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Sarah Mulkey

MRI and ultrasound imaging detect the spectrum of Zika’s impact

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Sarah Mulkey

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D.

Worldwide, thousands of babies have been born to mothers who were infected during pregnancy with Zika, a virus associated with neurological deficits, impaired vision and neurodevelopmental disabilities, among other birth defects. These birth defects are sometimes severe, causing lifelong disability. But they’re also relatively rare compared with the overall rates of infection.

Predicting how many Zika-exposed babies would experience neurological birth defects has been challenging.

However, an international study led by Children’s faculty suggests that ultrasound (US) imaging performed during pregnancy and after childbirth revealed most Zika-related brain abnormalities experienced by infants exposed to the Zika virus during pregnancy, according to a prospective cohort study published online Nov. 26, 2018, in JAMA Pediatrics. Some Zika-exposed infants whose imaging had been normal during pregnancy had mild brain abnormalities detected by US and magnetic resonance imaging (MRI) after they were born.

“A combination of prenatal MRI and US was able to detect Zika-related brain abnormalities during pregnancy, giving families timely information to prepare for the potential complex care needs of these infants,” says Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist at Children’s National Health System and the study’s lead author. “In our study, we detected mild brain abnormalities on postnatal neuroimaging for babies whose imaging was normal during pregnancy. Therefore, it is important for clinicians to continue to monitor brain development for Zika-exposed infants after birth.”

As of Nov. 20 2018, nearly 2,500 pregnant women in the U.S. had laboratory confirmed Zika infection, and about 2,400 of them had given birth, according to the Centers for Disease Control and Prevention (CDC). While more than 100 U.S. infants were born with Zika-associated birth defects, the vast majority of Zika-exposed U.S. infants were apparently normal at birth. The sequential neuroimaging study Dr. Mulkey leads seeks to determine the spectrum of brain findings in infants exposed to Zika in the womb using both US and MRI before and after birth.

The international research team enrolled 82 women in the study from June 15, 2016, through June 27, 2017. All of the women had been exposed to Zika during pregnancy; all but one experienced clinical symptoms by a mean gestational age of 8.2 weeks. Eighty of those women lived in or near Barranquilla, Colombia, and were exposed to Zika there. Two U.S. study participants were exposed to the primarily mosquito-borne illness during travel to Zika hot zones.

All women received fetal MRIs and US during the second and/or third trimester of pregnancy. After their infants were born, the children received brain MRI and cranial US. Blood samples from both mothers and babies were tested for Zika using polymerase chain reaction and serology.

Fetal MRI was able to discern Zika-related brain damage as early as 18 weeks gestation and picked up significant fetal brain abnormalities not fully appreciated in US imaging. In one case, the US remained normal while fetal MRI alone detected brain abnormalities. Three fetuses (4 percent) had severe fetal brain abnormalities consistent with Zika infection, including:

Seventy-five infants were born at term. One pregnancy was terminated at 23 weeks gestation due to the gravity of the fetal brain abnormalities. One fetus with normal imaging died during pregnancy. One newborn who was born with significant fetal brain abnormalities died at age 3 days.

Cranial US and brain MRI was performed on the majority of infants whose prenatal imaging had been normal.  Seven of 53 (13 percent) Zika-exposed infants had mild brain abnormalities detected by MRI after birth. In contrast, postnatal cranial US was better at detecting changes of lenticulostriate vasculopathy, cysts within the brain’s choroid plexus (cells that produce cerebrospinal fluid), germinolytic/subependymal cysts and/or calcifications, which were seen in 21 of 57 (37 percent) infants.

“Sequential neuroimaging revealed that the majority of Zika-exposed fetuses had normal brain development. Tragically, in a small number of pregnancies, Zika-related brain abnormalities were quite severe,” Dr. Mulkey adds. “Our data support the CDC’s recommendation that cranial US be performed after Zika-exposed babies are born. In addition, there is clearly a need to follow these babies over time to gauge whether the brain anomalies we see in imaging affects language, motor and social skills.”

