Journal of Neuro-Ophthalmology, March 2012, Volume 32, Issue 1

Reappraisal of the Optic Nerve Hypoplasia Syndrome

Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as "septo-optic dysplasia" or "de Morsier syndrome." More recent studies have suggested that these associations are independent of one another. This review was designed to assess the historical and recent evidence for associations of neuroradiologic, endocrinologic, and developmental problems in patients with ONH., Evidence acquisition: Historical and contemporary literature review., Results: The medical literature does not support the notion that Georges de Morsier ever described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt. Hypopituitarism and other more recently identified associations with ONH, such as developmental delay, hypothalamic dysfunction, and autism, are independent of septum pellucidum development. Other common neuroradiographic associations, such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia, may have prognostic significance., Conclusions: Children with ONH need to be monitored for many systemic, developmental, and even life-threatening problems independent of the status of the septum pellucidum. "Septo-optic dysplasia" and "de Morsier syndrome" are historically inaccurate and clinically misleading terms that should be abandoned., (C) 2012 Lippincott Williams & Wilkins, Inc.

Reappraisal of the Optic Nerve Hypoplasia Syndrome Mark Borchert, MD Background: Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congen-ital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as "septo-optic dysplasia" or "de Morsier syndrome." More recent studies have suggested that these associations are independent of one another. This review was designed to assess the historical and recent evidence for associations of neuroradiologic, endocrino-logic, and developmental problems in patients with ONH. Evidence acquisition: Historical and contemporary litera-ture review. Results: The medical literature does not support the notion that Georges de Morsier ever described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt. Hypopituitarism and other more recently identified associations with ONH, such as developmental delay, hypothalamic dysfunction, and autism, are independent of septum pellucidum development. Other common neuro-radiographic associations, such as corpus callosum hypo-plasia, gyrus dysplasia, and cortical heterotopia, may have prognostic significance. Conclusions: Children with ONH need to be monitored for many systemic, developmental, and even life-threatening problems independent of the status of the septum pelluci-dum. "Septo-optic dysplasia" and "de Morsier syndrome" are historically inaccurate and clinically misleading terms that should be abandoned. Journal of Neuro-Ophthalmology 2012;32:58-67 doi: 10.1097/WNO.0b013e31824442b8 © 2012 by North American Neuro-Ophthalmology Society This review will summarize the state of knowledge on optic nerve hypoplasia (ONH) and reanalyze the historical literature that led to misunderstanding of its asso-ciation with neurologic or endocrinologic abnormalities. The case will be made for abandonment of the terms septo-optic dysplasia (SOD) and de Morsier syndrome. HISTORICAL PERSPECTIVE The first description of ONH is ascribed to Briere in 1877 (1), but the first artistic rendering of the optic disc appear-ance was by Schwarz in 1915 (2) (Fig. 1). The first recog-nition of an association of ONH with agenesis of the septum pellucidum was by Dr David Reeves at Children's Hospital Los Angeles in 1941 (3,4). The purpose of Reeves' report was to demonstrate the youngest case of agenesis of the septum pellucidum diag-nosed by air encephalogram (Fig. 2). The 4-month-old patient was coincidentally blind, and examination under anesthesia by Dr S. Rodman Irvine revealed "bilateral pri-mary optic atrophy of undetermined origin, probably, how-ever, on the basis of a congenital aplasia." The association of ONH with absence of the sep-tum pellucidum was later erroneously attributed to Georges de Morsier (Fig. 3), who coined the term, "la dysplasia septo-optique" ( SOD) (5).However, the "optic dysplasia" recognized by de Morsier was not ONH. In his treatise on cranioencephalodysraphism, his third chapter highlighted his fascination with absence of the septum pel-lucidum that had incidentally been noted in postmortem brains. From this, he discovered that 1 brain had a unilater-ally vertically rotated optic tract (Fig. 4). This was from a woman who died of pyelonephritis at the age of 84 years without any history of vision problems. He also described the case of a living 44-year-old alcoholic man who had "slight narrowing of the visual field with enlargement of the blind spot," but was incidentally discovered to be missing the sep-tum pellucidum on air encephalogram. De Morsier supple-mented these 2 cases with 34 others (11 autopsy cases and 23 radiographic cases) from the literature that had agenesis of the septum pellucidum, 8 of which had some other eye or optic nerve problem. These included 1 case of bilateral anophthalmia, 3 cases of bilateral optic atrophy (1 with Apert syndrome and 1 with osteogenesis imperfecta), and 3 cases of unilateral optic atrophy (2 systemically normal and 1 with Keck Medical Center of the University of Southern California. The authors report no conflicts of interest. Address correspondence to Mark Borchert, MD, The Vision Center at Children's Hospital Los Angeles, 4650 Sunset Boulevard MS#88, Los Angeles, CA 90027; E-mail: [e-mail] 58 Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 State-of-the-Art Review Section Editors: Grant T. Liu, MD Randy H. Kardon, MD, PhD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. hemiparesis and mental retardation). The only case with definite ONH from the literature cited by de Morsier was the case that had been previously