Periventricular leukomalacia: an ophthalmic perspective

Abstract

Periventricular leukomalacia (PVL) is a common magnetic resonance imaging (MRI) finding in cases of hypoxic ischemic encephalopathy. PVL, in MRI, is identified by the increased signal intensity of periventricular white matter on T2-weighted sequences which is more conspicuous in the posterior cortex. It occurs because of perinatal damage to the cerebral cortex. This insult is in the form of hypoxia, metabolic insults, prematurity, seizures, or infection. Periventricular area is most prone to damage owing to its immaturity and vascular supply. PVL is proven to affect vision in children. Depending on the area and cause of affection, PVL is associated with variable ophthalmic manifestations. It is known that visual function is closely linked to the overall neurodevelopment of a child.

A multidisciplinary approach is required to promote the growth and development of these children, and in the midst of multiple disabilities, visual function should not be overlooked. A comprehensive knowledge of the ophthalmological presentation in the developing world can aid us in an early and accurate diagnosis and in intervention for better therapeutic recovery and rehabilitation of these children.

Introduction

Periventricular leukomalacia (PVL) is a common magnetic resonance imaging (MRI) finding in cases of hypoxic ischemic encephalopathy. PVL, in MRI, is identified by the increased signal intensity of periventricular white matter on T2-weighted sequences which is more conspicuous in the posterior cortex.¹ It occurs because of perinatal damage to the cerebral cortex.² This insult is in the form of hypoxia, metabolic insults, prematurity, seizures, or infection.^3,4 Periventricular area is most prone to damage owing to its immaturity and vascular supply.⁵

The term “cerebral visual impairment” has replaced terminologies such as “cortical blindness” and “cortical visual impairment” because of subcortical involvement of optic radiations in premature infants (PVL). Cortical visual loss occurs because of involvement of pathways of higher visual functions. Subcortical visual impairment, such as PVL, is associated with worse clinical outcomes as compared with cortical visual impairment.⁷ PVL is proven to affect vision in children.⁶ Depending on the area and extent of affection of the lateral geniculate body and optic radiations, as well as the cause of affection, PVL is associated with variable ophthalmic manifestations.⁷ Hence, the term “cerebral visual impairment” (CVI) is used to define the visual problems of such children. The earlier terminology of “cortical blindness” is not used now since the involvement of subcortical areas of the brain has also been reported, especially in preterm infants.

PVL, an important neuroradiological sign of perinatal cerebral damage, causes visual impairment in children. The criteria for accurate diagnosis of CVI has been differently described in different studies.^8,9 PVL shows subcortical white matter lesions in the areas surrounding the ventricles. Other than PVL, CVI could occur because of any kind of cerebral insult which adversely affects the functional or perceptual vision of the child. The associated neurological deficits affect the cognitive and motor abilities^4,10 as well as further hamper the functional vision. These include cerebral palsy, seizure disorders, hearing loss and ocular motility disorders. With better survival rates of neonates, the incidence of PVL is likely to be increasing in developing countries as well.

Epidemiology

With the increased survival rates of preterm babies, the incidence of PVL is on the rise. Olsén et al. reported the prevalence of PVL in premature children in their study as 32%.¹¹ Krägeloh-Mann et al. studied the presence of PVL in 56 children with bilateral spastic cerebral palsy and reported it to be 42% in term and 87% in preterm born children.¹² A study conducted in Europe found PVL in 53.6% of the high-risk preterm children.¹³ Being a neuroradiological sign, this incidence is that of the presence of PVL on MRI. This does not correspond to the incidence of CVI. Children with milder forms of PVL may not report to the ophthalmologists at all. Conversely, CVI may be diagnosed in the absence of PVL when other areas of the brain are involved. Visual impairment is seen in 10.5% of children with developmental anomalies.¹⁴ Ozturk et al. evaluated 695 patients with severe visual impairment between 2002 and 2014. They reported CVI as the leading cause of childhood blindness with a prevalence of 30.5%.¹⁵ On comparison with their previous published data collected before 2002, they found a significant rise in the prevalence of CVI (p = 0.04). Nowadays, it accounts as one of the leading causes of visual impairment in children in the developed countries.¹⁶

