Neuro-Ophthalmic Manifestations of Pediatric Neurodegenerative Disease

The topic of pediatric neurodegenerative disease is broad and ever expanding. Children who suffer from neurodegenerative disease often have concomitant visual dysfunction. Neuro-ophthalmologists may become involved in clinical care to identify corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases, to assess treatment efficacy. Ophthalmic findings also may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. The purpose of this review is to highlight common examples of the neuro-ophthalmic manifestations of pediatric neurodegenerative disease using a case-based approach in an effort to provide a framework for approaching these complex patients.

Original Contribution Neuro-Ophthalmic Manifestations of Pediatric Neurodegenerative Disease Gena Heidary, MD, PhD Abstract: The topic of pediatric neurodegenerative disease is broad and ever expanding. Children who suffer from neurodegenerative disease often have concomitant visual dysfunction. Neuro-ophthalmologists may become involved in clinical care to identify corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases, to assess treatment efficacy. Ophthalmic findings also may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. The purpose of this review is to highlight common examples of the neuro-ophthalmic manifestations of pediatric neurodegenerative disease using a case-based approach in an effort to provide a framework for approaching these complex patients. Journal of Neuro-Ophthalmology 2017;37(Suppl):S4-S13 doi: 10.1097/WNO.0000000000000549 © 2017 by North American Neuro-Ophthalmology Society T he topic of pediatric neurodegenerative disease is broad and the field ever expanding. Traditional classification schemes that stratify these diseases on the basis of gray matter disease and white matter disease are being increasingly complemented by a more granular classification based on a newer appreciation for underlying genetics or cellular mechanisms of disease (1). Children who suffer from neurodegenerative disease often will have concomitant visual dysfunction. In this setting, neuro-ophthalmologists frequently are consulted to look for corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases to assess treatment effiDepartment of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Presented at the 2016 Joint AAO-AAPOS Symposium entitled, "Pediatric Neuro-Ophthalmology: Kids aren't Little Adults" on October 16, 2016 in Chicago, Illinois. The authors report no conflicts of interest. Address correspondence to Gena Heidary, MD, PhD, Boston Children's Hospital Harvard Medical School, 300 Longwood Avenue, Fegan 4, Boston, MA 02115; E-mail: [e-mail] S4 cacy. In other instances, ophthalmic findings may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. From the neuro-ophthalmologist's perspective, a helpful approach to organizing the neuro-ophthalmic findings of pediatric neurodegenerative disease is to stratify them according to their afferent and efferent presentations. Afferent findings include vision loss, visual field loss, dyschromatopsia, retinal changes, and optic atrophy, or neuropathy; efferent findings include strabismus, ophthalmoparesis/ophthalmoplegia, nystagmus, and saccadic dysfunction. The purpose of this review is to use illustrative cases to highlight common examples of the neuro-ophthalmic manifestations of pediatric neurodegenerative disease in an effort to provide a framework for approaching these complex patients. ILLUSTRATIVE CASES Retinal Findings in Pediatric Neurodegenerative Disease Case 1 A 5-year-old boy presented to the neuro-ophthalmology service with vision decline over the past year. His parents noted that he was sitting increasingly closer to the television. The medical history was notable for a diagnosis of seizures that began before 1 year with no family history of epilepsy. He had met his developmental milestones and review of systems was notable for difficulties with impulse control. On examination, visual acuity was 20/125 in each eye. Pupils were responsive with no relative afferent pupillary defect. The ophthalmic sensorimotor examination was normal. Cycloplegic refraction revealed minimal myopia of 20.75 sphere in both eyes. Ophthalmoscopy revealed bilateral parafoveal pigmentary changes (Fig. 1A) consistent with