAT WE DON'T HAVE SO MANY CONDITIONS, ESPECIALLY INTENSIVE CARE SO I HAVE EXPERIENCE OF THREE PATIENTS THAT STILL IN INTENSIVE CARE UNTIL NOW, ONE OF THEM DIED LAST MONTH. WE HAVE TWO PATIENTS THAT NEED INTENSIVE CARE BUT IMPROVE -- THEY ARE OUT INTENSIVE CARE. >> BACK FIRST. >> ROBERTA (INAUDIBLE) FROM CHILDREN'S NATIONAL HERE IN D.C., BACK TO YOUR POINT ABOUT THE INFANTS THAT WERE THE MOM WAS PROVEN POSITIVE T BABY LOOKS FORMAL BUT THE TESTING ON THE BABY IS NEGATIVE. ARE LOCAL HEALTH DEPARTMENTS HAVE BEEN MAKING A RECOMMENDATION WE DO 18 MONTH NEUTRALIZING ANTIBODY, IS THAT STATE SPECIFIC OR MORE CENTRALIZED? >> WE HAVE SAID IF THERE'S QUESTION THAT YOU CAN DO 18 MONTH NEUTRALIZING ANTIBODY WE SAY THE SAME THING IN THE MWR SO WE RECOMMENDED THAT. BUT I DON'T THINK WE LEFT IT AS IT'S A POSSIBLE THING THAT YOU CAN DO, NOT SOMETHING THAT YOU MUST DO. IF THE CHILD IS LOOKING REALLY GREAT AT 18 MONTHS, I THINK WE FELT LIKE YOU DIDN'T HAVE TO DO THAT TESTING BUT IF THERE WAS SOME CONCERN THAT YOU COULD DO THAT AND THAT COULD HELP KNOW WHAT WAS GOING ON, IF IGM WANED BY TIME OF BIRTH. GOOD POINT. THANK YOU. >> >> HI. AUDREY STEWART, PARKLAND CHILDREN'S MEDICAL CENTER. SO LOOKS LIKE AN ALGORITHM YOU'RE ADVOCATING FOR DIAGNOSTIC ABR RATHER THAN AUTOMATED AB R. IT SEEMS TO PEA THAT IT WOULD MAKE MORE SENSE TO START OUT WITH AN AUTOMATED ABR AND THEN IF YOU DON'T PASS THAT, YOU GO TO SEDATE OR DIAGNOSTIC ABR. CAN YOU FURTHER ELABORATE WHERE THE DIAGNOSTIC OR SEDATED ARCBR CAME FROM? >> I'M NOT ENOUGH OF AN EXPERT ON THAT TO BE ABLE TO COMMENT. CINDY, I DON'T KNOW IF YOU ARE. THE KID -- THE CHILD WOULD GET REGULAR NEWBORN SCREEN AT BIRTH AND THEN IF THEY HAVE ALL THESE OTHER MICROCEPHALY OR SOME BRAIN PROBLEMS THAT PUT THEM INTO THAT CONGENITAL ZIKA SYNDROME CATEGORY, THEY WOULD GET THE DIAGNOSTIC ABR. SO PERHAPSES THAT'S -- WE ARE HAPPY TO HEAR THERE WERE HEARING EXPERTS NEWBORN HEARING -- >> MAYBE DR. VOHR CAN SPEAK TO IT. >> CERTAINLY WITH THE SCREENING ARCBR, AUTOMATED ARCBR, YOU WILL MISS MILD HEARING LOSS WITH DIFFERENT CONFIGURATIONS, I CERTAINLY AGREE THE INITIAL SCREEN SHOULD BE AUTOMATED ABR POSSIBLY, THE ONE MONTH BUT I HAVE A CONCERN ABOUT WAITING UNTIL FOUR TO SIX MONTHS WHERE YOU'RE DEFINITELY GOING TO NEED TO SEDATE IF SUSPICION IS RISING. BUT SOME POINT YOU HAVE TO DO THE DIAGNOSTIC EVEN IF THEY PASS IT. >> THANKS. >> UP TO A LIMIT BECAUSE WE HAVE TO MOVE ON. ONE MORE -- >> DR. BRITT FROM ALABAMA. THE QUESTION I HAVE IS -- ACTUALLY CAME TO ME TWO DAYS AGO, I SAW A ZIKA EXPOSED IN NORMAL NURSERY. SOME OF THESE BABIES WILL BE EXCRETING VIRUS FOR A LONG PERIOD OF TIME, PA BLOW ASKED BREAST MILK O. SO IF WE FIND BABIES THAT ARE EXPOSED THAT WE THINK ARE INFECTED, THEY'RE IN THE HOSPITAL, WHAT IS CDC RECOMMENDATION FOR INFECTION CONTROL AND EVERYTHING ELSE WITH THIS? >> CDC RECOMMENDATION ARE STANDARD PRECAUTIONS. JUST LIKE YOU HAVE TO ASSUME ANYBODY WHETHER BABY THAT MIGHT HAVE ZIKA OR SOMEONE WHO MIGHT HAVE HIV, YOU NEED TO FOLLOW STANDARD PRECAUTIONS. THERE WAS AN EARLIER MWR REPORT WE HAD THAT DISCUSSED THAT IN DETAIL, SO IF YOU WANT TO TALK ABOUT THAT, TALKING ABOUT OBGYN SETTINGS AND THE SAME RECOMMENDATIONS FOR A BYE-BYE BORN WITH CONGENITAL -- BABY BORN WITH CONGENITAL ZIKA. THANK. -- THANKS. >> SO MENTIONED ABOUT OCULAR, BABIES THAT ARE BORN WITH POSITIVITY FOR CONGENITAL ZIKA SYNDROME, WHAT WE'RE DOING IS WHEN WE EXAMINE THESE BABIES IN THE NICU WE THE SPECULUM WE USE, IT'S KIND OF AN INSTRUMENT WE USE TO EXAMINE THESE BABIES EYES, THEY ARE -- CHAI SHOULD BE DISPOSABLE BECAUSE IN LITERATURE, RECENTLY, IT HAD BEEN PUBLISHED IN MICE THAT THEY HAVE BEEN -- THEIR TEARS HAVE BEEN TESTED AND A LIVE VIRUS WAS SEEN, IDENTIFIED SO BECAUSE OF THAT, WE'RE DISPOSING ALL OF OUR MATERIAL INSTRUMENTS AS SOON AS WE FINISH, ALL OF US, WE HAVE LIKE PROTECTION WITH GLOVES AND ALL THAT AND THEN WE DECEMBER POSE -- DISCLOSE ALL OF THEM, WE DO NOT REUSE THE SAME MATERIAL SINCE THE TEARS CAN HAVE A LIVE VIRUS. Q. THANK YOU VERY MUCH, DR. RASMUSSEN, TERRIFIC PRESENTATION. NOW I WOULD LIKE TO ASK THAT OUR PANELISTS AND OUR PANEL MODERATOR, DR. JEANNE SHEFFIELD OBGYN JOHNS HOPKINS UNIVERSITY IN BALTIMORE, INTRODUCE THE PANEL AND THEIR AFFILIATIONS. AND THAT WILL LEAD US TO DISCUSSION OF THE OVERARCHING QUESTIONS. >> THANK YOU. SO LET ME ASK THE PANELISTS TO COME UP WHILE THEY ARE MAKING THEIR WAY UP, YOU HAVE ALREADY BEEN INTRODUCED TO FOUR OF THE SPEAKER, DR. VAN DER LINDEN AND DR. ZORRILLA IN THE MIDDLE OF THIS NOW BOTH IN BRAZIL AND PUERTO RICO. YOU MET DR. BRITT ALREADY, PEDIATRIC CMV EXPERT, I USED TO BE AT UAB MANY YEARS AGO AND KNOW HIS NAME WELL. OF COURSE DR. RASMUSSEN, EXCELLENT LAST TALK AND SHE WILL BE AVAILABLE CERTAINLY FOR MORE QUESTIONS, THE TWO YOU HAVEN'T MET YET ARE DR. PHIL HEINE, PROFESSOR OBGYN MEDICAL PROFESSIONNA T AT DUKE UNIVERSITY, INFECTIOUS DISEASE AND PREGNANCY MANY DECADES, I WON'T SAY HOW LONG, HE WOULD SHOOT ME BUT MANY DECADES. I WILL NEVER DO THAT TO HIM. BUT HE'S ALSO ONE OF THE FACES OF THE ZIKA EPIDEMIC RESPONSE FROM SOCIETY MATERNAL FETAL MEDICINE AND AMERICAN COLLEGE OF OBGYN, HE'S A NAME OUT THERE BECAUSE HE'S BEEN AT THE MEETINGS TO THE ADDRESS GUIDELINES BETWEEN THE SOCIETIES. LAST BRENDA HUGHES NOT ON THE ORIGINAL LIST BUT ALSO MATERNAL FETAL MEDICINE SPECIAL iINGS AT BROWN MANY YEARS AND JUST MOVED TO DUKE. SHE STARTED THREE WEEKS AGO. SHE'S ALSO WORKING WITH DR. HEINE. ALSO IN A VERY SMALL GROUP OF US, INFECTIOUS DISEASES AND PREGNANCY AND ONE OF HER AREAS OF EXPERTISE IS CMD SO WE ASKED HER TO COME UP BECAUSE WE HAVE THE PEDIATRIC SIDE AND BASIC SCIENCE RESEARCH BUT WE ALSO WANT #-D TO GET AN MFM PERSPECTIVE OF CMD. SHE'S THE PI FOR THE MULTI-CENTER NICHD MSM NETWORK CMV HYPERIMMUNOGLOBULIN TRIAL GOING ON NOW, SO HER EXPERTISE WITH CMV WILL MELD NICELY WITH WHAT WE'RE TRUE IING TO SET UP WITH ZIKA. SO WE WERE TASKED IN THIS HALF HOUR, THERE'S A NUMBER OF PANELS THROUGHOUT THE NEXT TWO WAY DAVIDS, BUT WE WERE TASKED WITH ADDRESSING A COUPLE OF QUESTIONS ON YOUR AGENDA. TWO ARE REALLY PERTINENT TO WHAT WHAT WE DISCUSSED THIS MORNING. THE FIRST ONE IS HOW CAN MANAGEMENT OF INTERVENTION FOR OTHER CONGENITAL SYNDROMES BE USEFUL TO THAT OF ZIKA VIRUS, INFECTION AND WE CAN START ADDRESSING SOME OF THE KNOWLEDGE GAPS. WE HAVE A PANEL COUPLE OF PANELS TOMORROW FOR KNOWLEDGE GAPS BUT WE CAN CERTAINLY TRY TO ADDRESS THOSE. SO JUST FROM THOSE TWO MAIN QUESTIONS, WE LOVE TO GET AUDIENCE QUESTIONS, RESPONSES, TO ANYTHING THAT YOU HAVE HEARD THIS MORNING. ANYTHING THAT PANEL CAN ADDRESS. WITH THEIR COMBINED EXPERTISE HERE. I WILL TAKE THE MODERATORS PREROGATIVE AND START WITH THE FIRST QUESTION. I'M CURIOUS ABOUT THIS. AS MATERNAL FETAL MEDICINE -- WE SIT ACROSS THE TABLE FROM CLINICIANS AND I WANT TO TELL THEM YOU'RE INFECTED IN FIRST TRIMESTER OR THIRD TRIMESTER, WHAT ARE YOUR RISKS, SO I'M KIND OF VERY INTRIGUED FIRST TO HEAR SOME OF THE INFORMATION FROM BRAZIL OF THE PATIENTS WITH NORMAL HEAD CIRCUMFERENCE AT DELIVERY BUT ENDED UP DEVELOPING ABNORMALLY LATER ON. ARE THESE WOMEN THAT WERE INFECTED IN THE THIRD TRIMESTER? WE'RE NOT SURE WHAT TO DO WITH THOSE. DO WE HAVE LABORATORY TESTING OF THESE MOTHERS TO SEE IF THEY WERE INFECTED OR JUST LABORATORY TESTING OF BABY? >> THE BABIES, THEY ARE (INAUDIBLE) SO WE DIDN'T HAVE THE LAB FOR MOTHERS AT THAT TIME. IT IS NOT PREFER FROM TIME THE MOTHER REFER THE -- BETWEEN SEVERE PATIENT AND LESS IS VEER PATIENTS. SO WE HAVE SOME PATIENTS NORMAL HEAD CIRCUMFERENCE, NEURONIC ENVIRONMENT AND TWO OR THREE MONTHS OF AGE OF PREGNANCY. SO (INAUDIBLE) BETWEEN THEM. >> SO GESTATIONAL AGE AND SEVERITY OF SYSTEMS DON'T -- THREE IN THE CASE YOU SEE SO FAR? >> IN MY CITY SOMETIMES THE MOTHER HAS TWO DIFFERENT (INAUDIBLE). I HAVE A PATIENT THAT HAS A VERY SEVERE BRAIN DAMAGE, NORMAL CURSE DEVELOPMENT SO WE KNOW (INDISCERNIBLE) INFECTION MUST BE UP TO FIVE MONTHS OF PREGNANCY AND THE MOTHER (INAUDIBLE) SEVEN MONTHS OF PREGNANCY SO PROBABLE HAVE -- DISEASE IN THE BEGINNING OF PREGNANCY AND AFTER THAT, SHE HAS A LOT OF RUSH. ZIKA, DENGUE, ANOTHER DISEASE (INAUDIBLE) WE DON'T HAVE THE LAB TO PROVE THIS, IT IS GOOD TO KNOW EXACTLY WHEN THE MOTHER HAS THE INFECTION THAT CAUSE THE DISEASE. >> DR. HEINE. >> ONE THING WHEN YOU LOOK AT, AGAIN, WE OTHER NOT LIVING IN THE MIDDLE OF THIS, BUT IF YOU LOOK AT THE DATA THAT'S BEEN REPORTED IN THE LANSETT ARTICLE, YOU CAN GET A GIST THAT MAKE SENSE WHEN COMPARING TO OTHER VIRUSES, IF YOU LOOK AT THE MICROCEPHALY WHEN THEY REPORTED BASED ON TIMING OF RASH, WHICH AGAIN HAS ISSUES, IF THEY WOULD HAVE REPORTED IT EARLIER IN PREGNANCY, THERE WERE A LOT MORE PATIENTS WITH IT. FROM IN THE THIRD TRIMESTER ONLY 5% OF TOTAL IN THIS GROUP OF PATIENTS WITH KNOWN MICROCEPHALY. THE MICROCEPHALY WAS NOT AS BAD AS THAT REPORTED IN THE FIRST TRIMESTER. WHICH MAKES YOU THINK, GOES ALONG WITH CMV, GOES WITH TOXOPLASMOSIS, GOES WITH MANY INFECTIONS, RUBELLA, MAYBE THE OUTLIER, GOES ALONG WITH MANY INFECTIONS THAT FIRST TRIMESTER EARLY SECOND, DABBING ALL OR NONE PHENOMENON -- DAMAGE, PROBABLY A LOT OF PREGNANCY LOSSES WITH THAT. BUT AS YOU MOVE UP PROBABLY NOT THE SEVERE CASES. SOME LIKE CMV THERE ARE SOME BUT WE DON'T KNOW WHAT THE SUBTLE THINGS ARE GOING TO HAPPENING DOWN THE LINE. THAT'S IMPORTANT FOR US WHEN YOU SIT ACROSS FROM SOMEBODY EXPOSED, YOU DON'T HAVE A LOT TO BASE ON EXCEPT YOUR EXPERIENCE WITH OTHER THINGS. TOLERANCE OR UNCERTAINTY DEPENDS HOW BAD WHAT YOU'RE LOOKING AT IF IT'S SOMETHING SOMETHING SUBTLE, 6, 12 MONTHS DOWN THE LINE THAT PATIENT PROBABLY HAS MORE TOLERANCE TO THAT UNCERTAINTY THAN IF THAT'S SIGNIFICANT MICROCEPHALY WITH TERRIBLE ULTRASOUND FINDINGS IN THIRD TRIMESTER. I THINK WE HAVE A LITTLE BIT OF DATA. TO BASE IT ON BUT WE NEED POPULATION BASED STUDIES FOLLOWING PROSPECTIVELY WITH SERO PREVALENCE RATES OF ALL PREGNANT WOMEN IN BRAZIL WHO DELIVER AND THEN FOLLOWING THEIR KIDS, WHICH WE JUST DON'T -- >> STUDY OF 10,000 WOMEN, ENROLLED IN THE FIRST THROUGHOUT PREGNANCY PROSPECTIVELY WILL BE HELPFUL. I KNOW YOU TOUCHED ON IT SLIGHTLY THIS MORN, DID YOU WANT TO MENTION THE TRIAL? KIND OF WHAT'S GOING ON? I KNOW IT'S NOT QUITE WHERE WE'RE AT BUT -- OKAY. PERFECT. DO YOU WANT TO MENTION, BECAUSE THAT ACTUALLY DOES LEAD INTO DISCUSSION OF WHAT WE'RE TALKING ABOUT HERE. >> IN THE FIRST TRIMESTER AND WE'RE FOLLOWING ON A MONTHLY BASIS WITH SEROLOGICAL TESTING AN ADDITIONAL TESTING FOR THE DURATION OF THE PREGNANCY AND UNTIL DELIVERY. THEN FOLLOWING THE INFANTS FOR AT LEAST A YEAR THE INFANTS WILL BE FOLLOWED FROM BIRTH THREE MONTH, SIX MONTHS, 12 MONTHS. AND WE HAVE STARTED AS DR. SMART WE STUDIED IN FIVE SITES, TWO SITES IN PUERTO RICO, THREE IN BRAZIL SO FAR. DO YOU WANT ME TO SAY ANYTHING SPECIFIC? >> I THINK A LOT OF US ARE WAITING ON THE RESULTS OF THAT. >> ABSOLUTELY. SO WE'RE HOPING THE FIRST INTERIM ANALYSIS WILL BE WHEN WE HAVE 20% OF THE DELIVERIES OCCURRING SO WE'RE NOT NECESSARILY GOING TO WAIT UNTIL THE END TO TURN IN ALL OF THEM SO WE'LL HAVE PRELIMINARY DATA, 20% OF THE DELIVERIES. >> JUST TO ADD TO THAT, THE PART OF THE STUDY ALLOWS US TO NOT ONLY LOOK AT SYMPTOMATIC AND ASYMPTOMATIC IN POTENTIAL CONFOUNDERS BUT ALSO WOMEN WHO ARE NOT INFECTED THEN FOLLOWING THOSE CHILDREN IF A CHILD IS INFECTED EARLY IN LIFE WE CAN FOLLOW THEM AS WELL. I KNOW THAT IS AN UNANSWERED QUESTION. >> ABSOLUTELY. THAT WOULD ADDRESS AN ANSWER SO MANY OF THE QUESTIONS WE HAD THIS MORNING ALREADY. >> THE BROAD IF YOU DON'T KNOW YET THE BABY WHEN THE MOTHER -- THE INFECTION WAS (INAUDIBLE) WE HAVE PATIENTS THAT -- MORE SEVERE AND WE HAVE PATIENTS WE HAVE INE IFS AT BEGINNING OF PREGNANCY BUT MOST OF MY PATIENTS HAVE SOME DEGREE OF (INAUDIBLE). I THINK WE DIDN'T KNOW, DIDN'T SEE IT, MAYBE HAVE A LOT OF KIND OF PRESENTATION, PATIENT MOTHER HAD ZIKA IN PREGNANCY, SO I DON'T KNOW. I THINK WE NEED MORE TIME TO UNDERSTAND BETTER THIS -- >> AGREED. YES, MA'AM. >> WANT TO COMPLICATE A LITTLE BIT MORE, FORTUNATE THE (INAUDIBLE) IS ENROLLING AT THIS TIME IN HISTORY WHERE WE DO HAVE EARLY EPIDEMONIC MANY COUNTRIES BUT ONE UNANSWERED, I DON'T KNOW IF WE WILL EVER HAVE ANY INFORMATION, WE HAVE BEEN ENROLLING WOMEN WHO ALREADY HAD ZIKA SIX MONTHS AGO OR A YEAR AGO. AND MIGHT HAVE SOME IMMUNITY SO THEY WILL NEVER DEVELOP IT SO THAT WOULD BE PART OF THE INFORMATION WE DON'T HAVE, RIGHT NOW, ACTUALLY COUNSELING WOMEN WHO HAD ZIKA BEFORE, THEY HAVE INFERTITY ISSUES AND PREGNANCY, NEW INFECTION, BASED ON ANIMAL STUDIES WE MIGHT WORK -- WE'RE CONFIDENT. >> THAT'S BEEN A BIG QUESTION, HOW DO WE COUNSEL WOMEN ABOUT REINFECTION. >> I THINK ANIMAL STUDIES ARE USEFUL. THEY GUIDE US BUT ANIMAL STUDIES ARE DONE UNDER LABORATORY SETTINGS, CAREFULLY CONTROLLED. WITH SINGLE EXPOSURE FREQUENTLY. NOT MULTIPLE EXPOSURE AND NOT WITH CONFOUNDERS SUCH AS OTHER INFECTIONS, THAT MAYBE PRESENT. OR EVEN MOST CASES ANIMAL STUDIES WHICH YOU GUYS KNOW THIS, THEY'RE NOT CONTROL FORD THEs TRUCE CYCLE OF THE ANIMALS FREQUENTLY. THEY' USEFUL TO GUIDELINES BUT NOT NECESSARILY ABSOLUTE. JUST TO FOLLOW-UP, I THINK AGAIN GOING INTO WHAT PA BLOW'S QUESTION ABOUT FEZ FRESNO, AND I REALLY DIDN'T THINK ABOUT THIS TOO MUCH UNTIL PREPARING FOR THIS MEETING, BUT WE DON'T HAVE ANY INFORMATION RATHER THIS THAN ABOUT ZIKA VIRUS ACQUIRED DURING THE TIME OF DELIVERY, FOR INSTANCE, WE DON'T KNOW IF THIS VIRUS IS TRULY A SIGNIFICANT NEUROTROPIC VIRUS, THIS COULD BE A MAJOR CAUSE OF MORBIDITY IN INFANT THAT REQUIRES IT. THE ZIP STUDY WILL APPROACH THAT, BUT I'M NOT SURE IT'S POWERED OR DESIGNED TO ADDRESS THAT QUESTION. IN MY VIEW MORE POWER TO LOOK AT CONGENITAL INFECTION SO IT MIGHT BE SOMETHING THAT NEEDS TO BE DURING THE EVALUATION -- DURING THE EVOLUTION OF THIS STUDY NEEDS TO BE CAREFULLY MONITORED THAT WE'RE ACTUALLY ACQUIRING THOSE KIND OF PATIENTS. THAT MAY NEED TO BE REDIRECTED AT LEAST NOT REDIRECT BUD ADDITIONAL DIRECTION TAKEN. >> I WANTED TO ADD THAT DR. RASMUSSEN POINTED OUT WE DON'T KNOW NECESSARILY WHAT HAPPENS WITH THE CHILDREN THAT MAY CLEAR THE IBM SO THEY'RE AFFECTED IN THE FIRST TRIMESTER, CLEAR THE IDM AT BIRTH, MAYBE THEY WERE. WE DON'T KNOW THAT FOR CMV, HOPEFULLY YOU'LL SEE THAT FROM OUR TRIAL BUT THAT WOULD BE POTENTIAL LOST OPPORTUNITY IF WE DON'T FOLLOW THOSE KIDS AS WELL THOUGH THEY'RE NEGATIVE AT BIRTH. >> KNOWLEDGE. NICHD. THANK YOU VERY MUCH FOR A NICE DISCUSSION. (INAUDIBLE) STEPPED DOWN SO IF YOU ALREADY COVERED IT, APOLOGIES, HAS ANYONE SEEN OR TREATED PATIENTS WITH (INAUDIBLE)MYELITIS IN CHILDREN? BECAUSE IT'S BEEN MENTIONERRED THAT -- MENTIONED THAT (INAUDIBLE) FOLLOWING ZIKA. THE CLINICAL COURSE OF THAT IS DIFFERENT FROM THE OTHER -- MAYBE DR. MILLER IN HIS TALK WILL BE ABLE TO SAY THAT BUT WANT TO KNOW THE EXPERIENCE FROM THE BRAZILIAN AND PUERTO RICAN COLLEAGUES OF OURS. >> WE'RE DOING A TALK ON NEUROLODGE UK COMPLICATIONS TOMORROW BUT DO Y'ALL HAVE ANY EXPERIENCE WITH MILY AT THIS ISSUES? -- MYHIGHTIS ISSUES? >> IMYELITIS ISSUES? >> I DON'T WORK IN HOSPITAL -- THERE ARE MANY CASES WITH (INDISCERNIBLE) OTHER NEUROLOGIC CONDITIONS. I HAVE TWO PATIENTS IN MY REHABILITATION CENTER, ONE GIRL FOUR YEARS OF AGE, VERY SEVERE, PCR WAS POSITIVE FOR ZIKA. IT WAS BEFORE THE REVIEW. NOW I THINK THAT SHE IS FIVE YEARS OF AGE. DIFFERENT FROM VIRUS BECAUSE (INDISCERNIBLE) IS MORE TEMPORAL, DIFFERENT, SHE HAS A WHOLE BRAIN VASCULAR AND SHE'S VERY SEVERE NOW. AND I HAD A LOT OF PATIENTS WITH ARE FEVER AND HEADACHE AND WE PERCEIVE THE CSF, ONLY NORMAL CELL AND PCR WAS POSITIVE FOR ZIKA VIRUS. BUT NOT SO COMMON LIKE YOU SEE IN OTHER PATIENTS, (INDISCERNIBLE) WE HAVE MORE PATIENTS WITH (INDISCERNIBLE) OTHER COMPLICATIONS OF VIRUS. >> I LIKE DR. MILLER, HE'S SPEAKING NEXT SO HE MAYBE ABLE TO ADDRESS THAT ALSO. DR. SAPP CHEZ. >> COUPLE -- SANCHEZ. >> COUPLE OF THINGS. I THINK THAT THERE'S TWO ISSUES. LOOKING BACK AT THE EXPERIENCE WITH OTHER CONGENITAL INFECTIONS. AND I REALLY THINK THAT IGM IN NEONATES AND NEWBORN IS VERY PROBLEMATIC. AND I REALLY THINK IT'S EXTREMELY IMPORTANT FOR US TO GET FOLLOW-UP SEROLOGIC ASSAY FOR NEUTRALIZING IDG TO ACTUALLY DOCUMENT BABY WHO IS PCR NEGATIVE IDM IS POSITIVE, IN NONENDEMIC AREA WITH IDG THAT PERSISTS BEYOND 18 MONTHS. SO THAT SHOULD BE AN