Cesare Lombroso MD, PhD (1917-2013)

By Robert S. Rust MA, MD

Born in Rome in 1917, Cesare Lombroso spent part of his childhood there, the rest in Palermo and Torino. His family included many authors, scientists, and physicians some of whom achieved international fame. His father was an internist and physiologist. His grandfather, for whom young Cesare was named, served as the first Professor of Mental Diseases at the University of Pavia. Grandfather Lombroso’s pioneering application of scientific/anthropological methods to the study of what he regarded as the evolutionary physiology of genius, madness, and criminal behavior earned him international attention. His opportunity to spend time with Leo Tolstoy as part of his studies of the intellectual and behavioral aspects of genius resulted in the unanticipated honor of serving as the model for a character in Tolstoy’s novel Resurrection. Grandfather Lombroso is credited as having been the person who first attracted medical student and future Nobel Prize recipient Camillo Golgi to the study of neuroscience. Golgi's neuroscientific studies were in fact first undertaken in the Lombroso laboratory at the University of Pavia. Cesare elder’s earnest methods of study—pioneering detailed and objective characterization of individuals experiencing complex diseases in order to apply statistical methodology certainly prefigured his grandson’s approach to neurological investigation. His interest in the cause and effects of pellagra on mental functions and his attempt to develop an electrophysiological machine (perhaps the first mechanical “lie-detector”) for the objective measurement of neuropsychiatric stress also interestingly prefigured his grandson’s future career interests.

Nor is thus not surprising that as a teenager, Cesare younger undertook, with similarly exceptional degree of earnestness, care, and devotion, investigations of the developmental changes in intermediary metabolism and in the homeostatic autonomic functions of the sympathetic nervous system. These studies proved relevant to digestion, malnutrition, hormonal functions, avitaminoses, temperature regulation, fever, infection, and to the effects of sensory deprivation. His studies included investigation of the role of the sympathetic nervous system in winking. Upon the basis of this work he was awarded a degree from the Garibaldi Lyceum in Palermo. However, further studies were interrupted when his father’s refusal to declare support for Mussolini resulted in the loss of his University Chair in 1937. In response, the Lombrosos were compelled to move to Paris, where his father had quickly been invited to take a position at La Sorbonne. In keeping with the strong political sentiments of his family, young Cesare had himself been active in the Italian Antifascist youth league, with which he retained ties when in France and subsequently in the United States. Nine papers, published between 1936 and 1939, resulted from Lombroso’s early research The last of these-concerning physiological effects of malnutrition and published in the Biochemische Zeitung--was awarded the Lattes Prize in 1939. A tenth paper concerned hepatic effects of experimental pancreatectomy, demonstrated a previously unknown pancreatic metabolic factor. For this work, ultimately published in Science in 1948, Dr. Lombroso received the prestigious Schering Award in in 1942.

As WWII broke out Lombroso travelled to Baltimore in order to have a three month educational sojourn. The multifaceted Cesare Lombroso paid for his travel expenses and initial support with a cash award he had received in a poetry contest. Interestingly Cesare Lombroso’s brother in law was the brilliant particle physicist Bruno Rossi who with his wife had also to find refuge at this time in the United States. Rossi, aside from his extraordinary contributions astronomy, served a key role in the Los Alamos Project that developed the atomic bomb. In Baltimore, young Lombroso came under the protection of Adolph Meyer. Neuro-anatomist and father of the American school of psychobiology Meyer arranged for Lombroso to have a job at the Phipps Clinic that paid for his expenses. Quite remarkably, his duties at the Phipps included responsibilities related to the use of one of the first of the EEG machines that had been designed by Albert Grass, a fact that Lombroso viewed later in life as having been an ironical occurrence. Meyer also exerted his influence to obtain a collegiate position and then a year of medical school at Johns Hopkins for the young Italian. It is of interest that Meyer had at almost the same time played a rather different critical role in the early career development of Lombroso’s future mentor, Raymond Adams. Adams travelled to Baltimore from Duke to meet with Meyer in order to secure advice and a training position in order that he might become a psychiatrist. The effect of his interview with Meyers, then widely regarded as among the leading American figures in psychiatry, was for Adams to conclude that Meyers’ ideas were confusing and superficial. Further, Adams was irritated by what seemed to him to be the attempt of Meyer, stroking his beard thoughtfully, to perform some sort of psychoanalysis of young Adams. The epochal effect of this reaction was for Adams irrevocably to change his ambition about becoming a psychiatrist to one of seeking neurological training and to do so elsewhere.

During his time in Baltimore that Lombroso made his first visit to Boston Children’s’ Hospital to visit his father’s friend, the famous Professor James Lawdor Gamble, Chief of Metabolic Diseases at the Children’s’ Hospital of Boston. Significantly, the initial phase of Gamble’s own celebrated career as a research physiologist involved what became a series of studies (1921-1927) of the management, metabolic effects, safety and efficacy of fasting-induced ketosis as a treatment for children with epilepsy. As the United States entered World War II in 1941, Lombroso jumped at the opportunity to place his strong anti-fascist sentiments into action. His prior antifascist activities in Italy and subsequently in France occurred under the leadership of Carlo Rosselli, whom the Fascists had murdered though he had sought refuge in France as had the Lombrosos. Lombroso found his educational activities in Baltimore of lesser importance compared to continued participation in anti-Fascist activities. He served from 1941-1944 in the Office of War Information and in the activities of the Office of Strategic Services (OSS). In Europe, the OWI served much the same function that Radio Free Europe would after the war, while the OSS (which in time became the CIA) served as an intelligence-gathering organization and in the coordination of espionage activities behind enemy lines in Europe and elsewhere. Lombroso became the Co-Chief of the Italian Short Wave Program. He also became a member of the Council of Free Italy, Vice-President of the Mazzini Society, and Co-Editor of Nazione Unite, a publication that championed Italy’s resistance movement. In 1942 he encountered at a White House meeting a young Polish émigré named Irena Kister. Their shared attraction and interests, including devoted championship of the redemption of Europe from the tyranny of Fascist and Nazi leaders resulted in courtship and an ensuing devoted marriage that was to lead in the long fullness of time to considerable happiness of a family that came to include three children and five grandchildren.