Companion editorial: Revealing the effects of Zika

In addition to Dr. Mulkey, study co-authors include Dorothy I. Bulas, M.D., Gilbert Vezina, M.D., Margarita Arroyave-Wessel, MPH,  Stephanie Russo, B.S, Youssef A. Kousa, D.O, Ph.D., Roberta L. DeBiasi, M.D., MS, Senior Author Adré J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; Christopher Swisher, BS, Georgetown University and Caitlin Cristante, BS, Loyola University, both of  whose contributions included research performed at Children’s National; Yamil Fourzali, M.D., Armando Morales, M.D., both of Sabbag Radiologos; Liliana Encinales, M.D., Allied Research Society; Nelly Pacheco, Bacteriologa, Bio-Nep; Robert S. Lanciotti, Ph.D., Arbovirus Diseases Branch, Centers for Disease Control and Prevention; and Carlos Cure, M.D., BIOMELAB.

Research reported in this news release was supported by the IKARIA fund.

Neonatal baby

Multidisciplinary experts help CDC’s Zika research

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“We are very excited about this next phase in our Zika research,” says Roberta L. DeBiasi, M.D., M.S. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

The Centers for Disease Control and Prevention (CDC) is funding three multidisciplinary experts from the Congenital Zika Virus Program at Children’s National Health System to collaborate on two of the CDC’s longitudinal Zika research projects in Colombia, South America.

“Zika en embarazadas y niños en Colombia” (ZEN) is a research study jointly designed by Colombia’s Instituto Nacional de Salud (INS) and the CDC to evaluate the association between Zika virus infection and adverse maternal, fetal and infant health outcomes. The study is following a large cohort of Colombian women from the first trimester of pregnancy, their male partners and their infants.

Under the six-month contract, Roberta L. DeBiasi, M.D., M.S., Sarah B. Mulkey, M.D., Ph.D., and Cara Biddle, M.D., M.P.H., will serve as consultants for the ZEN study providing expertise in pediatric infectious diseases, neurology, neurodevelopment and coordination of the complex care needs of Zika-affected infants.

The federal funding will underwrite the consultants’ work effort, as well as travel to the CDC’s headquarters in Atlanta and to research sites in Colombia. To that end, Drs. DeBiasi, Mulkey and Biddle participated in a December 2017 kickoff meeting, joining ZEN team leaders based in the U.S. at the CDC, as well as the INS in Colombia, with whom they will conduct research and collaborate academically.

Cara-Biddle-and-Sarah-Mulkey

Cara Biddle, M.D., M.P.H., and Sarah B. Mulkey, M.D., Ph.D., also will serve as consultants for the ZEN study.

“We are very excited about this next phase in our Zika research,” says Dr. DeBiasi, chief of the Division of Pediatric Infectious Diseases and co-director of the Children’s Zika program. “It is a natural extension of our earlier participation as subject matter experts assisting as the CDC developed and published guidelines to inform the care of Zika-exposed and Zika-infected infants across the nation and U.S. territories.”

Children’s National is leading its own longitudinal studies in Colombia that explore such questions as whether Zika-exposed infants whose neuroimaging appears normal when they are born experience any longer-term neurological issues and the role of genetics in neurologic injury following congenital Zika virus exposure and infection.

Roberta DeBiasi and Sarah Mulkey

Children’s National experts contribute to new Zika guidelines

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Roberta DeBiasi and Sarah Mulkey

Roberta DeBiasi, M.D., M. S., and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in a forum held in Atlanta at CDC headquarters in late August to formulate new Zika recommendations.

The Centers for Disease Control and Prevention (CDC) on Oct. 19, 2017 updated guidelines for evaluation of women, fetuses and infants exposed to the Zika virus during pregnancy. Although only women with symptoms will now be routinely tested, asymptomatic and symptomatic infants born to these women will still be tested for the Zika virus using blood and urine tests.

Infants who appear normal, whose mothers either had negative Zika results or who had not undergone testing, will not undergo Zika testing. These infants still will undergo a standard evaluation, including a detailed physical exam, hearing screen and routine developmental assessments. The revised Zika guidance includes input from practitioners on the front lines of the Zika epidemic, including Children’s National Health System clinicians.