IMPORTANT PART OF THE FOLLOW-UP, NOT JUST CONSIDER IT, BECAUSE WE DON'T KNOW IF THESE WELL PAIRED BABIES DID HAVE ZIKA. WE REALLY DOCUMENT ALL THE BABIES THAT ARE HE CAN POKESSED THAT SHOULD BE A STANDARD REG. WE DON'T KNOW HOW WELL THE IGM IS GOING TO WORK OR HOW WELL -- WE KNOW THERE'S FALSE POSITIVES AND NEGATIVES IN THE NEONATAL PERIOD FOR ALL CONGENITAL INFECTIONS SO I THINK THAT IT'S PROBABLY SIMILAR TO ZIKA HERE. I ALSO THINK THAT WE SHOULD TAKE THE OPPORTUNITY TO LEARN FROM OUR PAST EXPERIENCES WITH OTHER CONGENITAL INFECTIONS AND REALLY ADVOCATE A FULL EVALUATION OF THESE BABIES. I RECOGNIZE THAT ON A CLINICAL BASIS WE CAN'T GET AS MUCH STUDIES AS WE CAN. BUT IN RESERVING TRIALS, -- RESEARCH TRIALS IT WOULD BE GOD TO SEE HOW MANY ARE ANEMIC, THROMBO CYTOPENIC, BEYOND JUST NEUROIMAGING. OBVIOUSLY THE NEUROIMAGING IS THE MOST IMPORTANT, MOST CONCERNING BUT WE DON'T KNOW WHETHER NON-CNS DISEASE IS ASSOCIATED WITH OTHER ABNORMALITIES. SO I THINK THAT FULL EVALUATION IS REALLY IMPORTANT. WE'RE LEARNING A LOT FROM CONGENITAL CMV, SOME OF THESE NORMAL APPEARING BABIES MAY NOT BE NORMAL WHEN YOU DO MORE STUDIES. >> I WAS GOING TO ADD TO YOUR POINT, JUST AS I MAZING TO ME -- AMAZING TO ME THIS DAY AND AGE THE MOLECULAR REVOLUTION WE ARE FANTASTIC AS DR. FAUCI SAID AT DIAGNOSTICS OF ACUTE INFECTION BUT WE HAVE LOST OUR WAY. POINTED OUT WITH SEROLOGY FOR HISTORY OF INFECTION. WE ARE BLINDS ESSENTIALLY WITH THIS INFECTION RIGHT NOW. BECAUSE IGM IS TERRIBLE TEST. SO YOU IMAGINE, I WILL GIVE AN EXAMPLE, IN PUERTO RICO IN TWO YEARS PATIENTS WILL GET PREGNANT AGAIN, WOULDN'T BIT NICE TO HAVE IGG TO TELL THEM THEY HAVE HAD INFECTION IN THE EPIDEMIC TWO YEARS AGO? WE HAVE NO ABILITY TO DO THAT. WE NEED TO LEARN OUR LESSON FROM THIS. AS DR. FAUCI SAID, WE'LL HAVE OTHER FLAVIVIRUSES AND OTHER THING, IF WE IDENTIFY WE MAY SPEND TIME ON GOOD OLD FASHIONED SEROLOGY AN DEVELOP AN IGG TEST WE CAN DO THAT'S NOT SO LABOR INTENSIVE AND EXPENSIVE AND MAYBE I'M -- IT'S NOT POSSIBLE. BUT I CERTAINLY WOULD LIKE TO SEE US PUT THE EFFORT IN TO DEVELOPING THOSE. >> IT TAKES MONTHS FOR US TO EVEN KNOW NEUTRALIZING IDG WHETHER -- >> EXACTLY. >> I THINK ALONG WITH THAT, IMPACT TO DR. BRITT'S POINT, THE TIMING OF INFECTION. WE REALLY DO NEED TO TEST THESE BABIES FURTHER OUT TO SEE -- AND GET CERVICAL VAGINAL SECRETIONS TO SEE IF THEY'RE POSITIVE, SEE WHEN DOES TRANSMISSION OCCUR AND DOES THE TORNADO DIVISION VERSUS POSTNATAL PRE-FEEDING ACQUISITION, HOW IS THAT RELATED TO LONG TERM OUTCOMES. >> I WANT IDG WITH AVIDITY TESTING. EVEN BETTER. YES, MA'AM. >> I'M KATHERINE (INAUDIBLE) NEW YORK TIMES AND I HAD A QUESTION ABOUT THE RATIONALE BEHIND ONLY FOLLOWING THESE KIDS OUT A YEAR. DR. BRITTs PRESENTATION HE MENTIONED WHEN I COMES TO CMV, A LOT OF THE KIDS, 90% I THINK HE SAID, END UP WITH HEARING TROUBLES, MUCH LATER ON. SOME WAY PAST A AREA. SO I DON'T KNOW IF THAT'S ONE OF THE CHANGES COMING TO THE CDC GUIDANCE OR WHETHER OR NOT EVEN NIH STUDY WILL BE EXTENDED BEYOND TRACKING THESE KIDS WHO ARE EXPOSED TO ZIKA VIRUS IN UTERO PAST A AREA. MAYBE THERE'S RATIONALE FOR A YEAR, I DON'T KNOW BUT WOULD LOVE TO HEAR. >> I CAN CORRECT YOU. THE ZIP STUDY NOW IS PLANNING A FOLLOW-UP FOR TWO YEARS. AND MY UNDERSTANDING FOR PROGRAM WAS WE WANT TO FOLLOW THEM LONGER AND THAT WILL BE OBVIOUSLY DEPENDENT ON FUNDING. TO BE BLUNT. THE PLAN IS TO FOLLOW CHILDREN IDENTIFIED FOR AS LONG AS POSSIBLE. >> DR. RASMUSSEN, >> TO CLARIFY CDC GUIDANCE WHAT WE ARE TALKING ABOUT IS WHAT ARE RECOMMENDATIONS WE GIVE TO PEDIATRIC HEALTHCARE PROVIDERS THE FIRST YEAR OF LIFE. WE FELT LIKE EXTRAPOLATING OUT FURTHER THAN A FIRST YEAR OF LIFE WAS REALLY GETTING -- WE WERE ON THIN ICE SO WE WANT TO WAIT FOR ADDITIONAL INFORMATION FROM BRAZIL AND OTHER PLACES HOW KIDS ARE DOING OUT AND THEN WE CAN GIVE RECOMMENDATIONS OBVIOUSLY THOSE KIDS WILL BE FOLLOWED BY THEIR PEDIATRICIAN, EVEN WITHOUT CDC GUIDANCE, AND GET FOLLOWED IN NORMAL WAY BUT ONCE WE HAVE INFORMATION FROM PLACESNA HAVE KIDS THAT WILL BE AT THAT AGE, WE WILL BE ABLE IF GIVE CDC GUIDANCE FURTHER OUT. DIDN'T GIVE IT -- WE JUST COULD ONLY GO SO FAR WITH THE LIMITED DATA WE HAD AT THIS TIME. >> DON BAILEY RTE INTERNATIONAL. THIS UNDERSTANDING WHO IS AT RISK AND WHAT IS THE ULTIMATE RISK IS AN IMPORTANT QUESTION AND I KNOW IT WILL BE A LONG TIME BEFORE WE HAVE THE ANSWERS TO THAT. BUT I THINK THERE WILL BE POLICY DECISIONS THAT MIGHT HAVE TO HAPPEN EARLIER AND GUIDANCE MIGHT BE NEEDED. DR. RASMUSSEN TALKED REFERRING BABIES FOR EARLY INTERVENTION, TO QUALIFY FOR EARLY INTERVENTION YOU HAVE TO HAVE DOCUMENTED DEVELOPMENTAL DELAY WHICH THE KIDS CERTAINLY -- SOME OF THESE CHILDREN CLEARLY HAVE THAT, YOU HAVE TO HAVE A CONDITION THAT'S LIKELY TO LEAD TO A DEVELOPMENTAL DELAY. THOSE CATEGORIES HAVE TO BE SERVE AND STATES HAVE CHOICE OF EVERYBODY ISING AT RISK INFANTS. AND DEFINITION OF AT RISK VARY ACROSS STATES, IT COULD BE CO-OCCURRING, PRENATAL DRUG EXPOSURE, A VARIETY OF THINGS. SO THE QUESTION IS, SOME MOTHER WILL SAY I HAD ZIKA, I WAS INFECTED WITH ZIKA IN PREGNANCY, IS MY BABY AN AT RISK BABY AND THUS QUALIFYING FOR EARLY INTERVENTION PROGRAMS SO THERE'S NO GUIDANCE AVAILABLE RIGHT NOW, I KNOW THIS IS AN NIH MEETING BUT ULTIMATELY SOMEWHERE SOME GUIDANCE WILL NEED TO COME IN THAT AREA. >> NOBODY WANTS THE TOUCH THAT, I THINK EVERYONE AGREE, YES WE AGREE. THANK YOU. YES, SIR. >> QUESTION ABOUT MA SEN TA. BEING VERY SLOW TO UNDERSTANDING MORE ABOUT THE VASCULAR CHANGES WITH PRENATAL MALARIA AND POTENTIAL DEVELOPMENT, I'LL STRUCK BY THE IMAGES COMING FROM BRAZIL OF PLACENTAL CALCIFICATIONS WITH ZIKA VIRUS AND INTERESTED IN THOUGHT WHAT IS ARE THE GAPS AND WHAT WE NEED TO DO TO BETTER UNDERSTAND THE INTERFACE BETWEEN MOM AND BABY. >> I THINK DR. HUGHES OR, DO YOU WANT TO START WITH THAT ONE? >> YES. SO THERE'S THE PLACENTA PROJECT AT THE NICHD FOR THAT VERY REASON, THERE'S STILL MUCH WE DON'T UNDERSTAND ABOUT THE MA SEN TA AND WE SEE SIMILAR PRESENTATION WITH CMV, SEE CALCIFICATIONS, PLACENTA MEGALY, AT LEAST WITH CMV IT APPEARS THAT IT INFECTS THE PLACENTA PRIMARILY, REMY KATES THERE, TAKES A WHILE TO GET TO THE FETUS, THAT MAYBE WHY WE'RE SEEING DIFFERENTIAL INFECTION AT DIFFERENT POINTS THROUGHOUT THE COURSE OF THE PREGNANCY. WE DON'T KNOW IF THAT IS THE CASE WITH ZIKA. WHETHER THERE WAS TALK THIS MORNING ABOUT PRIOR TO EIGHT WEEKS WHEN THERE ISN'T PLACENTA, WHETHER OR NOT THERE WOULD BE PROTECTIVE EFFECTS WE SEE CMV INFECTION ALL THE WAY ACROSS, ALL THE WAY ACROSS GESTATION, BUT IT TAKES SIX WEEKS TO REALLY SET UP AN INFECTION IN A FETUS. AFTER MATERNAL INFECTION. THAT'S HOW -- WHY WE BASE TESTING AMNIOTIC FLUID TESTING ON THAT. IF YOU LOOK AT PLACENTA, CMV INFECTED INFANTS, THEY'RE VERY FULL OF INCLUSION BODIES. I THINK THAT'S A KEY FACTOR AND WE WILL TALK RESEARCH GOALS TOMORROW, I THINK THAT WILL BE A KEY FACTOR OF THINGS THAT WE'LL WANT TO LOOK FOR AS WE DEVELOP THIS. >> IF WE WERE SETTING UP RESEARCH PROJECTS, IT'S NOT JUST CMV BUT -- TOXO, LOOKING AT THAT IN PREGNANCY ONE THING WE LEARN OVER TIME IS MOM SERO CONVERTS, WE CAN'T STICK A NEEDLE NOW AND EXPECT THE AMNIOTIC FLUID TO BE POSITIVE. YOU HAVE TO WAIT A CERTAIN PERIOD OF TIME, INTERESTING THE TOXO RECOMMENDATIONS ARE FOUR WEEKS AND THE CMV RECOMMENDATIONS ARE SIX WEEKS. >> VERY SMALL STUDIES. >> EXACTLY. BUT YOU HAVE TO GET IT TIME. SO BASED ON THAT, USING THAT KNOWLEDGE IF YOU'RE SETTING UP STUDIES TO LOOK FOR TRANSMISSION TO THE FEE TURKS YOU HAVE TO TAKE THAT INTO ACCOUNT. >> THERE IS A RECOMMENDATION TO SEND PLACENTAINGS ZIKA POSITIVE OR SUSPECTED CASES FOR EVALUATION. HOPEFULLY HAVE SOME DATA. I DON'T KNOW WHAT YOU'RE DOING IN BRAZIL OR PUERTO RICO IF AVAILABLE, PLACENTAL EVALUATION IS BEING DONE ON ALL POSITIVE MOTHERS. DO Y'ALL KNOW HOE IN PUERTO RICO DOING ON ALL POSITIVE MOTHERS RIGHT NOW? >> THE IN PUERTO RICO DEPARTMENT OF HEALTH HAS POLICY OF CAPTURING ALL PLACENTAS AND (INAUDIBLE) CONGRESS ACCEPTING, WE SEEK DURING THE PREGNANCY AND THEY ARE SENDING ALL THESE TISSUES TO THE CDC FOR TESTING. WE ARE NOW GETTING INFORMATION BACK, CLINICIAN PROVIDERS TO THE PATIENT WHOSE DELIVERED, DO NOT HAVE ANY INFORMATION ON THE OUTCOMES OF THOSE STUDIES. AND IN ADDITION, THERE'S STILL THE ISSUE OF FOR EXAMPLE, FOR THE (INDISCERNIBLE) MOTHERS WOULD CONSENT FOR PLACENTA AND CON ACCEPTING TO BE PART OF THIS STUDY. THOSE CONVERSATIONS HAVE BEEN HAPPENED AND WILL CONTINUE TO NEED TO HAPPEN BECAUSE WE NEED TO MAKE SURE WE RESPECT PATIENTED DESIZER AND RIGHTS AND WE ALSO WANT THE RIGHT INFORMATION AS WELL. >> WE SHOULD BE GETTING INFORMATION HOPEFULLY WITH THAT. YES, SIR. >> MY NAME IS (INAUDIBLE), MEDICAL GENETICIST, LAST WEEK CAME ACROSS A VERY INTERESTING PAPER FROM -- ABOUT THE VIRUS, THE -- MAYBE THE HARPS VIRUS ENHANCE OR FACILITY AT A TIME ZIKA INFECTION, I THINK THIS IS A HUGE ISSUE TO BE DISCUSSED. AND MAYBE IN BRAZIL IT ALWAYS -- ALL THE OTHER VIRUS, DEFINITELY AFFECTED. DO WE HAVE A COMBINATION OF THEM, IS THERE A CHAPERONE EFFECT OR SOME CAN DO BETTER THAN OTHERS. IF SOMEBODY COULD COMMENT ON THIS, THANK YOU. >> THERE'S INTEREST IN CO-INFECTIONS CONFOUNDING VIRUSES. ANYBODY WANT TO ADDRESS THAT ON THE PANEL? >> I THINK HER PIECE VIRUS MAY CONTRIBUTE. FROM -- HERPES VIRUS MAY CONTRIBUTE. I DON'T THINK THERE'S QUESTION ABOUT IT THAT HAVING MULTIPLE VIRUSES MULTI-INFLAMMATORY REACTIONS IS INTERESTING THAT THE HERPES VIRUS INDUCES INCREDIBLE TYPE ONE INTERFERON RESPONSE AND SUPPOSEDLY ZIKA IS SENSITIVE TO THESE RESPONSES SO MAYBE IT'S PROTECTIVE. >> HI, (INAUDIBLE) FROM CHILDREN'S NATIONAL AGAIN. I THINK ANOTHER IMPORTANT QUESTION IS THE ROUTE OF INFECTION AND HOW THAT -- WHAT THAT CONFERS TO THE RISK OF THE VAGINAL VERSUS THE DIRECT VIRAL TRANSMISSION AND THERE WAS A GOOD PAPER IN CELL FROM YALE LAST COUPLE OF WEEKS THAT SHOWED IN THEIR MOUSE MODEL DIRECT INNOCULATION TO THE VAGINAL MUCOSA, MASSIVE AMOUNTS OF REPLICATION, IN THEIR WILD TYPE MICE, WITHOUT THEIR INTERFERON KNOCK OUT MODEL. THOSE BABIES, BORN TO THOSE MOMS HAD BRAIN INJURY WITHOUT VIREMIA. SO THERE IS POTENTIALLY MULTIPLE WAYS THAT THESE KIDS CAN BE INFECTED. WE HAVE TO TAKE THAT INTO CONSIDERATION AND AS A COROLLARY TO THAT, WHEN WE TALK ABOUT WE KNEW ABOUT CMV INFECTION AND RUBELLA INFECTION, THIS VIRUS IS REALLY KIND OF AMISH MASH BECAUSE IT'S LIKE CMV, IT COULD BE SEXUALLY TRANSMITTED BUT UNLIKE EITHER VIRUS, IT'S A ARBO VIRUS. SO THAT COMPLICATES EVERYTHING, WE SHOULD THINK ABOUT THAT WHEN WE DESIGN, WHATEVER INFORMATION WE COLLECT. >> I THINK ONE OF THE CHALLENGES IS especially in an area there's active Zika transmission it will be hard to know if it was sexually transmitted or somebody got from mosquito bite, I don't know how you difference rate those, I agree, that would be -- differentiate those. I AGREE THAT'S IMPORTANT QUESTION AND I DON'T KNOW HOW TO GET AT THAT. ONE MOTHER COMMENT BECAUSE I HEARD THIS ABOUT THE TIMING BEFORE EIGHT WEEKS. I THINK THE OTHER POSSIBILITY FOR AGO WEEKS IS THOSE PREGNANCIES ARE BEING LOST. SO I DON'T WANT -- I SAW SOMETHING ON THE TWEET SAYING THAT MAYBE IT'S SAFE BEFORE EIGHT WEEKS AND I DON'T WANT THAT TO BE THE MESSAGE THAT GETS OUT OF HERE, I WANT TO BE THAT BEFORE EIGHT WEEKS MAYBE WE'RE NOT SEEING PROBLEMS BECAUSE THOSE PREGNANCIES ARE BEING LOST. >> ARE WE OKAY TIME WISE? OKAY. PERFECT. FASCINATING DISCUSSION. SO YOU WILL LET ME KNOW. DR. BERG. >> THANK YOU. SO I THINK THAT THERE'S SO MANY UP KNOWNS AND I THINK ANOTHER UNKNOWN THAT WE NEED TO PAY ATTENTION A LITTLE BIT IS THAT THE FAMILY THE VIRUS BELONGS TO ALSO IS FAMILY HEPATITIS C BELONGS TO, PROVIDING VIRAL DIARRHEA VIRUS, IT HAPPENS ONLY IN CATTLE BUT APPARENTLY IT AFFECTS ON CALFS ARE SIMILAR TO THOSE FOUND IN ZIKA. AND IT IS ALSO SEXUALLY TRANSMITTED, IT IS NOT AN ARBOR VIRUS BUT IT'S SEXUALLY TRANSMITTED. IT ACTUALLY STAYS IN THE COW FOR FUTURE PREGNANCIES. SIMILAR TO HEPATITIS C, WHICH IS DIFFERENT STORY BUT IT ALSO HAS A REPRODUCTIVE ANGLE AND HAS PERSISTENCE AN AFFECTS MULTIPLE GENERATIONS, WE NEED TO LOOK AT THE WHOLE FAMILY, MAYBE ALSO LOOK WHAT HAPPENS WITH THESE WOMEN, FOLLOWING CHILD BARING AND PERSISTENCE, CAR IN THISTY OF THIS VIRUS. HOW MANY OF THESE WOMEN END UP CARRIERS OR WHAT ARE THE OUTCOMES OF NEUROPREGNANCY SO THEY NEED TO BE FOLLOWED FOR FUTURE CHILD BEARING. I DON'T KNOW IF YOU ARE DOING ANYTHING ALREADY -- >> LET ME ASK A QUESTION, WHO ARE YOU SUGGESTING FOLLOWING? >> WOMEN. IS IF YOU'RE IN BRA SEVERAL ARE YOU GOING TO SUGGEST ANY WOMAN THAT'S PREGNANT? >> THEY H COME BACK PREGNANT AGAIN, RIGHT? ASKING THIS ONLY TO COME BACK WHEN THEY GET PREGNANT, THERE'S GOT TO BE SOMETHING. >> YOU'RE NOT SUGGESTING SOMEBODY WITH DOCUMENTED INFECTION SUCH AS PCR HAS SYMPTOMATIC DISEASE COLLECT VAGINAL CERVICAL WASHINGS, BLOOD, WHATEVER, PCR, FOR MONTHS IF NOT YEARS, TO SEE HOW LONG THEIR CARRY, THEY HAVE HAD PERSISTENCE, PREGNANT WOMEN APPEARS TO BE LONGER. IT SEEMS TO GO AWAY. HAVE WE TESTED ENOUGH FOR # HUNDRED% CERTAINTY? I'M GOING -- I DON'T THINK SO. BUT >> IT DOESN'T LOOK LIKE THERE'S SIMILAR STORY LIKE HEPATITIS C OR BOVINE. (OFF MIC) >> WONDERFUL THANK YOU. >> THAT WILL BE USE. IF A CLINICAL STANDPOINT THAT'S WHAT OUR PATIENTS ARE ASKING, AM I NOT AT RISKER ONCE I GET BETTER, GET BETTER. AND AM I NOT AT RISK ANY MORE. THE NEXT PREGNANCY WILL BE FINE. RIGHT? AND I THINK THAT IS A QUESTION THAT I STILL WAFFLE A LITTLE BIT HOW I ANSWER. IF THERE ARE NO OTHER QUESTIONS FOR THE PANELIST, THANK YOU ALL VERY MUCH. WE WILL PROCEED ON TO THE NEXT. THANK YOU VERY MUCH, PANELISTS. [APPLAUSE] >> IF MY WATCH SEVEN MESS CORRECTLY, THIS IS TIME -- SERVES ME CORRECTLY, I THINK THIS IS TIME FOR A BREAK. WE'LL RECONVENE AT 3 O'CLOCK, PROMPTLY. WE'RE GOING TO TRY TO BRING THIS MEETING TO BACK TO ORDER. IT IS 3 P.M. ON THE DOT. IT IS MY DISTINCT PLEASURE TO INTRODUCE OUR THIRD SPEAKER THIS AFTERNOON UNDER THIS SESSION, IT'S MY PLEASURE TO INVITE DR. STEVEN MILLER HEAD OF DIVISION OF NEUROLOGY AND CENTER FOR BRAIN AND MENTAL HEALTH AT THE HOSPITAL FOR SICK CHILDREN. PROFESSOR OF PEDIATRICS UNIVERSITY OF TORONTO AND SENIOR SCIENTIST IN THE NEUROSCIENCE MENTAL HEALTH PROGRAM AT THE RESEARCH INSTITUTE OF SICK KIDS. HE LEADS A MULTI-DISCIPLINARY TEAM THAT FOCUSES ON BETTER UNDERSTANDING BRAIN INJURY AND DEVELOPMENT IN THE NEWBORN. HE AND TEAM USE ADVANCED BRAIN IMAGING AND DETAILED LONG TERM FOLLOW-UP TO HELP CHILDREN WHO WERE BORN WITH EARLY OR BORN EARLY OR WITH CONDITIONS THAT PUT THEM AT RISK OF NEUROLOGICAL AND NEURODEVELOPMENTAL DEFICITS. THE GOAL OF HIS TEAM WORK IS TO PROMOTE STRATEGIES TO PREVENT BRAIN INJURY AND PROMOTE RECOVERY OF THE BRAIN -- IF THE BRAIN IS INJURED TO IMPROVE LIFE LONG HEALTH OF CHILDREN AND FAMILIES. SO STEVEN WILL TALK TO US ABOUT NEUROLOGIC ABNORMALITIES. WELCOME. >> GOOD AFTERNOON, GRATEFUL TO BILL AND NICHD FOR HAVING ME WITH YOU. THANKS TO THE SPEAKERS THAT STARTED OFF TODAY, FROM WHAT I LEARNED A TREMENDOUS AMOUNT AND I SPEAK FOR CHANDY THEY CANNING Y'ALL FOR STICKING WITH IT UNTIL THE END. MY BRAIN ALREADY FEELS FULL. SO LET ME START WITH A DISCLOSURE. I'M PEDIATRIC NEUROLOGIST SO I THINK ABOUT THE BRAIN AND I THINK BRAIN HEALTH IS ESSENTIAL TO CHILD HEALTH AND IF I AM SUCCESSFUL OVER THE NEXT HALF HOUR I WILL CONVINCE EACH AND EVERY WOULD HAVE BEEN YOU TO BE THINKING OR ABOUT BRAIN DEVELOPMENT AND THINK ABOUT YOUR ROLE IN HOW YOU'RE PROMOTING BRAIN DEVELOPMENT FOR THE CHILDREN YOU CARE FOR, WHETHER INFECTIOUS DISEASE CLINIC, WHETHER IT'S LEADING THE NICHD OR WHETHER IT'S ADVOCATE FOR CHILD HEALTH AND ROLE IN THE MEDIA. I ALSO HOPE TO CONVINCE YOU THE IMPORTANT ROLE OF PARENT HAS TO PLAY, NOT ONLY IN MONITORING CHILDREN'S DEVELOPMENT BUT IN BEING AGENTS FOR INTERVENTION. IMPORTANT ADVOCATES FOR THE RESEARCH WE'RE PARTICIPATING IN. SO WHY THINK SO MUCH ABOUT BRAIN DEVELOPMENT? AT THE EXPENSE OF THINKING LESS ABOUT BRAIN INJURY. THESE ARE MRI IMAGES FROM BABIES BORN PRE-TERM, NOT A BABY WITH ZIKA VIRUS. THIS BEATTY WAS BORN 30 WEEKS GESTATION OR THREE MONTHS EARLY BROUGHT TO THE MRI SCANNER AS PART OF THE RESEARCH ARE PROJECT, TWO WEEKS OF AGE OR 30 WEEKS GESTATION AND MIGHT BE WEEKS LATER. FOR THOSE WHO MAY NOT SPEND AS MUCH TIME LOOKING AT MRI. IMAGINE OF THE BABY I