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Vanessa van der Linden has spent the past year caring for patients at the heart of Brazil’s Zika epidemic. She works at Barão de Lucena Hospital, in Recife. And many symptoms in her youngest patients worry her.
As a pediatric neurologist, Van der Linden specializes in children’s brains and nervous systems. And she was one of the first researchers to link the Zika virus to a birth defect known as microcephaly (My-kroh-SEFF-uh-lee). The term means “small head.” Afflicted babies are born with heads that are misshapen and smaller than normal. Sometimes their foreheads slope backward.
In the past year, microcephaly has emerged as the most common birth defect linked to Zika . But a host of other symptoms may also show up. Van der Linden has seen babies that cry for 24 hours straight. Some experience muscle spasms, extreme irritability and difficulty swallowing.
Emerging research now indicates that microcephaly is far from the only worry that parents of Zika-exposed children may face. Van der Linden described the growing list of health risks on September 22 at a workshop hosted by the National Institutes of Health in North Bethesda, Md.
Right now, no one knows how big the full problem is, says Peter Hotez. He is a pediatrician and microbiologist at Baylor College of Medicine in Houston, Tex. “That’s the big unknown,” he says. “There’s probably a spectrum of illness,” similar to autism, he says. And some symptoms, such as learning disabilities or developmental delays, might take years to emerge. Public health officials have been warning for months that exposure to the virus during pregnancy might be linked to even more Zika problems. Those health impacts now appear to comprise a list that affects the body from head to toe. Doctors have begun calling it congenital Zika syndrome.
Brazil is facing this challenge now. Zika also presents a growing threat in the U.S. territory of Puerto Rico. As of September 23, Puerto Rico reported 22,358 confirmed Zika infections, including 1,871 pregnant women.
Carmen Zorrilla works at the University of Puerto Rico’s Maternal-Infant Studies Center in San Juan. This obstetrician-gynecologist has examined some of these women and their babies. She now argues that it is essential that the medical community watch all babies exposed to Zika in the womb — including those with no visible birth defects.
Even when they look healthy at birth, she says, “it doesn’t mean they’ll be okay [later].”
A parade of problems
Zorrilla’s concern comes from a growing list of problems being linked to the virus. At the workshop, she described one of the first Puerto Rican babies born to a mother diagnosed with Zika. The baby didn’t have microcephaly. She did have one unusual problem, however: This newborn could not open her eyes.
A bad case of pinkeye, also known as conjunctivitis (Kon-JUNK-tih-VY-tus), left the baby unable to open her eyelids each morning on her own — even 27 days after birth!
Zorrilla can’t say for sure whether the problem was related to Zika. But “it really concerned me,” she said. “This is the first baby I’ve seen with conjunctivitis that lasted for so long.” The case may be a clue that Zika’s harm to the body is widespread.
Alberto de la Vega is another obstetrician-gynecologist at the University of Puerto Rico. Zorilla shared his early results from ultrasound scans of 228 pregnant women in Puerto Rico. Each had a confirmed Zika infection. Those scans turned up brain abnormalities in 13 fetuses. One of those babies had microcephaly. Most of the rest had somewhat small heads, although “still within the normal limits,” Zorrilla said. Fetal measurements of the leg bones and stomach show that the rest of the body was growing normally. For now, she says, it isn’t yet clear what these findings mean.
Other scientists have begun linking new symptoms to Zika infections in the womb. For some affected babies, Zika seems to have hurt their hearing. Among 70 Zika-exposed infants with microcephaly, one in every 10 had some hearing loss. The U.S. Centers for Disease Control and Prevention (CDC), in Atlanta, Gal., shared the disturbing statistic in a September 2 report.
Zika also can affect the eyes. Researchers studied 29 Brazilian babies with microcephaly. More than one in every three had some eye oddity. Impacts ranged from patchy pigments (coloring) to withered tissue. Bruno de Paula Freitas and his colleagues described these eye problems in the May issue of JAMA Ophthalmology.
Van der Linden has also seen a deformity called arthrogryposis (ARTH-roh-GRIP-oh-sis). It can leave a child’s with “contractures” — joints stuck in contorted positions. Their arms and legs, for instance, may not bend normally. It has shown up even in babies without microcephaly. She and her colleagues now suspect that it might trace to the virus infecting the babies’ motor neurons. These are the nerve cells that relay messages from the brain to the muscles. They reported this finding August 9 in BMJ.
Microcephaly or other brain defects may eventually develop even in babies born with normal size heads. Van der Linden saw one mother who brought in her five-month-old. She was worried that her baby wasn’t developing normally. Scans of the baby’s head showed “the same pattern of brain damage” as seen in children with congenital Zika syndrome, van der Linden reports. This included a malformed cerebral cortex, which is the wrinkled outer layer of the brain. The brain also contained strange lumps of calcium. These are known as calcifications.
