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1 Infants & HBOT Intrauterine Growth in Children with Cerebral Palsy Uvebrant P, Hagberg G Department of Pediatrics II, University of Goteborg, Sweden. The risk of cerebral palsy in connection with intrauterine growth retardation has been analyzed in a casecontrol study. The case series comprised 519 children with cerebral palsy born in in the west health-care region of Sweden and the control series 445 children born during the same years in the same region. The risk of cerebral palsy in small-for-gestational-age infants was significantly increased in term and moderately preterm infants. The highest proportion among infants with cerebral palsy born at term was found in tetraplegia, followed by diplegia and dyskinetic cerebral palsy. It was concluded that small for gestational age on the one hand reflects early prenatal brain damage, and on the other mediates prenatal risk factors compatible with fetal deprivation of supply and also potentates adverse effects of birth asphyxia and neonatal hypoxia. #2 Cerebral palsy. Eicher PS, Batshaw ML Department of Pediatrics, Children's Hospital of Philadelphia, Pennsylvania. Over the last century, our understanding of cerebral palsy has broadened. For example, we now know that it results more commonly from prenatal abnormalities than from perinatal difficulties. Yet, in most cases we are still no closer to understanding the operant mechanism of injury or how the injury results in the expressed motor disorder. Hopefully, the strides being made in neurodevelopmental physiology and neurotransmitter communication will help elucidate the mechanism of injury in cerebral palsy and thereby lead to methods of prevention. Meanwhile, comprehensive clinical evaluation and treatment and periodic reassessment will help tailor strategies to the individual needs of the child. This should enable the child with cerebral palsy to optimize his or her function in society. #3 Am J Perinatol 1994 Nov;11(6): Prevalence of prematurely, low birthweight, and asphyxia as perinatal risk factors in a current population of children with cerebral palsy. Naulty CM, Long LB, Pettett G Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC. To test the hypothesis that increasing survival of infants at highest risk for long-term neurological sequelae has strengthened the associations between perinatal events and subsequent cerebral palsy (CP), we compared the prevalence rates for prematurity, low birthweight, congenital malformations, and perinatal asphyxia from a current population of children with CP with those reported nearly 30 years ago by the National Collaborative Perinatal Project (NCPP, ) of the National Institute of Neurologic and Communicative Disorders and Stroke. Although we saw no differences in the proportion of children who were born prematurely, we did find a significant shift in the birthweight and gestational age distribution, with a nearly threefold greater prevalence of births less than 1501 g in our population (31.1% and 95% confidence interval [CI] of 20.6 to 41.7% Vs 9.1% and 95% CI of 5.0 to 13.2%). Nearly half

2 (43.5%) of these very low birthweight infants had evidence of brain injury (intraventricular hemorrhage), a diagnosis not commonly recognized in the NCPP. On the other hand, birth asphyxia and congenital malformations occurred no more frequently in our population than that reported earlier. Furthermore, the majority (60%) of full-term infants who develop CP continue to be the products of normal pregnancies and have no perinatal events that may have caused their neurological impairment. The increasing prevalence of births less than 1501 g among children with CP may well reflect the improving survival of very small infants over the last 30 years. PMID: , UI: #4 Article in French] Cerebral palsy and perinatal asphyxia in full term newborn infants Rumeau-Rouquette C, Breart Unite de Recherches Epidemiologiques sur la Sante des Femmes et des Enfants, INSERM U-149, Paris. Despite improvement in perinatal care, the prevalence of cerebral palsy has not decreased in France, Sweden, the United Kingdom or Australia. Based on a review of recent publications, the course of cerebral palsy can be partially explained by the increase in risk among very low birthweight and very preterm infants whose survival is now better. Until recently, many publications have supported the hypothesis that asphyxia at birth was the major cause of cerebral palsy. However, these results have been widely questioned; the role of asphyxia remained unclear. In 1993 and 1994, several publications showed that there is a significant relationship between asphyxia and cerebral palsy, but that the role of asphyxia was overestimated in the past. The role of maternal and antenatal risk factors must also be taken into account. The prevention of cerebral