Perspectives On Medical Research
Volume 4, 1993

Contents

The Clinical Relevance of Dr. Cohn Blakemore's Vision Research

Stephen R. Kaufman, Deanna Z. Macek, Marvin Kraushar

Terminology:

amblyopia -- loss of vision in an eye due to disuse of that eye; while amblyopia is reversible during early childhood, most amblyopia that persists beyond childhood becomes permanent

anisometropia -- difference in refractive states of the two eyes; in other words, difference between the eyes in the lens power needed to focus light on the retina

ocular dominance of cortical neurons -- greater response of cortical brain neurons to light coming from one eye compared to the other eye, determined by firing rates of individual neurons as recorded by microelectrodes

strabismus -- misalignment of the eyes; also known as "squint" and "crossed eyes"

Dr. Colin Blakemore's visual deprivation research has generated ongoing controversy in England. Animal protectionists have charged that Blakemore's research is cruel to animals and irrelevant to humans.(1-3) A leading advocate of animal research,(4) Blakemore has countered that his research is important to the management of amblyopia, a leading cause of uniocular visual deficit.(5) As ophthalmologists, we will attempt to determine whether Blakemore's claim is supported by fact.

In order to assess Blakemore's claim that his research is clinically relevant, we evaluated the four papers, co-authored by Blakemore that he himself cited in a May 1987 defense of his vision deprivation experiments.(5) First, we examined the clinical relevance of the four papers. Then, we reviewed citations to these works in order to determine whether clinicians found Blakemore's research valuable. Finally, we considered this research's applicability to the leading clinical issues in the management of strabismus and amblyopia.

Part 1: Review of Four of Blakemore's Papers

1) Blakemore C, van Sluyters RC. "Reversal of the physiological effects of monocular deprivation in kittens."(6)

Blakemore and van Sluyters studied the effect of suturing one eye in kittens on the sensitivity of visual cortex neurons. The main findings were a) "suturing the lids of one eye until 5 weeks of age leaves virtually every neurone in the kitten's visual cortex entirely dominated by the other eye," b) "reverse suturing at 5 weeks caused a complete switch in ocular dominance," and c) "between 5 weeks and 4 months of age, there is a period of declining sensitivity to both the effects of an initial period of monocular deprivation and the reversal of those effects by reverse suturing.(6)

a) Long before visual deprivation experiments on animals began in the early 1960s, it was known that occlusion of an eye in children, for example by cataract or corneal opacity, causes amblyopia.(7-11) The later animal experiments merely accorded with clinical studies. For example, Peter wrote in 1932, "Any interference with the clarity of the media in one eye will produce a definite delay in the completion of the development (which) may be . . . beyond the time when development is possible."(7) Blakemore and van Sluyters, as well as many other investigators, suggested that changes in ocular dominance due to occlusion of an eye during an early "critical period" accounted for amblyopia. However, there is good reason to doubt the validity of these findings for human amblyopia. It is well known that the vision of an amblyopic eye often improves at any age, if the patient is forced to use that eye.(12) For example, total therapeutic occlusion of the "good" eye in late childhood will improve the vision of the amblyopic eye, but this improvement is lost when occlusion of the good eye ceases. Similarly, an elderly patient who is blinded in the "good" eye, e.g., by cataract, will often experience substantially improved vision in a severely amblyopic eye. Removal of the cataract from the "good" eye will result in deterioration of vision in the amblyopic eye. Thus, Blakemore and van Sluyters' studies of cortical dominance in experimental animals may reflect artifacts of the extreme visual disability tested in the laboratory. The relevance of their research to normal or abnormal human physiology is questionable.

b) Blakemore and van Sluyters showed that kittens, like humans, have a period of visual system plasticity. While there is evidence that excessive therapeutic patching of a human patient's eye (to treat amblyopia) reverses the eye that develops amblyopia,(13) the extreme reverse patching in this experiment has no apparent clinical correlate. Thus, there are no clinical data to confirm or contradict Blakemore and van Sluyters' findings. Nevertheless, common sense tells us that extreme reverse patching will reverse the eye that becomes amblyopic. It was well known prior to this experiment 1) that cessation of "occlusion" of an eye (e.g., removal of a cataract) during the critical period will improve the vision of the amblyopic eye and also 2) that excessive occlusion during the critical period can cause amblyopia. Blakemore and van Sluyters merely did the former to one eye and the latter to the other eye.