Etiopathogenesis

Periventricular leukomalacia (PVL) occurs when the brain damage occurs in the third trimester or perinatally. Volpe has discussed the pathogenesis of PVL in premature infants.⁵ He described prematurity and maternal/fetal infections as its predisposing factors. Obstetric risk factors include premature rupture of membranes, antenatal hemorrhage, intrauterine infections, and maternal chorioamnionitis. Other etiological factors which play a role in predisposing to PVL include neonatal hypoglycemia, perinatal seizures, hydrocephalus, and oxygen therapy to the neonate. All these perinatal injuries lead to ischemic damage to the most prone area of the brain, the periventricular region, because this region is still in the phase of vascular immaturity till birth. Thus, perinatal ischemic damage, that is perinatal hypoxia, is the most common risk factor for PVL.²

In a preterm neonate, the germinal matrix in the subcortical areas is still producing neurons which migrate to the cerebrum. Fragile and immature vessels in this area give way to milder forms of ischemic insults and changes in blood flow, thus causing loss of tissue in the periventricular region. This leads to cortical and subcortical gliosis. All of this culminates into enlargement of the ventricles with a thinned out cortex.¹² Damage to the periventricular area is more so toward the posterior parietal lobe, adjacent to the trigone of the lateral ventricles. It readily involves the optic radiations and the nearby corticospinal tracts.⁶ This leads to the close association between visual impairment and cerebral palsy, besides other systemic involvement.

Clinical features

Periventricular leukomalacia (PVL) is the most common cause of cerebral visual impairment. Unexplained loss of vision along with systemic disabilities in a child with normal ophthalmological evaluation should raise a suspicion of CVI. Parents usually notice poor eye contact¹⁷ and absence of social smile as early as 2–3 months of age and present to the ophthalmologist, sometimes even before any systemic abnormality can be diagnosed. However, in some cases decreased vision may go unnoticed until the development of a squint.¹⁹ Moreover, children with PVL without strabismus may not be reporting to the ophthalmologist, especially if visual impairment is mild.¹⁸

Extensive history taking in a child with unexplained visual loss forms the cornerstone for suspecting PVL and thus directing our evaluation toward its diagnosis. Relevant antenatal, perinatal, and postnatal history gives us an insight into the timing and severity of PVL. Detailed antenatal history should include evidence of any gestational hypertension or infections. Birth history is of paramount importance and could lead to evidence of perinatal hypoxia. Complicated obstetric history should be elicited. Presence of prolonged labor, premature rupture of membranes, meconium aspiration, or any other risk factor causing fetal distress should be noted. History of hypoglycemia in neonatal period, neonatal seizures, fever, infections, pathological jaundice needing phototherapy, and feeding difficulties should be documented as red flags.

Visual assessment

Visual assessment in children with CVI is complex and extensive. Owing to the neurological disabilities, it is difficult to accurately gauge the visual acuity. Multiple evaluation modalities like response to Lea's paddles, Teller's acuity charts, Allen picture charts, and Cardiff acuity may be used to roughly establish the vision. In absolutely uncooperative cases or cases not responding to any of these charts, where vision may be expected to be poorer, response to light may be assessed in terms of fixing and following light. Ugetti et al. found out a positive correlation between the severity of PVL and the amount of vision loss in their study.¹ Huo et al.¹⁹ have described a classification of vision into 6 levels wherein level six is normal visual acuity and level 1 is only perception of light:

• level 1: Perception of light

• level 2: Occasional fixation on large objects, faces, or movements in the environment

• level 3: Variable visual function but some moments of good visual fixation as indicated by the ability to see small objects or reliably fixate on the face

• level 4: Reliable fixation on a small target or with visual acuity measured in the range of 20/200 to 20/400

• level 5: With one or both eyes open, vision between 20/50 and 20/200

• level 6: Normal sensory visual examination

Other than the visual acuity, visual behavior is important to be noted. Multiple questionnaires have been made to assess this.²⁰ The visual behavior stresses on the functional vision of the child rather than the visual acuity alone. These questions evaluate the functionality of the dorsal and ventral stream of the brain which cater to associated visual functions such as navigation skills, visual perception in crowded environment, color preference, hand eye coordination, gaze preference, visual fields, affinity for moving/stationary objects, and other environmental factors.

