J Neuropathol Exp Neurol
Vol. 75, No. 6, June 2016, pp. 558–566
doi: 10.1093/jnen/nlw023
AUTOBIOGRAPHY
Autobiography Series: A Celebration of Memorable and
Remarkable Teachers
Floyd Gilles, MD
Editors’ Introduction
The following reminiscence by Floyd Gilles is the eleventh autobiography in a series published in the Journal of Neuropathology and Experimental Neurology. These have been solicited from senior members of the neuropathology community
who have been noted leaders and contributors to neuroscience
and to the American Association of Neuropathologists
(AANP) and have a historical perspective of the importance of
neuropathology in diagnosis, education, and research. We hope
that this series will entertain, enlighten, and present members
of the AANP with a better sense of the legacy that we have inherited, as well as reintroduce our respected neuroscientists as
humans having interesting lives filled with joys and sorrows
and allowing them to present their lives in their own words.
MNH, RAS
Floyd Gilles, MD
INTRODUCTION
First, I would like to express my appreciation to the editors of the Journal of Neuropathology and Experimental Neurology for asking me to write this brief autobiography. My
background in neurology and neuroanatomy is unlike the standard training of today’s neuropathologists; but when I started,
neurology and neuropathology were “joined at the hip,” which
is reflected in the journal’s title. I would like to thank my colleagues in the AANP for welcoming me some 50 years ago.
I have been blessed with splendid teachers throughout my
life, not only for the facts they conveyed to me but also for imparting their attitudes about learning, criticism, skepticism, and
knowledge uncertainty. Perhaps the best of these teachers for me
were the “trainees” who survived our Longwood Neuropathology Training Program in Boston. These admirable teachers,
both budding and mature, also taught me that words must have
meaning. For instance, a pathologist cannot “see” a prior physiologic state, he or she can only interpret; just because a neuron is
eosinophilic does not mean that it was “hypoxic” sometime in
the past as there are other antecedents to neuronal eosinophilia.
At some point during my development, a skeptical attitude developed in me, and in fact, during my neurology residency at
Johns Hopkins, I was known as the “doubting Thomas.”
ELGIN YEARS
I’m a middle Westerner, having grown up at the edge of
town on a hill overlooking the Fox River in Elgin, a small town
40 miles northwest of Chicago in the middle of farming territory. Mom was a community schoolteacher, and Dad, while
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never finishing elementary school, learned on the job, became
an electroplater, and worked himself up to Watch Case Factory
plant manager for the Elgin Watch Case Company. Both Mom
and Dad were second-generation immigrants, her family from
Sweden and his from Germany; they both married late in life.
My schooling (K through 8) was at the Columbia elementary
school, about a mile from our home, and at the local high
school. My 2 younger brothers and I were encouraged to learn
a musical instrument; for me, it was the cello. As kids, we spent
much time bird watching or fishing on the river and sledding,
skating, skiing, or tobogganing. One of the highlights of growing up was the day when we realized that a spectacularly colored wood duck and his family had nested in the woods across
the street in front of our house. Unlike most waterfowl, wood
ducks perch and nest in trees and fly comfortably between trees
in the woods. Boy Scouts were important, and I made it to Eagle Scout. During elementary and high school education, I had
superb English, mathematics, and science teachers, even
though not realizing my good fortune at that time.
We lived through the Great Depression and World War II
and were lucky, as my Dad never lost his employment, although
money was quite short. Still, Mom and Dad went out of their
way finding tasks around the house for men out of work; I can’t
tell you how many times our dining room was repainted. The
bitterly contested 1940 presidential campaign of Roosevelt and
Willkie (interventionists and isolationists) generated strong feelings among my parents and their friends, particularly with World
War II beginning in Europe. I still remember being collected
C 2016 American Association of Neuropathologists, Inc. All rights reserved.
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J Neuropathol Exp Neurol • Volume 75, Number 6, June 2016
into the eighth-grade room at school for Roosevelt’s Pearl Harbor attack announcement in 1941 and the declaration of war.
Rationing of gasoline, oil, and most foodstuffs began. A victory
garden was important, even though not much would grow because of the tree density around our house; however, our cabbage crops were superb, and we made considerable quantities of
sauerkraut. Our refrigeration was an ice block delivered into an
insulated compartment in the kitchen wall near the back door.
Dad’s Watch Case Factory was converted to an artillery-shell
factory. For the war effort, we children helped the town recycle
a variety of basic materials: paper by railroad boxcar load and a
variety of metals, of course. Fortunately, my family members in
the armed services survived. Farms were shorthanded during the
war, and teenagers were recruited to work the farms. I spent
summers on my uncle’s farm learning to deal with horse teams;
hay mowing; and raking, silage, milking, and cleaning horse
stalls and cow-barn gutters. At the time, I couldn’t foresee how
much the latter experiences would influence me years later
when attempting to deal with administrators and bosses.
