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HISTORY CORNER
Year : 2020  |  Volume : 32  |  Issue : 1  |  Page : 91-93

Story of the first human fluorescein angiogram


Department of Regional Institute of Ophthalmology, Government Medical College, Trivandrum, Kerala, India

Date of Submission02-Feb-2020
Date of Acceptance02-Feb-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Dr. C Biju John
Regional Institute of Ophthalmology, Trivandrum - 695 035, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_11_20

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How to cite this article:
John C B. Story of the first human fluorescein angiogram. Kerala J Ophthalmol 2020;32:91-3

How to cite this URL:
John C B. Story of the first human fluorescein angiogram. Kerala J Ophthalmol [serial online] 2020 [cited 2020 May 25];32:91-3. Available from: http://www.kjophthal.com/text.asp?2020/32/1/91/282647



Serendipity plays a role in a lot of inventions and discoveries right from the humble matchstick to drugs such as penicillin and even viagra. We see a lot of such examples in ophthalmology also. One such discovery that changed the ophthalmology landscape forever was fluorescein angiography. As fate would have it, FFA was born in a laboratory of another specialty, royally rejected initially by ophthalmology literature but accepted and published by a journal outside ophthalmology.

The names of the two young medical students who discovered it jointly in 1959 – Harold Novotny and David Alvis may be familiar to all, but the story of the discovery may not be.

The two students began working under Professor John Hickam, Chairman of Medicine at Indiana University on a research project funded (in part) by the United States Air Force for different reasons.[1] Novotny was not very well off and needed money to get through the medical school and was supporting himself by doing part-time jobs. The job in Professor Hickam's laboratory was the third one of three simultaneous part-time jobs he was doing at that time. Alvis, on the other hand, was doing his senior year and wanted some exposure in medical research as well as internal medicine, particularly gastroenterology. However, since the only vacancy available was in Hickam's laboratory he reluctantly joined as Hickam's research assistant.

Dr. Hickam was interested in the retinal vascular bed as a visible segment of the cerebral circulation. He was searching for a photographic technique to estimate blood oxygen concentrations in retinal vessels. It was for this project that he had hired the two medical students.[1]

Novotny and Alvis started Dr. Hickam's research project by learning how to operate the Zeiss Fundus Camera. This was the first model available with an electronic flash. Next, they learned how to process film and to make prints. After much practice with a model eye, they were allowed to photograph patients.[1]

One day Harold was looking through the camera and he discovered the different colors in the crystalline lens which he had not seen before. He asked Alvis what he thought it was. The question and the answer was a history-changing moment and is better read in Dr. Alvis's own words written almost 20 years later. “One day Harold Novotny was observing the crystalline lens of a patient, and he commented that the lens appeared to give off an unusual type of light he had not been aware of before. For no apparent reason, I suggested that this light could be fluorescent. Harold responded by saying that fluorescent blood or blood vessels would be beautiful to observe and that he wondered if they could be photographed.”[2]

Even though no reason was apparent to Alvis as to what made him think of fluorescence, the fact that fluorescein and fluorescence were already there in his subconscious mind definitely might have helped. As chance would have it Alvis's father was an ophthalmologist who used to talk to his son a lot about the various medications used in his practice. One of them was topical fluorescein which he used for diagnosing injuries to the cornea.

Anyway the young researchers, especially Novotny was fascinated by the idea of fluorescence of blood and blood vessels. Novotny and Alvis researched the problem extensively. Harold went to the Medical Center Pharmacy and discovered that an injectable form of fluorescein was commercially available. Alvis reviewed the Index Medicus and discovered that cinematography and angiography had been performed in cats but not in humans.

The enthusiastic researchers discussed it with Professor Fred Wilson, the chair of ophthalmology, who told them it is unlikely to work as the lens fluorescence is going to interfere with the recognition of the dye in the retinal circulation. But this did not deter the young minds fixated strongly on the feasibility of their idea and they next tried to sell the idea to their employer.

Professor Hickam was interested to some extent in the project that the two students proposed (to explore dyes as a means of photographing the circulation) but saw it as a sideline of his studies on oxygen saturation. The students had to do the work strictly after hours when Novotny's primary laboratory assignments had been finished, and the equipment was free.

However, the Professor, a great researcher himself offered many helpful suggestions, the most important of them being that the students needed to find out the exciting and emitting wavelengths of light from fluorescein as it circulated in human blood. This was where Novotny's past training in pharmacology came handy. Novotny had actually completed his training as a pharmacist and had even practiced for some time before joining for Medicine. Hence, he knew enough about pharmacology to realize that they must find out the spectral properties of the dye, and he had the idea that one might be able to enhance the recognition of fluorescence in vessels by pairing two filters. They took a sample of Alvis's blood that had been injected with fluorescein to Eli Lilly and Co, who had spectrophotometers, to determine the absorption and emission curves. They learned that the dye absorbed maximally at about 490 nm and emitted with a peak at 520 nm, and they looked for filters that would enhance photographic separation. Luck was again with them as the standard Kodak Wratten filters 47 and 58 which was easily available had peaks in the blue and green, with a relatively little overlap at 500 nm.

The next step was obvious, which was to insert these filters into the fundus camera. But this could be suicidal for their research as both of them knew that Hickam was not going to allow them to fiddle with his precious fundus camera.[3] But what can stand in the way of young determined minds? The student researchers waited till the Professor was on a trip to try out their plans. Novotny removed the side panel of the camera to explore where to place the filters. The seemingly impulsive but inevitable actions of the young researchers almost killed the project as Hickam was furious when he returned seeing that his expensive instrument had been violated.

