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Fetal Antecedents of Cerebral Palsy

Fetal Antecedents of Cerebral Palsy. Sidhartha Tan Clinical Professor Department of Pediatrics. Definition. Cerebral palsy (CP) describes a group of permanent disorders of the development of movement and posture, causing activity limitation,

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Fetal Antecedents of Cerebral Palsy

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  1. Fetal Antecedents of Cerebral Palsy Sidhartha Tan Clinical Professor Department of Pediatrics

  2. Definition Cerebral palsy (CP) describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. Dev Med Child Neurol Suppl. 2007;109:8-14.

  3. Cerebral Palsy

  4. Cerebral Palsy

  5. Cerebral Palsy Our beautiful and precious Christopher Dylan was born on December 3, 2001. Christopher was not breathing when he was born, and was revived. He suffered acute oxygen loss, and as a result his brain was globally damaged. Christopher is unable to walk, speak, eat, or purposefully move or communicate. It is a struggle each and every day for him to breathe and experience normal bodily functions. Christopher was not supposed to have survived this long, however, with much love and care, he has physically thrived. Although he has little brain function, his organs are healthy. He has fought to stay alive, and we fight for him and pray for stem cell developments during his lifetime.

  6. Cerebral Palsy • 2-3 per 1,000 newborn babies • About 10,000 babies born every year in USA • Cost in 2002 for USA patients $ 8.2 billion • Over 800,000 Americans are impacted by Cerebral Palsy (CP) • Average cost $ 921,000 (2003) per CP patient in a lifetime

  7. CP PD • Life long consequences • Burden on individual • Burden on society • Burden of disease: loss of years, loss of productive years, effort of caretakers effect on siblings Onset 55-60 yr $ 6 billion $ 8.2 billion 500,000 800,000 $ 22 million $ 250 million FUNDING FROM NIH

  8. Legal Quagmire CerebralPalsy.org 4MyChild.com cerebralpalsysource.com cerebralpalsyinfo.org

  9. A Malpractice Lawyer’s View of Medical Science • something will go wrong with the birthing process, possibly causing disabilities like cerebral palsy in the child. There are undoubtedly all types of risks involved in childbirth, • When injury does occur during the birthing process, the results can be devastating. Medical mistakes are the cause of thousands of cerebral palsy cases. • Here are a few mistakes made during delivery that mean the medical team could be at fault, and a cerebral palsy lawyer is needed. • Leaving the child in the birth canal too long can result in hypoxia, or lack of oxygen to the brain, which causes cerebral palsy. Hypoxia can also be caused by the failure to detect a prolapsed umbilical cord, where it wraps around the neck of the child. Failure to perform a cesarean section in the event of fetal distress leaves the fetus in the birth canal too long where hypoxia can occur as well. In the case of a large birth weight infant, a c-section should be planned ahead of time. • During delivery, failure to respond to the mothers changing conditions, such as high blood pressure or toxemia, can affect the baby. • Failure to recognize and treat seizures following delivery could cause irreversible damage to the newborn. • Although medical malpractice is only the cause of cerebral palsy during a moderate percentage of cases, you have the right to know if your child’scerebral palsy was preventable.

  10. Remaining Pregnancy There has been a societal presumption that most, if not all, cases of hypoxic ischemic encephalopathy-induced cerebral palsy occur during the 3 hours that are related to the events of labor and delivery; society has tended to overlook the remaining 7000 hours of the pregnancy . Phelan et al, Clinics in Perinatology 32 (2005) 61– 76

  11. Timing of Injury Resulting in Cerebral Palsy • Most of the Injury is before birth ~70% • Birth Injury is only a fraction, 5-10% • Injury after birth, 10%

  12. Timing of Injury Resulting in Neonatal Encephalopathy Adapted from Badawi et al BMJ 1998, 317:1554-8

  13. Black Box of Fetal Brain I don’t want my private parts examined!

  14. Timing is Everything Donna Ferriero • Normal animals grow bigger • Some cells normally die and need to die • Vulnerable time periods • Insult at one time point? • Study dynamic change by non-invasive testing • Intervention as early as possible

  15. Inciting Event Single knockout punch Repeated episodes Dosage of stress Synergistic episodes

  16. Can we diagnose oxygen deficiency to fetal brain? NO Can we prevent oxygen deficiency to fetal brain? NO Can we treat oxygen deficiency to fetal brain?