palsy must be undertaken very early in pregnancy. Breart G, Rumeau-Rouquette C Inserm unite 149, Paris, France. Actual data on the frequency of cerebral palsy (CP) and "infirmite motrice cerebrale" (IMC), and their relationship with perinatal asphyxia and perinatal managements, are presented. In France, the frequency of IMC at 9 years of age, approximates 1 per thousand, for the 1972, 1976, 1981 generations. Three surveys, two English and one Australian, show an association between perinatal asphyxia and CP. However computation of percent attributable risk indicates that asphyxia can explain only one case of CP out of six among term neonates. These surveys show also that 10% of CP only could be prevented by improving perinatal managements. This, in addition to other factors such as the increase in survival of very preterm babies, explains the absence of a significant reduction of CP frequency despite improvements in the perinatal care. Davis DW Department of Pediatrics, University of Louisville, KY 40292, USA. Cerebral palsy (CP) is a nonprogressive disorder of motor function. Although it has been recognized for more than a century, much remains unknown regarding its etiology. It has been estimated that 17 to 60 percent of the cases of CP have no known perinatal or neonatal complications. Undocumented antenatal events may cause brain damage or increase the infant's vulnerability to future events. The prevalence of CP has remained relatively constant; however, its incidence in the preterm population has increased with the improving survival of the very low birth weight infant. #7 Early Hum Dev 1997 Apr 25;48(1-2):81-91 Antenatal and delivery risk factors simultaneously associated with neonatal death and cerebral palsy in preterm infants.

3 Spinillo A, Capuzzo E, Orcesi S, Stronati M, Di Mario M, Fazzi E Department of Obstetrics and Gynecology, IRCCS Policlinico San Matteo, Pavia, Italy. To evaluate the simultaneous effects of antenatal and delivery risk factors on neonatal death and cerebral palsy in preterm infants, we conducted a cohort study of 363 singleton pregnancies delivered between 24 and 33 weeks gestation. Neurodevelopmental outcome of the infants was evaluated at 2 years of corrected age. Risk factors associated with death or cerebral palsy were analysed by politomous logistic regression. Overall, the mortality rate was 14.6% (53/363) and the prevalence of cerebral palsy among surviving infants was 12.3% (38/310). Decreasing gestation and meconium-stained amniotic fluid were the only antenatal factors associated with increased odds for both death and cerebral palsy. The effect magnitude and the predictive value of gestational age were greater for death than for cerebral palsy. After adjustment for confounders, prolonged (> or = 48 h) rupture of membranes (odds ratio 2.98, 95% confidence interval ) and male sex of the infant (odds ratio 3.01, 95% confidence interval ) were significantly associated only with cerebral palsy. We conclude that neonatal death and cerebral palsy share few common antenatal risk factors. The characteristics of antenatal risk factors for cerebral palsy suggest that bacterial infestation of the amniotic cavity may be implicated in the etiology of the cerebral impairment. #8 Prenatal events and the risk of cerebral palsy in very low birth weight infants. O'Shea TM, Klinepeter KL, Dillard RG Department of Pediatrics, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103, USA. The purpose of this study was to analyze associations between prenatal factors and cerebral palsy in a geographically based cohort of very low birth weight infants. Cases (n = 80) and controls had birth weights of 500-1,500 g and were born in , to a resident of one of 17 counties in northwest North Carolina. Medical records were reviewed for data about prenatal and neonatal factors. Associations were analyzed separately for three clinical forms of spastic cerebral palsy (hemiplegia, diplegia, and quadriplegia) and for cerebral palsy with and without antecedent major cranial ultrasound abnormalities. The following factors were associated most strongly with an increased risk of cerebral palsy: multiple gestation, chorioamnionitis, maternal antibiotics, antepartum vaginal bleeding, and labor lasting less than 4 hours. Preeclampsia and delivery without labor were associated with a decreased risk. Evidence of confounding was found for each of these associations, except for those with chorioamnionitis and labor lasting less than 4 hours. The association with chorioamnionitis was stronger for diplegia (compared with hemiplegia and quadriplegia) and for cerebral palsy without major cranial ultrasound abnormalities. Associations with antepartum vaginal bleeding (increased risk) and preeclampsia (decreased risk) were stronger for cerebral palsy occurring with major cranial ultrasound abnormality. #9 