While this research's clinical relevance is questionable, Blakemore and van Sluyters made observations about ocular dominance associated with visual deprivation which may be of "basic science" interest. This area of inquiry, involving scores of investigators worldwide, was inspired by the Nobel Prize winning work of Hubel and Wiesel.(14) Such research has fascinated many people, but its clinical value has been challenged.(15) Studies designed to elucidate amblyopia's pathology at the cellular level do not necessarily advance our understanding of the conditions that cause amblyopia, our ability to treat amblyopia, or our ability to determine the prognosis for individual amblyopic patients (see section 3).

c) Blakemore and van Sluyters described a critical period for the development of amblyopia in kittens. Human children, too, have a critical period. However, the age at which visual deprivation causes amblyopia is species specific. Thus, full characterization of the critical period in cats or any other nonhuman species provides no useful information about the critical period for children. In fact, the animal research can be misleading. Vaegan and Taylor have noted, "Children appear to have a critical period which continues for longer than expected from animal models."(16) This critical period is being characterized by ongoing clinical investigation. For example, clinicians are assessing the amblyopia that develops from congenital cataracts removed at different times in childhood.

2) Blakemore C, van Sluyters RC. "Experimental analysis of amblyopia and strabismus"(18)

This paper is largely a review of animal "models" of amblyopia due to occlusion and to strabismus. As in the case of occlusive amblyopia, strabismic amblyopia was described in human patients long before the animal models were used.(19) In this paper, Blakemore and van Sluyters note that animals raised in a visual environment artificially restricted to striped lines retained binocular innervation of cortical cells. Presumably, the animals therefore possessed binocular vision, even if the eyes were strabismic.

Although Blakemore and van Sluyters suggest that therapy involving striped lines to stimulate the cortical cells may someday contribute to a therapy for strabismic patients, to our knowledge, no treatment of this kind is currently in use. Indeed, Blakemore has acknowledged, "If one keeps up the binocular stimulation of the cortex while not correcting the strabismus, then one may generate another problem -- a condition far worse than amblyopia, namely the diplopia (double vision) which should result."(18)

3) Eggers HM, Blakemore C. "Physiological basis of anisometropic amblyopia"(20)

Long before animal research on anisometropia began, clinicians knew that anisometropia can cause amblyopia.(21-23) In order to produce anisometropia in kittens, Eggers and Blakemore fitted them with glasses with one strong minus lens. Not surprisingly, the researchers found changes in ocular dominance in the cortex similar to, but not as complete as, those resulting from monocular occlusion. It is not certain if these data can be applied to human children. First, unlike the experimental kittens, nearly all children with clinically significant anisometropia have similar focusing power of the eyes. Their anisometropia results from differences in the size of the eyes. The larger eye generally has thinned tissues, which can adversely affect vision. The animal model does not parallel this problem. Second, the feline visual system is a poor analogue to the human one.(24-27) Von Noorden has noted:

Amblyopia has now been produced successfully in models of various species, but data from cats, squirrels, and dogs cannot be applied automatically to man. There are differences in the anatomic and functional organization of the visual system of cats and primates . . . Human amblyopia involves primarily fovea! vision rather than peripheral vision, and a cat has no fovea.(28)

4) Swindale NV, Vital-Durand F, Blakemore C. "Recovery from monocular deprivation in the monkey"(29)

Swindale, Vital-Durand, and Blakemore studied the effects of monocular deprivation on ocular dominance in a particular cortical layer of the Erythrocebus patas (Old World) monkey's brain. In this highly popular area of inquiry, researchers describe, in detail, the effect of visual deprivation on specific cortical areas. This research assists in the "mapping" of the visual system's neural pathways. The practical applications of such findings, however, appear to be nil. For example, assuming that the data derived from other animals can be extrapolated to humans, this line of research demonstrated that areas 2, 3, and 5 of each lateral geniculate body receive neurons from the eye on the same side, and that areas 1, 4, and 6 receive neurons from the eye on the opposite side. Although this information is generally taught to students of ophthalmology,(30) it has not, to our knowledge, changed our understanding or treatment of any eye disorder. Furthermore, some of this information can be safely and non-invasively obtained from human subjects with PET scans,(31-33) CAT scans,(34) and autopsy studies.(35)

This research should be considered "basic science," in that it attempts to add to our basic knowledge of the visual system. It is important to note, however, that Blakemore and van Sluyters did not study vision per se. They recorded electric firing of neurons, which is not the same as perception of visual images. The firing of neurons is certainly related to vision, but the nature of this relationship is not known.

Part 2: Science Citation Index Review

The Science Citation Index, through 1991, lists 376 citations to the four papers discussed above. We were able to obtain and review all but 12 of these articles. Several of the articles cited more than one of the four papers written by Blakemore and colleagues. In order to assess the clinical impact of the research of Blakemore and associates, we evaluated all 35 articles that involved research with human subjects. While one would expect animal researchers to focus on the laboratory research implications of the cited studies, investigators working with human subjects are more likely to accurately assess the laboratory's contributions to the understanding of human anatomy, physiology, and pathology. Review articles were omitted because it was not possible to determine whether the authors' primary interests were in laboratory science or clinical investigation. While most references to the four papers by Blakemore and associates are by fellow animal researchers, many clinical investigators have also cited them. Few clinical researchers, however, have credited Blakemore and colleagues with important contributions.