“These changes in the recommendations for Zika testing should not be interpreted as Zika infection risks subsiding for pregnant women and their infants in the United States. It’s simply an acknowledgement of the limitations of current testing methods – which must occur within a narrow window after Zika exposure – and the poor predictive value of Zika testing right now,” says Roberta L. DeBiasi, M.D., M.S., chief of Children’s Division of Pediatric Infectious Diseases. Dr. DeBiasi and Sarah B. Mulkey, M.D., Ph.D., members of Children’s multidisciplinary Congenital Zika Virus Program, were among the experts invited to participate in the Zika forum held in Atlanta at CDC headquarters in late August to formulate the recommendations.

While all infants will receive a standard evaluation, expanded evaluations that include an ophthalmologic assessment, more detailed hearing evaluation and ultrasound of the newborn’s head will be reserved for infants born to mothers confirmed to be Zika positive or Zika probable, or for infants born with abnormalities potentially consistent with congenital Zika syndrome, regardless of maternal status.

The majority of U.S. infants who have been exposed to Zika in the womb appeared normal at birth, according to CDC registries. Now, the next wave of these normal-appearing babies will receive standard evaluations when they are born, including a newborn hearing screening. At each well-child visit, these infants will receive:

  • A comprehensive physical examination
  • An age-appropriate vision screening
  • Developmental monitoring and screening using validated tools

“This is a natural evolution in the diagnosis and screening strategy now that the peak of the first wave of Zika transmission appears to be over,” Dr. DeBiasi says. “While we continue to evaluate new possible cases of Zika infection among pregnant women in our practice, a sizable proportion of Children’s cases are Zika-exposed infants whose physical exam and neuroimaging appeared normal at birth. Through ongoing monitoring, we hope to learn more about these children’s long-term neurodevelopment outcomes.”

Sarah Mulkey

Fetal MRI plus ultrasound assess Zika-related brain changes

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Sarah Mulkey

Magnetic resonance imaging and ultrasound provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero, says Sarah B. Mulkey, M.D., Ph.D.

For Zika-affected pregnancies, fetal magnetic resonance imaging (MRI) used in addition to standard ultrasound (US) imaging can better assess potential brain abnormalities in utero, according to research presented by Children’s National Health System during IDWeek 2017. In cases of abnormal brain structure, fetal MRI can reveal more extensive areas of damage to the developing brain than is seen with US.

“MRI and US provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero,” says Sarah B. Mulkey, M.D., Ph.D., a fetal/neonatal neurologist at Children’s National Health System and lead author of the research paper. “In addition, our study found that relying on ultrasound alone would have given one mother the false assurance that her fetus’ brain was developing normally while the sharper MRI clearly pointed to brain abnormalities.”

As of Sept. 13, the Centers for Disease Control and Prevention (CDC) reported that 1,901 U.S. women were exposed to Zika at some point during their pregnancies but their infants appeared normal at birth. Another 98 U.S. women, however, gave birth to infants with Zika-related birth defects.  And eight more women had pregnancy losses with Zika-related birth defects, according to CDC registries.

The longitudinal neuroimaging study led by Children’s National enrolled 48 pregnant women exposed to the Zika virus in the first or second trimester whose infection was confirmed by reverse transcription polymerase chain reaction, which detects Zika viral fragments shortly after exposure, and/or Immunoglobulin M testing, which reveals antibodies the body produces to neutralize the virus. Forty-six of the study volunteers live in Barranquilla, Colombia, where Zika infection is endemic. Two women live in the Washington region and were exposed to Zika during travel elsewhere.

All of the women underwent at least one diagnostic imaging session while pregnant, receiving an initial MRI or US at 25.1 weeks’ gestational age. Thirty-six women underwent a second MRI/US imaging pair at roughly 31 weeks’ gestation. Children’s National radiologists read every image.