documented by Reeves (3). It was from this compilation of disparate cases that an association of eye problems with agenesis of the septum pellucidum (i.e., SOD) was postulated. De Morsier believed that agenesis of the septum pelluci-dum and various ocular anomalies were "not fortuitous" associations (6). He hypothesized that the septum pelluci-dum served to connect the corpus callosum to the fornix and that lacking this supporting structure resulted in pene-tration of the chiasm by the third ventricle. This malforma-tion of the chiasm then somehow led to optic nerve or ocular anomalies. Three years following de Morsier's report, Gross and Hoff (7) reported their autopsy findings from 465 brains obtained from patients with severe neurologic problems or systemic malformations. They identified 13 brains with absence of the septum pellucidum. One of these had bilateral ONH and 7 (6 bilateral; 1 unilateral) had optic atrophy. They also FIG. 1. Appearance of ONH rendered by Schwarz in 1915. Reproduced with permission from Schwarz (2). FIG. 2. Air encephalogram from first case documenting absence of septum pellucidum in a child with ONH in 1941. Reproduced with permission from Reeves (3). FIG. 3. Photograph of Georges de Morsier (1894-1982) (courtesy of Avinoam Safran, MD, Geneva, Switzerland). FIG. 4. Histologic coronal section through the posterior optic chiasm demonstrates downward displacement and vertical rotation of the left optic tract (arrow) and cystic opening in floor of the third ventricle (V3). This is from the case that de Morsier called "septo-optic dysplasia." Reproduced with permission from de Morsier (5). Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 59 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. identified 12 cases of partial or complete corpus callosum agenesis. Two of these had microphthalmos with bilateral optic atrophy and 1 had unilateral ONH. Thus, prior to 1970, only 2 cases of ONH associated with absence of the septum pellucidum had been described in the medical literature, and neither of these had been identified by de Morsier. In 1970, Ellenberger and Runyan (8) described a 23- year-old woman with unilateral ONH, absent septum pel-lucidum, and dwarfism. In the same year, Dr William Hoyt wrote the landmark article recognizing the association of ONH with growth hormone (GH) deficiency and predicted the absent septum pellucidum in the case reported by Ellen-berger and Runyan. Hoyt et al (9) described 9 patients with ONH and pituitary dwarfism, 4 of whom were missing the septum pellucidum. They generously, but erroneously, attrib-uted recognition of the association of ONH with agenesis of the septum pellucidum to de Morsier and resurrected the term "septo-optic dysplasia," which is now commonly referred to as de Morsier syndrome. "Hoyt syndrome" would be a more appropriate eponym, particularly since the association of ONH with hypopituitarism, not septum pellucidum agen-esis, is the clinically important observation. De Morsier would scarcely have recognized the attribution to himself. Trained as a psychiatrist under de Clérambault, he spent his career at the University of Geneva. Lacking a suitable neuropathologist replacement after the death of Edouard Long, de Morsier was enjoined to lecture in neuropathology for 1 h/wk starting in 1933, during which time he attempted to catalog the various craniodysraphisms. Ultimately, he was appointed as head of neurology in 1960, a position that he held until his retirement in 1964. Arguably, de Morsier's greatest con-tribution to medicine was his description of the Charles Bonnet syndrome, which he named after the 19th cen-tury naturalist, who in 1760 had documented the visual hallucinations of his grandfather (10). There is no record of de Morsier ever identifying a case of ONH. PREVALENCE ONH has been recognized as an increasingly frequent cause of congenital blindness affecting one or both eyes. In 1997, bilateral ONH surpassed retinopathy of prematurity as the single leading cause of infant blindness in Sweden (11). Only cortical visual impairment of multiple etiologies was more common than ONH in blind children. The preva-lence of ONH in Sweden quadrupled between 1980 and 1999 to 7.1 per 100,000, while all other causes of child-hood blindness declined as diagnosed by the same major ophthalmic center (12). In 2006, the prevalence of ONH in England had risen to 10.9 per 100,000 children (13). Owing to incomplete registries of blindness, the preva-lence of ONH in North America is unknown. Prior to 1970, it was considered rare. In fact, prior to 1962, only 1 case had been diagnosed in British Columbia, Canada, but 20 cases were subsequently diagnosed by 1974, for an esti-mated prevalence of 1.8 per 100,000 (14). Acers noted a sim-ilar increase in the incidence of reported cases in the 1970s (15). ONH was identified in 12% of blind infants in Harris County in Texas in the early 1980s (16). Surveys of schools for the blind in the United States in 1999 revealed that ONH accounted for 5.7% to 12.9% of blind students (17,18). Such surveys underestimate the actual prevalence because cognitive or behavioral impairments exclude most children with ONH from schools for the blind. In 2007, the Babies Count registry reported ONH as the third most prevalent cause (behind cortical vision impairment and retinopathy of prematurity) of any vision impairment in children aged 3 years or younger in the United States (19). Of all conditions, ONH was the most likely to cause legal blindness. NEUROIMAGING Septum Pellucidum Following the resurrection of "SOD" by Hoyt et al, absence of the septum pellucidum garnered inappropriate dogmatic significance. Its association with pituitary dysfunction was documented in retrospective studies hampered by ascertain-ment bias (20,21). Other studies refuted the association, even to the point of showing no association of any