Marshall Parks Lecture Can Ophthalmologists Repair the Brain in Infantile ? Early Surgery, , Monofixation Syndrome, and the Legacy of Marshall Parks

Lawrence Tychsen, MD

Can ophthalmologists repair defects of visual cortex circuitry in infants who have esotropia? The answer to this question encompasses both sensory and motor behaviors because the clinical hallmarks of the disorder are stereoblindness and absence of motor fusion, which manifests as convergently deviated eyes. Functional recovery of sensory and motor fusion in was a consuming interest, if not career-defining passion, of Marshall Parks. The purpose of this work is to pay tribute to Parks’ legacy by showing how human and animal studies, conducted largely during the last 25 years, support both his clinical insights and treatment philosophy. (J AAPOS 2005;9:510-521)

discussion of Dr. Parks’ (Figure 1) contributions to COSTENBADER-PARKS AND THE fusion recovery can begin with the men whose ideas ROOTS OF EARLY REPAIR A helped refine his thinking. Marshall Parks’ clinical The publications of Chavasse had impressed Frank education—at the end of World War II—was shaped by a Costenbader, an American ophthalmologist practicing in debate between 2 competing 20th-century schools of Washington, DC. He had, uniquely for that time (the treatment philosophy, derived from the eminent British 1940s) established the only practice de- strabismologists, Claude Worth and Bernard Chavasse voted to pediatrics in the United States.3 Costenbader (Figure 2). Worth postulated, in 1903, that esotropic in- summarized his clinical observations of strabismic infants, 1 fants suffered “an irreparable defect of the fusion faculty.” gathered over a period of 2 decades, in a landmark article Their brain was congenitally incapable of achieving sub- published in the 1961 Transactions of the American Ophthal- stantial . Early surgical treatment was mologic Society.4 The article defined infantile esotropia and therefore unfounded because it was futile. Chavasse, on reported that 1 in 5 children could develop gross stereopsis the other hand—attracted by the Pavlovian physiology of if surgically aligned by age 1 year. the 1920s and 1930s—believed that the brain machinery Marshall Parks was Costenbader’s first fellow (circa for fusion was present in esotropic infants, but the devel- 1947) and first practice partner (1949) (Figure 3). As such, opment of “conditioned reflexes” for binocular fusion he was tutored in the Chavasse-Costenbader school, which were impeded by factors such as weakness of the motor favored early surgery. In the early 1960s, he succeeded limb.2 He postulated (in his text published in 1939) that if Costenbader as director–mentor to what would become in the eyes could be realigned during what he believed to be time a long succession of distinguished fellows-in-training a period of reflex learning, binocularity of some degree (see Appendix 1). By the time the article “Early Surgery for could be restored. Congenital Esotropia” was published (in 1966, written with the 7th Parks fellow, Malcolm Ing5), Dr. Parks was imprinting his own early surgery rationale on the con- science of each Washington trainee.

From the Department of Ophthalmology and Visual Sciences, Anatomy and Neurobiology, INFANT PSYCHOPHYSICS IN DALLAS, and Pediatrics, Washington University School of Medicine, St. Louis, Missouri TEXAS Supported by NIH grant EY10214 and a Walt and Lilly Disney Award for Research from Research to Prevent Blindness. The 19th Parks fellow was David Stager, Sr., who had Submitted February 4, 2005. established himself in Dallas, and was carrying out the Revision accepted June 20, 2005. Reprint requests: Lawrence Tychsen, MD, St. Louis Children’s Hospital, One Children’s Parks’ mandate to contribute to research in a Place, Room 2, South 89, St. Louis, MO 63110 (e-mail: [email protected]). private practice. In the mid-1980s, Dr. Stager teamed up Copyright © 2005 by the American Association for Pediatric Ophthalmology and with a gifted infant psychophysicist, Eileen Birch, to study Strabismus. 6 1091-8531/2005/$35.00 ϩ 0 the development and maldevelopment of stereopsis. The doi:10.1016/j.jaapos.2005.06.007 study was possible because of the invention a few years

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FIG 2. Left, Claud Worth (1869-1936); right, Bernard Chavasse (1889- 1941). Worth set up the first orthoptic clinic at Moorfields Eye Hospital in London. Chavasse trained at Moorfields before estab- lishing himself at the Eye and Ear Infirmary in Liverpool. He rewrote Worth’s Squint textbook, publishing the 7th edition in 1939.