WANT TO HIGHLIGHT JUST HOW INCREDIBLE A PERIOD BRAIN DEVELOPMENT IS HAPPENING OVER THIS THIRD TRIMESTER OF GESTATION. THROUGH THIS TALK I WILL TAKE A FEW STEPS BACKYARDS EARLIER INTO PREGNANCY, BUT LET'S LOOK AT THIS BABY, TWO WEEKS OF AGE SHOWN HERE ON THE -- MRI SCANS SO WE HAVE TAKEN OFF THE SKULL LOOKING DOWN ON THE BRAIN, FRONT HEAD IS HERE, BACK OF THE HEAD IS HERE. WE HAVE THIS DARK RIBBON, THE CEREBRAL CORTEX, THIS IS WHERE WE HAD BILLIONS OF NEURONS MAKING TRILLIONS OF CONNECTS. SENDING PROCESSES DOWN THROUGH THE WHITE MATTER BRIGHT ON THIS IMAGE TO CONNECT WITH THALAMUS, BASAL GANGLIA, WE HAVE SEEN IMPORTANCE OF BASAL GANGLIA FOR THE MOODIES ORDERS MOVEMENT WITH BABIES WITH ZIKA VIRUS INFECTION. PASSING THROUGH HERE ARE VOLUNTARY MOTOR PATHWAYS WHEN YOU SAY RAISE YOUR ARM BECAUSE THERE'S TRANSMISSION FROM NERVES IN THE CORTEX TRAVELING THROUGH THE CORTICO SPINAL TRACT HERE TO SYNAPSE SPINED CORD GET YOUR MUSCLE TO MOVE. PICK THE SAME BABY, NINE WEEKS LATER AND LOOK AT THE CEREBRAL CORTEX NOW, IT WENT FROM BEING THIS SMOOTH RIBBON TO THIS LUMPY BUMPY RIBBON FULL OF EYE RYE, LOOK AT THREE DIMENSIONS, IT LOOKS LIKE OUR BRAIN BUT A BUILT SMALLER. THIS INCREDIBLE PERIOD OF DEVELOPMENT IS HAPPENING OVER JUST NINE WEEKS. WHEN I LOOK AT BABIES BORN PRE-TERM I POINT TO MY COLLEAGUES IN THE NEONATAL INTENSIVE UNIT THIS BABY HAS UNDERGO SIX WEEKS OF INTENSIVE CARE AND IF WE THINK ABOUT CHALLENGING DIAGNOSING AND CARING FOR BABIES OF ZIKA VIRUS INFECTION WE HAVE TO ASK HOW IS THIS INFECTION IMPACTING THIS INCREDIBLE PERIOD OF BRAIN DEVELOPMENT. SO BILL GAVE US ALL A NUMBER OF QUESTIONS WE STARTED TO PREPARE FOR THESE TALKS SOILY RUN THROUGH THEM, YOU HEARD THEM IN THE OVERARCHING QUESTION, I WILL PRESENT SOME ANSWERS NOT AS A DEFINITIVE ANSWER AND CERTAINLY NOT MY OWN THOUGHTS BUT AS A PLACE TO START A DISCUSSION. WE HEARD ABOUT THE IMPORTANCE OF EVALUATING AT BIRTH, I WILL HIGHLIGHT THE IMPORTANCE OF MEASURING THE HEAD CIRCUMFERENCE, TO A NEUROLOGIST IS A VITAL SIGN BUT OFTEN DIFFICULT TO FIND IN THE MEDICAL RECORD. NEUROLOGICAL EXAMINATION EARLY HEARING ASSESSMENT AND EARLY EYE EXAMINATION ARE ESSENTIAL. I'M GOING TO POINT OUT, WE HEARD FROM THE CDC GUIDELINES FROM THE WHO, AGAIN, RAPID ADVICE GUIDELINES, NOT THE DEFINITIVE GUIDELINES BUT A STARTING PLACE FOR THINKING ASSESSING AND MANAGING NEONATES AND INFANTS WITH COMPLICATIONS WITH ZIKA VIRUS EXPOSURE IN UTERO. THEY HIGHLIGHT THE NEED FOR ONGOING ASSESSMENT OF GROWTH WITH FAIRLY INTENSIVE SCHEDULE OF FOLLOW-UP, BUT WHAT SHOULDN'T BE LOST IS FEEDING AND TRANSMISSION, IT'S HARD TO SEE THE BRAIN GROWING WITHOUT ADEQUATE NUTRITION, FROM THE VIDEOS FROM DR. VAN DER LINDEN THIS MORNING, FEEDING IS A CHALLENGE IN THESE BABIES, PEDIATRIC COMMUNITY SOMETHING WE HAVE TO ADDRESS. WE HAVE SEEN THEOR THOUGH PEEDIC ISSUES -- ORTHOPEDIC ISSUES, IT'S IMPORTANT FOR MOVEMENT AND PAIN AND COMFORT. EDUCATION OF PARENTS IS SOMETHING BROUGHT UP EARLIER TODAY TOO AND SOMETHING I THINK IS WORTHY OF FUTURE DISCUSSION. PARENTS DO HAVE AN ESSENTIAL ROLE IN MONITORING THEIR CHILDREN DEVELOPMENT AND GIVEN THE TREMENDOUS BURDEN OF EPILEPTIC ENACCEPT LOVETHY, AND THE EEG DATA IS STRIKING BY PROPENSITY OF SEIZURES IN ZIKA INFECTION, WE HAVE TO RELY ON PARENTS TO BE ALERT ABOUT THE SIGNS OF SEIZURES, INFANTILE SPASMS, SO THEY CAN BRING THOSE TO OUR ATTENTION. THEN WE HAVE TO BE ENGAGING CAREGIVERS IN DEVELOPMENT NOT ONLY FOR MONITORING BUT ALSO FOR INTERVENTION. AS WE THINK ABOUT RESPONSE TO ZIKA VIRUS INFECTION IT'S ALSO FAIR TO THINK ABOUT WHERE WE HAVE SUCCESSES AT MONITORING CHILDREN DEVELOPMENT OVER TIME PROACTIVELY, HERE, YOU CAN LOOK AT THE NICHD NEONATAL NETWORK, THE CANADIAN NEONATAL FOLLOW-UP NETWORK TO SEE SUCCESS HAD IN COHORTS OF BABIES BORN PRE-TERM AND VALUE OF STRUCTURED NEURODEVELOPMENTAL FOLLOW-UP. I SAY THIS WITH DUE RESPECT TO MY COLLEAGUES AT NEUROLOGISTS, THAT THE REFLEX HAMMER IS NOT ENOUGH. WE DO NEED ATTENTION TO HEAD CIRCUMFERENCE NEUROLOGICAL EXAMINATIONS ARE CLEARLY IMPORTANT TO IDENTIFY THE ISSUES OUTLOINED THIS MORNING AND I JUST SUMMARIZED, IF WE WERE TO UNDERSTAND THE IMPACT OF ZIKA VIRUS INFECTION ON CHILD DEVELOPMENT WE NEED STRUCTURED STANDARDIZED QUANTITATIVE TOOLS TO MEASURE DEVELOPMENT, AND HERE I GIVE YOU SOME EXAMPLES ONLY SO THE MOTOR SCALES, I START WITH THIS BECAUSE I'M CANADIAN, BUT THE TEST OF INFANT PERFORMANCE OR BAILEY SCALE OF INFANT DEVELOPMENT IS EARLY MEASURES OF CHILD MOTOR DEVELOPMENT SO WE CAN TRACK TRAJECTORIES IN DEVELOPMENT, THERE ICE TENSION ON THE 18 MONTH ASSESSMENT AND HERE THROUGH THE NICHD NETWORK OR FUN NETWORK IN CANADA, THE BAILEY SCALE OF INFANT DEVELOPMENT HAVE SHOWN PROMISE AT GIVING A MEASURE OF EARLY COGNITIVE DEVELOPMENT WITH MOTOR DEVELOPMENT BUT 18 MONTHS ASSESSMENT OF COGNITION ARE NOT SUFFICIENT, WE NEED TO BE LOOKING BEYOND THAT, ASSESSMENT OF 3 GETTING UP TOWARDS SCHOOL AGE IS CERTAINLY WHY PARENTS ARE HAVING MORE QUESTIONS ABOUT WHAT TO DO FOR CHILD SUPPORT AND SERVICES AT SCHOOL. BUT HERE WE CAN START TO TAP INTO THE RICH LANGUAGE THAT'S APPARENT AT AGE 3. AS WE MOVE TO SCHOOL AGE FIVE TO SIX WE CAN'T LOSE THAT QUANTITATIVE ASSESSMENT OF HOW A CHILD IS DOING AND OUR ATTENTION CAN SHIFT MORE TOWARDS LANGUAGE COGNITION, EXECUTIVE FUNCTION. OTHER ASPECTS OF DEVELOPMENT ARE ESSENTIAL AS WE HAVE HEARD EARLIER, HEARING AND CERTAINLY A LARGES THE NEED OF REPEAT HEARING ASSESSMENTS AND RISK FOR HEARING LOSS OVER TIME THAT MAY NOT BE APPARENT EARLY ON, VISION SCREENING WE WILL HEAR MORE OF TOMORROW AND THEN SUPPORT OF PARENTS, AND THIS IS WHERE TOO I THINK WE NEED TO LEARN FROM OUR EXPERIENCE IN THE NEWBORN INTENSIVE CARE UNIT, CARDIAC INTENSIVE CARE UNIT, HOW MANY PARENTS ARE BEING DISCHARGED FROM OUR HOSPITALS WITH POST TRAUMATIC STRESS DISORDER. HOW MANY MOMS ARE SUFFERING FROM DEPRESSION AND HOW IS THAT IMPACTING THE PROGRESSION OF CHILD DEVELOPMENT, PUT ANOTHER WAY SUPPORTING PARTS MENTAL HEALTH HOW ARE WE PROACTIVELY SUPPORTING HOW THE CHILD BRAIN IS DEVELOPING OVER THAT INCREDIBLE PERIOD OF BRAIN DEVELOPMENT? WE HEARD SOME COMMENTS ABOUT THE IMPORTANCE OF REPRODUCTIVE HEALTH AND CERTAINLY TREMENDOUS QUESTIONS THAT NEED TO BE ASKED. AS A NEUROLOGIST THINKING BRAIN, IT'S IMPORTANT WE ASK WHAT ARE MEASURES OF BRAIN HEALTH, TRACKING DEVELOPMENT I PRESENT QUANTITATIVE MEASURES WE CAN USE AT A CLINICAL BASIS, HOW THOSE CAN BE APPLIED PRENATALLY AND CERTAINLY OPEN QUESTION AND MEASURING THE BRAIN QUANTITATIVELY. THERE'S A LOT OF ATTENTION OR DISCUSSION AROUND MEASURING THE BRAIN WHETHER ULTRASOUND OR MRI AND THINGS PROGRESSED TO A POINT WE CAN MOVE BEYOND THE DIAGNOSTIC RADIO LOGICAL INTERPRETATION OF MRI SCAN FOR QUANTITATIVE ASSESSMENT OF BRAIN STRUCTURAL SIGNIFICANT DESTRUCTION WITH QUALIFICATION TO MEASURING BRAIN STRUCTURES HERE AND HERE, I'M GOING TO HIGHLIGHT THE BASAL GANGLIA, THE THALAMUS, CORTICO SPINAL TRACK, GIVEN THEIR IMPORTANCE THAT WE HEARD OF THIS MORNING. WE CAN ALSO MEASURE THE BRAIN MICROSCOPIC DEVELOPMENT, THIS IS A FRACTIONAL DIFFUSION TENSOR IMAGE. THIS COLOR CODED IMAGE LOOKS HOW DIRECTIONAL WATER MOTION IS IN THE BRAIN. INCREASING DIRECTIONALITY OF WATER MOTION, INCREASING MATURATION OF WHITE MATTER PATHWAYS. SO AS AXONS COMING THROUGH THAT BRIGHT WHITE MATTER BECOME MYELINATED BY OLIGODENDRIA GLIAL CELLS, WATER MOTION IS HIGHLY DIRECTIONAL AND WE CAN COLOR CODE THAT, SO WATER MOVING LEFT TO RIGHT IN THE BRAIN IS RED SO HERE IS THE CORPUS CASH FLOW SUM, CALLOSUM, SO HERE ARE THE VISION PATHWAYS FOR THE OPHTHALMOLOGIST, HERE IS THE CORTICO SPINAL TRACK IN AND OUT PLAIN IN BLUE, VOLUNTARY MOTOR PATHWAYS. MORE IMPORTANT THAN THE BEAUTIFUL COLOR CODED IMAGE, EACH PIXEL OF THIS IMAGE CONTAINS QUANTITATIVE INFORMATION THAT TRACKS WITH PROGRESSION OF THE OLIGODENDRIA GLIAL LINEAGE THAT CELL TYPE THAT IS CRITICAL FOR MYELIN FORMATION. SO WE CAN START TO ASK NOW HOW DO EARLY EXPOSURES IMPACT THE MICROSTRUCTURAL DEVELOPMENT OF THE BRAIN, WE CAN LOOK AT FUNCTION WHETHER EEG NEUROPHYSIOLOGY MEASURES OR FUNCTIONAL SPECTROSCOPY AND WE CAN ALSO QUANTIFY BRAIN METABOLISM LOOKING AT MEASURES OF NEURONAL INTEGRITY SUCH AS ASPARTATE. FOR THE MRI MEASURES HERE, THESE ARE ALL MEASURES THAT ARE ACQUIRED IN THESE IMAGES ON A ONE AND A HALF TEST CLINICAL MRI SCANNER, IT'S NOT THE SCANNER YOU HAVE, IT'S WHAT YOU DO WITH IT. SO WHY THESE ASSESSMENTS? THE SPEAKERS THIS MORNING DID A FAR BETTER JOB THAN I CAN. I WAS IN TORONTO, I HAVEN'T SEEN A BABY WITH ZIKA VIRUS EXPRESSION SO BORROW FROM COLLEAGUES IN BRAZIL TO HIGHLIGHT ZIKA VIRUS IN THE FETUS IS A PROBLEM WITH THE BRAIN. IT'S NOT MICROCEPHALY, IT'S DESTRUCTIVE BRAIN INJURY WE SEE INVOLVING NOT JUST CEREBRAL CORTEX BUT PATHOLOGY, WHITE MATTER AND VERY IMPORTANTLY THE BASAL GANGLIA. HERE IS AN IMAGE OF THE PLACENTA SHOWING MARKED CALCIFICATIONS AND THE RELATIONSHIP BETWEEN PLACENTAL HEALTH AND BRAIN HEALTH IS SOMETHING THAT NEEDS PARTICULAR ATTENTION IN THIS CONTEXT. SO THERE'S DISCUSSION WHETHER ZIKA VIRUS AND FETUS IS A DISEASE OF THE FIRST TRIMESTER. HERE TOO COLLEAGUES IN NEUROSCIENCE PROVIDE IMPORTANT DATA WE SHOULD BE KEEPING IN MIND AND THAT IS THE ZIKA VIRUS ASSOCIATED INFECTION OF FETAL BRAIN IS A PROBLEM OF THE NEUROPRECURSOR CELLS, THIS IS A BEAUTIFUL STUDY NOT FAR FROM HERE SHOWING HOW THERE'S PARTICULAR TROPISM OF ZIKA VIRUS TO NEURAL PRECURSOR CELLS. MUCH LESS TROPISM FOR MATURE NEURONS. YOU CAN SEE THAT QUANTITATIVELY HERE WHERE YOU HAVE FAR GREATER INFECTION RATES, ABOUT 80% IN NEURAL PRECURSOR CELLS, MUCH LOWER IN NEURON, DOESN'T MEAN THE NEURONS ARE COMPLETELY RESISTANT TO ZIKA VIRUS BUT THE PROBLEM IS NEURAL PRECURSOR CELLS AND RADIO GLIAL CELLS SO IF YOU GO BACK TO HOW THE BRAIN IS DEVELOPING, AS YOU GO FROM THE NEURAL TUBE AND YOU HAVE THIS FACTORY OF CELLS BEING FORMED NOW IN THE SUBVENTRICULAR ZONE, NEURONS BEING FORMED VERY CLOSE TO THE VENTRICLES THAT THEN MIGRATE ALONG THESE BEAUTIFUL RADIO GLIAL GUIDE UP TO FIND THEIR PLACE IN THE CEREBRAL CORTEX, ASK YOURSELVES WHAT HAPPENS IF NOW YOU DESTROY RADIO GLIAL CELLS, HOW ARE CELLS GOING TO GO FROM THE SUBVENTRICULAR ZONE, ZONE DEEP IN THE BRAIN TO FIND THEIR APPROPRIATE PLACE IN THE CEREBRAL CORTEX. AS WE THINK ABOUT THIS TROPISM FOR NEURONAL PRECURSOR CELLS IN RADIO GLIAL CELLS IT'S NO LONGER SURPRISING WHY WE SEE THESE DEVASTATING IMAGING OF THE DEVELOPING BRAIN NOT ONLY WITH DESTRUCTION BUT ALSO WITH MALL FOR MAYING. -- MALL -- MALL FORMATION. FROM THE LARGEST OUTBREAK OF FRENCH POLL KNEE SHAH, 66% OF THE POPULATION WAS AFFECTED BY ZIKA VIRUS, THERE WAS A ONE PERCENT RISK OF MICROCEPHALY WITH ZIKA VIRUS INFECTION IN THE FIRST TRIMESTER OF GESTATION SUCH THAT THERE WAS ALMOST A 1% RISK OF MICROCEPHALY RELATIVE TO THE BASELINE RISK OF 2 PER 10,000 BIRTHS. WHY? IT'S THE FIRST TRIMESTER SUCH A HIGH RISK PERIOD? THE NEUROSCIENCE DATA WOULD SUGGEST THIS IS THE PERIOD OF THE NEUROPRECURSOR CELL. IT MAY ALSO BE THERE'S SOME COMET POINT OF PLACENTAL MATURATION BEING PROTECTIVE OVER TIME. SO A LOT OF UNANSWERED QUESTIONS THERE. SO I WANT TO TAKE A MOMENT TO REMIND WHAT'S HAPPENING OVER THE HIGH RISK PERIOD FOR ZIKA VIRUS INFECTION IN NORMAL BRAIN DEVELOPMENT. FROM THE NEURAL TUBE TO DEFINE THE PRIMARY VESICLES OF THE BRAIN, THE PROSE ENCEPHLON, THE CEREBRAL CORTEX AN CEREBRAL HEMISPHERES THE MESA RECEIVE LON AND THE RAME RECEIVE LON THE HIND BRAIN, THE ENCEPHLON WILL SPLIT AND THIS IS WHAT WILL FORM OUR CEREBRAL HEMISPHERES. THIS IS AN EXAMPLE OF A BABY WITH GENETIC ENCEPHALY, ONE HAS A FAILURE OF THE DIVISION OF OUR TWO HEMISPHERES, THIS BABY HAS A SINGLE HEMISPHERE, WE DON'T HAVE THAT NORMAL SPLIT OF THE PRESENTATION ENCEPHLON TO THE TEAL ENCEPHLON. BECAUSE OF THAT WE KNOW THIS IS A PROBLEM THAT OCCURRED IN THE SECOND TO THIRD MONTHS OF GESTATION. WE THEN MOVE INTO A PERIOD OF RAPID PROLIFERATION. IN THE THIRD TO FOURTH MONTH OF GESTATION LOOK AT THE RELATIVE NUMBER WE HAVE IN THE BRAIN OVER THIS PERIOD. IT IS EXPONENTIAL AS WE FIRST MAKE NEURONS AND RADIO GLOBAL CELLS WE COMPLETE OUR NEURAL COMPLIMENT AND THEN WE TURN ON TO PRODUCING GLIAL CELLS SO AT THE TIME OF HIGHEST RISK TO THE BRAIN, THIS IS WHEN WE ARE PRODUCING OUR NEURONS AND OUR RADIO GLIAL CELLS. IF WE DECREASE PROLIFERATION, ONE HAS MICROCEPHALY. THERE'S MANY, MANY VARIATIONS OF MICROCEPHALY. ONE IS HAVE MICROCEPHALY WITH WHAT APPEAR AS TOTAL NORMAL CORTEX. ONE CAN HAVE IT WITH THICK CORTEX EASILY CONFUSED WITH THE FLAT CORTEX IN ENCEPHALY. OR ONE CAN HAVE MICROCEPHALY AS WE HAVE SEEN EARLIER WITH MULTIPLE ABNORMAL AT THIS OF BRAIN DEVELOPMENT AND DISRUPTION SO MICROCEPHALY IN AND OF ITSELF IS NOT SUFFICIENT TO KNOW WHAT'S HAPPENING IN THE BRAIN. ONCE WE PRODUCED OUR NEURONNINGS, THEY PROLIFERATED, THEY HAVE TO FOLLOW THE RADIO GLIAL GUYS UP TO FIND THEIR PLACE IN THE CEREBRAL CORTEX. AND HIGHLIGHT THIS IS BEAUTIFULLY AS YOU SEE MIGRATING NEURONS FOLLOWING THESE RADIO GLIAL GUIDES UP TO THE CEREBRAL CORTEX INTO THE CORTICAL PLATE. WHAT HAPPENSWHAT HAPPENS IF YOU DESTROY TH E GLIAL GUIDES, THE CORTEX WILL NOT FORM NORMALLY. THIS IS AN EXAMPLE OF MIGRATION DISTURBANCES, NOT FROM ZIKA VIRUS INFECTION BUT AGAIN GENETICALLY DEFINED. THIS IS AN EXAMPLE OF LIZ ENCEPHALY, WE HAVE THIS THICK SMOOTH CORTEX, I SHOWED YOU A THIN SMOOTH CORTEX IN PRE-TERM BABY, AS CELLS MIGRATE UP AND MIND PLACE IN THE CORTEX THEY NEED ROOM, THAT'S DRIVING THAT BEAUTIFUL PERIOD OF CELL AND GYRATION. THIS IS AN EXAMPLE OF HETERO TAUPEIA, THERE'S A FAILURE OF NEURONS TO MIGRATE UP COMPLETELY. IT'S HALF THE GENE DOSAGE HERE. YOU HAVE THIS MALL FORMATION OF A THIN CORTEX UNDERNEATH ALL THE NEURONS THAT NEVER MADE IT THEIR WAY UP. WHAT HAPPENS IF WE HAVE PROBLEMS WITH THE NEURAL PRECURSOR CELLS AND RADIO GLIAL GUIDES WE'LL HAVE PROBLEMS WITH WHAT THE CORTEX LOOKS LIKE. THESE ARE EXAMPLES OF INFECTIONS WE HEARD MORE OF THIS MORNING, CYTOMEGALO VIRUS WITH CHARACTERISTIC MARY VENTRICULAR CALCIFICATIONS AND ABNORMALITIES OF CORTICAL DEVELOPMENT AND RUBELLA CALCIFICATIONS AND GANGLIA OF THE THALAMUS TO CORTEX AND ABNORMALITIES OF THE NORMAL PROCESS OF GYRATION. THESE ARE BABIES WITH CONGENITAL ZIKA VIRUS INFECTION, ONE HAS THIS CHARACTERISTIC APOLOGY OF CALCIFICATIONS NOT IN THE PERIVENTRICULAR REGION BUT THE BORDER ZONE BETWEEN CEREBRAL CORTEX AND SUBCORTICAL WHITE MATTER AND AGAIN COMBINATION OF SMALL BRAIN WITH MULTIPLE ABNORMALITIES OF CORTICAL DEVELOPMENT, POLYMICROJARIA, IT APPEARS IN ENCEPHALY AND OTHER PLACES MASS VENTRICULAR ENCEPHALY TO CONTRIBUTE TO LOSS OF WHITE MATTER AND ABNORMALITIES OF THE BASAL GANGLIA AND THALAMUS. WE HAVE SEEN ABNORMALITIES OF THE CEREBELLUM AND HYPED BRAIN. SO THIS IS NOT A DISEASE ISOLATED TO ONE COMPONENT OF THE DEVELOPING NERVOUS SYSTEM. AN ISSUE OF NEURAL PRECURSOR CELLS AND RADIO GLIAL CELLS. I THINK WE HAVE HEARD THIS MORNING THAT WE PROBABLY HAVE NOT IDENTIFIED THE FULL SPECTRUM OF ZIKA VIRUS INFECTION, THIS IS A BEAUTIFUL PAPER BY (INAUDIBLE) AND COLLEAGUES IN THE LANSETT LOOKING AT REPORTED CASES WHERE ONE HAS A PROPENSITY TOWARDS PREGNANCY DOCUMENTATION OF ZIKA VIRUS INFECTION DURING PREGNANCY SEVERE MICROCEPHALY AND SIGNIFICANT IMAGING ABNORMALITIES. WHAT HAPPENS OUTSIDE THE BOX REQUIRES ARE ALL OUR ATTENTION. HOW DOES ZIKA VIRUS INFECTION IMPACT THIS INCREDIBLE PERIOD OF BRAIN DEVELOPMENT. I'M OPTIMIST BY NATURE SO I WANT TO NOT LEAVE THAT ON A DEPRESSING NOTE, I WANT TO SAY WE HAVE TOOLS TO NON-INVASIVELY QUANTIFIABLY ADDRESS IMPORTANT QUESTIONS. THIS BRINGS US BACK TO THIS PROFESSIONAL DIFFUSE SERUM IMAGINE, WE HAVE THE TRACKS SHOWN BEAUTIFULLY, THE CORPUS CALLOSUM HEMISPHERES THE OBJECT RADIATIONS ARE PRIMARY MOTOR PATHWAYS EACH PIXEL GIVING QUANTITATIVE INFORMATION ABOUT HOW THE BRAIN IS DEVELOPING, BUT TAKE THIS BACK NINE WEEKS. HERE VERY HARD TO MAKE UP THE OPTIC RADIATION. NOW YOU SEE IT BEAUTIFULLY. SO WE CAN QUANTIFY WHITE MATTER DEVELOPMENT. BUT WE CAN ALSO QUANTIFY CORTICAL DEVELOPMENT. WHAT WAS AMAZING IS WHEN WE FIRST SAW THESE IMAGES WE THOUGHT THIS WAS ARTIFACT, IT WAS BOB AND JEFF NEAL IN ST. LOUIS WHO POINTED OUT HIGH BAND SURFACE OF THE BRAIN IT'S NOT AN ARTIFACT, THIS IS THE RADIO ORGANIZATION OF THE CEREBRAL CORTEX. THINK ABOUT PUTTING A PROTON IN THIS CORTEX LINING UP WITH ALL THESE RADIO GLIAL CELLS. WATER WILL