DIFFERENCES AND SIMILARITIES BETWEEN IDIOPATHIC INTRACRANIAL HYPERTENSION, OCULAR MYASTHENIA GRAVIS, , AND HORNER’S IN CHILDREN VS. ADULTS

Grant T. Liu, MD University of Pennsylvania School of Medicine Philadelphia, PA

Learning Objective Idiopathic Intracranial Hypertension (IIH) Understand the differences and similarities between children Similarities between children and adults with IIH. and adults with common neuro-ophthalmic problems • Diagnosis is made similarly (, normal imaging, CME Questions: True/False elevated opening pressure on lumbar puncture) • Morbidity (vision loss) 1. Like adults, children with IIH tend to be obese and female. • Treatment algorithms (acetazolamide, weight loss, optic 2. lesions on MRI at presentation are predictive nerve sheath fenestration/shunting when vision loss is of conversion to MS in children with optic neuritis. severe or progressive despite maximal medical therapy) (Rangwala and Liu, 2007). 3. Carotid dissection is a primary consideration in children • Postpubertal patients tend to be female and with Horner’s syndrome. overweight (Balcer et al. 1999).

Differences between children and adults with IIH. Keywords 1. Idiopathic Intracranial Hypertension (Pseudotumor • In prepubescent children, more thin children, boys, and Cerebri) asymptomatic presentations. Fewer with headaches as well. (Balcer et al. 1999; Rangwala and Liu, 2007) 2. Pediatric Optic Neuritis • More sixth nerve palsies 3. Ocular Myasthenia Gravis • Young age makes following with computerized visual field testing difficult 4. Horner’s Syndrome • More cases associated with medication use (tetracycline derivatives, synthetic growth hormone, for instance) (Ko and Liu, 2010) Introduction • MRI-v recommended in addition to MRI in all cases for Pediatric neuro-ophthalmology is more than just neuro- diagnosis (Rangwala and Liu, 2007) ophthalmology of little people. Compared with neuro- • Definition of elevated opening pressure varies (280 mm ophthalmology in adults, in the pediatric subspecialty the H20 vs. 250 mm H20) (Avery et al. 2010) diseases are different, with greater emphases on congenital • Better visual prognosis (Soiberman et al. 2011) malformations and genetic disorders and less on vascular problems. The approach also varies, particularly with Ocular Myasthenia Gravis (OMG) regard to examination techniques and interaction with the . In many instances, it is still unclear from a Similarities between children and adults with OMG. physiologic standpoint why such striking differences exist between disease profiles in adults and children. • Juvenile and adult myasthenia gravis are both autoimmune disorders The purpose of this talk is to highlight the similarities and • Presentation with , , and/or differences between adults and children with four common ophthalmoplegia (Kim et al. 2003) neuro-ophthalmic problems. • Diagnosis with acetylcholine receptor antibody testing • Use of ice test or rest test • Treatment options include pyridostigmine, prednisone, immunosuppression, and thymectomy.