In midteen and early-college years, I worked in a small
community-hospital laboratory in Elgin, operated by an itinerant pathologist who was responsible for several small hospitals
northwest of Chicago. This turned out to be a perfect introduction to pathology for me as I learned to process, embed, cut,
and stain microscopic slides. (In fact, I learned some histology
and anatomy using road kills and other dead animals by slipping their tissues into the processing sequence unbeknownst to
the pathologist, until I got caught!). I learned to do rudimentary
blood chemistries and bacteriology, was the phlebotomist for
laboratory work, and cross-matched blood for transfusions. We
had to clean, sharpen, and sterilize our own needles, believe it
or not. But, most importantly, I was the pathologist’s scribe, recording as he dictated the surgical specimens or performed autopsies at the hospital or in several undertaking establishments
in Elgin. I still remember my first autopsies (and, particularly,
the aroma): a 33-year-old man dead of cyanide poisoning and a
term stillbirth lying side by side on the morgue table.
CHICAGO YEARS
The most remarkable years were ahead of me as I entered
the University of Chicago College after my third high school
year. The college was indeed noteworthy, particularly since these
were the last 4 years of Robert M. Hutchins’ tenure as chancellor;
his administration spanned both the great depression and World
War II. His emphasis on broad-based general liberal areas of
knowledge was especially important to me. Each day was filled
with required courses with much reading of original sources and
discussion. “Elective” courses were few and far between. I remember one course in particular, “O.I.I.”: “Organization, Methods, and Principles of Knowledge” or “Observation, Interpretation, and Integration,” in which I learned that observation and
interpretation are 2 different intellectual steps, with integration
into existing knowledge as a distinct third step. Although initially interested in chemistry, I found courses in zoology, comparative anatomy, and embryology far more appealing, since excellent teachers such as Lawrence Bogorad taught them. I did
summer work with Dan Harris in the biochemical synthesis of B
vitamins in fungi and received my BA in 1951.
Autobiography
FIGURE 1. Douglas Buchanan.
During Medical School at the University of Chicago,
I spent a year part-time with histologist William Bloom
radiating cells during mitosis with a proton microbeam (generated with a linear accelerator) and following them with
time-lapse photography; summer work was with neuroanatomist and zoologist Roger Sperry (PhD in zoology from The
University of Chicago); I encountered the neurosurgeon Theodore Rasmussen (who insisted that I read Henry Head’s 2
volumes on neurology based on brain-damaged World War
I survivors before working in his section); and I met Douglas
Buchanan who introduced me to pediatric neurology (Fig. 1).
Buchanan, a Glaswegian educated at Cambridge who took
neurologic training at Queen Square (the National Hospital
for the Epileptic and Insane), moved to the University of Chicago and Children’s Memorial Hospital to become 1 of the 3
individuals who established pediatric neurology as a specialty
in this country (along with Frank Ford at Hopkins and Bronson Crothers at Boston Children’s Hospital). A very shy man,
but a captivating teacher, he would invariably perspire freely,
developing a dense facial sweat requiring much mopping during each of his memorable lectures. Buchanan introduced me
to the importance of the history of each neurologic concept.
During the last 2 medical-school years, I attended each of his
clinics at the University of Chicago and the Children’s
Memorial Hospital and observed a superb compassionate clinician at work. Even though not writing much, Buchanan
loved rare neurologic books; at our graduation, 2 of us gave
him an original 17th-century Sydenham’s book that included
a section on chorea. The ophthalmoscope also fascinated Bu-
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FIGURE 2. Department of Pathology at the University of Chicago. First row: Paul Steiner, Paul Cannon, Eleanor Humphreys.
Second row: Robert Wissler, Earl P. Benditt.
chanan, and he suggested I go to Hopkins for my neurology
training where I could work with his trainee David B.
Clark, a pediatric neurologist, and with Frank Walsh in
neuroophthalmology.
The pathology department was of great importance to
me. I worked for Earl P. Benditt abstracting clinical charts
for the weekly clinical pathologic conference. Benditt
worked well with medical students, and most of us received
much of our pathology training from him. Robert Wissler
loved to teach medical students, but spent most of his time
on experimental atherosclerosis in rodents. Eleanor Humphreys was one of the few women on the medical-school
faculty. She did the surgical pathology, taught surgical pathology to medical students and residents, and was the student advisor for many medical-school classes. Paul Steiner
was interested in the causes of cancer, but didn’t seem to
like medical students much. Paul Cannon, the departmental
chairman at that time, was interested in nutritional pathology. I received my MD and BS in anatomy degrees in 1955
(Fig. 2).