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Invading the brain
Scientists still don’t know exactly how Zika damages the brain. But they have some ideas.
Marco Onorati is a brain scientist at Yale University in New Haven, Conn. He and his colleagues found that the virus can invade and kill two important types of brain cells. One type is known as neuroepithelial (NEUR-oh-ep-ih-THEE-lee-ul) stem cells. These can develop into many different types of brain cells.
Radial glial cells are a second type of brain cell that Zika can kill. Their loss is important because these cells in a newborn can make nerve cells, or neurons. These cells also help guide those nerve cells to their proper places in the brain.
Zika also blocks the radial glial cells from splitting into new cells. The Yale scientists described their disturbing findings September 6 in Cell Reports.
Stem cells and new neurons are crucially important in the brain of a developing baby, says Hotez, the Baylor pediatrician. These cells build the structures responsible for thought and learning and memory. As such, he concludes, “This is a virus that blocks the development of the fetal brain.” And that, he adds, is “about the worst thing you can possibly imagine.”
But the unborn might not be the only children at risk, he notes. “Kids in the first years of life also have growing, developing brains,” he points out. “What if they get infected with Zika?”
It’s not an easy question to answer. But another disease does offer clues.
Like Zika, malaria is another mosquito-borne disease that affects many parts of the body. In children, a condition called cerebral (Seh-REE-brul) malaria may be linked to mental health diseases. These include attention-deficit/hyperactivity disorder, antisocial behavior and depression. Researchers described these disorders, last March, in Malaria Journal.
So researchers will need to scout for long-term troubles even in Zika-exposed babies who had no obvious symptoms at birth. “We don’t want to make families too scared,” says Sonja Rasmussen, who works of the CDC. “But we do recognize the possibility of later-on seizures or developmental delay.” Seizures are uncontrolled electrical fireworks in the brain. Developmental delays refer to slower than normal acquisition of pivotal skills by children. These may range from crawling and speaking to playing, learning to read and more.
For an example of such delayed effects, researchers can look at another often-hidden viral infection that causes microcephaly. It’s known as CMV, which is short for cytomegalovirus (Sy-toh-MEG-uh-low-VY-rus). As with Zika, it can infect babies in the womb. Most CMV-infected babies show no symptoms. But even kids who at first appear fine may develop problems in coming years. These may include intellectual disabilities, hearing loss or cerebral palsy. Researchers in Japan described these long-term effects of fetal CMV infections in the October Brain and Development.
Most people infected with Zika don’t show any visible signs. This makes it nearly impossible to know how many pregnant women (and their babies) might have been infected.
In the Americas, at least, the number is likely to be enormous. Indeed, Hotez at Baylor predicts that tens of thousands of children may eventually suffer some sort of brain or behavioral illness triggered by Zika. He described these concerns in the August issue of JAMA Pediatrics.
Van der Linden can’t say whether the babies she has seen will develop learning disabilities, mental illnesses or other more subtle problems associated with brain processing. Right now, most of her patients are still between 9 months and a year old. But she plans to follow them for years. “We need time to better understand the disease,” she points out.
Hotez agrees. To figure this out, he predicts, it’s going to take a generation of pediatric brain specialists and infectious disease experts.
attention deficit hyperactivity disorder (ADHD) This is a disorder characterized by not being able to focus or pay attention, being physically overactive, not being able to control behavior, or a combination of these.
autism (also known as autism spectrum disorders ) A set of developmental disorders that interfere with how certain parts of the brain develop. Affected regions of the brain control how people behave, interact and communicate with others and the world around them. Autism disorders can range from very mild to very severe. And even a fairly mild form can limit an individual’s ability to interact socially or communicate effectively.
behavior The way a person or other organism acts towards others, or conducts itself.
calcium A chemical element which is common in minerals of the Earth’s crust and in sea salt. It is also found in bone mineral and teeth, and can play a role in the movement of certain substances into and out of cells.
cell The smallest structural and functional unit of an organism. Typically too small to see with the naked eye, it consists of watery fluid surrounded by a membrane or wall. Animals are made of anywhere from thousands to trillions of cells, depending on their size. Some organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.
