Lafora disease

Medical history teaches us where we come from, where we stand in medicine at the present time, and in what direction we are marching, It is the compass that guides us into the future. Henry Sigerist

The Government Hospital for the Insane, Washington, DC, was established by an act of Congress in 1855: "it is the desire of the President that the proposed hospital shall be a model institution embracing all the improvements which skill, science and experience have introduced into modern establishments." The hospital was charged by its founder, Dorothea Dix, the leading mental health reformer of the 19th century, to provide the "most humane care and enlightened curative treatment of the insane of the Army, Navy and District of Columbia" (Fig 1). Civil war casualties treated at the hospital, reluctant to write home from the Government Hospital for the Insane, dubbed it St Elizabeths after the land tract named by its original colonial titleholder in 1663. The name stuck, but it took until 1917 for Congress to officially recognize the change. This paper details the institutions pioneering efforts in neuropathologic studies and innovative research in the diagnosis of mental disorders.

ASSASSINATION SPURS SCIENCE

The hospital's earliest practices followed the prevailing science of "moral treatment," which gave primacy to life experiences over biology.l As the cures anticipated by this theory failed to materialize, the ever-restless pendulum of hope swung toward the newly emerging biological sciences.

In 1881, Charles J. Guiteau shot and killed President Garfield. He explained that the deity had instructed him to do this for the good of the nation. His trial was the first highly publicized forensic battle pitting the leading psychiatrists and neurologists of the day against one another. W W Godding, MD, superintendent of the Government Hospital for the Insane, held with the losing side that Guiteau was insane.2 After Guiteau was condemned and hung, Dr Godding was among the group of physicians who witnessed the autopsy performed by D. S. Lamb, MD, acting assistant surgeon general of the Army.

The official report of the gross autopsy findings was published in 1882 (The Medical News. Philadelphia, Pa, July 8, 1882). Some deviations from normal brain structure were described (eg, asymmetry of skull, adhesions of dura matter, focal thickening of membranes, and flattening of right parietal bone with corresponding flattening of the cortex), but these were said to be without pathologic significance. The microscopic brain examination published later in 1882 (The Medical News. Philadelphia, Pa, September 1882), however, described pathologic changes in cerebral blood vessels and perivascular spaces suggestive of chronic disease of cerebral vessels. From this point, the literature was flooded with articles supporting the contention that Guiteau had suffered from a mental illness, perhaps "Dementia Paralytica" or an allied disease, probably due to neurosyphilis of the brain.34 These findings galvanized Dr Godding's position at the hospital.

During the last quarter of the l9th century, pathology was developing both as a basic science and as a complement to clinical medicine. Neuropathologic correlation with clinical behavior had not yet developed. Dr Godding resolved to take "a new departure in the direction of thorough scientific work, which can hardly fail to result, in time, in the enlargement of our too shadowy knowledge of the most important subject of pathological changes left behind by insanity." He further stated, "there is probably no hospital in the country which affords better facilities for this pathological work than our own." 5

I. W. BLACKBURN

On July 1,1884, Isaac W. Blackburn, MD, was appointed a full-time special pathologist and was asked to create a scientific department (Figs 2 through 5). He stated:

My duties will be the making of post-mortem examinations both with regard to the naked eye appearances and with the microscope, for the purpose of trying to discover the causes of insanity as shown by lesions of the tissues of the brain and spinal cord. I shall have a special laboratory fitted up in the best style, and all that may aid me in my research.

Early in life, Dr Blackburn manifested a wonderful talent for landscape and portrait painting, which would hold him in good stead in the infant science of pathology. He had studied under Professors C. Schussels and T. Eakins of the Pennsylvania Academy of Fine Arts, Philadelphia, where lectures and demonstrations in artistic anatomy, essential to portrait painting, were given by the renowned surgeon, W W Keen, MD, of Jefferson Medical College, Philadelphia, Pa. Dr Keen was the first US surgeon to successfully remove a meningioma, and he assisted in President Cleveland's secret operation for oral cancer in 1893. From this introduction, Dr Blackburn became infatuated with the science of medicine. In 1882, he graduated with honors from the University of Pennsylvania Medical School, Philadelphia, receiving the Morbid Anatomy Prize for his thesis, "Microscopic Diagnosis of Lymphoid Structures." He decided to make pathology his specialty and remained at the University of Pennsylvania for 2 years of graduate work.