But luckily, Novotny was able to show him what the filtered camera could do and could reassure him that the camera can be easily restored to its original state. Hickam who recognized the potential power of angiography, let the experiments continue.

With the filters in place and with the flash system of the early Zeiss cameras, the brightness of vascular fluorescence was dim. Novotny and Alvis sought the fastest 35-mm film they could find and learned that Ansco Super Hypan film could be force developed to reach the equivalent of a 2400 ASA rating.[3]

So, now their equipment was ready and all that was remaining was to try it on a patient. The seemingly difficult situation was solved very easily by the enthusiastic and adventurous duo.

One of them will be the patient and the other the photographer. But who was going to be the first guinea pig and be ready for potential complications?

This was also solved in no time by tossing a coin. Alvis lost and thus became the first patient in whom a fluorescein angiography was performed.

Flashes could only be produced every 12 s, which they hoped would be fast enough to recognize an arterial filling phase and venous return. Call it beginners luck or the result of meticulous preparation, they were successful on the first attempt itself and fluorescein angiography was born [Figure 1].
Figure 1: Photographs from the first angiogram by Novotny and Alvis. The white artifacts in these prints are matchsticks that were placed on the printing paper to mark the timing sequence. Images courtesy of Tim Steffens CRA, and the Indiana University Medical Center[1]

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Novotny and Alvis took pictures of their own eyes and then recruited friends and associates to be participants. They accumulated normative data. Dr. Hickam was pleased with their efforts and suggested that Novotny and Alvis present their work to Dr. Fred M. Wilson, Sr., Chairman, Department of Ophthalmology, Indiana University Medical Center. Dr. Wilson received this discovery enthusiastically and requested that the same facilities be duplicated in the ophthalmology department. Dr. Hickam had always been interested in the devastating vascular complications of diabetic and hypertensive retinopathy. He put the word out that two medical students would like to photograph these complications for their research project, and in no time, the two young innovators had an immediate, unlimited supply of participants.

Both Hickam and Wilson recognized the potential value of fluorescein angiography and urged Novotny and Alvis to write a paper on the new technique. Hickam declined to be a co-author because he felt that he did not really contribute to the development of the technique. Wilson read the first draft, and Hickam read multiple drafts of the manuscript. He gave one especially important piece of advice: “Make it so anyone can do it.”[3]

When the manuscript was finally finished, it was a remarkable article as it described the technique, virtually as it was done till a few years back before the advent of digital fundus cameras. They sent it to the American Journal of Ophthalmology.

When the authors received a rejection letter from the American Journal of Ophthalmology, fluorescein angiography might have died had it not been for Professor Hickam.[3]

The reviewers had commented that the idea was not new because Chao et al. had already demonstrated circulation in the cat with fluorescein, and Swan and Bailey had demonstrated retinal cinematography. Furthermore, the photographic method of observation seemed too slow to be objective clinically. Novotny and Alvis had not been aware of the prior publications, as this was long before the era of PubMed and quick searches of the literature.

Neither Doctors Novotny, Hickam, Wilson, nor Alvis had any idea what the retinal circulation time in cats had to do with the fluorescence that they were reporting for the first time in humans.

Dr. Hickam came to their rescue by calling the editor of the journal “Circulation” who was a personal friend and long-time colleague.[3] Dr. Hickam's intervention on behalf of his two medical students worked. Their article “A Method of Photographing Fluorescence in Circulating Blood in the Human Retina” appeared in Circulation, Volume XXIV, July 1961.[4]

Following graduation, Dr. Novotny and Dr. Alvis went their separate paths. Novotny entered Psychiatry and Alvis following in the footsteps of his father and entered ophthalmology.

In February 1968, Dr. David Alvis was honored at theFirst International Symposium on Fluorescein Angiography at Miami. Dr. Alvis was asked to relate to those in attendance the story surrounding the development of fluorescein angiography. He mentioned about the rejection slip from the American Journal of Ophthalmology. Dr. Derrick Vail, who was the editor of the Journal and a participant in the symposium, apologized to Dr. Alvis for not publishing the article.[2]

Fluorescein angiography still is an indispensable tool in the diagnosis and management of retinal diseases, even though its use is gradually diminishing. However, it had served us all these years and for the success of this initially cumbersome procedure, we have to thank two persistent students who solved the problem of highlighting the vasculature with barrier filters, an insightful mentor who pushed them to write clear methodology and knew how to get a rejected paper published, other clinicians and researchers who refined it[3] and the technological advances, especially digitalization which gave it a new lease of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Timothy J. Bennett: TheFirst Successful Fluorescein Angiogram in a Human Subject. Available from: https://www.opsweb.org/page/FAhistory. [Last accessed on 2020 Feb 01].  Back to cited text no. 1
    
2.
Alvis DL, Julian KG. The story surrounding fluorescein angiography. J Ophthalmic Photogr 1982;5:1.  Back to cited text no. 2
    
3.
Marmor MF, Ravin JG. Fluorescein angiography: insight and serendipity a half century ago. Arch Ophthalmol 2011;129:943-8.  Back to cited text no. 3
    
4.
Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation 1961;24:82-6.  Back to cited text no. 4
    


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