2012 Annual Meeting Syllabus | 95 Differences between children and adults with OMG. one or more white matter lesions on MRI were more likely to develop MS (3/7 vs. 0/11, p=0.04, Fisher’s • Other forms to consider in infancy: neonatal exact test). We concluded that children with brain myasthenia gravis MRI abnormalities at the time of the diagnosis of optic • Use of the edrophonium test, repetitive stimulation, or neuritis have an increased risk of MS. single fiber EMG may not be possible in some children because of lack of cooperation. Differences between children and adults with optic • Therefore when the acetylcholine receptor antibody neuritis. testing is normal, the diagnosis of ocular myasthenia gravis in a child may lack confirmatory testing. • Visual acuities at presentation may be worse • due to ptosis (deprivational) and ocular (Bonhomme et al. 2009) misalignment (strabismic) make aggressive treatment more • More bilateral optic neuritis and optic neuritis with of a priority (Ortiz and Borchert 2008; Pineles et al. 2010) edema • Thymectomy in younger children can be performed • More optic neuritis in association with intercurrent illness transthorascopically rather than transcervically or • Presentation as ADEM, a demyelinating or inflammatory trans-sternally. event, and includes white or gray matter lesions on • Thymoma rare MRI, which is i) polysymptomatic and ii) includes • In our series (Pineles et al. 2010), the development encephalopathy (i.e. behavioral or mental status of generalized symptoms (23%) was lower than early change) (Krupp et al., 2007). Acute disseminated case series of pediatric OMG (36-43%) (Mullaney et al. encephalomyelitis (ADEM) is an autoimmune 2003; McCreery et al. 2002), and that of adult OMG demyelinating disease that typically follows an illness (31-49%) (Bever et al. 1983; Sommer et al. 1997). or vaccination. As opposed to MS, ADEM is typically These rates corroborate the notion that development a monophasic illness that does not require long-term of generalized symptoms may be less common in treatment. ADEM is more common in children than pediatric OMG than in the adult population. adults (Dale et al. 2000). Although patients with ADEM can present with fulminate neurologic signs and Optic Neuritis (ON) symptoms, most patients have an excellent recovery. • More recurrent optic neuritis in children. In our study Similarities between children and adults with optic neuritis. of pediatric optic neuritis (Bonhomme et al. 2009), nine patients (31%) had relapses of optic neuritis during the • Clinically, optic neuritis in the pediatric age group is study period and 5 had more than one relapse. diagnosed by the same criteria used in adults, including • Neuromyelitis optica (NMO), although seen, is less sudden or subacute visual loss, central or cecocentral common in children. visual field defect, impairment of color vision, afferent • Older age is a risk factor for development of MS. pupillary defect, and ocular pain on eye movements. (Waldman et al., in press). • Often the initial manifestation of multiple sclerosis (MS). • Postpubertal patients tend to be female and have a According to the ONTT, after acute unilateral optic neuritis, presentation (unilateral without disc swelling) and adults have a 50% chance of developing MS within 15 years course similar to adults. (Optic Neuritis Study Group 2008). Children with optic neuritis are also at risk for development of MS (29%, meta- Horner’s Syndrome analysis) (Waldman et al., in press). • White matter lesions on MRI are predictive of Similarities between children and adults with Horner’s conversion to MS. As established by the Optic Neuritis syndrome. Treatment Trial, an abnormal baseline brain MRI with white matter lesions is a strong predictor of MS after • Presentation with ptosis, , and anhidrosis isolated optic neuritis in adults. Fifteen years after • Neuro-anatomy is the same. Consideration of lesions a bout of optic neuritis, 72% of adults with one or affecting the first, second, and third-order neurons more brain MRI lesions at presentation developed MS, in contrast with a 25% conversion rate in those Differences between children and adults with Horner’s with no lesions (Optic Neuritis Study Group 2008). In syndrome. children, an abnormal MRI at presentation is likely also predictive. In our study (Bonhomme et al. 2009) 18 • Congenital cases, with birth trauma in the differential patients were followed for more than 24 months, and diagnosis (Weinstein et al. 1980) 3 of the 18 (17%) developed MS. All three patients had • More presentations with heterochromia an abnormal brain MRI scan at their initial presentation • Carotid dissection, lungancer, c and microvascular of optic neuritis. None of the patients with a normal causes more common in adults. brain MRI scan at presentation developed MS over • Need to avoid apraclonidine testing because of risk of an average follow-up of 88.5 months. Patients with drowsiness and unresponsiveness in young children

