Clinical and Experimental Vision and Eye Research

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Delayed visual maturation in infants
  CLEVER
REVIEW ARTICLE
Delayed visual maturation in infants
Andrew Tatham1, Saurabh Jain2
1Department of Ophthalmology, Princess Alexandra Pavilion, Edinburgh, Scotland
2Department of Ophthalmology, Royal Free Hospital, London,United Kingdom
Address for correspondence: Saurabh Jain, Royal Free Hospital, Pond Street,London NW3 2QG.
E-mail: saurabh.jain@nhs.net
Received: 02-01-2018;
Accepted: 26-02-2018
doi: 10.15713/ins.clever.6
 
ABSTRACT
Delayed visual maturation (DVM) is the condition wherein infants who appear blindat birth regains normal or near normal vision with time. We describe the modes ofpresentation along with an approach to the visually inattentive child and a differentialdiagnosis of the condition. We discuss the electrodiagnostic findings and indicationsfor further investigation. The pathophysiology of DVM is not known, but it may be dueto a fault of the sensory, motor, or visual attention systems, and these hypotheses aredescribed in detail. Finally, the term "temporary visual inattention" is proposed as a moreaccurate term that best describes our current understanding of DVM.
Keywords: Delayed, infants, maturation, vision
How to cite this article: Tatham A, Jain S. Survey ofophthalmology. Cli Exp Vis Eye Res J 2018;1(1): 23-34.
 
 

Introduction

The term delayed visual maturation (DVM) has been used todescribe infants who initially appear blind, but in whom, withtime, normal or near-normal vision develops.[1] The diagnosismay be reserved for infants with visual inattention whohave an otherwise normal ocular and systemic examination;however, some authors use the term more loosely to describeany infant with apparently poor vision that shows some signsof improvement.[2] Since the original description of DVM,[3] aclassification system has evolved.[4-6] The classification systemaims to group children according to other ocular or systemicabnormalities and therefore enable a better prediction ofprognosis.

More recently, our understanding of the basis of DVMhas improved, and the use of the term DVM has beenquestioned.[2] The term DVM suggests that the cause forvisual inattention in these children is a delay in the normalprocess of development in the visual system. There is littleevidence to support this notion; in contrast, many childrenwith visual inattention develop other neurodevelopmentalproblems. We support the view of Hoyt[2] that the termtemporary visual inattention best describes our currentunderstanding of this condition.

 
Definition and Classification

In 1947, Beauvieux initially reported that children who wereapparently blind could show complete visual recovery.[3] Theterm DVM was first suggested by Illingworth in 1961 whenhe described two infants with normal ocular examination whodisplayed visual unresponsiveness before the age of 6 months andwho then became attentive to visual stimuli after this age.[4] DVMhas previously been referred to as temporary visual inattention,la pseudo-atrophie optique des nouveau-nes,[3] papilla grisea,[7]myelogenesis retarda,[8] dissociated visual development,[8] andvisual developmental delay.[5,6]

Based on the presence or absence of associated abnormalities,Beauvieux considered DVM to exist in two forms.[3] In type 1DVM, the delay in visual maturation was an isolated finding,and full visual recovery could be expected by 4 months of age. Intype 2 DVM, there was an associated problem such as nystagmusor mental retardation, and in these cases, visual recovery wasslower and less complete.[3] DVM may be associated with otherocular and systemic abnormalities such as albinism, prematurity,or perinatal insult.[6,9,10]

A further category was later introduced by Uemera allowingspecification of whether the associated abnormality was ocularor non-ocular.[5] Uemera proposed that type 2 DVM shouldinclude infants with DVM who are mentally retarded or have aseizure disorder and type 3 include those with a primary visualabnormality.[5]

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In 1985, Fielder et al. examined the clinical features of 53infants from 3 centers with DVM.[6] A modified classification ofDVM was proposed based on Uemera's classification with twosubcategories of type 1 DVM.[6] Infants classified as type 1A werethose with a normal peri-natal history, while infants classifiedas type 1B had a history of perinatal problems. Group 1A wasfurther subdivided into 1Ai to include infants with poor vision onpresentation and group 1Aii for those whose vision had alreadyimproved by the time they were assessed by an ophthalmologist.Similarly, to the classification of Beauvieux,[3] DVM type 2was associated with non-ocular abnormalities such as mentalretardation. A final type was identified as DVM type 3 to includethose children with stable ocular abnormalities whose visionwas worse than could be attributed to the ocular problem aloneand who demonstrated an improvement of vision within a shortperiod of time.[6] In 1991, Fielder and Mayer introduced a type 4category of DVM by classifying children with albinism andidiopathic congenital nystagmus as type 3 and those with othersevere ocular disorders as type 4 [Table 1].[11]

The evolving classification system was complex and hadquestionable value. Recently, it has been suggested that we revertto the original term "temporary visual inattention."[2] Temporaryvisual inattention is a term applied to a clinical situation inotherwise healthy infants, who are initially visually inattentivebut become completely responsive by 4-6 months of age. Inthese children, there is no other known ocular or central nervoussystem (CNS) disorder. Despite the move away from the broaddefinition of DVM, an understanding of previous classifications ofDVM is necessary to adequately analyze the literature. Previousstudies of visually unresponsive children have included patientswith coexistent ocular and non-ocular conditions who would notbe considered to have simple DVM by today's standard.

The term DVM implies that there is a delay in a normalprocess of the development of the visual system. Beforeconsidering DVM, further it is helpful to consider the normaldevelopment of the human visual system.

Normal Development

Normal development of the visual system

The development of improved visual acuity from infancy toadulthood can be explained by the development of the visualsystem, which is far from maturity at birth. In the followingdiscussion, the maturation of each component of the visualsystem is considered separately.