Three of 48 pregnancies, or 6 percent, were marked by abnormal fetal MRIs:

  • One fetus had heterotopias (clumps of grey matter located at the wrong place) and abnormal cortical indent (a deformation at the outer layer of the cerebrum, a brain region involved in consciousness). The US taken at the same gestational age for this fetus showed its brain was developing normally.
  • Another fetus had parietal encephalocele (an uncommon skull defect) and Chiari malformation Type II (a life-threatening structural defect at the base of the skull and the cerebellum, the part of the brain that controls balance). The US for this fetus also detected these brain abnormalities.
  • The third fetus had a thin corpus callosum (bundle of nerves that connects the brain’s left and right hemispheres), an abnormally developed brain stem, temporal cysts, subependymal heterotopias and general cerebral/cerebellar atrophy. This fetal US showed significant ventriculomegaly (fluid-filled structures in the brain that are too large) and a fetal head circumference that decreased sharply from the 32nd to 36th gestational week, a hallmark of microcephaly.

After they were born, infants underwent a follow-up MRI without sedation and US. For nine infants, these ultrasounds revealed cysts in the choroid plexus (cells that produce cerebrospinal fluid) or germinal matrix (the source for neurons and glial cells that migrate during brain development). And one infant’s US after birth showed lenticulostriate vasculopathy (brain lesions).

“Because a number of factors can trigger brain abnormalities, further studies are needed to determine whether the cystic changes to these infants’ brains are attributable to Zika exposure in the womb or whether some other insult caused these troubling results,” Dr. Mulkey says.

What Children’s has learned about congenital Zika infection

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Roberta DeBiasi

Roberta DeBiasi, M.D., M.S., outlined lessons learned during a pediatric virology workshop at IDWeek2017, one of three such Zika presentations led by Children’s National research-clinicians during this year’s meeting of pediatric infectious disease specialists.

The Congenital Zika Virus Program at Children’s National Health System provides a range of advanced testing and services for exposed and infected fetuses and newborns. Data that the program has gathered in evaluating and managing Zika-affected pregnancies and births may offer instructive insights to other centers developing similar programs.

The program evaluated 36 pregnant women and their fetuses from January 2016 through May 2017. Another 14 women and their infants were referred to the Zika program for postnatal consultations during that time.

“As the days grow shorter and temperatures drop, we continue to receive referrals to our Zika program, and this is a testament to the critical need it fulfills in the greater metropolitan D.C. region,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-leader of the program. “Our multidisciplinary team now has consulted on 90 dyads (mothers and their Zika-affected fetuses/infants). The lessons we learned about when and how these women were infected and how their offspring were affected by Zika may be instructive to institutions considering launching their own programs.”

Dr. DeBiasi outlined lessons learned during a pediatric virology workshop at IDWeek2017, one of three such Zika presentations led by Children’s National research-clinicians during this year’s meeting of pediatric infectious disease specialists.

“The Zika virus continues to circulate in dozens of nations, from Angola to the U.S. Virgin Islands. Clinicians considering a strategic approach to managing pregnancies complicated by Zika may consider enlisting an array of specialists to attend to infants’ complex care needs, including experts in fetal imaging, pediatric infectious disease, physical therapists, audiologists, ophthalmologists and radiologists skilled at reading serial magnetic resonance images as well as ultrasounds,” Dr. DeBiasi says. “At Children’s we have a devoted Zika hotline to triage patient and family concerns. We provide detailed instructions for referring institutions explaining protocols before and after childbirth, and we provide continuing education for health care professionals.”

Of the 36 pregnant women possibly exposed to Zika during pregnancy seen in the program’s first year, 32 lived in the United States and traveled to countries where Zika virus was circulating. Two women had partners who traveled to Zika hot zones. And two moved to the Washington region from places where Zika is endemic. Including the postnatal cases, 89 percent of patients had been bitten by Zika-tainted mosquitoes, while 48 percent of women could have been exposed to Zika via sex with an infected partner.

Twenty percent of the women were exposed before conception; 46 percent were exposed to Zika in the first trimester of pregnancy; 26 percent were exposed in the second trimester; and 8 percent were exposed in the final trimester. In only six of 50 cases (12 percent) did the Zika-infected individual experience symptoms.

Zika infection can be confirmed by detecting viral fragments but only if the test occurs shortly after infection. Twenty-four of the 50 women (nearly 50 percent) arrived for a Zika consultation outside that 12-week testing window. Eleven women (22 percent) had confirmed Zika infection and another 28 percent tested positive for the broader family of flavivirus infections that includes Zika. Another detection method picks up antibodies that the body produces to neutralize Zika virus. For seven women (14 percent), Zika infection was ruled out by either testing method.

