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It is highly desirable at this time that there be established within Several of our university centers having access to large populations of neurologically defective individuals, research units d. to the study of neurochemistry. These centers must have a close affiliation with departments of pediatrics, neurology, and neurophysiology. Correlations will need to be made between the clinical picture presented, the disturbances of brain chemistry. Within such centers can be developed the potential for an attack on . basic mechanisms underlying these important neurological disOl'Olers. In addition, to their function in research, if extra laboratories were established, these laboratories can provide important centers for the training of additional personnel for this important and growing field of research. I would like also to say just a few words about strokes. I do not need to tell you gentlemen about the importance of strokes and the number of people each year who are killed by strokes, and, in addition, the * of people who are incapacitated partially or wholly by Strokes. Cerebrovascular disease, more commonly known, of course, as “stroke” is a major unsolved medical problem. It ranks third among all diseases as a killer and first as an adult crippler. It is estimated that over 1 million Americans today are disabled because of this condition. In 1955, over 175,000 persons in the United States died as a result of this disease. Although cerebrovascular death or disability can strike at any age, it is more common past middle age. Of the cerebrovascular deaths in 1955, 39,600 were in the “working age” group, the 25- to 64-years-of-age group. In spite of its scope as a public health problem, there is a great void in our knowledge of the subject. The research which has been done in this field, until recently, has been sporadic and scattered. It was early recognized at the Institute that the development of a cooperative research attack would prove difficult unless some standard method of classification for cases and diagnoses could be established. “Strokes,” which are the most serious manifestation of cerebrovascular disease, may result from any interference with the circulation within a blood vessel of the brain. Such interference may result from occlusion of a blood vessel by arteriosclerosis, by plugging of the vessel by a circulating blood clot, or by rupture of the vessel wall as a result of malformation or disease. The neurologist who is called upon to diagnose and treat the patient who has experienced such a catastrophy may find it difficult to be certain which of these processes is responsible for the damage. However, if treatment methods are to be accurately evaluated, a method of describing and categorizing all such patients is necessary. In June 1955, the National Advisory Neurological Diseases and Blindness Council appointed a committee under the chairmanship of Dr. Clark H. Milliken, of the Mayo Clinic, to attack this problem. This committee now has completed a manual for the classification of cerebral vascular disease. A large group of cases are available for study at cooperating institutions. The new classification will aid in the rapid evaluation of new forms of therapy. An evaluation is now being made of the effectiveness of anticoagulant drugs in preventing, strokes due to arteriosclerosis. Seven research teams are now participating in this project, and it is anticipated that others will be added during 1958. Ş. young people have suffered strokes caused by cerebral aneurysm. “Aneurysm” results from a weakness of the blood vessel wall. A ballonlike sac forms on the vessel; and when this ruptures, hemorrhage into the brain results. Recent advances in neurosurgical technique and especially the use of body-cooling in anesthesia have made it possible to cure many of these cases before fatal brain hemorrhage occurs. The mortality rate, which for many years remained at 50 percent, has, as a result, dropped below the 30 percent mark in some series of cases. Again, a cooperative investigation, involving the study of a large number of cases was required to bring these results. To achieve the best possible results in the many phases of the cerebrovascular problem, the number of participating institutions should be increased considerably over the long run. We must make advances not only in the testing of treatment, but we must increase our knowledge of the basic mechanisms of blood vessel response and of brain damage. Last year, I discussed with you in some detail the new collaborative perinatal study into the origin of cerebral palsy and mental retardation. You will be interested, I know, in the progress which is being made in this project. To speak to you on this subject I will later present to you Dr. Steward H. Clifford, of Harvard Medical School and the Boston Lying-in Hospital; and then following him Dr. Alson Braley. Last year, Dr. Alson Braley, head of the department of ophthalmology of the University of Iowa, spoke to you concerning research in the field of blinding diseases and hearing disorders. With your permission, I should like to present him again today to speak on the developments in the field during the past year. And, after they have finished, I would beg your indulgence to return for a few minutes to give you our budget forecast. Mr. Fog ARTY. That will be fine. Dr. Clifford.