FIG 1. Marshall M. Parks (1918-2005) delivering a lecture on infantile esotropia in the mid 1980s. earlier of a novel method for testing in infants: the preferential looking technique.7 The test was based on the observation that when given a choice of 2 images, infants tend naturally to look at the more interesting. Infants were fitted with polarizing goggles (to produce dichoptic viewing) and were seated on their mother’s lap. The goggles of strabismic infants also were fitted with prisms to optically realign the eyes (before any surgical correction) and allow binocular image correlation (corre- spondence). Pairs of polarized images, one containing ste- reoscopic depth cues, and the other nearly identical but FIG 3. Frank D. Costenbader (1903-1978) with Marshall M. Parks in flat, were shown simultaneously on opposite sides of the 1970, the year of Dr. Costenbader’s retirement. screen. The positions of the stereoscopic versus flat images were randomized from side-to-side in dozens of successive trials. If an infant possessed stereopsis, he or she would look Worth-Chavasse debate, the study dealt a serious blow to preferentially and consistently to the side of the screen the postulate of Worth. It is difficult to sustain an argu- displaying the (more interesting) stereoscopic image. By ment that esotropes congenitally lack “a fusion faculty” if comparing preferred gaze direction with the position of they show a capacity for stereopsis indistinguishable from the 3-D image, the presence of stereopsis (and stereo- that of normal infants in the first months of life. scopic thresholds) could be reliably inferred on a statistical REFINING THE TIME OF STEREOPSIS basis by the investigator.8,9 RESCUE BY EARLY SURGERY The Birch and Stager data on more than 50 infants, which are replotted in Figure 4, broadcast 3 important Knowledge of stereopsis development bolstered the ratio- messages: (1) stereopsis emerges abruptly in human during nale in favor of early surgery, as articulated by Chavasse, the first 3 to 5 months of postnatal life, (2) roughly equal Costenbader, and Parks. The knowledge prompted a grad- proportions of normal and (optically aligned) esotropic ual reexamination of old data and inspired important new infants possess the capacity for stereopsis, and (3) this case studies (in the 1980s and 1990s) on the efficacy of capacity does not merely arrest in development but degen- early , the majority conducted by Parks erates pathologically within a few months in uncorrected fellows, as summarized in the meta-analysis outlined in esotropes.6,10 Placed in the context of the 20th-century Table 1.6,11-26 These reports (Table 1) showed that if Journal of AAPOS 512 Tychsen Volume 9 Number 6 December 2005

the University of Southern California Medical Center.18 Wright operated on a series of esotropic infants at ϳ4 months of age. After 5 years of follow-up, the published results showed stable motor fusion in 100% of the chil- dren. Random dot stereopsis was restored in 60%. Most also exhibited no shift to cover testing or 4 diopter base- out prism testing. In Parks’ terminology, they displayed most of the features of (normal) “bifixators.” The criticisms leveled at Wright when this article appeared were reminiscent of those leveled a decade earlier at Creig Hoyt, of the University of California at San Francisco, who was chastised for advocating very early surgery in infant .27 Neonatal cataract sur- gery was unheard of at the time. The visual prognosis was considered uniformly dismal. Hoyt showed that lensectomy and contact fitting in the first months of life, followed by systematic occlusion therapy, could rescue acuity. Hoyt and colleagues helped raise the bar for treatment of . The early align- ment studies of the Parks’ fellows raised the bar for treatment of congenital esotropia. FIG 4. Prevalence of stereopsis as a function of postnatal age in a Obsessing over early alignment data in infantile esotro- population of normal (n Ͼ 50) versus esotropic infants (n ϭ 85). Tested using dichoptic viewing (polarized goggles and images) by pia can reveal more refined and forceful conclusions. Fig- the preferential looking method. Esotropic infants were aligned ure 5 is replotted data on the stereopsis outcomes in more using prisms and tested before any surgery. Data replotted from than 100 consecutive infantile esotropes as reported in the 6 10 Birch and Stager and Stager and Birch. year 2000 study by Birch et al.25 The y-axis is prevalence of stereopsis after surgical alignment, and the x-axis is age TABLE 1 Age of alignment and recovery of stereopsis in infantile of onset (Figure 5A) or duration of misalignment (Figure esotropia 5B) before surgery. Alignment age Prevalence* Investigator(s) The dashed line represents the average prevalence of stereopsis when all infants operated upon by 2 years of age Ͼ 24 mo 0% Taylor11 von Noorden, 198816 are grouped together, without regard to age at correction 7–24 mo 27–67% Hiles et al12 or duration before correction. What is apparent is that the Ing13, 14 noise in the data—relating age at alignment to stereopsis Zak and Morin15 outcome—occurs because onset of strabismus is idiosyn- 16 von Noorden cratic, varying considerably from infant to infant, and Birch and Stager6 distributed randomly in the interval 2 to 6 months of age. Birch et al, 199017, 19 Kushner and Fisher21 The graph of Figure 5A shows that there is no obvious Parks22 correlation between age of onset of misalignment and Յ 6 mo 40–86% Ing13, 14, 20 subsequent attainment of stereopsis. However, when the Wright et al18 data are reanalyzed with strict attention to duration of 23, 25 Birch et al misalignment, a strong correlation is evident: shorter du- Helveston24 rations mean better stereopsis. Excellent outcomes may be Ing and Okino26 achievable in infants operated upon within 60 days of *Averages from pooling of cited studies. strabismus onset. The clinical dictum that follows is that age at surgery stable, binocular alignment was not achieved until age 24 should be tailored to age of onset and not chronological months, the chances of repairing stereopsis were nil. If age. If onset was age 2 months, operate by age 4 months. stable alignment was achieved by age 6 months, the If onset was age 6- to 7 months, operate by age 8 to 9 chances of repairing stereopsis were good, and a substan- months. The message broadcast to ophthalmologists tial percentage of the infants in 3 of these 4 studies re- should therefore be updated: “For infantile esotropia, op- gained robust stereopsis, ie, random dot stereopsis with erate within 60 days of onset, rather than ‘operate early’.” thresholds on the order of 60 to 400 arc sec. And the accompanying message to pediatricians should be: The study that redefined early treatment was that by “When possible, refer cross-eyed infants for evaluation Kenneth Wright (Parks’ 73rd fellow), who was working at within weeks, rather than within months.” Journal of AAPOS Volume 9 Number 6 December 2005 Tychsen 513

FIG 6. Human and monkey infants with esotropia from the author’s clinic and laboratory.