Photoreceptors

The retinal photoreceptor cells are formed by 24 weeks gestation;however, at birth, they are still developing.[12,13] The neonatalfovea is anatomically immature. Cones do not reach adultdimensions until 14 months after birth and foveal cone densitydevelops even more slowly not reaching adult levels until a fewyears of [14,15] Despite structural immaturity, electrophysiologicaltests suggest that cones are functionally mature at birth.[16-18]

 
Table 1: Historical classification of delayed visual maturation
Delayed visual maturation in infants

Ganglion cells

The retinal ganglion cells are also immature at birth.[19] In themature retina, the retinal ganglion cells may respond to lightincrements (on cells) or light decrements (off cells). The dendritesof the on- and off-center retinal ganglion cells are stratified inthe different lamina of the inner plexiform layer. In contrast,in the immature eye, the immature ganglion cell dendrites arefound throughout the inner plexiform layer.[19] Studies of thedevelopment of optic nerves have shown that myelination of theanterior visual pathways increases up to 2 years of age.[20] Corticaldendrite growth and synapse formation also continue during thefirst 2 years of life.[21] If the visual pathways are immature at birth,it is predictable that the visual evoked potentials (VEPs) are alsoimmature. Children < 3-5 months of age have been shown to have adelayed VEP latency compared to adults.[22,23] Postmortem studieson premature infants have shown that the maturation of the VEPcorrelates with the degree of cortical dendrite formation.[24]

The cortex

Development of the visual cortex has been studied extensivelyin Macaque Monkeys. The lateral geniculate nucleus developsat 8-11 weeks and acquires characteristic lamination between22 and 25 weeks gestational age with concurrent developmentof the striate cortex. Formation of ocular dominance columnsdevelop between 26 weeks and term, and cortical developmentcontinues postnatally with the majority of interconnections inthe striate cortex complete by 8 months postnatal age.[25]

After birth, sensory experience and spontaneous activityplay a role in the development and remodeling of the retinalneural circuit.[26] Spontaneous activity is thought to drivesynaptic refinement around the time of eye opening, whilesensory experience is important for the maintenance of theseconnections.[27] Some types of developmental delay have beenattributed to delays in myelination of the brain; however, there isno evidence to support this in DVM.[28]

Normal formation of the visual cortex is thought to becontrolled by subplate neurons in the subependymal germinativezones.[29] The subplate neurons release neurotrophins that guidegeniculocortical afferent neurons toward the appropriate corticaltarget cells.[30] Subplate neurons also provide a site for synapseformation for axons ascending from the thalamus and othercortical sites.[31]

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Synapse formation in the subplate neurons occurs between22 and 34 weeks of gestation; however, at this stage, the corticalplate is not fully developed.[32] The ascending afferent pathwaysare held by the subplate neurons near the germinal matrix untilthe cortical plate has matured. The brain and blood supply tothe brain in a preterm infant are different compared to a terminfant.[33] The germinal matrix has fragile blood vessels, whichare vulnerable to changes in blood pressure.[33] Prematureinfants may be more vulnerable to hypoxic insults that lead tovisual problems. Studies in premature infants indicate that, ifthe subplate neurons are damaged, cortical structures, includingthe ocular dominance columns, may fail to develop normally.[34,35] It is not known if prematurity increases the risk of DVM.[36] Although subplate neuron dysfunction may explain visualimpairment in some premature infants, there is no evidence tosupport a role in DVM in children who are otherwise normal.Subplate neuron dysfunction is not supported by the normalVEP studies in infants with DVM, compared to age-matchedcontrols.

Cortical maturation during the first few months of lifehas been demonstrated by electroencephalogram studies.During early infancy, there are substantial changes in theelectroencephalography (EEG) which are so predictable thatthey can be used to estimate an infant's gestational age to within1 week.[37] It is at around 3 months of age that the saw-tooth wavecharacteristic of the adult EEG during the rapid eye movementphase of sleep begins to appear. Shortly following this, the EEGshows a 3-4 Hz 50-75 MV occipital rhythm when the child isawake which eye-opening interrupts. The frequency of thisgradually increases to 6-7 Hz by 5 months of age.[37]

The motor system

Normal visual maturation also depends on maturation ofthe motor system. For example, there is a period of postnatalmaturation in the mechanisms that allow ocular motor stability.Some infants develop transient idiopathic nystagmus during thisperiod.[38] As ocular motor stability improves, the nystagmusdisappears. During this period, nystagmus may appear andthen disappear.[38] Bianchi et al. described two children withwide-amplitude and high-frequency nystagmus who had poorvisual awareness.[39] By 5 months of age, nystagmus was nolonger detectable and both infants appeared to be visually,developmentally, and neurologically normal.

Visual acuity in infants

It is now possible to obtain quantitative measurements of visual acuity in infants by behavioral or electrodiagnostic techniques.Both methods have revealed that infant's vision is reducedcompared to adults.[40,41] Preferential looking tests are based onthe presentation of gratings of different spatial frequency. Whenthe infant is confronted by the grating and a blank stimulus, theinfant is expected to preferentially look at the latter. The gratingacuities are recorded in cycles per degree with 3c/° equivalent to6/60 and 30c/°to 6/6.[41] Neonates have been estimated to havevisual acuities of approximately 6/60-6/120. By 6-8 monthsof age, this has improved to 6/12.[40,41] Components of visualacuity include grating acuity, Vernier acuity, and contrastsensitivity. Grating acuity is a measure of the finest resolvabledetail, and Vernier acuity is a measure of sensitivity to relativepositions. Contrast sensitivity is calculated from the contrastthreshold, which is the lowest detectable contrast of a givengrating. Each component of vision has a different developmentalcourse, whether measured by preferential-looking orelectrodiagnostically.[42] Contrast sensitivity develops rapidly,whereas grating acuity is slower to mature and Vernier acuitydoes not reach maturity until adolescence.[43] Early preferentiallooking studies suggested that Vernier acuity was superior tograting acuity by 4-5 months of age.[42] However, these studieswere flawed as they used temporal stimuli in Vernier testingand stationary stimuli in the grating tests. Zanker et al. assessedVernier and grating acuities using stationary targets and foundthat Vernier acuity was better than grating acuity only after 4 yearsof age.[44] An analysis of several studies has found that Vernieracuity reaches adult levels between 5.7 and 8.7 years of age andresolution acuity between 1.4 and 2.2 years of age.[43] Good et al.found that two infants with DVM had normal Vernier acuity forage.[45] The finest resolvable acuity is limited by the density offoveal cone photoreceptors which is known not to reach adultlevels until several years of age.[46] As the receptor size and spacingmatures, the cortex receives finer information.[46] Grating acuityduring the 1st month of life is approximately 4.5 c/°, increasing to20 c/° at 8-13 months.[47] Norcia et al. found that, by 8 monthsof age, the VEP grating acuity was not reliably different fromadult levels.[47] Skoczenski et al. also found that grating acuitymatures quickly but in contrast to Norcia et al., at 50 weeks ofage, grating acuity was still less than adult levels.[48] Vernier acuitythresholds are markedly immature during the 1st year of life. By50 weeks of age, they are still 10 times lower than adult values.[48]With development, there are changes in retinal receptor sizeand density and a corresponding improvement in grating andVernier acuity.[49] The different components of visual acuitymay be affected to a varying degree by different conditions.For example, in amblyopic eyes, contrast sensitivity is relativelypreserved, and there is a moderate reduction in grating acuity buta large reduction in Vernier acuity.