In 1887, Dr Blackburn's first large study, "Dementia Paralytica or General Paresis,"6 was published as a supplement to the Annual Report of Saint Elizabeths Hospital. This study, as well as subsequent ones, was richly illustrated by his meticulous pen drawings and photographs and made an invaluable contribution to the interpretation of the pathologic lesions of neurosyphilis, then on its way to being understood as the first mental illness with an organic etiology. Dr Blackburn wrote extensively on both neurologic and general pathologic findings in general paresis, epilepsy, pachymeningitis, various atrophies, vascular anomalies, aneurysms and brain tumors. He also furnished the first large series of studies from the United States in several of these areas.6

At the request of the Association of Medical Superintendents of American Institutions for the Insane, Dr Blackburn wrote A Manual of Autopsies7 in 1892 with the intent to standardize the reporting and comparison of autopsies among the various hospitals. Intracranial Tumors Among the Insane8 was distributed to hospital superintendents, neurologists, and pathologists. His atlas, Illustrations of the Gross Morbid Anatomy of the Brain in the Insane,9 published in 1908, is unsurpassed to this day in clarity and accuracy. This text contains 75 plates illustrating pathologic conditions, accompanied by a brief clinical history of each case. At the time there were few, if any, illustrations that familiarized general practitioners with common pathologic conditions affecting the brain of the insane.

Dr Blackburn performed and meticulously recorded 2000 autopsies, including references and illustrations (Fig 6). By 1900, he had established a museum with over 1000 brain specimens, which helped establish a universal set of reference data for teaching and scientific purposes and would later become the nucleus of the famed BlackburnNeumann collection.

Dr Blackburn served 26 years at St Elizabeths, and also as chairman of pathology at Georgetown University Hospital, Washington, DC, and chair of morbid anatomy at George Washington University, Washington, DC. Dr Blackburn died a scientist's death in 1911, having developed sepsis from a cut sustained while dissecting a diseased brain.'o The Blackburn Laboratory archives preserves memorabilia of a remarkable career: lantern slides, microscopic drawings, hand-painted bromide enlargements of anatomy photographs, medical records, and reports.

By the turn of the century, pathology had matured as a specialty in the United States. While most leading hospitals and medical schools had established separate departments of pathology, progress in the practice of pathology at mental hospitals lagged. Among the mental hospitals, St Elizabeths was a role model.

PATHOLOGY RESEARCH FALTERS

Nicholas Achucarro, MD, former student of Marie, Kraeplin, and Alzheimer, arrived as histopathologist in 1909 at the age of 28 years. The new superintendent of St Elizabeths, William Alanson White, MD, was in the process of upgrading research in the enormous federal institution serving military, civil, and criminal populations. Dr Achucarro reorganized the anatomic pathology laboratory and introduced a silver stain and other techniques for studying neuroglia and glial cells.ll Dr Achucarro made important contributions to the anatomic pathology of rabies, general paresis, brain tumors, and Alzheimer's disease.12 In his years at St Elizabeths, he published five papers, all beautifully illustrated. He initiated a teaching program for mute and blind patients, created a consultation service for disabled children, organized a library, and organized a 3-month course for teachers on developmental disabilities. His return to Madrid, Spain, where Achucarro became the favorite disciple of Ramon y Cajal and the teacher of del Rio Hortega, meant the brilliant Spaniard would not succeed Dr Blackburn. Dr Achucarros career was cut short by an early death due to Hodgkin's disease. The neurology department at the Hospital del Estado in Madrid is named in honor of this great pathologist.l3