Boothe in the early 1980s,36 who later shipped similar animals to us for ocular motor and neuroanatomic exper- iments.) At Washington University, the animals were trained to perform visual fixation and eye tracking tasks. The experiments documented that the monkeys were a good behavioral model (Figure 6).37,38 They had the full constellation of deficits that serve as clinical markers for early onset esotropia in humans, including deficits in mo- tor fusion (disparity-driven vergence), latent fixation (fu- FIG 5. Prevalence of stereopsis after surgical realignment in chil- sion maldevelopment) , pursuit/optokinetic dren with infantile esotropia as (A) a function of age-of-onset of tracking asymmetries, and asymmetries of motion visually esotropia and (B) as a function of duration of esotropia before evoked potentials (motion VEPs).39 In normal monkeys, realignment. Testing performed at age 5 years. Surgical realignment neurons in the superficial layers (layers 2/3) of striate achieved generally by age 1 year for the population as a whole. cortex (area V1) are known to provide signals for fusion/ Dashed line at 40% indicates average prevalence for all the infants. Data from more than 100 consecutive infants, replotted from Birch disparity sensitivity, whereas neurons in the deeper layers et al.25 (layer 4B) are important for motion vision and eye tracking (Figure 7A).40,41 The behavioral deficits in the strabismic THE VISUAL CORTEX IN UNREPAIRED animals implied that they had structural deficits of binoc- ular connections at both superficial and deeper layers of ESOTROPIA V1. What happens to the brain if the “early surgery” message The structural question was addressed by a collabora- is ignored, if surgery is delayed considerably or not per- tion with Andreas Burkhalter, a colleague in the Depart- formed at all? What has basic science taught us about the ment of Anatomy and Neurobiology. To reveal the un- visual cortex in long-duration esotropia? The pioneering derlying circuitry, we injected tracer substances into neu- animal work of Hubel and Wiesel,28-32 and that of Craw- rons of area V1. The tracers were taken up by individual ford and von Noorden,33-35 2 decades ago (1977-1984), neuronal soma (pyramidal cell bodies) and actively trans- laid important groundwork. If monkeys were made stra- ported within the neurons so as to label their axonal bismic in infancy and were tested as adult using penetrat- connections. The visual cortex also was processed using ing electrodes, the majority of neurons within the striate labels that reveal metabolic activity. cortex showed deficient binocular responses and reduced Recall that in normal primates, V1 is organized into disparity sensitivity. These landmark experiments proved columns of neurons (ocular dominance columns, or that early eye alignment was necessary for development of ODCs) such that every other column is driven exclusively binocular responsiveness. However, several major ques- by the right or by the left eye (Figure 7A).32 Binocular tions remained unanswered. Were the animals an appro- vision and binocular motor fusion are made possible by priate behavioral model and did they have the visuomotor horizontal connections between these monocular columns. deficits of strabismic humans? And what happened struc- Binocular connections mediate sharing of information be- turally within the visual cortex to account for the loss of tween neighboring ODCs of opposite ocularity, like the binocular activity? horizontal wires interconnecting a row of telephone We set about answering the behavioral questions by poles.42-45 In normal monkeys, we found abundant binoc- studying macaque monkeys who had naturally occurring ular, horizontal, axonal connections joining neighboring esotropia. (First reported by Lynn Kiorpes and Ronald right and left eye columns at the cortical layers known to Journal of AAPOS 514 Tychsen Volume 9 Number 6 December 2005