Aust N Z J Obstet Gynaecol 1998 Nov;38(4): Antenatal and perinatal antecedents of moderate and severe spastic cerebral palsy. Dite GS, Bell R, Reddihough DS, Bessell C, Brennecke S, Sheedy M Department of Child Development and Rehabilitation, Royal Children's Hospital, Melbourne, Victoria, Australia. Routinely collected perinatal morbidity data were abstracted for 204 cases of moderate and severe spastic cerebral palsy and 816 matched controls. Separate analyses were conducted for cases with birthweight > or = 2,500 g and birth-weight < 2,500 g. The presence of a congenital abnormality was an important risk factor for cerebral palsy in both groups and further analyses were conducted after dividing the groups according to presence or absence of a congenital abnormality. In the < 2,500 g group, resuscitation needed was clearly identified as a risk factor for cerebral palsy in the group with no congenital abnormalities (adjusted OR=3.4; 95% CI= ) while in the group with congenital

4 abnormalities, none of the risk factors were clearly associated with an increased risk of cerebral palsy. Among the cases with birth-weight > or = 2,500 g, intrauterine hypoxia/birth asphyxia was clearly associated with an increased risk of cerebral palsy (adjusted OR=18.1; 95% CI= ) in the group with no congenital abnormalities while in the group with congenital abnormalities, none of the factors were clearly associated with an increased risk of cerebral palsy. #10 Antecedents of cerebral palsy. I. Univariate analysis of risks. Nelson KB, Ellenberg JH A large prospective study investigated prenatal and perinatal antecedents of chronic motor dysfunction (cerebral palsy [CP]), evaluating approximately 400 characteristics of the mothers, pregnancies, or deliveries. In addition to confirming some, but not all, of the classic risk factors for CP, this study observed relatively large increases in the CP rate in association with maternal mental retardation, seizure disorders, hyperthyroidism, or with the administration of thyroid hormone and estrogen in pregnancy. Some risk factors were predictive of CP only insofar as they were associated with low birth weight or low Apgar scores. Among factors not significantly related to CP rate were maternal age, parity, socioeconomic status, smoking history, maternal diabetes, first trimester vaginal bleeding, kidney or bladder infection, moderate hypertension, long cord, use of anesthetic agents, or use of oxytoxics for initiation or augmentation of labor. Duration of labor, whether precipitate or prolonged, was not a risk factor for CP. PMID: , UI: #11 Antecedents of cerebral palsy. Multivariate analysis of risk. Nelson KB, Ellenberg JH We examined prenatal and perinatal factors predicting cerebral palsy, using multivariate analysis to investigate which factors were most important and the proportion of cases for which they accounted. Maternal mental retardation, birth weight below 2001 g, and fetal malformation were among the leading predictors. Breech presentation was also a predictor, but breech delivery was not. A third of the children with cerebral palsy who had breech presentations had a major noncerebral malformation. Among 189 children with cerebral palsy, 40 (21 percent) had at least one of three clinical markers suggestive of asphyxia; only 17 of these 40 children (9 percent of all cases) lacked major congenital malformation or other intrinsic defects that might have contributed to an unfavorable outcome. When all the principal risk factors present by the time labor began were considered, the 5 percent of the population at highest estimated risk was seen to have contributed 34 percent of the cases. When all the risk factors present during the period beginning before pregnancy and extending through the nursery stay were included, the 5 percent at highest risk was seen to have contributed 37 percent of the cases. Thus, the inclusion of information about the events of birth and the neonatal period accounted for a proportion of cerebral palsy only slightly higher than that accounted for when consideration was limited to characteristics identified before labor began. #12 Am J Dis Child 1987 Dec;141(12): The asymptomatic newborn and risk of cerebral palsy. Nelson KB, Ellenberg JH Neuroepidemiology, Branche, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, MD We investigated whether infants weighing over 2500 g who had experienced one or more of 14 late pregnancy or birth complications, but who were free of certain signs in the nursery period were at increased risk of cerebral palsy (CP). The signs evaluated were decreased activity after the first day of life, need for incubator care for three or more days, feeding problems, poor suck, respiratory difficulty, or