In 1945, Lombroso returned to Italy and was awarded his M.D. degree from University of Genoa in 1946. He resumed his various pre-war physiological investigations, characterizing a novel liver factor involved in lipid metabolism. Dr. Lombroso completed a two year residency in pediatrics at Genoa, passing his Boards in 1950, under the direction of Professor Giovanni deToni. De Toni was the highly distinguished physician and physiologist whose investigations contributed greatly to the understanding of infantile nephrosis, renal tubular acidoses, and deamination disorders. With his colleagues he had identified the deToni-Debre-Fanconi syndrome. Importantly, Dr. deToni viewed the field of developmental science from a broad perspective and he recognized and encouraged Dr. Lombroso’s interest in the role that neural development played in vulnerability to childhood-onset disease. Dr. Lombroso’s early interests in developmental physiology of alimentation prompted him to engage in clinical studies of cystic fibrosis and of f protein metabolism in malnourished children. Always keen to improve the lot of children, he developed and tested casein-derived feeding supplements for oral and parenteral administration. He was thus a pioneer of hyperalimentation. In the laboratory of Professor Arturo Bonsignore Dr. Lombroso investigated autonomic regulation of protein catabolism. Dr. Lombroso published eight papers from 1948-1950, expanding and completing the clinical and experimental metabolic investigations he had initiated prior to WWII. Upon the basis of this work Dr. Lombroso was awarded a Ph.D. in physiology by the University of Rome in 1950.

In the course of completing these various studies, Dr. Lombroso had become keenly interested in the neurophysiological aspects of the various clinical conditions that he encountered, particularly epilepsy. Considering what to do next, Dr. Lombroso and his wife decided that academic prospects were brighter in the United States than in Italy. Lombroso was aware that the clinical aspects of epilepsy—especially treatment—had been studied by Stanley Cobb for several decades at the Boston City Hospital, and that Cobb had attracted William Lennox to join him in compiling in 1928 an important early monograph on the physiology and treatment of epilepsy. He was also aware that the Harvard programs had included additional early luminaries in the scientific study of epilepsy as Houston Merritt, Tracy Putnam, and the pioneering electrophysiologists F. A. and E.L. Gibbs and J. K. Merlis, Dr. Lombroso successfully application to become, in 1950, the first matriculant in Lennox’s new Epilepsy Fellowship housed in Seizure Unit in the old Carnegie Building at Harvard opened his clinical career as one of the world’s first “card-carrying” epileptologists. But neither then nor subsequently did he Dr. Lombroso loose interest in developmental neuroscience—as had always been the case, he continued to be a true “clinician-scientist.” One important source of Dr. Lombroso’s interest in epilepsy,one that Lombroso soon found to be shared by Dr. Lennox: was that each had a daughter with epilepsy. Fortunately, both daughters did quite well despite that affliction—indeed Margaret A Lennox became an important epileptologist who established the EEG laboratory at Yale and subsequently engaged in research at the Institute of Neurophysiology in Copenhagen.

Dr. Lombroso’s decision to become an epileptologist caused him first to pursue, as had been the pattern throughout his academic life, studies of the basic science of epilepsy. He engaged in the study of experimental neurocortical reflex myoclonus in the laboratory of the distinguished physiologist and epileptologist Jerome K. Merlis. Dr. Lombroso was the co-author of three and first author of three papers concerning this important subject that were to be published between in 1953 and 1955. This fundamental work, studies of the developmental physiology of reflexive motor activities related to myoclonus, characterization of normal features of the auditory evoked response, and the reflexive/voluntary orientational coordination of ear positioning to environmental sounds In 1950 Dr. Lombroso became the first clinical fellow of William Lennox’s seizure unit at the Boston Children’s Hospital. In 1953 his clinical and scientific training in epilepsy were further supported by was supported for the ensuing four years by the award of one of the earliest NIH Career Development Fellowships.

Dr. Lombroso had great interest in refinement of the approach to the prevention and treatment of epilepsy and also concerning the effects that epilepsy produced on the cognition, emotions, and educational, vocational, and social aspects of the lives of individuals with epilepsy. In 1952 Dr. Lombroso published the first of six papers demonstrating the safety and efficacy of the use of acetazolamide for the treatment of epilepsy. His pioneering observations concerning the anti-seizure effects of carbonic anhydrase inhibition long preceded the mechanistic understanding of the beneficial effects that resulted for individuals with epilepsy due to alteration in GABA receptor ion channel activity—a principle much more recently demonstrated to occur as the result of administration of topiramate. Dr. Lombroso He also participated in the introduction of methsuccinamide for clinical use (1955). With trainee Gordon Millichap and William Lennox Dr. Lombroso reported in 1955 the clinical and epileptiform electroencephalographic features of childhood cyclic vomiting. In 1956 Lombroso was the co-author of a lengthy article in the New England Journal concerning recent progress in understanding and care of epilepsy.