Gonzales Lafora, MD, another gifted Spanish neuropathologist and neurologist, who came to St Elizabeths at age 25 to do neuropathology research after extensive work with the latest techniques in Germany, would also not succeed Blackburn. Following Dr Achucarro in 1910, he published four papers, including original work on familial myoclonic epilepsy ("Lafora's disease"),14 neuroglia karyorrhexis, and amyloidosis. However, after Dr Blackburn's death, Dr White ordered Dr Lafora to do general pathology. Pursuing his own research at night, Dr Lafora published papers on poliomyelitis, tumors of the fourth ventricle, connective tissue plaques in infectious pachymeningitis, and central nervous system changes in pernicious malaria in the 1912 Hospital Bulletin.

Dr Lafora wrote to Dr White protesting the autopsy duties: "... you would have unlimited privileges on my personality and on my work . . . appoint me without my consent to perform many other duties; the concept of personal freedom and will . . . would then be swept away." Granted no relief, he resigned.

For some years, pathology research languished. Hospital staff performed postmortem examinations on a rotational basis. Staffing further deteriorated as many physicians were called to serve in World War I. During this period, there was no pathologist at St Elizabeths. Eventually, James Ewing, MD, the noted Cornell pathologist, and D. C. Nolan Lewis, MD, then working for the surgeon general of the Army, were detailed to perform autopsies at the hospital.

PSYCHOLOGY RESEARCH ADDED

Dr William Alanson White, superintendent of St Elizabeths from 1903 through 1937, had studied mechanisms of mental dissociation and was one of the first American psychiatrists to take seriously the psychological mechanisms proposed by Sigmund Freud. Dr White considered psychology to be on an equal footing with pathology and in 1910 appointed Shepard Ivory Franz as director of laboratories. Franz had received his PhD in physiology and psychology from Columbia University in 1899. Franz sought to integrate the neurologic, neuropathologic, and psychological aspects of each case. He studied cerebral localization in brain-injured soldiers from World War I and in laboratory monkeys.ls l6 During his tenure, research output at the hospital flourished. Dr Franz himself published over 32 articles and several books, including A Handbook of Mental Examination Methods 7 in 1919 and "Studies in reeducation: aphasia" in the Journal of Comparative Psychology18 in 1924. He left St Elizabeths in 1924 to become the first chairman of the Department of Psychology at the University of California at Los Angeles, where the health sciences building now bears his name.

WALTER JACKSON FREEMAN: SCIENTIST AND ZEALOT

The Laboratory had specially rigged out a small building, euphemistically called "The Rest," with a dissection room on the first floor for Blackburn's scientific work. A focal point for research, education, and training, the laboratory department outgrew its quarters and in 1924 The Rest was replaced by a new building that bore Dr Blackburn's name (Fig 7). Its first director was Walter Freeman, MD, a grandson of the same Dr W W Keen who was Dr Blackburn's mentor. After medical school and internship at the University of Pennsylvania, Dr Freeman did postgraduate work in psychiatry and neurology at the Salpetriere in Paris, France, and at the Clinica Psichiatrica in Rome, Italy. On returning home, Dr Freeman was offered the laboratory director's position at St Elizabeths. Having practically lived in laboratories abroad, he accepted the new challenge with alacrity. Dr Freeman often sheltered himself from patients by delving into laboratory work because he found communication with incoherent patients frustrating. He grew accustomed to losing patients with irreversible damage from fulminant neurosyphilis, cancer, and other brain-destroying diseases, but he never lost his ardent desire to study the damaged area at autopsy for clues to the nature of the disorder.

