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Show LEGACY Irene E. Loewenfeld, PhD Physiologist of the Pupil H. Stanley Thompson, MD and Randy H. Kardon, MD, PhD Abstract: Irene E. Loewenfeld, PhD has devoted a long and vigorous professional life to understanding the workings of the pupil of the human eye. Her interest in the pupil began in 1940 when she went to work as a technician in the pupillog-raphy laboratory of Professor Otto Lowenstein at New York University. It culminated in her widely admired textbook The Pupil, published in 1993. Among her many contributions, Loewenfeld provided rigorous observations about Adie tonic pupil, anisocoria in optic tract lesions, Argyll Robertson pupil, oculomotor paresis with cyclic spasms, and innovations in electronic recordings of pupil movement. (/ Neuro- Ophthalmol 2006; 26: 139- 148) rene Loewenfeld, PhD was born in Munich, Germany in 1921. Her grandfather, Theodor Loewenfeld, had been a distinguished professor of law in Munich. He was born in 1848 into the family of a Munich chocolate manufacturer. A top performer in his class at the Wilhelm Gymnasium, he later studied law at the University of Munich, supporting himself by tutoring other students. He had obtained his law degree and was admitted to the bar at age 23. For his law school dissertation, he tackled the prize question posed by the University, winning the prize and graduating summa cum laude. After winning his doctorate in law, he joined the law faculty of the University of Munich, editing the law school's journal and teaching law students continuously for 82 semesters without a break ( 2) As a Jew, he could never expect to receive a professorship, but he was elevated to Honorary Professor, a non- salaried position, and later received the Gold Medallion of the Bavarian Academy of Sciences and the title of " Geheimer Justitzrat," an honor equivalent to Queen's Counsel in England that recognizes life accomplishment in jurisprudence. In 1882, he married Sophie Marx. Philipp ( 1887- 1963), their third child, was Irene Loewenfeld's father. As a youth, Philipp's chief interest was music. He had perfect pitch and could sing melodies before he could talk. He had lessons in piano, cello, music theory, and voice. It was his ambition to become a professional musician, but he chose law. Philipp married Charlotte Winkler, who was not Jewish, in 1914, and they had three daughters: Ann and the twins, Irene and Eva. He set up a busy law practice in Munich. Politically active in the Social Democratic Party, Philipp watched Hitler's National Socialist ( Nazi) party gain strength in Munich and knew well their anti- Semitic agenda. At a meeting of the Association of Social Democratic Jurists in Berlin in 193 3, he presented a paper entitled " The Use of Criminal Law as a Political Weapon" ( 5). As a refugee in Switzerland, he would later publish a book entitled " Political Murder" ( 6), a legal history of assassination for political purposes. Many years later, in New York, he wrote an autobiographic account of the rise of the Nazi party ( 16). FIG. 1. Irene E. Loewenfeld, PhD on her 80th birthday in New York. J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 139 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Thompson and Kardon FIG. 2. Professor Theodor Loewenfeld ( 1848- 1919), Irene's grandfather, in 1912, when he was a law professor at Munich University. When Hitler came to power, Philipp knew that on short notice he might soon have to run for his life. In conversation with us on several occasions, his daughter Irene Loewenfeld picked up the storyline. HST & RHK: What of your childhood in Germany? IEL: In 1932, when I was 11, the Nazis started gearing up for a national election. There were billboards everywhere. I remember one of them clearly: it showed a beautiful blond man using a club to beat a cluster of ugly wretches, and the message read, " Kill the Jews!" I wondered whether that had anything to do with us or not. In school, we were in a Catholic class but did not participate in religious instruction. My father was Jewish, but my mother was Lutheran. FIG. 3. Lottie Winkler and Philipp Loewenfeld, Irene's father, on their wedding day in 1914. My father's law practice was nourishing. It consisted chiefly of criminal cases, but he and his associates were also involved in a number of important political cases against Hitler, Roehm, Hans Frank, and others. Frank, his frequent opponent, had often threatened him in open court