Optic nerve hypoplasia

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Disease ICD 9  Optic nerve hypoplasia 377.43 ICD 10  Optic nerve hypoplasia, right eye H47.031  Optic nerve hypoplasia, left eye H47.032  Optic nerve hypoplasia, bilateral H47.033


Disease Entity

Optic nerve hypoplasia is characterized by decreased number of optic nerve axons. It can present unilaterally or bilaterally1. It may present as an isolated anomaly or be associated with midline brain structural defect, such as septum pellucidum absence, agenesis of corpus callosum, cerebral hemisphere abnormalities, or pituitary gland abnormalities. Septo – Optic dysplasia (de Morsier syndrome) is used to describe the association between optic nerve hypoplasia and the absence of septum pellucidum and agenesis of corpus callosum.

Image source: AAO website3

History

Image source: AAO website2

First optic nerve hypoplasia case was described by Briere in 1877, and the first schematic drawing of optic disc appearance of optic nerve hypoplasia was done by Schwarz in 1915. In 1941, Dr. David Reeves at CHLA first described the association of optic nerve hypoplasia with agenesis of septum pellucidum. And subsequently the term of “la dysplasia septo –optique” was described by Georges de Morsier in 1956. In 1970 Dr. William Hoyt’s landmark paper recognized the association between optic nerve hypoplasia and growth hormone deficiency. And Dr. Hoyt attributed the discovery of the association of optic nerve hypoplasia with septum pellucidum agenesis to de Morsier, and resurrected the term of septo-optic dysplasia syndrome4.

Epidemiology

In 2007, ONH is considered as the 3rd most prevalent cause for any vision impairment in children < 3yo5 after cortical vision impairment and retinopathy of prematurity. Optic nerve hypoplasia was identified in 12% of blind infants in Harris County in Texas in early 1980s6. In more recent studies, the incidences of ONH in all living children under the age of 18 is reported to be 10.9 per 100,000 in England and 17.3 per 100,000 in Sweden7, 8. In 2013, a study based in Mayo Clinic reported an incidence of 1/2287 live births and 2.4/100,000 in patients less than 19 years old. ONH is usually diagnosed at 2 years of age9.

Genetics

A number of gene mutations have been associated with ONH: 

Gene Function Clinical feature/Associated disorders
HESX1 Transcription regulation gene that is critical

to the development of the forebrain, midline brain structures, and pituitary

Combined pituitary hormone deficiency or

septo-optic dysplasia10

PAX6 Transcription regulation gene that guides neural

and ocular development

Abnormalities

in the iris, nystagmus and foveal hypoplasia, cataracts, corneal abnormalities, glaucoma and bilateral ptosis11

SOX2 Transcription factor that plays an important

role in embryogenesis

Bilateral ONH, absent septum pellucidum,

bilateral schizencephaly, right porencephalic cyst12

NR2F1 Transcription regulation gene that is critical

to neurodevelopment, optic development, oligodendrocyte differentiation, etc

Intellectual disability seen with ONH/optic

atrophy13

OTX2 Transcription factor that affects brain

development. Family screening for a possible mutation is important as mutations tend to be hereditary

Anophthalmia/microphthalmia,

brain malformations, pituitary abnormalities; short stature, intellectual disabilities, feeding difficulties14

VAX1 Transcription regulation gene in eye development Bilateral microphthalmia, cleft

lip/palate,  corpus callosum defects, hippocampal defects, absent pineal gland15

ATOH7 Transcription regulation gene that controls

ocular development and formation of retinal ganglion cells

Smaller optic disc16
KANSL1 Transcription regulation through histone

acetylation

Strabismus, astigmatism, myopia17
 

Risk Factors

Although a number of risk factors have been reported, young maternal age, maternal diabetes, and primiparity have the highest association with ONH9. Additionally, preterm labor, vaginal bleeding during pregnancy, low maternal weight gain, and maternal weight loss during the first and second trimesters increase the risk of ONH. Recent studies demonstrate that maternal use of alcohol, recreational drugs, anticonvulsants, antidepressants, and viral infections during pregnancy appear to play a smaller role in the development of ONH than previously thought18.

General Pathology

In optic nerve hypoplasia, retinal nerve fiber layer and ganglion cell number are decreased, while the outer retinal layer is generally less unaffected19, 22.