 
Quantitative techniques have allowed us to better appreciatethe normal process of visual development. It is not clear whateffect DVM might have on each of these components of vision.[50]

The maturation of the VEP

Studies in pre-term infants have also allowed research into thematuration of the VEP.[51] With increasing age, the latency ofthe Pl00 VEP decreases.[20] Postmortem studies have shownthat changes in the VEP latency correlate to an increase inmyelination. The waveform components of the VEP have alsobeen shown to be affected by factors such as maternal smokingand fetal growth retardation.[52]

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Developmental Delay

A delay in development is thought to affect 5-10% of children.[53]Delay may affect gross and fine motor skills, speech and language,cognition,personal and social development, and activities of dailyliving. Normal childhood development may proceed at differentrates, and there is no consensus on the specific definition ofdevelopmental delay. Significant developmental delay, however,is defined as a child which is 2 standard deviations behind themean in the age of reaching a developmental milestone.[53]Global developmental delay is a delay in two or more spheresof development. Causes of developmental delay can be genetic(e.g. chromosomal abnormalities), neurological (cerebral injuryor malformations), metabolic, toxic, endocrine, or environmental.Ocular abnormalities including refractive errors and strabismushave been found in 13-25% of children with global developmentaldelay.[54] DVM may be an isolated defect or occur in associationwith delays in other spheres of development. Children with poorvision in one eye (e.g., enucleation due to retinoblastoma) generallyfunction normally in terms of physical health and mental andmotor development; however, children who have bilateral visualimpairment are more likely to be delayed developmentally.[55]

It is well recognized that children with DVM may have delaysin other developmental milestones. There seems to be a relativelyhigh prevalence of developmental delay in children with DVM.This suggests a generalized neurological problem. Lambert et al.found that four of the nine children they studied were delayed inachieving motor milestones.[56] One of these children had globaldevelopmental delay at 3 years of age. An magnetic resonanceimaging (MRI) scan of the brain showed cortical atrophy anda thalamic lesion. Fielder et al. found a delay in orientation tosound[6] and seven of eight children studied by Hoyt had generalmotor delay.[9]

Modes of Presentation

Infants with DVM show poor visual behavior and are unable tofixate and follow a light or respond to preferential looking cards.Aside from poor visual responses, their ocular and systemicexamination is normal. Lambert et al. reported a mean age atpresentation of 3.4 months in their series.[56] Infants becamevisually response at a mean of 5.5 months (range 3-8 months).[1] In Fielder's series of 42 infants with type 1 DVM, the medianage of visual responsiveness was 14 weeks of age; however, infantswith type 1A responded at 9-18 weeks of age, while infants withtype 1B were 11-40 weeks of age.[6,11] Infants with type 2 DVMoften have significant associated structural CNS pathology,demonstrable on neuroimaging. This is frequently accompaniedby a seizure disorder and may be related to birth trauma or otherinsult. Sometimes, the visual responsiveness of a child with type 2DVM improves with control of the seizures.[57] The improvementin vision in these patients is slower, later and often less completethan for infants with type 1 DVM.[6] Infants with type 3 DVM havean associated ocular abnormality such as nystagmus, albinism, orcataract; however, their vision is worse than would be expectedfrom the disease alone. Children with type 3 DVM have a slowerand later improvement in vision than those with type 1 DVM. InFielder's series, the median age of improvement was 20 weeksfor children with ocular abnormalities.[6] A high frequency, wideamplitude, transient jerk nystagmus that improves as visualresponsiveness improves has also been reported in patients withDVM.[39] It follows that the prognosis for vision in these childrendepends on the underlying ocular abnormality.

 
An Approach to Child Who is Visually Inattentive
History


Children with DVM may present due to parental concern orfollowing routine screening. A detailed visual history includingtime of onset of reduced vision, time and speed of visual recovery,and associated visual and ocular symptoms is important.Other data collected included sex, ethnicity, and details ofthe pregnancy, birth weight, perinatal period, and the infant'ssubsequent development including age at onset of smiling.The comprehensive history should include a detailed prenatal,perinatal, and postnatal history. Ask the mother about drugingestion or systemic infection during pregnancy. It has beensuggested that DVM might be caused by gestational nutritionaldeficiency or toxins leading to delayed cortical myelination orparietal cortex structural defects.[58] Ascertain whether there hasbeen developmental delay or regression.