adverse outcome with agenesis of the septum pellucidum (22-24). Indeed, as with de Morsier's experience, most cases of agen-esis of the septum pellucidum are detected accidentally and not associated with optic nerve or hormone problems. The prevalence of absent septum pellucidum in the general pop-ulation is unknown. In the only prospective study of ONH, absence of the septum pellucidum was not associated with laterality of ONH, vision, pituitary dysfunction, or devel-opmental outcome (25,26). Nonetheless, the term "septo-optic dysplasia" has persisted and its definition has evolved to include midline brain abnor-malities, such as hypoplasia of the corpus callosum or pitui-tary anomalies on MRI, in addition to absent septum pellucidum. This definition has served to focus investigators on morphogenetic mechanisms. It disregards the fact that a small corpus callosum frequently denotes hemispheric dis-ease and that most neuroradiographic abnormalities associated with ONH are not midline (26). These include hydroceph-alus, white matter hypoplasia, cortical heterotopia, pachygy-ria, polymicrogyria, schizencephaly, and arachnoid cysts. Rather than reassessing the appropriateness of the nomencla-ture, investigators recognizing these nonmidline findings sim-ply expanded the terminology to include "SOD plus" as a more severe expression on the spectrum of ONH (27). Corpus Callosum Corpus callosum hypoplasia is the most prevalent neuro-imaging abnormality associated with ONH (Fig. 5). It is 60 Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. commonly associated with absence of the septum pelluci-dum; however, absence of the septum pellucidum cannot serve as a surrogate for corpus callosum hypoplasia, as par-tial agenesis of the corpus callosum may not be associated with absence of the septum pellucidum. Corpus callosum hypoplasia has been associated with developmental delay but not with hypopituitarism in children with ONH (26). Corpus callosum hypoplasia is detected in 1.8 to 2.05 per 10,000 live births and in 2.3% of developmentally disabled individuals (28,29). Forty-nine percent of patients with cor-pus callosum hypoplasia have other central nervous system abnormalities, including nonmidline defects typically associ-ated with ONH (cortical heterotopias, schizencephaly, white matter hypoplasia, polymicrogyria) (28). However, ONH occurs in less than 10% of children with corpus callosum hypoplasia (29). Corpus callosum hypoplasia is associated with a myriad of syndromic conditions and chromosomal abnormalities, but pituitary dysfunction in those without ONH is uncommon (30). Although both ONH and corpus callosum hypoplasia may be the consequence of more gen-eralized problems with CNS development, the presence of ONH appears to be uniquely associated with hypothalamic dysfunction. Pituitary Gland Pituitary abnormalities on neuroimaging include empty sella, ectopic posterior pituitary, nonvisualized infundibulum and posterior pituitary. These findings occur in 13%-34% of children with ONH, and nearly all of those have hypopitu-itarism (26,31). However, hypopituitarism occurs in 75% of patients with ONH, the majority of whom have no pituitary abnormalities on neuroimaging. It is also interesting that absence of the posterior pituitary bright signal on T1 MRI has been associated with anterior pituitary function (31). However, most of these patients do not have diabetes insip-idus, as would be expected if vasopressin granules are the cause of the bright signal (32). Optic Nerve Attempts to diagnose ONH based on neuroimaging mea-surements of the optic nerve or chiasm have been promising (33,34). Such studies have been retrospective, lacked con-trols with normal and atrophic optic nerves, or failed to adjust for age in young patients. With continued improve-ment, it seems likely that high-resolution MRI could be used to distinguish ONH from optic atrophy. Assessment of the intracranial portion of the optic nerves is more reli-able for detecting ONH than assessment of the orbital component (35). CLINICAL DIAGNOSIS The diagnosis of ONH is made by ophthalmoscopic confirmation of a small optic disc. This may be difficult with the binocular indirect ophthalmoscope due to limited magnification. With inadequate resolution, small pale optic discs may be difficult to distinguish from the surrounding hypopigmented scleral canal and therefore misdiagnosed as normal-sized discs with optic atrophy. The optimal method for diagnosing ONH in a young child is with direct ophthalmoscopy. This is usually not difficult in visually impaired children who have minimal objection to the light or the proximity of the examiner, as long as the examiner does not touch the child's face. There are several fundu-scopic findings that assist the clinician in establishing the diagnosis of ONH. First, and most important, is an assess-ment of the area of the disc relative to the size of the central retinal vessels overlying it. Second, tortuous retinal arterioles, venules, or both may accompany ONH (Fig. 6). Alternatively, the vessels may be uncommonly straight with decreased branching (Fig. 7). Such a nonbranching vascular pattern has also been recog-nized in children with primary GH deficiency (36). It is not known if these vascular patterns in ONH correlate with endocrine dysfunction. FIG. 5. ONH is commonly associated with ectopic posterior pituitary (A) or other pituitary abnormalities. The corpus callosum may be normal (B) or hypoplastic (C). Hypoplastic corpus callosum is frequently associated with cortical dysgenesis, such as polymicrogyria (D). Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 61 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Finally, in patients with ONH, a ring of hypopigmen-tation or hyperpigmentation often, but not always, sur-rounds the disc defining the area of the putative scleral canal (Figs. 6, 7). This is presumably caused by migration of sensory retina and/or pigment epithelium from their origi-nal margin at the edge of the optic canal to a new position at the border of the hypoplastic optic disc (37). This "double ring" sign does not define ONH as a similar appearance may be present in other conditions, such as myopia. Although generally impractical, many authors have suggested that ONH can be confirmed with measurements of the optic disc from fundus photographs, particularly disc diameter (DD) or area relative to various retinal landmarks. In normal children, the ratio of the horizontal DD to the distance between the macula and the temporal edge of the disc (DM) is greater than 0.35 (25,38,39) (Fig. 7). DD/DM ratios less than 0.35 somewhat correlate with vision outcomes (40). Although most patients with DD/DM ratios less than 0.35 have generally been des-cribed as having ONH, some with DD/DM ratios of 0.30-0.35 have normal vision. Some overlap in optic disc size between normal and ONH is not surprising. The precise risk for systemic complications in these borderline cases has not been determined. De Silva et al (41) found that the average DD/DM ratio at birth of preterm, but otherwise normal, infants was 0.26. Compared with measurements from adults made by other investigators, they estimated that the DD increases 44% in a lifetime compared with increases in DM of only 11%. This results in increased DD/DM ratio with age. Therefore, the age of the patient may need to be considered when mea-suring DD/DM ratios. Attempts to diagnose ONH or predict vision from other imaging modalities, such as optical coherence tomography (OCT), have not been reported. Eyes with ONH may have a poorly developed foveal umbo on OCT in spite of a normal foveal appearance on ophthalmoscopic examination (42). The foveolar thickness is normal, but absence of the ganglion cell and nerve fiber layers results in a retina of uniform thick-ness, in which the umbo cannot be distinguished with OCT. Some authors have broadly defined ONH to include any optic disc with congenitally decreased neuronal area (43). As such, those eyes with a normal-sized optic discs, but with enlarged cups, would qualify as having ONH. This appear-ance typically occurs in premature infants with periventric-ular leukomalacia (44). Although such optic nerves have fewer than the normal number of axons and may be tech-nically hypoplastic, these children are not at risk for the same developmental and endocrinologic complications as children with small discs of typical ONH. They should, therefore, not be considered in the same diagnostic cate-gory. A similar argument can be made for eyes with major congenital malformations, such as microphthalmos, large colobomas, or persistent hyperplastic primary vitreous, which may consequently have small optic nerves. VISION Poor visual behavior is usually the first sign of ONH. Nystagmus usually develops at 1-3 months of age followed FIG. 6. Photograph of severe ONH (filled arrow) with a par-tially pigmented double ring (unfilled arrow) and tortuous vessels. FIG. 7. Photograph of mild ONH with DD/DM ratio of 0.23; hypopigmented double ring (unfilled arrow); straight vessels. 62 Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. by strabismus, typically esotropia, in the first year of life. Children with markedly asymmetric or unilateral ONH may present primarily with strabismus rather than nystag-mus. Patients with relatively symmetric hypoplasia may have asymmetric vision from superimposed amblyopia due to strabismus or anisometropia. Approximately 80% of children with ONH are bilaterally affected and two thirds of those are asymmetrically affected (26). The unilateral cases are usually detected at a later age than those with bilateral involvement. Children with unilat-eral ONH are at risk for hypothalamic/pituitary dysfunction (69%) and developmental delay (39%), although that risk is significantly lower than patients with bilateral ONH (81% and 78%, respectively) (25,26). Visual acuity ranges from no light perception to near normal. More than 80% of bilateral cases are legally blind (45). Most children experience some improvement in their vision in the first few years of life. This may be due to optic nerve myelination that occurs in the first 4 years of life, leading to improved axonal conduction (46). HYPOTHALAMIC DYSFUNCTION Hypothalamic dysfunction is the most common nonvisual problem in patients with ONH and results in loss of regulation of homeostatic mechanisms controlling behavior and pituitary gland function. Hypopituitarism In most cases of ONH, hypopituitarism is believed to be due to hypothalamic dysfunction rather than pituitary dysgenesis. Children with ONH and hypopituitarism usually have moderately elevated serum prolactin levels, as this hormone is normally suppressed by the hypothalamus. In a prospective study, hypopituitarism was not correlated with laterality of ONH (25). GH deficiency was the most common endocrinopathy (70%), followed by hypothyroid-ism (43%), adrenocorticotropic hormone deficiency (27%), and diabetes insipidus (5%). This high prevalence of endo-crinopathy is consistent with previous retrospective studies (47,48). Delayed or precocious puberty is common, but the incidence is unknown. Evolving pituitary dysfunction in children with ONH is poorly understood, but cases of acquired hypopituitarism have been reported (48,49). Normal pituitary function at the time of initial evaluation does not preclude development of endocrinopathy in the future. Thirst/Hunger Ventromedial nuclei within the hypothalamus suppress hunger and eating in response to leptin, whereas lateral hypothalamic nuclei stimulate feeding behavior and regulate metabolism (50). Children with ONH frequently exhibit hyperphagia with obesity or hypophagia, with or without wasting. Some children also have an aversion to certain textures of