In 1928, Dr Freeman became George Washington University's first professor of neurology and chairman of its new Department of Neurology and Neurological Surgery. He had a flamboyant appearance-tall, goatee, sporting a sombrero and cane-and gave dramatic lectures, illustrated by drawing complex brain sections on the blackboard with both hands simultaneously. He taught his students that it was essential not only to scrutinize cultures, smears, and sections of brain in the laboratory, but also to examine the bedside history of the patient. In 1931, he gave a talk for the American Psychiatric Association on "psychochemistry," a term he coined as a marriage between the fields of biochemistry and psychiatry. He stated: "advances in science emanate from those who, already versed in two different disciplines, work in the field of knowledge lying between them." He himself received a doctorate in neuroanatomy from Georgetown University. A Time magazine article quoted Dr Freeman as suggesting, "dementia praecox, which affects so many people in the U.S., may be a deficiency disease comparable to scurvy or rickets." The neuropathology exhibit for which he was awarded a bronze medal is still on display in the laboratory.

By 1932, Dr Freeman had studied cerebral localization and was using the technique of ventriculography, pioneered by Egaz Moniz, MD, in Portugal, along with cerebral angiography. Dr Moniz's experiments with prefrontal leukotomy arrested Dr Freeman's attention.

Around this time the overactive Dr Freeman suffered a depressive breakdown, following which he left St Elizabeths. His departure perhaps was hastened by the opposition of Dr White to brain ablative procedures. After leaving St Elizabeths in 1934, he perfected the transorbital approach to frontal lobotomy, traveling the country to perform thousands of these operations as office procedures.'920 Dr Freeman produced more than 200 articles and four books, including Neuropathology2l and Psychosurgery.22 When he moved from Washington, DC, in 1954, Dr Freeman donated a bound edition of 70 articles on lobotomy to the hospital library; the work spanned 18 years of research, from 1936 to 1954.

LATER LABORATORY CHIEFS

In 1934, Nolan C. Lewis, MD, became the director of the laboratory. His expertise included a broad range of psychiatric and neurologic disorders, especially schizophrenia. He was a pioneer in art therapy. After leaving St Elizabeths, he became director of the Neurologic Institute of Columbia University in New York and later served as a psychiatric consultant at the Nuremberg war crime trials.

In 1938, Solomon Katzenelbogen, MD, became director of the laboratory. Born in Russia, he received his medical training in Geneva and Zurich, Switzerland, and was an associate professor of psychiatry at The Johns Hopkins School of Medicine, Baltimore, Md, for 10 years before coming to St Elizabeths. His primary focus was on the physiologic and biochemical aspects of psychiatric illnesses. His research interests included the blood-brain barrier, the effects of sleep on blood, the causes of hypertension, and psychotherapy.2324

Winifred Ashby, PhD, a noted scientist, joined St Elizabeths during Freeman's tenure; she published extensively on the standardization and sensitivity of serologic tests for syphilis.25 During the 1940s, Dr Ashby was internationally recognized for studies on the carbonic anhydrase activity of the central nervous system.26

Following World War II, St Elizabeths' Superintendent, Winfred Overholser, MD, hoped the hospital would become the national research center. His hopes were dashed when Congress created the National Institute of Mental Health as an independent entity. Yet, the service and research missions of the hospital remained.

Following World War II, it was evident that manual laboratory procedures were not equal to a population that peaked near 7500 patients. James Solomon, MD, PhD, appointed laboratory director in 1958, brought in the latest automated technologies. In 1959, he created a nuclear medicine department and later acquired an electron microscope. In 1963, St Elizabeths became the first mental institution to establish a pathology residency.

END OF AN ERA

Meta Neumann came to work as a histology technician in 1924 during Dr Freeman's tenure. Later, she received her MS degree from George Washington University, Washington, DC. From 1934 to 1942, she served as assistant scientist in the laboratory. In 1942, her expertise in neuropathology led to an appointment as the hospital's neuropathologist. She served as the vice president of the American Association of Neuropathologists and was nationally recognized as an authority on the degenerative diseases of the brain. She was the first to describe the findings in primary subcortical gliosis (Pick's disease). Among the 50 publications she authored or co-authored were papers on Alzheimer's disease and on the pathology of the reticular system.27-30 She could not have foreseen that she would serve over 50 years or that she would become the hospital's last neuropathologist (Fig 8).

