Optic Nerve Hypoplasia (ONH)
The Spectrum with a Practical Approach
Revised for MacFarland Seminar
International AER meeting, Jacksonville, Florida
July 20, 2016
Linda Lawrence MD
Jane Edmonds MD
(Note: this information relies on Dr. Mark Borchert’s work at CHLA and his publications. Any omissions or errors however are ours)
Introduction:
The Optic Nerve Hypoplasia (ONH) is a Spectrum Disorder
What is the current knowledge of ONH, and how do we apply this practically for our babies, students and families to enhance learning, independence, and quality of life?
All persons are unique regardless of abilities or diagnoses.
No two persons with ONH or the spectrum of ONH are the same.
ONH is emerging as a leading single ocular (or brain?) causes of childhood blindness and visual impairment in the USA and Europe.
Clinically there are small optic nerves by ophthalmoscopic examination of the eyes.
One or both nerves may be affected.
ONH is rarely isolated, more often is part of other functional and anatomical abnormalities of the central nervous system. There is a diverse impact on growth and development.
There is an increasing frequency of the spectrum of ONH for uncertain reasons.
Definitions: What is Optic Nerve Hypoplasia (ONH)?
Definition of HYPOPLASIA:
“a condition of arrested development in which an organ or part remains below the normal size or in an immature state “
The optic nerve is a collection of thousand of nerve fibers transmitting signals from the eye to the brain where you “see”.
ONH is a congenital anomaly of the optic nerve(s), confined to the ganglion cells, the optic nerve is underdeveloped, and there is excessive loss of neurons before the nerve is fully developed. This happens in utero.
ONH is a non-progressive condition. The nerve(s) may just be “small” and not dysplastic (formed abnormally).
ONH is often confused with optic nerve atrophy (ONA), or “pallor”, or “pale nerve”.
Anatomy
Eye
Optic Nerve: a collection of thousands of nerve fibers that transmit visual signals from each eye to the brain. It is the only cranial nerve directly synapses with the brain.
Optic disc: refers to the portion of the optic nerve visible with the ophthalmoscope by looking inside the eye.
“Cup” refers to the indention in the center of the “disc” or the optic nerve head.
Diagnosis: how is ONH diagnosed?
Small optic disc must be made by direct ophthalmoscopy, clinically.
Newer scanning methods may change this (OCT).
1. Ophthalmic findings: disc diameter measurements based on photographs. Disc area or diameter in relationship to retinal vessels or distance to macula, the distance from the temporal nerve to the center of the macula ratio is measured.
2. (About 3 optic nerves should fit in this space, if more fit, and then the nerve is small.) May have a pigmented ring partially pigmented, or no ring.
3. What about the kids with enlarged cups and thin rims? This occurs in infants with PVL (peri-ventricular leukomalacia). They are “hypoplastic” because have fewer than normal number of axons, but these children not at same risks for developmental consequences as those with “typical “ONH.
4. Ophthalmologist examines because of decreased vision or referral from neonatologist.
5. Neonatologist sees baby because of unstable course in the nursery.
6. Both may see because part of syndrome.
7. Not associated with prematurity.
Histology: scarce
Neuro-anatomy:
1. Optic chiasm: located in the forebrain directly in front of the hypothalamus. The left and right optic nerves intersect at the chiasm; half of each nerve’s axons enter the opposite tract at this location.
2. Pituitary gland: Lies in pocket of skull called sella turcica and connected to the hypothalamus by the pituitary stalk; there is an anterior and posterior gland.
3. Hypothalamus: Located in the midbrain, between the cerebral hemispheres, the hypothalamus is the body’s regulatory center. It is not much bigger than the end of your little finger. It helps as a regulatory center for the autonomic nervous system, blood pressure, pulse, breathing, sweating, digestion, arousal and more. It also regulates the endocrine system for control of growth, metabolism, and reproduction. Its main job is the “Balancer”. It is part of the limbic system that gathers sensory data to generate emotional responses. Diurnal rhythms are controlled here. The MRI might look normal, as we do not have the technology to image this area yet.
4. Optic tracts: continuation of the optic nerves out after the chiasm, relays information from the optic chiasm to the lateral geniculate nucleus (LGN). The fibers leave the LGN in the optic radiations to the occipital lobe.