96 | North American Neuro-Ophthalmology Society • Confirmation with cocaine drop testing preferred Ocular Myasthenia Gravis • Neuroblastoma is a consideration, so workup should 1. Bever C, Aquino A, Penn A, Lovelace R, Rowland L. Prognosis of include urine vanillylmandelic acid (VMA) and ocular myasthenia. Ann Neurol. 1983;14:516-519. homovanillic acid (HVA) testing. 2. Kim J, Hwang J, Hwang Y, Kim K, Chae J. Childhood ocular • Despite opinion to the contrary (Smith et al. 2010), we myasthenia gravis. Ophthalmology. 2003;110:1458-1462. believe that all patients with an obvious or confirmed 3. McCreery K, Hussein M, Lee A, Paysse E, Chandran R, Coats D. Horner’s syndrome also should undergo MR imaging Major review: the clinical spectrum of pediatric myasthenia of the head, neck, and upper chest to rule out a gravis: blepharoptosis, ophthalmoplegia, and strabismus. A report of 14 cases. Binocul V Strabismus Q. 2002;17:181-186. responsible mass lesion. In our study (Mahoney et 4. Mullaney P, Vajsar J, Smith R, Buncic J. The natural history and al. 2006), of 18 children who had complete imaging ophthalmic involvement in childhood myasthenia gravis at The and urine studies, and the diagnosis was unknown, Hospital for Sick Children. Ophthalmology. 2000;107:504-510. responsible mass lesions were found in six (33%). 5. Ortiz S, Borchert M. Long-term outcomes of pediatric ocular • Even children with a history of birth trauma or myasthenia gravis. Ophthalmology. 2008;115:1245-1248. those with Horner’s at birth (“congenital”) should 6. Pineles SL, Avery RA, Moss HE, Finkel R, Blinman T, Kaiser be evaluated, as these patients may still harbor an L, Liu GT. Visual and systemic outcomes in pediatric ocular underlying neoplasm (Mahoney et al. 2006) myasthenia gravis. Am J Ophthalmol 2010;150:453-459. • Caution also should be applied when 7. Sommer N, Sigg B, Melms A, et al. Ocular myasthenia gravis: hydroxyamphetamine is used in children with Horner’s response to long term immunosuppressive treatment. J Neurol syndrome. The normal development of the third-order Neurosurg Psychiatr 1997;62:156-162. oculosympathetic neuron and its synaptic connections Optic Neuritis depends on the integrity of the first and second 1. Bonhomme GR, Waldman AT, Balcer LJ, Daniels AB, Tennekoon neuron. In congenital preganglionic lesions, therefore, GI, Forman S, Galetta SL, Liu GT. Pediatric optic neuritis: brain it is possible that hydroxyamphetamine will completely MRI abnormalities and risk of multiple sclerosis. Neurology 2009;72:881-885. or partially fail to dilate the involved because of transsynaptic degeneration of postganglionic fibers 2. Dale RC, de Soussa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic (Weinstein et al. 1980). disseminated encephalomyelitis and multiple sclerosis in • Carotid dysgenesis is in the differential diagnosis of children children. Brain 2000;123:2407-2422. with congenital Horner’s syndrome, so we also recommend 3. Krupp LB, Banwell B, Tenembaum S, and the International MRI-angiography of the neck as part of the workup. Pediatric MS Study Group. Neurology 2007;68(suppl 2):S7-S12. 4. Optic Neuritis Study oup.Gr Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch CME Answers Neurol 2008;65:727-732. 5. Waldman AT, Stull LB, Galetta SL, Balcer LJ, Liu GT. Pediatric 1. false optic neuritis and risk of multiple sclerosis: meta-analysis of 2. true observational studies. J AAPOS (in press). Horner’s Syndrome 3. false 1. George NDL, Gonzalez G, Hoyt CS: Does Horner’s syndrome in infancy require investigation? Br J Ophthalmol 1998;82:51-54. 2. Jeffery AR, Ellis FJ, Repka MX, et al.: Pediatric Horner syndrome. References J AAPOS 1998;2:159-167. Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) 3. Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, 1. Avery RA, Shah SS, Licht DJ, Seiden JA, Huh JW, Boswinkel J, Maris JM. Pediatric Horner’s syndrome: etiologies and roles of Ruppe MD, Chew A, Mistry RD, Liu GT. Reference range of imaging and urine studies to detect neuroblastoma and other cerebrospinal fluid opening pressure in children undergoing responsible mass lesions. Am J Ophthalmol 2006;142:651-659. diagnostic lumbar puncture. N Engl J Med 2010;363:891-893. 4. Smith SJ, Diehl N, Leavitt JA, et al.: Incidence of pediatric 2. Balcer LJ, Liu GT, Forman S, Pun K, Volpe NJ, Galetta SL, Maguire Horner syndrome and the risk of neuroblastoma. Arch MG. Pediatric pseudotumor cerebri: relationship of age and Ophthalmol 2010;128:324-329. obesity. Neurology 1999;52:870-872. 5. Weinstein JM, Zweifel TJ, Thompson HS: Congenital Horner’s 3. Ko MW, Liu GT. Pediatric idiopathic intracranial hypertension syndrome. Arch Ophthalmol 1980;98:1074-1078. (pseudotumor cerebri). Hormone Research in 6. Woodruff G, Buncic JR, Morin JD: Horner’s syndrome in 2010;74:381-389. children. J Ped Ophthalmol Strab 1988;25:40-44. 4. Rangwala L, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol 2007;52:597-617. 5. Soiberman U, Stolovitch C, Balcer LJ, Regenbogen M, Constantini S, Kesler A. Idiopathic intracranial hypertension in children: visual outcome and risk of recurrence. Childs Nerv Syst 2011 [Epub ahead of print].

2012 Annual Meeting Syllabus | 97 98 | North American Neuro-Ophthalmology Society The Accessory Optic System: The Fugitive Visual Control System in Infantile strabismus

Michael C. Brodsky, MD Mayo Clinic Rochester, MN

Learning Objectives These binocular deviations all correspond to normal visuo- 1-4 1. To review the organization of the accessory optic system vestibular reflexes that are operative in lateral-eyed animals. Evolutionarily, these visual reflexes antedate development 2. To review the dissociated eye movements that of the visual cortex, which does not generate torsional eye characterize dissociated infantile strabismus. movements in humans.5 Any attempt to anatomize infantile strabismus must therefore explain the reemergence of 3. To examine the potential role of the accessory optic these atavistic reflexes, as well as their prominent torsional system in generating dissociated strabismus components. I propose that the accessory optic system, an atavistic, subcortical visual motion detection system, could generate the dissociated and nondissociated torsional eye CME Questions movements that accompany human infantile strabismus. 1. Are the torsional components of dissociated eye movements in infantile strabismus modulated by visuo- What is the AOS? vestibular pathways? The AOS consists of three nuclei at the mesodiencephalic border that receive direct retinal input from the accessory 2. What subcortical generates visuo- optic tract (AOT). 6-9 The AOT comprises an inferior and vestibular eye movements? superior fasciculus, with its superior fasciculus divided 3. In what coordinate system is the accessory optic into a posterior branch, a middle branch, and an anterior system organized? branch that is identical to the original transpeduncular tract (tractus peduncularis transversus) discovered in 1870 by Gudden.10,11 The number of accessory optic fibers is Keywords relatively small.7 In most mammalian species, the majority of optic fibers reach the accessory optic nuclei via the 1. Accessory Optic System transpenduncular tract, which is visible as it courses over 2. Inferior Olive the brachium of the superior colliculus.12