  17. Fetal Distress • Non-reassuring fetal heart rate pattern • Intermittent auscultation • Continuous electronic fetal heart rate monitor • Continuous monitoring does not decrease the incidence of cerebral palsy

  18. Laennec’s discovery of Stethoscope 1816 Laennec Listening to the Chest of a Patient (c 1910) by Ernest Board

  19. Hippocrates 350 BC

  20. Timing of Antenatal Events • Fetal heart rate • Computer based algorithms • Fetal pH, base deficit • Fetal pulse oximetry • Fetal ST waveform analysis • Near infrared spectroscopy • Nucleated cord blood cells • Lactate • Oxidative stress markers • Activin • S100

  21. Why We Need Better Markers • Despite improvements in perinatal practice during the past several decades, the incidence of cerebral palsy (CP) has remained essentially unchanged. • 25-70% of CP is antenatal • Biophysical profile is inversely related to CP • Many cases of CP have no FHR abnormalities • Unexplained stillbirths • Fetal growth restriction increases CP

  22. Advances in Obstetrics • The use of electronic fetal heart rate monitoring to detect fetal distress • Emergency C-section for patients with fetal distress has not decreased the incidence of CP. • Unfortunately neither of these tell anything about fetal brain function

  23. Epidemiological Study of CP • Spastic quadriplegic or dyskinetic CP “are the only types of cerebral palsy associated with acute hypoxic intrapartum events” according to ACOG. • 6,145,357 deliveries reviewed in California from 1991 to 2001 from 3 large databases. • 8,946 CP cases – 1.45 per 1000. • 7,242 were spastic quadriplegic or dyskinetic CP (81%) – 1.18 per 1000. Gilbert et al, Am J Obstet Gynecol 2010;203:328.e1-5.

  24. Demographic Risk for CP • CP patients identified by encounter in a database and birth records then linked. • Increased risk for demographic factors: • Maternal age >40 • Increasing parity • Non-Hispanic Whites in preterm group. • Limitations: adminstrative databases, no chart review, low Apgar score and HIE not available. Gilbert et al, Am J Obstet Gynecol 2010;203:328.e1-5.

  25. Pregnancy Risk for CP Not Found • Chronic hypertension • Preeclampsia • Pregestational diabetes • Gestational diabetes in preterm deliveries.

  26. Pregnancy Risk for CP • Gestational diabetes in term 1.19 (OR 1.03-1.37) • Maternal infection in term (25.6% CP vs 10.3% controls). • Maternal infection in preterm (9.0% vs 6.2%) • Neonatal infection in term (1.9% vs 0.3%) • Neonatal infection in preterm (0.3 vs 0.05).

  27. Perinatal Causes • Six adverse events were identified that were likely to be associated with CP • Placental abruption in term (2.4 vs 0.5%) • Abruption in preterm (10.8 vs 3.8%) • Uterine rupture during labor in term (1.0 vs 0.06%) • Uterine rupture in preterm (0.2 vs 0.07%). • Fetal Distress in term (19.4 vs 7.7%) • Fetal Distress in preterm (20.6 vs 8.6%)

  28. Perinatal Causes • Birth trauma in term (8.1 vs 4.9%) • Birth trauma in preterm (7.2 vs 4.0%) • Cord prolapse in term (1.2 vs 0.2%) • Cord prolapse in preterm (2.2 vs 0.6%). • Birth asphyxia in term (6.3 vs 0.4%) • Birth asphyxia in preterm (4.6 vs 0.8%)

  29. Any of 6 Events • Placental abruption, uterine rupture, fetal distress, birth trauma, cord prolapse, birth asphyxia • In term (28.3 vs 12.7%) • In preterm (36.8 vs 15.9%)

  30. Non reassuring fetal status Acute intrapartum hypoxic event

  31. Summary • Intrapartum events do not explain the majority of CP. The legal climate has somewhat skewed medical terminology. • Postnatal events are also not an explanation. • Majority of events are probably antenatal. • As long as we are unable to monitor the status of the fetal brain, we can only guess as to the cause. • “Straw that broke the camel’s back”. We tend to focus on the straw.