Blackburn Laboratory's centennial was celebrated with great fanfare in 1984. A scientific symposium included Walle Nauta, MD, Massachusetts Institute of Technology, Cambridge, and Janice Stevens, MD, Fuller Torrey, MD, and Richard Wyatt, MD, all from the National Institute of Mental Health (The Washington Post. May 19,1984). A few years later, in 1987, Congress passed public law 98-621, transferring ownership of St Elizabeths from the federal government to the District of Columbia to merge into a community-based system. Even the name St Elizabeths Hospital was abolished and replaced with "Commission on Mental Health Services." Over the years, all research had been transferred from the hospital to the National Institute of Mental Health. The research era begun by Dr Blackburn was over. What remained was the major task of sorting out the legacy.

BLACKBURN-NEUMANN COLLECTION TRANSFERRED TO ARMED FORCES INSTITUTE OF PATHOLOGY

Surya Kanhouwa, MD, appointed as the director of Blackburn Laboratory in 1983, labored with her staff to salvage the remarkable materials known as the BlackburnNeumann collection and to transfer it to the Armed Forces Institute of Pathology. This task was accomplished in 1989. The collection contains some 15 000 complete case studies, 100000 glass slides, 1350 formalinized brains, and over 5000 photographs representing the full spectrum of mental and neurologic disorders. A complete study set consists of (1) clinical history, (2) autopsy report, (3) slides with special stains, (4) a paraffin block of brain tissue, (5) fresh brain tissue in formalin, and (6) photographs. Over 100 original articles pertain to the collection. Specimens of treated patients include malarial therapy, shock therapies (electroshock, metrazol, insulin), and lobotomy. The youngest lobotomy patient was an 8-year-old boy. It is hoped the old materials may be probed by new and not-yet-developed techniques. The Armed Forces Institute of Pathology has computerized the collection, and one can search by disease, by diagnosis, by neuropathology, by clinical features, by demographic criteria, by publications, and by type of brain specimen.

SUMMARY

The historic appointment of the first full-time pathologist to an American mental institution in 1884 emphasized the need for neuropathologic studies in the United States. Since that time, the traditions of innovative research, training, and service have flourished at the Blackburn Laboratory of St Elizabeths Hospital, originally named the Government Hospital for the Insane. Starting with the appointment of Isaac W Blackburn (1884-1911) as "special" pathologist and continuing through the term of Meta Neumann (19241980), the laboratory made important contributions to the science of medicine; the discovery of new diseases, the further characterization of infectious diseases, and the study of mental diseases have culminated in the publication of the innovative investigations of Isaac Blackburn, Nicholas Achucarro, Nolan Lewis, Walter Freeman, Winifred Ashby, Meta Neumann, and others.

The studies performed initially at "The Rest," and later at Blackburn Laboratory, helped set the standards in the fields of pathology, neuropathology, psychiatry, neurology, and psychology. As the research mission of the hospital ended, the legacy of this tradition, in the form of the Blackburn-Neumann collection, was transferred to the Armed Forces Institute of Pathology, where it is available to today's researchers.

References

1. Bockoven )S. Moral Treatment in American Psychiatry New York, NY: Springer Publishing Co; 1963.

2. Godding WW. The last chapter in the life of Guiteau. Alienist and Neurologist. 1882;iii:550557.

3. Guiteau's Brain. Boston Med Surg J. 1882;CVII, September 12:21. 4. Rosenberg CE. The Trial of the Assassin Guiteau: Psychiatry and Law in the Gilded Age. Chicago, Ill: University of Chicago Press; 1968. 5. Godding WW. Annual Report of the Government Hospital for the Insane. Washington, DC: Government Printing Office; 1884.