DIFFUSE PERPENDICULAR TO SURFACE OF CORTEX SO WE SEE WATER DIFFUSION FRONT TO BACK, FRONT OF THE BRAIN, SIDE TO SIDE IN RED ON THE SIDES OF BRAIN. WHAT HAPPENS WHEN YOU BRING THIS TO TERM OVER THIS NINE WEEK PERIOD THE RADIO GLIAL CELLS HAVE GONE AWAY, INSTITUTED TO BECOME ASTROCYTES, NOW THE NEURONS AREN'T BOUND BY THESE RADIO GLIAL ORGANIZATIONS, THEY'RE MAKING EXPANDING DENDRITES TO MAKE SYNAPSES, YOU LOSE, THAT RADIAL ORGANIZATION OF THE CEREBRAL CORTEX, LOST. SO WE CAN QUANTITY FIDE BRAIN DEVELOPMENT AS A SAID NOTE IN THE PRETERM BABY, WHAT IS THE BEST PREDICTOR OF THIS INCREDIBLE PERIOD OF DEVELOPMENT, HOW WELL YOU'RE GROW, IT'S ABOUT NUTRITION. SO HOW CAN MANAGEMENT INTERVENTION FOR OTHER CONGENITAL SYNDROMES BE USEFUL TO THAT IN ZIKA VIRUS INFECTION. SO THE PREVALENCE OF NEUROLOGICAL DISORDERS ASSOCIATED MICROCEPHALY IS HIGH BUT VARIABLE BECAUSE THERE'S SO MANY DIFFERENT CAUSES OF MICROCEPHALY IN THE INFANT. CEREBRAL PALSY TO UP TO A QUARTER INTELLECTUAL DISABILITY IN TWO-THIRDS, EPILEPSY OVER A THIRD, OPTHALAMOLOGIC DISORDERS IN A THIRD. THE BRAIN, THE EYE IS THE ONE PART OF THE BRAIN WE CAN SEE, IT'S VERY IMPORTANT TO ENGAGE OPHTHALMOLOGISTS IN THIS DISCUSSION. THERE IS UNFORTUNATELY NO TREATMENT FOR MICROCEPHALY, IT'S ABOUT SYMPTOM MANAGEMENT AS WE HEARD THIS MORNING, AND I THINK CRITICALLY IMPORTANT IS SUPPORTIVE FAMILIES. BACK WITH BOTOX REHABILITATION IMPORTANT FOR MOTOR IMPAIRMENT, SWALLOWING AND FEEDING SUPPORT IS IMPORTANT FOR HOW THE CHILDREN ARE GROWING. AND HOW THE CHILD GROWS IS IMPORTANT FOR HOW THE SER BILL CORTEX IS DEVELOPING. WE MUST BE TREATING SEIZURES AND ONE DISCUSSION WE WERE HAVING OVER THE BREAK IS HOW PROACTIVE SHOULD WE BE BEING IN MONITORING CHILDREN WITH SERO EEG, SO WE CAN CAPTURE EPILEPTIFORM ABNORMALITIES BEFORE THEY BECOME ENCEPHALOPATHY AND EARLIER PROACTIVE TREATMENT OF SEIZURE IMPROVE OUTCOMES. THERE'S A SPECTRUM OF NEUROLOGICAL DISORDERS WITH CONGENITAL INFECTIONS THAT INFORM OUR CONVERSATION WHETHER IT'S TOXO SYPHILIS RUBELLA, CMD PARVOVIRUS AND ZIKA VIRUS INFECTION, THERE IS NOT AN EVEN BURDEN OF MICROCEPHALY INTRACRANIAL CALCIFICATION OCULAR DISEASE AND HEARING DEFICITS ACROSS THE DISORDERS AND LET ME POINT OUT, TOXOPLASMOSIS IS PROBABLY THE DISEASE CLOSELY OR STRONGLY PREDICTIVE OF HYDROSYPHILIS. SO IF THERE ARE IMPACT OF CO-INFECTION IN OUR BABIES WITH ZIKA VIRUS, WHO ARE COMING BACK WITH HYDROCEPHALUS. ONGOING CARE OF THESE PATIENTS IS ESSENTIAL, I MENTION CEREBRAL PALSY AND KEEP STRESSING FEEDING AND NUTRITION ORTHOPEDIC ISSUES AS CHILDREN ARE OLDER WE HAVE TO PAY MORE ATTENTION TO COGNITIVE IMPAIRMENT, AS WE LEARN ABOUT MORE BABIES WITHOUT MICROCEPHALY AND AVERT DESTRUCTIVE BRAIN LESIONS, UNDERSTANDING THE CAUSE SEQUELLA OF THE INFECTION IS CRITICALLY IMPORTANT. SO WHAT'S THE ROLE OF PARENTS AND CAREGIVERS IN INTERVENTIONS? HERE I WILL TAKE A STEP BACK TO THE WHO DEFINITION OF HEALTH AS STATE OF PHYSICAL SOCIAL AND MENTAL WELL BEING. NOT MERELY ABSENCE OF DISEASE OR DISABILITY. AND PEDIATRIC NEUROLOGIST, I CARE FOR MANY CHILDREN AND YOUTH WITH BRAIN BASED DEVELOPMENTAL DISABILITIES WHO DESCRIBE THEMSELVES AS HEALTHY. THEY ARE LOVED, THEY PARTICIPATE IN THEIR COMMUNITIES AND THEY FEEL THEY HAVE AN IMPORTANT ROLE WITH US. SO I ALSO THINK IT'S IMPORTANT TO CONSIDER THE SOCIAL CONTEXT IN WHICH WE'RE CARING FOR CHILDREN AND THAT WAS ALLUDED TO VERY IMPORTANTLY IN THE PANEL DISCUSSION WHEN PEOPLE LOOKED AT WHO GETS FOLLOW-UP AND WHAT DOES AT RISK MEAN. THESE ARE IMPORTANT DATA FROM HART AND GRIZZLY, I'M GOING TO ADMIT I FIRST CAME ACROSS IN THE NEW YORK TIME SOME YEARS BACK. LOOKING AT VOCABULARY OF THREE-YEAR-OLDS AND THEY LOOK AT THREE GROUPS OF CHILDREN BASED ON PARENTS' EDUCATION TO DEFINE HIGH SES GROUP MIDDLE SES GROUP AND LOW SES GROUP. HOW MANY WORDS ONE HAS THREE-YEAR-OLD TURNS OUT TO BE A ROBUST PREDICTOR HOW YOU WILL DO THROUGH UNIVERSITY AND INTO PROFESSIONAL LIFE. AND AT AGE 3 IN THE HIGH SES GROUP ON AVERAGE CHILDREN HAD 1200 WORDS IN VOCABULARY. IN THE MIDDLE SES GROUP, JUST OVER 600 AND LOW SES GROUP, 5850. THESE DATA MADE ME QUESTION WHAT I WAS DOING AS A NEONATAL NEUROLOGIST BECAUSE FEW CONDITIONS IN BABIES I WAS LOOKING AFTER THAT WOULD HAVE A HALF LOSS OF THEIR VOCABULARY BASED ON MEDICAL ILLNESS. SO WHEN WE THINK ABOUT HOW TO CARE FOR CHILDREN AT RISK FOR SEQUELLA WE HAVE TO PAY ATTENTION -- UNFORTUNATELY THE CHILDREN IN THIS GROUP, HERE I WILL SPEAK FOR CANADA, HAVE THE MOST DIFFICULTY ACCESSING THE RESOURCES TO HELP SUPPORT THE CHILD DEVELOPMENT. WHY IS IT SO IMPORTANT? HERE INDEBTED NEONATOLOGIST AND VANCOUVER HAS BEEN A COLLEAGUE FOR MANY YEARS AND BUGGED ME ALL THAT TIME, HOW COME MY PERCEPTION OF BRAIN PROTECTION HAS TO END NICU DISCHARGE? BABIES LEAVE THE NEWBORN INTENSIVE CARE UNIT CAN WE NOT IDENTIFY THE OPPORTUNITIES TO PROMOTE BRAIN HEALTH. (INAUDIBLE) DEVELOPMENTAL PSYCHOLOGIST, WHO HAS BEEN I KNOW GRATEFUL FOR AS MUCH -- AND HER STUDIES OF PAIN DEFINED MANY YEARS HOW PRE-TERM BABY HOW MUCH PAIN THE BABY IS EXPOSED TO IS A PREDICTOR OF COGNITIVE IMPAIRMENT AND DEVELOPMENTAL CONCERNS LATER ON. WE HAVE BEEN WORKING TOGETHER THE LAST NUMBER OF YEARS TO IDENTIFY IMPACT OF PAIN ON THE BRAIN. BUT TAKING MORE HOLISTIC VIEW OF BRAIN PROTECTION BEYOND NICU DISCHARGE WE WORKED WITH JILL WHO COMPLETE COMPLETED HER Ph.D. WITH RUTH AND I NOT ONLY TO LOOK AT THE LINK BETWEEN HOW MUCH PAIN YOU HAD SKIN BREAKING PROCEDURES AS BABY AND INTERNALIZING BEHAVIORS AND HERE ARE HIGHER SCORES ARE WORSE, BUT HOW IS THAT MODIFIED BY HOW THE PARENT IS INTERACTING WITH THE CHILD? I WILL ADMIT THIS IS MOSTLY MOMS TO CHILD. I THINK WE HAVE A LOT MORE WORK TO DO WITH DADS TO CHILD. BUT IN THE PAST WORK OF RUTH'S GROUP WE HAVE SEEN THIS VERY CLEAR LINK BETWEEN MORE SKIN BREAKING PROCEDURES AND MORE INTERNALIZING BEHAVIOR DISTURBANCE THROUGH CHILDHOOD. WHEN ONE HAS MORE OPTIMAL PARTING AND PARENT INFANT INTERACTION, THAT LINK WAS BLUNTED. SO PERHAPS PAYING ATTENTION TO PARENTS' MENTAL HEALTH IS NOT ONLY IMPORTANT TO THE PARENT BUT IT'S GREAT PROTECTION. OVER THE LAST NUMBER OF MONTHS I HAVE HAD THE PRIVILEGE OF CO-LEADING A NEW NETWORK IN CANADA, THIS IS PART OF A CANADIAN INSTITUTE OF HEALTH RESEARCH STRATEGY ON PATIENT ORIENTED RESEARCH, THEY HAVE NOW FUNDED FOREIGN NETWORKS IN CHRONIC DISEASE AND I'M THRILLED THAT ONE OF THOSE NETWORKS IS FOCUS ON BRAIN BASED DEVELOPMENTAL DISMENTS. WE WERE TOLD ORIGINAL -- DISABILITIES. WE WERE TOLD THERE WOULDN'T BE A CHILD BASED NETWORK GIVEN THE PROBLEMS IN CANADA AROUND OBESITY AND DIABETES. SO THIS WAS ANT EFFORT CO-LED WEED MANIMER VICE DEAN OF MEDICAL SCHOOL AT MCHAIL AND REHAB SPECIALIST AND DAN GOLD WITS, A NEUROSCIENTIST IN VANCOUVER. THIS IS A PATIENT ORIENTED RESEARCH NETWORK. SO WE HAD TO HAVE THE PATIENT, IN THIS CASE THE FAMILIES DEFINE RESEARCH PRIORITIES OF THIS FIVE YEAR NETWORK. I HAD TO LEARN WHAT PATIENT ORIENTED RESEARCH WAS AND THE MOST IMPORTANT LESSON LEARNED WAS IF YOU WANT TO DO PATIENT ORIENTED RESEARCH YOU HAVE TO ASK THEM WHAT'S IMPORTANT. AND I THINK AS WE PLAN FOR THE CARE OF PATIENT EXPOSED TO ZIKA VIRUS INFECTION OF THE WOMB WE NEED TO ENGAGE PARENTS EARLY IN THE CONVERSATION SO THAT WE ADDRESS ISSUES OF GREAT IMPORTANCE TO THEM. I FOUND INVOLVE GROUP IN THE UK, YEARS AHEAD OF WHAT WE'RE DOING IN CANADA, HELPFUL, WE NEEDED TO BRING RESPECT SUPPORT, TRANSPARENCY AND RESPONSIVENESS TO THE DISCUSSION WITH CHILDREN AND FAMILIES. THE NETWORK REACHED OUT TO ALMOST 1,000 FAMILIES IN CANADA WITH CHILDREN WITH BRACE BAINED DISABILITIES AND WE'RE INDEBTED TO THEM FOR MAKING THE TIME FOR US GIVEN THE OTHER IMPORTANT DEMANDS FOR THEIR ATTENTION. WE DID IT BY SURVEY, TELECONFERENCES, FACE TO FACE MEETINGS, AND WHAT WE HEARD LOUD AND CLEAR FROM FAMILIES WAS A HOLISTIC VIEW OF THEIR CHILD, THAT WENT FROM BRAIN DYSFUNCTION TO COMMUNITY INTERVENTION INTEGRATION. IF I BORROW FROM JACK AND HIS WORK IN THE U.S. FROM THE NEURON TO THE NEIGHBORHOOD. THEY WANTED US TO BE NON-CATEGORICAL. NOT TO FOCUS ON A SPECIFIC DISEASE BUT TO FOCUS ON THE COMMON CHALLENGES THESE CHILDREN FACE, WHETHER THAT FEEDING AND SWALLOWING OR HOW WE ADDRESS THEIR PAIN OR THEIR ORTHOPEDIC ISSUES OR COGNITIVE IMPAIRMENT, THE DIAGNOSIS WAS LESS IMPORTANT TO THEM. AND THEY WANTED US TO TAKE A LIFE COURSE PERSPECTIVE TO ACCOUNT FOR EVOLVING NEEDS THEIR CHILD HAS MOVING FROM THE FETAL PERIOD TO ADULTHOOD. THOUGH THESE PARENTS ARE READ THE MISSION STATEMENT OF NICHD BEFORE THEY COMPLETED THE SURVEY. SO AS WE'RE GETTING CLOSE TO LAUNCHING JUST OVER TEN CLINICAL TRIALS, MANDATES CHR HAS FOR US FIRST IN HUMAN CLINICAL TRIALS, FOCUSING ON PREVENTION OF BRAIN INJURY AND PROMOTION OF REPAIR. HOW CAN WE USE NOVEL STRATEGIES TO ENHANCE WHAT ARE STEM CELLS -- OUR STEM CELLS ARE DOING. THAT'S RELEVANT TO THE ISSUE OF NEUROPRECURSOR DAMAGE THERE ARE NOW EXCITING NEUROSCIENCE AS TO TRY THE ADDRESS THAT. FOCUS ON BEHAVIOR PARTICIPATION LEARNING AND PAIN MANAGEMENT AND PARENTS WANT SUPPORT WE HAVE A COMPLEX HEALTHCARE SYSTEM, AS COMPLEX SOUGHT OF BORDER AND PARENTS NEED WAYS TO NAVIGATE THE SYSTEM AND WE NEED TO BE PROVIDING THAT SO WE'RE GOING TO BE TESTING WEB BASED INTERVENTIONS AND NAVIGATOR AND COACHES. SO THE LAST FEW MINUTES, I HAVE WHAT ARE THE KNOWLEDGE GAPS? I REALIZE THERE ARE MANY, MANY HAVE BEEN ALLUDED TO ALREADY, BILL ASKED ME TO EXPAND ON THESE. CAN NEURAL STEM CELLS BE PROTECTIVE FROM ZIKA VIRUS? I LEARNED LAST WEEK THE IMPORTANT PAPER ON CELL REPORT THERE'S IN VITRO EVIDENCE THAT NUCLEOTIDE ANALOG THAT INHIBIT HEP C ARE PROTECTIVE OF PRECURSOR CELLS FROM ZIKA VIRUS INFECTION. SO MORE ACTIVITY I EXPECT WILL HAPPEN IN THAT ARENA. WHAT IS THE RANGE OF ABNORMALITIES WE HEARD OF TODAY BUT WHAT MODIFIES THAT, THE TIMING OF INFECTION, THE ENVIRONMENT, THE CHILD GOES HOME TO, CO-INFECTION, I KNOW ADAM IS INTERESTED IN WHAT ARE THE IMMUNE MEDIATED EFFECT OF ZIKA VIRUS INFECTION AND HOW THOSE CAN BE MODULATED. PLACENTAL FINDINGS, PREDICT BRAIN HEALTH. CAN WE PREDICT FOLLOW-UP NEEDS BASED ON HEAD SIZE AND BRAIN IMAGING FINDINGS GIVEN RESOURCE CONSTRAINTS WE NOT ONLY HAVE HERE BUT THAT WE SEE GLOBALLY. HOW CAN WE BEST DIRECT CHILDREN TO THE SUPPORTS THAT THEY NEED. WHAT IF YOU DON'T HAVE DEFICITS EARLY ON THEN LATER IDENTIFY CONCERNS, IDENTIFY THE ROLE OF ZIKA VIRUS INFECTION. HOW DO THESE OUTCOMES EVOLVE OVER TIME AND WHAT IS THE LIFE EXPECTANCY OF THESE CHILDREN SO WE CAN PLAN APPROPRIATELY FOR THEIR CARE ACROSS THE LIFE COURSE. SO I HOPE I CONVINCED YOU WE HAVE A LOT TO LEARN. WE NEED RIGOROUS ATTESTMENT TO START THAT JOURNEY. WE DON'T KNOW WHAT THE BEST MEASURES ARE BUT I SUSPECT WE HAVE BEST GUESSES. WE HAVE TO BE MINDSFUL OF RESOURCE LIMITATIONS, PARTICULARLY IN THE AREAS MOST IMPACTED BY ZIKA VIRUS, THAT'S STILL NOT A REASON NOT TO IMPLEMENT RIGOROUS TESTING AND HOW CAN WE ENGABLING PARENTS NOT TONAL SUPPORT THE PARENTS BUT HOW CAN WE ENGAGE THE PARENTS TO BE AGENTS OF BRAIN PROTECTION. I'M INDEBTED TO JOHN FINALLY MR PHYSICIST WHO IS TURNING HIS ATTENTION TO NIH PLACENTA PROJECT, SHARING HIS THOUGHTS SO LIBERALLY AS WELL AS JOHN MORRIS, CLINICIAN SCIENTIST TEACHING ME WHAT I KNOW ABOUT ZIKA VIRUS INFECTION. THANK YOU AGAIN FOR HAVING ME. [APPLAUSE] >> THANK YOU, DR. MILL LEXER TERRIFIC PRESENTATION. BEFORE I BEGIN WITH QUESTIONS FROM THE AUDIENCE, TAKE THE CHAIR PREROGATIVE TO FOR THE FIRST QUESTION, I HAVE I WAS INTRIGUE BY SOME OF THE GAPS THAT YOU PUT UP THERE. AND ONE OF THE QUESTIONS THAT CAME UP IN MY MIND THAT'S BEEN SOMETHING THAT'S BEEN PERCOLATING AROUND, WHEN YOU HAVE A CLINICALLY ASYMPTOMATIC INFANT, THAT THEN WHETHER YOU BELIEVE THE IDM ASSAY BEING REALLY SENSESIVE, IGM ICEY, WHATEVER THE RESULT OF THAT IS, BUT CLINICALLY FIND HEARING ED TALK IN ATLANTA EARLIER THIS YEAR, THE ISSUE OF POTENTIALLY EPILEPSY COMING UP IN SOME OF THOSE KINDS OF CHILDREN THAT ARE NORMAL BUT AS THEY'RE GROWING SUDDENLY THERE'S A SEIZURE. HAVING A VERY FOCAL SMALL ABOUT FORNALTY. ARE THERE SYMPTOMMINGS OR SIGNS OR TESTS SCREENING TESTS YOU MIGHT BE ABLE TO DO TO EVALUATE FOR THAT KIND OF THING OR DO YOU REALLY BASICALLY HAVE TO WAIT FOR THE PROCEDURE TO DEVELOP IN SOMETHING LIKE THAT CASE? >> I THINK HERE TOO I WILL COME BACK TO THE LESSONS LEARNED FROM THE NICHD NEONATAL NETWORK AND CANADIAN NEONATAL FOLLOW UP NETWORK AND BABIES PRE-TERM RIGOROUS STANDARDIZED FOLLOW UP IS THE WAY TO ADDRESS THE QUESTION AT A POPULATION LEVEL, WHO NEEDS SCREENING WHEN AND FOR WHAT. OPEN QUESTION IS ROLE OF EEG TO LOOK FRO ACTIVELY FOR SEIZURES. THERE'S LITTLE EVIDENCE THAT FINDING EPILEPTIFORM DISCHARGES ON EARLY EEG IS PREDICTOR WHO WILL HAVE EPILEPSY LATER ON. LESS YOU'RE EVOLVING TO ENACCEPT ENCEPHALOPATHY. SO MULTIFOCAL INDEPENDENT SPIKE DISCHARGES, THESE ARE THE CHILDREN THAT WE DO WANT TO CAPTURE EARLY. CLOSE ATTENTION, EARLY ATTENTION I THINK IS IMPORTANT FOR GOOD ANSWER TO YOUR QUESTION. >> INTEREST PRESENTATION, I APPRECIATE THE FINDINGS FOR THE STEM CELLS AND DEVELOPMENT OF THE CORTEX. LESIONS ARE OFTEN SYMMETRIC IMAGING STUDIES PRESENTED FROM BRAZIL AND CERTAINLY WITH CMV. AND WOULD IT BE EXPLAINED BY INFECTION OF STEM CELLS AND IMPAIRMENT BUT WHAT ABOUT VASCULARITY? THERE ISN'T LITERATURE ALSO IN CONGENITAL CMV SUGGESTED SOME OF THE LESIONS WE SEE WITH THE CORTEX M ACTIONL DEVELOPMENT ARE DUE TO VASCULAR NEARLY LIKE VASCULAR ACCIDENTS IN TERMS OF SUPPLIES REGIONS OF THE BRAIN. AND ESPECIALLY BETWEEN THE WHITE AND GRATE MATTER. I REALIZE THAT'S CONTROVERSIAL BECAUSE PEOPLE SAY IT CAN BE EXPLAINED BY DISORDERS MIGRATION RADIO GLIAL MIGRATION BUT WHAT DO YOU THINK ABOUT THAT? >> I THINK IT'S AN IMPORTANT ISSUE IN PART BECAUSE WE HAVE DON'T HAVE MEASURES OF THE CEREBRAL VASCULATURE LEVEL NEEDED TO KNOW HOW THESE INFECTIONS MIGHT BE IMPACTING THE DEVELOPMENT OF THE VASCULATURE. WE TEND TO SPLIT THE VASCULATURE AWAY, FIRST NEUROSCIENTISTS FOCUS ON NEURONS AND APPRECIATE THE ROLE OF THE GLIA, NOW IT'S A QUESTION HOW THE CEREBRAL VASCULATURE IS DEVELOPING. WORK BY DAVID ROWAGE FROM PRE-TERM BIRTH FOCUS, HE SHOWS HOW THE OLIGODENDRIA SITES CELLS CRITICAL FOR MYELIN DEVELOPMENT, REGULATES ANGIOGENESIS THROUGH HYPOXY INDUCIBLE FACTOR. SO I CAN'T IMAGINE THE CEREBRAL VASCULATURE NEEDS BABIES DEVELOPING NORMALLY BECAUSE IT IS SO INTERCONNECTED THAT THERE HAS TO BE ROOM FOR BOTH. AND I COULDN'T ACCEPT AN EITHER/OR ANSWER. I WOULD SAY NOT EVERY GENETIC MAL FORMATION WE SEE IS PERFECTLY SYMMETRIC. SO PERFECT IMPERFECT SYMMETRY OR SOME ASYMMETRY DOESN'T MEAN THERE WAS VASCULAR EVENT BUT I THINK THE VASCULATURE IS BEING IMPACTED BY HYPOXIA ISCHEMIA, AT THE SAME TIME THE CELL TYPES ARE. SO I SUSPECT THAT THE ANSWER IS BOTH. THE OTHER ASPECT OF THE VASCULATURE THAT I THINK NEEDS ATINGES IS VASCULATURE OF THE PLACENTA AND THE DATA COMING FROM CONGENITAL MALARIA EXPOSURES. HOW THE PLACENTAL VASCULATURE DEVELOPS IN RELATION TO BRAIN VASCULATURE IS OF INTEREST THROUGH PLACENTA PROJECT AND RELEVANT TO THIS CONVERSATION. >> ONE FROM THE BACK. THEN DR. MOORE. >> STEVE, THAT WAS REALLY EXCELLENT. THIS IS A CRYSTAL BALL QUESTION, SO WE HEARD THIS MORNING IT'S A VERY HETEROGENEOUS PRESENTATION FOR ZIKA EXPOSED KIDS. BESIDES OBVIOUS NEURODEVELOPMENTAL SEQUAL LAY LIKE INTELLECTUAL DISABILITY, IF YOU PROJECT AHEAD FIVE TEN YEARS ABOUT THE PATHOPHYSIOLOGY, WHAT DO YOU HAVE THE DO YOU THINK THESE KIDS WILL BE LIKE AT SCHOOL AGE? >> OF THE SEVERELY AFFECTED KIDS OR ONES WE'RE NOT SURE ABOUT? >> YEAH. >> THE ANSWER TO BE HONEST NOT SURE HOW MANY SEVERELY AFFECTED KIDS GET TO SCHOOL AGE. AND THAT'S GOING TO BE AN IMPORTANT ISSUE. A LOT OF THAT WILL DEPEND ON FEEDING AND NUTRITION. >> WHAT ABOUT THE MILDLY AFFECTED KIDS? >> BIG UNKNOWN, WE HAVE NEURAL PRECURSOR CELLS IN OUR BRAIN. IF WE THINK WHERE CELLS ARE LIVING AND CAMPUS, IF YOU WALK AWAY FROM ANYTHING TODAY, IT'S GOING TO BE BECAUSE THERE'S SOME NEW CONNECTION IN YOUR HIPPOCAMPUS. AND WHAT HAPPENS IF WE DON'T HAVE THE NEURAL PRECURSOR CELLS FOR THAT? HERE IS AN AMAZING STORY EVOLVING FROM FREE DA MILLER AT SICK KIDS, NO RELATIONSHIP, WHERE SHE'S IDENTIFIED HOW METAPHOR MAN, DRUG FOR TYPE 2 DIABETES ENHANCES NEURAL PRECURSOR CELLS IN -- ENHANDS NEURAL PRECOURT CURSOR CELLS, BROUGHT TO TRIAL IN CHILDREN WITH MEDULLAR BLASTOMAS, WE WILL LOOK AT IT