BALTIMORE AND BETHESDA YEARS
I interned at Johns Hopkins Hospital in internal medicine and then spent 3 years in general neurology under Jack
Macladery, Charles Luttrell, David B. Clark, John O’Connor,
and Frank Ford. The Hopkins neurology residents learned neuropathology from Richard Lindenberg during his Mondaynight sessions at the Baltimore City Morgue. The morgue was
unique; it was located on a Baltimore harbor wharf adjacent to
the east Baltimore Sewage Pumping Station. Long gone now,
it would have been on the wharf just east of the current
National Aquarium in downtown Baltimore. Lindenberg’s
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Monday-night sessions were popular and well known; residents came from both Baltimore teaching centers, the Armed
Forces Institute of Pathology in Washington, and from disciplines other than neuropathology or neurology. Imagine 12–
15 trainees crowded around a table in the morgue with trays
containing 10–12 coronally cut brains, each with an abnormality, and centrally a tall commanding individual in a white
jacket supporting a large round head with large ears sticking
straight out (Fig. 3). Lindenberg had a great sense of humor,
but he was dogmatic, dramatic, didactic, and always “dead
right”; being also completely color blind led to many vigorous
discussions! He was sufficiently color blind to be unable to
see the eosin in hematoxylin and eosin–stained slides; in fact,
he only used Nissl-stained slides.
Jack Macladery, a Canadian, Queen Square–trained
neurologist and clinical neurophysiologist, was austere, demanding, and with high expectations, giving his neurology
residents considerable clinical decision-making responsibility.
Expecting us to be correct in our reasoning, he distinctly
spelled out to us on day 1 of our training program that if we
made an incorrect clinical decision for the wrong reason,
he would publically reprimand us, and so he did. Charles Luttrell was a research neurologist interested in neurovirology
and induced myoclonus. David Clark, having a PhD in neuroanatomy from the University of Chicago (the same department
founded many years earlier by C. Judson Herrick in comparative neuroanatomy), did most of the Hopkins pediatric neurology. His Tuesday-evening rounds were outstanding and
widely attended (Fig. 4). David and I became great friends.
Frank Ford had recently completed his large catalogue of
childhood neurologic conditions, but usually sat in the clinic
answering resident and faculty questions. Frank Walsh was a
neurology resident’s favorite; not only well versed in ophthal-
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Autobiography
FIGURE 3. Richard Lindenberg.
FIGURE 4. David B. Clark.
mology with a superb command of cranial nerve impairment,
but also had a great sense of humor; residents would try to get
him for consultations as often as possible because, as a
teacher, he gave each trainee his full attention. During his
residency, Walsh organized the legendary Saturday-morning
neuroophthalmology conferences at Wilmer, which attracted
experts in neurology, neurosurgery, ophthalmology, neuropathology, and internal medicine; these continued throughout his
faculty years. He was a great man, and I think he was probably
the most-loved individual that ever came through the Wilmer
Institute (Fig. 5). Walsh had just published the first compendium of neuroophthalmologic conditions, establishing the
discipline of neuroophthalmology (although not the first to
write about neuroophthalmology). Lindenberg and Walsh
would subsequently publish a joint book on the Neuropathology of Vision. Fortunately, I was able to spend a rewarding 6
months with Walsh, which developed into a warm personal
relationship.
The Hopkins neurology residency program was responsible for the neurologic and poliomyelitis services at Baltimore City Hospital (the collection point for all Maryland
poliomyelitis cases), as well as for the chronic neurology
ward. Many poliomyelitis patients had severe respiratory insufficiency, and neurology residents cared for these patients
using the old Drinker Tank Respirators. The chronic neurology ward was a 90-bed ward with many kinds of neurologic
disease other than strokes (which were housed elsewhere in
the hospital). We usually had patients with several varieties of
neurosyphilis, multiple patients with Huntington chorea, 1 or
2 with Sydenham chorea, and multiple genetic abnormalities
at any 1 time. While I was a Hopkins neurology resident, I
taught neuroanatomy to Hopkins medical students under David Bodian (who had obtained his PhD in neuroanatomy, as
well as his MD, from the University of Chicago). My first contact with the Carnegie Collection was during this time in Baltimore. The collection was a valuable resource of serially sectioned human embryos and fetuses. It was first started by His
and Mall between 1882 and 1884 in Leipzig and then continued by Mall and Streeter at Johns Hopkins. After Mall died,
George Streeter markedly enlarged the collection. The collection was eventually moved to The University of California at
Davis under the care of Ronan O’Rahilly and Fabiola Müller
and remained there until it was finally transferred to its final
resting place, the National Museum of Health and Medicine in
Washington. I was amazed at how little I understood of embryonic and fetal brain developmental neuroanatomy relative
to adult neuroanatomy. During these years, I wrote my first paper with Joseph French on sciatic palsies from injection needles inserted into the gluteus muscle for penicillin administration but actually inadvertently inserted into the sciatic nerve
via the greater sciatic notch in 22 skinny babies and kids. I like
to think that this paper helped push pediatricians toward using
the anterolateral thigh for an injection site, rather than the
buttock.