In their citations, many clinical scientists note that Blakemore and colleagues found a critical period for occlusion amblyopia (36-45) and for anisometropic amblyopia.(46-49) One report mentions that reverse patching can reverse the eye that develops amblyopia,(50) two papers note that occlusion causes amblyopia,(45,51) and two papers state only that amblyopia has been studied in animals.(52-53) As was discussed above, before the work by Blakemore and associates, it was already well known that human children have a critical period for the development of amblyopia. Indeed, some of the clinical researchers citing Blakemore and colleagues also cite human clinical reports on amblyopia's critical period that were published before 1974 (the date of the earliest paper discussed above)(36,38,39,43,44,49) Two authors add that, while the critical period has been described in certain laboratory animals, more human clinical research is needed to determine the critical period for humans.(39,41) Campbell et al. have written:

The time course of these improvements and the age at which they occur (in children) do not tally in any simple manner with the numerous studies of the ‘critical period' for visual deprivation in cats and monkeys. It is very unlikely that the amblyopes that we have studied have actually lost neurones which subsequently regenerate with treatment. It seems more probable, in the light of the treatment time course, that neurones in amblyopia have reduced function.(37)

Some papers discussed the specific findings of cortical neuron recordings. Four of these mention reversal of cortical dominance patterns with reverse patching (42,45,54,55); one also comments on the finding that reverse patching reduces the number of binocularly driven cells.(44) Both points were discussed above. This information may be of intellectual interest, but its clinical relevance is doubtful.

Several papers cite the work of Eggers and Blakemore (20) for demonstrating that, in anisometropic amblyopia, most cortical neurons are monocularly driven (56-58) and that those cortical cells that respond to the blurred eye (57-69) show decreased contrast sensitivity. The first point is an electrophysiological representation of a phenomenon that can easily be demonstrated in people. Loss of binocular vision can be seen and tested in amblyopes. The questionable value of this electrophysiological research has been discussed above. The second point is not directly applicable to contrast sensitivity as a measure of visual acuity. Eggers and Blakemore did not study visual contrast sensitivity, but the contrast sensitivity of cortical neurons as determined by their firing rates. The correlation between their electrophysiological studies and vision is not known. Interestingly, tests of visual acuity as measured by contrast sensitivity were done with human patients prior to Eggers and Blakemore's work. One clinical report (64) cites three papers on contrast sensitivity in human amblyopes that precede Eggers and Blakemore's 1978 study.

Two papers warrant further discussion. Thomas (70) cited Blakemore and van Sluyters (6) in support of a theory that amblyopia involves larger receptor fields. At present, this speculation can be neither confirmed nor refuted. Current technology does not permit microelectrode studies of cortical receptive fields in humans.
Only one clinical paper explicitly endorses the animal model.(43) Jastrzebski et al. have written:

Examination of the effects of compromised visual experience on the young visual system in animals has been useful as a probe into its structure, function, and development. The importance of the animal model to the clinician arises from a need for some physiological basis for the cause, diagnosis, therapy, and prognosis of stimulus deprivation amblyopia. . . . The benefit of reverse deprivation in improving the amblyopic eye is apparent both from the animal data and clinical practice. It is also clear that reverse deprivation must take place during a sensitive period.(43)

The first sentence notes that the animal research has provided information on neuroanatomy, visual system development, and visual electrophysiology. The clinical value of this research, to date, has been questionable. The second sentence, a broad endorsement of animal research, provides no details of how the animal model may be used to address these clinically important issues. The last two sentences discuss the existence of the critical period for the development and for the reversal of amblyopia in both people and animals. Interestingly, one of the many citations used in support of this point was a clinical study from 1959.

Few clinicians credit the animal research with important contributions. Indeed, Hess et al. have noted that the relevance of the animal research to humans remains unclear:

It is obviously much more difficult and hazardous to compare the present psychophysical findings on pattern deprived humans with neurophysiological data from pattern deprived animals. This difficulty in relating single cell responses and psychophysics is further clouded by the conflicting nature of the neurophysiological findings as to the exact physiological consequences of, and structures involved in, monocular pattern deprivation in animals.(51)

Part 3: Relevance of the Research to Clinically Important Issues

It does not appear that visual deprivation experiments, despite their widespread use, have assisted the prevention or treatment of any human patients. While it is not possible to predict the future with certainty, the likelihood of benefit to humans can be assessed by evaluating the relevance of the animal research to the leading clinical questions that concern ophthalmologists.