IN CHILDREN WITH CEREBRAL PALSY, CAN WE LOOK AT THESE WAYS OF ENHANCING NEURAL PRECURSOR CELL DEVELOPMENT PHARMACOLOGICALLY FOR CHILDREN THAT MAY NOT BE AS SEVERELY IMPACTED BY ZIKA VIRUS EARLY ON. >> DR. MOORE. >> THIS IS A QUESTION ALSO REGARDING PLASTICITY AMONG THOSE LESS SEVERELY INVOLVED. YOU MENTIONED THE HART AND GRIZZLY STUDY, AND YOU MENTIONED ACCESS TO SERVICES BUT YOU MADE REALLY IMPORTANT COMPONENT OF THAT WAS THAT IT WAS RECORDINGS TRANSCRIBED OVER A PERIOD OF TIME WITHIN THE HOMES AND THE MORE THE PARENTS TALKED TO THEIR CHILDREN, THE COMPLEXITY OF THE TALK, AND THE SENSITIVITY OF THE TALK AND THE LOWER INCOME HOMES THERE WAS MORE DIRECTIVE TALK LIKE NO, STOP, DON'T DO THAT. SO CERTAINLY THAT RELATES SO WELL TO EARLY INTERVENTION AND TO ENCOURAGING PARENTS TO HAVE THIS TYPE OF SENSITIVE INTERACTION BUT I THINK WHAT I GOT FROM THEIR STUDY IS THAT THERE IS THE OPPORTUNITY FOR RECOVERY OVER TIME OR BRAIN DEVELOPMENT. WE SEE THIS IN CHILDREN WITH HEARING LOSS TOO. THE EARLIER THEY'RE AMPLIFIED, THE EARLIER THEY GET THEIR COCHLEAR IMPLANT YOU SEE MORE ENHANCED DEVELOPMENT OF THE AUDITORY PATHWAY. SO I WOULD LIKE YOU TO COMMENT ON THAT. >> THANK YOU FOR THE QUESTION AND COMMENT. I PARTICULARLY FOR THE OPPORTUNITY TO CLARIFY THAT I SHOW DATA NOT BECAUSE THEY'RE DETERMINISTIC BUT BECAUSE IT'S CALL TO ACTION BECAUSE THERE IS ROOM TO IMPROVE THINGS. LOOK AT THE NORTH CAROLINA PROJECT, ABC PROJECT, HAVE SHOWN ENTEREBB INTERVENTION PROMOTES NOT ONLY SCHOOL PERFORMANCE BUT HEALTH OUTCOMES, 30 YEARS DOWN THE ROAD. EVER SINCE I BECAME AWARE OF DATA I STARTED ASKING PARENTS IN THE CLINIC DO YOU READ TO YOUR CHILD? I'M SHOCKED HOW FEW REGULARLY HAVE READING TIME AT HOME. I WOULD BE HARD PRESSED TO FIND SOMEONE HERE IN THIS ROOM THAT KNOWS PEOPLE WHO DON'T REGULARLY READ TO THEIR CHILDREN. BUT THAT'S NOT THE NORM TO BE EXPECTED AND I THINK IT'S NOT AN EXPENSIVE INTERVENTION TO HELP PROMOTE READING IN THE HOME. LISTENING TO MUSIC TOGETHER. SPEAKING TO YOUR CHILDREN TOGETHER. AND THAT SHOULDN'T BE LOST FROM OUR CLINICAL EVALUATION BECAUSE OF THE ROOM FOR PLASTICITY AND IMPROVEMENT. >> THANK YOU. >> DR. BRUSH, >> NATIONAL INSTITUTE OF MENTAL HEALTH. IT IS QUITE INTERESTING YOU MAKE A LOT OF RELATIONS BETWEEN BRAIN AND BEHAVIOR BUT BEHAVIOR YOU SEEM TO SPECIFICALLY OR ALMOST EXCLUSIVELY FOCUS ON COGNITION. OBVIOUSLY THERE'S A LOT OF EVIDENCE THAT PERINATAL AND IN UTERO INFECTIONS ALSO CAUSE PSYCHIATRIC ABNORMALITIES, ARE YOU ALSO SCREENING THESE KIDS FOR EXAMPLE FOR AUTISM SPECTRUM DISORDER, ATTENTION DEFICIT DISORDER AND MAYBE SOME OF THE EARLIER BEHAVIOR SUCH AS ATTACHMENT THAT BASICALLY CAN ALSO PREDICT THOSE KIDS THAT ARE HIGHER RISK? >> THANK YOU FOR THE COMMENT. I STOP AT COGNITION BECAUSE BILL TOLD ME HE WAS GOING TO DO SOMETHING IF I WENT OVER 30 MINUTES. >> I DON'T HAVE A GUN. >> SO -- (INAUDIBLE) NOW WE TRY TO ANALYZE OLDER PATIENT (INAUDIBLE) FIND A SCALE FOR THE PATIENTS BECAUSE MOST OF THEM TRY TO USE BABIES BUT IT'S IMPOSSIBLE BECAUSE THE PATIENT WE DEALT WITH INTERACTION WE CAN'T DO THIS SO WE ARE GOING TO (INAUDIBLE) ONLY ON MEDICAL PATIENTS. NOT VALIDATED FOR PATIENTS WITH NEUROLOGICAL PROBLEMS, ONLY FOR FOLLOW-UP OF PATIENTS PRE-TERM PATIENTS OF RISK OF NEUROLOGICAL DISEASE, NOT FOR PATIENTS WITH DISEASE. WE TRY -- MY TEAM OF -- THEY TRY TO USE GMFM ONLY BECAUSE WE CAN DO IT (INDISCERNIBLE) BUT IT IS DIFFICULT BECAUSE MOST PATIENTS 0, (INAUDIBLE) WE DON'T KNOW HOW TO (INAUDIBLE) PATIENT AND TRY TO COMPARE WITH THE OTHER THINGS THAT SPACIOUS PRESENT. WE DISCUSSED LAST SIX MONTHS EVERYONE MEETING ABOUT SCALE FOR BABIES AND DISCUSS EXPERTS IN THESE THINGS AND WE DIDN'T FIND BETTER WAY TO ANALYZE PATIENTS SO IF YOU HAVE SOME IDEA TO HELP US. ANOTHER THING WE WORK WITH THE PARENTS, WE -- MOST OF THE PATIENTS VERY (INAUDIBLE) SO WE DEVELOP A GROUP OF PATIENTS, A GROUP OF PARENTS PSYCHOLOGISTS SO WE CALL GROUP OF PSYCHOLOGISTS THAT PSYCHOLOGIST WORK WITH THE PARENTS, AND WE DID MORE GROUPS WITH SPEECH THERAPISTS, LANGUAGE GROUP, AND FEEDING GROUP. SO WE WORK WITH THE PATIENTS, WE MAKE PRESENTATIONS. AND WE TRY TO PUT THE PARENTS TO MAKE THE STIMULATE WITH BABIES, IT WORKS WELL. >> BEFORE YOU LEAVE THAT MICROPHONE, I'LL PUT YOU ON THE SPOT A SECOND. THE QUESTION THAT I -- CAME TO MIND WHEN I SAW YOUR SLIDE ABOUT HYDROCEPHALUS, AND YOU ASKED IT, DO YOU HAVE ANY DATA ON TOXOPLASMOSIS WITH THE KIDS YOU HAVE SEEN WITH HYDROCEPHALUS? >> IN MY SERIES OF CASES WE DON'T HAVE -- WE HAVE ONLY ONE TOXOPLASMOSIS IN THIS PERIOD BUT THE DIFFERENCE WITH PATIENTS WITH CONGENITAL TOXOPLASMOSIS AND ZIKA, (INDISCERNIBLE) THEY HAVE HYDROCEPHALUS AT BIRTH, DIFFERENT FROM PATIENTS WITH ZIKA. MY PATIENTS THEY HAVE NORMAL NOT HYDRORECEIVELY OR NORMAL THEY DEVELOP HYDRORECEIVELY, IT'S DIFFERENT FOR PATIENT -- HYDRORECEIVELY, IT'S DIFFERENT FOR PATIENTS WITH HYDROCEPHALUS. >> THANK YOU. >> THANK YOU, DR. MILLER. >> ANECDOTALLY WE HAVE BEEN HAPPIER WITH THE AIMS IN CHILDREN WHO ARE SEVERELY AFFECTED AND WE DON'T -- WE RECOGNIZE HOW IT WAS VALIDATED BUT WE FIND IT AS A TOOL, WE FIND THE T BODY TO BE HELPFUL AT LOWER RANGES LAP ALMOST >> IT BECOMES A LANGUAGE THAT WE'RE SPEAKING THAT WE CAN CONTINUE THE CONVERSATION WITH EACH OTHER AND WITH THE FAMILIES OVER TIME TO LOOK AT PROGRESS AND THEN WE'RE ALSO BECOMING MORE INTERESTED IN THE APPROACH THAT ADAM CURTAIN AND OTHERS HAVE TAKEN IN THE CT FEEL, ASKING PARENTS WHAT THEY WANT US TO TRACK AND WE FIND WHAT'S MOST IMPORTANT TO THEM AND WE QUANTIFY THAT OVER TIME. >> THANKS AGAIN. OKAY. [APPLAUSE] >> MY PLEASURE TO INVITE DR. CHANDY JOHN, RYAN WHITE ENDOWED CHAIR OF PEDIATRIC B IF HE CAN SHUTS DISEASE AND DIRECTOR OF THE RYAN WHITE CENTER FOR PEDIATRIC INFECTIOUS DISEASE IN GLOBAL HEALTH, INDIANA UNIVERSITY. HE JOINED FACULTY THERE IN 2015, AFTER SERVING AS DIRECTOR FOR DIVISION OF GLOBAL PEDIATRICS, UNIVERSITY OF MINNESOTA FOR TEN YEARS, HIS RESEARCH FOCUS ON MALARIA, PATHOGENESIS EPIDEMIOLOGY, SOME OF HIS COLLABORATIVE RESEARCH TEAM WORK INCLUDES PROSPECTIVE STUDIES THAT ESTABLISH SEVERE MALARIA IS ASSOCIATED WITH LONG TERM COGNITIVE IMPAIRMENT IN CHILDREN AND HE'S AUTHOR OF MORE THAN 110 POOR REVIEWED RESEARCH PUBLICATIONS, 26 BOOK CHAPTERS AN SERVES ON THE THRASHER RESEARCH SCIENTIFIC ADVISORY COMMITTEE AS WELL AS CHAIR AT NUMEROUS NIH AND NATIONAL INTERNATIONAL STUDY SECTIONS AND REVIEW BOARDS. I WILL INVITE HIM TO TALK TO US ABOUT SCREENING AND MONITORING FOR NEUROBEHAVIORBNORMALITIES. SEE IF WE CAN HELP YOU GET THAT GOING. >> THANK YOU VERY MUCH, BILL AND CATHY FOR INVITING ME. I'M GOING THE TALK NEURODEVELOPMENTAL BEHAVIOR, START THIS TALK WITH AN IMPORTANT CAUTION SLIDE, THE CAUTION IS THAT YOU'RE ABOUT TO HEAR TALK ON NEURODEVELOPMENT FROM PEDIATRIC INFECTIOUS DISEASE RESEARCHERS AND AS IF THAT WASN'T BAD ENOUGH, AREA OF INFECTIOUS DISEASE SPECIALTY IS MALARIA. I HAVE A NEURAL DEVELOPMENT NOR ZIKA VIRUS EXPERT. SO WHY AM I HERE? I THINK I WAS INVITED, BILL AND CATHY TELL ME IF I'M WRONG AT THE TALK TO TALK WHETHER STUDIES WE AND OTHERS HAVE DONE ON NEURODEVELOPMENT AND BEHAVIORAL PROBLEMS IN SEVERE MALARIA AND A STUDY THAT WE'RE STARTING IN MALARIA AND PREGNANCY CAN INFORM ZIKA VIRUS AND NEURODEVELOPMENT. SO I'M GOING TO TALK ABOUT SOME LESSONS WE LEARNED ABOUT MALARIA NEURODEVELOPMENT STUDIES, PART ONE IS BIG PICTURE PRINCIPLES THAT MAY HAVE SOME APPLICATION TO THINKING ZIKA VIRUS AND PART 2 IS REAL NUTS AND BOLTS STUFF ALONG THE WAY ABOUT ISSUES WITH TESTING THAT COME UP. AND IT'S BEEN QUITE INFORM ACTIVE TO DO THIS BECAUSE AS SOMEBODY NOT A NEURODEVELOPMENT EXPERT I HAVE EXPERTS WITH ME WORKING ON THIS BUT A NUMBER OF THESE THINGS ARE NOT CLEARLY SOLD ANYWHERE, NOT EVEN IN THE U.S. SO I THINK IT'S WORTH DISCUSSING AS WE THINK ABOUT STUDIES IN ZIKA VIRUS. THIS IS VERY, VERY NON-COMPREHENSIVE LIST OF THINGS THAT ARE DIFFERENT AND THINGS THAT ARE THE SAME ABOUT MALARIA AND ZIKA VIRUS INFECTION SO (INAUDIBLE) VERSUS VIRUS OBVIOUSLY THE MALARIA PARASITE, NONE PARASITE CROSS THE BLOOD BRAIN BARRIER SO IT DOESN'T INFECT BRAIN TISSUE, VERY BIG DIFFERENCE, THE EFFECTS ARE FROM BODY RESPONSE TO THE PARASITE AND IN MALARIA YOU DON'T SEE ANY MICROCEPHALY OR OVERT NEUROLOGIC DISEASE DISEASE WITH PREGNANCY, THIS IS WHY WE HAVEN'T HAD MANY STUDIES OF CHILD NEURAL DEVELOPMENT IN CHILDREN BORN TO MOTHERS WITH MALARIA IN PREGNANCY. THERE ARE SIMILARITIES INFECTION AND PREGNANCY LEADS THE ADVERSE OUTCOMES IN MALARIA, THE ONES WE KNOW ABOUT SO FAR ARE THAT THEY ARE HIGHER RISK FOR IUGR, LOW BIRTH WEIGHT, AND PREMATURITY, CO-FACTORS MAY INCREASE EFFECT OF PATERNAL INFECTION ON CHILD NEURAL DEVELOPMENT, THIS IS TO BE DISCOVERED BUT PROBABLY TRUE IN BOTH. THE EXTENT MATERNAL INFECTION THAT IS ASYMPTOMATIC INFECTION VERSUS DISEASE, AFFECTS THE CHILD IS UNKNOWN IN BOTH. TO DATE THEY BOTH HAVE BEEN PROBLEMS PRIMARILY IN LOWER AND MIDDLE INCOME COUNTRIES SO SOME OF THIS STUFF THAT I WILL DISCUSS FOCUSES ON AREAS WITH LESS RESOURCES HOW TO DO THIS TESTING AND CULTURALLY APPROPRIATE TESTING. FINALLY, PROBABLY MOST IMPORTANTLY, THE FULL EFFECT OF MATERNAL INFECTION OR DISEASE ON CHILD NEURODEVELOPMENT ARE UNKNOWN IN BOTH SITUATIONS. AND I WILL COME BANG TO THIS -- BACK TO THIS A MINUTE, IT'S BEEN DISCUSSED EXTENSIVELY SO FAR. SO GETTING TO OUR STUDIES OF MALARIA AND NEURAL DEVELOPMENT, ENGENDERED BY THIS INTERESTING FINDING IN CEREBRAL MALARIA WHICH IS CLINICALLY IMFROM PRESSSIVE SYNDROME WHERE -- INPRESSSIVE SYNDROME, A CHILD COMES IN WITH COMA DOESN'T KNOW A CAUSE FOR THE COMA, HIGH MORTALITY RATE FROM 20 TO 40% BUT STRIKINGLY AT THE TIME OF DISCHARGE ANYWHERE FROM A QUARTER TO 40% OF THESE CHILDREN HAVE GROSS NEUROLOGIC DEFICITS, EVERYTHING FROM HE MA PARESIS AND CORTICAL BEHINDNESS TO PRESY SEVERE HYPERTONIA. IF YOU FOLLOW THESE KIDS 3 TO 6%, THROUGH 12 AND 24 MONTHS, DOWN TO 1 TO 2%, GENERAL THINKING IF YOU CAN SURVIVE THE TERRIBLE DISEASE THAT IS CEREBRAL MALARIA AND MAKE IT OUT LONG ENOUGH YOU WILL DO BETTER BUT A NUMBER OF RETROSPECTIVE STUDIES BY MICHAEL BOYDMAN, PENNY HOLDING, JULIA AND CHARLES NEWTON AND OTHERS SUGGESTED THAT THERE WERE -- THERE WAS LONG TERM NEURODEVELOPMENTAL IMPAIRMENT OFFICER BRAIL MALARIA, THESE WERE RETROSPECTIVE STUDIES SO IT WAS CLEAR PROSPECTIVE STUDIES WERE NEEDED BECAUSE THERE COULD BE SELECTION BIAS AND THERE COULD BE PROBLEMS WITH THE INFORMATION ABOUT WHAT WE KNEW ABOUT THE CHILD WHEN THEY HAD THE EPISODE. NONETHELESS THEY WERE SUGGESTIVE. THAT BRINGS US TO THE SALIENT POINT ABOUT OUR STUDIES IN MALARIA THAT MAY APPLY TO ZIKA VIRUS INFECTION THOUGH DIFFERENT INFECTIONS. IN MALARIA YOU SAW THIS -- DEFICITS BUT THE SUSPICION IS THIS MIGHT BE THE TIP OF THE ICE BESTING AND MAYBE CHILDREN WHO HAD LONG TERM DEVELOP MENTAL BEHAVIORAL PROBLEMS BECAUSE THEY WEREN'T DETECTED ON A STANDARD PHYSICAL EXAM NEUROLOGIC TEST. IN PARALLEL WITH ZIKA WOULD HAVE BEEN HINTED AT AND DISCUSSED TO SOME EXTENT THAT I'M GOING TO HIGHLIGHT, WHILE PROBLEMS WITH MICROCEPHALY AND GROSS NEUROLOGIC DEFICITS ARE A BIG PROBLEM AND PROBLEM TO ADDRESS NOW, IT'S QUITE POSSIBLE IN TERMS OF PUBLIC HEALTH THERE'S BIG OR BIGGER PROBLEM WITH CHILDREN BORN TO MOTHERS ASYMPTOMATIC AND NOT FOLLOWED AND DON'T HAVE GROSS NEUROLOGIC PROBLEMS AND I WILL EXPLAIN WHAT WE HAVE SEEN IN MALARIA AND WHITE'S SALIENT TO THIS HYPOTHESIS. BEFORE I TALK ABOUT STUDIES IN MALARIA, I WANT TO MAKE CLEAR AS WE ALL KNOW, ALL THESE STUDIES ARE THE WORK OF A LARGE TEAM OF PEOPLE AND WE HAVE TEAMS IN UGANDA, UNIVERSITY OF MINNESOTA, THIS IS THE MINNESOTA STATE -- MY LAB IN MINNESOTA STATE FAIR, I HIGHLY RECOMMEND IF YOU ATTEND IN SEPTEMBER AND THE GROUP AT INDIANA UNIVERSITY. SO THE CLINICAL AND NEUROPSYCHOLOGY LAB TESTING AND DATA ANALYSIS BY THIS LARGE GROUP, I WANT TO PARTICULARLY MENTION DR. BOB POKE AND (INDISCERNIBLE) PRIMARY EPIDEMIOLOGY AND NEUROPSYCHOLOGY COLLEAGUES IN UGANDA WHO ARE CRITICAL TO THESE STUDIES. SO TO GO THROUGH A FAIR AMOUNT OF WORK IN ONE SLIDE, WE DID FIND THAT CEREBRAL MALARIA IN CHILDREN WAS ASSOCIATED WITH LONG TERM, KIDS ABILITY A QUARTER OF THEM HAVE COGNITIVE IMPAIRMENT TWO YEARS AFTER THE EPISODE OF CEREBRAL MALARIA. RETROSPECTIVE STUDY DATA SUGGESTED THIS GO ON A BIT LONGER SIX TO TEN YEARS AFTERWARDS. WE ALSO FOUND THAT GETTING TO A POINT THAT ONE OF THE OTHER SPEAKERS OR PEOPLE ASK QUESTIONS BROUGHT UP WE ALSO FOUND OUT THAT CEREBRAL MALARIA IS ASSOCIATED WITH LONG TERM MENTAL HEALTH DISORDERS. I DID A FOLLOW-UP SURVEY OF KIDS ENROLLED FOR NEURODEVELOPMENT STUDIES AND A SCREENING TEST WAS DONE AND IF THEY DON'T PASS IT IN DEPTH NEUROPSYCHIATRIC ASSESSMENT, WE FOUND THEY HAD HIGH PREVALENCE OF MENTAL HEALTH DISORDERS THAN COMMUNITY CHILDREN FROM THE SAME EXTENDED HOUSEHOLD. SO THIS SEEMED LIKE A BIG DEAL BUT WHAT MAYBE AN EVEN BIGGER DEAL IS THAT WE IN THE FIRST -- IN THE STUDY WE DID KIDS 18 MONTHS TO 12 YEARS WE DECIDED TO INCLUDE KIDS WITH SEVERE MALARIA AS IMPERATIVE GROUP, THEY DON'T HAVE OVERT CLINICAL NEUROLOGICAL SIGNS, VEERLY ANEMIC, HEMOGLOBIN LESS THAN 5, BLOOD SMEAR, WE SELECTED THESE KIDS SO THEY DON'T EVEN HAVE SEIZURES. MANY KIDS HAVE SEIZURES BUT THESE DON'T, THEY HAVE NO OVERT NEUROLOGIC SIGNS AND I WILL SHOW YOU THE ACTUAL DATA A FEW SLIDES FROM NOW THAT THEIR NEUROCOGNITIVE IMPAIRMENT WAS VEER AS THOSE WHO HAD CEREBRAL MALARIA. THIS IS GERMANE, ALMOST TOTALLY DIFFERENT POSTNATAL POPULATION TO ZIKA VIRUS, THESE ARE KIDS WITHOUT OVERT NEUROLOGIC DISEASE PRESENTING WITH LONG TERM IMPAIRMENT, FROM THE SAY PARASITE, PERHAPS THE SAME HOST RESPONSES WITHOUT OVERT NEUROLOGICAL SCIENCE. IN THE SAME FASHION WE ARE JUST ABOUT THE PUBLISH A PAPER ON LONG TERM BEHAVIORAL PROBLEMS AND THESE WERE ALSO PRESENT IN CHILDREN WITH SEVERE MALARIA AKNEEIA AND CEREBRAL MALARIA. SO THE LONG TERM CONSEQUENCES ARE NOT LIMITED TO CHILDREN WITH OBVIOUS NEUROLOGICAL SCIENCE. SO ONE OF THE PRINCIPLES WE THOUGHT WAS IMPORTANT WHEN STUDYING MALARIA, IN THESE CHILDREN WAS THAT WE NEEDED TO TRY TO UNDERSTAND WHAT SEEMED TO LEAD TO NEURODEVELOPMENT IN THESE KIDS, SO IN THESE STUDIES WE'RE LOOKING AT GENETIC FACTORS, AT FACTORS RELATED INFLAMMATION SUCH AS NITRIC OXIDE PATHWAY, OXIDATIVE STRESS AND ENDOTHELIAL ACTIVATION. MICRONUTRIENT DEFICIENCY, IRON DEFICIENCY AND METABOLIC FACTORS WHICH MAY RELATE TO EACH OTHER TO THREE TO FIGURE OUT WHAT SEEMS TO BE LEADING TO NEURAL DEVELOPMENTAL IMPAIRMENT OF THESE CHILDREN WITH THE GOAL ADDRESSING NOT ONLY MALARIA, BUT FACTORS LEADING TO NEURAL DEVELOPMENTAL DEVELOPMENT AND PREVENTING OR AMELIORATING THE NEURAL DEVELOPMENTAL IMPAIRMENT. WITH ALL THESE STUDIES AND NUMBER OF STUDIES THAT I DON'T HAVE TIME THE GO INTO FROM A NUMBER OF OTHER DIFFERENT RESEARCH GROUPS, THAT SUGGESTED THIS NOSE NEURODEVELOPMENTAL IMPAIRMENT IN CHILDREN WITH UNCOMPLICATED MALARIA, NOT JUST SEVERE, WE TURNED ATTENTION TO MALARIA AND PREGNANCY. IT'S A COMMON THING IN SUBSAHARAN AFRICA, I MENTIONED BEFORE, CHILDREN BORN TO MOTHER THISES WITH MALARIA PREGNANCY HAVE UTERINE GROWTH RETARD AND MORE LIKELY PREMATURE ALL FACTORS RELATE TO CHILD NEURODEVELOPMENT SO BUT AMAZINGLY UP TO THIS POINT THERE HAD BEEN NO STUDIES OF NEURODEVELOPMENT IN THESE CHILDREN WITH BORN TO MOTHERS WITH MALARIA AND PREGNANCY SO WE WERE FORTUNATE TO HAVE COLLEAGUES AT THE UCSF TO HAD JOINED WITH COLLEAGUES AT MCCARRY UNIVERSITY TO STUDY CHEMOPROPHYLAXIS IN AREAS THERE'S MALARIA. SO THREE DIFFERENT TEAM OF PROPHYLAXIS REGIMENS IN THE MOTHER, TWO IN THE CHILDREN, TO TRY TO PREVENT MALARIA, AND OVER THE TERM OF PREGNANCY AND FOLLOWING UP THESE KIDS FOR THREE YEARS, SO THIS GAVE US THE OPPORTUNITY TO LOOK AT WHETHER NEURODEVELOPMENT WOULD BE AFFECTED BY PREVENTION OF MALARIA. SO OUR END POINT ARE A NUMBER OF NEURAL DEVELOPMENTAL BEHAVIORAL OUTCOMES I WILL REVIEW SHORTLY IN CHILDREN IN THE DIFFERENT TREATMENT ARMS AT 12, 24, 36 MONTHS AN HYPOTHESIS IS FREQUENT CHEMOPREVENTION WITH DP OR (INDISCERNIBLE) A VERY GOOD MALARIA CHEMOPREVENTION DRUG, IN MOTHERS AND CHILDREN WOULD RESULT IN BETTER NEURODEVELOPMENTAL AND BEHAVIORAL OUTCOMES AND LESS FREQUENT CHEMOPROPHYLAXIS AND CHEMOPROPHYLAXIS WITH STANDARD PARAMETH MEAN WHICH IS NOT AS GOOD A. JUST TO MAKE THE SCHEMATIC OF THE STUDY A BIT CLEARER, THE DARK SHADED BOXES ARE WHAT WE WOULD