3. Cerebellar Flocculus In most mammalian species, the AOS is composed of three 4. Infantile Strabismus paired terminal nuclei: the dorsal terminal nucleus (DTN), the lateral terminal nucleus (LTN), and the medial terminal 5. Dissociated Strabismus nucleus (MTN) which receive innervation from primary optic fibers.7-9 Input to these three accessory optic terminal nuclei is predominantly from the contralateral eye.7-9,11,12 Along with Introduction the nucleus of the optic tract (NOT), these three terminal Infantile strabismus is characterized by dissociated nuclei project differentially to the dorsal cap of the inferior , which is the normal condition in lateral- olive,14-16 which provides the only source of climbing fibers to eyed animals.1,2 Early binocular misalignment gives rise the flocculonodular lobe of the cerebellum. 7-9,14-17 In this way, to dissociated eye movements (changes in eye position cells of the AOS converge with those of the vestibular system evoked by unequal visual input to the two eyes).3 These in the vestibulocerebellum.7-9 include latent , dissociated vertical divergence, and dissociated horizontal deviation,1-3 all of which have a Despite its name, the AOS is a primary visual system prominent torsional component. Primary oblique muscle receiving direct visual information from the via one overaction, which accompanies infantile strabismus but or more accessory optic tracts13 which are responsible for is not dissociated in nature, is also characterized by a visuo-vestibular interaction in afoveate animals.7,16,17 Its torsional misalignment of the eyes.4 retinal input is derived from ON-type direction-sensitive ganglion cells that characteristically have large receptive fields (averaging about 40 degrees vertical and 60 degrees horizontal), are direction selective, and have a preference 2012 Annual Meeting Syllabus | 99 for slow-moving stimuli.7-9,12,13 The AOS processes must be derived from the synthesis of bilateral floccular information about the speed and direction of movement representations.27 Thus, the flocculus provides a subcortical of large textured parts of the visual world.7-9 The accessory binocular visual system that generates asymmetrical optic system signals self-motion as a function of slip of torsional eye movements under dissociated conditions of the visual world over the retinal surface, and generates optokinetic stimulation.27 corrective eye movements to stabilize the retinal image.7-9 As an analyzer of self-motion, the AOS subserves visual Studies using decortication have revealed contributions from proprioception in the afoveate animal.7-9 the visual cortex to the AOS.31-33 Disruption of contributions from the visual cortex to the AOS by strabismus may alter the The AOS is a visual system that is organized in vestibular inherent biases of the accessory optic nuclei. The ipsilateral coordinates.7-9 Experimental studies by Simpson and visual cortex is necessary for a number of response properties colleagues indicate that visual and vestibular signals which that distinguish DTN and LTN neurons in the cat from those in produce compensatory eye movements are organized the rabbit. Following decortication, cat DTN and LTN neurons about a common set of axes derived from the orientation lose their binocularity and become nearly totally dominated of the semicircular canals.7,9,12,13,16,17 Because the AOS is by the contralateral eye.33 For example, LTN neurons excited directionally-sensitive to low velocity movements while the by upward movement which in the cat are equal in number vestibular system typically responds to movements of higher to those excited by downward movement, become less velocity, the accessory optic system and vestibular labyrinths numerous so that the cat LTN becomes like that of the rabbit, form two complementary systems to detect self motion and consisting of neurons excited by slow downward movements promote image stabilization so that objects in the visual to the contralateral eye.33 Unlike the LTN and DTN, neurons world can be quickly and accurately analyzed.7,8,12,13 in the cat MTN are largely monocular and therefore similar to those in the rabbit.12 The monocular nasotemporal optokinetic The AOS exists in all vertebrate classes6,7,18,19 including asymmetry that characterizes infantile strabismus is known humans,20 but it has been studied most extensively in to result from monocular cortical input to the NOT/DTN,34 the rabbit. The three preferred directions for cells in the unmasking a subcortical visuo-vestibular bias that generates accessory optic terminal nuclei define three directions in latent nystagmus.35 The AOS provides a neuroanatomical visual space: horizontal from posterior to anterior for the substrate whereby vertical monocular subcortical motion DTN, vertical up and down for the MTN and vertical down biases could generate the canal-based torsional eye for the LTN.7-9,11-14,21 Its three pretectal accessory optic nuclei movements that characterize primary oblique muscle are closely related to the nucleus of the optic tract (NOT) overaction and DVD.2,4 Although we observe and analyze these and receive input predominantly from the contralateral eye movements in yaw, pitch, and roll,2 they are encoded in eye.7-9,12,13 Direction-sensitive ON-type retinal ganglion cells a canal-oriented, push-pull bilateral coordinate system that encode retinal image slip22,23 and transmit this information detects optokinetic flow in every direction.36 to the accessory optic system, inferior olive24 floccular climbing fibers,25 and floccular Purkinje cells26 These three Photic stimulation can activate the accessory optic tract pairs of channels remain anatomically distinguishable in the rabbit.4,37 AOS neurons show the same responses within the AOS, the inferior olive and in floccular zones to retinal illumination as ON-type direction-sensitive which, when stimulated, elicit eye movements organized retinal ganglion cells, being excited only at the onset of in a canal-like coordinate system27-29 Each pair conveys retinal stimulation, 23 and generate a firing response that signals about flow of the visual surround about one of is related to light intensity.32 In this way, the AOS may three rotations axes, which are approximately collinear with implement the visuo-vestibular reflexes that characterize the best response axes of the semicircular canals and the infantile strabismus.1,2 Since the AOS is primarily a motion rotation axes of the .27 detector, however, central modulation of the primitive luminance reflexes that characterize infantile strabismus The rabbit flocculus ipsilateral to the seeing eye is optimally may require input from other subcortical visual pathways. sensitive to optokinetic stimulation about a 135 degree It is possible that other primitive luminance pathways axis while the flocculus contralateral to the seeing eye is may provide parallel subcortical luminance input to the optimally sensitive to optokinetic stimulation around a visuo-vestibular system.38 Like the accessory optic system, horizontal 45 degree axis.25-29 For horizontal stimulation, luminance input that modulates the dorsal light reflex in the DTN and its adjacent NOT are selectively sensitive fish (which corresponds to dissociated vertical divergence to nasally- directed optokinetic stimulation presented and primary oblique muscle overaction in humans with to the contralateral eye.7,8,12,13 Conversely, electrical infantile strabismus)1,2 is transmitted to the central microstimulation in the alert rabbit’s flocculus produces pretectal nucleus in the contralateral midbrain, then down abduction of the ipsilateral eye,28-30 or dissociated torsional to the vestibulocerebellum which integrates visual and and vertical rotations of the two eyes corresponding to vestibular input.39 These luminance and motion pathways the plane of one semicircular canal.25-30 Because floccular may constitute the subcortical equivalents of the what and motion detection for each eye is not fully represented on where visual streams within the association visual cortex. its own side of the body, monocular optokinetic responses How these subcortical visual streams intercommunicate