ment of the eyes would have caused conflicting (decorre- lated) activity in right and left eye ODCs, promoting abnormal, inhibitory interactions, mediated presumably by the 50% of connections that remained. The suppres- sion had caused down-regulation of the neuronal activity within every other row of ODCs. Summarizing these findings, the neuroanatomy of unrepaired, infantile esotropia was bad news: chronic metabolic of at least one-half of V1 input neurons and loss of an average of one-half of V1 bin- ocular connections. The good news—implied by the functional recovery after early surgery in humans—was that the cortex appeared to be able to repair these horizontal connections so long as the conflicting activity in neighboring ODCs, caused by image decorrelation, was not allowed to persist longer than a few months. The most recent work from our laboratory reinforces this point. When esotropia is repaired in infant monkeys by age 3 weeks (the equivalent of 3 months in human), they regain normal fusion and the full complement of V1 binocular connections.53,54 They also show normal metabolic activity, ie, no suppression. (Marshall Parks preferred that the terms suppression and ARC not be used in the context of infantile esotropia or monofixation syndrome. For an explanation, see Appendix 2.) An additional clinical implication can be drawn from the metabolic suppression findings. Arthur Jampolsky has long advocated alternating occlusion of strabismic infants FIG 7. Neuroanatomic abnormalities found in area V1 of monkeys up to the date of surgical repair.55,56 His argument, dating with natural infantile esotropia who alternated fixation and had from 1978, assumes that alternating occlusion abolishes normal visual acuity in both eyes: lack of binocular connections and the conflicting (decorrelated) signals that give rise to in- metabolic suppression. A, Normal monkey has an abundance of binocular connections between ODCs of opposite ocularity. Meta- terocular suppression. The metabolic findings support his bolic activity (dark staining) is uniform and high within layer 4C of all recommendation. ODCs. Neurons in layers 2/3 of the interblob pathway play a role in mediating stereopsis. Neurons in layer 4B contribute to motion VISUAL CORTEX MECHANISMS IN perception and eye movement. B, Strabismic monkey has a paucity PARKS’ MONOFIXATION SYNDROME of horizontal connections within layers 2 to 4 for binocular vision; neurons are connected within individual ODCs but there are few When disparity-driven, fusional vergence was tested in connections to neighboring ODCs of the opposite ocularity. Monoc- monkeys with large-angle esotropia, we found a complete ular connections to other ODCs of the same ocularity (eg, right eye absence of motor fusion that was similar to what is ob- to right eye ODCs) remain intact. Layer 4c shows lower/suppressed 57 metabolic activity (evident as paler cytochrome oxidase staining) in served clinically in humans with large-angle esotropia. opposite-eye ODCs. But in other monkeys with strabismus, we found angles of heterotropia ϳ4 deg (8 prism diopter [PD]) and some capacity for fusional vergence.38,57 In other words, their mediate fusion/stereopsis (layers 2/3) and eye tracking/ ocular motor behavior resembled that of humans with motion vision (layer 4B). monofixation syndrome. V1 of the monkeys with unrepaired esotropia showed 2 The major sensory and motor features of monofixation major abnormalities (Figure 7B). The first was a ϳ50% syndrome are listed in Table 2. These features were de- reduction of binocular connections.46,47 Monocular con- lineated by Marshall Parks in his 1969 magnum opus on the nections were preserved. Right eye ODCs connected to topic, which described 100 cases and coined the term.58,59 other right eye ODCs, and left eye ODCs to other left eye Pondering neural mechanisms for the Parks syndrome, the ODCs, but right eye ODCs made substantially fewer con- first two clinical features listed in Table 2, are not difficult nections to left eye ODCs. The second was a striking to explain. Receptive fields in V1, representing the fovea, pattern of “suppression” evident in every other row of are tiny and have narrow tolerances.28,60 Any defocusing columns, as revealed when flattened sections of V1 were or other decorrelation of one eye’s inputs would produce processed for cytochrome oxidase48-50 (an enzyme within a conflict in neighboring foveal V1 columns and promote neurons that reveals premortem activity51,52). Misalign- suppression of ODCs corresponding to the weaker eye. Journal of AAPOS Volume 9 Number 6 December 2005 Tychsen 515

TABLE 2 Monofixation syndrome Clinical feature Proposed neural mechanism Foveal suppression of 3–5 deg in the nonpreferred eye* Inhibitory-connection-mediated metabolic suppression of decorrelated activity in when viewing binocularly VI foveal ODCs of non-preferred eye Subnormal stereopsis (threshold 60–3000 arc sec) Broader disparity tuning of parafoveal neurons in VI/MT (foveal neurons suppressed) Stable microesotropia† less than ϳ4–8 PD (ϳ2.5–5 deg) Small angle Ϸ average horizontal neuron length in VI, eso by default to convergent disparity coding of major MST population Fusional vergence amplitudes intact for disparities Ͼ2.5–5 deg VI excitatory horizontal binocular connections (and VI/MT/MST disparity neurons) (Ͼ4–8 PD) intact beyond region of foveal suppression *Subnormal acuity (amblyopia) in the non-preferred eye in 34% of corrected infantile esotropes and 100% of anisometropes. †Microexotropia in Յ10%.