It was evident from the start of his career as an epileptologist that Dr. Lombroso was exceptionally adept and keenly interested in combining the carefully ascertained semiological observations with precisely adapted physiological assessments in order properly to label conditions that were epileptic, identify causes, study the effects of various possible treatments, and chart the natural history, including the various risks and deficits associated with each. Highly important to him as a clinician was the refinement of the semiological appreciation of epileptic events capacity to identify the associated electrophysiological manifestations. He retained throughout his career to instill this meticulous capacities of observation and judgment in those whom he trained. He fell into the habit of drawing attention to such subtle things not in the form of lectures or handouts, but by emitting soft coughs or other polite noises at the bedside or as EEGs, or once they became available videos were reviewed—especially when such important information appeared to have been overlooked by others. Dr. Lombroso was not one to allow interesting phenomena to be unconsidered or overlooked, part of the reason that he was able to add so many important additions to phenomenological understanding of the seizures or other phenomena occurring in individuals suspected of having epilepsy in association with a widening variety of possible underlying diseases.

Dr. Lombroso’s interest in the broad spectrum of neurological disease and neuropathology had led him to spend parts of four years (1953-1956) to obtain formal training in these disciplines under Raymond Adams and colleagues at the Massachusetts General Hospital (MGH) The connection that he established with Dr. Adams led to Lombroso’s being called upon by Adams, prior to the establishment of a formal child neurology training program by Philip Dodge in 1956, to consult with him on children admitted to the MGH with neurological complaints and to comment on teaching rounds on the nature and management of their diseases. This experience widened the spectrum of illnesses possibly associated with seizures in which Dr. Lombroso was interested. Thus, for example, Dr. Lombroso’s interest in the convulsive and epileptic manifestations of heritable metabolic diseases in conditions associated with nephrosis and in infectious and other encephalitic conditions caused him to devote considerable effort to the characterization of the seizures and electrophysiological changes that might alert clinicians to a correct clinical diagnosis and prompt quick and effective treatment. This complex set of issues are reminiscent of his approach to the energetic and indeed untiring approach that he had taken to the manner in which a wide variety of conditions were shown to cause disturbances of function in the sympathetic nervous system. Dr. Lombroso would continue the studies of heritable metabolic diseases with particular concentration into the decade of the 60s and in fact beyond, whenever an interesting case promised the possibility of expanding and refining knowledge pertinent to the welfare of children with metabolic disturbances.

Dr. Lombroso achieved Board Certification in Neurology and Psychiatry in 1956. Due to the considerable attention that Dr. Lennox wished to devote at that time to the writing of his textbook, Epilepsy and Related Disorders, he asked Dr. Lombroso to assume a steadily increasing share of responsibility for the clinical and training activities in the Seizure Unit. With Dr. Lennox’s retirement 1960 and his death shortly afterwards, Dr. Lombroso was in 1962 appointed (in the usual slow manner of the Harvard system) Acting Chief of the Epilepsy Unit and Acting Director of the Division of Neurophysiology and its associated laboratories. The “Acting” designations were removed in 1968, although Dr. Lombroso’s remarkable success in expanding and improving these programs was already well underway, supported by federal and other forms of grant support for the high quality ambitions concerning educational, clinical, and research objectives that the programs aimed to achieve.

During the1960s, Dr. Lombroso devoted his attention to a remarkably broad spectrum of important topics. The topics that attracted his attention combined his longstanding interest in meticulous characterization of the physiological aspects of both normal and abnormal neurologic function in order to define distinct disease entities for which specifically selected and properly timed interventions might prove most effective. The physiological aspects upon which he concentrated included not only epilepsy, but also the intellectual, behavioral, social, and emotional issues encountered by an individual with epilepsy as well as those issues encountered by the parents and loved ones of individuals with epilepsy. Moreover, he was interested not only in the immediate challenge of such issues, but also the manner in which future challenges of such issues could be foretold and prepared for. He recognized the importance of providing such treatment during such window of opportunity as might exist to ameliorate a problem before neurological dysfunction worsened or became permanent. He was committed to refining the capacity not only of physicians, but also of parents to recognize seizures and to be equipped with methods of treatment. His quiet and highly organized earnestness was applied to improving the capacity of specialists to investigate possible seizures, to refine their clinical and electrographic characterization, to discover specific underlying causes and to find for them the best possible treatments. He recognized the importance of defining the natural history of epilepsies in order define prognosis and also favorably to influence that prognosis by the discovery of the nature and duration of such windows of opportunity for treatment that could produce that benevolent influence. In the pursuit of such effects, Dr. Lombroso’s contributions to demonstrating the importance and effectiveness of the use of intravenous diazepam for urgent treatment of status epilepticus were of fundamental importance. He introduced the subject almost simultaneously with Henri Gastaut in 1966. Thirteen subsequent papers refined understanding of oral, intravenous and rectal kinetics and dosage, and efficacy in various clinical settings.