SUSPECT WOULD BE LESS GOOD MALARIA PROPHYLAXIS, WOULD BE EXPECTED TO BE BETTER SO THE MOTHERS THREE DOSE SP WOULD BE THE MONTHLY WOULD BE THE BEST AND KIDS BORN TO THAT MOTHER WITH THREE DOSE SB HAD THREE MONTH BP WOULD HAVE BEEN THE WORST AND MONTHLY BP WOULD BE THE BEST. OUR HYPOTHESIS IS THOSE WHO GOT WORST CHEMOPROPHYLAXIS BECAUSE WE THOUGHT NEURODEVELOPMENTAL OUTCOMES THOSE BECOME THE BEST WOULD HAVE THE BEST. AND THE UCSF GROUP PUBLISHED FINDINGS ON MATERNAL CHEMOPREVENTION AND HYPOTHESIS WAS CORRECT. MONTHLY DP WAS SIGNIFICANTLY BETTER THAN EITHER OTHER TWO ARMS PREVENTING MALARIA AND PREGNANCY SO WE STARTED ONE YEAR WE COMPLETED ONE YEAR FOLLOW-UP, DOING ANALYSIS OF THAT FOLLOW-UP FOR THESE KIDS NEURAL DEVELOPMENTAL OUTCOMES. BECAUSE WE HAD A LOT OF DISCUSSION OF HOW ZIKA VIRUS IN PREGNANCY LEAD TO ADVERSE OUTCOMES, I WANT TO OUTLINE WHAT WE'RE LOOKING AT MALARIA, NOT SUGGESTING THE SAME FACTORS WILL BE IMPORTANT BUT SUGGESTING SOME OF THE SAME PRINCIPLES HOW YOU LOOK AT THESE MAYBE IMPORTANT. THE BOXES SHOW DIFFERENT THINGS LOOKING AT IN THE MOTHER AND THE PLACENTA, IN CORD BLOOD AS REFLECTION WHAT HAPPENS IN THE FETUS AND THEN ASSESSING NEURODEVELOPMENTAL IMPAIRMENT SO IN THE MOTHER WE LOOK AT ANEMIA AND DEFICIENCY AMONG OTHER THINGS, LOOKING AT PLACENTAL HISTOPATHOLOGY AND PLACENTAL PCR POSITIVITY IN MALARIA AND CHILD -- SORRY CORD BLOOD LOOKING AT NUMBER OF FACTORS IMPAIRED OXYGEN DELIVERY, INFLAMMATION, MICRONUTRIENT DEFICIENCY AND ANEMIA, YOU CAN IMAGINE THAT FOR EXAMPLE IF YOU CAN BLOCK PLACENTAL MALARIA, WHICH WOULD BE THE GOAL OF GIVING MATERNAL CHEMOPREVENTION, THAT YOU WOULD THEN POTENTIALLY BLOCK ALL THESE OTHER PATHS THEREFORE ALL BLOCK IEGR PREMATURITY AND LOW BIRTH WEIGHT AND AFFECT NEURODEVELOPMENTAL SCORES IN A GOOD WAY, BY DOING THAT PRIMARY PRIA RESEARCHES, ONE REASON WE'RE LOOKING AT THE PATHWAYS IS THAT A NUMBER OF MOTHERS ARE GOING TO COME TO US WITH PLACENTAL MALARIA THAT HAVEN'T BEEN ON CHEMOPREVENTION, IF THAT'S THE CASE IF WE LEARNED ABOUT IT INFLAMMATORY PATHWAY, THAT WAS RELATED TO NEURODEVELOPMENTAL IMPAIRMENT COULD WE BLOCK THAT AND IN BLOCKING THAT POTENTIALLY BLOCK IRON DEFICIENCY, RELATED TO INNAMATION, INFLAMMATION INCREASES UPTAKE AND DISTRIBUTION OF IRON, THEREFORE BLOCKS SOME DEGREE OF ANEMIA AND BLOCKS NEURODEVELOPMENTAL IMPAIRMENT IN THAT WAY. ALTERNATIVELY, IF WE FOUND THAT IRON DEFICIENCY WAS PRIMARY PROBLEM, IF WE DID IRON SUPPLEMENTATION, COULD WE BLOCK THAT PATHWAY, BLOCK ANEMIA, AND LEAD TO BETTER SCORES. THINKING ABOUT THE DIFFERENT WAYS TO LEAD NEURODEVELOPMENTAL TO COME UP WITH VARIOUS SOLUTIONS. THE PRIMARY PREVENTION BY THE MOST IMPORTANT THING BUT THOSE NOT PRIMARILY PREVENTED, EVERYTHING FROM BETTER DIAGNOSTICS TO MAY LAYERIA, PREVENTING SEQUESTRATION WHICH HAPPENS WITH INFECTED RED BLOOD CELLS CLOGGING UP DECREASING ENDOTHELIAL ACTIVATION WITH STATINS, SPECIFIC INHIBITORS IN INFLAMMATION, TREATING MICRONUTRIENT DEFICIENCIES OR ANEMIA, COULD BE WAYS TO INTERVENE AND IMPROVE NEURODEVELOP MENTAL OUTCOMES IN THESE CHILDREN, WE HAVE TO KNOW THE PATHWAY TO KNOW THEY MIGHT POSSIBLY WORK. COP FOUNDERS OR CO-FACTORS DISCUSSED A LOT, I WON'T MENTION THIS, THEY'RE IMPORTANT BECAUSE -- I WOULD LIKE TO HEAR A DISCUSSION OF THIS FROM OUR COLLEAGUES FROM BRAZIL BUT MALARIA IS -- HAS SEVERE MALARIA IN SUBSAHARAN IN POVERTY, THEY OCCUR IN BETTER OFF FAMILIES BUT NOT AS FREAKILY AS OCCUR IN FAMILIES WITH LOW SORB ECONOMIC STATUS SO ALL THESE THINGS -- SOCIO ECONOMIC STATUS SO MAYBE CONFOUNDERS TO YOUR ASSESSMENT OF THE CHILD NEURODEVELOPMENTAL STATUS. I THINK ENVIRONMENTAL FACTORS, I WAS TALKING TO A COLLEAGUE OF MINE ENVIRONMENTAL HEALTH EXPERT AND HOW A LOT OF TOXIC RECYCLING IS OUTSOURCED TO COUNTRIES LIKE SUBSAHARAN AFRICA AND NOT STUDIED MUCH IN THESE COUNTRIES BUT ALSO GETTING INFORMATION ON WHAT THE RATES OF THAT IS AND WHETHER THOSE MIGHT BE CONFOUNDERS AS WELL AND PEOPLE IN LOW SOCIO ECONOMIC, MAYBE LIVING IN AREAS THAT'S A PROBLEM. THERE'S BEEN QUITE A BIT OF DISCUSSION ON WHEN TO DO TESTING AN HOW LONG. PARTLY DEPENDS WHEN THE EFFECT IS EXPECTED EARLY OR LATE, I'M TALKING KIDS WE DON'T KNOW LIKE EXPOSED WITH ASYMPTOMATIC INFECTIONS AND DON'T COME OUT WITH MICROCEPHALY. THE VALUE OF COHORTS WE KNOW THIS, DOING THE STUDY THEY HOPE AND WE HOPE THEY WILL BE ABLE TO STUDY CHILDREN OVER TIME IN MALARIA THE ORIGINAL COHORTS ENROLLED ALMOST 15 YEARS AGO, SO WE NOW HOPE TO FOLLOW-UP THAT RELATIVELY SMALL GROUP BUT TO ACTUALLY START LOOKING AT FUNCTIONAL LIKE DO THEY COMPLETE SECONDARY SCHOOL, DO THEY GO TO COLLEGE, ACADEMIC ACHIEVEMENT, WHAT WORK DO THEY DO, INCOME LEVEL, BECAUSE THIS GIVES A SENSE OF THE SOCIETAL LEVEL OF THE COST OF THIS DISEASE AT EARLY TIME. IT'S BEEN DISCUSSED SEVERAL TIMES BUT I THINK THAT ALTHOUGH IT'S CLEAR THAT FROM SOME OF THE THINGS STEVEN SAID ABOUT WHERE ZIKA GOES AND WHAT IT ACTS ON, THAT A MAJOR OR THE MAJOR FOCUS NEEDS TO BE ON CHILDREN WHO ARE EXPOSED IN UTERO, WE KNOW IN MALARIA KIDS COMPLICATED MALARIA HAVE NEURODEVELOP MENTAL IMPAIRMENT AND SEVERE MALARIA HAVE BEHAVIORAL PROBLEMS AS DISCUSSED WITH THE TYPE SYNDROME, ZIKA VIRUS INFECTION SO I THINK THAT THE QUESTION OF THE POTENTIAL LONG TERM NEUROLOGIC AND NEURODEVELOPMENTAL AND BEHAVIORAL CONSEQUENCES OF ZIKA VIRUS INFECTION IN CHILDREN SHOULDN'T BE NEGLECTED. SO BEFORE I MOVE ON, THE KEY PRINCIPLES LEARNED FROM STUDIES ARE THAT IT IS IMPORTANT TO DETERMINE PATHOGENESIS OF NEURODEVELOPMENTAL AND CLUES FOR PATHOGENESIS MAY NOT GIVE YOU IDEAS ABOUT INTERVENTIONS BUT HOW TO INFORM THE TYPE OF TESTING YOU DO, IT'S IMPORTANT TO CONSIDER CO-FACTORS BECAUSE MANY AREAS CO-FACTORS COULD BE A MAJOR CONFOUNDER TO WHAT YOU'RE LOOKING AT. THAT LONG TERM ASSESSMENT IS IMPORTANT OR CONSIDERING OF AFFECTING IN UTERO ADD INFECTION AS A CHILD IS IMPORTANT. SO MOVING TO PRACTICE, SOME OF THE NUTS AND BOLTS STUFF WE LEARNED ABOUT CONDUCTING THESE TYPES OF ASSESSMENTS IN LOW INCOME COUNTRIES, I'LL GO INTO ETCH O OF THESE IN A BIT MORE DETAIL IN THE FOLLOWING SLIDES BUT AMONG THESE DO YOU DO SCREENING TESTS OR COMPREHENSIVE TESTS, WESTERN TEST OR LOCALLY DEVELOP A TEST? AND IF YOU'RE DOING BEHAVIORAL ASSESSMENT SHOULD YOU USE A CHECKLIST LIKE THE CHILD BEHAVIOR CHECKLIST OR DO OBSERVATIONAL ASSESSMENTS, HOW DO YOU TEST THE VALIDITY OF THE TEST, TO DETERMINE WHETHER IT'S TESTING THE DOMAIN YOU THINK IT'S TESTING. AND WHEN CHILDREN CROSS AGES, MOST BATTERIES ARE FOR KIDS UNDER 3 OR 5, OVER THAT AGE SO CROSSING AGE WHAT DO YOU DO WHEN WANT TO COMPARE THE KIDS OVER TIME. ASSESSING RELIABILITY IS INCREDIBLY IMPORTANT AND SOMETHING PROBABLY NOT DONE ENOUGH. WHETHER YOU USE LOCAL OR U.S. NORMS. HOW YOU USE SCALE SCORES AND IF YOU ARE CROSSING AGES WHETHER YOU USE IMPAIRMENT AS A YES, NO THING, MORE THAN MINUS TWO STANDARD DEVIATIONS BELOW THE MEAN, RATHER THAN USING A SCORE BECAUSE YOU CAN'T USE THE SCORE FOR ONE TEST COMPARABLE TO THE SCORE FOR ANOTHER. I'M NOT GOING TO GET INTO THE DETAILS OF THE NEURODEVELOPMENTAL PART BECAUSE I AM NOT AN EXPERT, AS MENTIONED IN THE BEGINNING BUT I WILL REFER YOU TO A COUPLE OF THINGS, A COUPLE OF PUBLICATIONS, ONE THAT WAS POLISHED FROM THE WORLD BANK BY LEAH AND PATRICIA AND THEIR COLLEAGUES THAT IS A TOOL KIT FOR ASSESSMENT OF CHILDREN FIVE YEARS OF LIFE AND ANOTHER THAT WAS PUBLISHED LAST MONTH BY (INAUDIBLE) UNIVERSITY OF MINNESOTA AND RITA AND MYSELF AND OTHER AUTHORS ON HOW TO SELECT MEASURES FOR NEURODEVELOPMENTAL IN LOW AND MIDDLE INCOME COUNTRIES, THIS IS NOT A PRESCRIPTIVE PAPER, IT DOESN'T TELL YOU WHICH IS THE BEST TEST BECAUSE THERE IS NO SUCH THING, IT JUST SAYS WHAT THE HOW EXTENSIVELY IT HAS TO BE STUDIED IN WHAT AREAS STUDIED, WHAT THEY PURPORT TO TEST, HOW IT'S VALIDATED AN WHETHER IT'S USED. YOU CAN DECIDE WHICH OF THESE TESTS MIGHT BE APPROPRIATE FOR THE DISEASE YOU'RE STUDYING. CHUCK NELSON REMINDED ME IN AN EMAIL ABOUT LOOKING AT THE RISK INFANTS AND STEVE BROUGHT THIS UP IN HIS TALK SO THERE'S A NUMBER OF THINGS YOU CAN DO AND I THINK THESE EARLY STAGES ZIKA VIRUS THIS IS NOT A POPULATION BASIS BUT UNTIL WE KNOW BETTER, USING MORE SOPHISTICATED MODALITIES TO LOOK AT WHICH KIDS ARE AT RISK AND GET A CLUE, THAT MAYBE SIMPLIFY AFTER THAT, I THINK WILL BE IMPORTANT AS WELL. SO I WILL TALK JUST BRIEFLY ABOUT THE TESTS WE DID AND WHY WE DID THEM. NOT GOING INTO DETAILS OF THE TEST BUT PRACTICAL STUFF THAT MAYBE USEFUL AND THINKING ABOUT TESTING FOR KIDS, LONGITUDINAL TESTING FOR KIDS WITH ZIKA REQUIRES. IN KIDS LESS THAN FIVE YEARS MODEL SCALE EARLY LEARNING, TWO TESTS FOR ATTENTION AND ASORBIATIVE MEMORY DEVELOPED AT THE UNIVERSITY OF MINNESOTA AND KIDS THIS YOUNG THAT LOOKED AT THOSE DOMAINS SO WE HAD TO VALIDATE THEM WITHIN THE POPULATION IN UGANDA, THEN THE CHILD BEHAVIOR CHECKLIST. KIDS OLDER THAN FIVE WE USE THE KAUFMANN ASSESSMENT BATTERY FOR CHILDREN, IT'S BEEN USED A LOT HERE FOR ADHD AND THE CHILD BEHAVIOR CHECK LIST. I JUST WANT TO MENTION THAT WE KNEW FROM PRIOR STUDIES OF OLDER CHILDREN, THIS STUDY WAS STUDY OF CHILDREN FROM 18 MONTHS TO 12 YEARS, STUDIES FROM FROM KIDS OVER FIVE YEARS, THAT ATTENTION IS VERY IMPORTANT SO THIS IS WHY WE MADE AN EFFORT TO LOOK AT THAT IN YOUNGER CHILDREN AS WELL DESPITE THE FACT THERE'S NOT GREAT TOOLS ANYTHING ELSE IS NOT PERFECT FOR DOING THAT BUT IT IS A MEASURE OF RETENTION. FOR THE NEW STUDY WE'RE DOING ON MALARIA AND PREGNANCY WE DID A DIFFERENT SET OF TESTS, FOR THE KIDS 12 MONTHS OLD, WE USE THE BAILEY SCALE AND ELICITED IMITATION TESTING WHICH IS A TEST THAT LOOKS AT IMMEDIATE RECALL, DELAY RECALL AND WORKING MEMORY, ALL WHICH MAYBE RELATED AMONG OTHER THINGS TO IRON DEFICIENCY. AT 24, 36 MONTHS WE DID LARGER BATTERY OF TESTS DOING BAILEY SCALES, BCT ENCODE, IE TESTING AND BEHAVIOR RATING SCALES DEVELOPED BY BETSY LOZOF, COATED WAY OF LOOK AT BEHAVIOR AS WELL AS CBCL AND CHECKLIST TEST FOR EXECUTIVE FUNCTION. WHY DID WE DO WHAT WE DID? THE BAILEY VERSUS THE MULLEN SEVERE MALARIA PROJECT WE NEED AD TEST TO BRIDGE THE UNDER 5 AND OVER 5, THE KABC WENT DOWN TO FIVE YEARS OF AGE SO WE CAN ONLY TEST ACCURATELY IN CHILDREN UP TO FIVE YEARS OF AGE SO USING THE BAILEY LEFT A GAP THAT IF WE ENROLLED A KID AT TWO AND A HALF YEARS, THREE AND A HALF YEARS WE WOULDN'T HAVE A TEST TO TEST THEM ON AT ONE YEAR. SO WE USE IT FOR CONTINUITY, THE -- STARTS AT THREE YEARS AND THE BABY GOES THREE YEARS YOU CAN HAVE MORE CONTINUITY, WE ARE ONLY STUDYING THESE FOR NOW UP TO THREE YEARS, SO WE CAN USE THE BAILEY FOR THE WHOLE TIME. THE BAILEY IS MORE WIDELY USED, SIMPLER AND HAS MORE RECENTLY UPDATED NORMS FOR ALL THOSE REASONS SEEMED TO BETTER TEST USE FOR THIS STUDY. WE ADDED IMPLEMENTATION BECAUSE OF IRON DEFICIENCY ANDkT DEFICIENCY RELATED ACTIVITIES AND FOR THE SAME REASON ADDED BEHAVIOR RATING SCALES, JUST A WAY OF THINKING ABOUT WHAT IS IMPORTANT IN THE DISEASE AND WHAT SHOULD YOU TEST. IT IS NOT EASY TO ASSESS BECAUSE IT'S EASY IN POPULATIONS DOING NEURAL DEVELOPMENT, IT'S DIFFICULT IN POPULATIONS YOU'RE DOING NEURODEVELOPMENTAL TESTING FOR THE FIRST TIME TO SAY WHAT A GOLD STANDARD IS. YOU CAN LOOK AT A SECOND TEST BUT IS THAT TEST REALLY A GOLD STANDARD? YOU CAN LOOK AT INTERNAL RELIABILITY OF THE SUBTESTS SO LOOKING AT HOW THEY RELATE TO EACH OTHER, IN THIS POPULATION IS THE SAME WAY AS ANOTHER POPULATION THAT'S KIND OF A SURROGATE MARKER OF VALIDITY, OR YOU CAN HAVE A SECOND TEST DONE WITH CHILD IS OLDER COMPARED THE (INAUDIBLE) WE SAW IN KIDS WHO CROSSED FROM ONE TO THE OTHER THE RESULTS WERE VERY SIMILAR. THIS IS NOT AS BIG A QUESTION FOR BIRTH COHORTS BUT GROUPS THAT ARE NOT BIRTH COHORTS, YOU WANT TO HAVE SOME LOCAL NORMS BECAUSE YOU HAVE LOCAL COMPARE HOW KIDS ARE DOING ON SITE TO THE KIDS IN THAT COMMUNITY, NOT TO U.S. CHILDREN, WHICH MAY NOT BE PERFECT, THIS IS DATA LOOKING AT THAT, SO WALKING YOU THROUGH THIS, THESE ARE COMMUNITY CHILDREN IN THE DARK LINE, THE BIG DASHES ARE CHILDREN WITH SEVERE MALARIAL ANEMIA AND THE SMALL DASHES ARE KIDS WITH CEREBRAL MALARIA, IS COGNITIVE ABILITY ATTENTION AND ASSOCIATIVE MEMORY, LOWER Z SCORES ARE WORSE, OVER TIME THE KIDS WITH CEREBRAL MALARIA STARTED BADLY AND THEY STAYED BADLY, THEY DIDN'T IMPROVE BUT STRIKINGLY, THE KIDS WITH SEVERE MALARIA ANEMIA HAD SCORES COGNITIVE ABILITY AS THE KIDS WITH CEREBRAL -- THIS IS A FULL STANDARD DEVIATION BELOW THE MEAN AS THE MEAN SCORE FROM KIDS WITH CEREBRAL MALARIA. AND IN ATTENTION WE SAW THE SAME THING, THE KIDS WITH SEVERE MALARIA WERE NEVER DIFFERENT FROM THE CONTROL GROUP, WHEREAS THE KIDS WITH CEREBRAL MALARIA WERE ALWAYS DIFFERENT SO ANOTHER CLUE THAT NOT EXACTLY THE SAME THING IS GOING ON IN THESE TWO FORMS OF THE SAME DISEASE, AND THAT YOU MAY WANT TO LOOK AT MORE THAN JUST A FULL BATTERY OR THAT STANDARD YOU MAY NEED SPECIFIC AREAS OF THAT BATTERY LIKE ATTENTION AND MEMORY. VERY BRIEFLY I WANT TO TALK ABOUT THE MAL AWI DEVELOPMENTAL ASSESSMENT TEST AS EXAMPLE OF LOCALLY DEVELOPED TEST BECAUSE IT'S A VERY NICE EXAMPLE OF ONE DEVELOPED BY MELISSA GLAD STONE AN COLLEAGUES THAT DOESN'T EVALUATE COGNITION BUT THOUGH -- THE QUESTIONS THAT COME UP WITH IT ARE IF YOU DEVELOP SOMETHING VERY INTENTIONALLY FOR ONE SPECIFIC POPULATION, IT'S GOING TO HAVE TO BE VALIDATED ACROSS OTHER POPULATIONS IN THAT COUNTRY LET ALONE OTHER AFRICAN POPULATIONS, THE FACT THIS IS A TEST DEVELOPED IN OF AFRICA DOES NOT MEAN IT WILL PERFORM BETTER THAN TESTS DEVELOPED IN THE WEST, IT MEANS THEY HAVE TO BE COMPARED. THIS IS JUST AN EXAM FELONY, IT DOESN'T COME I A CROSS BUT DIAGRAMS AND DESCRIPTIONS IN THE LOWCAL LANGUAGE OF HOW TO DO THE TESTS, THIS WAS GROSS MOTOR DOMAIN. FOR TESTS AND BEHAVIOR, THE QUESTION OF WHETHER TO DO ON VARIATION VERSUS CHECKLIST, IS AN IMPORTANT ONE, THERE ARE ISSUE -- OBSERVATIONAL ALLOWS YOU TO SEE SOME THINGS BUT THAT YOU WOULDN'T SEE ON A CHECK LIVE, PARENTS MAY NOT NOTICE BIT'S A TIME POINT SO THAT'S ONE ISSUE. ANOTHER ISSUE THAT'S JUST COME UP RECENTLY AS WE HAVE GONE THROUGH THIS IS THAT DEVELOPMENT OF PROFICIENCY AND CODING TAKES MONTHS, YOU HAVE TO HAVE SOMEBODY RELIABLE AND YOU CAN CERTIFY ACCURATE ENCODING BUT THAT PERSON IF THEY ARE DOING THE CODING IN THE U.S. MAY CODE SOMETHING AS ABNORMAL THAT FOR PEOPLE WITHIN THAT CULTURE THEY SEE AS QUITE NORMAL AND ACCEPTABLE. AND THIS IS COME UP. SO I THINK WHENEVER YOU'RE DOING THIS, YOU'RE DOING CODING, THE SELF-DECODER HAS TO GET INPUT FROM THE PEOPLE IN THE LOCAL AREA. WE ARE WORKING ON GETTING CODING EXPERTISE IN -- ON SITE SO THE CODING CAN BE DONE ON SITE. RELIABILITY IS INCREDIBLY IMPORTANT, SO IT SEEMS TO CUT TO THE CHASE HERE DOING REPEAT TESTING IN CHILDREN OR CODING ARE INCOMPLETE WAYS OF DOING REPEAT TESTING IN THE SAME DAY THE CHILD IS EXHAUSTED, IT DOESN'T WORK VERY WELL, IF YOU DO ATE COUPLE OF WEEKS FROM THEN THE CHILD IS ALREADY DONE THE TEST. SO YOU MAY HAVE A PRACTICE EFFECT SO WE FOUND THE BEST WAY TO DO THIS IS TO HAVE TWO PEOPLE ASSESS AT THE SAME TIME BUT YOU HAVE TO BE SURE THEY'RE DOING INDEPENDENT CODING WHICH IS NOT -- WHICH IS YOU HAVE TO WATCH TO MAKE SURE. SOMETIMES A SECOND PERSON IN THE ROOM IS DESCRIBED. I TALKED ABOUT PREDICTORS AND OTHERS TALKED ABOUT TIMING. SYMPTOMATIC INFECTION, SEVERITY AND MALARIA, PLACENTA PATHOLOGIST IS PROBABLY INCREDIBLY IMPORTANT SAME MAYBE TRUE IN INFECTION AND FINALLY ANALOGIES UTERO INFECTIONS DR. BRITT TALKED NICELY ABOUT THE CMV, I THINK THE THING IS THAT DIFFERENT INFECTIONS HAVE DIFFERENT THINGS THAT ARE ANALOGOUS TO ZIKA SO FOR MALARIA, IT'S THE QUESTION OF WHETHER OUTCOMES IN CHILDREN'S BORN TO MOTHERS WITH INFECTION VERSUS DISEASE ARE IMPORTANT BECAUSE YOU CAN AND MOSTLY DO HAVE INFECTION WITHOUT SYMPTOMS. BUT IF IT WORSE IN MOTHER WHOSE DO HAVE SYMPTOMS AND WHAT ARE OUTCOMES FOR FETAL VERSUS CHILDHOOD EXPOSURE. SO CONCLUDING WHAT ARE THE RESEARCH QUESTIONS, MOVING THE RESEARCH AGENDA FORWARD FOR ZIKA VIRUS, WHAT ARE THE RESEARCH QUESTIONS? IN TERMS OF ININFECTION A BIG ONE IDENTIFIED SEVERAL TIMES IS HOW DO WE IDENTIFY EXPOSURE AND DISEASE DURING PREGNANCY, THIS QUESTION HOW GOOD IS IGM, WHAT OTHER TESTS CAN WE USE, HOW DO WE DO IT AFTER THE EVENTS OCCURRED. TO IDAHO FID POTENTIAL AT RISK INFANT, IS THERE A DOSE AFFECT OF MATERNAL ZIKA VIRUS ON CHILD NEURODEVELOPMENT AND BEHAVIOR INTO