Following Hopkins neurology training I spent an obligatory 2 years in the Navy in the Berry Plan. Fortunately,
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FIGURE 5. Frank Walsh.
I was assigned to the Bethesda National Naval Medical Center (now the Walter Reed National Military Medical Center)
just across Wisconsin Avenue from the National Institutes of
Health (NIH). I was head of neurology and responsible for the
naval Neurology Residency Training Program. As the referral
center for all complex neurologic conditions originating in
the navy internationally, this was an exceptional neurologic
experience. We were also responsible for all Drinker respirators, commonly used for infectious polyneuritis cases. Every
Monday evening, I took my neurology residents over to Baltimore for Lindenberg’s neuropathology sessions. Separately
and simultaneously, I was also exposed to the large naval bureaucracy and became responsible for providing expert testimony defending the navy in legal matters involving neurology.
Subsequently, I had an NIH neuropathology fellowship
at the Baltimore Central Anatomic Laboratory with Richard
Lindenberg. Hugo Spatz in Germany was Lindenberg’s neuropathology teacher; he also mentored K.J. Zülch and E.P. Richardson, Jr. In Spatz’s pedigree, we see the importance of good
teachers. Spatz had been taught by both Franz Nissl and Walther Spielmeyer and went on to succeed Oskar Vogt at the Kaiser-Wilhelm Institute for Brain Research. Spielmeyer’s background included training by Eduard Hitzig, who, in turn, had
been mentored by Rudolf Virchow. Virchow was 1 of the 4
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well-known individuals (Schleiden, Schwann, Remak, and
Virchow) taught by Johannes Peter Müller, who, along with
Vogel, brought cell theory into being. It was Matthias Schleiden who discovered the importance of the relationship between plant cells and their nuclei, and inspired by this finding,
Theodor Schwann looked for cells in animal tissue. In 1839,
Schwann published his studies of cellular theory in biology;
however, he shares the credit for cell theory with others including Purkinje, who in 1837, had described structures in animal tissues that he likened to the cells found in plants. The
third and fourth members of Johannes Müller’s group were
Robert Remak and Rudolf Virchow (1821–1902). Virchow,
who is considered the “Father of Pathology,” also founded the
field of social medicine. Virchow saw the importance of the
microscope that ultimately led him to develop his basic concepts of cellular pathology, culminating in his 6-volume Textbook of Special Pathology and Therapy. In 1856, Virchow became chair of Pathological Anatomy at the University of
Berlin, and in 1858 published one of the most consequential
books of the modern era of medicine, Cellular Pathology as
Based Upon Physiological and Pathological Histology. For
the first time, a relationship was drawn between cellular morphology and cellular function in health and disease. However,
Virchow based this theory on F.V. Raspail, who in 1825 had
postulated that all cells come form other cells, and dedicated
Cellular Pathology to J. Goodsir for the same reason. This had
a profound influence on the development of medicine. It was
Virchow who realized that all cells are derived from other
cells and went on to expand this concept to malignant cells
arising from once normal cells. The disciplines of cellular pathology and comparative pathology are a direct continuation
of Virchow’s work. That this remarkable legacy of the German/Austrian universities and research institutes, anticipating
modern pathology, was however distorted by the National
Socialist German Workers’ Party into an instrument of hate
that supported and exploited the most extensive organized program of human destruction in the history of civilized society,
is a different subject entirely.
Lindenberg had extensive knowledge of brain trauma,
having been a neuropathologist for the German air force
during WWII, working on airplane crash fatalities and developing an antigravity suit. He was director of the neuropathology laboratory at the University of Frankfurt-am-Main,
1945–1947. In 1947, he moved to Randolph Field in Texas to
do research on the behavior of astrocytes after acute and subacute death. Subsequently, he was a research neuropathologist at the Army Chemical Center in Edgewood, Maryland. In
1951, he became Director of Neuropathology and Legal Medicine in the Maryland State Department of Health and Mental
Hygiene in Baltimore and was consultant to the Chief
Medical Examiner of the State of Maryland. His academic appointments were at the University of Maryland and the Johns
Hopkins School of Medicine. Lindenberg was recognized as
the foremost forensic neuropathologist in the United States;
his 2 chapters on trauma and forensic neuropathology in Minckler (Minckler J. Pathology of the Nervous System, 1968) are
probably the best available. He provided a wonderful setting
for the budding neuropathologist. First, he was a remarkable
teacher; second, he showed me various autopsy approaches to
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Autobiography
the spinal cord, to the cervicomedullary junction, and multiple intracranial approaches to the orbit, petrous bone, sphenoid bone, and skull base; third, he provided me with a wideranging exposure to brains (approximately 1500 a year), receiving all trauma cases from the Baltimore Medical Examiner’s Office, consults from many states and all Maryland
State Hospital cases (supplying 20–40 brains a week). I
learned the basics of brain swelling, brain trauma, and herniation pathology; the cerebral and spinal vascular beds and
border zone vascular disease; and the variability of arterial
border zone lesions related to cardiac arrest, all of which provided the background material for a future paper on selective
symmetrical hypotensive tegmental brainstem necroses. This
large number of cases also brought to my attention the great variability in the secondary gyral pattern of the human brain. The
state hospital cases in particular yielded a trove of malformed or
perinatally damaged brains, furnishing an in depth familiarity
with adult brains that had been either abnormally formed or
damaged prematurely or in early life. These cases included most
common malformations, perinatally damaged brains, and multiple genetic conditions. While at that time (and still today) many
brain lesions were arbitrarily attributed to hypoxia, Lindenberg
helped me move intellectually away from the albatross of hypoxia as an explanation for most cerebral lesions.