about " rolling heads" once the Nazis came to power. ( Hans Frank was later condemned at the Nuremberg Trials for his involvement in the massacre of 40,000 Polish Jews and hanged in 1946.) One day in March 1933, Frank bragged in his own law office that he had obtained a warrant for my father's arrest and that " Loewenfeld would not leave the country alive." However, a secretary from Frank's office called my father's secretary and suggested that my father quickly flee the country. He had an international law matter pending in Zurich, so he grabbed his briefcase and took the next train to Zurich. He later found out that the Gestapo had missed him at the Swiss border by 15 minutes. HST & RHK: Did he get work in Zurich? IEL: He applied for asylum in Switzerland and was accepted as a " resident foreigner," but he was not permitted to practice law. Instead he used his knowledge of the law to get endangered people and their belongings out of Germany; he knew all the loopholes in Nazi law and Swiss law. He had been able to get a number of South Bavarian poachers out of jail, and they all seemed to know his name. He would not take money from these men because of his promise to the Swiss authorities that he would not practice law. But the poachers helped him by 140 © 2006 Lippincott Williams & Wilkins Irene E. Loewenfeld, PhD J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 FIG. 4. The Loewenfelds and their twin daughters Eva and Irene on the back steps of their apartment at Pinzenauerstrasse 5, Munich, in 1926, when Irene was five years old. smuggling Jews over the mountains on narrow trails and across the border to safety in Switzerland. HST & RHK: Did the rest of the family join him in Switzerland? IEL: Within a year, my sister Ann was sent to Switzerland. By 1933, the Nazis were in complete control, and my sister Eva and I were being called names in school. HST & RHK: Were your mother's relatives supportive? IEL: My mother was furious that most of her relatives seemed to think that Hitler wasn't all that bad. We were often accused of inventing stories about the Nazis, and this just added to her outrage. In July 1934, my mother, Eva, and I went on a vacation to visit my father in Switzerland. When we got there, my mother refused to go back to Germany. My parents went to the Swiss authorities and had our entrance legalized. But even in Switzerland, our future seemed ominous and uncertain. The Germans were invading everywhere. If the Nazis got their hands on us, they would of course have killed my father, and perhaps all of us. If Hitler came south, we could not escape through Italy because of Mussolini, and my father didn't trust the French. Since my father couldn't work at his profession in Switzerland, he soon started planning to take his family to America. 141 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Thompson and Kardon FIG. 5. Irene ( inset) in school in Munich, in 1928, at age seven. HST & RHK: How did you get away? IEL: We went across France on an overnight train and felt very lucky to get the last boat out of Le Havre. We were on the ship at the time of the Czechoslovakian crisis in late September 1938, when Chamberlain said that he had " saved the world for democracy." HST & RHK: How did your mother's family react to all this? IEL: The oldest of my mother's brothers was kind and supportive, but the youngest was an out- and- out Nazi. My mother's mother never understood why we slipped quietly out of Switzerland. She thought it was inexcusable that we didn't visit her before we left Europe. My mother wrote back to her saying that she too regretted this, but it was impossible for her to put her family at such risk. Grandmother wrote back to say that mother was entirely wrong, because " nowhere on earth does one travel more safely than here with us in Germany." HST & RHK: How old were you when you arrived in America? IEL: Eva and I were 17 years old. Ann, who had preceded us to America, was then 21 years old. HST & RHK: Was your father able to practice law in New York? IEL: They offered him the bar without examination. But he was already over 50 years old and just beginning to learn English. His Bavarian accent was very marked, and he felt that his English would make it difficult for him in criminal litigation where an actor's facile tongue and skill with subtle inflexions are important. Besides, he still had a lot to learn about American law. He ended up helping FIC. 6. The Loewenfeld daughters Irene, Ann, and Eva in