Diagnosis

Signs

In optic nerve hypoplasia, optic disc is often pale or gray and appears to be half the size of a normal optic disc or smaller20. Optic discs often present with a double ring sign – yellow to white ring around the disc. A ring of hypopigmentation or hyperpigmentation often, but not always, surrounds the disc defining the area of the putative scleral canal. The outer ring represents the normal junction between the sclera and the lamina cribrosa; the inner ring represents the abnormal extension of retina and pigment epithelium over the outer portion of the lamina cribrosa. Tortuous retinal arterioles, venules, or both may accompany ONH, but retinal vessels can also present with normal caliber. Assessment of area of disc relative to the distance between fovea to temporal edge of the disc often reveals the small disc diameters: DD/DM ratio < 0.35. (DD: disc diameter; DM: distance between fovea and temporal edge of the disc.) Patients’ age needs to be considered when evaluating the DD/DM ratio. In premature infants, the normal DD/DM ratio has been reported as DD/DM ≥ 0.2621. Additionally, Optical Coherence Tomography (OCT) studies reveal foveal thinning of several retinal layers including the RNFL (retinal nerve fiber layer), GCL (ganglion cell layer), IPL (inner plexiform layer), OPL (outer plexiform layer), ONL (outer nuclear layer), and IS (inner segment) layers. The retinal changes observed are similar to foveal hypoplasia; however, ONH results in more severe changes in the RNFL and GCL retinal layers19

Symptoms

In optic nerve hypoplasia patients’ visual acuity can range from normal to light perception. Most patients suffer from a visual acuity of 20/200 or worse20.  Visual acuity in optic nerve hypoplasia patients is related to the structure of the macula and is often not correlated with overall size of the disc19. Visual field often has localized defects combined with visual field constrictions, commonly in nasal or inferior fields22. ONH can occur unilaterally, bilaterally symmetric, or bilaterally asymmetric. In unilateral and asymmetric bilateral ONH, relative afferent pupillary defects can be seen as well. Congenital sensory nystagmus often presents in bilateral ONH cases at 1-3 month of age, followed by strabismus development by 1 year of age, often esotropia. Primarily strabismus often develops in markedly asymmetric or unilateral cases. Hypothalamic dysfunction is the most common nonvisual problem in ONH cases and is reported to be present in 69% of unilateral cases vs 81% of bilateral cases23. Absence of septum pellucidum was not associated with poor vision, pituitary dysfunction or development outcomes24. It has been reported that 13-34% of optic nerve hypoplasia cases have pituitary abnormalities: empty sella, ectopic posterior pituitary, non-visualized infundibulum and posterior pituitary. Endocrine abnormalities are associated with the absence of the infundibulum which results in the lack of communication between the hypothalamus and the anterior pituitary. As a result, the hypothalamus is unable to properly stimulate the anterior pituitary leading to low levels of anterior pituitary hormones and hypopituitarism.  The following hormonal dysfunctions have been seen in patients with ONH20: growth hormone deficiency (70%), moderately elevated serum prolactin (normally suppressed by hypothalamus), hypothyroidism (43%); adrenocorticotropic hormone deficiency (27%) leading to hypercortisolism, and diabetes insipidus (5%) due to posterior pituitary abnormalities. Normal pituitary function at initial evaluation does not preclude development of endocrinopathy in the future. Additionally, early diagnosis of endocrine dysfunction and proper treatment with hormone replacement therapy is critical to reducing mortality.  Developmental delays occur in 75% of ONH cases23, 25, 26, with higher incidence in bilateral cases (78%) vs unilateral cases (39%). Patients can present with motor delays (75%), and communication delays (44%). Other abnormalities include hypoglycemia (transient or permanent), microgenitalism, and hyperbilirubinemia27.    

Diagnostic procedures/Laboratory test

MRI studies are suggested in patients suspected of having ONH. The diameter of the intracranial optic nerve and thinning of the optic chiasm can be assessed on MRI scans. Additionally, the presence of midline abnormalities can be visualized to confirm the diagnosis of SOD20. Optical coherence tomography (OCT) is also an effective tool for measuring foveal parameters and detecting ONH19.  

Differential diagnosis

Optic nerve atrophy, optic nerve coloboma, peripapillary staphyloma, morning glory disc anomaly, tilted disc syndrome, glaucoma.

Management

An ophthalmic evaluation is recommended for all neonates with jaundice and recurrent hypoglycemia. Additionally, an ophthalmic evaluation is recommended for infants with poor visual behavior, strabismus, or nystagmus by 3 months of age. MRI brain is recommended for confirmed ONH cases to evaluate for hydrocephalus, corpus callosum hypoplasia, schizencephaly or polymicogyria. Positive MRI brain should prompt to neurologic exam. Endocrinologic and pituitary function evaluations are recommended regardless of the status of septum pellucidum. Endocrine workups include: fasting morning cortisol and glucose, TSH, free4, growth hormone surrogates (IGF-1, IGFBP-3), LH, SFH, and testosterone (if < 6mo age).