Dr. Lombroso was also an early and quite influential proponent of oral and rectal home treatment with diazepam, just one aspect—though an exceedingly important one--of his critical advocacy of prompt treatment of seizures. Aside from the question of effectiveness, Dr. Lombroso’s encouragement of this approach was one element of what has become known as “empowerment” of patients and parents. He recognized that even if rectal diazepam were never used, it was a considerable alleviator of anxiety on the part of parents who might otherwise choose not to travel with a child who had epilepsy because of fear that while on the road, a seizure might occur in some location where they would not be able to find an emergency room or during an airline flight. Dr. Lombroso was keen to achieve a situation where it could be assured that the range of activities and opportunities of a child with epilepsy was as broad as possible and in order as well that the child might spend as little time as possible in emergency rooms and as inpatients. Rapid treatment provided the opportunity not only to prevent the worsening of existing epilepsy, but in the case of such entities as febrile seizures, the opportunity to prevent transition into an epileptic state. Dr. Lombroso exhibited intelligent pioneering interest in establishing the earliest period during which the epileptic state of patients could be approached surgically in order not only to alleviate an epileptic focus, but also to take advantage of the degree of early developmental plasticity that might be available in the brains of young individual that could avail that individual to heal in a manner that might be restorative of function. On the other hand, Dr. Lombroso was keenly interested in the identification of conditions associated with seizures that, when properly managed, might simply represent a transient vulnerability without long-term consequences. He emphasized in particular the usual benignity of febrile seizures and the importance of distinguishing such typically benign conditions as breath-holding spells, shuddering spells, self-gratification episodes, pseudoseizures, or sleep related paroxysms of the newborn from epileptic seizures.

Dr. Lombroso was particularly keen to clarify not only the clinical manifestations of distinct forms of epilepsy, but also the nature and significance of the associated electrographic manifestations. He regarded it particularly important to evaluate the significance of a number of previously described electrographic paroxysms. He and his trainees and colleagues were particularly keen to identify and report electroencephalographic paroxysms that were non-epileptic such as infantile drowsy bursts and various other artifacts. In 1966 Lombroso demonstrated the particular care and extent of investigation he was willing to undertake in the establishment or dismissal of assignation of significance to electrographic variants as he engaged in the first extensive normal control study of the 14- and 6 cycle per second positive spiking during light sleep childhood and early adolescence, a phenomenon that had first been described by Gibbs and Gibbs in 1951. He enlisted, with remuneration of $3.00 per boy for their time and trouble, 212 quite normal students of the Phillips Andover Academy. Dr. Lombroso, an exceptional linguist, provided the term ctenoids for these spikes, derived from the Attic Greek term (κτενος) for a comb. The importance of the study was that these spikes had previously been associated in poorly controlled studies published in over 200 papers with conditions ranging from migrainous headaches to a novel conception of “autonomic epilepsy” to a rather ominous implication that it was indicative of behavioral, emotional, or “destructive-regressive” disturbances, and even “criminal tendencies.” Dr. Lombroso’s study demonstrating the presence of this normal variant in 58% of these normal 13-15 year old Phillips Andover boys. .

This was a particularly interesting contribution to have been made by the grandson of the Cesare Lombroso the man whose most famous book L’uomo delinquente originated the scientific study of the “criminal mind. In 1967 Dr. Lombroso provided one of the earliest careful descriptions (preceded by papers of Bancaud, Blom) of benign epilepsy of childhood with centrotemporal spikes. Lombroso also refined the clinical semiology of this condition, having observed that the lingual sensory ***manifestations of this disorder enhances the likelihood that that have subsequently proven so important in supporting clinical suspicion that a nocturnal seizure in a child was Rolandic in evolution. Other important contributions of Lombroso and his group in this era were characterization of cyanotic and pallid infantile breath-holding spells (1967).

It is a fitting the Dr. Lombroso, the grandson of the pioneer in academic and scientific consideration of the “criminal mind” debunked the then prevalent notion that 14 and 6 positive spikes were indicators of criminal tendencies rather than one of a number of normal variants he authoritatively characterized during his career. With regard to EEG changes that were significant indicators of a particular form of epilepsy, he was keen about refining the understanding not only of paroxysms, but also of background activity. He conceived that the study of the clinical evolution of individuals with a particular form of epilepsy and of whatever transiently associated stresses as may have occurred at the onset of epilepsy or subsequently (e.g. lengthy duration of paroxysms, hypoglycemia, ischemia, asphyxia) provided information that permitted refinement of the outlook that could be forecast for these children. Moreover, the determination that particular stresses worsened the outlook for a particular epilepsy greatly enhanced the emphasis that could be placed on particular management principles.

A remarkable attribute of Dr. Lombroso was his capacity to enlist the efforts of an extraordinary series of talented collaborators at career stages ranging from training to all subsequent career phases. Many were already keenly motivated by their encounter with Dr. Lombroso and by his capacity to refine such projects as they may have had in mind. Dr. Arthur Rose was one such individual, whose persistent and intelligent interest in neonatal seizures had prompted him to seek electrophysiological training under Dr. Lombroso. Together, the pair completed a pioneering prospective study of 137 neonates with seizures that concentrated attention on the importance of achieving prompt and effective treatment of seizures. Published in 1970 and cited 222 times to date, this paper remains a classic. It meticulously characterizes the manner in which the study of specific forms of neonatal neurological stress and the associated clinical and electrographic features of the seizures that result may intelligently characterize treatment efficacy as well as prognosis. Dr. Lombroso and many ensuing trainees and colleagues continued to devote attention to this important subject, producing 34 more original papers, largely prospective, and many chapters over more than four and a half ensuing decades, including several of the earliest studies of the use of ultrasonography in characterization of abnormalities in early developing brain that were published in 1965-1967. These papers and chapters addressing a wide range of important questions have provided one of the world’s great sources of information concerning not only neonatal epileptology, but also normal neonatal and infantile neuroelectrophysiological development.

