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.
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, I 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?
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.
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 Jüdische Gelehrte An Der Münchener Juristichen Facultät. Landau P, Nehlsen H, eds. Münchener Universitätsschriften. Juristische Facultät. Abhandlungen zur rechtswissenschaftlichen Grundlagenforschungen. Band 84. Activ Druck u. Verlag: Ebelsbach; 2001:45-62.
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-Zürich; 1936.
7. Loewenfeld IE. Mechanisms of reflex dilatation of the pupil: historical review and experimental analysis. Doc Ophthalmol
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
10. Jones IS. Anisocoria: attempted induction by unilateral illumination. Arch Ophthalmol
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
13. Loewenfeld IE, Thompson HS. Oculomotor paresis with cyclic spasms: a critical review of the literature and a new case. Surv Ophthalmol
14. Loewenfeld IE, Thompson HS. Fuchs's heterochromic cyclitis: a critical review of the literature, I: clinical characteristics of the syndrome. Surv Ophthalmol
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: Erinnerung von Philipp Loewenfeld. Landau P, Riess R, eds. Münchener Universitätsschriften. Juristische Facultät. Abhandlungen zur rechtswissenschaftlichen Grundlagenforschungen. Band 91. Activ Druck u. Verlag, Ebelsbach; 2004.
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 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).
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.”