Munich, in 1930, when Irene was nine years old. 142 © 2006 Lippincott Williams & Wilkins Irene E. Loewenfeld, PhD J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 FIG. 7. Philipp Loewenfeld in 1939 on his arrival in New York. people out, as he had done in Switzerland, by offering advice on how to invest their money, resolve rent disputes, and so on. He was an excellent pianist, and he finally bought an old restored Steinway that he loved. He died at age 76 in 1963. HST & RHK: Did you go to school in New York? IEL: In retrospect, I must have been a difficult teenager. My education ended up being spectacularly irregular. After I finished middle school in Zurich at age 14, I went to art school because it was made clear to us that no Swiss medical school positions would ever be open to foreigners like me. On arriving in New York, I could have entered high school as a senior, but my English was terrible, and I would have had to struggle with social pressures and learn English and other subjects all at the same time. I knew that I already had a better- than- average general education from my own personal reading, so I stayed out of school. HST & RHK: How did you start to work for Dr. Lowenstein? IEL: My parents knew the Lowenstein family. They too had fled from Germany to Switzerland and then to America, so when I was struck on the back of the neck by a hard rubber Frisbee at the beach in 1939 and developed severe neck pains shooting into my arm and hand, I was taken to see Professor Lowenstein, who had recently arrived in New York. He reassured me, and the pain did eventually clear up. Lowenstein needed someone to help in his pupil lab- someone who was careful, accurate, and good at drawing and measuring- and I was at loose ends. I was fascinated by the pupillary movements. I was just 18 when I started to work in that lab. I took my New York Regents examination as an external student and then college courses one after another at New York University and Columbia University while working full time in the lab. In 1948, we transferred the lab to Columbia University's Eye Institute. I remained in a pupil lab for the rest of my professional life. HST & RHK: Where did you write your thesis on reflex dilatation of the pupil? IEL: In 1955, the University of Bonn decided that Dr. Lowenstein, their former professor in Neuropsychiatry, who as a Jew had been forced to leave his position and his country in 1933, should be formally reinstated. FIG. 8. Irene Loewenfeld in 1961. 143 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Thompson and Kardon FIG. 9. Irene Loewenfeld with her collaborator, Professor Otto Lowen-stein, in 1963. FIG. 10. Irene Loewenfeld's magnum opus entitled The Pupil: Anatomy, Physiology and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993 and 1999. While he was there for this ceremony, he made inquiries into the university rules for foreigners to get a doctorate in natural history from the university. He found that he could be my sponsoring professor and that my period of residency in Bonn could be waived because I could already speak German, but that I would have to personally submit my thesis in Bonn and defend it before a local committee. That thesis, on the mechanisms of reflex dilation of the pupil, was later published in 1958 ( 7). Upon returning to New York, I was now " Doctor" Loewenfeld, and it became possible for me to apply for National Institutes of Health ( NIH) research support. We received one of the first NIH research grants and took on some research fellows, starting with Drs. Heiichiro Kawabata and Shinji Oono from Japan. HST & RHK: When did you decide to write " The Book" ( 1)? IEL: From the early 1950s, Dr. Lowenstein had thought of writing a book about the pupil. At first it was to be a summary of our experimental findings, but it soon became clear that a more complete text was needed. Existing summaries were outdated and spread out over many branches of science, in several languages, and filled with controversies. 