The Lombroso group considered the manner in which various stages of brain development influence vulnerability to particular types of seizures and demonstrate the possible association between particular seizures and disruption--in some instances by little more than a single seizure even in an otherwise normal baby--of the ensuing phases of brain maturation may occur. Lombroso and his associates also demonstrated the possibility that some seizure-evoked developmental loss is regressive, the neonate reverting to an earlier phase of brain maturation. In some instances such regression was shown on follow-up to be transient, while in others it was found to be persistent. They have clarified classification of the causes and nature of diseases states, efficacy of various forms of treatment, and remarkably extended demonstration of outcome including the distinction between transient and permanent forms of brain dysmaturity. Where possible, Dr. Lombroso sought, as he demonstrated in a 1975 paper, to correlate neuropathological changes observable in the brains of infant that died in order to establish the location and nature of acute brain injuries and long-term follow-up clinical studies to establish which neurological abnormalities may be transient. In order that these functional disturbances, particularly seizures, might be followed intelligently, it was clear to Dr. Lombroso that improvements were required in their clinical and electrophysiological characterization.

The currently employed system of classification of neonatal seizures employed today sits firmly upon the foundation that Lombroso and Rose established in 1965 based on 137 neonates. In addition to other refinements, two highly cited detailed papers by Lombroso and Greg Holmes, published in 1993 summarized in detail all that had been learned concerning interpretation of the neonatal EEG at varying stages of development and the prognostic value of what was found. Many individuals in the Lombroso and other laboratories, of course, participated in the work that refined these data and placed them within the context of pertinent clinical and basic science investigations completed in many laboratories. Dr. Lombroso seldom if ever permitted the fine studies produced by his own group or generated in other laboratories to be the last word on a subject in which he was interested. If the Rose/Lombroso study provided a firm foundation for diagnostic refinement, time alone could add to the properly classified seizure type, pathogenesis, and notation of approach to treatment the “last word”: the outcomes to be anticipated for every subcategory. Lombroso provided this data for 190 full-term neonates in 2007, 35 years after the publication of the Rose study. This paper confirmed the supposition that outcome of these infants could best be classified by etiology and that clinical information could be supplemented by experimental basic science investigations that had been designed upon the basis of the best clinical information then available. Putting all of this data together, Lombroso’s review provided another characteristic feature: he condensed all that known both clinically and experimentally upon this subject as of 2007 and provided to all who were interested a list of the gaps that remained between clinical and experimental data concerning this subject.

Many other exceptionally talented individuals were attracted to train and work with Dr. Lombroso, benefiting from his own exceptional scientific and clinical capacities and providing in return their diligent and devoted work in return that only a few representative examples of those who trained with him can be provided in this space. Dr. Lombroso’s interest in distinguishing normal from abnormal complex physiological functions led him in the 60’s to enlist a highly gifted fellow, Frank Duffy, to study of the electrophysiological aspects of voluntary saccadic eye movement, to characterize visual evoked responses to various stimuli and also the electrophysiological characteristics of amblyopia. Dr, James Burchfiel joined Duffy in performing quite important and elegant visual cortical single unit studies of the transience or permanence of seizure-related eye movement inhibition. They were designed to identify key elements in the Lombroso approach to the study of outcome of neurological disturbances. The studies were designed to identify the source of dysfunction, the reasons why a particular child was vulnerable to its effects, whether such disturbances were to prove transient or permanent, and which were responsible to an appropriately selected treatment. Dr. Duffy was to remain Dr. Lombroso’s colleague throughout his own ensuing career, collaborating on 11 papers and the development of brain electrical mapping (BEAM) the report of the methodology and utilization of which to make highly sensitive analyses of clinically relevant data contained in the background of the EEG are among the most highly cited papers of the work of the Lombroso group.

Giuseppe Erba also joined the Lombroso team as a fellow in the 1960s. The thirteen papers that he published with Lombroso made contributions that were diverse in topic and methodology and quite important. These included three pioneering ultrasonographic studies of neonatal brain, preceding by more than a decade the work by Hill, Volpe, and others that would render this imaging modality an essential element of neurological management of neonates. The most influential and durable contributions by Erba and Lombroso were seven remarkable papers that employed data gathered from prolonged EEG and EMG monitoring sessions to produce a durable taxonomic classification of primary or secondarily generalized epilepsies arising in the neonatal and subsequent periods of life.

The taxonomy established by Lombroso together with Erba was based on clinical and electrographic as well as electromyographic distinctions between seizures that were partial or generalized in onset, tonic, atonic, myoclonic, or without physical convulsive activity. In addition to prolonged video EEG recording, infants and children with these conditions were studied with EMG. Among the various differential considerations were autonomic disturbances, clinical entities upon which Lombroso had “cut his teeth” as a researcher when a teenager. Movement disorders constituted another class of differential considerations. The mix of conditions clarified by the Lombroso laboratory included conditions that had been previously poorly recognized and mislabeled, such as breathholding spells, reflex syncopes, hyperekplexia, paroxysmal dyskinesias, and nocturnal frontal loe epilepsy. Giuseppe Erba played an especially important role in meticulously carrying out these studies. The result was that these various, often glibly and inaccurately labelled seizures acquired a considerably greater degree of respectable diagnostic accuracy. Elegance of detail and accuracy permitted the etiologies of those conditions found to be epileptic seizures to be much more reliably ascertained, including seizures and epilepsies that were genetically determined and those that arose because of various forms of brain injury. Lombroso and his colleagues demonstrated the careful observation and electrophysiological testing reduced the untidiness and expense associated with large panels of metabolic and genetic tests. Dr. Lombroso’s highly cited review of the results obtained in his laboratory concerning the characteristics of the early myoclonic and early infantile epileptic epilepsies has proven a classic.