food. Water-seeking behavior (and consequent enuresis) is also common and may be mistakenly attributed to diabetes insipidus. Sleep The biological clock is generated within the suprachiasmatic nuclei of the anterior hypothalamus above the optic chiasm. These nuclei receive photic information via the optic nerves to synchronize the clock to the 24-hour light-dark cycle. The circadian pacemaker is reset each day with visual stim-ulation (51-53). Disturbance of the circadian system can have significant pernicious effects on physiology and behavior (54,55). Many children with ONH have sleep or wakefulness disturbances over the 24-hour day (56,57). Alternatively, they may have inadequate retinohypothalamic input to daily entrain the circadian clock, resulting in free-running sleep-wake cycles asynchronous with other family mem-bers. In either case, such sleep irregularities commonly result in behavioral difficulties and disruption of family life. Temperature Regulation The medial preoptic region of the hypothalamus is involved in body temperature regulation and, through communication with the paraventricular nucleus, regulates fever response (58). It is not surprising that many infants and children with ONH have problems with body temperature regulation and may be frequently hospitalized to rule out sepsis (59). DEVELOPMENTAL OUTCOMES In 1984 Margalith et al (60) were the first to report devel-opmental delays in ONH, estimating neuropsychological handicaps in nearly three fourths of cases of ONH. Burke et al (61) estimated delayed development, based on neuro-logic examination, at a similar frequency. Observations of developmental delay in association with ONH range from isolated focal defects to global delay (62,63). Garcia-Filion et al (26) found developmental delays in 71% of ONH patients using standardized neuropsychological instruments in a prospective study. Motor delays were the most common (75%) and communication delays were the least common (44%). Independent risk factors for significantly delayed cog-nitive and overall development included hypoplasia of the corpus callosum and hypothyroidism but not absence of the septum pellucidum. Developmental delay occurred in unilateral (39%) and bilateral (78%) cases of ONH. Autism spectrum disorders are overrepresented in the visually impaired population, with prevalence estimates up to 25% in children (64). The prevalence of autism appears even higher in children with ONH. In a group of 13 Swedish children with ONH and blindness, 6 had autism and 3 had an "autistic-like" condition (65). Parr et al (66) reported that, in a sample of 83 children with ONH and moderate to severe vision impairment (worse than 6/30), 37% (31 of 83) had social, communicative, and repetitive or restricted Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 63 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. behavioral difficulties and the majority of those (26 of 31) had a clinical diagnosis of autism spectrum disorder. Precise prevalence estimates of autism require modifications of the autism diagnostic instruments for visually impaired subjects. Such modifications have not yet been validated. PATHOGENESIS AND GENETICS The presumed association of midline cerebral defects with ONH has led to a focus on the genetic mechanisms involved in division of the prosencephalon into cerebral hemispheres and formation of the pituitary gland. Several candidate genes have been identified as responsible for cases of septo-otpic dysplasia. These include mutations of HESX1 associated with holoprosencephaly and SOX2 associated with anterior pituitary hypoplasia and hypogo-nadism. Only 5 cases of ONH in humans have been associated with the HESX1 mutation (67,68). Some of these were in cases of severe forebrain malformation, such as alobar holoprosencephaly (69). Such major malforma-tions would be expected to impact the development of subsequent structures, such as the optic nerves, corpus cal-losum, and septum pellucidum. The vast majority of cases of ONH cannot be attributed to specific mutations. In fact, less than 1% of cases of ONH in large series were found to have an HESX1 mutation, and none were found to have SOX2 mutations (70,71). The dearth of families with more than 1 affected child and the lack of substantiated reports of transgenerational transmission argue against a hereditable cause for most cases of ONH. Fundus photographs from the only mul-tigenerational report are not convincingly representative of ONH (72). There have been no reports of affected iden-tical twins. PRENATAL RISK FACTORS Lack of definitive genetic associations has led to a search for prenatal environmental or biological risk factors for the development of ONH. Nearly all prenatal associations with ONH originate from retrospective review of records or anecdotal reports. The most commonly reported asso-ciations include young maternal age and/or primiparity (60,68,70,73,74), maternal use of recreational drugs (8 total cases) (13,45,60,75,76), anticonvulsants (9 total cases) (59,75,77), antidepressants (3 total cases) (20,73,78), and viral infections during pregnancy (4 total cases) (60,61,79). In small case series, ONH has been reported in 25%-48% of children with fetal alcohol syndrome (80,81), but in large series of near-consecutive cases of ONH, any prenatal alco-hol exposure was reported in 6%-33%, and there were no reports of excessive prenatal alcohol consumption (82,83). Two studies have systematically and sequentially inves-tigated prenatal correlates in large cohorts of patients with ONH. The first was a case-control study of 100 severe bilateral cases in Sweden, and data were obtained from interviews conducted in the first trimester of pregnancy by a variety of midwives (73). Those data have the advan-tage of being relatively unbiased by recall or pregnancy outcomes but have the disadvantage of not capturing asso-ciations