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the project are taught to specialists, general practitioners, and allied medical personnel. After observing and perfecting themselves in the new techniques of diagnosis and therapy of these diseases, they later incorporate these added skills into their own private practice. In the field of neurologic and sensory diseases, these demonstration projects are urgently needed now for such disorders as multiple sclerosis, epilepsy, cerebral palsy, muscular dystrophy, leprosy, bulbar poliomyelitis, glaucoma, and retrolental fibroplasia. These demonstrations are valuable not only in advancing diagnosis and therapy, but in improving rehabilitation techniques. Until recently the extent to which lareg groups of these patients could be rehabilitated had been grossly underestimated, and as techniques are improved the proportion who can be rehabilitated will increase.
When the National Institute of Neurological Diseases and Blindness was founded in 1950, a number of new discoveries in the field of neurological and sensory disorders had secured the scientific beachhead indispensable to an effective large-scale research offensive. The creation of air encephalography, electroencephalography, and electromyography provided new diagnostic tools, without which much further work would have been impossible. The introduction of radioisotope tracer techniques for the diagnosis of tumors, and other lesions of the brain marked another advance whose potentialities are far from exhausted. The discovery of new chemical complexes in the nervous system provided a clue, not yet tracked down, to the basic mechanisms of multiple sclerosis. Recent studies on pregnant mothers may help unravel the mysteries of cerebral palsy.
The creation of this Institute, through its direct or indirect support, has given impetus to the exploitation and elaboration of these lines of research. As an example, new antiseizure drugs have been developed so that 80 percent of all epileptic seizures can be controlled. Prior to the use of neostigmine, myasthenia gravis was often rapidly fatal-about half of the patients died within weeks or months after the diagnosis was made. Now 80 percent of these patients at all ages, if adequately maintained on neostigmine, may expect to survive the disease.
In the 242 years during which the Institute's research grants program has been actively in existence, not only have current ideas been more effectively exploited but additional findings of great potential significance have been made.
Grantees at the University of Utah, for example, have found that the adrenal hormone, desoxycorticosterone, greatly increases the effectiveness in animals of antiepileptic drugs presently in use, in some case extending their antiseizure activity more than 10 times the usual period. If these same results obtain for humans, another significant step toward the practical control of epilepsy will have been made.
At the University of Tennessee, investigators under Institute support hare been establishing the normal brain activity of newborn infants through the use of the electroencephalograph. This technique has already permitted the investi. gation of those factors occurring during labor and delivery which might adversely affect the brain of the child.
Further investigations at the Harvard Medical School under a grant from the National Institute of Neurological Diseases and Blindness have cast light on when various parts of the developing nervous system of the embryo are most liable to damage and the exact nature of the damage incurred. Such findings may lead to further modes of prevention of such disorders as epilepsy and cerebral palsy. As further information concerning the biochemical and metabolic changes occurring during embryonic development is derived, new modes of treatment may evolve.
At Columbia University researchers have been able to successfully grow outside of the body nerve tissue capable of carrying electrical impulses. This technique provides an invaluable method for studying the composition of nerve cells. More significant, it offers promise that the functional regeneration of nerve tissue will become a reality.
In the field of ophthalmic research, substantial research accomplishments have also been made under the Institute's support.
At Georgetown University, substantial evidence suggests strongly that prolonged and high oxygen normally given to premature infants in hospital nurseries plays the most significant role in the development of retrolental fibroplasia, the leading cause of blindness in children. (The work at Georgetown has stimulated the establishment of a broad research project under the support of the Institute, in cooperation with the National Society for the Prevention of Blindness and other agencies, which will undertake to obtain a decisive yes or no answer concerning the causative role of oxygen administration.)
At the Harvard Medical School, a grantee has developed the electrical tonometer, which now provides a method for measuring continuously the facility and rate of flow of aqueous humor in the eyes of patients. This technique both assures the accurate diagnosis of the type of glaucoma and provides an invaluable tool for the investigation of the causes of this disorder.
The development of an artificial plastic cornea at the Massachusetts General Hospital shows considerable promise that a replacement for damaged corneas may be obtained. (The present method of replacing damaged corneas through corneal transplant usually fails in 60 to 70 percent of the cases because the transplant clouds over.)
So far, we have spoken of the broad category of neurological and sensory disorders. Within this category is research on the important sensory end organ of the brain-the eye. Since the function of the eye is so critical to productive life adjustment, research in this field merits special commentary.