Throughout his career, Dr. Lombroso strove to establish the etiology and mechanisms of injury to tissues caused by a wide variety of pathogenic mechanisms. In addition to the identification of causes and where possible effective treatments, he strove to establish which forms of injury were transient and which permanent and whether careful long-term clinical and electrographic follow-up could distinguish likely transience from likely permanence. Elegant papers reported the evaluation, classification and prognostic significance of EEG and evoked response patterns of children in coma. Such determinations provided a foundation upon which the pioneering concentration of the Lombroso based their observations as to which infantile or childhood epilepsies might lend themselves to treatment with lesionectomy and which to subtotal or total hemispherectomies. Such considerations, Dr. Lombroso recognized had to be placed within the context of the positive or negative effects that such interventions might have on the ill developing brain of a child. Given his experience and his thoughtful and intelligent approach to this complex set of questions, it is not surprising that Dr. Lombroso was approved for the first important NIH grant for the study of such diagnostic and therapeutic approaches to the management of childhood epilepsies.

The Lombroso group concentrated particular attention on establishing the value and reliability of the combination of clinical and electrophysiological in making decisions concerning treatment and they did so with critical awareness of the challenges that such decisions posed with regard to developing brain. They were aware that treatment decisions had as well to consider the contribution that might be made by heritable developmental or metabolic conditions. They sought to refine all of these elements in order not only to develop and select therapeutic interventions, but also to prepare the parents of children with the best possible understanding of the natural history of brain dysfunctions that arose not only from metabolic or genetically determined vulnerabilities, but also from various prenatal and birth injuries to brain. The collaboration of Drs. Lombroso and Erba, already noted, proved quite durable, lasting many decades. Their long-term collaboration generated hundreds of citations to their papers clarifying much that has proven to be of great importance in the understanding of the clinical and electroencephalographic features that distinguished of the early infantile benign from severe myoclonic encephalopathies. Lombroso summarized the contributions of his group and those of other groups in an elegant, highly cited paper, in 1990.

The approach that characterized the investigational activities of Lombroso, his fellows, and his colleagues, was one of collecting for study largest possible number of patients organized upon the basis of meticulously characterized clinical and physiological similarities and differences, to apply what treatments seemed appropriate, and thereafter to follow these patients as long as possible in order to characterize the efficacy of treatments and the outcome of patients as consequences of their particular disease and treatment. Fellows of the highest quality were attracted to devote considerable effort to Lombroso’s intelligently designed projects, acquiring in the process skills and approaches that would pass on the “Lombroso methods” to ensuing generations. Individuals who trained with Lombroso could rely upon the fact that whatever course their studies might take, their mentor knew the importance of their assumption of as much responsibility as they were capable of, gently nudging the course of investigation into the correct path until completed. Among the projections undertaken by individuals that resulted in exceptionally highly cited papers wereYukio Aoki’s investigations of the electroencephalographic features of Reye syndrome (1973), Generoso Gascon’s of the mysterious pathophysiology of Landau-Kleffner syndrome (1973) and the complex matters of diagnosis and limbic multifocality of gelastic seizures (1974),

Genjiro Hirose’s consideration of the neurophysiological and clinical characteristics and advisability of resection of thalamic tumors of children (1975) was a critical consideration of a quite difficult and previously unresolved set of clinically questions. Dr. Lombroso examined with similar care the nature and importance of electroencephalographic features of underlyibng disturbances ranging from brain edema to nephrotic conditions. He was a operson with remarkably diverse curiosity, an urge apparently unquenchable by anything short of finding an accurate answer to whatever might be said of such things not only electroencephalographically, but also with regard to such meaningful significance as might reliably be found in association with those EEG disturbances. His goal was not one of demonstrating remarkable sensitivity to trivialities. It was one of finding things that meant something either to the patient at hand, or to improving the understanding of the pathophysiology of disease—understanding that might be employed to identify an hitherto unidentified pathological mechanism that might change from irreversible to traisient and reversible if an intelligently designed therapeutic intervention couild be identified and validated. With Natalio Fejerman Dr. Lombroso published the first description of benign myoclonus of infancy (1977). Mohammed Mikati’s large classic study of pyridoxine-dependent epilepsy, a study that included the then oldest survivor of the condition at 28 years of age (1991) was another landmark paper of the Lombroso group. Mikati and E. J. Carrazana of the Lombroso group provided a quite elegant demonstration of the facilitation of infantile spasms by partial seizures (1992, 1993). Mikati, Carrazana, and the Lombroso group also established the fact that the origin of infantile spasms themselves in is in cortex rather than, as had previously been suggested, subcortex of brain. It should be remembered that Dr. Lombroso was one of the great figures in the modern history of the diagnosis and management of infantile spasms, having published in 1983 two papers that were the first prolonged prospective studies of large cohorts of children with infantile spasms on either and idiopathic or symptomatic basis. His group importantly demonstrated the superior efficacy of natural to synthetic ACTH in the treatment of infantile spasms not only in control of seizures, but also with regard to prevention of cognitive injury.