The parent's assessment of their child's visual behavioris helpful but not always an accurate reflection of the child'strue visual acuity. Tressider et al. found that some parents didnot think that their child could see until the visual acuity was3.0 c/° ,whereas others thought that they could see at 0.2 c/°.[59]

Examination

The examination of the child should include an assessment ofvision, qualitatively by the fixation and following response to alight, toy, or face, and if possible quantitatively using preferentiallooking techniques. There should be an assessment of ocularmotility, pupillary reactions, refraction, and dilated fundoscopy.It is important to test the brainstem saccadic function of any childwith poor visual behavior. Harris et al. have shown that binocularOKN is normal in children with DVM; however, the monocularOKN is asymmetrical.[60] Lambert et al. found that infants withDVM had poor nasotemporal following.[56] The vestibuloocularresponse (VOR) is usually normal; however, Hoyt and Eviatarhave shown that preterm infants with normal visual behaviormay lack a fast-phase component to vestibuloocular testing.[9,61]The fast phase became presented by 1 month of age. If saccadictesting is abnormal, an MRI scan of the brain is indicated.Examine the child for dysmorphic features. Early studies ofDVM thought that the pupil responses were absent.[7] Anotherstudy concluded that both behavioral and pupillary responsesto gratings were delayed in DVM, indicating that although theunderlying defect is primarily subcortical, secondarily it delaysthe emergence of cortically mediated responses.[62]

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Investigations

The investigations required for a visual inattentive child dependon the age of the child, duration of visual inattention, examinationfindings, and whether there is delay in any other developmentaldomains.

Systemic investigations should be considered, especiallyif there is a delay in more than one developmental sphere. Forexample, the first-line investigations for global developmentaldelay might include chromosomal analysis, full blood count, ureaand creatinine, creatinine kinase, lead toxicity screening, thyroidfunction tests, urate (for purine disorders), and ferritin. Theseinvestigations are best done in conjunction with the pediatricianin addition to a thorough systemic examination.

An EEG and neuroimaging should be done if there is a historysuggestive of seizures, an abnormal head size, or focal neurologyor if the poor vision persists beyond 6 months of age. Metabolictests may also be considered as should referral to the geneticsdepartment.[63] The assessment of visual acuity in infants is notalways easy. Many of the clinical methods rely on an intact sensoryand motor system. Interestingly, children with DVM, althoughseemingly having visual inattention, may have good grating andVernier acuities. Vernier and grating acuity thresholds, measuredelectrophysiologically, were normal in two children with DVMeven though their visual behavior was deemed abnormal.[45]

Visual unresponsiveness in children may be due touncorrected refractive error; therefore, retinoscopy in any caseof suspected DVM is essential. Winges et al. described twopatients aged 4 and 5 months who were felt to have DVM.[64] Onrefraction, these infants had 4-9 diopters of myopia. When themyopia was corrected, the children had normal visual behavior.Another test to consider is a hearing evaluation.

DVM has been associated with auditory neuropathy/dyssynchrony, a condition of hearing impairment associatedwith absent or severely abnormal brainstem auditory evokedpotentials but normal cochlear functions. Aldosari et al. describeda single case and suggested that a detailed hearing evaluationshould be performed for all children with DVM.[65]

Some investigators have found children with DVM to haveabnormalities on neuroimaging. This may be attributed to manyof these patients having type 2, 3, or 4 DVM. Hoyt et al. foundthat 5 of 14 patients with type 1 DVM had abnormalities onMRI.[9] Fielder et al. and Russell-Eggitt et al. have suggested thatsome children with type 1 DVM may have suffered unrecognizedperinatal insult.[11,66]

Fielder revisited the patients he had originally labeled astype 1A DVM and found that 6 out of 16 had actually hadperinatal problems.[11]

By definition, neuroimaging of children with type 1 DVMis normal. Some studies have reported abnormalities, butthere are certainly no consistent findings.[1,67] We recommendneuroimaging only in cases where other ocular or systemicanomalies are present or suspected.

 
Electrodiagnostics

Electrodiagnostic tests including flash visual evoked response(VER) and photopic and scotopic electroretinography (ERG)may be performed. The assessment of visual acuity in infantsin the clinic depends on both sensory and motor systems.Electrophysiological tests assess the sensory system alone andare a useful tool in children with DVM. Electrodiagnostic testsdo not rely on the infant's ability to generate an appropriatebehavioral motor response.

Most authors are in agreement that infants with DVM have anormal ERG. Fielder et al. found normal ERGs in all 33 cases ofDVM that they tested.[6,11]

In contrast, several authors have described abnormal flashand pattern VEPs in infants with DVM.[8,9] Abnormalities ofVEPs have included prolonged latencies, abnormal waveforms,and decreased amplitudes. Mellor reported an absence or delayof flash VEPs in four children with DVM.[8] Maturation of theVEP was seen as visual responsiveness improved.[8] Harel hadstudied three children with DVM, all of which had delayedlatency of their VEPs. By 6 months, the children had normalvision and normal electrodiagnostic investigations.[68] Kraemeret al. also reported a series of children with initially abnormalflash VEPs that improved as an appropriate visual responsedeveloped.[69] In 1983, Hoyt described a series of 8 children withDVM. 7 of the children also had delays in motor development. 6of the children had been premature or low birth weight. In eachchild, there was a normal ERG, but the pattern onset-offset VEPwas absent or attenuated.[9] Fielder and Russel-Eggitt found that78% (32/41) of children with DVM that they investigated hadabnormal flash VEPs.[6] The abnormalities included abnormalwaveforms, prolonged latency, and decreased amplitudes.

A major limitation of the majority of the VEP studies is that theelectrodiagnostic responses of these patients with presumed DVMwere not compared with age-matched controls. Visual function,assessed by VEP, varies among normal healthy newborns. TheVEP is initially of long latency and duration before it becomes morecompact and of shorter latency. A more mature VEP develops byapproximately 5 weeks of age corresponding to the developmentof responsive smiling and responsive visual behavior. Therefore, anormally developing infant may be expected to have some changein VEP as they mature. Previous studies in healthy children haveshown a prolonged latency of flash and pattern VEPs comparedto adults.[40,70] Therefore, the abnormal latency in children withDVM may be normal for their age and the changes in latency overtime may reflect normal maturation.