Centers for Disease Control and Prevention (CDC) An agency of the U.S. Department of Health and Human Services, CDC is charged with protecting public health and safety by working to control and prevent disease, injury and disabilities. It does this by investigating disease outbreaks, tracking exposures by Americans to infections and toxic chemicals, and regularly surveying diet and other habits among a representative cross-section of all Americans.
cerebral cortex The outermost layer of neural tissue covering the front part of a vertebrate animal’s brain.
cerebral palsy A group of disorders that affect someone’s ability to move. It stems from damage to the developing brain during pregnancy, at birth or shortly thereafter. Symptoms can include poor muscle coordination, loss of muscle tone (strength), poor reflexes and balance. The disease has no cure, but its effects can improve or worsen as someone ages. Some patients also may have other brain impairments that affect speech, hearing, sight and more.
colleague Someone who works with another; a co-worker or team member.
congenital A term that refers to conditions that are present from birth, either because they were inherited or occurred as a fetus developed in the womb.
conjunctivitis (or pinkeye) An irritation or inflammation of the conjunctiva — the outermost layer of the white part of the eye — and sometimes the inner surface of the eyelid. It can be caused by bacteria, viruses or by allergies. The type caused by germs can be very contagious.
contractures Symptoms of a syndrome that include a shortening and hardening of muscles, tendons or other tissues. Affected individuals may develop structural deformities and a rigidity of their joints.
control A part of an experiment where there is no change from normal conditions. The control is essential to scientific experiments. It shows that any new effect is likely due only to the part of the test that a researcher has altered. For example, if scientists were testing different types of fertilizer in a garden, they would want one section of it to remain unfertilized, as the control. Its area would show how plants in this garden grow under normal conditions. And that give scientists something against which they can compare their experimental data.
cytomegalovirus A virus related to the germs that cause chickenpox and infectious mononucleosis (also known as mono). At least half of American adults will have become infected by age 40. There is no cure. The germ spreads through close contact with another person’s bodily fluids, such as saliva, blood, urine and breast milk. People who become infected as adults usually develop no symptoms and therefore don't realize they are infectious to others. But in babies and people with weak immune systems, this virus can cause fever, pneumonia, seizures, a rash or blotchy skin, blindness or coma.
depression A mental illness characterized by persistent sadness and apathy. Although these feelings can be triggered by events, such as the death of a loved one or the move to a new city, that isn’t typically considered an “illness” — unless the symptoms are prolonged and harm an individual’s ability to perform normal daily tasks (such as working, sleeping or interacting with others). People suffering from depression often feel they lack the energy needed to get anything done. They may have difficulty concentrating on things or showing an interest in normal events. Many times, these feelings seem to be triggered by nothing; they can appear out of nowhere.
development (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape. (in economics and social sciences) The conversion of land from its natural state into another so that it can be used for housing, agriculture, or resource development.
developmental (in biology) An adjective that refers to the changes an organism undergoes from conception through adulthood. Those changes often involve chemistry, size and sometimes even shape.
disorder (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.
epidemic A widespread outbreak of an infectious disease that sickens many people (or other organisms) in a community at the same time. The term also may be applied to non-infectious diseases or conditions that have spread in a similar way.
generation A group of individuals born about the same time or that are regarded as a single group. Your parents belong to one generation of your family, for example, and your grandparents to another. Similarly, you and everyone within a few years of your age across the planet are referred to as belonging to a particular generation of humans. The term also is sometimes extended to year classes or types of inanimate objects, such as electronics or automobiles.
gynecologist A doctor who specializes in the women’s health, especially the health of women’s reproductive organs.
infection A disease that can spread from one organism to another. It’s usually caused by some sort of germ.
infectious An adjective that describes a type of germ that can be transmitted to people, animals or other living things.
journal (in science) A publication in which scientists share their research findings with the public. Some journals publish papers from all fields of science, technology, engineering and math, while others are specific to a single subject. The best journals are peer-reviewed: They send out all submitted articles to outside experts to be read and critiqued. The goal, here, is to prevent the publication of mistakes, fraud or sloppy work.
malaria A disease caused by a parasite that invades the red blood cells. The parasite is transmitted by mosquitoes, largely in tropical and subtropical regions.
microcephaly A condition that leaves babies with abnormally small heads and partially developed brains.
motor (in medicine) An adjective for things having to do with movement.
muscle A type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in a protein, which is why predatory species seek prey containing lots of this tissue.
National Institutes of Health (or NIH) This is the largest biomedical research organization in the world. A part of the U.S. government, it consists of 21 separate institutes — such as the National Cancer Institute and the National Human Genome Research Institute — and six additional centers. Most are located on a 300 acre facility in Bethesda, Md., a campus containing 75 buildings. The institutes employ nearly 6,000 scientists and provide research funding to more than 300,000 additional researchers working at more than 2,500 other institutions around the world.
nerve A long, delicate fiber that communicates signals across the body of an animal. An animal’s backbone contains many nerves, some of which control the movement of its legs or fins, and some of which convey sensations such as hot, cold, pain.
nervous system The network of nerve cells and fibers that transmits signals between parts of the body.
neuron The impulse-conducting nerve cells that make up the brain, spinal column and nervous system.
obstetrics A field of medicine that deals with birth and women during the process of childbirth. Doctors who work in this field are known as obstetricians.