5 neonatal seizures. More than 90% of the infants weighing over 2500 g had none of these signs. In asymptomatic infants with one or more birth complications, the rate of CP by 7 years of age was 2.3/1000; among asymptomatic infants whose births were uncomplicated, the rate of CP was 2.4/1000. The risk for CP rose with number of abnormal neonatal signs, and children with sustained neonatal abnormalities were at higher risk than those whose abnormalities were transient. Most children with CP did not derive from groups at increased risk. The full-term infant whose birth was complicated but who was free of certain abnormal signs in the newborn period was not at increased risk of CP. #13 Pediatrics 1988 Aug;82(2):240-9 Intrapartum asphyxia and cerebral palsy. Freeman JM, Nelson KB Department of Neurology, Johns Hopkins Medical Institution, Baltimore, Maryland. Signs of presumed hypoxia/asphyxia of the fetus are not uncommon and can be detected during labor, in the delivery room, and during the early neonatal period. Virtually no single sign or symptom has sufficient correlation to enable prediction of later cerebral palsy with a reasonable degree of medical certainty. To attribute cerebral palsy to prior asphyxia with reasonable certainty, there must be evidence that a substantial hypoxic injury occurred and that a sequence of events ensued which would prove the clinical impact of that hypoxic insult. #14 Am J Obstet Gynecol 1998 Aug;179(2): Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Nelson KB, Grether JK Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA. OBJECTIVE: Our purpose was to examine the association of cerebral palsy with conditions that can interrupt oxygen supply to the fetus as a primary pathogenetic event. STUDY DESIGN: A populationbased case-control study was performed in four California counties, 1983 through 1985, comparing birth records of 46 children with disabling spastic cerebral palsy without recognized prenatal brain lesions and 378 randomly selected control children weighing > or = 2500 g at birth and surviving to age 3 years. RESULTS: Eight of 46 children with otherwise unexplained spastic cerebral palsy, all eight with quadriplegic cerebral palsy, and 15 of 378 controls had births complicated by tight nuchal cord (odds ratio for quadriplegia 18, 95% confidence interval 6.2 to 48). Other potentially asphyxiating conditions were uncommon and none was associated with spastic diplegia or hemiplegia. Level of care, oxytocin for augmentation of labor, and surgical delivery did not alter the association of potentially asphyxiating conditions with spastic quadriplegia. Intrapartum indicators of fetal stress, including meconium in amniotic fluid and fetal monitoring abnormalities, were common and did not distinguish children with quadriplegia who had potentially asphyxiating conditions from controls with such conditions. CONCLUSION: Potentially asphyxiating conditions, chiefly tight nuchal cord, were associated with an appreciable proportion of unexplained spastic quadriplegia but not with diplegia or hemiplegia. Intrapartum abnormalities were common both in children with cerebral palsy and controls and did not distinguish between them. Comments: Comment in: Am J Obstet Gynecol 1999 Jan;180(1 Pt 1):251 PMID: , UI:

6 #15 Neurol Clin 1999 May;17(2): The Neurologically Impaired Child and Alleged Malpractice at Birth. Nelson KB Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. [Record supplied by publisher] Controlled studies, improved epidemiologic and statistical techniques, and an increase in biological information on mechanisms of fetal and neonatal brain injury or maldevelopment have led to a better, although still imperfect, understanding of the cause of developmental disabilities. The role of asphyxia during the birth process is smaller than was once believed. Intrauterine exposure to infection, autoimmune and coagulation disorders, and problems specific to multiple pregnancies are risk factors for cerebral palsy. Electronic fetal monitoring and other observations during birth are unsatisfactory management guides, having enormously high rates of false-positive identification. There is no evidence that caesarean section can prevent cerebral palsy in term infants. PMID: #15 Dr James MD on Hyperbaric Oxygen therapy and C/P 1999 HYPERBARIC OXYGEN THERAPY FOR CEREBRAL PALSY CHILDREN Philip James MB ChB, DIH, PhD, FFOM, Wolfson Hyperbaric Medicine Unit, The University of Dundee, Ninewells Medical School, Dundee DD1 9SY. To significantly increase the delivery of oxygen delivery to the tissues requires the use of hyperbaric conditions, that is, pressures greater than normal sea level atmospheric pressure. When tissue is damaged the blood supply within the tissue is also damaged and too little oxygen may be available for recovery to take place. Hyperbaric medicine is not taught in most medical schools and is often dismissed by doctors as "alternative" medicine, but it is drugs that