about 124 individuals, 3 of whom were subsequently awarded
Harvard professorships (Leviton, Hedley-Whyte, and Hannah
Kinney).
Donald Matson put pediatric neurosurgery on the map
as a discipline. He loved to show off his operative skill, often
inviting me to the operating room to show some remarkable
neuroanatomic views (such as the view of the vertebral arteries looking down the clivus during a subfrontal approach for
craniopharygioma) or a difficult operative procedure. Matson
trained a generation of pediatric neurosurgeons and worked
closely with us in neuropathology. Each Saturday morning,
we would review the week’s surgical slides from Children’s or
the Brigham using an old carbon arc projector. The light was
so strong that it would bleach the slide if one stayed in 1 spot
too long. We had weekly neuropathology-neurosurgery slide
sessions consuming most of each Saturday morning; most of
his neurosurgical trainees were quite comfortable with brain
tumor histology.
During these years, I also spent considerable time, along
with Pasco Rakic, studying developmental fetal neuroanatomy
with Paul Yakovlev in the serially sectioned fetal brains from
the National Institute of Neurological and Communicative
Disorders and Stroke (NINCDS) Collaborative Perinatal Project. In parallel, I became persuaded of the importance of understanding the historic development of ideas in neuropathology, for which the leaders were Virchow and Cruveilhier.
At appropriate times during each year, I taught neuroanatomy and neuropathology at Harvard Medical School. Despite
the promotional politics at the Harvard Medical School, I was
promoted and given tenure in 1983. Harvard, being Harvard,
would not give a tenured appointment to anyone without a Harvard degree, so I was awarded an honorary AM degree.
BOSTON YEARS
In 1962, Sidney Farber (pathology chairman) and Lahut
Uzman (pediatric neurology chairman) appointed me as head
of Pediatric Neuropathology at Boston Children’s Hospital.
This was an exposure to the politics and bureaucracy of large
academic institutions (indeed, almost as limiting as the naval
bureaucracy, although in Boston it seemed like everyone
wanted to make decisions, and in the Navy, no one would
make a decision), but also to the Countway Library and its
rare books collection (almost next door to Children’s Hospital). E.T. Hedley-Whyte joined our neuropathology faculty after her neuropathology training and helped me organize an
ideal pediatric neuropathology training program combining
the resources of Boston Children’s, Peter Bent Brigham, New
England Deaconess, and Beth Israel Hospitals. D.R. Averill,
veterinary neuropathologist, joined us, thereby adding a comparative neuropathologic component to our training program.
At one time, 7 neuropathologists were working on our service.
Once a month we invited all New England neuropathologists
from each of the local academic centers for a slide session; we
provided the coffee and doughnuts, and the participants provided the slides of unknown cases. Participants came from the
Massachusetts General Hospital, Dartmouth, Tufts, and the
University of Connecticut.
Many accomplished trainees in pediatric neuropathology and neurology, such as Alan Leviton, ET Hedley-Whyte,
and Sean Murphy, also taught me. Leviton showed me how to
apply epidemiological principles to autopsy and surgical
specimen populations and, eventually, to brain tumor populations. Sean Murphy helped me show that there were neonatal
white-matter abnormalities besides white-matter focal necroses,
which had been in the literature for over a century. Between
1962 and 1983, we taught pediatric and adult neuropathology to
FAMILY
I had been married during my last medical-school year,
and during those Boston years, helped 5 wonderful children
develop into their own remarkably different persons.
LOS ANGELES YEARS
In 1983 I moved to Los Angeles to assume a newly endowed chair in pediatric neuropathology (The Burton E. Green
Chair) at the Children’s Hospital of Los Angeles and the University of Southern California.
Marvin Nelson, Jr
Nelson is a superb neuroanatomically oriented neuroradiologist and an organizational master. As radiology chairman,
he created a strong department with a prominent neuroradiology emphasis. His major goal, however, was to organize a research-radiology imaging section and, to that end, has been attracting superb basic scientists since, with currently 9 imaging
research faculty.