Indeed, compared to adults, healthy neonates have beenshown to have prolonged latency of the P100 of the flash andpattern-reversal VEP. Maturation does not occur until up to6 months of age.[26] Normal infants also have decreased VEPamplitudes, which mature more slowly than VEP latency.[71]

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Lambert et al. conducted a prospective longitudinal studyof nine infants with presumed isolated DVM.[56] The ERGs andVEPs of the infants with DVM were compared to age-matchedcontrols. Eight of nine patients had normal flash and patternVEPs, and all of the children had normal ERGs. Children aged< 3 months were found to have a prolonged P100 latency;however, there was no significant difference when these childrenwere compared normal children of a similar age.[56]

Discrepancies in the VEP studies may be due to theheterogeneous nature of DVM. Russell- Eggitt et al. suggestedthat some children with DVM may have had resolvedperiventricular hemorrhages, a known cause of immatureand delayed VEP waveforms.[66] A further difficulty in theinterpretation of electrodiagnostic tests is the wide variation inthe normal waveform. In summary, electrodiagnostic tests mayserve as a prognostic marker in DVM. While the presence of anormal VEP is reassuring an abnormal pattern or even flash VEPdoes not mean, the baby will not see.

Differential diagnosis

The differential diagnosis of the apparently blind child with anormal examination includes:

Cortical visual impairment

Cortical visual impairment is an important cause of visualunresponsiveness in children. This may be permanent ortemporary. The term cortical visual impairment is misleadingbecause in most cases it is the insult to deep subcortical whitematter (periventricular leukomalacia) that is responsible forthe visual impairment. For this reason, the term "cerebral visualimpairment" has been suggested as a replacement.[72]

Cortical visual impairment is characterized by the infantwith poor vision, no nystagmus, and a normal eye examination,including normal pupillary light reactions and unremarkable fundi(at least initially). It may, however, be accompanied by restrictedvisual fields, reduced accommodative function and disordersof ocular motility including strabismus, nystagmus (which isa common accompaniment of periventricular leukomalacia),dystonic eye movements, and disorders of pursuit and saccade.[73]

Good et al. have extensively reviewed cortical visualimpairment.[74] Prognosis for recovery depends on etiology, ageof onset, and severity of brain damage. Cortical visual loss fromperinatal hypoxic-ischemia has a particularly poor prognosisif congenital, but up to a 70% recovery rate if acquired.[10]Investigations including VEP, OKN and neuroimaging are oftenabnormal unlike in infants with DVM. Children with corticalvisual impairment may demonstrate some improvement invision. For example, Lambert et al. reported on visual recoveryfrom hypoxic cortical blindness.[75]

These children can also have associated neurological defectsthat require ongoing management and interfere with visualfunction. Some children may have transient cortical blindnessdue to seizure activity. Seizure activity can also affect corticalvisual attention mechanisms.[76,77]

 
Ocular motor apraxia

Eye movement abnormalities may be misinterpreted as poorvision as assessment of visual behavior in infants is to largedegree interpreted based on visually directed ocular movements.Congenital abnormalities of saccades may be due to CNSabnormalities, lipid storage disorders, or perinatal insults;however, if no abnormality is found, this is termed ocular motorapraxia. Children with abnormal saccades compensate usinghorizontal head thrusts to overcome the lack of saccadic driveto follow a target. This compensatory mechanism takes time todevelop, and until then, children may appear visually unresponsive.Demonstration of vertical saccades or pursuit responses, OKNresponses in any direction, or normal visual acuity on VER testingmay confirm the diagnosis of congenital ocular motor apraxia.[78]

Retinal dystrophies

Leber's congenital amaurosis is an autosomal-recessive retinalrod/cone disorder that causes poor vision from birth and may beconfused with DVM. Although initial fundus examination maybe unremarkable, pigmentary retinopathy, vessel attenuation, andoptic atrophy occur over time.[79] The ERG shows unrecordableor grossly attenuated electrical potentials of both rods and cones(the "flat ERG"). No treatment is available for this condition.Achromatopsia (rod monochromatism) is an autosomal-recessiveor X-linked disease characterized by a partial or complete absenceof retinal cone function. Visual acuity is generally better than inLeber's amaurosis and frequently exceeds 20/200. In this condition,the rod ERG is normal, whereas the cone ERG is significantlyimpaired. Photophobia, which may be marked, is quite common,and these children show a marked preference for dim lighting.[79]

Global developmental delay

DVM may be due to global developmental delay as discussedpreviously.

Epilepsy and drugs

Children with type 2 DVM often have epilepsy; however, achild who is experiencing frequent seizures or is being treatedwith sedatives may also appear visually unresponsive. Once theepilepsy is optimally controlled, these children may becomemore responsive. DVM has also been described in childrenwhose mothers were users of cocaine during pregnancy.[80]

Associated findings

Most of the series demonstrate that children with DVM willdevelop normal vision; however, the recovery period andeventual outcome depend on the underlying cause and associatedfeatures of DVM. Tresidder et al. investigated 26 childrenand divided them into four groups (type 1A, type 1B, type 2,and type 3 DVM).[59] Tresidder found the age at which visualimprovement began differed in each group. For type 1A, visionimproved at 10-18 weeks of age (mean 15 weeks), for type 1B,at 7-34 weeks (mean 15.7), for type 2, at 22-78 weeks (mean45.7), and for type 3, at 13-28 weeks (mean 24).[59] Therefore,infants with type 3 DVM, with nystagmus or other ocular defects,attained normal vision but had a slower recovery than infantswith type 1 DVM. Infants with type 2 DVM had persistentneurodevelopmental abnormalities and did not develop normalvision. Appropriate visual development is not the only concernwhen assessing children with DVM. Further follow-up of cases ofisolated DVM type 1 have shown delays in other developmentalmilestones such as walking.[3,10,53] This observation suggests thatDVM is more complex than just delayed visual behavior.

