Optic Atrophy due to Hypoxia-Ischemia

2 shows significant functional overlap with OPA1, the protein underlying dominant optic atrophy, and with the mitochondrial encoded oxidative phosphorylation components as seen in Leber hereditary optic atrophy.961

The Rosenberg–Chutorian syndrome, a variant of Charcot–Marie–Tooth syndrome, comprises the triad of deafness, sensorimotor polyneuropathy, and visual loss.734 In most pedigrees, the visual loss has been attributed to optic neuropathy on the basis of normal full-field electroretinogram and funduscopic findings.366,667 In a recent case,691 electrophysiologic testing suggested visual loss at the level of amacrine cells, suggesting that more than one mechanism can contribute to the visual loss.691 It is unclear whether mitochondrial dysfunction underlies this condition.

Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are storage diseases caused by a deficiency of certain lysosomal enzymes, leading to abnormal degradation of one or several mucopolysaccharides (e.g., dermatan, heparan, keratan sulfate). These materials then accumulate in multiple organ systems, leading to progressive clinical disorders.612

The ophthalmologic findings in MPS include corneal clouding, retinal pigmentary dystrophy, glaucoma, optic nerve head swelling, or optic atrophy. Collins et al167 reviewed the ocular findings in 108 patients with MPS, with attention to optic disc appearance. They concluded that patients with Hurler, Hurler–Scheie, Maroteaux–Lamy, and Sly syndromes showed a greater than 40% chance of developing optic nerve head swelling, whereas the chance in those with Hunter's and Sanfilippo's syndromes was 19.7% and 4.6%, respectively. Some patients showed optic nerve head swelling in one eye and optic atrophy in the other. In others, the optic atrophy was documented to follow disc swelling. The authors concluded that optic nerve head swelling precedes the development of optic atrophy in patients with systemic MPS. The cause of disc swelling is not always obvious, but hydrocephalus plays a role at least in some cases.435

Optic Atrophy due to Hypoxia-Ischemia

One of the most difficult aspects of pediatric neuro-ophthalmology involves the diagnostic evaluation of optic atrophy in the child with perinatal hypoxic-ischemic injury to the visual system, because a significant percentage show some degree of pallor or hypoplasia.97,302 Associated neurologic handicaps often preclude sensory visual tests such as color vision testing,

stereopsis, and visual fields. In this setting, neuroimaging has often been obtained at some remote point prior to the consultation. Because some degree of optic disc pallor so frequently accompanies cortical visual insufficiency (CVI), neuroimaging is not necessarily warranted for the evaluation of optic atrophy unless symptoms of progressive visual dysfunction or other progressive neurologic symptoms are elicited. When visual acuity is good, the finding of normal color vision using HRR plates provides corroborative evidence of a noncompressive lesion.

In a retrospective study, Brodsky and Fray97 found normal optic discs in 56% of children with term injury producing CVI, with isolated optic atrophy in 24% and combined hypoplasia and atrophy in 20%. In children with preterm injury and periventricular leukomalacia, 24% had normal optic discs, 50% had optic nerve hypoplasia with some degree of atrophy, and 26% had isolated optic atrophy. Another quantitative study740 found that patients with cortical visual impairment have, on average, smaller optic nerve heads, with increased excavation and increased temporal pallor. Optic atrophy is also common in premature children with a history of high-grade intraventricular hemorrhage.152,640 Because optic atrophy is so commonly seen in children with a history of hypoxic ischemic injury, it is not routine to obtain neuroimaging in this setting. The parents should be questioned thoroughly about the perinatal and neonatal period of their child and, if available, the related medical records should be reviewed. Only when the clinical history suggests acquired or progressive visual loss is diagnostic neuroimaging obtained to rule out an unrelated compressive lesion. The optic atrophy in the setting of prematurity879 may take the form of large optic cups.97,402

Cicatricial retinopathy of prematurity, cortical visual impairment, and optic atrophy are the major causes of significant visual loss in patients with a history of premature birth.451,551 One Danish study675 found that perinatal stress factors (e.g., prematurity, low birth weight, perinatal asphyxia) accounted for a significant percentage of cases of optic atrophy in children reported to the Danish National Register. Significantly, they found that all children with optic atrophy attributed to perinatal difficulties showed one or more additional handicaps (e.g., cerebral palsy, epilepsy, psychomotor retardation). This is supported by other studies551 and may attest to the relative resilience of the anterior as compared with the posterior visual pathways to hypoxia. It also argues against attributing perinatal hypoxic damage to solitary cases of optic atrophy in otherwise healthy children.302