are alternative. Some raise fears about toxicity but in practice this is not a problem. More is known about oxygen and its dosage than any pharmaceutical. There is no more important intervention than to give sufficient oxygen to correct a tissue deficiency but, unfortunately, oxygen is only given in hospital to restore normal levels in the blood. The increased pressure has no effect on the body, although the pressure in the middle ear and sinuses in adults has to be equalized. When does the damage occur? Ultrasonic scanning of the brain has shown that in most children the events which cause the development of cerebral palsy (CP) occur at the time of birth, 1 although it may be many months before spasticity develops.2 Where does the damage occur? The areas affected in CP are in the middle of the hemispheres of the brain and one side or both sides may involved. These critical areas, called the internal capsules, are where the fibres from the controlling nerve cells in the gray matter of the brain pass down on their way to the spinal cord. In the spinal cord they interconnect with the nerve cells whose fibres activate the muscles of the legs and arms. Why does the damage occur?

7 Unfortunately, the internal capsules have a poor blood supply, shown by the frequent occurrence of damage to these areas in younger patients with multiple sclerosis and in strokes in the elderly by Magnetic Resonance Imaging (MRI). When any event causes lack of oxygen the blood vessels leak, the tissues become swollen and there may even be leakage of blood. The increased water content, termed edema, reduces the transport of oxygen. This applies to any tissue, but especially too the brain where a sufficient quantity of oxygen is vital both to the function and, in children, its development. What causes paralysis and spasticity to develop? When the controlling nerve cells in the brain are disconnected from the spinal cord, the signals to the arms and legs cannot pass and the ability to move is lost. Eventually, because the nerve cells in the spinal cord are separated from the control of the brain, they send an excess of signals to the muscles, causing the uncontrolled contractions known as spasticity. The areas carrying the nerve fibres to the legs are the closest to the ventricles of the brain where the blood supply is poorest3 so the legs are the most commonly affected. The is called diplegia, to indicate that the problem is in the brain and distinguish it from paraplegia where the damage is in the spinal cord. Why is spasticity delayed? This is a crucial question that is, at present, not adequately explained or even raised. Children who develop spasticity often appear to develop normally for several months and then lose function gradually. Because in many children there is voluntary movement for a time after birth, the connections must still be intact. Why then are they lost allowing spasticity to develop? The answer almost certainly is due to the failure of the coverings of the nerve fibres, known as myelin sheaths, to develop. This evidence has come from MRI.2 Myelin sheaths envelop the nerve fibres like a Swiss roll in order to increase the speed of impulse transmission. Myelination normally begins about a month before birth and progresses to completion by the age of two. If there is tissue swelling in the mid-brain the delicate cells that form myelin die and the nerve fibres, left exposed, slowly deteriorate with the ultimate development of spasticity. What may be possible? Loss of function in the brain can be either due to tissue swelling, which is reversible, or tissue destruction, which is not. The recoverable areas can now be identified by a technique called SPECT imaging. The initials stand for Single Photon Emission Computed Tomography. It can demonstrate blood flow which is linked to metabolism of the brain which is, of course, directly related to oxygen availability. By giving oxygen at the high dosages possible under hyperbaric conditions, areas which are not ''dead but sleeping'' can be identified. This phenomenon has been discussed for many years in stroke patients and authorities have even stated that the critical parameter is not blood flow it is oxygen delivery.4 Under normal circumstances, blood flow and oxygen delivery are inextricably coupled, but the use of hyperbaric conditions can change this situation. Tissue edema and swelling may persist in, for example, joints, for many years and SPECT imaging has now revealed that this is true in the brain.5 Suggesting that more oxygen, that is additional oxygen supplied under hyperbaric conditions may be of value generates further questions: What does hyperbaric mean? It means a pressure greater than normal sea-level atmospheric pressure. Atmospheric pressure at sealevel varies with the weather and on a high pressure day more oxygen is available to the body. Aches and pains may be worse on a low pressure day because of the reduction of oxygen pressure. A hyperbaric chamber allows much more oxygen to be dissolved in the blood. An indication of the power of this technique is that at twice atmospheric pressure breathing pure oxygen the work of the heart is reduced by 20%. So much can be dissolved in the plasma that life is possible for a short time without red blood cells. The research behind the development of hyperbaric oxygen therapy has been undertaken by doctors