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Delayed developmental milestones

Hoyt found that 7 of 8 patients with DVM also had delayedmotor development.[9] Cole and Fielder have described childrenwith DVM who are also slow to speak and hear.[10,11] In Fielder'sdescription of 53 infants with DVM, there was a delay in hearingreported in 6. The onset of smiling was delayed beyond 6 weeksof age in 31 children.[6]

Neuropsychiatric disorders

Recently, Hoyt has reported a series of 98 patients with isolatedDVM.[2] 93% of infants in this series eventually developed a bestcorrectedvisual acuity of 20/20 or better. In contrast, many ofthese children were subsequently diagnosed with neuropsychiatricdisorders including 22 patients with learning difficulties, 11with attention deficit disorder, 4 with autism, and 5 with otherpsychiatric disorders. Nine patients subsequently developedseizure disorders and 5 had cerebral palsy. An interesting aspect toDVM is that many children who are initially felt to have an isolateddelayed development in vision have been found on follow-upstudies to have evidence of other neurological damage.[6,9,10] Hoythad suggested that we should not use the term DVM as this impliesthat DVM is an isolated prolonged normal maturation.[2] Somechildren with DVM who seem otherwise normal later developneurodevelopmental problems. It has been suggested thatabnormal vision might indicate neurological impairment due to aperinatal insult. In Lambert's study, children with DVM becamevisually responsive at a mean age of 5.5 months.[56] Lambertet al. suggested that DVM is due to an abnormality of the visualassociation areas. Tresidder et al. also conducted a prospectivestudy.[59] They examined 26 children and found that those withisolated DVM had the earliest onset of visual improvement. Thosethat had a perinatal insult had a slower recovery and one-thirddeveloped a neurodevelopmental abnormality.

Other ocular abnormalities

Strabismus is very common during the period of visualinattentiveness. Tresidder found that all infants with type 1ADVM had strabismus.[59] In contrast, and by definition,nystagmus is not a feature of type 1 DVM, although Tresidderet al. found that patients with type 3 DVM developed nystagmusaround the time of visual improvement.[59] Fielder found that15 of 29 patients with DVM also had a divergent squint, 8 wereconvergent, and only 6 orthotropic.[11] With follow-up, all ofthe divergent squints resolved but only one of the convergentsquints. Bianchi et al. had reported two cases of children withapparent visual inattention who also had nystagmus.[39] Thefirst child presented at the age of 3 months with horizontaljerk nystagmus with high frequency and wide amplitude. By5 months, the nystagmus was resolving and visual behaviorhad improved. By 8 months, the nystagmus had disappearedcompletely. The second patient presented at 2 months, unable tofix, and following. There was also jerk nystagmus with a verticalcomponent. At 4 months of age, the nystagmus had almostdisappeared and visual awareness was almost normal. Thenystagmus in both consisted of horizontal jerks and a verticalcomponent.[39]

 
In a further study, Fielder and Tressider examined 26 infantswith DVM.[59] The visual acuity of these children was assessedusing the acuity card PF procedure. Of 26 infants, only 8 hadisolated DVM with no perinatal problems (although 3 of thesechildren were preterm). In 8 children with isolated DVM, visualimprovement occurred at a mean of 15 weeks of age (range 10-18 weeks). Once vision had begun to improve, normal levels ofvision were reached rapidly. For 7 of 8 infants, normal vision wasachieved between 12 and 17 weeks of age. Fielder et al. foundthat patients in Group 1 had a rapid improvement in vision oftenover just a few days and at a median age of 14 weeks.[6]

Prognosis

The prognosis of a child with DVM depends very much on thedefinition of DVM chosen. Children with associated ocularand systemic problems can be expected to have a slower andless complete recovery. Children with isolated DVM recovervision during a narrow time frame. Cole et al. also conducteda prospective study of 16 children with DVM.[10] All of thesechildren developed visual responsiveness between 4 and 6 monthsof age. However, some of the children developed neurologicalabnormalities after long-term follow-up. Children with corticalor ocular abnormalities may show some visual recovery. Rolandet al. found that 50% of children with visual impairment due tobirth asphyxia had some degree of visual recovery.[81] Childrenwith ocular disorders who initially appear blind may also showsome improvement in vision. In Fielder's series of 11 patientswith conditions such as coloboma and optic nerve hypoplasia, 8children showed visual improvement.[82] Evidence suggests thatchildren with DVM often do not have an isolated, temporaryvisual problem. Goodman et al. described 3 boys who presentedwith DVM which spontaneously resolved.[83] However, they laterdeveloped severe autistic impairment, general developmentaldelay, hypotonia, and clumsiness. It was proposed that awidespread delay in brain maturation could account for this.

Several authors have noted a high incidence of prematurity inchildren with DVM.[3,6] It has been suggested that some childrenwith DVM may have had undetected neurological insults.[66]Fielder et al. reexamined their original DVM study populationand found that many of the children originally thought to haveType 1a DVM had actually had a history of perinatal trauma.An interesting study was conducted by Hungerford et al. 177preterm infants born at < 33 weeks' gestation were examined.[33] This study was unusual compared to other studies of DVMin that the children received repeated cerebral ultrasoundscans, daily for the 1st week of life, and a regular intervalthereafter. 9 (5%) children were diagnosed with DVM. 7 of9 children were found to have periventricular hemorrhageson ultrasound scanning. 2 had evidence of hypoxic-ischemicbrain injury. 5 children had neurodevelopmental disorders atfollow-up. Hypoxic-ischemic injuries are closely associatedwith neurodevelopmental problems.[85] If children with DVMhad unrecognized hypoxic injuries, this might explain the highincidence of neurodevelopment problems in these children.

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Discussion

The etiology of DVM

Several authors have found a high incidence of perinatalproblems in patients with DVM and have suggested that DVMmay be secondary to perinatal hypoxia or hemorrhagic insultswhich may not have been apparent at the time.[9] In some studiesof DVM, infants that initially seemed normal (type 1 DVM) havelater developed neurological problems and have been shown tohave structural abnormalities on neuroimaging.[59] In the seriesby Hoyt et al., one-third of patients with type 1 DVM were laterfound to have structural abnormalities on MRI.[9] Other authorshave argued that patients with structural abnormalities shouldnot be classified as having DVM.[66]

The pathophysiology of DVM

The pathophysiology of DVM is not known; however, severaltheories have been proposed. Each component of the visualsystem has been considered as a casual candidate for DVM. DVMmay be due to a fault of the sensory, motor, or visual attentionsystems. The fault may represent a delay in normal developmentor a pathological process.