Early in Nelson’s career at Los Angeles Children’s Hospital, we became concerned about the lack of neuroanatomic
knowledge in young trainees in neuroradiology, neuropathology, pediatric neurology, and neurosurgery. (The situation is
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worse today as several young neuropathologists I’ve recently met know so little of neuroanatomy they will likely
have difficulty communicating with clinical neurologists
and neurosurgeons.) Subsequently, we initiated an annual
Retzius neuroanatomy competition for trainees in any discipline dealing with the nervous system. This exercise remained in existence for 21 years. Retzius was the last great
19th-century gross neuroanatomist who was interested in
brain development. The awards for the winners included
handsome checks and a medallion with a bust of Retzius on
1 side and a sagittal brain view on the other with the motto
ad agusta per angusta (“no pain, no gain”).
Nelson discovered that the Carnegie Collection had been
moved to the University of California at Davis. Thus, we were
able to spend many hours working on angiogenesis in this collection, first with the direction and support of Ronan O’ Rahilly
and then at the Armed Forces Institute of Pathology before its
transfer to the National Museum of Health and Medicine in
Washington. These studies complemented our earlier angiogenesis studies, resulting in 2 manuscripts. Separately, he and I
then wrote many manuscripts correlating neuroradiologic images with neuropathologic or neuroanatomic observations in
various sites, eg, developing children’s craniovertebral junction and brains in children with brain tumors or with posterior
fossa cysts. Finally, with one of Nelson’s faculty members,
Stefan Blüml, we delimited the newborn metabolic maturation
brain using magnetic resonance spectroscopy.
and cell biology, and the 9 research neuroimaging members in
our new laboratory facilities.
Larry Swanson
Larry Swanson is a comparative neuroanatomist and
neuroanatomic historian who changed the way I envisioned
neuroanatomy. In addition to his extensive work on hypothalamic connections, his systemization of neuroanatomical nomenclature resulted in Brain Maps: Structure of the Rat Brain,
the third edition of which was published in 2004. His brain flat
map is probably generalizable to all vertebrate brains, and in
Neuroanatomical Terminology: A Lexicon of Classical Origins and Historical Foundations, which was published in
2015. He was even more distressed about the confusion of
neuroanatomic names developed over the past 2000 years than
I was about neuropathologic names. He was kind enough to invite me to help teach University of Southern California graduate and undergraduate courses on brain and emotion and central nervous system organization. I also spent much time
teaching neuroanatomy and neuropathology at the Keck
School of Medicine
Pediatric Neurology
While sidetracked into running clinical pediatric neurology at Children’s Hospital, Los Angeles, for a dozen years, I
spearheaded development of a Pediatric Neuroscience Center with developmental neurobiology as its core, utilizing
many individuals from most pediatric clinical neurologic
disciplines. Currently, we have 7 developmental neurobiology
PhDs, 1 pediatric neuropathologist with a PhD in molecular
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Kurt Benirschke
Kurt was a wonderful pediatric and neonatal pathologist,
an organizational genius, with a primary interest in comparative placentology, particularly that of the armadillo. Kurt was
on the Harvard faculty as head of pathology at the Boston Hospital for Women but escaped Harvard politics to become head
of pathology at Dartmouth Hospital. He subsequently moved
to the chairmanship of pathology at UC San Diego. Invited to
become chairman of pathology and assume the Wolbach chair
at Boston Children’s after Sidney Farber died, he rejected Harvard to become chairman of comparative pathology at the San
Diego Zoo, thus choosing the zoo over Harvard. He eventually
became zoo board president and established a research program at the zoo. Kurt and I interacted many times but never
did a project together.
PROJECTS: THE DEVELOPING HUMAN BRAIN
The developing human brain has long been the center of
my attention. Early in my tenure at Boston Children’s Hospital, we performed around 360 autopsies a year on all ages of
fetuses, infants and children, ranging from fetal to late adolescence; thus, we had considerable material. For special fetal
brain projects, we had additional fetal and newborn neuropathologic material from many Boston obstetric hospitals and
eventually obtained access to the 1500 premature and term
neonatal brains of the National Collaborative Perinatal Project
through a contract with the NINCDS. Paul Yakovlev had serially sectioned some of the latter brains. This wealth of fetal
material opened my eyes to the fact that the neuropathology of
the fetus was very different from that of the mature individual
because the natural phenomena of growth were superimposed
on the ongoing neuropathologic reactions to fetal brain insult.
In fact, the timing of mobilization of astrocytes and macrophages differs in the fetus and the adult.
We were interested in various parameters of fetal
brain growth, such as brain-weight accretion, but immediately ran into the problem of normal biologic variability.