Sixty Americans become blind each day—420 each week—22,000 each year. Defective eyesight costs our country about 7 percent of her potential military manpower, and slows down the production efforts of nearly 40 percent of her industrial workers. To prevent this distressing social and economic burden, the causes of blindness must be attacked. This objective demands an understanding of the diseases which lead to visual loss. It is not surprising that the causes of blindness in children differ greatly from those for adults, and that relative changes in the incidence of the blinding eye disorders in both groups have been evident in recent years as the impact of medical research has made itself felt. For example, there has been a 54-percent drop in blindness of children due to venereal disease since 1936; and a 96-percent reduction in blindness from babies sore eyes since 1908.
Current analysis of blindness in children shows that 50 percent are due to prenatal defects and retrolental fibroplasia ; 16 percent are hereditary in nature; 14 percent are due to infectious diseases; 7 percent are due to injuries; and 14 percent are due to miscellaneous causes such as tumor and general diseases. (See diagram in appendix, p. 5.)
In the adult age group, causes of blindness may be divided as follows: 25 percent due to cataract; 12 percent due to glaucoma ; 16 percent due to opacity of the cornea ; 15 percent due to primary cranial nerve disorders; 12 percent due to affections of the choroid and retina; 11 percent due to various affections of the eyeball; and 2 percent of miscellaneous causes. (See diagram in appendix, p. 6.)
Cataract is most common in people over age 50 and hits peak incidence at age 60. Census estimates tell us that by 1960 we will have a 250-percent increase in the number of people in this age group over the 1900 census.
More than 1 person in 50 of all people over age 40 suffer from glaucoma. With our present population we may estimate that 800,000 people suffer from this disease. By 1960 our aging population will have placed one-third of all people in the glaucoma age group. Uveitis, or infection of the inner eye, accounts for 12 percent of blindness in adults and corneal opacity for 16 percent.
Although no aspect of blindness has been neglected in the program of the National Institute of Neurological Diseases and Blindness, it has largely focused attention on the major economic problems in these early months of existence. Cataract, glaucoma, uveitis, retrolental fibroplasia, and prenatal defects are the items of major concern.
INTRAMURAL RESEARCH PROGRAM
In the laboratories, including the new clinical center in Bethesda, the research program is geared to finding improved methods of diagnosis, prevention, treatment, and rehabilitation of neurological and sensory disorders with special reference to epilepsy, cerebral palsy, multiple sclerosis, muscular dystrophy, glaucoma, cataract, and retrolental fibroplasia. The potential facilities of the Bethesda program provide a unique opportunity for the first telling attack on these crippling disorders.
To unravel fully the basic mechanisms of the nervous system and its wide ramifications throughout the body-extending from its apex, the brain, to all organs of the body and their important sensory endings, will require crossfertilization of newer technics developed from many disciplines in all the clinical and basic sciences. And it is this type of unique cross-fertilization that the clinical-center facilities were designed to give.
This cross-fertilization of clinical and laboratory disciplines within the Institute and among all the National Institutes of Health will make possible the first complete frontal attack in history against neurological and sensory disorders. Such a comprehensive attack, we are convinced, will eventuate in “yes” and “no" answers to the problem of the crippling disorders which is our responsibility to resolve. But the practical consequences in research to be achieved by the work in the Bethesda program are not its only contribution. In fact, it might well be that its greatest contribution will reside in the stimulus and special facilities it offers to visiting scientists from all parts of the country, who may come to Bethesda, participate in the program, and then return home with fresh concepts and technical formulations for their own special projects.
Keeping this orientation in mind and the fact that neurologic and ophthalmic disorders are more closely coupled to basic anatomy, physiology, and chemistry than other areas of investigation, the Institute's clinical staff has been organized along the principles of a research team approach aiming to attack specific disease areas. The majority of the members of the clinical research team have both medical and basic science degrees, thus preserving a solid link between clinical and laboratory research in clinical problems and an intimate liaison of the clinical program as a whole with the program in basic laboratory research, which we shall outline later,
It is, of course, the ultimate objective to attack, eventually, all the major disease areas in the neurologie and ophthalmic field. However, in its present organizational phase and with resources at its disposal, the Institute can investigate only some of the many "gap" areas in neurologic and ophthalmic research.