that may have occurred after the interview. That study found increased risk with young maternal age, primi-parity, and early prenatal smoking exposure but not with drug or alcohol exposure. The second study used a postnatal questionnaire and compared exposures with national registry data from preg-nant women during the same period (83). This study con-firmed that young maternal age and primiparity were independent risk factors but refuted an association with tobacco, alcohol, or drug exposure. In addition, it suggested prenatal maternal weight loss or poor weight gain and pre-mature labor (without premature birth) as additional risk factors. MANAGEMENT Since ONH is particularly associated with abnormal hypothalamic function, physicians should be vigilant for signs of hypothalamic dysfunction along with any vision problems in children and vice versa. All neonates with jaundice and recurrent hypoglycemia should have oph-thalmoscopic evaluation, especially if associated with tem-perature instability. Similarly, all infants with poor visual behavior, strabismus, or nystagmus by 3 months of age should have an ophthalmoscopic examination to rule out ONH. Once ONH is confirmed ophthalmoscopically, MRI of the brain should be obtained. The MRI can rule out treatable conditions such as hydrocephalus but can also be used to anticipate developmental delay associated with corpus callosum hypoplasia or other major malformations. Findings of schizencephaly or polymicrogyria should prompt neurologic examination in anticipation of focal deficits or seizures. In the past, MRI of the brain was used to identify absence of the septum pellucidum in order to determine the need for endocrinologic evaluation. This feature can now be disregarded, as all children with ONH regardless of the septum pellucidum status need pituitary function evaluated. Endocrinologic workup should include fasting morning cortisol and glucose, thyroid-stimulating hormone, free T4, and the GH surrogates-insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3). If the child is less than 6 months of age, luteinizing hormone, follicle-stimulating hormone, and/or testosterone levels should be checked in order to anticipate delayed sexual development. Beyond 6 months of age, sex hormones are not normally produced until puberty, and thus cannot be tested. Micro-penis, also a harbinger of delayed puberty, can be treated with testosterone during infancy. 64 Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Children should be monitored at least semi-annually for growth. With growth deceleration, thyroid function tests should be repeated and provocative GH testing should be performed. These should also be done if IGF-1 or IGFBP-3 is low, even if the child is growing normally. Free T4 should be rechecked at least semi-annually until 2 years of age and annually thereafter until at least 4 years of age. If fasting morning cortisol is low, it should be repeated or provocative testing for cortisol should be done. This can often be done simultaneously with GH testing, using glucagon as the provocative agent. Children with inade-quate cortisol response to provocative tests should be given both oral and injectable forms of glucocorticoids for admin-istration during illness or physical stress. Occupational, physical, and/or speech therapy are fre-quently needed by children with ONH. Attention should especially be given to early development of oral motor skills and acclimation to textured foods for those children resis-tant to eating. Incorporating dialogue into song can some-times ameliorate delayed verbal communication. Children with autistic behaviors should be evaluated by a neuropsychologist skilled in autism assessment as well as experienced in dealing with visually impaired children. Lacking such experience, the autism expert should enlist assistance from a teacher for the visually impaired to appropriately modify the testing instruments. Sleep dysre-gulation can sometimes be alleviated by entraining the circadian clock with low doses (0.1-0.5 mg) of melatonin in the evening or, alternatively, with soporific doses (3-5 mg) at bedtime (56). The vision of young children with ONH should be monitored at least annually, and any refractive errors should be treated when the visual acuity reaches a functional level. Patching of the better eye can result in improvement of vision in the worse eye. However, if the ONH is asymmetric, maintenance of improved vision requires prolonged patching that can be disruptive to development in a child with many other handicaps. Thus, amblyopia therapy should be reserved for those cases in which the potential vision in each eye is felt to be fairly good. Children with unilateral or markedly asymmetric ONH should not be treated with patching. Early surgical correction of strabismus should be reserved for children who have symmetrical functional vision in the eyes, and thus some potential for binocularity. Otherwise, correction of strabismus should be deferred until it is an impending psychosocial issue. CONCLUSIONS ONH is an increasingly prevalent, probably nonhereditary, cause of congenital blindness that is the unifying feature of a syndrome that usually includes developmental, hypotha-lamic, and/or neuroanatomical abnormalities. The first recognized association was with absence of the septum pellucidum, yet it has now been shown that this is the least significant, and least prognostic, of the associated abnor-malities. The presence of ONH imparts risk for serious systemic and neurologic problems that need to be carefully monitored. Focus on the septum pellucidum has distracted physicians from the serious and complicated nature of the syndrome. "Septo-optic dysplasia" and "de Morsier syn-drome" are inappropriate and historically inaccurate terms that should be abandoned. REFERENCES 1. Briere W. Absence des papiller, cecite absolue. Ann Ocul. 1877;78:41-42. 