Cortical and subcortical pathways

It has been proposed that DVM may be a disorder of thesubcortical visual pathways. Children with DVM tend torecovery between 3 and 5 months of age and often over theperiod of just a few days. These improvements occur at aroundthe time some cortical functions are thought to emerge.[11,59,62]Some electrophysiology studies of children with DVM haveshown prolonged latency on VEP. When visual interest andresponsive smiling develop, there is maturation of the VEP.[69] Indeveloping animals, geniculocortical and extrageniculate visualafferent pathways evoke two types of VEPs. The VEP responsesseen in infants have been noted to be similar to recordings fromchildren with lesions of the geniculostriate pathway or primarycortex.[84-86] This observation has led to the understandingthat extrageniculate visual afferent pathways mature beforethe geniculocortical system and that vision in early infancy ismediated by subcortical pathways. Cortical processes developby 3 months of age, which is often the time of improvement inDVM. It has been suggested that DVM has a subcortical basis.

 
Investigators have tried to measure the function of thecortical and subcortical systems separately in children withDVM. Pupil responses to gratings reflect cortical activity aloneand normally become measurable at 1 month of age. In contrast,the acuity card procedure reflects both subcortical and corticalfunction and can be detected at birth. In one infant assessed byCocker et al., the development of both behavioral and pupillaryresponses was delayed.[62] This implicates both the subcorticaland cortical visual systems in DVM. In the normal developingvisual system, VEP Vernier acuity and grating acuity developat different rates. Grating acuity approaches adult levels earlierthan Vernier acuity.[48] Vernier acuity is believed to be corticallymediated and has been shown to be relatively lower than gratingacuity in children with cortical visual impairment. NormalVernier acuity in children with DVM suggests normal corticalfunction.[87]

Cocker et al. studied the possible roles of the cortical andsubcortical visual systems in a DVM twin study.[62] The children'svisual acuity was assessed using the acuity card procedure andalso by assessing the finest grating that could elicit a pupillaryresponse. Whereas a behavioral response to a patterned stimuluscan be detected at birth,[88] the pupil response to a grating stimulusdoes not develop until 4 weeks after term. The pupil responseto a patterned stimulus is thought to be a measure of corticalactivity.[89] Cocker et al. found that, in children with DVM, thereis delayed development of the behavioral and pupillary responseto gratings. Based on these observations, Cocker et al. suggestedthat DVM affects a segment of the visual pathway common toboth the acuity card and pupil grating response.[62]

Some authors have proposed that the existence of two visualsystems may explain DVM.[90] A subcortical, extrageniculostriatesystem was thought to be responsible for vision in the first fewmonths of life before the geniculostraite system matures. Thisconcept was supported by the observations of Dubowitz thatlesions near the thalamus were more likely to affect visual behaviorthan lesions in the visual cortex.[37] Young infants were thought tobe dependent on subcortical pathways (extrageniculostriate visualsystem) for visual function with cortical visual functions developinglater. There are descriptions of visual function in premature infantswith cortical lesions being similar to infants with no such lesions,but infants with subcortical lesions display abnormal visualfunction.[91] Cortical function is also believed to be responsiblefor binocular visual responses and smooth eye movement, bothof which develop at around 6-8 weeks. This is the time of visualattentiveness of normal infants but is delayed in DVM.

Cortical function matures between 3 and 5 months of age,thus coinciding with the period when DVM often improves.[92]The similar recovery pattern seen in patients with DVM suggestsa common process. Cocker et al. investigated the contribution ofthe cortical and subcortical visual systems in infants by assessingpreferential looking and pupillary responses to pattern stimuli.[62]Preferential looking can be elicited from birth and is thought tobe mediated by subcortical pathways, whereas the response topattern stimuli cannot be detected before 4 weeks and is thoughtto be mediated by cortical pathways. Interestingly, Cocker founddelayed development of both responses suggesting involvementof both cortical and subcortical systems in DVM.[62]

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Retina

In the normal infant, maturation of the macula continuesfollowing birth with central retinal cones taking at least14 months to reach adult dimensions.[93] However, flash ERGstudies in children with DVM show normal age-adjustedresponses and suggest that the retina is functionally mature atbirth.[16] Therefore, DVM is not likely to be due to immaturityof the retina.[5] Infants with DVM have a dense visual deficit, onethat cannot be accounted for by delayed foveal development.

Optic nerve

Beauvieux was first to suggest that DVM might be due to a delay inmyelination of the visual pathways.[3] The infants he studied hada black discoloration of the optic discs. In 1947, Beauvieux notedthe optic disc in some children with DVM appeared slate gray butbecame normal as vision improved.[3] A delay in myelination ofthe optic nerve was considered a likely cause of DVM. However,children with DVM have normal pupillary responses and tendto improve between 3 and 5 months of age. Myelination of thedistal optic nerve continues up to 2 years of age.[20] The latencyof pattern evoked VEPs reaches adult levels by 3-5 months andis not significantly different between infants with DVM and agematchedcontrols.[23] Delayed myelination of the posterior visualpathways has also been implicated in DVM; however, in mostcases, MRI shows age-appropriate myelination.[94] Visual recoveryoccurs too rapidly to be due to myelination of the visual pathway.