Ocular movements

Children with CVI may have associated gaze palsies and gaze preferences. Strabismus in children with associated neurological disease shows variable presentation. Esotropia is more common in PVL along with dissociated vertical deviation and A pattern.⁵ A large variable angle is a common presentation. Owing to the presence of accommodative anomalies in children with PVL, the angle of deviation may even change from esotropia to exotropia in one to two evaluations done on the same day. This fact stresses on the importance of dynamic retinoscopy in such children. A lead or lag of accommodation must be deciphered by monocular estimation method before prescribing glasses and measuring the strabismus. Krägeloh-Mann¹² described that horizontal conjugate gaze deviation and exotropia were commoner in cortical than in subcortical visual loss.

It has been previously thought that nystagmus is rare in CVI because of a probable prerequisite of intact geniculostriate pathways for development of congenital nystagmus.²¹ However, latent and less commonly manifest nystagmus, has been described in children with PVL because of subcortical rather than cortical vision loss in a study by Jacobson et al.²² In this study, they recorded jerk nystagmus in 12 out of 19 children. They studied its waveform and found it to be consistent with latent manifest nystagmus.

Refraction

A clearer and sharper image by prescribing glasses is always preferred in children with PVL for a better response in visual rehabilitative measures. A cycloplegic refraction is must in all children with PVL. Owing to the presence of other neurological disorders in children with CVI, cyclopentolate is best avoided in them. Atropine ointment 1% remains to be the preferred drug for cycloplegic retinoscopy. As previously mentioned, dynamic retinoscopy should also be performed. Glasses should be prescribed based on the readings and the presence of squint, by the same protocols as used in non-CVI children. In cases of an accommodative lag or accommodative paresis, pupil bisecting bifocal glasses may be required.

Periventricular leukomalacia (PVL) and retinopathy of prematurity are both more common in preterm babies. As already known, children with ROP generally develop myopia with age. Thus, myopia may be common in children with PVL as well as ROP. Conversely, cerebral palsy has been associated with hyperopia. Children with PVL are also prone to develop astigmatism. A rare case of −16DS myopia in a 2.5-months-old infant has been reported in PVL by Jayaseelan et al.²³ Ganesh et al.²⁴ found simple hyperopic astigmatism as the most common type of refractive error in their study on PVL.

Optic disc

There is a debate whether optic atrophy can be described as a manifestation of CVI considering the definition of CVI being a retrogeniculate affection.²⁵ Optic atrophy may exist as a concurrent finding because of combined damage of the anterior visual pathways and hence be unrelated to PVL.¹⁹ Both optic atrophy and PVL show variable visual loss. Though optic atrophy adversely affects visual acuity, there is poor correlation between disc appearance and vision in children with PVL.

Other aspects of visual function such as visual field defects, dysfunctions of visual perception, and integration may also be associated.²⁶ However, this is not always practically possible in a subset of patients depending on visual response and cooperation. Another rationale of not being able to record these findings is the inability to objectify some of these functions. Lack of objective tests for many of these functions causes a lacuna in our knowledge of the same. However, functional vision assessment including visual field, gaze preference, hand eye coordination, recognition skills, visual memory, and perceptual skills are an utmost important part of visual assessment in children with PVL, especially when looking toward the plan of rehabilitation of the child to the best possible level.

Damage to the periventricular region usually also involves the corticospinal tracts leading to close association between CVI and cerebral palsy. Association of neurological and ophthalmic deficits in CVI has been noted in as high as 46% patients.¹⁵ Other associated neurological conditions include hydrocephalus, seizures, microcephaly, and degenerative diseases of the central nervous system.