“Tragically, four fetuses had severe Zika-related birth defects,” Dr. DeBiasi says. “Due to the gravity of those abnormalities, two pregnancies were not carried to term. The third pregnancy was carried to term, but the infant died immediately after birth. The fourth pregnancy was carried to term, but that infant survived less than one year.”

Children’s National expert joins a national discussion on Zika and other emerging threats

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Roberta DeBiasi

“Our goal is to provide the earliest and most accurate information to women affected by Zika exposure and infection during pregnancy, including capability for fetal MRI,” says Roberta DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National Health System.

An expert roundtable discussion, “Facing the Zika Crisis and Other Emerging Threats,” organized in collaboration with Purdue University, the Gallup Organization and the Bipartisan Policy Center, was recently held at the U.S. Capitol. Chief of the Division of Pediatric Infectious Diseases and Co-Director of the Congenital Zika Program at Children’s National Health System, Roberta DeBiasi, M.D.,M.S., weighed in on the discussion, sharing knowledge on the challenges to the United States health system and the continuous research and work that the Children’s National Congenital Zika program does.

Eighteen months ago, Children’s National received its first referral for a Washington, D.C. woman who had a Zika infected pregnancy in January 2016. This case prompted the development of the Congenital Zika program to serve as a consultation resource for affected women and infants, and to perform research to address the knowledge gaps concerning Zika infection during pregnancy: Young researchers tackle Zika’s unanswered questions.

“Our goal is to provide the earliest and most accurate information to women affected by Zika exposure and infection during pregnancy, including capability for fetal MRI,” says Dr. DeBiasi.

Since then, the Zika team has evaluated 65 mother-fetus/infant pairs. Researchers are actively learning the best methods for detection of infection and neurologic injury by continually conducting research and obtaining new and useful information that can be shared with others. The research mission of the Congenital Zika program is now focusing on several areas, which include the study of biomarkers to predict if the infant could be affected by the disease, the utility of a fetal MRI in conjunction with ultrasound, genetic risk factors in mothers and infants that might explain why some infants become infected and some do not, long term neurodevelopment of babies that are infected, and neuropathologic evaluations of brains from fetuses that have died from Zika.

The challenges and concerns that were presented for the United States health system include the willingness and ability to share information, the acceptance of the need for data sharing between institutions and determining if testing resources are adequate and appropriate.

Dr. DeBiasi says, “Institutions have become much better at looking at how to prepare for emerging infectious diseases on a broader level.” Proactively thinking, Dr. DeBiasi finds it useful for health systems to use their own task forces, such as the Ebola Response Task force at Children’s National, as a cohesive existing team that will be prepared for additional infectious disease threats that may arise.

Roberta DeBiasi

Panel: Significant Zika risks linger for pregnant women and developing fetuses in US

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Roberta DeBiasi

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National Health System.

The Zika virus epidemic may have fallen off the radar for many media outlets, but significant risks continue to linger for pregnant women and developing fetuses, a panel of experts told staff working for U.S. Congressional leaders.

“The threat of this virus is real, and the threat continues,” Margaret Honein, Ph.D., M.P.H., of the Centers for Disease Control and Prevention’s (CDC) pregnancy and birth defects task force, said during the July 13 briefing held in the Russell Senate Office Building.

Dr. Honein told about 100 attendees that more than 200 Zika-affected babies have been born in the United States suffering from serious birth defects, such as rigid joints, inconsolable distress that causes them to cry continuously and difficulties swallowing. Some of these infants experience seizures that cause further brain damage.

Predicting what Zika will do next in the United States is very difficult, Dr. Honein said, adding that local outbreaks could occur “at any time.” A map she displayed showed Zika’s impact in shades of blue, with Zika infections documented in nearly every state and the highest number of infections – and deepest shade of blue­ – for California, Florida and Texas.

The threat from Zika “is not over. It is just beginning for the families who are affected by this,” agreed Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National Health System.