144 © 2006 Lippincott Williams & Wilkins Irene E. Loewenfeld, PhD J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 In 1956, we started making preparations. Dr. Lowenstein would handle the clinical areas, I would concentrate on the basic science aspects, and we would work together on the overlapping areas. By 1964, Dr. Lowenstein had written about 3,000 pages of manuscript for the clinical parts of the book, and we were about to condense and edit those pages when he learned that he was fatally ill. After his death in 1965,1 found that as a physiologist, I had difficulty doing the revising and pruning without his advice and clinical judgment. I therefore spent the next seven years reading and analyzing the clinical literature and tracking down the chief controversies to their sources. I began writing the final text in 1973, about a year after I followed Robert Jampel, MD, to the Kresge Eye Institute at Wayne State University in Detroit. At that time I hoped to complete the book in two years, but it took much longer. With the help of a grant from the National Library of Medicine, I was able to turn the manuscript over to Wayne State University Press in 1983. Publication was delayed because of administrative changes, so the manuscript was updated in 1986 and again in 1988. In the meantime, the original press director moved to Ames, Iowa, to direct the Iowa State University Press, so we decided on joint publication by both university presses. At this point, Mr. Joseph Piscopo, because of his interest in narcolepsy, made a generous contribution to the Iowa State University Press to support the publication of the book. Five hundred copies were printed in 1993, and they were soon sold out. A second edition, with minimal changes and identical pagination, was then published in 1999 by Butterworth- Heinemann. HST & RHK: You worked on the pupils for over 60 years. Looking back, what pleases you most? IEL: I was always proud of being able to work with Professor Otto Lowenstein. He had been thinking about the workings of the pupil for twenty years before I met him. It was his detailed knowledge of the people who did the significant work on the pupil during those interwar years that kept the literature alive for me. It was his enthusiasm about pupillary size and pupillary movement as an indicator of mental activity that led to my thesis work on the mechanisms of arousal mydriasis and stimulated others to use the pupil as an indicator of wakefulness. REFERENCES 1. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. ( 2nd edition). Ames, Iowa: Iowa State University Press; 1993. ( 2nd edition, Butterworth- Heinemann/ Elsevier; 1999). 2. Landau P. Theodor Loewenfeld ( 1848- 1919). In: Grosse Jiidische Gelehrte An Der Miinchener Juristichen Facultat. Landau P, Nehlsen H, eds. Miinchener Universitatsschriften. Juristische Facultat. Abhandlungen zur rechtswissenschaftlichen Grundlagenforschun-gen. Band 84. Activ Druck u. Verlag: Ebelsbach; 2001: 45- 62. 3. Deleted in proof. 4. Deleted in proof. 5. Loewenfeld Philipp. Das Strafrecht als politische Waffe. Heft 1 in " Die Sozialistische Rechtsidee". Schriftenreihe der Vereinigung Sozialdemokratischer Juristen herausgegeben. Berlin: Verlag J. H. W. Dietz, nachf; 1933. 6. Kilian H. Der Politische Mord. Europa- Verlag- Ziirich; 1936. 7. Loewenfeld IE. Mechanisms of reflex dilatation of the pupil: historical review and experimental analysis. Doc Ophthalmol 1958; 12: 185^ 148. 8. Loewenfeld IE. Injury and repair in the nervous system. In: Loewenfeld IE The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993: 518- 627. 9. Loewenfeld IE, Thompson HS. The tonic pupil: a re- evaluation. AJO 1967; 63: 46- 87. 10. Jones IS. Anisocoria: attempted induction by unilateral illumination. Arch Ophthalmol 1949; 42: 249- 53. 11. Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993: 927, 930- 93. 12. Loewenfeld IE. Pupils in optic tract lesions [ letter to the editor]. J Clin Neuro- ophthalmol 1983; 3: 221- 2. 13. Loewenfeld IE, Thompson HS. Oculomotor paresis with cyclic spasms: a critical review of the literature and a new case. Surv Ophthalmol 1975; 20: 81- 124. 14. Loewenfeld IE, Thompson HS. Fuchs's heterochromic cyclitis: a critical review of the literature, I: clinical characteristics of the syndrome. Surv Ophthalmol 1973; 17: 394^ 157. 15. Loewenfeld IE. Signs and syndromes mentioned in the clinical pupil literature: facts and fancy. In: Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, Iowa: Iowa State University Press; 1993: 1244- 163. 16. Landau P. Philipp Loewenfeld's Memories. Recht und Politik in Bayern zwischen Prinzregentenzeit und Nationalsozialismus: Erin-nerung von Philipp Loewenfeld. Landau P, Riess R, eds. Miinchener Universitatsschriften. Juristische Facultat. Abhandlungen zur rechtswissenschaftlichen Grundlagenforschungen. Band 91. Activ Druck u. Verlag, Ebelsbach; 2004. 