5. Occipital Lobe: This is the smallest but most important of the brain’s 4 lobes. It focuses on vision. Injury may result in difficulty with reading, identification of color, locating nearby objects, interpreting drawings, recognizing words, distorted vision and hallucinations
6. Septum pellucidum: runs from corpus callosum to fornix, separates lateral ventricles, very little function
7. Corpus callosum: transmits information between the brain’s right and left hemisphere. Highway of thick band of 200 million nerve fibers. If absent (agenesis), the two hemispheres of the brain cannot communicate typically. Agenesis means partly developed or absent altogether (Birth defect). This is a clue that there may be cognitive disabilities.
8. Pineal body: controls internal clock, circadian rhythms, by secreting melatonin
Endocrine function:
Corpus callosum or septum pellucidum abnormalities are not associated with hypopituitarism.
Only 9% have abnormal pituitary gland on MRI, but incidence of hypopituitarism much higher
In the neonatal period, neonatal jaundice, hypoglycemia, apnea, or seizure, failure to thrive or delayed development may signal endocrine dysfunction.
Older children can have a spectrum of problems related to endocrine dysfunction. Hypothalamic dysfunction causing poor sleeping and eating may disrupt school day and family life.
What causes ONH?
History
1. Who was De Morsier? Coined term septo-optic dysplasia. Described an association of absent septum pellucidum with malformation of optic chiasm in an 84yo woman. He also described 8 other cases in the literature of agenesis of the septum pellucidum; this was his main area of interest. The descriptions of the optic nerves was not done, visual complaints not documented, nor ophthalmoscopic abnormalities documented.
2. What does Septo-optic dysplasia mean? ONH with absence of septum pellucidum, may also have dysgenesis of corpus callosum
3. Hoyt’s contributions: 1970 described pituitary dwarfism in 9 cases of ONH, 4 with missing septum pellucidum , called septo-optic-pituitary
4. Current research
It is now known that absence of the septum pellucidum does not impart risks for the collection of problems found with ONH, and that associated problems are due to miswiring of the brain, especially in the hypothalamus which may not be detected with neuroimaging
5. In 50 years of epidemiologic research, there has been little progress in the identification of causes of ONH.
Prevalence
Poor documentation, unknown. Is the increase because of increased detection sensitivity?
1. 12% of blind infants in Harris Co. in early 1980s had ONH.
2. Surveys for Schools for the blind in USA reveal prevalence of 5.7% to 12.9% of blind children. This may underestimate.
3. Babies Count Sept 2012 national data (APH, personal communication Dr. Hatton) 679 of 5,953 children or 11% of sample with ONH
Epidemiology
Prenatal Risk Factors
Likely multi-factorial involving gene-environmental interaction: gene variants modify susceptibility to “injury” that influences biological response/growth.
So there is a combination of factors that interrupt early brain and optic nerve development during a window of time in gestation when there is high vulnerability of this developing system.
1. Genetic risks: there are genetic mutations. Only HESX1 reported to affect optic nerve development as well as anterior pituitary gland formation in humans. This is less than 1% of a large sample of ONH.
2. All ethnic groups, but in USA lower in persons of Asian decent
3. Male/female ratios reported variable, but other studies no gender predilection
4. Gestational and exposure history: Numerous reports of perinatal and prenatal risk factors. Only significant are young maternal age and primiparity. Could youth be a surrogate for multiple health and demographic factors? Primiparity, unclear significance. Risky behavior, this has not been shown to be significant. Literature reviews show:
A. Risk factors based on anecdotal reports (recreational drugs, prescription drugs, infectious agents), none statistically significant
B. Risk factors based on case series or epidemiologic studies: UK study (6. P. 613) showed positive correlation with unemployment, low- income household, and teenage pregnancy.
5. Few familial cases and lack of monozygotic twins argues against an inheritable cause.
6. Spatial (geographical) clusters: this has not been published yet. Even if we find there are spatial clusters, not sure of the significance, but may give us a better idea.
7. Prematurity and ONH
A. Early WMDI (white matter disease of infancy) before gestational week 28, may be associated with small optic discs, the ONH may result from trans-synaptic degeneration of optic nerve axons caused by primary bilateral lesions in optic radiations.
B. Normal size optic nerves with large cupping and reduced neuronal rim area with later lesions after 28 weeks. The supportive structures of optic nerve already established, so the size of disc may not be reduced.
C. In children after 33-34 weeks, optic nerve normal size.
In summary: we don’t know what causes ONH!
Clinical Association
Visual Acuity:
Quality of the Image
Visual Acuity: no light perception to near normal.
One or both eyes may be affected. 80% bilateral. 2/3 asymmetrical.
Cannot predict the vision from the clinical or radiological appearance of the optic nerves, nor from the initial exam.
Electrophysiology: ERG may be normal, not helpful
80% legally blind.