a "bull's eye maculopathy." He underwent a diagnostic skin biopsy that revealed intracytoplasmic inclusions Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Neuronal ceroid lipofuscinosis. A. The left fundus shows a characteristic bull's eye maculopathy. The white ringshaped area is a photographic artifact. B. Electron microscopy of skin biopsy reveals intracytoplasmic curvilinear bodies (arrow). C. Sagittal T1 MRI demonstrates cerebral and cerebellar atrophy. characterized by their curvilinear appearance on electron microscopy (Fig. 1B). Magnetic resonance imaging (MRI) of the brain showed cerebral and cerebellar atrophy (Fig. 1C). Genetic testing demonstrated a homozygous mutation in the CLN2 gene confirming the diagnosis of neuronal ceroid lipofuscinosis (NCL) or Batten disease. The neuronal ceroid lipofuscinoses are a group of fatal, neurodegenerative diseases characterized by cognitive decline, seizures, cerebellar atrophy, and retinal degeneration (2). NCL constitutes the most common cause of pediatric neurodegeneration with a reported incidence in the United States up to 2.4/100,000 (2). Historically, NCL was subclassified into 4 disease entities depending on age of onset: infantile, late infantile, juvenile, and adult onset with Batten disease as the eponym used for NCL, generally, and for the juvenile form, specifically (2). Because of the more recent characterization of the molecular genetics of NCL, a classification scheme based on the genetic and biochemical basis of these diseases has led to a new nomenclature (3). To date, 14 NCL loci have been mapped within which mutations in 13 genes have been identified; these genes encode lysosomal enzymes, transmembrane proteins, and proteins involved in the secretory pathway that, when deficient, result in an accumulation of fluorescent proteins in the lysosome of neuronal tissues and subsequent neuronal loss. The marked expansion of the molecular understanding of these diseases has yielded potential targets for enzyme replacement and gene therapy (2,4). Clinically, patients will experience a progressive and profound visual decline toward blindness secondary to retinal degeneration affecting both the inner and outer layers of the retina. Retinal abnormalities include a parafoveal pigmentary maculopathy or "bull's eye maculopathy" that precedes further degenerative changes in the retinal periphery (5) with accumulation of autofluorescent lipopigment granules within the cytoplasm of retinal cells (6). Additional findings may include peripheral bone spicule formation similar in appearance to retinitis pigmentosa Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 (6), attenuation of the retinal vasculature, and optic atrophy (7). Optical coherence tomography (OCT) may reveal subtle changes in the outer retinal layers that progress to diffuse disruption of the retinal architecture corresponding to disease severity (7,8). Electroretinogram findings are varied initially depending on the extent of disease involvement and subtype of NCL; with time, the electroretinogram (ERG) is "ablated" (9,10). Treatment has been primarily supportive. Clinical trials are underway for patients with CLN2 (a subtype of NCL) with a focus on enzyme replacement therapy as well as gene therapy. A Phase 2 clinical trial using mycophenolate mofetil in patients with CLN3 (also a subtype of NCL) was recently completed (11). Classifying the Retinal Findings in Pediatric Neurodegenerative Diseases When considering the retinal findings in pediatric neurodegenerative disease, a useful approach is to classify diseases according to the part of the retina that is predominantly affected: inner retinal layers, outer retinal layers, or in some, diffuse degeneration involving all layers of the retina (12). Table 1 provides an overview of these disease processes using this classification scheme and is discussed in further detail below. The diseases which predominantly affect the inner retinal layer are lysosomal storage disorders that characteristically have the ophthalmic finding of a "cherry red spot" on fundus examination (Fig. 2A) (13); a list of diseases that commonly present with a cherry red spot is shown in Table 1. Because of an abnormality in lipid metabolism, sphingolipids in these conditions accumulate within the retinal ganglion cells. Parafoveally, the retinal