100 | North American Neuro-Ophthalmology Society to consolidate spatial and temporal summation of visual References information at the subcortical levels remains a mystery. But 1. Brodsky MC: Dissociated vertical divergence: A righting reflex gone the likelihood that they provide the innervational substrate wrong. Arch Ophthalmol 1999;117:1216-1222. for the atavistic eye movements that characterize infantile 2. Brodsky MC: Visuo-vestibular eye movements. Infantile strabismus in 3 strabismus should not be ignored. dimensions. Arch Ophthalmol 2005;123:837-842. 3. Brodsky MC: Dissociated horizontal deviation: clinical spectrum, Conclusion pathogenenesis, evolutionary underpinnings, diagnosis, treatment, The AOS is uniquely suited to generate the dissociated and potential role in the development of infantile (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc eye movements that characterize infantile strabismus. It is 2007;105:272-293. atavistic, present in humans, subcortical, crossed, sensitive 4. Brodsky MC, Donahue SP: Primary oblique muscle overaction: The brain to optokinetic motion, and it generates dissociated throws a wild pitch. Arch Ophthalmol 2001;119:1307-1314. torsional eye movements (Table 1). It provides the 5. Brodsky MC: Is DVD cortical or subcortical in origin? Strabismus necessary neuroanatomical substrate to process binocular 2011;19:67-68. visual motion in a semicircular canal-based coordinate 6. Marg E: The accessory optic system. Ann NY Acad Sci 1964;117:35-52. system. The fact its retinal fibers terminate in the three nuclei of the AOT along with the adjacent NOT (a part 7. Simpson JI, Soodak RE, Hess R: The accessory optic system and its relation to the vestibulocerebellum. Prog Brain Res 1979;50:715-724. of the pretectal nuclear complex that generates latent nystagmus) lends further credence to this hypothesis. Its 8. Simpson JI, Leonard CS, and Soodak RE: The accessory optic system: Analyzer of self-motion. Ann NY Acad Sci 1988;545:170-179. fundamental role in modulating visuo-vestibular tonus suggests that it may also provide a neuroanatomical 9. Simpson JI: The accessory optic system. Annu Rev Neurosci 1984;7:13-41. substrate for dissociated eye movements in humans with 10. Gudden B: Ueber einen bisher nicht eschriebenen Nervenfasernstrang im Gehirne der Säugethiere und des Menschen. Arch Psychiat infantile strabismus. Dissociated binocular vision in infancy 1870;2:364-366. may unlock this atavistic visual system, generating canal- 11. Gudden B: Ueber den Tractus peduncularis transversus. Arch Psychiat based ocular rotations that we anthropomorphize to 1881;11:415-423. diagnose “torsion” in the frontal plane. 12. Simpson JI, Giolli RA, Blanks RHI: The pretectal nuclear complex and the accessory optic system. In Büttner-Ennever (eds): Neuroanatomy of the Oculomotor System. Elsevier Science Publishers BV, 1988 pp 335-364. Table 1: Characteristics of the Accessory Optic System 13. Giolli RA, Blanks RHI, Lui F: The Accessory Optic System: Basic Organization with an Update on Connectivity, Neurochemistry and - Atavistic Function. Progress Brain Res 2006;151:409-433. - Subcortical visual system 14. Takeda T, and Mackawa K: The origin of the pretecto-olivary tract. - Crossed input from nasal retina A study using the horseradish peroxidase method. Brain Res - Sensitive ot full field optokinetic motion 1976;117:319-325. - Binocular representation in the cerebellar flocculus 15. Maekawa K, and Takeda T: Afferent pathways from the visual system to - Operates in a canal-based vestibular coordinate system the cerebellar flocculus of the rabbit. In Control of Gaze by Brain Stem - Generates dissociated eye movements with torsional Neurons, R Baker and A Berthoz (Eds). Elsevier/North-Holland Biomed. components Press, Mai JK: The accessory optic system and the retino-hypothalamic system. A review. J Hirnforsch 1978;19:213-288. - Provides a neuroanatomic substrate for bilateral 16. Maekawa K, Simpson JI: Climbing fiber activation of Purkinje cells in the oblique muscle overaction flocculus by impulses transferred through the visual pathway. Brain Res 1972;39:245-251. 17. Maekawa K, Simpson JI: Climbing fiber response evoked in This analysis implies that mutations involving the accessory vestbulocerebellum of rabbit from visual system. J Neurophysiol optic system or its target zones within the cerebellar 1973;36:649-666. flocculus could provide a potential template for infantile 18. Ebbesson SO: On the organization of central visual pathways in strabismus. If so, then the age-old dichotomy of Worth vertebrates. Brain Behav Evol 1970;3:178-194. (congenital defect in cortical fusion) and Chavesse (early 19. Cooper HM, Magnia M: A common mammalian plan of accessory optic binocular misalignment)40 may have to be expanded to system organization revealed in all primates. Nature 1986;324:457-459. include binocular subcortical dysfunction intrinsic to the 20. Fredericks CA, Giolli RA, Blanks RH, Sadun AA: The human accessory visuo-vestibular system. optic system. Brain Res 1988;434:116-122. 21. Simpson JI, Leonard CS, Soodak RE: The accessory optic system of rabbit: II. Spatial organization of direction selectivity. J Neurophysiol CME Answers 1988;60:2055-2072). 22. Oyster CW,: The analysis of image motion by the rabbit retina. J Physiol 1. yes Lond 1968;199:613-635. 2. accessory optic system 23. Soodak RE and Simpson JL: The accessory optic system of rabbit: I. Basic visual response properties. J Neurophysiol 1988;60:2037-2054. 3. a vestibular semicircular canal-oriented coordinate system