Basic science was not neglected by members of the Lombroso group. A particularly outstanding example was exemplified by Frances Jensen’s characterization, with Holmes and Lombroso, of variation in long-term susceptibility to encephalopathy or of epilepsy generated by perinatal hypoxia or anoxia depending upon the developmental age of the neonate (1992) and investigation of the value of excitatory amino acid antagonists for the management post-hypoxic seizures—early phases of an ensuing highly productive and influential career applying clinical sophistication to basic science studies of epilepsy. It is of interest that Dr. Lombroso’s successor as Chief of the Boston Children’s’ epilepsy unit manifested a similar pattern of leadership, publishing seven important papers together with Dr. Lombroso and other members of the group that further characterized aspects of neonatal seizures, infantile spasms. Among the collaborations of Drs. Lombroso and Holmes were papers published in 1993 characterizing the significance of background EEG abnormalities and the other the prognostic value of the EEG’s obtained from neonates with seizures.

Dr. Lombroso was fastidious in his recognition with first-authorships of the contributions of those he trained—as indeed was his successor Dr. Holmes. He provided highly active and intelligent leadership in study design, execution, and interpretation of results. Dr. Lombroso was quite legitimately the first or sole author of many papers, including various pioneering studies that identified the characteristics of various epilepsies. These include first or early detailed descriptions seizures and epilepsy associated with inborn metabolic errors (1962), a category that would continue to engage the attention of Dr. Lombroso and his laboratory for several ensuing decades. It was in 1965 the that Dr. Lombroso first localized of the electrographic and motor phenomena of subacute sclerosing panencephalitis (SSPE) to the basal gangliar reticular formation. Dr. Lombroso also contributed exceedingly important emphasis on the critical diagnostic fact that in the early clinical stages of SSPE the disorder was often and quite unfortunately mistaken for a primary psychiatric disturbances (1965). It was in 1965 that he also described the value of thiopental in EEG activation. In that same year he published his first of what would become many popular contributions to the education of parents about the nature of epilepsy.

Papers [published in the 1970s included a lengthy consideration of the differentiation of of transient from permanent neurophysiological dysmaturity of neonates dying in infancy (1975), the highly cited first description of benign myoclonus of early infancy (1977), and several papers providing detailed quantification of normal and abnormal electroencephalographic developmental scales for premature and full-term neonates (1979 and 1985). Other first-authored papers include his well-known prospective studies of the clinical and therapeutic study of infantile spasms (1983) and his study of paroxysmal choreoathetosis (1995). In 1997 Dr. Lombroso published a remarkable long-term follow-up of individuals with primary generalized epilepsies. He devoted meticulous attention to epileptic conditions associated with inborn errors of metabolism throughout the ‘60s. In 1990 he published a classic review concerning the distinction of benign and severe forms of early myoclonic epilepsies. Dozens of important papers concern the diagnosis and treatment of infantile spasms, including the role that focal cortical dysplasia may play as an inciting and remediable influence. In 1990 Dr. Lombroso published a classic review concerning the distinction of benign and severe forms of early myoclonic epilepsies. Dozens of important papers concern the diagnosis and treatment of infantile spasms, including the role that focal cortical dysplasia may play as an inciting and remediable influence.

Dr. Lombroso was interested throughout his career in the characterization of the differences of epileptic movements from those arising on the basis of toxic effects of medications, metabolic disturbances, infections or genetic determination. Dr. Lombroso published a demonstration of the induction of a tic disorder with lamotrigine treatment (1997), a detailed study of the pathophysiological findings of paroxysmal non-kinesigenic dyskinesia.(1999), and a report of nocturnal paroxysmal dystonia associated with epilepsy and with cortical dysplasia (2000). He distinguished features of hyperekplexias and paroxysmal dyskinesias from severe myoclonic epilepsy of infancy and the features that suggest channelopathic conditions that provoke unusual movements. His study of epileptic pavor nocturnus (2000) nicely amplified information provided in 1995 by Sam Berkovic and colleagues in Australia and Montreal—a somewhat embarrassing set of revelations to neurological and pediatric communities that had long mislabeled and misclassified this condition as a sleep or psychological/psychiatric disorder. Psychologists M.J. McIntyre and P.B. Pritchard collaborated with Dr. Lombroso in several highly cited studies of the psychological and electrophysiological differences (1976) and the psychological complications of epilepsies arising in the right as compared to the left temporal lobe (1980).