145 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Thompson and Kardon TEN MAJOR CONTRIBUTIONS OF IRENE E. LOEWENFELD, PHD 1. Reflex pupil dilation 2. Adie tonic pupil 3. Anisocoria in optic neuropathy 4. Anisocoria in optic tractopathy 5. AR pupil 6. Oculomotor paresis with cyclic spasms 7. Fuchs heterochromia iridocyclitis 8. Electronic Pupillograph 9. Pupil colloquium 10. Pupil textbook 1. Reflex Pupil Dilation In her PhD thesis ( 7) based on work done in Lowenstein's laboratory from 1948 to 1956, Loewenfeld demonstrated how the pupil dilates in response to a sudden noise or pain ( or any psychosensory stimulus). She showed that not only was there a discharge along sympathetic nerves to the pupillary dilator muscle but that this was made more effective by a simultaneous inhibition of the iris sphincter nucleus in the midbrain and sometimes enhanced and prolonged by humoral mechanisms. She summarized the evidence for the existence of the pupillary dilator muscle, finally dismissing Albrecht von Haller's eighteenth century suggestion that congestion of the iris vessels contributed to pupillary contraction. 2. Adie Tonic Pupil Loewenfeld's efforts to understand the mechanisms involved in the repair of nerve damage ( 8) led her to explanations of many odd pupillary behaviors, chiefly the mechanism of the strong, tonic near reaction of the Adie pupil. She had rejected every possible existing explanation for the tonic contraction of the Adie pupil. In 1954, the anatomist Warwick had shown that the ciliary ganglion contained 30 times more neurons destined for the ciliary muscle than for the iris sphincter muscle. This ratio roughly matched the relative masses of the two muscles. One morning, Dr. Loewenfeld said, " I've got it! Let's say that in a given fresh Adie's pupil, a random 70% of the cells in the ciliary ganglion stop working ( for reasons presently unknown); and that, in a couple of months, these neurons re- grow and randomly re-innervate both intraocular sphincters ( the ciliary muscle and the iris sphincter). Some parasympathetic light- reaction neurons that were originally destined for the iris sphincter will end up innervating the ciliary muscle. But there will not be enough of them to budge that big muscle, so there will be no detectable accommodation or pseudomyopia with exposure to light. The other way around, it is a different story. There will be plenty of accommodative neurons re- growing into the iris sphincter ( 30 to one, remember?), and it won't take very many of them to make a little muscle like the iris sphincter contract. This means that every time the patient accommodates her gaze to a near object, some of the innervation to the ciliary muscle will spill over into the iris and constrict the pupil." In 1967, she published a hypothesis for the light- near dissociation of the Adie pupil ( 9). The important new concept was that the pupillary response to near was not so much " spared" as " restored" by aberrant regeneration. 3. Anisocoria in Optic Nerve Lesions In the first half of the twentieth century, there was considerable confusion between an input pupillary defect and an output defect. At mid- century, students were still being taught that the pupil of an eye with acute optic neuritis is usually the larger one and that anisocoria could be used to identify the damaged optic nerve. The idea that an input defect in one eye produced a larger pupil in that eye was formally put to rest in 1949 when Ira S. Jones, MD, an ophthalmology resident 146 © 2006 Lippincott Williams & Wilkins Irene E. Loewenfeld, PhD J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 TEN MAJOR CONTRIBUTIONS OF IRENE E. LOEWENFELD, PHD ( Continued) 1. Reflex pupil dilation 2. Adie tonic pupil 3. Anisocoria in optic neuropathy 4. Anisocoria in optic tractopathy X 6. Oculomotor paresis with cyclic spasms 7. Fuchs heterochromic iridocyclitis 8. Electronic Pupillograph 9. Pupil colloquium 10. Pupil textbook at Columbia University working in the lab of Lowenstein and Loewenfeld, demonstrated pupillographically that unilateral optic nerve dysfunction did not produce anisocoria ( 10). 