ganglion cells are densely packed and surround the fovea that is devoid of retinal ganglion cells. The contrast between the engorged retinal ganglion cells and the fovea creates the characteristic cherry red spot in the macula (13). Within this category are the gangliosidoses such as the pediatric form of Tay-Sachs S5 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Retinal findings in pediatric neurodegenerative disease Bull's Eye Maculopathy (Inner and Outer Retinal Layers) Neuronal ceroid lipofuscinosis Methylmalonic aciduria and homocystinuria cobalamin C type Cherry Red Spot (Inner Retinal Layers) Pigmentary Retinopathy (Outer Retinal Layers) Gangliosidoses (e.g., Tay-Sachs disease) Sialidosis Mitochondrial disorders (e.g., Kearns-Sayre, MELAS) Pantothenate kinase-associated neurodegeneration (66) Other sphingolipidoses (e.g., Niemann-Pick disease) Spinocerebellar ataxia Type 7 (67) Refsum disease (68) Abetalipoproteinemia (68) Mucopolysaccharidoses (69) disease and the sphingolipidoses such as Niemann-Pick Type A disease. Outer retinal disease often manifests as a pigmentary retinopathy. Representative diseases are shown in Table 1 and discussed further below in Case 4. The retina may have a "salt-and-pepper" appearance (see below, Case 4, Fig. 5) with photoreceptor degeneration and more advanced cases may demonstrate peripheral bone spicule formation consistent with retinal pigment epithelium (RPE) dysregulation and dysfunction. These disease processes are varied and included among them are the mitochondrial encephalopathies (discussed below). With respect to bull's eye maculopathies, in addition to NCL, cobalamin C type methlymalonic aciduria and homocystinuria (cblC), the most common inborn error of vitamin B12 (cobalamin) metabolism, deserves mention as a condition that may present with an early onset, infantile maculopathy and progressive neurologic dysfunction (14- 18). This condition is caused by mutations in the MMACHC gene (OMIM 609831) and is estimated to occur in approximately 1 in 100,000 newborns in the United States with a higher prevalence in children of Hispanic descent (15). The disease has an infantile form and later onset form. In the infantile form, neurologic findings include intrauterine growth retardation, developmental delay, and leukoencephalopathy (15,16). Infants may develop nystagmus or roving eye movements because of macular degeneration, and vision loss typically progresses to the level of legal blindness (15,16,18). Retinal manifestations may include the development of a bull's eye maculopathy, atrophy of the macular region (Fig. 2B), and a peripheral pigmentary retinopathy with areas of corresponding retinal thinning and disorganization detected with OCT (14). Strabismus and optic atrophy also may be present. (15,16,18). Electroretinography may be normal or show decreases in both scotopic and photopic responses depending on disease severity (17,18). The disease may be treated with supplementation of hydroxocobalamin, but there is insufficient data to determine the impact of early treatment on progressive retinal degeneration (15). Optic Atrophy Associated With Pediatric Neurodegenerative Disease Case 2 A 7-year-old boy was referred to the neuro-ophthalmology service for progressive visual decline. His medical history was notable for mild cognitive delay and a family history of a younger sister with similar cognitive and visual issues. The patient had been followed since infancy for nystagmus that FIG. 2. A. Tay-Sachs disease. There is a cherry red spot in the right macula (courtesy of Ankoor Shah, Boston, MA). B. Cobalamin C methylmalonic aciduria and homocystinuria. The left fundus shows macular atrophy. S6 Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Leigh-like encephalopathy. A. The fundus photo of the right eye reveals diffuse optic atrophy. B and C. Axial fatsuppressed T2 MRI reveals hyperintense, paramedian symmetric lesions (arrows) within the brainstem. had been noticed at the age of 9 months. By 2 years, visual acuity was slightly subnormal for age at 20/130 in each eye measured by preferential looking testing, and bilateral optic atrophy was noted (Fig. 3A). At that time, neuroimaging revealed thinning of the optic nerves consistent with atrophy but was otherwise normal. At age of 7 years, he noted a precipitous decline in the vision