It is quite remarkable to consider the evolution of the Children’s Seizure Unit under Dr. Lombroso’s direction after 1962. The Unit grew in staff size from fifteen to fifty-two as of the nineteen seventies, replete with physicians, nurses, neuropsychologists, neuropsychiatrists, research and clinical technicians, social workers, and vocational counselors. In this fashion the unit had been rendered truly comprehensive. Dr. Lombroso was remarkably successful in attracting Federal, State, and private foundation grants in order to support the research activities of the Unit, building first the Lennox Foundation, subsequently the Lombroso Foundation, and finally the combination of these two large funds. The technical capacity of the unit included continuous long-term video EEG and sleep polygraphy monitoring; Dr. Lombroso collaborated with pioneer pediatric neurosurgeons Franc D. Ingraham, Don Matson and John Shillito in pioneering work in pediatric epilepsy surgery, some sixty children having experienced this therapeutic approach by the mid-1960s. The Unit also became involved in, under the leadership of Italian neurophysiologist Ruggiero Corazza, experimental and clinical studies of the neurophysiology of the central visual system. The productivity of the unit benefited greatly from the fact that Dr. Lombroso had a clear vision of what was required to prepare his unit to undertake highly important clinical and basic science studies and his success in providing for such needs. The additional critical elements were his capacity to engage and engender cooperation of other scientists, physicians, and surgeons within the Harvard system as well as to recruit and inspire several ensuing generations of outstanding individuals to participate in the studies he envisioned. Between 1962 and his “technical” retirement in 1988, Dr. Lombroso directed the training and/or research activities over an average of 16 months of more than 240 postgraduate fellows, 82% of whom held MD and 18% PhD degrees. More than one-third of these individuals then pursued academic careers, most rising to the level of tenured professorships. The cadre of trainees was strikingly international, including individuals who returned to 28 different countries to establish epilepsy programs.

Dr. Lombroso’s pioneering concern about what is now called “quality of life” for patients with epilepsy and their families led him to publish papers on the subject of “Living with Epilepsy.” Among the important pioneering examples of Dr. Lombroso’s program was the establishment of the Family Service Team that he assembled consisted of professionals dedicated to the characterization and amelioration of the cognitive, psychological, psychiatric, emotional, and social disturbances experienced by children with epilepsy. One important element was concern regarding the economic impact of epilepsy with application of ameliorative approaches that included education and employment of individuals with epilepsy. The unification of various clinical and support services not only rendered the best possible care, it enriched research efforts. It alleviated the possibility that consulting services regarded the expedient care of patients with epilepsy as less urgent than Dr. Lombroso did. It led him, as well, to expand his definition of care of patients with epilepsy to incorporate diseases of other organ systems. Dr. Lombroso followed in Dr. Lennox’ large footprints regarding the mission to educate not only neurologists and technicians regarding epilepsy, but also non-neurological physicians, nurses, psychologists, social workers, teachers, and the general public.

Over more than half a century of mentorship, Dr. Lombroso attracted trainees from throughout the world, individuals who would carry his methods and program model back to their hospitals of origin. He has trained more than 240 post-graduate fellows, 82% of whom were physicians and 18% PhDs. As the mean training for these individuals has been 1.4 years, this represents 336 years of aggregate effort on behalf of enlarging the cadre of individuals devoted to the study and treatment of epilepsy. Dr. Lombroso’s many distinctions include Presidency of the American EEG Society and the American Epilepsy Society as well as distinguished positions and important in numerous American and International professional societies. He received the Gold Medal and Special Award in Clinical Neurophysiology from the International League Against Epilepsy, the Herbert Jasper Award of the American Clinical Neurophysiology Society, and the William Lennox Award of the AES, and the Silver Medal of the Italian CNS. He received honorary degrees from universities in Argentina, Italy, Brazil, and Czechoslovakia.and Honorary Membership in national neurological societies of Japan, Italy, Brazil, Argentina, Great Britain, Canada, France, and from the European Brain Research Association.

In 1988 Dr. Lombroso became Emeritus Professor at Harvard, and in 1989 Chief Emeritus of the seizure unit at the Children’s Hospital. In 1990 joined his old friends and long-term colleagues Drs. Erba and Burchfiel at Rochester, where he became Adjunct Professor in Neurology. After exerting his usual remarkable energies and expertise in that position for a number of years, he finally “retired” to Boston, though he continued to write and to analyze and publish the results of prior research. He has also maintained an office to see patients in a rather constricted space that included a venerable and indestructible rather early Grass electroencephalograph. This permitted him to continue, as he was asked, to combine clinical and electrophysiologic bedside expertise in the care of patients. Dr. Lombroso was of course multilingual--if at times his English and perhaps a few other languages were heavily accented. But his capacity to clearly convey concise and elegant observations and ideas—together with equally eloquent in facial expressions and occasional gestures was inspiring. Sometimes his mode of expression consisted of soft throaty noises that together with his obvious concentration on a page of an EEG containing a significant finding that had apparently been overlooked by the crowd of colleagues, fellows, and residents gathered for EEG reading quickly alerted all to the fact that something had been overlooked and deserved intelligent commentary by someone. Similar subtlety alerted those who rounded with him to events at the bedside.

Dr. Lombroso was one of the most observant and good natured of men, traits that do not always combine so beautifully with perfectionism. However, his sense of humor and good nature made him inveterately patient with the very large number of people who required his subtle cues in order that they might note, appreciate, and understand things that he wished for them to note, appreciate, and understand. His own understanding and appreciation extended as well to history, music, art, and literature. Among other things that he appreciated so deeply as to have spent a fair portion of his life to trying to assure for others were fine things of life that he had tried to protect from the depredations of European dictators for all peoples of the world. It was an ambition that he had shared during dark days of a World War with the earnest young woman whom he married. Both of these remarkable people shared these ideas with their children. The children to whom they devoted considerable attention and understanding came to include a nurse, a psychologist, and a molecular neuropsychiatrist. Dr. Lombroso’s friends included not only clinicians, scientists, therapists, and technicians, but also noteworthy people of letters and famous musicians. Dr. Lombroso died on October 13, 2013.