May have superimposed amblyopia (asymmetry in any part of the eye can cause strabismus, anisometropia, amblyopia).
First few years of life may have improvement in vision, reason uncertain, maybe because of improved axonal function due to optic nerve myelination in first 4 years of life; also we see improved use of residual vision with intervention and there may be overlapping cerebral visual impairment (CVI) which improves with interventions and time.
Decline in VA may not be noted in unilateral ONH unless there is associated strabismus with amblyopia.
Functional Vision:
1. Nystagmus: may be noted when both eyes affected, develops at 1-3 months of age.
2. Strabismus in first year of life, typically esotropia, those with unilateral present with strabismus rather than nystagmus
3. Variable visual field defects dependent on multiple factors including the extent of ONH, chiasmal involvement, optic tract involvement, or other brain involvement such as schizencephaly, effects from hydrocephalus
4. Variable color vision deficiency as in any other optic nerve disorder.
Non-visual
Isolated ONH is uncommon, even when neuro-imaging is normal.
There are associated developmental midline brain abnormalities.
Pituitary hormones may be affected due to defects in hypothalamus, infundibulum, or pituitary gland.
Unilateral ONH, 69% risk of hypothalamic/pituitary dysfunction, developmental delay 39%.
Bilateral ONH, 81% hypothalamic/pit dysfunction, developmental delay 78%.
Hypothalamic dysfunction
Loss of regulation of homeostatic mechanisms controlling behavior and pituitary gland function: diurnal rhythms, feeding, temperature regulation, mis-wiring in the hypothalamus. The hypothalamus controls the autonomic system.
Thirst/hunger: may have feeding behaviors including overeating with obesity, poor eating with wasting, and aversion to certain food textures.
Water seeking behavior may be mistaken for diabetes insipidus.
Sleep: biological clock, may have loss of rhythmicity and sleep or wakefulness, may cause disruption to family life (circadian rhythms)
Temperature regulation: body temperature regulation and frequently hospitalized to rule out sepsis
May have obsessive–compulsive behavior.
Hypopituitarism:
(low output of pituitary gland, “panhypopit” means more than 2 hormones involved)
What are the hormones and why do teachers need to know?
75-80% of patients with ONH have hypopituitarism in some form.
Growth Hormone
70% may have abnormal growth hormone, which may cause stunted growth, may grow normally up to age 6 even with GH deficiency
Short stature, hypoglycemic events including seizures, prolonged jaundice, micropenis; delayed dentition may be additional affects of GH deficiency
Hypothyroid
43% may have: In ONH is a secondary dysfunction, it is a central hypothyroid, men age of presentation 15 months but can evolve up to at least age 4years, so needs continued monitoring.
Poor growth, prolonged jaundice, delayed puberty, very important for cerebral development and attaining developmental milestones, may be missed at neonatal screening that use TSH (Thyroid stimulation hormone) measurement.
Causes further brain damage if not detected early, this is one of the most important tests for the infant.
Adrenal Insufficiency
27% have abnormal ACTH
Can cause death, lead to cardiovascular collapse, sudden death in 2% of children with ONH, parents and teachers should be informed of this, so they have an emergency plan for the child
Neonatal cholestasis, jaundice and hypoglycemia are early indications
Diabetes Insipidus
Up to 10% lack ADH, or antidiuretic hormone, which leads to abnormal urination and water seeking
Hyperprolactinemia
62% may have
This is marker for hypothalamic dysfunction, but not necessarily pituitary dysfunction, implies either hypothalamic dysfunction or disconnection between hypothalamus and pituitary.
Developmental Delays (DD)
Common, wide spectrum of delays.
¾ have neuropsychiatric disorders, some with autism, ADD.
Motor delays 75% including cerebral palsy and global delays.
Communication delays 44% as in autism, and also other speech disorders.
Risk factors for DD include hypoplasia of corpus callosum (93% may have DD) and hypothyroid (93% have DD if abnormal, vs. 50% if normal thyroid)
Absence of septum pellucidum not risk factor for developmental delays or visual impairment.
Unilateral ONH 18-39% DD
Bilateral ONH 72-78% DD
Autism Spectrum Disorders (ASD)
There are other overlapping symptoms with ASD and ONH. ASD may be misdiagnosed by standard screening tools, or if evaluator is not familiar with children’s development and behavior who are congenitally blind. ASD may be missed and the behaviors attributed to “blindisms”. Further training across the professions in vision rehabilitation and autism should be sought.
May children have auditory and tactile defensiveness. Children with ONH may have rigid routines, and obsessive-compulsive behaviors.