Since Children’s National launched its Zika program in May 2016, the multidisciplinary team has consulted on 65 mother-fetus/infant pairs, Dr. DeBiasi said. Because in utero Zika infection can result in a wide range of side effects, the Children’s team includes pediatric infectious diseases experts, fetal/neonatal neurologists to consult on seizures, audiologists to assess hearing, physical therapists and orthopaedists to contend with limb contractures, pulmonologists to relieve breathing problems and ophthalmologists to diagnose and treat vision disorders – among other specialists.

“You really need a program that has all of these areas of expertise available for a family,” Dr. DeBiasi told attendees. “It is not possible for a family to organize 27 different appointments if you have a child with these needs.”

Children’s Zika experts also collaborate with researchers in Colombia to gauge the ability of magnetic resonance imaging to produce earlier Zika diagnoses, to assess the role of viral load as biomarkers and to document Zika’s long-term impact on children’s neurodevelopment. The Colombia study has enrolled an additional 85 women/infant pairs.

In one presentation slide, Dr. DeBiasi showed sharp magnetic resonance imaging scans from their research study of a fetal brain at 18 and 22 weeks gestation that indicated clear abnormalities, including abnormal cortical folding. Ultrasound images taken at the exact same time points did not detect these abnormalities, she said.

Asked for advice by an attendee whose clinic treats women who regularly travel between California and Mexico, Dr. DeBiasi underscored the fact that Zika infection poses a risk to developing fetuses even if the pregnant woman has no symptoms of infection. “Whether or not they’re symptomatic, the risk is the same. It’s hard for people to understand that. That is No. 1,” she said.

Another challenge is for women who scrupulously follow the CDC’s guidance on lowering their infection risk while traveling. Upon return, those women may be unaware that they could still be exposed to Zika through unprotected sex with their partner who also has travelled, for as long as six months after travel.

Sarah Mulkey Columbia Zika Study

Damage may lurk in “normal” Zika-exposed brains

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Sarah Mulkey Columbia Zika Study

An international study that includes Sarah B. Mulkey, M.D., Ph.D., aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions? Dr. Mulkey presented preliminary findings at PAS2017.

It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.

Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.

Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?

“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”

According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.

“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.

Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.

“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”

As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.

The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.

Among the 48 study participants, 45 had “normal” fetal MRIs.

Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:

  • One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
  • One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
  • One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.

“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”

Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”

Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.

“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.

Drs. DeBiasi and du Plessis

Zika virus, one year later

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Drs. DeBiasi and du Plessis

A multidisciplinary team at Children’s National has consulted on 66 Zika-affected pregnancies and births since May 2016.

The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.

Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.

The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.

The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.

In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.

The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.

According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.

“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”

Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”

In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.

In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.

The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.

In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.

“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

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Youssef A. Kousa

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving  some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

Thrasher Research Fund supports Zika virus neurologic outcomes study

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The Thrasher Research Fund will fund a Children’s National project, “Neurologic Outcomes of Apparently Normal Newborns From Zika Virus-Positive Pregnancies,” as part of its Early Career Award Program, an initiative designed to support the successful training and mentoring of the next generation of pediatric researchers.

The project was submitted by Sarah B. Mulkey, M.D., Ph.D., a fetal-neonatal neurologist who is a member of the Congenital Zika Virus Program at Children’s National. During the award period, Dr. Mulkey will be mentored by Adre du Plessis, M.B.Ch.B., director of the Fetal Medicine Institute, and Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases. Drs. du Plessis and DeBiasi co-direct the multidisciplinary Zika program, one of the nation’s first.

In the award letter, the fund mentioned Children’s institutional support for Dr. Mulkey, as demonstrated by the mentors’ letter of support, as “an important consideration throughout the funding process.”

Fetal medicine update: fetal brain development, zika virus

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May 2, 2016 –Impaired global and tissue-specific brain development in the growth-restricted fetus.
A team of researchers applied an advanced imaging technique, three-dimensional MRI, to study brain development in high-risk pregnancies and are the first to report regional, tissue-specific volume delays for the developing fetal brain in FGR-affected pregnancies. The team compared overall fetal brain volume as well as regional brain volumes for a control group of healthy young pregnant women with a group of young women whose pregnancies were complicated by FGR. While fetuses in both groups grew exponentially as pregnancies progressed, the researchers began to see dramatic differences when they compared the volumes of specific regions of the brain, including the cerebellum, which coordinates balance and smooth movement; the deep gray matter, which also is involved in complex functions, such as memory and emotion; and the white matter, which is made up of millions of nerve fibers that connect to neurons in different regions.