Jim McLennan, a neurosurgical trainee, spent a year with
us and developed a model of fetal brain-weight accretion
that displayed, I believe for the first time, the wide variation in fetal brain weight at each gestational age and also
showed the marked inflections in brain-weight accretion at
second-trimester end (when brain-weight accretion accelerated) and at the end of term gestation and early postnatal
life (when it slowed down). The same type of normal biologic variability occurs with the onset of gyrus formation,
as shown in studies with J.G. Chi and E.C. Dooling. Chi
and Dooling also showed right-left asymmetries in fetal gyrus formation. Another finding was that hemispheral glial
cells, just before and during myelination, accumulated
large amounts of cholesterol esters, which were subsequently incorporated into the myelin sheath. Another interest was the concomitant timing of myelination in individual
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tracts. These studies (with E.C. Dooling, B.A. Brody, A.C.
Kloman, and H. Kinney) resulted in the first fetal, as well
as postnatal, tract myelination schedules showing wide biologic variability in individual tract timing; thus, nullifying
the prevalent textbook idea that myelin appeared in specific tracts only at specific fetal ages. We also did quantitative studies of the development of germinal matrix volume
and cortical surface area in serially sectioned brains from
the National Collaborative Project.
lished with all the “icals” retained. I later discovered that the
editor was a Scot.
FURTHER STUDIES OF FETAL AND
NEWBORN BRAINS
Not having the option to experiment in human neuropathology, we worked therefore with the random events resulting
in brain tumor biopsies or autopsies, and thus our studies considered events in brain tumor populations or autopsy
populations. Alan Leviton helped me clarify interrelationships among neonatal white-matter histologic abnormalities in autopsy populations by using clustering strategies.
Because, in human neuropathology, there is usually no 1 precise cause, we looked for associations between clusters of
histologic abnormalities and clinical events (potential risk
factors), instead of a priori hypothecating that the abnormalities were all related to hypoxia. These studies were published
as the Perinatal Telencephalic Leucoencephalopathies (PTL),
and their risk factors included markers of infection but not of
hypoxia. Then, based on our models indicating the importance of neonatal or late fetal infection (which, at that time,
were mainly Gram negative), we created an endotoxin leucoencephalopathy in kitten, monkey, and rat and subsequently were able to demonstrate the age-related brain
changes in neonatally induced lesions. Similarly, the epidemiology of the histologic components of PTL was examined in
the extensive autopsy material from the National Collaborative Project, largely confirming our original findings.
Additional studies explored the epidemiology of delayed
myelination, fetal subarachnoid hemorrhage, and ganglionic
eminence hemorrhage, all demonstrating specific changes in
growth and vulnerability at second-trimester end and that histologic responses to neural damage are inconstant during gestation. Finally, we investigated thymic changes in infants
with the PTL with Gordon Vawter.
In several studies of fetal angiogenesis, Karl Kuban,
Marvin Nelson, Ignacio Gonzalez-Gomez, and I, using 3dimensional views of Microfil-filled vascular beds of fetal
brains (as well as the Carnegie Collection of embryonic and fetal material of various ages), showed that there were no deep
white-matter arterial border zones, no recurrent collaterals, and
no transependymal arteries (all ideas popular at that time).
Alan (Leviton) and I did many projects together, collecting a remarkably long list of manuscript rejection notices in
the process. One memorable exchange with an editor was over
the use of the adjectival suffix “ic” or “ical.” Following Fowler’s (an Englishman) Modern English Usage (1952), Alan
and I preferred “historic” rather than the widely used “historical.” We sent our objections off to the editor who had changed
all our “ics” to “ical,” heard nothing, and the paper was pub-
CHILDHOOD BRAIN TUMORS
Large numbers of children with brain tumors died in
those years. Don Matson’s cases required brain-tumor histologic evaluations. When viewing the histologic-feature heterogeneity revealed in these brain tumors, I was struck by the inadequacy of the original Bailey and Cushing brain-tumor
classification, the del Rio Hortega classification, the Kernohan
grading scheme, and that great “democratic” World Health
Organization (WHO) brain-tumor classification in dealing
with this heterogeneity. Many “experts” wrote large tomes on
brain-tumor classification, but their opinions often rested entirely on influence rather than on a classification system logical enough to foster effective brain-tumor histology teaching.
There was remarkable variability of diagnoses provided by
differing neuropathologists. Subsequently, Al Leviton, E.T.
Hedley-Whyte, and I began a series of studies: first, my own
reliability in seeing the same histologic features in childhood
post fossa brain tumors on a second review of the same slides
and, second, other pathologists’ diagnostic reproducibility in
brain tumor diagnoses and histologic feature recognition.