(Figure 8)? And if the heterotropia exceeds that range, why is fusional vergence typically absent? Studies of fusional anatomy and neurophysiology in primates have revealed candidate mechanisms. THE REACH OF V1 HORIZONTAL AXONS AND PARKS’ 8PD RULE In V1, the overall pattern and width of ODCs (ϳ400 microns [0.40 mm]) is the same in normal and strabismic monkeys, as is horizontal axon length across ODCs.62,63 Axon length within the V1 region corresponding to visual field eccentricities of 0 to 10 deg (ie, the representation of the fovea, parafovea, and macula) is, on average, ϳ7 mm.63 In a primate with normal eye alignment, the ODC repre- senting the foveola (or 0 deg eccentricity) of the left eye is immediately adjacent to the column representing the fo- veola of the right eye (Figure 9). The side-by-side arrange- ment of the “foveolar” columns in normal V1 is well within the range of horizontal axonal connections needed to allow those ODCs to communicate for high-grade bin- ocular fusion. FIG 8. Paradigmatic monofixator/microesotrope exhibits a deviation In a primate with microesotropia and a left eye fixation of the visiual axes on cover testing of approximately 4.4 PD (2.5 deg), preference (Figure 8), a neuron within a foveolar (0 deg) which in this case is shown as a right eye microesotropia. When column of the fixating, left eye must link up with a non- fusional vergence or prism adaptation is tested in such a patient, the angle of deviation tends to persistently return to that 2.5 deg angle. adjacent column representing the pseudofoveola of the deviated, right eye (Figure 9). Based on retinotopic maps of V1 in macaque monkey, a horizontal axon ϳ7mmin The fovea subtends ϳ5 deg of the retinotopic map of V1, length could join ODCs (and receptive fields) that were up thus a suppression scotoma of Յ5 deg (Feature 1 of the to but not further than 2.5 deg apart, or converting deg to syndrome) makes sense. (Regional suppression of meta- PD, not more than 4.4 PD. Figure 10 is a 2-dimensional bolic activity [an anatomic “suppression scotoma”] has map representing V1 from the right cerebral hemisphere been documented in V1 of strabismic monkeys.42,43) Fea- (left visual hemi-field) of a microesotropic macaque. The ture 2, subnormal stereopsis, could be explained the same sulci and gyri have been unfolded and the visual field way. Stereoacuity decreases exponentially from the fovea representation superimposed using standard retinotopic to more eccentric positions along the retinotopic map of landmarks.64-66 One horizontal axon, originating within the visual field.61 If foveal ODCs are suppressed and the foveal representation at 0-1 deg eccentricity, could link parafoveal ODCs are left to mediate stereopsis, stereopsis to a receptive field shifted 2.5 deg or 4.4 PD distant. Two is degraded but not obliterated. But it is features 3 and 4 of neurons strung together could join receptive fields 5 deg Parks’ list that are most intriguing. If binocular develop- or 8.7 PD apart. The conclusion that emerges is that the ment is perturbed so that right and left eye foveal ODCs 4-8 PD “rule” of Parks’ syndrome is explicable as a com- (receptive fields) do not enjoy correlated activity, why bination of innate V1 neuron reach and V1 topography. should the fall back position of visual cortex be set so The visuomotor system of the strabismic primate appears predictably ϳ2to4deg(ϳ4-8 PD) of microesotropia to achieve subnormal, but stable binocular fusion so long Journal of AAPOS 516 Tychsen Volume 9 Number 6 December 2005

as the angle of deviation is confined to a distance corre- sponding to not more than one-to-two V1 neurons. A CONVERGENT DISPARITY SET-POINT FOR V1/MT/MST NEURONS There is another interesting visual cortex property that war- rants comment and may help explain vergence behavior in Parks’ syndrome. That is the disparity tuning of area V1 and regions of extrastriate visual cortex, the medial temporal and medial superior temporal areas (MT/MST) that receive downstream projections from V1.67-70 The majority of bin- ocular neurons in V1 and MT/MST encode absolute dispar- ity.71 Sensitivity to absolute disparity (the location of an image on each with respect to the foveola [0 deg eccentricity]) is what guides vergence, as distinguished from relative disparity (the location of an image in depth with FIG 9. Distance spanned by the average V1 horizontal axon in normal respect to other images), which is necessary for stereopsis. and strabismic primates. Normal: In a primate with normal eye The largest number of disparity-sensitive neurons in V1 and alignment, the ODC representing the foveola (or 0 deg eccentricity) MT/MST of normal monkeys respond at 2.0 to 2.5 deg of of the left eye (L) is immediately adjacent to the ODC representing the foveola of the right eye (R). The side-by-side arrangement of the convergent (crossed) disparity, with fewer neurons respond- “foveolar” ODCs in this case (white arrowheads) would be well ing at disparities greater than and less than 2.5 deg (it is within the range of horizontal connections needed to allow those interesting to note but currently unknown whether this tun- ODCs to communicate for binocular fusion. Micro-eso: In a primate ing is related to the 2.5 deg average span of horizontal axons with microesotropia, a neuron within a foveolar (at 0 deg eccen- in foveal V1). Areas V1 and MT/MST provide signals for tricity) ODC of the fixating eye can only span a distance in the visual cortex corresponding to an angle of strabismus of approximately 4 vergence in monkey, and normal humans and monkeys have PD (dark arrowhead ϭ ODC corresponding to pseudofovea position the strongest short-latency vergence responses to convergent of deviated eye). disparities of 2 to 3 deg.72,73

FIG 10. Two-dimensional map representing V1 from the right cerebral hemisphere (left visual hemi-field) of a microesotropic primate. The sulci and gyri have been unfolded and the visual field representation superimposed using standard retinotopic landmarks. One horizontal axon, originating within the foveal representation at 0 to 1 deg eccentricity, could link to a receptive field shifted 2.5 deg or 4.4 PD distant. Two neurons strung together could join receptive fields 5 deg or 8.7 PD apart. The conclusion that emerges is that the 4-8 PD “rule” of monofixation/microesotropia syndrome is explicable as a combination of innate V1 neuron size and V1 topography. The visuomotor system of the strabismic primate appears to achieve subnormal, but stable binocular fusion so long as the angle of deviation is confined to a distance corresponding to not more than one-to-two V1 neurons. Journal of AAPOS Volume 9 Number 6 December 2005 Tychsen 517