6. Blackburn IW. Pathological Studies; Supplement to the Annual Reports of the Government Hospital for the Insane. Washington, DC: Government Printing Office; 1884-1904.

7. Blackburn IW. A Manual of Autopsies. Philadelphia, Pa: Blackiston Son and Co; 1892.

8. Blackburn IW. Intracranial Tumors Among the Insane. Washington, DC: Government Printing Office; 1902.

9. Blackburn IW. Illustrations of the Gross Morbid Anatomy of the Brain in the Insane. Washington, DC: Government Printing Office; 1908. 10. White WA, Blackburn IW. Proceedings of the American Medico-Psychology Association. 68th Annual Meeting; May 28-31, 1912; Atlantic City, NJ,

11. Haymaker W. A Guide to the Exhibit on the History of Neuropathology Washington, DC: Army Institute of Pathology; 1948 12. Achucarro N. The stand point of histopathology in the study of mental diseases. St Elizabeths Hosp Bull.1909;3:43-53.

13. Moya G. Nicholas Achucarro. 1880-1918. Su Vida y Su Obra. Madrid: Taurus Ediciones; 1968.

14. Lafora GR. Contributions to the histopathology and pathogenesis of myoclonic epilepsy. St Elizabeths Hosp Bull. 1911;3:96-107. 15. Franz SI. Study of Cerebral Functions, I-IX. Berkeley, Calif: University of California Press; 1933.

16. Franz SI. Psychological Monographs. Chicago, III: University of Chicago Press and Princeton, NJ: Psychology Review Co; 1911.

17. Franz SI. A Handbook of Mental Examination Methods. New York, NY: Macmillan; 1919.

18. Franz SI. Studies in re-education: aphasia. J Comp Psychol. 1924:349 429. 19. Lebensohn ZM, Freeman W. Am J Psychiatry. 1972;3:129. 20. Shutts D. Lobotomy Resort to the Knife. New York, NY: Van Nostrand Reinhold Co; 1982.

21. Freeman WJ. Neuropathology; the Anatomical Foundation of Nervous Diseases. Philadelphia, Pa and London: WB Saunders Co; 1933. 22. Freeman WJ. Psychosurgery; Intelligence, Emotion and Social Behavior Fol

lowing Prefrontal Lobotomy for Mental Disorders. Springfield, Ill and Baltimore, Md: Charles C Thomas Publisher; 1942.

23. Katzenelbogen 5. Biochemical studies on patients with schizophrenia. Arch Neurol Psychiatry. 1944;51:469-471.

24. Katzenelbogen 5. A critical appraisal of the shock therapies in the major psychoses and psychoneuroses. Psychiatry. 1940;3:409420.

25. Ashby W. An evaluation of the Kolmer, Kahn and Kline tests in 1,346 sera. St Elizabeths Hosp Bull. 1930;6:57-65.

26. Ashby W. On the quantitative incidence of carbonic anhydrase in the CNS. J Biol Chem. 1944;155(2):671-679.

27. Neumann MA. Pick's disease. J Neuropathol Exp Neurol. 1949;8:255-282. 28. Neumann MA. Chronic progressive subcortical encephalopathy. J Gerontol. 1947;2:57-64.

29. Neumann MA. The incidence of Alzheimer's disease in a large mental hos pital. Arch Neurol Psychiatry. 1953;69:615-636. 30. Neumann MA, Progressive subcortical gliosis. Brain. 1967;90(part II):405418.

Surya Kanhouwa, MD, Kenneth Gorelick, MD

Accepted for publication August 20, 1996. From Blackburn Laboratory (Dr Kanhouwa) and the Continuing Medical Education Department (Dr Gorelick), Commission on Mental Health Services, Saint Elizabeths Campus, Washington, DC. Reprint requests to Blackburn Laboratory, Saint Elizabeths Campus, Washington, DC 20032 (Dr Kanhouwa).

Copyright College of American Pathologists Jan 1997
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