Dr. CLIFFORD. Thank you, Mr. Chairman. I am Dr. Stewart, H. Clifford, assistant clinical professor of pediatrics, Harvard Medical School, and also for the past 20 years pediatrician in chief at the Boston Lying-in Hospital, which runs about 6,000 babies a year. I am also chief of the newborn service, Children's Medical Center, Boston; so that naturally my interest over my entire professional life has been devoted to the problems of the perinatal period primarily. That, of course, as you all know, includes reducing mortality both for mothers and for infants. In certain fields that has been extremely important, particularly in babies after they have survived the critical period of the first 24 hours of life; but, unfortunately, our most important problem of all—namely, deaths that take place in the first 24 hours—has had very little attention, and there has been very little real progress in this field.

Until January 1 of this year, my life had been devoted to the private practice of pediatrics, and I had derived my support completely from this practice. In January, because of my conviction of the importance of the Institute's present perinatal study into the origin of cerebral palsy and mental retardation, I gave up my private practice to devote myself to this study, on a full-time basis, as coinvestigator and project director at Boston Lying-in Hospital. Also, because of my great interest, I have agreed to serve as a consultant on a national scale to other groups throughout the country collaborating on this project. I would like to summarize briefly the progress to date in the cerebral palsy project at the Boston Lying-in Hospital. We have had our grant slightly less than a year, the original grant had been made as of April 1, 1957. However, before I go further into that, I would like to revert to the matter of the babies surviving the critical day, the natal day. Our experience there has been the same as reported by Dr. Bundy from Chicago. There has been no single drop in loss of life in the first 24 hours. This is important because in this period occurs 60 percent of our infant mortality, and the vast majority of the deaths in this field are premature babies. It is perfectlv clear to all that if a baby is only able to survive a few hours after birth, that no amount of care given after birth is going to save him. You have got to extend your help back and help the baby in the mother’s womb or the uterus in order to have a baby not only living but living in a normal, healthy manner. So, the problem is very, very real: and we have all come to the conclusion that we have to know more about the baby in the uterus and more about conditions during that period. It was thought at one time that with the prematures, the ones that survive. which is where vou have the highest percentage of damage, is due to their very delicacy and small size at birth. One thing that has been very confusing is that the percentage of their deaths or brain damage at birth varies with the social and economic situation. The babies in the lowest group have suffered a much greater frequency in this than is encountered in the more fortunate people who are in the middle income or upper income brackets. These socioeconomic factors are very important and should be studied: so we are not only interested in the problem of saving lives, but we are primarily interested in those babies who are saved and having them undamaged so the v can grow up not damaged. The greatest tragedy of all is the tragedv of a brain-damaged birth; so we were interested in this perinatal study long before this perinatal project came into being. There is another reason we became interested in this. Phillip Dodge has inst concluded 2 vears’ study of admissions to the children’s service at the Massachusetts General Hospital, and he has come up with some very intriguing features and facts, and has come up with the same figure that was arrived at at the University of Minnesota. We were extremely interested because taking any one item. Such as cerebral palsy, our experience is so limited that to attack the problem requires a large series of cases that could be delivered only by the type of collaborative study that you have seen organized and set up under the National Institutes of Health. I, therefore, when the opportunity came to apply and become a member of this study, my hospital and my trustees were all very enthusiastic and joined in carrying out the protocol of the institute collaborative study on this perinatal problem, and I personally was so convinced of its importance so that I gave up my own private practice, as I mentioned before. As you know, this project has only been going a short time. We are one of the third or fourth groups admitted to the perinatal study, and there was a great deal of preliminary tightening up and still is a great deal to do. It is an entirely new approach to this vast problem, so that we actually only began operating 6 months ago, in August; but thus far in the brief 6 months that have elapsed since we ourselves became interested in the project, there have been discoveries—we ourselves were quite amazed to find the advances and the