4. Anisocoria in Optic Tract Lesions There was confusion for several decades about what was meant by " Behr's pupil," offered as a sign of an optic tract lesion. In 1909 and 1913, Behr ( 11) had drawn attention to three signs: the light reaction was weaker in the eye with the temporal field loss; the eye contralateral to the tract lesion sometimes had a larger pupil; and the contralateral eye had a wider palpebral fissure. Clinicians remembered only the part that they understood, so " Behr's sign of an optic tract lesion" went into the textbooks as a dilated pupil contralateral to the tract lesion. The associated contralateral afferent pupillary defect was forgotten. Loewenfeld pointed out in 1983 ( 12) that the ipsilaterally smaller pupil and contralaterally widened palpebral fissure in some of Behr's patients should have suggested that the mass damaging the optic tract had perhaps also damaged the ipsilateral descending sympathetic fibers and produced a central Horner syndrome. However, she emphasized ( 9) that anisocoria is extremely rare in optic tract lesions and that the only pupillary abnormality is an afferent pupillary defect contralateral to the tract lesion ( 11). 5. The Argyll Robertson Pupil After reading the many descriptions of the Argyll Robertson pupil, Loewenfeld documented pupillographically that the near response is not tonic. Therefore, she localized the process, not to the peripheral autonomic nervous system where tonicity was expected, but to the central nervous system. She suggested that in neurosyphilis, there may be damage to the dorsal midbrain sufficient to cause a loss of the light reaction without affecting the more rostro- ventral path of the near reflex to the iris sphincter nuclei. 6. Oculomotor Paresis with Cyclic Spasms In a thoughtful review ( 13), Loewenfeld pointed out that this condition had been incorrectly called " cyclic oculomotor palsy" and was actually a third cranial nerve paresis with apparent subsequent retrograde damage in the oculomotor nucleus, resulting in some unusual episodic manifestations ( 13). 7. Fuchs Heterochromic Iridocyclitis Loewenfeld's review of this topic summarized the literature and dismissed the idea that eyes with this condition have a loss of sympathetic function and reached similar conclusions with regard to Parry- Romberg's facial hemiatrophy, Marfan syndrome, and " status dysraphicus" ( 14). 147 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Thompson and Kardon TEN MAJOR CONTRIBUTIONS OF IRENE E. LOEWENFELD, PHD { Continued) 6. Oculomotor paresis with cyclic spasms 7. Fuchs heterochromic iridocyclitis 8. Electronic Pupillograph 9. Pupil colloquium 10. Pupil textbook 8. The Electronic Pupillograph Together with her mentor Lowenstein, Loewenfeld was responsible for developing sophisticated electronic techniques for recording pupil movements. When Loewenfeld started in 1940, the custom was to take motion pictures of the pupils on infrared- sensitive film. The developed film was projected frame by frame onto a screen. In every tenth frame, the pupil diameter was measured from the screen with calipers and plotted on a chart. In the early 1950s, as the production of television images was understood, Lowenstein and Loewenfeld made a mechanically- generated infrared flying spot scanner, the forerunner of most modern pupillographic devices. The raster generated by the reflection of the flying spot from the iris produced an image of the pupil from which the widest horizontal diameter was selected and continuously recorded, each eye in a separate channel. This machine became commercially available in 1957 and proved to be accurate and dependable. 9. The Pupil Colloquium At Columbia University in 1963, Loewenfeld hosted a meeting of investigators in pupil physiology. From this meeting, begun in 1961 by Larry Stark, PhD, there grew The Pupil Colloquium, a society that has been meeting ever since. For the next 25 years, Loewenfeld was its main spark, hosting the colloquium three times. In 1997, its members established The Loewenfeld Lecture. 10. The Pupil Textbook Her magnum opus entitled The Pupil: Anatomy, Physiology, and Clinical Applications ( 1), published in 1993, consists of 1590 pages of text in the first volume, 632 pages of index and bibliography in the second volume, and more than 18,000 references. After many decades of being saturated with pupillary lore, Loewenfeld defined, explained, endorsed, or dismissed 225 pupillary eponyms, syndromes, and diagnostic signs ( 15). She reviewed iridology and pupillary tests of pregnancy before consigning them to the dust bin of baseless pseudoscience. Throughout the more than 25 years it took to bring this work to publication, she was thinking of how to help the next generation of students past the rough spots. She dedicated it " To those who came before us and to those who will follow. May this book form a bridge between them." 148 © 2006 Lippincott Williams & Wilkins |