Any insult to binocular development in early infancy, mediating fusion in the cortex to be separated by no more eg, strabismus or anisometropic amblyopia, would devas- than 1 to 2 horizontal neuron lengths. If the surgeon tate the entire population of binocular V1/MT/MST neu- accomplishes that job within ϳ60 days after onset of stra- rons. The probability of surviving an insult would be bismus, a substantial number of infants can regain high- highest among those neurons that originally were most grade fusion and stereopsis—in Parks’ nomenclature, numerous, ie neurons encoded for 2.5 deg of convergent nearly normal bifixation. If the surgeon accomplishes that disparity. Studies of vergence in microesotropic monkeys job beyond ϳ60 days of deprivation, the majority of in- from our laboratory support this notion; their vergence is fants will miss out on bifixation but will still benefit from sluggish when compared with normal, but the peak re- Parks’ monofixation. sponse remains at convergent disparities of 2 to 3 deg. The St. Irenaeus said that God’s greatest glory is man implication is that the vergence system of Parks’ monofix- fully alive.74 Marshall Parks discerned that early in his ator defaults to a 4.4 PD ϭ 2.5 deg angle of convergent ophthalmic career. He encouraged legions of students, misalignment because most of the neurons that have sur- fellows and colleagues to make esotropic infants more vived the insult are encoded for that. fully alive by straightening their eyes and repairing their brains. Dr. Parks was—in this important cause—a “good THE JOB OF THE STRABISMUS and faithful servant”; an inspiration to everyone in- SURGEON AS PROMULGATED BY volved not only in clinical care but also the neuroscience MARSHALL PARKS of strabismus. Extrapolating to the clinical problem of the human infant, This work was updated from an article presented as the inaugural the job of the ophthalmic surgeon is to realign the eyes to Marshall Parks Lecture, American Academy of Ophthalmology Meet- within an envelope of 2.5 to 5.0 deg. That allows ODCs ing, Orlando, Florida, November 1999. Journal of AAPOS 518 Tychsen Volume 9 Number 6 December 2005