Needless to say, reread recognition reliability of these studies
left much to be desired for all of us. For these reasons, Leviton
and I developed the Childhood Brain Tumor Consortium after
much discussion with neuropathologists around the country;
3291 childhood brain tumors without regard to specific braintumor diagnosis were culled from 10 institutions across North
America. Leviton and others (after my move to Los Angeles)
helped to define histologic feature relationships in childhood
brain tumors. Auxiliary studies included observational variation in cerebellar gliomas in children; the classification of cerebellar gliomas; survival status of children with cerebellar gliomas; and age-related changes in diagnoses, histologic
features, and survival in children with brain tumors from
1930–1979. What became apparent was that the WHO braintumor system for astroglial or neuroglial tumors does not provide homogeneous histologic groups or provide clean survival
distributions, merely relative survival estimates, and the Daumas-Duport grading system similarly does not provide histologically homogeneous grades with single survival distributions for children. In other words, many WHO diagnoses and
most grades for childhood neuroglial tumors contain subgroups with differing histologies or with unclear or differing
survival expectations.
Measured histologic feature associations are more important than a priori nomenclature systems, such as the WHO
manual, arbitrary a priori grading systems such as the Daumas-Duport, or, I suspect, systems utilizing a single genetic
defect (or even a group of related defects), to characterize adequately childhood brain tumors. Each histologic feature in
a childhood neuroglial tumor is present because of some
genetic, environmental, reactive, or other cause. Groupings
of histologic features within neuroglial tumors are not random
but result from the various forces driving brain tumor development and course. The interaction of these forces results in sub-
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J Neuropathol Exp Neurol • Volume 75, Number 6, June 2016
TABLE. Other Studies
Sjögren-Larsson disease
Posterior fossa cysts
Ganglionic eminence fibrinolytic activity
Infantile neuroaxonal dystrophy
Persistent Blake’s pouch
Spinal cord vulnerability in cardiac arrest
Acrylamide neuropathy
Limbic dementia
Neonatal bacterial meningitis
Fasciculus gracilis degeneration in cystic fibrosis
Fetal brain ependymal changes
Infantile atlanto-occipital instability during head extension
Corticospinal fluid production in acute ventriculitis
Aspergillosis myelopathy
Ventricular size changes in newborns following vaginal delivery
Substantia nigra underpigmentation following chronic childhood illness
stantial histologic heterogeneity as manifested in the many different histologic patterns found in these tumors. Leviton, C.J.
Tavaré, and Eugene Sobel helped in describing reliably recognized histologic features in childhood brain tumors and to establish their relationships using factor analysis and clustering.
Analyzing these associations allowed us to provide specific
survival distributions for children with infratentorial or supratentorial neuroglial tumors, as well as factors for grouping
childhood infratentorial or supratentorial tumors (potentially
useful in molecular pathology), clusters of histologic characteristics in infratentorial or supratentorial neuroglial tumors
(also potentially useful in molecular pathology), and clinical
and survival covariates in infratentorial and supratentorial
neuroglial tumors. These strategies delineate a method allowing neuropathologists to discard a priori diagnoses names and
grades and to identify measured relationships among histologic features as a basis for a diagnostic classification. This approach permits neuropathologists to improve their diagnostic
reliability and to provide specific survival distributions for
each diagnostic class rather than the relative survival information available in WHO classification or grades.
We did multiple studies of childhood brain tumor:
risk factors; secular trends, in general, and secular trends in
cerebellar gliomas; epidemiology of headache and seizures in
children with brain tumors; multicompartment brain tumors;
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Criteria for definition of a syndrome
Arachnoidal cysts in Hurler-Hunter syndrome
Morquio syndrome
Dysplastic parasagittal arachnoidal granulations
Neonatal posterior fossa subdural hematoma
Trisomy 17-18
Childhood Huntington disease
Childhood cerebral infarcts
Parturitional spinal cord transection and its effects on myelination
Methotrexate leukoencephalopathy
Long-term retrograde corticospinal degeneration following transection
Dorsal mesodiencephalic junction
Delayed myelination in sudden infant death syndrome
Functional imaging and somatosensory lateralization in newborn brain
Abducens nerve length and vulnerability
Globus pallidus glial pigment accumulation following chronic childhood illness
cytogenetic studies; temporal trends in brain tumor biopsies;
and Collins’ law in medulloblastoma. Additional studies included pediatric intracranial hemangioendotheliomas, choroid
plexus tumors, embryonal rhabdomyosarcoma of the middle
ear cleft, melanotic neuroectodermal tumor of infancy and its
similarity to the fetal pineal, stromal invasion in choroid
plexus tumors, and histologic feature importance in prognosis
of medulloblastoma. Studies with Stefan Blüml, PhD (magnetic resonance spectroscopist), working with us defined the
importance of taurine in spectroscopy of primitive neuroectodermal tumors, and citrate in pediatric astrocytomas with malignant progression. There were also multiple clinical projects
with several pediatric neuro-oncologists. Other studies we pursued are listed in the Table.
PRESENT
Currently, I am retired but continue to work a little less
than half time. On workdays, I do frozen sections and muscle
biopsies and continue to work on manuscripts. But my most
important activity is teaching, which I hope is a continuation
of the standards set by those who taught me. Children’s Hospital Los Angeles has kindly allowed me to retain my office and
to have access to secretarial services.