General treatment

All optic nerve hypoplasia patients with central nerve system abnormalities or endocrinolopathies would benefit from a multi-disciplinary team of physicians including a neurologist, neurosurgeon, endocrinologist and/or other specialists from respective fields. The recommended follow-up is semiannually for growth patterns and annually for visual function. Surgical correction for strabismus is reserved for patients with symmetrical functional vision in both eyes, and patients with some potential for binocularity. Otherwise, surgical strabismus can be deferred for psychosocial issues.

References

1. Kanski J, Clinical Ophthalmology, A Systemic Approach. 6th edition. 2007.

2. Image source: AAO

3. Image source: AAO

4. Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS. Septo-optic dysplasia and pituitary dwarfism. Lancet. 1970;1:893–894

5. Hatton D, Schwietz E, Boyer B, Rychwalski P. Babies Count: the national registry for children with visual impairments, birth to 3 years. J AAPOS. 2007;11:351–355.

6. Williamson WD, Desmond MM, Andrew LP, Hicks RN. Visually impaired infants in the 1980s. A survey of etiologic factors and additional handicapping conditions in a school population. Clin Pediatr. 1987;26:241–244.

7. Patel L, McNally R, Harrison E, Lloyd IC, Clayton PE. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr. 2006;148:85–88

8. Teär Fahnehjelm K, Dahl S, Martin L, et al. Optic nerve hypoplasia in children and adolescents; prevalence, ocular characteristics and behavioural problems. Acta Ophthalmologica. 2014;92:563-570.

9. Mohney BG, Young RC, Diehl N. Incidence and Associated Endocrine and Neurologic Abnormalities of Optic Nerve Hypoplasia. JAMA Ophthalmology. 2013;131:898-902

10. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Mårtensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998;19:125–33.

11. Hingorani M., Kathleen A. Williamson, Anthony T. Moore, Veronica van Heyningen; Detailed Ophthalmologic Evaluation of 43 Individuals with PAX6 Mutations. Invest. Ophthalmol. Vis. Sci. 2009;50(6):2581-2590. doi: 10.1167/iovs.08-2827.

12. Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. The Journal of clinical investigation. 2006;116:2442-2455.

13. Bosch DGM, Boonstra FN, Gonzaga-Jauregui C, et al. NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability. American Journal of Human Genetics. 2014;94:303-309.

14. Schilter K, Schneider A, Bardakjian T, et al. OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype. Clinical Genetics. 2011;79:158-168.

15. Slavotinek AM, Chao R, Vacik T, et al. VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: The first description of a VAX1 phenotype in humans. Human Mutation. 2012;33:364-368.

16. Macgregor S, Hewitt AW, Hysi PG, et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Human molecular genetics. 2010;19:2716-2724.

17. Zollino M, Marangi G, Ponzi E, et al. Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients. Journal of medical genetics. 2015;52:804.

18. Garcia-Filion P, Fink C, Geffner ME, Borchert M. Optic nerve hypoplasia in North America: A re-appraisal of perinatal risk factors. Acta Ophthalmologica. 2010;88:527-534.

19. Pilat A, PhD, Sibley D, BMBS, McLean RJ, MSc, Proudlock FA, PhD, Gottlob I, MD. High-Resolution Imaging of the Optic Nerve and Retina in Optic Nerve Hypoplasia. Ophthalmology. 2015;122:1330-1339.

20. Smith PM, Rismondo V. Diagnosing Septo-Optic Dysplasia. https://www.aao.org/eyenet/article/diagnosing-septo-optic-dysplasia. Accessed April 23, 2018.

21. Kaur S, Jain S, Sodhi HBS, Rastogi A, Kamlesh. Optic nerve hypoplasia. Oman journal of ophthalmology. 2013;6:77-82.

22. Ouvrier R, Billson F: Optic nerve hypoplasia: a review. Journal of child neurology 1986, 1(3):181-188.

23. Garcia-Filion P, Epport K, Nelson M, Azen C, Geffner ME, Fink C, Borchert M. Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics. 2008;121:e653–e659

24. Ahmad T, Garcia-Filion P, Borchert M, Kaufman F, Burkett L, Geffner M. Endocrinological and auxological abnormalities in young children with optic nerve hypoplasia: a prospective study. J Pediatr. 2006 Jan;148(1):78-84.

25. Margalith D, Jan JE, McCormick AQ, Tze WJ, Lapointe J. Clinical spectrum of optic nerve hypoplasia: a review of 51 patients. Dev Med Child Neurol. 1984;26:311–322

26.  Burke JP, O'Keefe M, Bowell R. Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol. 1991 Apr;75(4):236-9. PubMed PMID: 2021594; PubMed Central PMCID: PMC1042331.

27. Ryabets-Lienhard A, Stewart C, Borchert M, Geffner ME. The Optic Nerve Hypoplasia Spectrum: Review of the Literature and Clinical Guidelines. Advances in pediatrics. 2016;63:127.