APPENDIX 1 Marshall Parks’ trainees listed consecutively by year of fellowship, 1957 to 2004. Parks’ fellows are members of the Costenbader Society Year(s) of Year(s) of Year(s) of Trainee fellowship Trainee fellowship Trainee fellowship 1. Leonard Apt 57–59 50. Peter Shelley 77 99. Felipe Escallon 87–88 2. Alfred Smith 60–61 51. Jeffrey Bloom 77–78 100. David Plager 87–88 3. Elsa Rahn 61 52. Sherwin Isenberg 77–78 101. William Madigan 88–89 4. Carl Troia 62 53. Leon-Paul Noel 77–78 102. Jose Portal 88–89 5. Donald Mousel 62–63 54. Gary Diamond 78– 103. David Weakley, Jr. 88–89 6. Earl Stern 63–64 55. Allan Eisenbaum 78–79 104. Leonard Johnson 89–90 7. Malcolm Ing 63–64 56. John Lee 78–79 105. Thomas Shuey, Jr. 89–90 8. Rodger Hiatt 63–64 57. James Richard 78–79 106. Elias Traboulsi 89–90 9. S. Fleetwood Maddox 64 58. J. Allen Gammon 79 107. Linda Fundenberger 90–91 10. David Friendly 64–65 59. J. Bronwyn Bateman 79 108. David Johnson 90–91 11. John O’Neill 65 60. Warren Broughton 79–80 109. Robert Morello 90–91 12. Donald Texada 65 61. Norman Katz 79–80 110. A. Gwedolyn Noble 91–92 13. David Hiles 65–66 62. Sebastian Troia 79–80 111. William Raymond, IV 91–92 14. Richard Simmons 66 63. Fredrick Wang 79–80 112. Mark Scott 91–92 15. Edward Raab 66–67 64. David Martin 80 113. John Avallone 92–93 16. Lawrence Hamtil 66–67 65. Mark Greenwald 80–81 114. Denise Chamblee 92–93 17. Donelson Manley 67 66. Leonard Nelson 80–81 115. Mary Louise Cullins 92–93 18. Phillip Diorio 67–68 67. Avery Weiss 80–81 116. Scott McClatchey 93–94 19. David Stager, Sr. 67–68 68. Marilyn Mets 81 117. Steven Rimmer 93–94 20. Davis Wyatt 68 69. Monte Del Monte 81 118. Patrick Tong 93–94 21. Thomas Frey 68–69 70. Georgia Chrousos 81–82 119. Adam Abroms 94–95 22. Martin Lederman 69 71. Carolyn Oseterle 81–82 120. Brian Mohney 94–95 23. Everett Moody 69 72. Richard Simon 81–82 121. Dawn Rush 94–95 24. Thomas France 69–70 73. Kenneth Wright 82 122. Joseph Zarzor 95–96 25. Robert Strome 69–70 74. Pamela Gallin 82 123. David Stager, Jr 95–96 26. Richard Elliott 70 75. Norman Johnson, Jr. 82–83 124. Lisa Verderber 95–96 27. Blackwell Bruner 70–71 76. Mary Ann Lavery 82–83 125. Selim Koseoglu 96–97 28. Ronald Price 70–71 77. Edward Parelhoff 82–83 126. James Lai 96–97 29. Richard Manson 71 78. George Ellis, Jr. 83 127. Carolyn Lederman 96–97 30. Moshe Oliver 71–72 79. Yoon Ae Cho 83 128. Jane Hughes 96–98 31. William Scott 71 80. Ann Ballen 83–84 129. John Tong 97–98 32. Florencio Ching 71–72 81. Alan Chow 83–84 130. Carolina Cantu-Lee 98–99 33. John Baker 72 82. Craig McKeown 83–84 131. Mustafa Mehyar 98–99 34. Raymond Portela 72–73 83. Ross Kennedy 84 132. Steven Bullard 98–99 35. Robert Polomeno 72–73 84. Fred Chu 84 133. John Donahue 99–00 36. William Mears 73 85. John Bishop 84–85 134. Mitra Maybodi 99–00 37. Gary Rogers 73–74 86. Maury Marmor 84–85 135. Dwayne Roberts 00–01 38. Giacomo Guggino 73–74 87. Ghislain Boudreault 85 136. Lisa Wei 00–01 39. J. Denis Catalano 73–74 88. H. Sprague Eustis 85 137. Lejing Yao 00–01 40. Magda Homsy 74 89. Sheryl Handler 85–86 138. M. Rebecca Abes 01–02 41. Gordon Smith 74–75 90. Irene Ludwig 85–86 139. Mohamed Awadalla 01–02 42. Roger Niva 74–75 91. Michael Spedick 85–86 140. Sasi Doddapaneni 01–02 43. Alfred Cossari 75 92. Jeri Salit 86 141. Al-Mutez Gharaibeh 02–03 44. Earl Crouch, Jr. 75–76 93. K. Frederick Ho 86–87 142. V. Kevin Maldonado 02–03 45. Herbert Gould 75–76 94. Jose Poliak 86–87 143. Dorothy Reynolds 02–03 46. George Beauchamp 76 95. Aron Tischler 86–87 144. Nathaniel Chan 03–04 47. Paul Mitchell 76–77 96. M. Edward Wilson 86–87 145. Earl Crouch, III 03–04 48. Nancy Ronsheim 76–77 97. Lee Hunter 87–88 146. Al-Mutez Gharaibeh 03–04 49. Paul Steinkuller 76–77 98. Bruce Schnall 87–88 Journal of AAPOS Volume 9 Number 6 December 2005 Tychsen 519

APPENDIX 2 Parks avoid the term “suppression” when discussing both infantile esotropia and the Monofixation Syndrome? Likewise, why did he prefer “NRC with Students of clinical ophthalmology and visual neuroscientists who are peripheral, extra-macular fusion” to the term ARC? Dr. Parks advocated a unfamiliar with the nuances of Parksian terminology can get lost in discus- dichotomous concept of binocular vision, divided into “macular” and “extra- sions with Parks trainees, who may appear to be speaking a special dialect of macular”. Macular and extra-macular in this scheme are not a biological binocular vision. Studies in humans and monkeys have revealed that infantile continuum, rather, they are different realms, with distinct causes, effects and esotropes and monofixators suppress, and they fuse outside the zone of etiologic implications. The following is a guide and translation. Quotations suppression by anomalous binocular correspondence. Why did Marshall are from Parks references1–6; this author’s clarifications are in brackets.

Parks’ macular vision Parks’ extramacular vision “Central 3–5 deg” [foveal, the primate fovea subtends the central 5 deg] “” [nonfoveal] “Conscious of object of regard” “Subconscious” “Physiologic macular scotoma”; “not suppression (active cortical “Pathologic suppression”; a “peripheral adaptation to ” inhibition) but merely an inability to enjoy bimacular function” [foveal [adopted from Burian] suppression due to decorrelation of right vs. left eye images] The scotoma is primary, causal, “congenital or before the establishment [Suppression in this scheme is always extra-macular and never primary] of binocular single vision” [mechanism for a 1° scotoma unexplained] “NRC peripheral fusion”; “stretched Panum’s space” [outside the “ARC is a peripheral adaptation to diplopia” [adopted from Burian, who boundaries of the foveal scotoma, “peripheral fusion” here is juxta- claimed ARC was common in deviations up to 30 PD] foveal/macular despite the term peripheral; “stretched Panum’s space” concept adopted from 1956 paper of Jampolsky] 0–8 PD deviation [heterotropia; over 90% microesotropia] Ͼ 8 PD deviation Stereopsis [100 to 3000 arc sec stereoacuity] Stereoblindness [threshold beyond 3000 arc sec] “Normal fusional vergence amplitudes”; provided by “NRC peripheral No fusional vergence [a “prism adaptation” long-latency, very slow fusion outside the macular scotoma” [vergence response to large vergence response requiring hours or days may be retained] disparity (2–20 deg) prisms; eye movement recordings reveal that monofixators have prolonged latencies, more trial-to-trial variability, and less accuracy than normal subjects] 4 PD base-out test positive [note that this test is actually not a marker Test positive [and remains “positive”/abnormal even for disparities for a macular scotoma, but rather a marker for reduced disparity much Ͼ 4 PD] sensitivity across the entire visual field of the non-preferred eye]