2012 Annual Meeting Syllabus | 101 24. Leonard CS, Simpson JI, Graf W: Spatial organization of visual messages 32. Grasse KL, Cynader MS: The accessory optic system of the monocularly- of the rabbit’s cerebellar flocculus. I. Typology of inferior olive neurons of deprived cat. Dev Brain Res 1987;31:229-241. the dorsal cap of Kooy. J Neurophysiol 1988;60:2073-2090. 33. Grasse KL, Cynader MS, and Douglas RM: Alterations in response 25. Simpson JI, Graf W, Leonard CS: Three-dimensional representation of properties in the lateral and dorsal terminal nuclei of the cat accessory retinal image movement by climbing fiber activity. Exp Brain Res 1989, optic system following visual cortex lesions. Exp Brain Res 1984;55:69-80. Springer Verlag, Berlin, Series 17, pp 323-337. 34. Hoffmann KP:Cortical versus subcortical contributions to the optokinetic 26. Graf W, Simpson JI, and Leonard CS: Spatial organization of visual reflex in the cat. In G Lennerstrand et al (Eds.) Functional Basis of Ocular messages of the rabbits’s cerebellar flocculus. II. Complex and simple Motility Disorders, Pergamon, Oxford pp 303-310. spike response of Purkinje cells. J Neurophysiol 1988; 60:2091-2121. 35. Brodsky MC, Tusa RJ: Latent nystagmus: Vestibular nystagmus with a 27. Tan HS, Van der Steen J, Simpson JI, and Collewijn: Three dimensional twist. Arch Ophthalmol 2004;122:202-209. organization of optokinetic responses in the rabbit. J Neurophysiology 36. Simpson JI, and Graf W: The selection of reference frames by nature 1993;69:303-316. and its investigators. In: Adaptive Mechanisms and Gaze Control. Facts 28. Simpson JI, Van der Steen J, Tan J, et al: Representations of ocular and Theories. (Eds). Berthoz A and Melvill Jones . 1985, Elsevier Sciences rotations in the cerebellar flocculus of the rabbit. In Allum JHJ and Pulishers, Amsterdam, pp 3-16. Hulliger M (Eds): Progress in Brain Research 1989;80:213-223. 37. Hamasaki D and Marg E: Microelectrode study of accessory optic tract in 29. Van der Steen J, Simpson JI, and Tan J: Representation of three- the rabbit. Am J Physiol 1962;202:480-486. dimensional eye movements in the cerebellar flocculus of the rabbit. In: 38. Schiller PH: Parallel information processing channels created in the Oculomotor Control and Cognitive Processes, edited by R Schmid and D. retina. PNAS 2010;107:17087-17094. Zambarbieri,. Amsterdam: Elsevier, 1991;pp 63-77. 39. Yangagihara D, Watanabe S, Mitarai G: Neuroanatomical substrate 30. Ito M, Nisimaru N, and Yamamoto M: Specific neural connections for the dorsal light response. II: effects of kainic acid-induced lesions for the cerebellar control of vestibule-ocular reflexes. J Physiol Lond of the valvula cerebelli in goldfish (Carassius auratus). Neurosci Res 1977;265:833-864. 1993;16:33-36. 31. Grasse KL, Cynader MS: Response properties of the single units in 40. Chavesse FB, Worth CA, Lyle TK: The Binocular Reflexes and Treatment of the accessory optic system of the dark-reared cat. Dev Brain Res Strabismus. Philadelphia, Blakeston, 1950. 1986;27:199-210.