2. Schwarz O. Ein Fall von mangelhafter Bildung beider Sehnerven. Albrecth von Graefes Arch Klin Ophthalmol. 1915;90:326-328. 3. Reeves D. Congenital absence of the septum pellucidum. Bull Johns Hopkins Hosp. 1941;69:61-71. 4. Straatsma BS. S. Rodman Irvine, MD. Trans Am Ophthalmol Soc. 2000;98:9-10. 5. de Morsier G. Etudes sur les dysraphies cranio-encephaliques: agenesis du septum lucidum avec malformation du tractus optique. La dysplasie septo-optique. Schweiz Arch Neurol Psychiatr. 1956;77:267-292. 6. De Morsier G. Median cranioencephalic dysraphias and olfactogenital dysplasia. World Neurology. 1962;3:485-504. 7. Gross H, Hoff H. Sur les malformations ventruculaires dependantes des dysgenesies commisurales. In: Heuyer G, Feld M, Gruner J, eds. Malformations congentales du cerveau. Paris, France: Masson, 1959:329-351. 8. Ellenberger C, Runyan TE. Holoprosencephaly with hypoplasia of the optic nerves, dwarfism, and agenesis of the septum pellucidum. Am J Ophthalmol. 1970;70:960-967. 9. Hoyt WF, Kaplan SL, Grumbach MM, Glaser JS. Septo-optic dysplasia and pituitary dwarfism. Lancet. 1970;1:893-894. 10. Hedges TR. Charles Bonnet, his life, and his syndrome. Surv Ophthalmol. 2007;52:111-114. 11. Blohme J, Tornqvist K. Visual impairment in Swedish children. III. Diagnoses. Acta Ophthalmol Scand. 1997;75:681-687. 12. Blohme J, Bengtsson-Stigmar E, Tornqvist K. Visually impaired Swedish children. Longitudinal comparisons 1980-1999. Acta Ophthalmol Scand. 2000;78:416-420. 13. 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. 14. Jan J, Robinson G, Kinnis C, McLeod PJ. Blindness due to optic-nerve atrophy and hypoplasia in children: an epidemiological study (1944-1974). Dev Med Child Neurol. 1977;19:353-363. 15. Acers TE. Optic nerve hypoplasia: septo-optic-pituitary dysplasia syndrome. Trans Am Ophthalmol Soc. 1981;79:425-457. 16. 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. 17. DeCarlo DK, Nowakowski R. Causes of visual impairment among students at the Alabama School for the Blind. J Am Optom Assoc. 1999;70:647-652. 18. Mets MB. Childhood blindness and visual loss: an assessment at two institutions including a "new" cause. Trans Am Ophthalmol Soc. 1999;97:653-696. 19. 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. 20. Birkebaek N, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 65 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003;88:5281-5286. 21. Patel H, Tze WJ, Crichton JU, McCormick AQ, Robinson GC, Dohnan CL. Optic nerve hypoplasia with hypopituitarism. Septo-optic dysplasia with hypopituitarism. Am J Dis Child. 1975;129:175-180. 22. Williams J, Brodsky MC, Griebel M, Glasier CM, Caldwell D, Thomas P. Septo-optic dysplasia: the clinical insignificance of an absent septum pellucidum. Dev Med Child Neurol. 1993;35:490-501. 23. Wilson DM, Enzmann DR, Hintz RL, Rosenfeld G. Computed tomographic findings in septo-optic dysplasia: discordance between clinical and radiological findings. Neuroradiology. 1984;26:279-283. 24. Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol. 1993;111:66-74. 25. 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;148:78-84. 26. 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. 27. Miller SP, Shevell MI, Patenaude Y, Poulin C, O'Gorman AM. Septo-optic dysplasia plus: a spectrum of malformations of cortical development. Neurology. 2000;54:1701-1703. 28. Glass HC, Shaw GM, Ma C, Sherr EH. Agenesis of the corpus callosum in California 1983-2003: a population-based study. Am J Med Genet A. 2008;146A:2495-2500. 29. Szabó N, Gergev G, Kobor J, Bereg E, Turi S, Sztriha L. Corpus callosum anomalies: birth prevalence and clinical spectrum in Hungary. Pediatr Neurol. 2011;44:420-426. 30. Schell-Apacik CC, Wagner K, Bihler M, Erti-Wagner B, Heinrich U, Klopocki E, Kalscheuer VM, Muenke M, vonVoss H. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients. Am J Med Genet A. 2008;146A:2501-2511. 31. Phillips PH, Spear C, Brodsky MC. Magnetic resonance diagnosis of congenital hypopituitarism in children with optic nerve hypoplasia. J AAPOS. 2001;5:275-280. 32. Kucharczyk W, Lenkinski RE, Kucharczyk J, Henkelman RM. The effect of phospholipid vesicles on the NMR relaxation of water: an explanation for the MR appearance of the neurohypophysis? AJNR Am J Neuroradiol. 1990;11:693-700. 33. Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature. J Pediatr. 2004;145:536-541. 34. Hellström A, Wiklund LM, Svensson E. Diagnostic value of magnetic resonance imaging and planimetric measurement of optic disc size in confirming optic nerve hypoplasia. J AAPOS. 1999;3:104-108. 35. Brodsky MC, Glasier CM, Pollock SC, Angtuago EJ. Optic nerve hypoplasia: identification by magnetic resonance imaging. Arch Ophthalmol. 1990;108:1562-1567. 36. Hellstrom A, Svensson E, Carlsson B, Niklasson A, Albertsson-Wikland K. Reduced retinal vascularization in children with growth hormone deficiency. J Clin Endocrinol Metab. 1999;84:795-798. 37. Mosier MA, Lieberman MF, Green WR, Knox DL. Hypoplasia of the optic nerve. Arch Ophthalmol. 1978;96:1437-1442. 38. Borchert M, McCulloch D, Rother C, Stout AU. Clinical assessment, optic disk measurements, and visual-evoked potential in optic nerve hypoplasia. Am J Ophthalmol. 1995;120:605-612. 39. Zeki SM, Dudgeon J, Dutton GN. Reappraisal of the ratio of disc to macula/disc diameter in optic nerve hypoplasia. Br J Ophthalmol. 1991;75:538-541. 40. McCulloch DL, Garcia-Filion P, Fink C, Chaplin CA, Borchert MS. Clinical electrophysiology and visual outcome in optic nerve hypoplasia. Br J Ophthalmol. 2010;94:1017-1023. 41. De Silva DJ, Cocker KD, Lau G, Clay ST, Fielder AR, Moseley MJ. Optic disk size and optic disk-to-fovea distance in preterm and full-term infants. Invest Ophthalmol Vis Sci. 2006;47:4683-4686. 42. Srinivasan G, Venkatesh P, Garg S. Optic nerve head, retinal nerve fiber layer, and macular thickness characteristics on optical coherence tomography in optic disk hypoplasia. J Pediatr Ophthalmol Strabismus. 