Dr. Parks emphasized that the hallmark — the sine qua non —of tropia).14 These authors, by-and-large, couched their discussions in ARC monofixation syndrome is a “physiologic macular scotoma,” present in all terms (Lang even suggested that it was caused by a primary, inheritable form patients. His thesis was that the scotoma is primary, preventing normal of micro-ARC). Marshall Parks acknowledged and discussed, in scholarly fusion (“bifixation”). He did not elaborate on why patients should be born fashion (see his 1969 article in particular), the contributions of these authors, with a scotoma, a notion closely resembling Worth’s contention that but believed that his non-ARC, nonsuppression conceptual framework had early-onset strabismics had a “congenital defect of the fusion faculty.” He the advantage of accounting for all microtropic-monofixational phenomena, did allow that the scotoma may appear after birth but before 6 months of both primary and secondary (e.g., repaired infantile esotropes who do not age, thereby blocking “the conditioned reflexes for bifixation” (reminis- regain fully normal single binocular vision). cent of Chavasse). The macular scotoma eliminates foveal fusion, sparing “peripheral” fusion References (parafoveal fusion). Dr. Parks contended that “peripheral fusion” does not require ARC, so long as one adopts Jampolsky’s (1956) notion7 that micros- 1. Parks MM. Second thoughts about the pathophysiology of mono- trabismics use a “normal stretched-out peripheral Panum’s space” for fusion. fixational phoria. Am Orthopt J 1964;14:159–66. The width of Panum’s space does increase along the horopter at more 2. Parks MM. The monofixation syndrome. Tr Am Ophth Soc 1969; eccentric positions from the fovea, but only ϳ10% at an eccentricity of 4 deg 67:609–57. 3. Parks MM. Single binocular vision. In: Duane TD, editor. Clinical (8 PD).8 It would be difficult to account for retained fusion in microstrabis- Ophthalmology. Volume 1. Philadelphia: Harper & Row; 1987. p 1-13 mic monofixation without anomalous right and left eye ODC correspon- 4. Parks MM. Sensorial adaptations in strabismus. In: Duane TD, dence, ie, some short-range ARC, as shown schematically in Fig 9. editor. Clinical Ophthalmology. Volume 1. Philadelphia: Harper & Row; Suppression and ARC, as described and discussed in the 1950s, have 1987. p 1-6 connotations Dr. Parks wanted to avoid. The 2 terms had been defined 5. Parks MM. Sensory tests and treatment of sensorial adaptations. (notably by Burian working at Iowa9–11) as adaptations to heterotropic ϳ In: Duane TD, editor. Clinical Ophthalmology. Volume 1. Philadelphia: diplopia. However, 33% of monofixaton patients are orthophoric (by Harper & Row; 1987. p 1-14 clinical observation), ie, they display no shift to the single-, and 6. Parks MM. Monofixation syndrome. In: Duane TD, editor. Clin- therefore have no reason to be diplopic. Moreover, patients with ARC 9–11 ical Ophthalmology. Volume 1. Philadelphia:Harper & Row; 1987. p were said (by Burian ) to be stereoblind and lacking fusional vergence. 1-10 But all monofixators—by Parks’ criteria—retain some stereopsis and 7. Jampolsky A. Esotropia and convergent fixation disparity of small have superficially normal fusional vergence. Regarding infantile esotro- degree: differential diagnosis and management. Am J Ophthalmol 1956; pia, Dr. Parks’ aversion to the terms “suppression” and “ARC” was stated 41:825–33. forcefully: “Patients with congenital strabismus do not develop suppres- 8. Ogle KN. Researches in binocular vision. Philadelphia: W. B. sion and ARC since they are devoid of single binocular vision; only Saunders; 1950. p 345 patients who developed single binocular vision prior to onset of strabis- 9. Burian HM. Normal and anomalous correspondence. In: Allen, mus develop suppression and ARC.”5 JH, editor. Strabismus Ophthalmic Symposium. St. Louis: C. V. Mosby; Strabismologists, writing in the 1950s and 1960s, had described patients 1950. p 130-145 indistinguishable from Parks’ monofixators using other proprietary terms, 10. Burian HM. Normal and anomalous correspondence. In: Allen e.g. Jampolsky (1956; convergent fixation disparity of small degree)7, Lang JH, editor. Strabismus Ophthalmic Symposium. St. Louis: C. V. Mosby; (1967; microtropia)12, 13, and Helveston and von Noorden (1967; micro- 1958. p 184-200 Journal of AAPOS 520 Tychsen Volume 9 Number 6 December 2005

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