Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease



Alex V. Levin

Thomas W. Wilson

  1. Raymond Buncic

During embryogenesis, the brain and many ocular structures are derived from neuroectoderm. Therefore, many structural abnormalities of the brain will be associated with ocular anomalies. Optic nerve hypoplasia is associated with anterior pituitary abnormalities, agenesis of the corpus callosum, absence of the septum pellucidum, and schizencephaly.

Morning glory disc can be associated with basal encephalocele, and tilted disc syndrome can be associated with suprasellar tumors.

Nystagmus and abnormalities of extraocular eye movements are commonly external signs of neurologic abnormalities. Infants with constant exotropia will often have developmental delay. Specific nystagmus patterns can help localize structural pathology (downbeat nystagmus—Arnold Chiari malformation). Myasthenia gravis, multiple sclerosis, mitochondrial diseases, and storage disease will often present with ocular/visual abnormalities prior to systemic symptoms.

Increased intracranial pressure from brain tumors or pseudotumor cerebri can present as vision loss and examination of the optic disc reveals papilledema. Headaches are a common reason for referral to an ophthalmologist. The cause of headache is rarely secondary to strabismus or refractive error. However, careful neuro-ophthalmic examination, including evaluation of the visual acuity, visual fields, color vision, pupils, and extraocular movement as well as visualization of the optic disc, is required to exclude any underlying pathology.



Figure 21.1 Schizencephaly

Schizencephaly is an abnormality of brain cell migration during embryogenesis. Normal cell migration is dependent upon a radial glial fiber system that orients the neuronal tissue into its proper anatomic location. Schizencephaly represents abnormal clefting within the cerebral hemispheres. These defect(s) may be unilateral or bilateral, fused or unfused, large or small. Porencephaly refers to enclosed cysts within the cerebral tissue. Associated clinical findings with schizencephaly include severe mental retardation and associated seizures, which are often unresponsive to conventional treatment.


Figure 21.2 Holoprosencephaly

Holoprosencephaly is an abnormality of development of the midline structures of the brain and face. Clinical features of holoprosencephaly include agenesis of the premaxilla, cleft upper lip (left image), hypotelorism, mental retardation, microcephaly, and oligodontia. A mild form of the disease will present as hypotelorism and mild changes of the midface. A severe form of holoprosencephaly with cyclopia is incompatible with life (right image). Multiple genetic and chromosomal abnormalities have been identified in holoprosencephaly. Surgical reconstruction of the face, including cleft palate repair, are indicated for severe defects.


Figure 21.3 Arnold-Chiari Malformation

Arnold-Chiari malformation is characterized by extension of the brainstem and cerebellar tissue into the cervical canal (right image). The inferior part of the fourth ventricle may also be displaced downward. It is commonly associated with spina bifida and myelomeningocele (Arnold-Chiari type II). Patients typically present with signs of increased intracranial pressure, including headache and visual loss. Patients may also demonstrate downbeat or seesaw nystagmus, ataxia, multiple cranial neuropathies, and quadriparesis. Stretching of the trigeminal nerve can cause corneal anesthesia with painless scarring of the cornea (left image). Posterior fossa decompression and/or shunting may be required.




Figure 21.4 Aicardi Syndrome

Aicardi syndrome is an X-linked dominantly inherited disorder that is lethal in males and involves the brain and eye. Infant girls present with infantile spasms and seizures and have significant developmental delay and mental retardation. This computed tomography scan of the brain shows a sagittal midline view, demonstrating absence of the corpus callosum. The brain shows a variety of anatomic abnormalities including schizencephaly, cysts, hemispheric asymmetry, and migration abnormalities (pachygyria and microgyria). The corpus callosum is formed from the commissural plate, and insults to this embryologic tissue cause agenesis.


Figure 21.5 Aicardi Syndrome—Ocular Findings

Characteristic ocular findings of Aicardi syndrome include well-circumscribed lacunae in the retina. Histopathologically, these lesions represent defects in the chorioretina, including the retinal pigment epithelium, to variable depths. Patients may also have optic disc colobomas or other less specific optic disc anomalies. The retinal lacunae are multiple and are concentrated about the optic disc. These lesions are classic for Aicardi syndrome. Patients may also have abnormalities of the vertebrae. The disease is lethal in males. A careful family history, including a history of multiple miscarriages during pregnancy, should be obtained in cases where Aicardi syndrome is suspected.


Figure 21.6 Acquired Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder characterized by abnormal transmission at the neuromuscular junction. Infants born to myasthenic mothers will often have a transient abnormality of neuromuscular transmission. Patients with ocular manifestations of myasthenia gravis may have associated systemic findings, including difficulty swallowing, facial weakness, and difficulty breathing. Ocular manifestations include a variable strabismus that is worse in the evening and ptosis with fatigue. Other associated systemic diseases include thyroiditis and thymoma. The diagnosis is confirmed by serologic demonstration of antiacetylcholine receptor antibodies, single muscle fiber electromyography, Tensilon testing, and the ice test. Treatment includes the anticholinesterase agent pyridostigmine bromide (Mestinon), systemic steroids, and thymectomy. Patients with ocular myasthenia will often respond better to systemic steroids than neostigmine.