March 30, 2016 – Congenital Zika viral infection linked to significant fetal brain abnormalities, despite ‘normal’ ultrasounds.
Infectious Zika virus was isolated from the brain of a 21-week-old fetus after causing extensive damage to brain tissue – despite ultrasounds that showed no sign of microcephaly at weeks 13, 16, and 17, according to a report published online in The New England Journal of Medicine. “While this is a single case, it poses troubling questions that could inform future research,” says the study’s co-senior author, Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute and Chief of the Fetal and Transitional Medicine Division at Children’s National Health System. “Evidence is mounting that the Zika virus can persist in pregnant women’s bloodstreams weeks after their initial infection, arguing for changes to how these pregnancies are monitored,” Dr. du Plessis said. Six of the named authors are affiliated with Children’s National, where the pregnant woman sought more thorough assessment after testing positive for the Zika virus herself following international travel.

Congenital Zika Viral Infection Linked to Significant Fetal Brain Abnormalities

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mosquito

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What’s Known
According to the Centers for Disease Control and Prevention, Zika viral transmission is occurring extensively throughout Central and South America. Like other mosquito-borne viruses, Zika virus can be passed by pregnant women to developing fetuses. Unlike these other viruses, Zika has been implicated in a growing number of cases of Brazilian infants born with microcephaly, a condition characterized by undersized heads and severe brain damage. The precise strategy that the Zika virus uses to elude the immune system and the reason why fetal brain cells are particularly vulnerable remain unknown.

What’s New
A 33-year-old Finnish woman was 11 weeks pregnant when she and her husband traveled on vacation to Mexico, Guatemala, and Belize in late November 2015. The pair was bitten by mosquitoes during their trip, particularly in Guatemala. One day after returning to their Washington, DC home, the woman got sick, experiencing eye pain, muscle pain, a mild fever, and a rash. A series of early ultrasounds showed no sign of microcephaly or brain calcifications. A fetal ultrasound at the 19th week and a fetal MRI at the 20th week, however, revealed severe brain damage.

The brain of the 21-week-old aborted fetus weighed only 30 grams. Zika RNA, viral particles, and infectious virus were detected, and Zika virus isolated from the fetal brain remained infectious when tested. The concentration of virus was highest in the fetal brain, umbilical cord, and placenta. The mother remained infected with Zika virus at 21 weeks, some 10 weeks after her initial infection.

Questions for Future Research

  • Could serial measurements and blood tests more accurately detect and, ultimately, predict fetal abnormalities following Zika virus infection?
  • Why does the Zika virus replicate with ease within the womb?
  • At which stage of pregnancy are fetuses most vulnerable?
  • Which specific brain cells does Zika target?

Source: “Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities.” R.W. Driggers, C.Y. Ho, E.M. Korhonen, S. Kuivanen, A.J. Jääskeläinen, T. Smura, D.A. Hill, R. DeBiasi, G. Vezina, J. Timofeev, F.J. Rodriguez, L. Levanov, J. Razak, P. Iyengar, A. Hennenfent, R. Kennedy, R. Lanciotti, A. du Plessis, and O. Vapalahti. The New England Journal of Medicine. June 2, 2016.
Drs. DeBiasi and du Plessis

Suspected domestic zika virus infection in Florida underscores the importance of ongoing vigilance

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Drs. DeBiasi and du Plessis

Federal health officials continue to investigate the first possible cases of domestic Zika virus transmission in Florida. In light of the growing number of Zika infections, the vast majority of which have been associated with foreign travel, vigilance for additional cases is warranted – particularly as summer heat intensifies and mosquito populations grow. The Centers for Disease Control and Prevention (CDC) now advises that all pregnant women in the continental United States and U.S. territories be evaluated for Zika infection at each prenatal care visit. The CDC also recognizes that Zika-exposed infants will require long-term, multidisciplinary care.