Diagnosis

An MRI is mandatory in any infant who has history of any of the predisposing factors. Even a transfontanelle ultrasound of the brain on the first day of life may reveal PVL. It should be performed for every high-risk preterm neonate with a low appearance, pulse, grimace, activity, and respiration (APGAR score) (<7).^27,28 However milder forms of PVL may need more specific modes of MRI. Functional MRI done with different visual stimuli helps in better understanding of the pathophysiology of the damage because it shows an increase or decrease in contrast flow with a particular visual stimulus. Diffusion tensor imaging and tractography are highly sensitive in picking up findings which could be missed on a normal non-contrast MRI. These scans not only reveal the structural damage but also are capable of correlation with the degree of visual field loss.⁹ CT scan, though not preferred, may be done in the absence of the MRI facilities. MRI findings of PVL include scarcity of white matter in the periventricular area (Fig. 1), more so in the posterior regions associated with dilated and irregularly outlined ventricles.⁶ Increased periventricular signal intensity is seen in T2 weighted images. Any positive finding on MRI warrants complete ophthalmic evaluation for early diagnosis of CVI and prompt initiation of rehabilitative measures to reach a better visual outcome. However, it must be kept in mind that an absence of findings in MRI may need a repeat scan after 3 months in the presence of risk factors. Conversely, in the absence of risk factors but presence of unexplained poor vision in a child, the differential diagnosis of delayed visual maturation should be kept in mind before aptly counseling the parents.

Fig. 1.

Axial sections of MRI of a 7-year-old female with symptoms suggestive of cerebral visual impairment. MRI images reveal abnormal subcortical and periventricular white matter. T2-weighted hyperintensity with isointensity on T1-weighted image with suppression on FLAIR image with bilateral volume loss in parieto-occipital region with thinning of cerebral white matter. MRI, magnetic resonance imaging.

Visual evoked potential

Accurate recording of visual acuity is difficult in children with PVL because of co-existent neurological deficits. Role of flash as well as sweep visual evoked potential (VEP) in estimating visual acuity has been studied in children with intracranial damage and has also been evaluated for its precision against other subjective behavioral tests.²⁹ Kato et al.³⁰ and Jethani et al.³¹ conducted a study to evaluate flash VEP responses of infants with PVL. They concluded that a latency delay is noted at 8Hz frequency but is normal at 14Hz. However, amplitude may even be normal in cases of PVL.

Visual fields

Children with reduction in their geniculostriate projections may have an inferior field defect.⁹ However, injury to the optic radiations during the third trimester of gestation may show normal visual field function. This could be attributed to neuroplastic reorganization of early periventricular damage.³² Homonymous hemianopia can be suspected in cases associated with hemiplegia because of the close proximity of optic radiations with corticostriate pathways. Dutton et al. studied the association of binocular lower field impairment in 40 children with CVI and found normal visual fields in 12 cases, homonymous hemianopia in 3 cases and lower field defects in 25 cases.³³ Visual field defects are usually checked by confrontation method that rely on maintenance of central attention while attractive targets are suddenly presented in the peripheral fields, and the examiner looks for a shift of attention from central object to peripheral one. However, clinically evaluating the presence of such field defects, even by confrontation method, is sometimes challenging in these uncooperative children. Moreover, visual inattention, which is more common in PVL than field defects, may be misdiagnosed as the latter. The best prediction of such defects is by enquiring with the parents about difficulty while negotiating stairs, frequent toppling over small objects on the floor or not noticing the feeding spoon until it is brought in the central field of vision. Newer techniques of visual field assessment in children are being developed so that the test could be carried out in a non-verbal child too, even in supine position.

Localization of area of brain damage by visual field analysis has been attempted in a few studies.^33,9 Merabet et al. did a case study to characterize visual field deficits in CVI using combined diffusion–based imaging and functional retinotopic mapping.⁹ Structural integrity of optic radiations could not be deciphered on MRI in their case which was associated with binocular inferior field defects. However, white matter reconstruction by high angular resolution diffusion–based imaging (HARDI) revealed a generalized reduction in geniculostriate projections. Another study uses ganglion cell topography to indicate pre or postnatal damage to retrogeniculate pathway, thus predicting visual field function.³⁴ Continuous research using multimodal imaging techniques may help in further correlating visual field functions with structural damage in the brain.