Despite the frequency of hypoxia-ischemia in the perinatal period, damage to the anterior visual pathway with optic atrophy appears to occur less frequently than damage to the posterior visual pathway. Six of 30 children with hypoxic cortical blindness described by Lambert et al481 showed mild optic atrophy. In a retrospective study,302 28% of all infants

who had documented hypoxic encephalopathy showed optic atrophy and, essentially, all of these showed significant neurological dysfunction. The authors considered these findings to indicate a relative resilience of the optic nerve to hypoxia. Besides the possibility that the concurrent optic atrophy described in such cases may represent primary damage to the retinogeniculate pathway, some cases may represent transsynaptic degeneration. Therefore, it has been concluded that in the presence of normal neurologic findings and neuroimaging results, optic atrophy should not be attributed to perinatal hypoxia.302

Patients in cardiovascular shock with hypotension due to acute blood loss are at risk of ischemic damage to the optic nerves. Shock patients who are on positive pressure ventilation may be at an increased risk for such damage. The increased intraocular pressure associated with positive pressure ventilation along with the low systemic perfusion pressure may compromise the perfusion of the optic discs.144 Posterior ischemic optic neuropathy (PION) following spine surgery has been reported in both adults and children.112a,446a,665a

As detailed in chapter 3, primary nonarteritic optic neuropathy is rare in children and usually occurs under pathological circumstances,158 as in diabetic papillopathy. Children with vigorous treatment of accelerated hypertension and children with migraines and prothrombotic disorders have also developed AION.89 Secondary nonarteritic ischemic optic neuropathy is a rare event in childhood, occurring mostly in the setting of spinal surgery or peritoneal dialysis, and hypovolemia was postulated to be the major etiology.82a,322,473a Diagnosis may be delayed in this age group because visual loss may not be noticed in a timely manner.82a Treatment of pulmonary hypertension with sildenafil may have led to the development of ischemic optic neuropathy in one 5-year-old child.473a

A rare idiopathic disorder, termed anterior ischemic optic neuropathy of the young, has been reported to affect teenagers and young adults.224,340 It is included in this section because of its designation as ischemic, which is adopted due to certain resemblance to the adult variety of ischemic optic neuropathy. Differentiation from optic neuritis, however, cannot be made with certainty. Unlike the variety affecting older patients, the disorder displays a propensity for recurrence in the same eye, which may lead to significant visual impairment. Affected patients are otherwise healthy.

ophthalmoscopic evidence of injury to the eye and related structures (e.g., shaken baby syndrome). The possible pathophysiologic mechanisms of traumatic optic neuropathy of childhood are not different from the adult variety and include tears or avulsion of the optic nerve; laceration of the nerve substance by bone fragments; hemorrhage into the optic nerve sheath spaces or into the dura itself; and contusion, necrosis, or edema of the optic nerve tissue.534 Traumatic chiasmal syndromes may also occur.

The optic disc appears normal in typical traumatic cases involving the intracanalicular or intracranial portion of the nerve. Optic atrophy eventually ensues. A 4- to 6-week latent period has been demonstrated in primates between optic nerve disruption and subsequent development of optic atrophy, regardless of the site of damage.701 Although visual recovery is sometimes seen, the prognosis for recovery of vision is poor.

Cases due to remote trauma that the patient does not specifically recollect may pose a diagnostic quandary. If such trauma had been associated with blunt injury to the globe itself, as well as to the head or orbit, ophthalmologic signs such as iris sphincter tears, angle recession, lens subluxation, corneal scarring, chorioretinal scarring, and bony defects of the cranium may provide valuable clues to the traumatic etiology.

Traumatic optic neuropathy in children is caused by mechanisms similar to those that cause it in adults. The severity of visual loss as well as the rate and degree of improvement are also similar.301 Although there is anecdotal evidence of the efficacy of high-dose corticosteroids in this condition, there are no prospective, randomized trials to attest to its benefits.822 The largest retrospective study499 showed no benefit from high-dose corticosteroids in the treatment of traumatic optic neuropathy. There is some evidence that this treatment is actually harmful if administered more than 8 hours after injury.93 A recently reported placebocontrolled randomized clinical trial of high-dose corticosteroids in head injury729 was stopped prematurely because of a significantly greater mortality in the corticosteroid-treated patients. Other experimental studies also suggest that methylprednisolone may be harmful to the optic nerve. Although surgical decompression of the optic canal may be helpful in selected cases,781 it showed no clear indication of benefit in a larger multicenter trial.500

Trauma is a significant cause of optic nerve damage in children.534 Damage to one or both optic nerves may result from direct or indirect trauma. Direct trauma is commonly associated with penetrating injuries or severe blunt trauma to the globes and orbit. Indirect trauma occurs without external or