In mid-May, Children’s National Health System Fetal Medicine Institute and Division of Pediatric Infectious Disease announced the formation of a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and for pregnant women to receive counseling and science-driven answers about the impact of the Zika virus on pregnancies and newborns. Children’s clinicians have consulted on 30 pregnancies or births with potential Zika virus exposure and/or infection. As of Aug. 31, eight were Zika-positive or probable. One of the pregnancies was the subject of an article published by The New England Journal of Medicine.

”While we’re hopeful there are few local cases, the Congenital Zika Virus Program has been developing emergency response plans in collaboration with local departments of health to prepare for any eventuality,” says Roberta DeBiasi, MD, MS, Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader.

Over the years, Children’s National has invested in equipment and highly trained personnel, building world-class expertise in infectious diseases, pediatric neurology, pediatric cardiology, genetics, neurodevelopment, and other specialties. Children’s clinicians are recognized leaders in next-generation imaging techniques, such as fetal MRI, which detects more subtle and earlier indications of impaired brain growth. A variety of divisions work together to offer multidisciplinary support and coordinated care to infants born with special needs. As the nation braces for the possible expansion of Zika virus infection to other states, Children’s National is facilitating the multi-step process of testing blood, urine, and tissue with state health departments, helping to ensure timely and precise information. Children’s National specialists guide Zika-affected pregnancies through the fetal period and are able to oversee and coordinate the care of Zika-affected infants after delivery. Care and clinical support is provided by a multidisciplinary team of pediatric neurologists, ophthalmologists, audiologists, physical and occupational therapists, infectious disease experts, and neurodevelopmental physicians.

The Children’s National multidisciplinary team includes:

  • Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute, Chief of the Fetal and Transitional Medicine Division, and Congenital Zika Virus Program co-leader;
  • Roberta DeBiasi, M.D., M.S., Chief of the Division of Infectious Disease and Congenital Zika Virus Program co-leader;
  • Cara Biddle, M.D., M.P.H., Medical Director, Children’s Health Center, and a bilingual expert on complex care;
  • Dorothy Bulas, M.D., Radiologist in the Division of Diagnostic Imaging and Radiology;
  • Taeun Chang, M.D., Director, Neonatal Neurology Program in the Division of Neurophysiology, Epilepsy and Critical Care Neurology;
  • Sarah Mulkey, M.D., Ph.D., Fetal-Neonatal Neurologist, Fetal Medicine Institute;
  • Lindsay Pesacreta, M.S., F.N.P.-B.C., Board-Certified Family Nurse Practitioner; and
  • Gilbert Vezina, M.D., attending Radiologist in the Division of Diagnostic Imaging and Radiology and Director of the Neuroradiology Program.

Related Resources: Research at a Glance | Guidelines for Referring Clinicians
[Updated Sept. 13, 2016]

New program provides science-driven answers about zika virus’s impact on pregnancies

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Drs. DeBiasi and du Plessis

Each week, as temperatures rise, the likelihood increases that the United States will experience domestic Zika virus transmission. Indeed, such domestic Zika transmission already is occurring in Puerto Rico and the U.S. Virgin Islands. The Children’s National Health System Fetal Medicine Institute and Division of Pediatric Infectious Disease announced the formation of a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and for pregnant women to receive counseling and science-driven answers about the impact of the Zika virus on their pregnancies.

Over years, Children’s National has invested in equipment and highly trained personnel, building expertise in infectious diseases, pediatric neurology, pediatric cardiology, genetics, neurodevelopment, and other specialties. Children’s clinicians are recognized as national leaders in next-generation imaging techniques, such as fetal MRI, and a variety of divisions work together to offer multidisciplinary support and coordinated care to infants born with special needs. As the nation prepares for the Zika virus, Children’s National is facilitating the multi-step process of blood testing, helping to ensure timely and precise information. Children’s National specialists are able to guide Zika-affected pregnancies through the fetal period and can oversee the care of Zika-affected infants after delivery. Care and clinical support is provided by a multidisciplinary team of pediatric neurologists, physical therapists, infectious disease experts, and neurodevelopmental physicians.