Saccadic eye movements

Another hypothesis is that eye movement abnormalities(apraxia) may be misinterpreted as poor vision. The assessmentof visual behavior in infants is to a large degree interpretedbased on visually directed ocular movements. The assessmentof visual acuity in children often relies on accurate fixing andfollowing however normal fixing and following relies on saccadicand pursuit functions as well as visual acuity. To perform wellin preferential looking tests, it is necessary for the patient togenerate adequate saccades. The apparently inattentive childshould have saccadic function tested to distinguish a saccadicpalsy. By definition, children with DVM have normal saccadicfunction.[60] Tressider et al. found that infants with DVM hadseverely reduced visual acuities when assessed by Teller forcedchoicepreferential looking.[59] In contrast, patients with DVMhave normal VEPs when compared to age-matched controls.Harris et al. considered whether an abnormality of saccadesmight be responsible for apparent visual inattention in thesechildren.[60,75] Infants with poor visual behavior should havean assessment of their saccadic function and VOR. The VORshould be normal; however, a lack of the fast phase of the VORhas been reported in some normal preterm infants.[61] Theassessment of saccades is crucial to help differentiate DVMfrom a global saccadic palsy or ocular motor apraxia. Brainstemsaccadic dysfunction does not appear to be the cause of DVM asinfants with DVM have been shown to have normal binocularfull-field optokinetic nystagmus.[66]

 
Cortex

Another requirement of good visual behavior is visual attention.Hoyt had suggested that there is no evidence for failure of anyprimary visual system and that temporary visual inattention is thecause of apparent poor vision.[2] Dubowitz found that thalamiclesions had a greater effect on visual function in infants thanlesions of the visual cortex.[91] This was thought to be becausethe subcortical system was responsible for early visual function;however, this may also reflect an abnormality of visual attention.Harris et al. proposed that apparently poor vision in childrenwith DVM is due to difficulty in distinguishing objects fromtheir background perhaps due to an abnormality in the parietalcortex.[60] This is perhaps due to a disorder of higher corticalfunction and the visual association areas. Harris et al. wereunable to elicit saccades or visual tracking to visual objects, butthere was a normal full-field rapid build-up OKN response.[60]The normal OKN response was only present when the infantwas viewing binocularly or during monocular stimulation in thetemporonasal direction. There was almost no monocular OKNin the nasotemporal direction. Harris concluded that infants withDVM are delayed in orientating to local regions of the visual field,perhaps due to delayed development of the extrastriate corticalstructures.[60] Children with DVM may have an abnormality offigure-ground separation or attentional pathways. The normalOKN suggests normal brainstem function, the normal patternVEP, and normal retinogeniculostriate pathway.

The observation that children with DVM have age appropriateVEPs and ERGs strongly suggests that DVM is not a disorder ofthe macula or visual pathways. It is more likely that DVM is causedby a problem with the visual association areas. It seems most likelythat DVM is due to an abnormality in the attention-inattentionmechanism. We, therefore, support the idea that Beauviuex'soriginal term, temporary visual inattention, more aptly describesthis condition and should be adopted in place of DVM.[2] When weare presented with several objects in our visual field, they competefor neural representation. The visual network consists of a "bottomup"stimulus driven process and a "top-down" executive functionto detect the stimulus of attention. Functional MRI studies haveshown that the bottom-up system depends on the frontal eye fields,globus pallidus, caudate, and putamen.[95] The top-down responseis also controlled in areas outside the visual cortex, namely, theparietal cortex, superior colliculus, and pulvinar.[96] In infants,lesions of the thalamus have a greater impact on visual functionthan lesions of the visual cortex.[91] This is probably because lesionsin the thalamus affect visual attention mechanisms.

Summary of pathophysiology

The evidence suggests that infants with DVM have normallyfunctioning retina, optic nerves, visual cortex, and saccades. Theetiology of DVM is unknown but is perhaps multifactorial. Forexample, DVM has been observed in infants whose mothers usecocaine, perhaps secondary to a neurotransmitter imbalance.[80]A recent update of DVM by Russell-Eggitt et al. summarizesthat DVM is likely to represent a spectrum of neurologicalabnormalities with multifocal involvement of most probablyparietal cortical function.[66] However, most of the currentstudies have been relatively small retrospective case series. Therehave been two prospective studies, namely, by Lambert et al. andTresidder et al. which will be discussed further.[56,59] Despite thefindings of Lambert et al., many studies have found children withDVM to have abnormal VEPs. Russell-Eggitt et al. had suggestedthat this may be because DVM has more than one cause.[66]Children who have had neonatal periventricular hemorrhageshave been shown to have immature and delayed VEP waveformscompared to normal premature children. Perhaps, some infantswith DVM have had unrecognized periventricular hemorrhages.A perinatal insult may affect the visual association areas andattentional mechanisms. The most likely cause of DVM is adisorder of visual attention mechanisms.[67]

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Conclusion

Delayed maturation of vision is a diagnosis of exclusion andretrospection, the exact etiology of which is unknown. Mostchildren with DVM will present to the ophthalmologist duringthe first 12 weeks of life with concerns about reduced visualawareness. Visual maturation may be considered the process ofdevelopment of adult levels of visual acuity or the attainmentof maximal visual potential for an individual (own definition).Opinions vary as to whether the term DVM should only applyto those infants who display such visual behavior and who havenormal systemic and ocular examinations or whether it maybe associated with other ocular or non-ocular abnormalities.The creation of a classification system for DVM aids ourunderstanding of the condition and may help when counselingparents regarding their child's prognosis. Children with differenttypes of DVM show different recovery patterns and have differentlong-term prognoses. Electrodiagnostic testing (ERG and flashand pattern VEPs) may also help predict the visual prognosisand exclude other causes of visual inattention. Unfortunately,the interpretation of VEPs requires large numbers of healthyage-matched controls, something that is difficult to achieve inmost centers. The heterogeneity of DVM and the difficulty incomparison between electrodiagnostic tests in different centersmeans comparison between studies of children with DVM is alsodifficult. DVM is a retrospective diagnosis, but it is characterizedby absolute visual inattentiveness and a rapid recovery, often over2-3 days. Newer techniques such as functional neuroimagingmay provide further understanding to the etiology of DVM.

Method of Literature Search

Papers and abstracts relevant to DVM were identified by aMEDLINE literature search covering the years 1980-2018 andincluded articles published in the English language. Search termsincluded DVM, delayed visual development, dissociated visualdevelopment, and visual developmental delay. Additional sourceswere identified from references in the appropriate articles.[97,98]

 
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34 Clinical and Experimental Vision and Eye Research, January-June, Vol 1, 2018