Management and prognosis

Children with PVL do not show progressive vision loss. Infact, the aim of regaining maximum visual acuity is the foremost priority in children with PVL. Vision usually improves over time.¹⁹ Once the child has better vision, rehabilitation exercises for cognitive disabilities, hand eye coordination, and even for systemic motor disabilities becomes easier to conduct. Defective vision is the most important variable in determining the neurodevelopment in children with multiple disabilities.⁷ A visit to the pediatric ophthalmologist and neuro-ophthalmologist as early as possible or in the first 2–3 years of life is of paramount importance for early visual rehabilitation. Visual acuity rehabilitation by prescribing accurate glasses, inculcating occlusion therapy wherever required as well as maintaining compliance of both is a prerequisite, and the first step in management of children with PVL.³⁵ Evaluation for strabismus as well as its correction is challenging in these children but should always be attempted. Though early surgery for esotropia is advocated, the unpredictability of surgical outcomes must always be borne in mind. Few cases may undergo spontaneous resolution with age. Undercorrection of esotropia by 10–15%, and slight overcorrection of exotropia must be targeted to prevent postoperative exotropia on follow-up. Long-term follow-up is a must in all cases of PVL undergoing surgery for strabismus.

A multidisciplinary approach with involvement of the physiotherapist, special education therapist, speech therapist, pediatrician, and ophthalmologist is required for optimum rehabilitation of the child. Use of betamethasone in preventing cystic PVL in infants born between 24 and 31 weeks of gestation has been published and needs further research.³⁶ In addition, hypothermia is now used as a treatment modality in conjunction with neuroprotective management in cases of hypoxic ischemic brain injuries.³⁷ Visual rehabilitative exercises include visual stimulation exercises, activities targeting improvement in hand eye coordination, recognition in cluttered environment, and improvement of attention span of the child. Visual stimulation is usually performed by showing brightly illuminated objects in a dark room and enforcing visual fixation and followability. Stimulation of cognitive functions is important to enable the child to understand and recognize common shapes and objects in his/her environment. The earlier the diagnosis of PVL is made, the better is the response to rehabilitative measures. Thus, prompt diagnosis and early intervention is the key to better prognosis. However, the extent, timing of damage, and etiology of PVL plays an important role in prognostication. Children with CVI having involvement of periventricular region carry a poorer prognosis than those who show cortical affection. The involvement of the peritrigonal cortex and the calcarine cortex is associated with poorer visual prognosis.¹ Children with ischemic injury in late gestation may show spontaneous improvement with time.^19,38 Subtle changes of PVL may go unnoticed till teen age or later are associated with good prognosis. Thus, long-term prognosis of a child with PVL may be variable depending on the extent and etiology of damage as well as on the time of onset of rehabilitative measures. Moreover, it should be borne in mind that even with tremendous improvement in their functional vision, it is always preferable to maintain rehabilitative measures till a later age.

Recent advances

The upcoming awareness of this condition and the availability of all rehabilitative measures under one roof in developing countries, in the future, would ensure faster and more efficient response to therapy in these children. Moreover, development of sensitive and customized equipment for objective ophthalmic evaluation is underway and may help devise improved rehabilitative measures in the coming few decades. Further, better neuroclinicoradiological correlation may improve management and prognostication of children with PVL. Use of single-photon emission computerized tomography (SPECT) and positron emission tomography (PET) scans to study change in cerebral blood flow may be better than MRI in prognostication, though invasive.³⁹ Functional MRI is a promising diagnostic tool as it demonstrates metabolically active areas of the brain. However, it requires an alert and cooperative patient. With advent and further development of HARDI and tractography, the white matter organization and structural integrity of optic radiations can be better analyzed. These multimodal imaging techniques will help in defining structural–functional correlations in patients with CVI,⁹ which in turn will help in better prognostication and management.

Conclusion

This review provides an ophthalmic perspective of PVL and gives a baseline description of the ophthalmic manifestations and associated systemic conditions in patients with PVL. Early diagnosis and rehabilitative intervention in cases of PVL is of utmost importance for better outcomes. It is known that visual function is closely linked to the overall neurodevelopment of a child.⁴⁰ A multidisciplinary approach is required to promote the growth and development of these children and in the midst of multiple disabilities, visual function should not be overlooked. A comprehensive knowledge of the ophthalmological presentation in the developing world can aid us in earlier and accurate diagnosis and in intervention for better therapeutic recovery and rehabilitation of these children.

Disclosure of competing interest

The authors have none to declare.