2007;44:140-141. 43. Jacobson L, Hellstrom A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol. 1997;115:1263-1269. 44. Brodsky MC. Periventricular leukomalacia: an intracranial cause of pseudoglaucomatous cupping. Arch Ophthalmol. 2001;119:626-627. 45. Siatkowski R, Sanchez J, Andrade R, Alvarez A. The clinical, neuroradiographic, and endocrinologic profile of patients with bilateral optic nerve hypoplasia. Ophthalmology. 1997;104:493-496. 46. Magoon EH, Robb RM. Development of myelin in human optic nerve and tract. A light and electron microscopic study. Arch Ophthalmol. 1981;99:655-659. 47. Reidl S, Mullner-Eidenbock A, Prayer D, Bernert G, Frisch H. Auxological, ophthalmological, neurological and MRI findings in 25 Austrian patients with septo-optic dysplasia (SOD). Horm Res. 2002;58(suppl 3):16-19. 48. Haddad NG, Eugster EA. Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab. 2005;18:853-858. 49. Ma NS, Geffner ME, Borchert M. Evolving central hypothyroidism in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab. 2010;23:53-58. 50. Elmquist JK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Physiol Behav. 2001;74:703-708. 51. Moore RY. Circadian rhythms: basic neurobiology and clinical applications. Annu Rev Med. 1997;48:253-266. 52. Panda S, Hogenesch JB, Kay SA. Circadian rhythms from flies to human. Nature. 2002;417:329-335. 53. Weaver DR. The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms. 1998;13:100-112. 54. Edgar DM, Dement WC, Fuller CA. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci. 1993;13:1065-1079. 55. Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers. N Engl J Med. 1983;309:469. 56. Rivkees SA. Arrhythmicity in a child with septo-optic dysplasia and establishment of sleep-wake cyclicity with melatonin. J Pediatr. 2001;139:463-465. 57. Rivkees S, Fink C, Nelson M, Borchert M. Prevalence and risk factors for disrupted circadian rhythmicity in children with optic nerve hypoplasia. Br J Ophthalmol. 2010;94:1358-1362. 58. Scammell TE, Elmquist JK, Griffin JD, Saper CB. Ventromedial preoptic prostaglandin E2 activates fever-producing autonomic pathways. J Neurosci. 1996;16:6246-6254. 59. McMahon C, Braddock S. Septo-optic dysplasia as a manifestation of valproic acid embryopathy. Teratology. 2001;64:83-86. 60. 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. 61. Burke J, O'Keefe M, Bowell R. Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol. 1991;75:236-239. 66 Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 62. Garcia ML, Ty EB, Taban M, David Rothner A, Rogers D, Traboulsi EI. Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol. 2006;21:949-956. 63. Griffiths P, Hunt S. Specific spatial defect in a child with septo-optic dysplasia. Dev Med Child Neurol. 1984;26:395-400. 64. Brown R, Hobson RP, Lee A, Stevenson J. Are there "autistic-like" features in congenitally blind children? J Child Psychol Psychiat. 1997;36:693-703. 65. Ek U, Fernell E, Jacobson L. Cognitive and behavioural characteristics in blind children with bilateral optic nerve hypoplasia. Acta Paediatrica. 2005;94:1421-1426. 66. Parr JR, Dale NJ, Shaffer LM, Salt AT. Social communication difficulties and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia. Dev Med Child Neurol. 2010;52:917-921. 67. Tajima T, Hattorri T, Nakajima T, Okuhara K, Sato K, Abe S, Nakae J, Fujieda K. Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab. 2003;88:45-50. 68. Webb EA, Dattani MT. Septo-optic dysplasia. Eur J Hum Genet. 2010;18:393-397. 69. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC. Mutations in the homeobox gene HESX1/Hesx1 associate with septo-optic dysplasia in human and mouse. Nat Genet. 1998;19:125-133. 70. McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R, Papadimitriou A, Keller E, Keller A, Haufs N, Krude H, Shalet SM, Dattani MT. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92:691-697. 71. Mellado C, Poduri A, Gleason D, Elhosary PC, Barry BJ, Partlow JN, Chang BS, Shaw GM, Barkovitch AJ, Walsh CA. Candidate gene sequencing of LHX2, Hesx1, and SOX2 in a large schizencephaly cohort. Am J Med Genet A. 2010;1562A:2736-2742. 72. Hackenbruch Y, Meerhoff E, Besio R, Cardoso H. Familial bilateral optic nerve hypoplasia. Am J Ophthalmol. 1975;79:314-320. 73. Tornqvist K, Ericsson A, Kallen B. Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand. 2002;80:300-304. 74. Murray PG, Paterson WF, Donaldson MD. Maternal age in patients with septo-optic dysplasia. J Pediatr Endocrinol Metab. 2005;18:471-476. 75. Hoyt C, Billson F. Maternal anti-convulsants and optic nerve hypoplasia. Br J Ophthalmol. 1978;62:3-6. 76. Hotchkiss M, Green W. Optic nerve aplasia and hypoplasia. J Pediatr Ophthalmol Strabismus. 1979;16:225-240. 77. West J, Burke J, Strachan I. Carbamazepine, epilepsy, and optic nerve hypoplasia. Br J Ophthalmol. 1990;74:511. 78. Hellstrom A, Wiklund L, Svensson E. The clinical and morphological spectrum of optic nerve hypoplasia. J AAPOS. 1999;3:212-220. 79. Hittner H, Desmond M, Montgomery J. Optic nerve manifestations of cyto-megalovirus infection. Am J Ophthalmol. 1976;81:661-665. 80. Stromland K. Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol. 1987;31:277-284. 81. Ribeiro IM, Vale PJ, Tenedorio PA, Rodrigues PA, Bilhoto MA, Pereira HC. Ocular manifestations in fetal alcohol syndrome. Eur J Ophthalmol. 2007;17:104-109. 82. Roberts-Harry J, Green S, Willshaw H. Optic nerve hypoplasia: associations and management. Arch Dis Child. 1990;65:103-106. 83. Garcia-Filion P, Fink C, Geffner M, Borchert M. Optic nerve hypoplasia in North America: a re-appraisal of perinatal risk factors. Acta Ophthalmol Scand. 2010;88:527-534. Borchert: J Neuro-Ophthalmol 2012; 32: 58-67 67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. [KBDdcaopticnervehypoplasia]