Figure 21.7 Mitochondrial Abnormalities—Stroke Findings in a Nonvascular Pattern

Mitochondrial abnormalities with ocular involvement include chronic progressive external ophthalmoplegia (Fig. 21.8 and Chapter 1: Strabismus, Fig. 1.72), MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and stroke), MERRF syndrome (myoclonus, epilepsy, and ragged red fibers), and Leber hereditary optic neuropathy (Chapter 9: Optic Nerve, Fig. 9.35). Patients with MELAS syndrome present with seizures, significant development delay, hemiparesis, short stature, and elevated serum lactate levels. Ragged red fibers are demonstrated on muscle biopsy, which are indicative of abnormalities in electron transport within the mitochondria. Patients have a progressive decline and no treatment is yet effective for this disease. MERRF is another progressive mitochondrial disorder presenting after several years with myoclonic seizures, ataxia, and nystagmus.




Figure 21.8 Mitochondrial Abnormalities—Retinopathy

Chronic progressive ophthalmoplegia may be associated with atypical retinitis pigmentosa and complete heart block in Kearns-Sayre syndrome and is caused by deletions in mitochondrial DNA. Fundus examination shows mottling of the retinal pigment epithelium with or without peripheral bone spicules. This patient has no eye movements and almost complete ptosis. Electroretinogram findings are typically normal or minimally reduced early and then later decline. The complete heart block associated with Kearns-Sayre can lead to sudden death and often requires a pacemaker. Patients with significant strabismus may improve their binocular function with eye muscle surgery. Coenzyme Q10 may improve the cardiac dysfunction but has minimal effect on chronic progressive ophthalmoplegia, retinopathy, ptosis, and orbicularis weakness.


Figure 21.9 Craniopharyngioma

Craniopharyngioma is the most common supratentorial brain tumor in children. Craniopharyngiomas arise from remnants of the Rathke pouch and are located with the sella turcica. The mass may extend outside the sella to compress on the chiasm, third ventricle, and pons, causing hydrocephalus, growth abnormalities, and bilateral temporal hemianopia. Craniopharyngiomas contain multiple cystic areas and may contain typical calcifications, which can be visualized on computed tomography scan imaging. Treatment includes resection, radiation, and endocrine management.


Figure 21.10 Neuroblastoma

Neuroblastoma is the most common solid tumor in children, is derived from neural crest cells within the sympathetic chain, and can be found in the adrenal glands (most common), mediastinum (paravertebral ganglia), cervical sympathetic chain, and pelvis. The oncogene N-myc will normally suppress tumor growth. Visceral neuroblastoma will often present with opsoclonus (rapid uncontrollable saccadic movements). Neuroblastoma is the most common cause of acquired Horner syndrome (ptosis, miosis, and anhydrosis) in children. Patients may also have heterochromia (lighter color) if the neuroblastoma presents in the first year of life. Localized tumor of the orbit and periorbital region can be secondary to metastasis of neuroblastoma from a distal site, usually to the bones of the lateral orbital wall(right image). Patients have a characteristic periorbital ecchymosis (“raccoon eyes”). Urine should be tested for catecholamines, vanillylmandelic acid, and homovanillylmandelic acid. Treatment for neuroblastoma includes complete surgical resection and chemotherapy. Radiation therapy has also been used to reduce the size of tumors.




Figure 21.11 Multiple Sclerosis

Multiple sclerosis is an inflammatory condition with demyelination of white matter. The neurologic abnormalities are separated in time and location and vision loss is commonly the presenting symptom. Clinical evaluation may reveal profound decrease in color perception, visual field defects, afferent pupillary defect, and decrease in visual acuity as well as ocular motor problems. The optic nerve may appear swollen (papillitis, Chapter 9: Optic Nerve, Fig. 9.27) or normal. The vision loss is typically sudden and slightly progressive with improvement over weeks to months. Pain with eye movement is a common feature of optic neuritis secondary to multiple sclerosis. Multiple sclerosis may also cause internuclear ophthalmoplegia (INO), skew deviation, and, less commonly, retinitis, retinal vasculitis, anterior uveitis, and pars planitis. Magnetic resonance imaging reveals characteristic bright spots of demyelination in periventricular distribution typically. Treatment should be according to the optic neuritis treatment trial (IV steroids followed by an oral taper).


Figure 21.12 Batten Disease

Batten disease is a group of disorders with abnormal neuronal storage of lipofuscin. Patients may present with delayed development, seizures, ataxia, or visual loss. The diagnosis can be confirmed in suspected cases with increased levels of urine dolichol and curvilinear bodies (inclusions within the cytoplasm of neurons) located within lymphocytes or conjunctival biopsy. Batten disease is inherited as an autosomal recessive trait and a deletion in the CLN3 gene has been mapped to chromosome 16p in cases with juvenile onset. Patients can often present with deteriorating night vision and clinical signs of retinitis pigmentosa (retinal arterial narrowing, optic atrophy, and pigment disturbances within the fundus). The electroretinogram is significantly reduced in most patients and no specific treatment is available at this time.


Figure 21.13 Facial Nerve Palsy

Isolated facial nerve palsy in children is rare. Patients will present with inability to completely close the eyelids. Differential diagnoses includes myasthenia gravis, Bell palsy, trauma, brainstem tumors, demyelination, ischemia, mastoiditis, postviral, and Moebius syndrome. In managing patients with facial nerve palsy, it is important to assess their Bell phenomenon (reflexive supraduction with stimulation of the corneal nerves) and corneal sensation. Patients with decreased Bell phenomenon and corneal anesthesia are at increased risk of exposure keratopathy. Lubrication and sometimes tarsorrhaphy are the mainstays of treatment.