Accordingly, the neurology investigative program will concentrate its efforts during fiscal year 1955 on that group of disorders generally known as neuromuscular. This group comprises muscular dystrophy, myositis, dermatomyositis, myotonia, myasthenia gravis, and amyotrophic lateral sclerosis. Most promising research needs in these disorders concern their underlying pathophysiological and chemical factors. To tackle this problem, a clinical research team has been organized consisting of scientists qualified in neuromuscular chemistry; unstable isotopic techniques (to trace ionic metabolism in these diseases); and personnel trained in the electronics of nerve and muscle conduction and in the application of pharmacological agents. This clinical team will attempt to determine the factors which influence the basic mechanism of neuromuscular disorders. Chemical studies will be performed on the primary muscular proteins, particularly myosin and actin which, when reacting with a chemical termed "adenosine triphosphate," forms one of the bases of neuromuscular contraction. Studies of the effect of radioactive potassium (K) on the contractile power of these muscle proteins will be specifically studied and correlated with electrical responses.
As part of the same program, in the clinical follow-up area, an investigation and evaluation by means of electromicrophoresis of protein excreted at the cerebrospinal axis, particularly in the study of multiple sclerosis, will be undertaken. It is hoped that these studies will supply clues to the basic mechanisms involved in neuromuscular activity both in health and disease.
Paralleling these medical investigations, surgical studies will be made of epileptic patients whose seizures cannot be controlled by modern medical therapy. During surgery, extensive recordings will be taken with a conscious patient's response to electric stimulation of the brain, with special reference to the effect on memory, speech, perception, and sensation. Such pathological tissue as is reinoved at surgery will be subjected to chemical analysis and, on the basis of these findings, new approaches to the medical treatment of epilepsy will be made. Finally, investigations will be undertaken for the surgical control of the incapacitating involuntary movements often displayed in patients with cerebral palsy.
In the intramural program in eye research, emphasis will be placed on the major causes of blindness-cataract, glaucoma, uveitis, retrolental fibroplasia, and prenatal defects. Other disorders will be studied later. Each clinical investigation will be paralleled by simultaneous and analogous studies on animals. A well-equipped clinical laboratory has been planned and is to be staffed with specialists in optics, biochemistry, bacteriology, and pharmacology. The effects of new drugs on glaucoma are to be studied.
A keynote of the eye program is collaboration with the other institutes. For example, the National Institute of Microbiology provides special serological testing in the studies on uveitis; the National Heart Institute provides patients and special materials for research on hypertensive retinopathy; and the National Institute of Arthritis and Metabolic Diseases wishes to collaborate in studies on diabetic retinopathy.
Extensive researches have been planned on cataract, corneal opacity, glaucoma, and uveitis. Local institutions have indicated their willingness to provide patient material. A clinic for crosseyed children has been placed in operation at Howard University, and other studies will be conducted at Gallinger Hospital, Georgetown University, and the Episcopal Eye and Ear Hospital. Various practicing physicians are cooperative in offering to provide patients.
These clinical programs in neurologic and ophthalmic research are centered on the patient with a specific disease. The studies are carried out both at the bedside and in the clinical laboratory. The results of these studies are continually correlated with a program in basic laboratory research whose principal objective is to discover more fundamental knowledge on the working of the nervous system in health and in disease. There are numerous instances in the history of medical achievements to substantiate the thesis that basic as well as clinical research is essential for the conquest of disease. The discovery of insulin for the treatment of diabetes was accomplished by a program in basic research which pointed to the pancreas as an essential organ in sugar metabolism. Methods for the extraction and testing of secretions from the pancreas were developed in the course of the basic studies. The application of these findings to the patient with diabetes was only the last though the most dramatic step in the successful control of diabetes.
The basic research program of the Neurology and Blindness Institute at Bethesda is administered jointly with the program of the National Institute of Mental Health under a single scientific director, who is an international authority on the circulation of the brain. This joint program has established laboratories in the neuroanatomical sciences, physiology, neurochemistry, and other basic neurologic sciences of interest to both Institutes.
The recently appointed chief of neuroanatomy has had a long and distinguished career. Not long ago he discovered a substance which has the remarkable property of producing regeneration of injured nerve tissue in the central nervous system, a process which for decades has been regarded impossible. For the first time, therefore, there is a ray of hope that the spinal cord damaged by injury or disease with resulting paraplegia may be caused to heal and regenerate with restoration of function.
A section in experimental neuropathology will study how diseases of the nervous system develop and how they can be modified by various factors. A young scientist is being appointed to head this section who has made remarkable strides in the comprehension of how a viruslike poliomyelitis attacks an isolated portion of the nervous system and how it produces its well-known clinical effects.