8 involved in aviation, space exploration and diving. This critical information is not yet taught in our Medical Schools, despite many thousands of published articles including controlled studies in many conditions. How can cerebral palsy children be helped? Clearly the appropriate time to use of oxygen is at the start of a disease process, not after a delay of months or years. Nevertheless, a course of oxygen therapy sessions at increased pressure has been shown to resolve tissue swelling after the lapse of years. It works by constricting blood vessels and interrupting the vicious cycle where oxygen lack leads to tissue swelling, which then leads to further oxygen deficiency. Although formal studies have yet to be undertaken in children with cerebral palsy there is every reason to believe that exactly the same effect that is seen in stroke patients can occur. Also in children the brain is still developing and therefore the prospects for improvement are very much greater than in adults. Recovery of brain damage in children resulting from cardiac surgery has been documented using X ray scanning.6 Will oxygen therapy cure cerebral palsy? Hyperbaric oxygen therapy is not a miracle cure for children with cerebral palsy, it is simply a way of ensuring the most complete recovery possible. It should be used with exercise programs, because lack of use in muscles and joints leads to changes that can only be reversed by exercise. Why are there no formal studies? Unfortunately most of the medical research in the UK is funded by the drug industry and the costs involved are enormous. As the use of oxygen cannot be patented, there is no way that the cost of trials could be recouped and no finance is available for the promotion of the therapy. Because of the great advances made in the use of drugs a climate has been created in which doctors are conditioned to expect a drug-based solution to every disease. Oxygen has been available in Medicine for over a hundred years so it is difficult to accept that it is not being used properly, but over 500 chambers are now operating in the USA and Japan, 1500 in Russia and a similar number in China. As is so often the case much of the original research was undertaken and published in the UK. In many diseases the cost of investigations is often a great deal more than the cost of providing hyperbaric oxygen therapy. MRI and SPECT imaging may allow the benefit to be demonstrated, but they are not in any way therapeutic. There is no better assessor of a child suffering from cerebral palsy than a parent or carer involved in day-to-day hands on care. Are there dangers? The only risk with hyperbaric conditions properly supervised is to the ear drum, just as when aircraft - which are hyperbaric chambers - descend. There are limits to oxygen delivery, for example, the very high pressures used in diving can cause convulsions, but the Chinese have shown that epilepsy is actually treated by hyperbaric oxygen therapy at lower pressures. There is no evidence of either eye or lung toxicity at atm abs. References 1. Pape KE, Wiggleworth JS. Haemorrhage, ischaemia and the perinatal brain. Clinics in developmental medicine. Nos. 69/70 William Heinemann Medical Books, London, Dubowitz LMS, Bydder GM, Mushin J. Developmental sequence of periventricular leukomalacia. Arch Dis Child 1985;60: Takashima S, Tanaka K. Development of cerebrovascular architecture and its relationship to periventricular leukomalacia. Arch Neurol 1978;35:11-16.

9 4. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia; the ischemic penumbra. Stroke 1981;12: Neubauer RA, Gottlieb SF, Kagan RL. Enhancing idling neurones. Lancet 1990;336: Muraoka R, Yokota M, Aoshima M, et al. Subclinical changes in brain morphology following cardiac operations as reflected by computed tomographic scans of the brain. J Thorac Cardiovasc Surg 981;81: Printed with Permission Legal Disclaimer The content and information provided within this site is for informational and educational purposes only. Consult a doctor before pursuing any form of therapy, including Hyperbaric Oxygen Therapy. The Information provided within this site is not to be considered Medical Advice. In Full Support of the F.D.A., Hyperbaric Oxygen Therapy is considered Investigational, Experimental, or Off Label. Please consult with your Treating Medical Physician