TIMING, SEVERITY AND EXPOSURE VERSUS DISEASE. AND DO INFECTIOUS IN CHILDHOOD ITSELF POSTNATALLY HAVE NEURODEVELOPMENTAL CONSEQUENCES, THESE GET TO THE POINT OF DO EXPOSED CHILDREN WHO DON'T HAVE RADIOGRAPHIC EVIDENCE OF BRAIN INJURY DEVELOP LONG TERM NEURAL DEVELOP MENTAL AND BEHAVIORAL IMPAIRMENT BECAUSE THAT'S AN IMPORTANT PUBLIC HEALTH QUESTION. IN TERMS OF PATHOGENESIS, THERE'S A LOT TO LEARN, SOUNDS LIKE THERE IS A DIRECT VIRAL AFFECT BUT WHAT IS AFFECT OF INFLAMMATION AND OTHER THINGS THAT ARE HAPPENING, WHAT'S HAPPENING LEVEL OF PLACENTA. HOW CO-FACTORS AFFECT THIS, A LOT OF THESE ARE LOOKED AT BECAUSE THAT'S VERY, VERY IMPORTANT. HOW DO YOU DO THE TESTING, WHAT IS THE PATHWAY SUGGEST ABOUT THE DOMAINS AFFECTED WHAT ARE THE BEST TESTS FOR THOSE AREAS, SHOULD THERE BE SCREEN COMPREHENSIVE TESTING MY VOTE WOULD BE THAT YOU START OFF WITH A RELATIVELY SMALL GROUP OF KIDS, HELP DO COMPREHENSIVE TESTING AND FIND OUT WHAT'S WRONG. THEN NARROW DOWN RATHER THAN STARTING NARRATIVE TO BEGIN WITH, THE BEST WAY OF ASSESSING FOR BEHAVIOR. HOW LONG SHOULD THE CHILDREN BE -- I THINK THERE'S A RECURRING THEME, WE ALL FEEL THAT THEY SHOULD BE FOLLOWED A LONG TIME. LONG TERM GOALS WILL BE PREVENTATIVE PRIMARY INFECTION BUT ALSO IDENTIFICATION OF THE RISK FACTORS FOR BRAIN INJURY, INTERVENTIONS FOR THE EXPOSED FETUS TO PROTECT THE BRAIN SO NOT -- AHEAD OF EYE ROLLS MAYBE BUT OTHER INTERVENTIONS, FOR KIDS AFFECTED EARLY AND THIS IS AGAIN TALKING ABOUT MAYBE NOT THE OBVIOUSLY SEVERE KIDS NEED THIS AS WELL BUT MAYBE KIDS THAT AREN'T AS SEVERE EARLY COGNITIVE REHAB AND BEHAVIORAL INTERVENTIONS FOR AT RISK CHILDREN TO MAYBE TRY AND PREVENT THINGS RATHER THAN DEAL WITH WHAT'S ALREADY HAPPENED. I'LL END WITH COLLEAGUES AT MCCARRY UNIVERSITY OF MINNESOTA, INDIANA AND FUNDING FROM A NUMBER OF GROUPS AND BE HAPPY TO TAKE QUESTIONS. THANK YOU. >> THANK YOU FOR THAT WONDERFUL PRESENTATION. [APPLAUSE] >> WE HAVE TIME FOR COUPLE, MAYBE A FEW QUESTIONS. >> BEN ROCHE NATIONAL INSTITUTE OF MENTAL HEALTH. SO ONE OF THE THINGS WITH THE VALIDITY AND RELIABILITY OF THESE TESTS IS NOT SO MUCH THE TYPE OF TEST, BUT PARTICULARLY THE PERSON ADMINISTERING IT. SO WHAT ARE YOU DOING IN THESE ENVIRONMENTS IN ORDER TO MAKE SURE THAT THE PERSON THAT'S ADMINISTERING THESE TESTS CAN DO THIS WITH FIDELITY SO WE CAN GET GOOD DATA AND WHAT KIND OF RECOMMENDATIONS WOULD YOU GET FOR THE TYPE OF TRAINING THAT WE NEED THE GIVE, SO THAT PARTICULARLY IN THESE COUNTRIES WE CAN GET GOOD DATA. >> I CAN GIVE A PARTIAL ANSWER TO THAT, NEURODEVELOPMENTAL COLLEAGUES CAN PROBABLY ANSWER THAT IN MORE DEPTH BUT YOU'RE ACTUALLY RIGHT, THIS IS AN INCREDIBLE -- APPROPRIATE TRAINING OF THE RIGHT PEOPLE, IS INCREDIBLY IMPORTANT AND SO OUR NURSE ONCOLOGY TESTERS UNDERSTOOD GO AN UNDERSTANDING OF THEORETICAL CONSTRUCTS THEY LOOK AT AS WELL AS PRACTICAL TRAINING AND THEN THEY ARE SCORE -- THE RELIABILITY IS INCREDIBLY IMPORTANT. SO THEIR METHODS OF SCORING COMPARED TO SOMEBODY WHO IS ALREADY EXPERT IN SCORING, AND WE DON'T EVEN ALLOW THEM TO START DOING TESTING ON ACTUAL KIDS, WE'RE GOING TO GET DATA FROM UNTIL THEY HAVE RELIABILITY.9 OR HIGHER SO HIGH RELIABILITY, THERE'S SOME VARIABILITY SO WE EXPECT THAT. BUT THAT WAY WE ARE QUITE SURE THAT THEY -- THEIR ASSESSMENTS WOULD AGREE WITH EXPERT ASSESSMENTS, WE ALSO VIDEOTAPE ALL OF OUR TESTING AND WE DO REGULAR QC SO THE HEAD NEUROSIGH WHICH WILL GIST EVERY WEEK REVIEWS A SUBSET OF TESTS LOOKING AT ALL THREE OR FOUR TESTERS, AND IDENTIFIES AREAS WHERE THERE WERE PROBLEMS AND THEN GOES THROUGH THEM WITH THEM SO IT'S AN ONGOING PROCESS, NOT A ONE TIME THING. >> YOU WOULD CONSIDER THAT ESSENTIAL TO GET GOOD DATA? >> YES. ABSOLUTELY ESSENTIAL. BECAUSE WE HAVE SEEN PROBLEMS WHEN THAT WAS NOT -- WHEN IT WAS DONE. >> JOSE CORD ROW, UNIVERSITY OF GEORGIA. PLAID GLAD TO SEE THERE'S (INAUDIBLE) THAT'S THE TITLE OF OUR PROJECT. IN OUR CASE PUERTO RICO TEST SIZE FOR EXPLORING CONTAMINATION AND WHAT WE'RE LOOKING AT IS A COHORT IN A COHORT STUDY LOOKING AT ENVIRONMENTAL RISK FACTORS OF PRE-TERM BIRTH BUT BECAUSE OF (INAUDIBLE) ZIP STUDY WHICH IS NEURODEVELOPMENTAL STUDY AND ONE THING WE'RE LOOKING AT IS NEARLY 20% OF CHILDREN WE'RE FOLLOWING, THIS IS A GROUP THAT HAS A LOT OF SIGNIFICANT ENVIRONMENTAL EXPOSURES ESPECIALLY IN ENDOCRINE DISRUPTERS. A VERY SIGNIFICANT PART WE HAVE TO LOOK IN TERMS OF PRE-TERM BUT SEEMS TO BE AN INTERACTION WITH THAT BETWEEN INFLAMMATORY RESPONSE FROM ENDOCRINE DISRUPTERS AND ACCESS TO INFECTION IN CELL LEVEL AND SO TO WHAT EXTENT YOU'RE DOING MEASURING ENVIRONMENTAL FACTORS LIKE ENDOCRINE DISRUPTERS THINGS THAT ARE VERY COMMON IN PLACES LIKE MALAWI IN PARTICULAR IN URBAN AREAS. SO WE HAVE -- I WOULD LOVE TO TALK TO YOU ABOUT ENDOCRINE DISRUPTERS BECAUSE THAT'S NEW INFORMATION TO ME BUT WE'RE LOOKING FOR INFORMATION ON THINGS THAT WE HAVEN'T CONSIDERED. WE'RE WORKING WITH BOB WRIGHT AT MOUNT SINAI, AN ENVIRONMENTAL -- I WANTED TO TALK TO HIM ABOUT WHAT WE SHOULD LOOK AT IN THESE KIDS AND WHAT TYPE OF SAMPLES WOULD YOU NEED. SO WE HAVE SETTLED ON AT LEAST LOOKING AT -- IF WE CAN GET SUFFICIENT SAMPLE, LOOKING AT HEAVY METAL EXPOSURE, PESTICIDE EXPOSURE, THAT'S WHERE WE ARE FOR NOW. >> (INAUDIBLE) HOUSER NICHD. VERY NICE TALK. CHANGE THE SCOPE A LITTLE BIT BASED ON THE FACT YOU'RE DOING WORK UGANDA AN ZIKA VIRUS WAS FIRST AFFECTED. IN YOUR WORK THERE, HAVE ANYONE REPORTED FETAL BRAIN DISRUPTION SEQUENCE WITH ZIKA VIRUS IN AMERICA AND ASSUMING NOT, CARE TO SPECULATE WHY WE HAVE NOT SEEN THAT IN UGANDA? >> THIS IS THE GREAT QUESTION. AND OUR VIROLOGIST I'M SURE LOOK -- MUCH BETTER SPECULATIVE ANSWERS THAN I WOULD BUT IT IS ALL SPECULATIVE. WHAT I DO KNOW IS WE THOUGHT ABOUT LOOKING AT PREVALENCE OF AT LEAST ZERO POSITIVITY IN OUR POPULATION BUT IT'S BEEN DONE BY THE UGANDA RESEARCH INSTITUTE, IT'S VERY LOW. SO I CAN SAY THAT FOR WHATEVER REASON ZIKA VIRUS THOUGH DESCRIBED FOR -- ZIKA IN UGANDA HAS NOT TAKEN OFF. I DON'T KNOW WHY. I CAN ALSO SAY THERE'S TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST I'M ABAN DOPPING THOSE QUESTIONS BASED ON THE PRESENTATIONS TODAY BUT I WANT TO START BY ASKING TO LEARN A LOT FROM OTHER CONGENITAL INFECTIONINGS I LIKE THE PANEL'S THOUGHTS ON WHAT MAYBE UNIQUE ABOUT ZIKA AND WHETHER THERE'S AN OPPORTUNITY TO LEARN SOMETHING NEW WE MAY NOT HAVE LEARNED BEFORE, USING ZIKA AS A MODEL FOR A DIFFERENT KIND OF CONGENITAL INFECTION. ANYONE? ANYONE? BHULLAR? ANYONE ON THE PANEL? >> I DON'T KNOW IF IT'S UNIQUE BUT I HAVE BEEN LEARNING A LOT TODAY ABOUT ZIKA AND HAVING SEEN THE VIDEOS OF MANIFESTATIONS AND THE MOST SEVERELY INVOLVED WAS CERTAINLY AN EYE OPENER, HOWEVER I WAS MORE IMPRESSED WITH THE FACT THAT THERE ARE SEVERAL CHANGES IN ZIKA THAT MAY IMPACT ON THE GROWTH TRAJECTORY OF HEAD CIRCUMFERENCE AND THE BRAIN. ALSO THE FACT THAT THE POSSIBILITY THAT SOME OF THESE BRAIN CHANGES MAY OCCUR CONTINUE NEONATALLY SO THE BRAIN IS DEVELOPING THE FIRST THREE YEARS. SO I'M THINKING MORE AND MORE OF THE IMPORTANCE OF LONG TERM LONGITUDINAL STUDIES OF BEHAVIOR AND COGNITION LOOKING AT THE TRAJECTORY OF DEVELOPMENT OF THESE CHILDREN, WHICH CHILDREN ARE GOING TO IMPROVE OVER TIME AND HAVE RESILIENCE ORPLASTITY AND -- PLASTICITY AND WHICH WILL WORSEN OVER TIME. MY THOUGHTS. >> I WAS STRUCK BY THE SLIDE I THINK THAT HAD OF THE -- HEAD CIRCUMFERENCE WHERE IT WASN'T THREE STANDARD DEVIATIONS BELOW, BUT THE MEAN HEAD CIRCUMFERENCE WAS WAY BELOW THE MEAN. TO ME THE THING, I HOPE LIKE SOMETHING TO LEARN FROM THIS BUT I HOPE WE DONE ENCOUNTER -- THE SCOPE OF THE POPULATION WITH EVERYTHING HE WILL AFFECTS A SUBSET OF THE POPULATION BUT WITH ZIKA VIRUS A LOT OF PEOPLE GET INFECTED AND SEEMS LIKE THE POTENTIAL PUBLIC HEALTH SIGNIFICANCE PARTICULARLY, BOTH THINGS THAT HAVE MICROCEPHALY BUT ORCHIDS THAT HAVE MICROCEPHALY THEY PROBABLY ARE GOING TO HAVE SOMETHING LONG TERM, EXTRAORDINARY, SO I THINK THAT'S SOMETHING NEW WITH ZIKA VIRUS, ON A DIFFERENT SCALE THAN WE HAVE SEEN WITH THE OTHER (INAUDIBLE). >> THE OTHER PIECE I FIND STRIKINGLY DIFFERENT TO OTHER CONDITIONS IS THIS SELECTIVE VULNERABILITY OF THE NEURAL PRECURSOR CELL AND RADIO GLIAL CELL AND GENETICALLY MEDIATED DISORDERS, I'M NOT AWARE OF OTHER ACQUIRED CONDITION THAT HAVE SUCH TROPISM FOR SPECIFIC CELL TYPES. GIVEN SOME OF THE QUESTIONS THAT CAME UP LATER ON, FOR THE TRAJECTORY OF DEVELOPMENT PARTICULARLY IN BABIES WHO MIGHT NOT BE AS AFFECTED AS THE ONES SAMPLES SAMPLES WITH THE PROFOUND MICROCEPHALY AND SEVERE DESTRUCTIVE LEAGUES, IT'S AN OPPORTUNITY -- LEAGUES IT'S AN OPPORTUNITY TO UNDERSTAND BETTER HOW PARTICULAR CELL TYPES ARE GOING TO IMPACT BRAIN DEVELOPMENT INCLUDING THINGS -- QUESTION ABOUT THE VASCULATURE WAS RIGHT ON. SO WHAT'S THE LINK BETWEEN EARLY NEURONAL DEVELOPMENT, EARLY GLIAL DEVELOPMENT AND HOW VASCULATURE DEVELOPS SO ZIKA VIRUS OFFERS POTENTIAL FOR US TO BETTER UNDERSTAND VERY UNFORTUNATE CIRCUMSTANCES BRAIN DEVELOPMENT. >> I WOULD LIKE TO ADD THAT I THINK ONE CONCERNING ASPECT OF ZIKA VIRUS INFECTION IS WE DON'T KNOW FLEECE SAFE POINT WHICH WE CAN SAY SOMEONE IS OUT OF THE WOODS YET, IF THEY HAVE BEEN EXPOSED PRENATALLY AND TODAY'S TALKS REINFORCED THAT. WE WILL GO BACK TO ONE OF THE QUESTIONS. IF ANYONE ELSE HAS QUESTIONS, BY ALL MEANS. >> GO TO THE MICROPHONE AGAIN BUT TWO NEUROLOGISTS ARE UP THERE, AND AT PREVIOUS ZIKA CONFERENCES SEVERAL TALKED ABOUT THE REAL DIFFERENCE BETWEEN GEON BURR RAISIN DROPPLE ASSOCIATED WITH ZIKA VERSUS THE IDIOPATHIC ONES IN THE UNITED STATES. I DON'T KNOW THE RESOLUTION THAT BECAUSE SOME OF THE PEOPLE FROM BRAZIL SUGGESTED THAT THE GEOM BER AREE THING WAS A MORE AGGRESSIVE DISEASE, SUGGESTING PERHAPS THE NEUROTROPISM OF THIS VIRUS FOR THE PERIPHERAL NERVOUS SYSTEM, ANY COMMENTS FROM EITHER ONE OF YOU ON THAT? ARE YOU AWARE OF THAT INFORMATION RESOLUTION OF THAT DISCUSSION. >> NOT AWARE RESOLUTION OF THAT DISCUSSION, I HAVE BEEN FOLLOWING THE LITERATURE CLINICIAN WHEN OUTSIDE OF THE NICU AND CHILDREN WITH THAT SYNDROMEMYELITIS WE HAVE SO MUCH TO LEARN ABOUT WHAT IS MEDIATING THE SEVERITY OF THAT DISEASE, THAT I HAVE -- I DON'T FULLY UNDERSTAND ZIKA VIRUS ITSELF VERSUS OTHER POTENTIAL MODIFYING CONDITIONS, I THINK THAT'S AN AREA WHERE WE STILL HAVE MORE TO LEARN. >> I THINK THERE WILL BE -- I KNOW THERE WILL BE SOME FORTHCOMING LITERATURE IN THE NEXT FEW WEEKS ABOUT THAT. IN THE PERIOD -- BUT IT'S A VERY IMPORTANT QUESTION. THE NEXT QUESTION THAT SOME OF THE ANSWERS RAISE IS WHICH POPULATION FOR THE PURPOSE OF UNDERSTANDING THE UNDERLYING PATHOPHYSIOLOGY OF THE INFECTION WHICH POPULATION WHICH PATIENT POPULATION SHOULD WE BE TARGETING. SO THE RANGE THE MOST SEVERELY AFFECTED INFANT, INFANT WHO ARE NOT AS SEVERELY AFFECTED INFANTS EXPOSURE NOT NECESSARILY INFECTION SO WHAT'S THE PATIENT POPULATION THAT MAY GIVE US THE GREATEST AMOUNT OF INFORMATION ABOUT THE PATHOPHYSIOLOGY. >> TWO WAYS TO APPROACH THAT, ONE WOULD BE THE CLINICAL LENS VERSUS RESEARCH LENS, THE ANSWERS ARE GOING TO BE DIFFERENT FROM A RESEARCH LENS. I THINK THE LOW HANGING FRUIT WILL BE SEVERELY AFFECT THE KIDS AND NO ONE WILL BE SURPRISED WITH NO GOOD OUTCOMES AND I'M CONCERNED ABOUT THE IMPACT OF NEUROPROGENITOR CELLS AND RADIO GLIAL CELLS BECAUSE THE ABLE TO COMPENSATE FOR THAT UPSTREAM IS DIFFERENT THAN HIGH HYPOXIC ISCHEMIC INJURY OR SOMETHING LIKE THAT. SO THE MORE INTELLECTUAL CHALLENGE ARE THE MILDLY AFFECTED KIDS BECAUSE WE NEED MORE SENSITIVE ASSAYS FIGURING OUT EXACTLY WHAT IS GOING WRONG IN BRAIN DEVELOPMENT BUT ON THE CLINICAL SIDE I THINK THE ANSWER IS GOING TO BE WHICH POPULATION -- MICROCEPHALY IS A RELATIVELY SMALL SUBSET OF THE OVERALL INFECTED KIDS. WHETHER WE LOOK AT THE DISTRIBUTION OF SEVERE VERSUS MILD BUT OF COURSE THEN WE HAVE THE PROBLEM OF TALKING ABOUT SEVERE VERSUS MILD FUNCTIONAL IMPAIRMENT OR STRUCTURAL IMPAIRMENT. WE SAW REALLY HORRIBLE LOOKING SCANS THROUGHOUT THE DAY BUT WE HEARD ALMOST NOTHING ABOUT BEHAVIOR. SO SHOULD WE TARGET KIDS WITH SEVERE INTELLECTUAL DISABILITIES OR TARGET KIDS WITH A VERY THIN LAYER OF CORTICAL MAN TALL BECAUSE OF INJURY, AND I DON'T KNOW THE ANSWER TO THAT. >> I THINK THAT WE NEED TO LOOK BEYOND THE SEVERELY AFFECTED CHILDREN BECAUSE SOME OF WHAT I'M HEARING IS WE REALLY NEED TO UNDERSTAND THE FULL BREADTH OF HOW ZIKA VIRUS IMPACT IT IS BRAIN AND WHAT THAT BEHAVIORAL AND COGNITIVE SEQUELLA IS THAT ARE SO IF WE JUST FOCUS ON THE CHILDREN THAT ARE READILY IDENTIFIED, I THINK WE'RE GOING TO REMAIN IN THE DARK ABOUT WHAT MAY BE THE LARGEST PROPORTION OF CHILDREN IMPACTED. >> I AGREE, THAT WAS SORT OF THE WHOLE ICEBERG THING, I'M GLAD THE STUDY IS GOING ON, THE PROMISE OF THAT IS A VERY LARGE COHORT BEING FOLLOWED AND YOU CAN SEE THE FULL SPECTRUM. I THINK THAT OBVIOUSLY THE KIDS WITH SEVERE DISEASE HAVE TO BE ADDRESSED BUT I THINK NOW DURING -- IN A PERIOD YOU HAVE THIS OPPORTUNITY WITH THE EPIDEMICS ARE OCCURRING NOW IS THE TIME TO REALLY DO AS COMPREHENSIVE ASSESSMENT AS YOU CAN ON AS LARGE A NUMBER OF CHILDREN AS YOU CAN, UNTIL YOU DEFINE THE PROBLEM YOU DON'T KNOW WHAT THE LONG TERM ISSUES ARE. IT COULD BE THAT ALTHOUGH THE KIDS WHO ARE EXPOSED ARE NOT NEARLY AS HEAVILY AFFECTED AS THE KIDS WITH MICROCEPHALY, THAT THEIR PROFOUNDLY AFFECTED, THAT IS GOING TO MAKE A DIFFERENCE HOW THEY CAN DO AT SCHOOL AND CAREERS AND EVERYTHING ELSE. I THINK THE UP FRONT BROAD APPROACH LOOKING AT EXPOSED CHILDREN IS THE WAY TO GO. >> I LIKE TO COMMENT AND SUPPORT THAT STATEMENT BECAUSE IF YOU THINK IN TERMS OF POPULATION, IMPACT, IF TEN PERCENT HAS SPARE MICROCEPHALY ET CETERA BUT 90% HAVE LESSER AFFECTS THAT MAY IMPACT ON IQ BY FIVE OR TEN POINTS, OR THE ASSOCIATED WITH SUBSEQUENT -- SIGNIFICANT BEHAVIORAL OR NEUROPSYCHIATRIC DISORDERS, AUTISM, SCHIZOPHRENIA, ET CETERA, WE DON'T KNOW. AS WHICH LOOK MORE AT LONG TERM STUDIES I HAVE IMPRESSED OUT OF THE -- I WAS IMPRESSED FROM THE SCANDINAVIAN STUDIES FOLLOWING POPULATIONS UP TO 68 YEARS OF AGE, WHERE EVEN MODERATE PRE-TERM INFANTS AND LATE PRE-TERM INFANTS HAVE IMPACTS ON DEVELOPING EARLY DEMENTIA. SO I THINK IT'S CRITICAL TO LOOK HAT THE TOTAL POPULATION PARTICULARLY WHEN WE KNOW THE MORE SUBTLE EFFECTS, I DON'T KNOW HOW MANY TIMES WE SAW ICEBERGS TODAY, THAT'S THAT WHOLE AREA THAT WE NEED TO LOOK AT. >> ONE MORE THING THAT KNOWED ON THIS, WHICH IS THAT I THINK WE HAVE TO BE CAREFUL NOT TO DISASSOCIATE CLINICAL OUTCOMES BEHAVIORAL OUTCOMES FROM BRAIN OUTCOMES AND UNDERSTANDING, BRAIN IMAGING OF THE BRAIN FUNCTION, I THINK SOME OF THE MOST INFORMATIVE CHILDREN THAT WE HAVE STUDIED BORN PRE-TERM WITH CONGENITAL HEART DISEASE OR OTHER HIGH RISK POPULATIONS ARE WHERE THOSE TWO FACTORS DIVERGE. SO THE CHILDREN THAT DO REMARKABLY WELL DESPITE BRAIN CHANGES THAT HAVE SO MUCH TO TELL US. >> QUESTION. >> I'M A FELLOW IN NEURODEVELOPMENTAL DISABILITY CHILDREN'S NATIONAL. AGREE WITH EVERYTHING EVERYBODY IS SAYING, I WANT TO REALLY SAY THAT DEFINITELY THESE CHILDREN SHOULD BE FOLLOWED REGARDLESS OF WHEN THE TRANSMISSION OF THE INFECTION HAPPENED TO THE MOTHER FOR SECOND TRIMESTER, THESE KIDS SHOULD BE FOLLOWED UP UNTIL INITIATION OF SCHOOL AGE, BECAUSE WE STILL FIND THAT THOSE KIDS WHEN FIVE, SIX YEARS OLD ARE STARTING TO SEE BEHAVIORAL EFFECTS. WE KNOW THIS BUT JUST TO MAKE IT CLEAR. WHAT ABOUT KIDS IN ENDEMIC AREAS SHOWING SIGNS OF DEVELOPMENTAL ISSUES WHETHER GREG WHICH CONCERNING, OR EVEN JUST BEHAVIORAL ISSUE LEARNING DISABILITIES ON THE MILD SIDE. WOULD WE FEEL LIKE STARTING NOW WE NEED TO KEEP OUR SURVEILLANCE UP FOR THOSE KIDS BECAUSE MAYBE THE MOTHERS DIDN'T KNOW THEY WERE INFECTED AS WE DISCUSSED THROUGHOUT TODAY BUT ALSO MAYBE THOSE KIDS WERE AFFECTED POSTNATALLY AND DURING EARLY YEARS WHERE THEIR BRAIN IS STILL IN CRITICAL PHASE OF DEVELOPMENT. >> I WOULD CERTAINLY AGREE WE NEED TO BE ABLE TO FOLLOW THESE HIGH RISK POPULATIONS AND ENDEMIC AREAS EVEN IF THERE ISN'T DOCUMENTED OR KNOWN ZIKA VIRUS INFECTION. THE CHALLENGES REALLY FINDING THE RIGHT BIOMARKERS TO GIVE US CLUES WHETHER OR NOT THERE WAS A ZIKA INFECTION THAT MAY BE CAUSATIVE OR TRIGGER FOR THOSE MANIFESTATIONS. WE HEARD EARLIER TODAY ABOUT CHALLENGES WITH THE SEROLOGY, MEASUREMENTS THAT EXIST AND THIS IS A REAL NEED IN THE RESEARCH COMMUNITY TO REALLY HAVE BETTER BIOMARKERS SO THAT