A section on developmental neurology was initiated a year ago under a scientist world famous for his work on the embryology of the nervous system. This section will continue studies in this field of fundamental importance in various congenital abnormalities, such as certain types of cerebral palsy, spina bifida, encephalitis, and malformations of the eye.
A new laboratory in neurochemistry is being established in which there will be a section on lipid metabolism. There is a higher percentage of complex fatlike substance in the nervous system than in most other tissues. One of the most important of these substances is myelin which insulates most of the nerve fibers in the body. Present knowledge of the formation, metabolism, and regeneration of this substance is lacking, yet it is probable that a defect in the formation or regeneration of myelin is responsible for demyelinating diseases which include multiple sclerosis and amyotrophic lateral sclerosis.
Since there is no mandatory reporting system for chronic disease and disability, there are no validated figures on the morbidity of many of the disabling neurologic conditions. The estimates we have are based, in many instances, on spot checks and experience. To meet this deficit the National Institute of Neurological Diseases and Blindness has organized an Epidemiological Section to gather more reliable statistics on the mortality and morbidity of crippling neurological and sensory disorders.
The activities of an epidemiological program, of course, goes beyond the collection of mortality and morbidity reports. Epidemiological research can disclose leads to the cause of disease. For example, the cause of pellagra was uncovered through epidemiological research.
In 1952 and 1953 it was reported that the incidence of amyotrophic lateral sclerosis was greater among the Chamorros on the island of Guam than in the United States and Canada. Amyotrophic lateral sclerosis, more commonly known as Lou Gehrig's disease because the noted baseball player died from this condition, is a serious neurologic disorder which kills its sufferers in about 3 years.
Inasmuch as the original reports from Guam appeared to be reliable, the Institute organized an epidemiological project to survey the incidence and mortality of the disease in Guam, Rota, Saipan, and Moen Island in the Truk Archipelago. The project was set up in collaboration with the Navy Department and the Department of the Interior. The preliminary survey (the first phase of the operation) was undertaken in the summer of 1953 and it was found that amyotrophic lateral sclerosis was 50 times more prevalent on Guam than the reported incidence in the United States. Now, plans for the second phase of the project are in the making, namely: To find out why the disease is so much more prevalent in Guam than in the United States, which may eventually lead us to its cause.
In every area in which the vistim of the neurological or sensory disorders might benefit, the National Institute of Neurological Diseases and Blindness has actively cooperated with voluntary health agencies, professional societies and foundations, universities, medical schools, and hospitals. The fact that members of the staff as a whole are medical consultants to every major voluntary health agency in the field and are officers in the major professional societies has eliminated useless duplication of research and has contributed to careful definition of research responsibilities on the part of all groups concerned. The National Committee for Research in Neurological Disorders, composed of the voluntary health agencies and national professional societies, consults frequently with staff members of the National Institute of Neurological Diseases and Blindness, and acts as the semiofficial clearinghouse for information on broad aspects of neurological research in the country.
This cooperation is extremely active. In some cases, as in the broad study of retrolental fibroplasia now being conducted, in which the National Society for the Prevention of Blindness and the National Foundation for Eye Research participate along with the Institute, the merging of funds and manpower in planning and execution has permitted the initiation of broad studies which might not otherwise be undertaken and has brought together a wide variety of views and disciplines for the greater benefit of the research attack. The participation of the Institute's research staff in the research problems of local hospitals and the participation of many non-Federal scientists, on either a long- or short-term basis, in the research being conducted at the clinical center, also illustrates that exchange of special views and skills which contributes so successfully to medical investigation.
Until recently many of the neurological disorders were shrouded in mystery and guilt. Families hid afllicted persons. Many victims shunned active social life. These taboos are being broken gradually, with quite concrete positive results. More patients are brought into the open for therapy. The intangible weight of shame and distress on parents is being lifted. Further progress depends on education.
While the Institute is limited in the breadth of its information and educational program, it has cooperated where it can in the production of special materials for the public and the patient. A multiple sclerosis pamphlet, for example, has been produced in cooperation with the National Multiple Sclerosis Society; another pamphlet is presently in draft on cerebral palsy and its responsibilities are shared with the United Cerebral Palsy Association. In these and other similar projects in the planning stage, such cooperation has been found to be advantageous in that it combines the views of both physician and scientist to the greater clarification for the neurological patient of those facts concerning diagnosis, treatment, rehabilitation, and research which might best help him to adjust to his problems.
It is clear that if a total research attack can be mounted by all agencies, public and private, and maintained at the high degree of close correlation of effort now established, many of the neurological and sensory disorders can be brought under