102 | North American Neuro-Ophthalmology Society What’s New (and Old) in Hypoplasia

Mark Borchert, MD Childrens Hospital Los Angeles University of Southern California Los Angeles, CA

Learning Objectives Review of the literature reveals that de Morsier, who 1. The attendee will be able to understand the historical coined the term, “septo-optic dysplasia” was not referring confusion that led to the inappropriate significance of to ONH, and in fact, never described a case of ONH. When absence of the septum pellucidum. referring to ONH, the terms, septo-optic dysplasia and de Morsier’s syndrome, are historically inaccurate and 2. The attendee will be able to identify key clinical diagnostically misleading associations commonly found in patients with optic nerve hypoplasia. This review will summarize the state of knowledge on optic 3. The attendee will be able to describe the appropriate nerve hypoplasia and reanalyze the historical literature that work-up and follow-up of patients with optic nerve led to misunderstandings of its association with neurologic hypoplasia. or endocrinologic abnormalities. The case will be made for abandonment of the terms, septo-optic dysplasia and de Morsier’s syndrome. CME Questions 1. True or false? Patients with ONH and normal septum Prevalence pellucidum do not need endocrinology evaluation. Optic nerve hypoplasia (ONH) has been recognized as an increasingly frequent cause of congenital blindness 2. Which endocrinopathies have been documented affecting one or both eyes. In 1997, bilateral ONH to evolve post-natally in children with optic nerve surpassed of prematurity as the single leading hypoplasia? cause of blindness in Sweden.1 Only cortical visual 3. True or false? Children with unilateral ONH are at high impairment of multiple etiologies was more common than risk for endocrinopathy and developmental delay. ONH in blind children. The prevalence of ONH in Sweden quadrupled between 1980 and 1999 to 7.1 per 100,000, while all other causes of declined as Keywords diagnoses from the same major ophthalmic center.2 In 2006, the prevalence of ONH in England had risen to 10.9 1. Septo-Optic Dysplasia per 100,000 children.3 2. Hypopituitarism Owing to incomplete registries of blindness, the prevalence 3. MRI of ONH in North America is unknown. Prior to 1970, it 4. was considered rare. In fact, prior to 1962, only one case had been diagnosed in British Columbia, but 20 cases 5. were subsequently diagnosed by 1974, for an estimated prevalence of 1.8 per 100,000.4 Acers noted a similar increase in incidence of reported cases in the 1970s.5 ONH Introduction was identified in 12% of blind in Harris County in Optic nerve hypoplasia has been recognized as a leading Texas in the early 1980s.6 Surveys of schools for the blind cause of childhood blindness, and its association with in the United States in 1999 revealed that ONH accounted hypopituitarism has been known for four decades. It for 5.7% to 12.9% of blind students.7,8 Such surveys has more recently been recognized that the majority of underestimate the actual prevalence, because cognitive the systemic problems associated with ONH are due to or behavioral impairments exclude most children with dysfunction of the hypothalamus and cortical miswiring. ONH from schools for the blind. In 2007, the Babies Count Absence of the septum pellucidum is not associated with registry reported ONH as the third most prevalent cause the major neurologic or systemic consequences, and in (behind cortical vision impairment and retinopathy of general, MRI scans or laterality of disease cannot be used to prematurity) of any vision impairment in children age three predict hypothalamic dysfunction. years or younger in the United States.9 Of all conditions, ONH was the most likely to cause legal blindness.