of his left eye. Visual acuity had been 20/200 bilaterally but was now 20/ 200 right eye and 8/200 left eye. There was a new esodeviation worse at distance than near and abduction limitation of the right eye consistent with a sixth nerve palsy. In addition to the previously reported optic atrophy, followup neuroimaging showed bilateral T2 prolongation extending through the brainstem (Fig. 3B, C). Although the neuroimaging findings were consistent with Leigh syndrome, genetic testing was positive for compound heterozygous mutations in the C12orf65 gene consistent with the diagnosis of combined oxidative phosphorylation deficiency Type 7. The patient was treated with ubiquinol and a multivitamin with stabilization of his vision at 20/ 200, right eye, and 6/200, left eye. The sixth nerve palsy resolved. Additional details regarding his case and similar findings in his affected sister have been previously published (19). This case represents a novel form of hereditary optic neuropathy associated with genetic changes in the C12orf65 gene. The first 2 families with this genetic muta- tion were described in 2010 with a phenotype similar to what is seen in patients with Leigh syndrome. In affected family members, MRI revealed bilateral T2 hyperintensities within the brainstem. Associated ophthalmic findings included optic atrophy and nystagmus (20). In other patients, mutations in C12orf65 have been associated with spastic paraplegia and optic atrophy (21). In the setting of optic atrophy combined with MRI abnormalities within the brainstem, genetic testing for combined oxidative phosphorylation deficiency Type 7 should be considered (19,22,23). Classifying the Pediatric Neurodegenerative Diseases With Associated Optic Atrophy The number of neurodegenerative processes that have optic atrophy as a disease manifestation are myriad (1). Table 2 highlights several of these conditions among which are the hereditary optic neuropathies and the leukoencephalopathies. Hereditary optic neuropathies, as in our Case 2, typically present with painless, bilateral symmetric vision loss. These conditions may result in isolated vision loss but many have optic atrophy in association with neurologic dysfunction, hearing loss, cardiomyopathy, and endocrine dysfunction (24). Many of these disorders occur secondary to mitochondrial dysfunction from genetic changes in mitochondrial or nuclear genes that encode proteins important for energy metabolism in the mitochondria. TABLE 2. Pediatric neurodegenerative diseases with optic atrophy Mitochondrial Disorders Leukoencephalopathies Combined Optic Atrophy and Retinal Degeneration Leigh disease and Leigh-like encephalopathies Neonatal adrenoleukodystrophy Spinocerebellar ataxia Type 7 (67) Myoclonic epilepsy and ragged X-linked adrenoleukodystrophy Neuronal ceroid lipofuscinosis red fibers (MERFF) Pelizaeus-Merzbacher Canavan disease Krabbe disease Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 S7 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Two conditions that are more commonly encountered as isolated optic atrophy but which may have an associated neurologic component are dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON). DOA is autosomal dominantly inherited, caused predominantly by mutations in the OPA1 gene (OMIM 605290), and is the most common inherited optic neuropathy (25,26). Although vision loss is the predominant symptom in patients with DOA, a "DOA-plus" phenotype exists. Additional findings include external ophthalmoplegia, ataxia, hearing loss, and peripheral neuropathy (27). Leber hereditary optic neuropathy (LHON, OMIM 535000) is mitochondrially inherited and characterized by bilateral, painless subacute/acute vision loss without associated systemic findings. In the "LHON-plus" phenotype, cardiomyopathy, and neurologic findings including peripheral neuropathy, brainstem dysfunction, and early onset of dystonia in pediatric patients have been reported (28-39). In addition, a multiple sclerosis in combination with LHON phenotype, Harding syndrome, has been described (31,32). 3-methylglutaconic aciduria Type III (Costeff syndrome) is recessively inherited and associated with mutations in the OPA3 gene (33). The condition is rare with a high prevalence in patients of Iraqi Jewish heritage (34). Early developmental delay and optic atrophy may be initial findings with progression of neurologic dysfunction including spastic paraplegia and chorea (34). Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) is an autosomal recessively inherited condition and caused by mutations in 2 genes (OMIM 222300, 604928): wolframin (WFS1) and CISD2 (WFS2) (35,36). The disorder is characterized by an asynchronous onset often with diabetes mellitus and optic atrophy as the initial manifestations (37). Vision loss may be minimal to severe. In addition to optic atrophy, children may have nystagmus, cataracts, and strabismus (38). Neurologic complications include psychosis, brainstem dysfunction, and cerebellar dysfunction (39). Retinal nerve fiber layer thinning on OCT has been corre- lated with disease severity and may serve as an adjunct toward monitoring disease progression (38). The leukoencephalopathies refer to a group of childhood neurodegenerative diseases that predominantly affect white matter structure and function (Table 2) (1,40). These conditions may result from destruction of myelin vs hypomyelination of the white matter tracts (1). Pelizaeus-Merzbacher is an X-linked leukodystrophy caused by gene duplication or mutations in the PLP1 gene (OMIM 300401) that encodes lipophilin, the main component of myelin; disruption of lipophilin synthesis results in hypomyelination of the central nervous system (41). Age of onset is during infancy, and neuro-ophthalmic findings include nystagmus and a head bobbing. Using eye movement recordings, the nystagmus has been found to have a unique elliptical pendular pattern coupled with the presence of upbeat nystagmus in primary gaze that may help to distinguish this condition from other causes of infantile nystagmus (42). Optic atrophy may be present (1,40) and neurologically, infants display hypotonia, cognitive delay, and may develop spasticity and ataxia as the disease progresses (43). Neuro-Ophthalmic Findings in Mitochondrial Encephalomyopathies Case 3 A 15-year-old girl with a history of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) experienced an acute change in vision. Her medical history was notable for seizures. Visual acuity was 20/40, right eye and 20/30, left eye. Pupils were responsive with no relative afferent pupillary defect. No dyschromatopsia was noted. Goldmann kinetic perimetry revealed a left homonymous hemianopia (Fig. 4A) and funduscopy was normal in both eyes. MRI revealed changes in the right parietal and occipital lobes consistent with an ischemic insult (Fig. 4B). Magnetic resonance angiography was normal. The diagnosis was acute stroke-like episode with visual field loss in the setting of MELAS. FIG. 4. MELAS. A. Goldmann kinetic perimetry demonstrates a complete left homonymous hemianopia. B. Axial FLAIR MRI shows hyperintensity in the left occipital lobe (arrow) consistent with an ischemic infarction. This was confirmed on diffusionweighted imaging and apparent diffusion coefficient map (not shown). MELAS, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. S8 Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Kearns-Sayre syndrome. A. The patient has bilateral ptosis and an exotropia. The fundus of the left eye shows characteristic pigmentary retinopathy parafoveally (B) and peripherally (C) (courtesy of Joseph Rizzo, Boston, MA). Case 4 A 21-year-old woman was evaluated by the neuroophthalmology service for bilateral blepharoptosis and acquired ophthalmoparesis since her mid-teens. She had mild hearing loss since the age of 10 years. Visual acuity was 20/20 in each eye. Pupils reacted normally, color vision was intact, and visual fields were full. There was bilateral blepharoptosis (Fig. 5A) and the sensorimotor examination revealed nearcomplete external ophthalmoplegia. Funduscopy showed diffuse retinal pigmentary changes (Fig. 5B, C). A muscle biopsy Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 FIG. 6. Ataxia telangiectasia. A. There are telangiectatic vessels (arrows) on the bulbar conjunctiva of the left eye. Axial T2 MRI shows progressive cerebellar atrophy from age 34 months (B) to 11 years (C). S9 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Conditions associated with efferent visual dysfunction in pediatric neurodegenerative diseases Ophthalmoparesis/-plegia Nystagmus Saccadic Dysfunction Mitochondrial encephalomyopathies (e.g., Kearns-Sayre) Leigh syndrome Friedreich ataxia Leigh syndrome Pelizaeus-Merzbacher (elliptical pendular) (42) Methylmalonic aciduria and homocystinuria cobalamin C type Ataxia telangiectasia Ataxia with ocular motor apraxia Type 1 and 2 Niemann-Pick Type C disease (vertical saccades) Gaucher disease showed demonstrated ragged red fibers and the diagnosis of Kearns-Sayre syndrome was made. These 2 cases represent mitochondrial encephalomyopathies for which the neuro-ophthalmic manifestations are diverse. These conditions are mitochondrially inherited with involvement of the central nervous system and skeletal muscle. The most common diseases include MELAS (44,45), Kearns-Sayre syndrome (46), and myoclonic epilepsy with ragged red fibers (MERFF) (47). MELAS presents in early childhood with seizures, encephalopathy, recurrent headaches and vomiting, exercise intolerance, and stroke-like episodes that may result in visual field loss or cortical blindness. Mutations in the MT-TL1 gene account for most cases of MELAS (44,45). Additional ophthalmic findings may include pigmentary retinopathy, optic atrophy, and ophthalmoplegia. On OCT, atrophy of the RPE, outer nuclear layer, and ellipsoid zone has been described (48). Kearns-Sayre syndrome is characterized by the triad of a pigmentary retinopathy, progressive external ophthalmoplegia (PEO), and onset of symptoms before the age of 20 years (46). Kearns-Sayre syndrome is one of several large mitochondrial deletion syndromes including PEO and Pearson syndrome; these large deletions account for the vast majority of cases of Kearns-Sayre. The pigmentary retinopathy is described as having a "salt-and-pepper" appearance. Children may have associated cerebellar dysfunction and importantly can have cardiac conduction abnormalities as well as endocrinopathy. Seizure is rare in Kearns-Sayre syndrome (49). MERFF manifests in childhood with onset of myoclonus, generalized epilepsy, ragged red fibers on muscle biopsy, and cognitive impairment. These patients commonly have optic atrophy although a pigmentary retinopathy occasionally has been reported. Ophthalmoparesis may be a feature of MERFF. Mutations in the MT-TK gene account for approximately 90% of MERFF (47). S10 Gaze Abnormalities Downgaze palsy, ataxia-athetosis, and foam cells in the bone marrow syndrome (a.k.a. Niemann-Pick Type C disease) (65) Gaucher disease (horizontal) Abetalipoproteinemia (internuclear ophthalmoplegia with nystagmus of adducting eye) (65) Although each of these conditions has characteristic clinical features, there are many cases with phenotypic overlap (50). The frequency of ophthalmic findings in patients with mitochondrial disease including MELAS, Kearns-Sayre, MERFF, and other mitochondrial conditions ranges from 35% in one cohort of 74 patients (51) to 81% in a group of 59 patients (52). Abnormalities of the Efferent Visual System in Pediatric Neurodegenerative Diseases Case 5 A 9-year-old girl with a history of ataxia telangiectasia was referred to the pediatric ophthalmology service for evaluation of difficulties with eye tracking. Visual acuity was 20/ 60, right eye and 20/100, left eye. Sensorimotor examination revealed mild convergence insufficiency, difficulty initiating horizontal saccades, jerky pursuit movements, and a 30-prism diopter exotropia. There was no nystagmus. Slit-lamp examination showed dilated, tortuous vessels of the bulbar conjunctiva in both eyes (Fig. 6A). Visual fields were full and funduscopy was normal in each eye. Neuroimaging showed cerebellar atrophy (Fig. 6B, C). These clinical findings were consistent with the diagnosis of ataxia telangiectasia. Ataxia telangiectasia (A-T, OMIM 208900) is an autosomal recessive condition caused by mutations in the ATM gene with an incidence reported up to 1/40,000 live births. A-T is characterized by early-onset cerebellar dyfunction, immunodeficiency, susceptibility to lymphoid tumors, ocular and skin telangiectasias, and oculomotor dysfunction (53,54). Neurologic findings in classic A-T include postural difficulty and ataxia and are often apparent in infancy as the child is learning to sit or to walk (54). Progressive cerebellar atrophy is a characteristic finding on MRI (55). Telangiectatic conjunctival vessels in the interpalpebral zone of the bulbar conjunctiva is a common finding of A-T and in Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution a study of 58 A-T patients, these telangiectasias were present in 91% of patients; there are atypical forms of A-T in which the conjunctival findings are not present (53,56,57). The oculomotor findings may include strabismus, oculomotor apraxia with an associated head thrust, hypometric saccades, abberant smooth pursuit, deficiency of involuntary saccades, and nystagmus (53,58). As in our patient, there may be accommodative insufficiency and difficulty with convergence (53). This constellation of eye movement abnormalities may aid the clinician in narrowing the diagnosis to A-T (57). Classifying the Efferent Findings in Pediatric Neurodegenerative Diseases Sensorimotor abnormalities often accompany afferent dysfunction in pediatric neurodegenerative diseases. Diseases that commonly present with ophthalmoparesis/ ophthalmoplegia, nystagmus, saccadic dysfunction, and/ or gaze palsy are shown in Table 3. These findings are not mutually exclusive and many patients will have complex sensorimotor dysfunction as the child in Case 5 or the combination of afferent and efferent dysfunction as in Case 4. Several additional conditions have efferent manifestations. A-T belongs to a group of recessively inherited cerebellar ataxias that include ataxia with ocular motor apraxia Type 1 (AOA1), ataxia with ocular motor apraxia Type 2 (AOA2), and Friedreich ataxia. AOA1 is caused by mutations in the APTX gene (OMIM 606350) with an average age of onset in the first decade of life. Children with this condition frequently have hypoalbuminemia and hypercholesterolemia. Ocular motor apraxia is characteristic in these patients and has been reported in 86% of a large cohort of patients with AOA1 (59). AOA2 is caused by mutations in the senataxin gene (OMIM 608465). The age of onset is the second decade of life and patients with AOA2 often have elevated levels of alpha-feto-protein (60). Ophthalmic findings include ocular motor apraxia and strabismus, but the frequency of ocular motor apraxia is less in AOA2 than in AOA1 (59,60). Friedreich ataxia, which is caused by mutations in the frataxin gene (OMIM 606829), is the most common in this group of diseases. The age of onset is varied but may occur within the second decade of life. Ophthalmic findings include saccadic intrusions or square wave jerks and saccadic dysmetria (61). Friedreich ataxia is distinguished from this group of recessively inherited cerebellar ataxias by the finding of optic atrophy (61). Gaucher disease is a lysosomal storage disease with the systemic findings of developmental decline, hepatosplenomegaly, and seizures (62). In the juvenile onset form, Gaucher disease Type 3, a supranuclear horizontal gaze palsy with head thrusts and movements that mimic oculomotor apraxia may be seen (63-65). In other cases, an unusual movement or "looping" of the eyes during Heidary: J Neuro-Ophthalmol 2017; 37(Suppl): S4-S13 horizontal saccades may be seen. Vertical saccades are not involved (40). THE ROLE OF THE NEUROOPHTHALMOLOGIST In the setting of neurodegenerative disease, the importance of a neuro-ophthalmic evaluation cannot be overemphasized. Although a mastery of the subtleties of each possible condition may not be feasible, with our unique purview into the nervous system, we may be the first to identify findings that may contribute to the diagnostic evaluation of children with pediatric neurodegenerative disease. In these patients, the neuro-ophthalmologist may initiate further evaluation with neurology and genetics/metabolism and through a multidisciplinary, collaborative approach arrive at a correct diagnosis. Furthermore, we contribute by providing continued monitoring for disease progression and when relevant, assess for treatment efficacy. In the future, we may more actively be involved in cases where gene therapy becomes available for treatment of some of these disorders. REFERENCES 1. Brodsky MC. Pediatric Neuro-Ophthalmology. 3rd edition. New York, NY: Springer, 2016. 2. Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord. 2016;18:73-88. 3. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012;79:183-191. 4. Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta. 2015;1852:2237-2241. 5. Traboulsi EI, Green WR, Luckenbach MW, de la Cruz ZC. 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