  32. No, seriously. I am in Medical Research. Cutting edge stuff.

  33. Why Rabbit?

  34. Brain Development in Mammals Cetacea Prenatal Artiodactyla Perissodactyla Carnivora Pangolins Bats Hedgehogs/Shrews Insectivora Moles Cavies/Nutrias Porcupines Postnatal Mice / Rats Rodentia Beavers Glires Chipmunks Perinatal Rabbits Prenatal Primates Topaias Sloths Xenarthra Anteaters Armadillos Manatees Elephants Hyraxes Tenrecs Aardvarks Murphy WJ et al, NATURE 409:614-618, 1 Feb 2001 | Elephant shrews Marsupials

  35. Humans: Perinatal Developers Prolonged development 1-2 years for CP to develop

  36. Timing is Everything! Cetacea Ante-, Postnatal Artiodactyla Perissodactyla Carnivora Pangolins Bats Hedgehogs/Shrews Insectivora Moles Cavies/Nutrias Porcupines Postnatal Mice / Rats Rodentia Beavers Glires Chipmunks Antenatal Rabbits Antenatal Primates Topaias Sloths Xenarthra Anteaters Armadillos Manatees Elephants Hyraxes Tenrecs Aardvarks Elephant shrews Marsupials

  37. Timing is Everything ! Cetacea ? Antenatal Artiodactyla Perissodactyla Carnivora Pangolins Bats Hedgehogs/Shrews Insectivora Moles Cavies/Nutrias Porcupines Subtle Postnatal Mice / Rats Rodentia Beavers Glires Chipmunks CP phenotype Antenatal Rabbits Moderate motor Antenatal Primates Topaias Sloths Xenarthra Anteaters Armadillos Manatees Elephants Hyraxes Tenrecs Aardvarks Elephant shrews Marsupials

  38. Xanthine Oxidase Xanthine Uric acid O2 H2O2 • Circulating xanthine oxidase is very high ~5 mU/ml in rats and mice • Rabbits are like humans, low circulating xanthine oxidase

  39. Oligodendroglial Development Fimbria fornix Buser et al, J Cereb Blood Flow Metab 2010 May;30(5):1053-65.

  40. Rabbits vs Rodents • Circulating xanthine oxidase similar to humans • Perinatal development, especially for white matter • Definite hypertonia by fetal hypoxia • Movement disorders found by LPS injection • High levels in rodents • Postnatal • Half of the brain can infarct with no or subtle behavioral abnormalities

  41. Rabbits vs Ungulates • Perinatal development, especially for white matter • Inexpensive • Our model is acute placental insufficiency • Average litter size 8 • Prenatal • Expensive • Umbilical cord occlusions • Better physiological parameters • No behavioral abnormalities

  42. Rabbits vs Primates • Perinatal development, especially for white matter • Motor development more similar to humans at birth • Inexpensive • Our model is acute placental insufficiency • Average litter size 8 • Prenatal • Hypertonia not reported after hypoxia-ischemia • Cognitive development • Very Expensive • Umbilical cord occlusions

  43. Objectives • Determine whether the initial response to hypoxia-ischemia is crucial to development of hypertonia.

  44. Preterm Hypoxia in Magnet 22 25 31.5 0 Gestation (Days) 32=P1 Neuro- behavior tests Sustained Hypoxia-Ischemia

  45. Measure of Diffusion of Water In pure water, a water molecule moves randomly, in every possible direction BROWNIAN MOTION Dampened in brain tissue by cell membranes, cell bodies, large molecules The Diffusion Coefficient is a measure of this molecular motion

  46. Fetal Brain ADC • Apparent Diffusion Coefficient does not change much over first 15 min • Rapid decrease only in hypertonia group • Continued decrease in ADC in reoxygenation phase

  47. 1.3 1.2 1.1 C 1.0 D A 0.9 0.8 No hypertonia Hypertonia 0.7 HYPOXIA 0.6 -1 0 1 2 3 4 5 20 25 Time (hr) Fetal ADC Delineates Fetus Destined to be Hypertonic

  48. ADC is predictive 1.2 1.1 1.0 C 0.9 D A 0.8 0.7 0.6 0.5 No hypertonia Hypertonia

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