WE CAN IDENTIFY INFANTS WHO HAVE BEEN EXPOSED OR CHILDREN WHO HAVE BEEN EXPOSED AND ARE SHOWING MANIFESTATIONS LATER. >> SO I WANT TO GO BEYOND A COMMENT YOU JUST MADE. SEVERAL PEOPLE NOW HAVE TALKED ABOUT THE NEED TO FOLLOW-UP THESE KIDS FOR LONG TERM. AS SOMEONE WHO HAS MORE PRINCIPALLY DOING LONGITUDINAL STUDIES, I'M SYMPATHETIC -- MORE THAN A NATURAL HISTORY STUDY. WHAT WE NEED TO DO IS WHAT WOULD BE AGE SPECIFIC INTERVENTIONS WE COULD DO, SO GIVEN WHAT WE KNOW ABOUT PLASTICITY AND WHATEVER RESERVE REMAINS IN DEVELOPMENT HERE, WHAT WOULD WE DO TO TWO-YEAR-OLD OR FOUR OR SIX-YEAR-OLD THAT WOULD BE DIFFERENT RATHER THAN GARDEN VARIETY LET'S PUT INTO EARLY INTERVENTION WHAT YOU AND I WERE TALKING ABOUT EARLIER. I'M NOT SURE HOW TO DO THAT. SO I THINK IF WE DO FOLLOW-UP STUDIES, I THINK WE WOULD BE MORE POWERFUL WOULD BE BUILT INTO AN INTERVENTION ARM AS WELL. I THINK WE NEED TO THINK CAREFULLY WHAT THAT LOOKS LIKE AND THE INTERVENTION SHOULD BE BASED ON ANYTHING WE KNOW ABOUT BRAIN DEVELOPMENT RATHER THAN JUST TARGETING IMPROVING COGNITIVE SCORES ON THE VALLEY. >> ANYONE ELSE WANT TO REACT TO THAT? >> ABSOLUTELY. >> GREAT. >> IF I CAN COMMENT, ONE THING IN THE -- OUR SEVERE MALARIA THAT EXISTS WE DISCOVERED THESE KIDS HAD IMPAIRMENT IN COGNITION AND ATTENTION AND MEMORY. AND THEN WE WERE LEFT WITH WHAT, HERE THEY ARE, WE'RE GOING TO DO ANOTHER STUDY IN YOUNGER KIDS. SO WITH MICHAEL WE STARTED SOME TRIALS OF COMPUTERIZED COGNITIVE REHAB, NOT SORT OF THE ULTIMATE SOLUTION BUT AS BEGINNING ATTEMPT AT DOING SOMETHING BECAUSE I THINK THE SAME QUESTIONS CAME UP FROM OUR COLLEAGUES, YOU CAN'T JUST ENDLESSLY FOLLOW KIDS AND SHOW THAT THEY'RE DEFISH, TOUGH HAVE SOMETHING, SOME SORT OF BEING OF HOPE FOR -- BEGINNING OF HOPE FOR THEM. >> IT RAISES AN IMPORTANT ETHICAL QUESTION TOO, DOESN'T IT? >> (INAUDIBLE) TAKEN IN THIS CHILD NETWORK, PARENTS WERE FAR MORE INTERESTED IN ENGANGING IN INTERVENTION STUDIES THAN LONGITUDINAL STUDIES AND THOUSAND BEST ENHANCE PARENT INFANT INTERACTION. AND THIS HAS BOTHERED ME ABOUT NEUROPROTECTION BEYOND THE NICU. I PUSH BACK HOW TO USE FOLLOW-UP ADS AN INTERVENTION, WHAT DO WE BUILD INTO THAT. I THINK YOU HIT THE NAIL ON THE HEAD. >> YOU HAVE A QUESTION? >> YES. (INAUDIBLE) PUERTO RICO. TODAY WE'VE COME, WE ARE LEAVING WITH MANY MORE QUESTIONS THAN WE ARRIVE THAT'S A GOOD THING. THAT'S THE -- WHAT WE -- IF WE KNOW EVERYTHING IT'S A WASTE OF TIME, TWO THINGS, FIRST THE ADDRESS THE QUESTION, IF WE'RE -- WE BASICALLY AGREE THAT WHAT HIT US IN THE FACE WHICH IS THE MICROCEPHALY SICK KID IS ONE OF THE PROBLEMS BUT THE OTHER PROBLEMS IS WHAT WE TALK, WHAT ABOUT THE WELL KIDS WHO WE DO NOT KNOW WHAT'S GOING TO HAPPEN TWO, THREE, FOUR YEARS AND HOW WE'RE GOING TO FOLLOW THEM, WHAT ARE WE GOING TO DO, WHAT SPECIFIC STUDIES OR ANALYSIS AND THAT'S WHAT'S ONE OF THE THINGS, AS SCIENTISTS, WE SHOULD BE KEEPING WATCH. MY COMMENTS IS ANOTHER THING WE SHOULD BE DOING IS CONVEYING THIS TO THE NON-SCIENTISTS TO THE CLINICS, THE FIRST RESPONDERS TO THIS ZIKA INFECTION, THE PRIMARY PHYSICIANS, THE PATIENT, HOW ARE WE GOING TO CONVEY THAT THIS IS VERY IMPORTANT ESPECIALLY IN AREAS WHERE THEY THINK THAT THIS IS JUST A DISEASE FOR THE POOR, OR DISEASE FOR THE PEOPLE WHO ARE IN THE 14 STATES WITH (INDISCERNIBLE). WE SHOULD TRY TO CONVEY THIS, CONVEY THE IMPORTANCE AND THE -- THE WIDESPREAD MANIFESTATION THIS COULD HAVE ON LONG TERM BASIS. >> I'M GOING THE MAKE A COMMENT THAT I THIS I THAT'S A REALLY IMPORTANT POINT. AND I THINK THE CDC GUIDELINES FOR SURVEILLANCE ARE A GOOD STARTING POINT FLOOR, I THINK THEY NEED TO BE TAILORED TO THE INDIVIDUAL HEALTH SITUATION IN THE VARIOUS COUNTRIES FOR WHICH THE VIRUS IS ENDEMIC AND PROBABLY THAT WILL CONTINUE TO INCREASE. BUT I THINK THAT SENDS A VERY STRONG MESSAGE THAT EVEN IF YOU HAVE AN ASYMPTOMATIC CHILD WITH A LIKELY PRENATAL EXPOSURE THAT STILL NEEDS TO BE FOLLOWED. HERE A SCHEDULE TO START TO TRY TO FOLLOW THAT CHILD LONGITUDINALLY. >> I WANTED TO RESPOND TO THE QUESTION ENGAGING PARENTS IN PARTICIPATION, CERTAINLY OFFERING THEM OPTIONS THAT WOULD BE RANDOMIZED FOR INTERVENTION ARE IMPORTANT. WE HAVE HAD GOOD RESULTS IN OUR CENTER BY USING PARENT MENTORS WHO HAVE COME FROM THE SAME CULTURES, SPEAK THE SAME LANGUAGE, TO SUPPORT THE FAMILY, IDENTIFY BARRIERS, ENCOURAGE THEM TO RETURN FOR VISITS AND WE HAVE FAIRLY SIGNIFICANT IMPACT ON LONG TERM COMPLIANCE BY LINKING THEM WITH ANOTHER PART WHO'S -- IN OUR CASE IT'S ANY PARENT WHO HAS HAD A BABY IN THE NICU THEMSELVES WHO MAY HAVE HAD COMPLICATIONS. SO SOMETHING TO THINK ABOUT IN TERM OF MORE PARENT INVOLVEMENT IN THE PROCESS. >> IF I CAN ADD ONE THING. ONE NEW FINDING THAT'S COME OUT FROM OUR MALARIA STUDY, Ph.D. STUDENT UGANDA Ph.D. STUDENT WORKING ON THIS, INTERESTED IN THE EFFECTS OF THE CHILD MALARIA ON THE FAMILY RELATING TO WHAT THEY SAID, WE REALLY NEED TO WORK ON SOME OF THOSE THINGS BECAUSE THE TURNS OUT REPEATED ATTACKS IN FAMILIES THAT DON'T HAVE VERY MUCH TO BEGIN WITH ARE INCREDIBLY STRESSFUL AND WE FOUND AMAZINGLY A MUCH HIGHER RATE OF DIVORCE THAT'S THESE FAMILIES, DESCRIPTIONS OF INCREDIBLE STRESS LAID ON THE FAMILY. SO THE AFFECTS OF THE DISEASE GO WAY BEYOND THE CHILD. SO EARLY FAMILY INTERVENTION THINKING EFFECTS ON FAMILY LOOKING AT THAT WITH ZIKA. >> I LIKE TO THINK OF IT PROVIDING SERVICES, NOT JUST FOR THE INFANT BUT FOR THE MOTHER INFANT DYAD IN THE FAMILY. >> LET ME ASK THIS, BECAUSE I SAW THE INFANT VIDEO THIS MORNING IT WAS IMPRESSIVE, IN THE MALARIA STUDY HAVE YOU SEEN INCREASE IN CHILD MAL TREATMENT? CHILD ABUSE? >> WE HAVE -- WE SHOULD LOOK AT THAT. WHAT WE HAVE SEEN IS CHILD ABANDONMENT USUALLY BY THE FATHER. SO THE DIVORCES ARE USUALLY THE FATHER SAYS I DON'T WANT THE DEAL WITH THIS ANY MORE AND IT'S LEFT TO THE MOTHER TO DEAL WITH IT. WE HAVE SPECIFICALLY (INAUDIBLE) ABUSE. >> HAVE YOU SEEN ABUSE IN BRAZIL, CHILD ABUSE? CHILD M ACTL TREATMENT? -- MAL TREATMENT? WITH ZIKA? (OFF MIC) >> ABANDONMENT. >> NEXT QUESTION. >> I DIDN'T HAVE A QUESTION, IT WAS ACTUALLY A COMMENT, ECHOS ALL THOSE THINGS, AS MATERNAL FIELD MEDICINE SPECIALIST I HAVEN'T SEEN THAT MANY WOMEN WHO HAD ZIKA. THE ONE PATIENT THAT I HAD WHOSE COMMENTS RING TRUE TO THIS, WHEN I TOLD HER THERE'S NO VACCINE, THERE'S NO TREATMENT WE'RE GOING TO HAVE TO WAIT AND SEE AND FOLLOW WITH ULTRASOUND, SHE SAT BACK AND LOOKED AT ME AND SAID WHAT CAN I DO? BECAUSE I CAUSED THIS. I THINK FOR THE -- FOR WOMEN, FOR THE PARENTS, IT MAY BE BEING PART OF AN INTERVENTION TRIAL THAT SOMEHOW CAN CHANGE YOUR CHILD'S OUTCOME, IS PROBABLY IN SOME WAYS EMPOWERING BECAUSE THEY TAKE ON SO MUCH GUILT FOR THE WHOLE THING HAPPENING IN THE FIRST PLACE. SO JUST MAYBE YOU THINK THIS MIGHT BE EVEN ESPECIALLY THE POPULATION YOU WANT TO BRING IN EARLY AND NOT WAIT UNTIL THE KID IS BORN BUT START TEACHING PARENTING CLASSES OR WHATEVER BEFORE THE BABY IS BORN. TO SEE IF THERE'S ANY OPTION OF CHANGING THE KIDS LONG TERM OUTCOME. >> LET ME ASK THIS, IS THERE EQUIPOISE FOR THAT KIND OF TRIAL? OR IS IT COMPARATIVE EFFECTIVENESS TRIAL? HOW WOULD THAT LOOK? YOU CAN SEE HOW BIOETHICIST MIGHT HAVE A PROBLEM WITH PLACEBO OR TREATMENT. >> THIS IS A ONE OFF ANSWER. BUT IN SAO PAULO I HAVE A PROJECT WITH YOUNG GIRLS WHO GET PREGNANT, THEY'RE 12 TO 16 I THINK. THEY ARE IDENTIFIED EARLY IN PREGNANCY. AND WE DO SOMETHING LIKE A VISITING NURSE PROGRAM, WE CAN WEEKLY THROUGHOUT PREGNANCY AND POST POST NAY IT WILY, I SEE THE KIDS AFTER BIRTH. THE INTERVENTION ARM CERTAIN GETS WHATEVER SERVICES ARE AVAILABLE IN THE IMMUNITY FOR THESE GIRLS WHETHER -- COMMUNITY FOR THE GIRLS WHO HAVE BEEN CONCEIVED OUT OF SEXUAL ABUSE. WE STRUGGLE WITH THAT, BUT THERE'S ONLY SO MUCH TREATMENT TO GO AROUND SO HERE THE ISSUE WOULD BE -- IF WE DID SOMETHING LIKE THAT, THE MINUTE THESE MOMS ARE IDENTIFIED, AS CARRYING A ZIKA INFECTED BABY, WE DO PARENTING INTERVENTION, YOU REAR REALLY ASKING WOULD IT BE ETHICAL TO HAVE AN ARM WHERE THERE WAS NO INTERVENTION? ONE COULD ARGUE UNTIL WE KNOW WHETHER THE INTERVENTION HAS ANY EFFECT THEN THERE'S EQUIPOISE BUT THE INTUITION IS IT HAS SOME EFFECT. THEREFORE WHAT'S THE COMPARABLE OTHER ARM? I'M STUMPED WITH THAT, THE QUESTION THEN, IS IT ETHICAL NOT TO DO A TRIAL BECAUSE IT MIGHT BE UNETHICAL YOU SEE WHERE I'M GOING? BIOETHICISTS TO THINK ABOUT THIS. >> ANYONE ELSE ON THE PANEL HAVE A COMMENT? SORRY FOR THE MONKEY WRENCH, FROM OFFICE OF CLINICAL RESEARCH YOU HAVE TO THINK ABOUT THIS. >> GILLMAN GRAVE CHILD HEALTH INSTITUTE. AND I WAS STRUCK BY DR. VOHR'S COMMENT ABOUT SCHIZO EFFECTIVE DISORDERS LATER IN LIFE AND HOW LONG TO FOLLOW KIDS THAT ARE INFECTED. WE HAVE STUDIED -- WE HAVE SUPPORTED I SHOULD SAY, THE CHILD HEALTH AND DEVELOPMENT STUDIES FOR MANY YEARS, STUDY OF 20,000 PREGNANCYIES, DATA ARE AVAILABLE BY THE WAY IN OUR DASH AND BIOSPECIMENS ARE AVAILABLE ALSO. YOU MIGHT THINK OF THAT. BUT ANYWAY, WITH REGARD TO DR. VOHR'S COMMENT ABOUT SCHIZOPHRENIA, TURNS OUT THAT ALAN BROWN AT HARVARD STUDIED SOME OF THE BIOSPECIMENS THAT WE HAVE HAD, STORED FOR MANY YEARS. HE FOUND THAT WOMEN WHO HAD TOXOPLASMOSIS IN THE FIRST BUT NOT THE SECOND OR THIRD TRIMESTER AND WOMEN WITH INFLUENZA TYPE A OR B, ONLY IN THE FIRST TRIMESTER, GAVE RISE TO OFFSPRING WHO 20 YEARS LATER OR MORE DEVELOPED SKIT SEW AFFECTIVE DISORDERS SO IT SHOWS YOU'RE A COMPLETELY RIGHT, THIS KIND OF THING ESPECIALLY IN INFECTIONS THAT AREN'T MAJOR AND RIPPING THE BRAIN APART, BUT JUST SUBTLE, YOU HAVE TO FOLLOW FROM DECADES TO FIND OUT WHAT EVENT THAT MIGHT TURN UP LATER IN LIFE. >> BY THE WAY, YOU ARE ALL FREE TO -- (OVERLAPPING SPEAKERS) >> PARDON ME? >> UNLESS WE CAN IDENTIFY PROGRAMS SO EARLY BIOMARKER THAT WE KNOW CORRELATES WITH THAT OUTCOME. IN THE FIRST YEARS OF LIFE, THERE'S BEEN DONE IN SCHIZOPHRENIA AS WELL. >> THANK YOU. >> THANK YOU. >> YES. >> HELLO, MICHAEL DONOFRIO UNIFORM SERVICES UNIVERSITY AT HEALTH SCIENCES. MY QUESTION IS A TAG TON THE QUESTION ABOUT THE CHILD ABANDONMENT, HAS THERE BEEN SEEN ANY EITHER CULTURAL AFFECTS OF INFECTION OF CHILDREN PERHAPS ANY SOCIETAL NORMS AND THESE POPULATIONS THAT PERHAPS EITHER CERTAIN BEHAVIORS ARE VIEWED AS BEING AT RISK FOR ZIKA AND MICROCEPHALY OR ANY OF THOSE TABOOS? >> COULD YOU ENCAPSULATE YOUR QUESTION? >> I THINK TO SIMPLIFY, ARE THERE ANY NEW TABOOS THAT HAVE ARISEN AS A RESULT OF THE ZIKA VIRUS OUTBREAK? >> STIGMAS? >> SOCIAL AVOIDANCE OR OTHER NEGATIVE -- CONSEQUENCES. SOME IDENTIFIED HAVING A BABY WITH ZIKA SO THEY'RE SHUNNED BY THE COMMUNITY, THAT'S THE SOFTER THING YOU'RE ASKING? >> YES. >> WE HAD A MEETING WITH (INAUDIBLE) TWO MONTHS AGO WITH THE MOTHER. THE PARENTS AND EXPERTS AND PEOPLE FROM GOVERNMENT. MOST OF THE MOTHERS TALKING ABOUT THIS, THEY SAID IN (INAUDIBLE) LOOK AT THE BABY DIFFERENT AND THEY POINT FOR THE BABY, SAY BABY WITH THE ZIKA. I THINK THERE IS DIFFERENT BECAUSE IN TWO MONTHS AND LAST YEAR SUDDENLY WE HAVE MANY PATIENTS WITH THE SAME APPEARANCE, DIFFERENCE -- APPEARANCE OF THE BABIFUL BUT THEY IMPROVE A LOT. THE MOTHER -- THEY MAKE LIKE ASSOCIATION, THEY (INAUDIBLE) OF A MOTHER OF ANGELS AND THEY WORK TOGETHER INCLUDING GOING TO THE GOVERNMENT TO (INDISCERNIBLE) GO THEY NEED SOME HELP. THEY ARE WORKING TOGETHER, U THINK NOW IT'S BETTER. LAST YEAR I THINK THE PICTURE IS LIKE THIS, THE (INDISCERNIBLE) OF THE BABIES, RIOT NOW I THINK THEY ARE BETTER. THEY ARE WORKING -- RIGHT NOW THEY ARE BETTER AND WORKING TOGETHER TO IMPROVE THIS. >> DR. ZORRILLA YOU WANTED TO ADD SOMETHING? >> IN OUR CARE WE HAVE GROUP PREFATAL CARE SO WE HAVE FOUR GROUPS OF WOMEN WITH ZIKA, WE GROUPED THEM TOGETHER SO STIGMA AND FEAR OF DISCLOSURE IS VERY STRONG. MOST OF THEM HAVE NO DISCLOSURE DIAGNOSIS OF JUST BEING PREGNANT WITH ZIKA INFECTION, TWO OF THE PARTNERS HAVE ABANDONED THESE WOMEN DURING THE PREGNANCY BECAUSE OF THE DIAGNOSIS OF ZIKA. AND THESE ARE WOMEN WHO HAVE NORMAL BRAIN (INAUDIBLE) SO FAR NORMAL (INAUDIBLE) SO CERTAINLY THERE IS A LOT OF PERCEIVED STIGMA AMONG THIS POPULATION AND THIS IS WHY THROUGHOUT THE PAST FEW MONTHS WE DIDN'T HEAR THEIR VOICES, BECAUSE WE WERE SO VULNERABLE AND AFLAYED OF SPEAKING OUT. SO NOW SLOWLY SOME OF THEM ARE COMING OUT AND BEING ARE ALLOWING TO BE INTERVIEWED BUT CERTAINLY WE ALSO SAW A PATIENT WHO PRESENTED IN LABOR AND DELIVERED AND THEN LATER ON SHE SAID OH BY THE WAY, I HAD THIS DIAGNOSIS DURING PREGNANCY. BECAUSE THEY ACTUALLY ARE AFRAID OF BEING STIGMATIZED. >> I AGREE. I THINK TIME IS THE ANSWER BECAUSE WHEN WE FIRST STARTED SEEING THESE MOTHERS AND BABIES BECAUSE WE SEE BOTH OF THEM IN THE INSTITUTION, WE WOULD SEE LIKE HOW MOTHERS THEY WOULD COVER THEIR BABIES, THEY DIDN'T WANT TO TALK OR MENTION ANYTHING TO SOCIETY OR MEDIA. WITH TIME MONIQUE (INAUDIBLE) EXPLAIN THEY GOT TOGETHER AND FORMED THE SUPPORT GROUP AND STRENGTHENING EACH OTHER. EDAND THEY ARE TALKING MORE ABOUT IT AND FIGHTING FOR THEIR CHILDREN'S RIGHTS AND THIS HAS CHANGED. SO I THINK IN THE BEGINNING WHEN WE FIRST SAW THESE FAMILIES, OF THESE CHILDREN WERE SO IRRITABLE THEY COULDN'T STOP CRYING THE FATHERS WERE THE FIRST TO LEAVE IN THE FAMILY, AND SOME OF THE MOTHERS THEY GAVE THESE CHILDREN FOR ADOPTION, BUT WITH TIME WE SEE THEY ARE STRONGER AND DEALING BETTER WITH THEIR -- WITH THE -- THEIR CHILDREN AND WITH ALL THE DISABILITIES, THEY -- DIFFERENT. SO WHAT I WANT TO LEAVE HERE IS A MESSAGE THAT A SUPPORT, PSYCHOTHERAPY, PSYCHIATRY, IS VERY IMPORTANT NOT ONLY GIVING THE SUPPORT FOR THE BABIES BUT FOR THE PARTS BECAUSE THIS -- PARENTS BECAUSE THIS MAKE AS CHANGE IN THESE FAMILIES AS A WHOLE, NOT JUST THE CHILD. >> QUESTION. >> DON BAILOR RTI INTERNATIONAL. I WANT TO GO BACK TO THE DISCUSSION ABOUT A TREATMENT STUDY FIRST MAKE A COMMENT. THERE'S NOT GOING TO BE A PURE NATURAL HISTORY STUDY OUT THERE BECAUSE EVERY -- THESE BABIES ARE GETTING TREATED ALREADY. BEING LOTS OF THINGS TRIED WITH THEM SO WE'RE NOT GOING TO BE ABLE TO FIRST OF ALL JUST SAY HERE IS THE UNTREATED CHILD. SO IT WOULD BE GREAT TO HAVE A TREATMENT STUDY BUT JUST NOT CONFIDENT WE'RE AT A POINT IN OUR KNOWLEDGE THAT WE'RE READY TO INVEST A LOT OF MONEY INTO SOMETHING LIKE THAT. LOTS OF PARENTING INTERVENTION STUDIES, IF WE DID ONE IN ZIKA WOULD SHOW WE CAN CHANGE PARENT BEHAVIOR TO A CERTAIN EXTENT AND MODIFY INFANT BEHAVIOR SLIGHTLY DOING THAT. PARENT ADAPTATION AS OUTCOME-ON OPPOSED TO IMPROVEMENT OF CHILDREN. SO I DON'T KNOW WHAT WHAT THE RIGHT ANSWER IS, YOU CAN CERTAINLY DO QUALITY EXPERIMENTAL TYPES OF STUDIES BUT I THINK SOME KIND OF COORDINATED BOTTOM UP APPROACH WHERE WE TAKE THE EXPERTISE OF CLINICS WORKING WITH FAMILIES AND CHILDREN RIGHT NOW, AND TRY TO BUILD KNOWLEDGE BASE FROM THAT SO WE CAN ULTIMATELY DESIGN A USEFUL INTERVENTION STUDY WOULD BE REALLY WHERE WE NEED TO GO. BUT IT WILL TAKE EVERYBODY IS WORKING ON THEIR OWN WITH THESE BABIES AND COLLABORATION COORDINATION ACROSS THE SITES COMING UP WITH CONSENSUS OF WHAT MIGHT BE THE INTERVENTION PACKAGE, HAVING SAID THAT, THE CRITICAL VARIABILITY IN THESE BABIES MEANS THAT EF TREATMENT IS INDIVIDUALIZED. -- EVERY TREATMENT IS INDIVIDUALIZED SO HOW YOU COMBINE INDIVIDUALIZED TREATMENT INTO OVERALL PACKAGE AND EVALUATE THAT WILL BE ANOTHER INTERVENTION CHALLENGE. >> ANY LAST COMMENTS FROM THE PANEL? THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU, ADAM. THANK YOU TO EVERYBODY ON OUR PANEL FOR A WONDERFULLY THOUGHT PROVOKING ENGAGING DISCUSSION. I AGAIN WANT TO REITERATE MY THANKS TO ALL OF OUR PRESENTERS TODAY AS WELL AS THE PANELISTS AND MODERATORS. COUPLE OF HOUSEKEEPING NOTES, AS YOU ARE ALL AWARE, FROM BEFORE, THE CONFLICTS OF LOOKING ACROSS THE STREET SO YOU KNOW GO GO TO REGISTRATION DESK FOR DIRECTIONS IF YOU NEED THE GET TO THAT OR GET INFORMATION ABOUT TAXIS FOR DINNER AND OTHER ENGAGEMENTS. SO LIKE TO SEE EVERYBODY HERE TOMORROW BRIGHT AND EARLY, EIGHT O LOCK SHARP FOR CONTINUATION OF SESSION 2, WE'LL DIVE TYPE THE SCREENING MONITORING FOR SENSORY OUTCOMES ABNORMALITIES AS WELL AS FOR OTHER NON-CNS ABNORMALITIES AND EXCITING SESSION ON THE ROLE OF PARENTS AND CAREGIVERS IN INTERVENTIONS SO ENJOY YOUR EVENING. THANK YOU AGAIN. AND I WOULD LIKE TO ASK DR. VENTURA DR. VAN DER LINDEN AND DR. BRITT IF WE CAN CHAT OUTSIDE FOR A MOMENT. HAVE A NICE EVENING, EVERYONE. [APPLAUSE]