Vigabatrin

Vigabatrin (Sabril, Avenbtis Pharma, Laval, Canada) is an effective and popular GABA-ergic anticonvulsant used in the management of infantile spasm (West syndrome), in seizures

associated with tuberous sclerosis, and in partial seizures of adults as adjunctive therapy. It acts through the irreversible inhibition of GABA transaminase, with the resultant accumulation of the inhibitory neurotransmitter GABA in the brain and even higher concentrations in the retina. Thirty percent to 40% of treated patients develop peripheral visual field constriction that is usually asymptomatic.230,426,486,929 Vigabatrin visual field loss has been associated with evidence of reduced cone b-wave response, decreased amplitude of the 30-Hz flicker response, abnormalities in photopic and scotopic oscillatory potentials,169,186,353,470 and reduced visualevoked responses.467 Buncic et al112correlated this visual field loss with a characteristic “inverse” form of secondary optic atrophy with nasal optic atrophy and relative sparing of the macular nerve fiber layer and temporal aspect of the disc. OCT is useful in monitoring patients taking vigabatrin. Visual field loss in vigabatrin is associated with selective thinning of the nasal retinal nerve fiber layer, with sparing of the temporal nerve fiber layer, and variable involvement of the superior and inferior nerve fiber layer. This pattern of nerve fiber layer loss can precede the visual field loss.487 Because most children with epileptic syndromes taking vigabatrin cannot complain about their eye symptoms, regular ophthalmologic and electrophysiologic follow-up is necessary to elicit these changes.467

Carboplatin

Periocular carboplatin injection to avoid systemic complications in patients with advanced retinoblastoma has recently been reported to cause ischemic necrosis and atrophy of the optic nerve.771

Summary of the General Approach to the Child with Optic Atrophy

Important clues to the etiology, nature, and location of the lesion underlying optic atrophy are often provided by the age of the patient, best corrected visual acuity, laterality of optic atrophy, funduscopic appearance of the disc and retina, color vision anomalies, the natural history (onset and rate of progression), visual field defects, and other associated ophthalmologic, neurologic, and systemic findings. The combination of a thorough, tailored medical and family history with physical, neurological, and ophthalmologic examination should pinpoint at least the general category of optic atrophy in most cases.

The medical history is of paramount importance. In infants and children with optic atrophy and poor vision, the answers to certain questions can be very important diagnostically.

Are there any identifiable factors in the medical and family history that can help in the diagnosis, specifically, perinatal hypoxia, prematurity, intracranial hemorrhages, meningitis, encephalitis, hypoxia-ischemia, trauma, poisoning, maternal toxin intake, etc. (e.g., optic atrophy due to hypoxia-isch- emia, transsynaptic degeneration, maternal alcohol intake, traumatic optic neuropathy)? Again, optic atrophy due to hypoxia-ischemia is commonly associated with brain damage and generally indicates that the insult was severe. Is there a family history of blindness or consanguinity (e.g., inherited optic atrophy, neurodegenerative disorders)? Was the child normally sighted at some point before losing vision (e.g., Leber hereditary optic atrophy, neuronal ceroid lipofuscinosis), or was the vision always impaired (congenital optic atrophy)? Aside from the visual impairment, is the child otherwise neurologically and systemically normal in all respects? If neurologic or systemic disease exists, are there known causes for these findings, such as perinatal hypoxia, intracranial hemorrhages, trauma, or a family history of similar affliction?

This history helps differentiate these disorders from metabolic, neoplastic, and neurodegenerative disorders. If no known cause for the neurologic or systemic disease exists, at what age did these findings present; specifically, was the child normal initially before developing these disorders (e.g., Batten disease, X-linked adrenoleukodystrophy), or had these disorders been present in the neonatal period? Has the visual impairment been stable since onset, or has the visual impairment progressed (e.g., compressive intracranial lesions, neurodegenerative disorders)? Has there been any progression in the neurologic and/or systemic disease (neurodegenerative or metabolic disorders), or have these been stationary since onset (static encephalopathy, mental retardation, hydrocephalus)? We recognize that exceptions to these generalizations exist, but believe that the general framework is helpful.

The clinical examination can further narrow down the diagnostic possibilities raised by the medical and family history. The presence of nystagmus probably excludes all disorders with onset after 2 years of age. The presence of deafness suggests one of the disorders associated with optic atrophy and deafness. Cerebellar signs suggest one of the cerebellar ataxias or spinocerebellar degeneration associated with optic atrophy. Static encephalopathy, most commonly encountered in the setting of prematurity, suggests that the optic atrophy is either due to primary damage to the anterior visual pathways due to hypoxia-ischemia or associated hydrocephalus or due to secondary transsynaptic degeneration following perinatal brain damage. The presence of café au lait spots, emaciation, spasmus nutans, or unilateral proptosis or a family history of neurofibromatosis suggests optic pathway glioma.

Ancillary testing (e.g., neuroimaging, metabolic workup) is not necessary to arrive at the diagnosis in most children with optic atrophy. Any associated ocular abnormalities must