pediatrics A field of medicine that has to do with children and especially child health. A doctor who works in this field is known as a pediatrician.
pigment A material, like the natural colorings in skin, that alter the light reflected off of an object or transmitted through it. The overall color of a pigment typically depends on which wavelengths of visible light it absorbs and which ones it reflects. For example, a red pigment tends to reflect red wavelengths of light very well and typically absorbs other colors. Pigment also is the term for chemicals that manufacturers use to tint paint.
range The full extent or distribution of something. For instance, a plant or animal’s range is the area over which it naturally exists. (in math or for measurements) The extent to which variation in values is possible. Also, the distance within which something can be reached or perceived.
risk The chance or mathematical likelihood that some bad thing might happen. For instance, exposure to radiation poses a risk of cancer. Or the hazard — or peril — itself. Among cancer risks that the people faced were radiation and drinking water tainted with arsenic.
seizure A sudden surge of electrical activity within the brain. Seizures are often a symptom of epilepsy and may cause dramatic spasming of muscles.
stem cell A “blank slate” cell that can give rise to other types of cells in the body. Stem cells play an important role in tissue regeneration and repair.
subtle Some feature that may be important, but can be hard to see or describe. For instance, the first cellular changes that signal the start of a cancer may be visible but subtle — small and hard to distinguish from nearby healthy tissues.
symptom A physical or mental indicator generally regarded to be characteristic of a disease. Sometimes a single symptom — especially a general one, such as fever or pain — can be a sign of any of many different types of injury or disease.
syndrome Two or more symptoms that together characterize a particular disease, disorder or social condition.
tissue Any of the distinct types of material, comprised of cells, which make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues. And brain tissue will be very different from bone or heart tissue.
ultrasound (adj. ultrasonic) Sounds at frequencies above the range that can be detected by the human ear. Also the name given to a medical procedure that uses ultrasound to “see” within the body.
virus Tiny infectious particles consisting of RNA or DNA surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as live or dead, in fact no virus is truly alive. It doesn’t eat like animals do, or make its own food the way plants do. It must hijack the cellular machinery of a living cell in order to survive.
womb Another name for the uterus, the organ in mammals in which a fetus grows and matures in preparation for birth.
Zika A viral disease that can be transmitted to humans via mosquitoes. About 20 percent of infected people get sick. Symptoms include a slight fever, rash and pinkeye and usually fade quickly. A growing body of evidence suggests that the virus could also cause a devastating birth defect — microcephaly. Evidence suggests it may also cause neurological conditions such as Guillain-Barré syndrome.
Journal: M. Uematsu et al. Asymptomatic congenital cytomegalovirus infection with neurological sequelae: a retrospective study using umbilical cord. Brain & Development. Vol. 38, October 2016. doi: 10.1016/j.braindev.2016.03.006.
Meeting: V. van der Linden. Clinical manifestations and complications of congenital ZIKV infection in Brazilian infants and the evaluation, monitoring, and treatment currently used. Bridging Knowledge Gaps to Understand How Zika Virus (ZIKV) Exposure and Infection Affect Child Development. September 22-23, 2016. North Bethesda, Md.
Meeting: C. Zorrilla. Case examples of infants exposed to ZIKV. Bridging Knowledge Gaps to Understand How Zika Virus (ZIKV) Exposure and Infection Affect Child Development. September 22-23, 2016. North Bethesda, Md.
Journal: M. Onorati et al. Zika virus disrupts phospho-TBK1 localization and mitosis in human neuroepithelial stem cells and radial glia. Cell Reports. Vol. 16, September 6, 2016, p. 2576. doi: http://dx.doi.org/10.1016/j.celrep.2016.08.038.
Journal: M.C. Leal et al. Hearing loss in infants with microcephaly and evidence of congenital Zika virus infection — Brazil, November 2015–May 2016. Morbidity and Mortality Weekly Report, Vol. 65, September 2, 2016, p. 917. doi: 10.15585/mmwr.mm6534e3.
Journal: V. van der Linden et al. Congenital Zika syndrome with arthrogryposis: retrospective case series study. BMJ. Vol. 354, August 9, 2016, p. i3899. doi: 10.1136/bmj.i3899.
Journal: P.J. Hotez. What does Zika virus mean for the children of the Americas? JAMA Pediatrics. Vol. 170, August 2016. doi: 10.1001/jamapediatrics.2016.1465.
Journal: B. de Paula Freitas et al. Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmology. Vol. 134, May 2016, p. 529. doi: 10.1001/jamaophthalmol.2016.0267.
Journal: R. Idro et al. Cerebral malaria is associated with long-term mental health disorders: a cross sectional suvey of a long-term cohort. Malaria Journal. Vol. 15, March 31, 2016, p. 184. doi: 10.1186/s12936-016-1233-6.