1) What are the critical periods for the different types of amblyopia (e.g., occlusive, strabismic, anisometropic) in children? The answers would help ophthalmologists determine when to attempt surgical correction of the underlying defect(s). The age at which human children are at risk for the development of amblyopia depends on the time course of the human ocular system's development. Since different species have different critical periods, the human critical period can be determined only by studies and observations of human children. The critical periods of other animals may be determined in the laboratory, but such information cannot be extrapolated to humans. Amblyopia's development from vision deprivation has been common knowledge for decades, and characterization of the human critical period began long before the animal experiments. In 1921, Juler commented on traumatic cataracts in children, "There is a striking line of difference between the final vision results depending on the age at which the injury occurred."(71)

Having performed extensive research on visual deprivation in animals, von Noorden has concluded:

This period of susceptibility of the visual system to unilateral visual deprivation, whatever the cause, has been well defined in kittens and monkeys but not in children. Such information is needed, however, to determine how soon to operate on a congenital cataract or traumatic cataract during childhood, the age at which to consider a cornea! transplant for a congenital or acquired corneal opacity, or when to correct anisometropia to preserve sight in an eye that otherwise will become irreversibly amblyopic. . . . The only information available at this time is that gleaned from retrospective analysis of individual cases.(72)

2) What is the effect of amblyopic conditions on binocular vision and stereovision? It is difficult to test binocular vision in laboratory animals. The inability of animals to articulate their perceptions is a barrier to assessing small changes in visual function. While clinicians have the same problem with infants, small children can describe what they see, enhancing the informative value of visual tests. Blakemore and van Sluyters have acknowledged, "Our tests of behavioral function are extremely crude by the standards that are applied to humans, and they would probably only reveal a deficit so great that it would be regarded in the human as some form of blindness, not amblyopia."(18)

3) When should we operate to straighten the eyes in strabismic children? This complicated issue has generated much debate among ophthalmologists. Von Noorden has addressed this issue in the 1987 Jackson Memorial Lecture. Discussing essential esotropia, a category that includes the majority of strabismus cases in children, he has noted that an understanding of the condition's etiology is critical. Some investigators believe that the strabismus is due to a congenitally defective fusional mechanism; consequently the children do not have the normal ability to fuse the images of the two eyes. Others maintain that a defect in the neuronal innervation of the muscles causes misalignment of the eyes. The former theory would favor conservative treatment, while the latter theory would suggest that early surgery may be warranted to improve vision, even though the risks of anaesthesia are greater for younger infants. Von Noorden has observed:

These two opposing views have far-reaching therapeutic implications. If esotropia is caused by an inborn defect of the fusion faculty, no treatment, no matter how early in life, will restore normalcy. If, on the other hand, no such defect exists, a cure could be accomplished by aligning the eyes as early as possible.(12)

He continues:

We must ask whether animal experiments have helped us to better understand the pathophysiology of essential infantile esotropia. Such experiments are cited by proponents of early surgery as they allegedly show an irreversible deterioration of binocular pathways in cats and monkeys with strabismus during infancy. . . However . . . there is no evidence from animal research that binocular functions other than stereopsis, such as sensory and motor fusion, are similarly affected by abnormal visual experience early in life. There is currently no animal model for essential infantile esotropia.(72)

Strabismus is created in experimental animals by surgical manipulation of muscles. This is different from either of the two mechanisms proposed for the development of human essential esotropia, i.e., congenital deficiency of innate fusion or abnormal innervation of the eye muscles. Artificially induced misalignment of the eyes is not the same as spontaneous strabismus in children; the etiology of human strabismus cannot be determined by studies with laboratory animals,

Finally, two valuable observations of visual function in amblyopia could have been derived only from human clinical investigation. Amblyopes can read smaller letters on a vision chart if the letters are isolated than if they are one of a series or field of letters. This is known as "crowding phenomenon."(75) Also, the amblyopic eye can see as well, or almost as well, as the normal eye under conditions of reduced illumination.(76) These observations, which are much easier to evaluate with human subjects, offer insights into the nature of amblyopia that electrophysiological testing cannot address.

Conclusions

Blakemore and colleagues have studied various forms of visual disability in laboratory animals. In extensive review of the literature, we found no evidence that our understanding amblyopia's causes or treatments have improved as a consequence of this research. Furthermore, because experimental models of amblyopia cannot address the issues of critical importance to practicing clinicians these models' future benefit to human patients is doubtful. It is unlikely that the public would wish scarce financial resources to be allocated to such research for the sake of "pure knowledge." Unfortunately, Blakemore has defended his work on the grounds that it is important to human patients.(1) The claim appears to lack factual support.

Acknowledgement

We would like to thank Gill Langley, Ph.D. for invaluable research and editorial assistance.

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