leads and the payoffs that we have already encountered as a result of the opportunity given us by this collaborative study. One of the things that has happened is that we have in our preliminary study various chemical changes in the blood of the newborn. We have noted this, with a view to seeing if there were any abnormal o that relate to damaged tissue, such as abnormal sugars and to forth. One of the leads that has come out is that we have found that in the babies of diabetic mothers, the bilirubin levels tend to run higher than levels in infants of nondiabetic mothers. This points us to a group of patients whose neurological development may be correlated with the concentration of a specific substance in the blood. Thus, another group of patients is defined in whom followup neurological evaluations should add to our findings. Since last August we have been striving to correlate placental pathology with neonatal diseases. Since then, 900 placentas have been examined by gross and microscopic examination. This constitutes all ward delivery placentas. In addition, a large number of placentas of private patients and all placentas of twins and babies who died were studied. The incidence of pathologic findings in this material is astonishingly high. At the moment, we are compiling the figures, and we are attempting a correlation with fetal and neonatal diseases of the nervous system. From previous studies here and in other laboratories, it is evident that many placentas which appear normal, show histologic features on inspection which may reflect an abnormal physiology of the infant. It is this category of placentas whose prompt examination may contribute to the understanding and treatment of diseases of the newborn. Two findings specifically merit mention at this time: (1) A large number of placentas, approximately 15 to 20 percent show some degree of inflammation. We are accumulating proof that this inflammation starts at the internal mouth of the uterus and contributes to premature delivery-rupture of the membranes.

Often bacteria are found in the microscopic sections. While most commonly the membranes are ruptured in this inflammatory disease, we have recently published a case with intrauterine extensive monilial infection in the absence of history of ruptured membranes. When the membranes are inflamed, the umbilical cord vessels often shown an inflammatory response and we assume that this indicates fetal infection. We see this in approximately 10 percent of routine placentas. Presently, obstetricians and pediatricians ask us to do quick frozen sections of umbilical cords in suspect cases at least once a day, and they base antibiotic treatment of the newborn on our findings. Routine umbilical cords not uncommonly show a congenital absence of one umbilical artery. This finding has been published previousl by us, and it is significant that it occurs often in association wit other fetal anomalies. Our alerting the pediatricians has led to the discovery of unsuspected congenital anomalies in a number of instances. * If no anomalies are suspected, one must consider the possibility that such become manifest in later life. The finding is frequent in one of twins. Approximately one in 200 routine placentas is so affected. We have recently observed a second neonatal death attributable to intrauterine infection with coxsackie virus. Because our hospital is now geared to this kind of unsuspected infection, it was possible to obtain the placenta and to perform all of the extensive studies which are being published. Briefly, this baby is the third child of a healthy mother delivered at term. Six days prior to delivery, the mother and her family experienced a cold which was accompanied my some chest pain. This went away spontaneously. The baby appeared normal at first but expired within 36 hours. At autopsy, the principle findings were myocarditis, encephalomyelitis, extensive adrenal and liver necrosis and pulmonary hemorrhage. Coxsackie B–4 virus was isolated from various organs of the baby and the maternal stool. There is no doubt that this baby was infected in the uterus and probably so during the cold of the mother. Also, had this baby survived, undoubtedly, the cerebral and other lesions would have meant some form of physical and mental retardation. On numerous occasions, I have had an opportunity to meet with other collaborators in the Institute's perinatal project.. I can testify concerning the enthusiasm which all groups have in this project and the deep conviction which we all have that something of great value to children will emerge. Since the program is new, all the groups are in various stages of tooling up at the present time. There has been a wonderful spirit of cooperation. Certain of the universities and hospitals have been particularly skillful in particular branches of the problem. For instance, the #. at Yale Universtity has been interested for years in the neuroogical growth and development of babies and children. - §. have sent some of our workers from Boston Lying-in to Yale to become conversant with their techniques. In a similarly coopera

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