2012 Annual Meeting Syllabus | 103 Historical descriptions Three years following de Morsier’s report, Gross and Hoff The first description of ONH is generally ascribed to Magnus reported their autopsy findings from 465 brains from patients in 1884,10 but the first artistic rendering of the optic disc with severe neurologic problems or systemic malformations.16 appearance was by Schwarz in 1915.11 The first recognition of an They identified thirteen brains with absence of the septum association of ONH with agenesis of the septum pellucidum was pellucidum. One of these had bilateral ONH, and seven (six by Dr. David Reeves at Children’s Hospital Los Angeles, in 1941.12 bilateral; one unilateral) had optic atrophy. They also identified 12 cases of partial or complete corpus callosum agenesis. Two The purpose of Reeves report was to demonstrate the of these had microphthalmos with bilateral optic atrophy and youngest case of agenesis of the septum pellucidum one had unilateral ONH. diagnosed by air encephalogram. The 4-month-old patient was coincidentally blind, and examination under anesthesia Thus, prior to 1970 only two cases of ONH associated with by Dr. S. Rodman Irvine revealed “bilateral primary optic absence of the septum pellucidum had been described atrophy of undetermined origin, probably, however, on in the medical literature, and neither of these had been the basis of a congenital aplasia.” Dr. Irvine was a famous identified by de Morsier. member of a prominent ophthalmological family in Southern California, and was also the first to describe the association In 1970, Ellenberger and Runyan described a case of of cystoid with surgery.13 unilateral ONH, absent septum pellucidum and dwarfism in a 23-year-old woman.17 Dr. William Hoyt, who nearly The association of ONH with absence of the septum simultaneously wrote the landmark report that recognized pellucidum was later erroneously attributed to Georges de the association of ONH with growth hormone deficiency, Morsier, who did, indeed, coin the term “la dysplasia septo- predicted the absent septum pellucidum in Ellenberger and optique (septo-optic dysplasia).”14 However, the “optic Runyan’s case.17,18 In their paper Hoyt et. al. described nine dysplasia” recognized by de Morsier was not ONH. In his patients with ONH and pituitary dwarfism, four of whom treatise on cranioencephalodysraphism, his third chapter were missing the septum pellucidum. They generously, but highlighted his fascination with absence of the septum erroneously, attributed the association of ONH and agenesis pellucidum that had incidentally been noted in post- of the septum pellucidum to de Morsier, and resurrected mortem brains. From his post-mortem collection of brains the term “septo-optic dysplasia,” which is now commonly with absent septum pellucidum, he discovered that one referred to as de Morsier’s Syndrome. “Hoyt’s Syndrome” brain had a unilaterally vertically rotated optic tract. This would be a more appropriate eponym, particularly since was from a woman who died of pyelonephritis at the age the association of ONH with hypopituitarism, not septum of 84 years without any history of vision problems. He also pellucidum agenesis, is the clinically important revelation. described the case of a living 44 year-old alcoholic man who had “slight narrowing of the visual field with enlargement De Morsier would scarcely have recognized the attribution of the blind spot,” but was incidentally discovered to be missing to himself. He was trained as a psychiatrist in Geneva the septum pellucidum on air encephalogram. De Morsier under de Clérambault. Lacking a suitable neuropathologist supplemented these two cases with 34 others (11 autopsy cases replacement after the death Edouard Long, de Morsier was and 23 radiographic cases) from the literature that had agenesis enjoined to lecture in neuropathology one hour per week of the septum pellucidum, eight of which had some other eye starting in 1933 during which time he attempted to catalogue or optic nerve problem. These included one case of bilateral the various craniodysraphisms. Ultimately he was appointed anophthalmous; three cases of bilateral optic atrophy (one with head of neurology in 1960, a position at which he served Apert’s Syndrome, and one with osteogenesis imperfecta); three until his retirement in 1964. Arguably, de Morsier’s greatest cases of unilateral optic atrophy (two systemically normal and contribution to medicine was his description of the Charles one with hemiparesis and mental retardation). The only case Bonnet Syndrome, which he named after the nineteenth with definite ONH from the literature cited by de Morsier was century naturalist, who in 1760, had documented the visual the case that had been previously documented by Reeves.12 It hallucinations of his grandfather.19 There is no record of de was from this compilation of disparate cases that an association Morsier ever identifying a case of optic nerve hypoplasia. of eye problems with agenesis of the septum pellucidum (i.e. septo-optic dysplasia) was postulated. Radiographic correlates

De Morsier believed that agenesis of the septum Septum Pellucidum pellucidum and various ocular anomalies were “not Following the resurrection of “septo-optic dysplasia” by fortuitous” associations.15 He hypothesized that the septum Hoyt et. al., absence of the septum pellucidum garnered pellucidum served to connect the corpus callosum to the inappropriate dogmatic significance. Its association with fornix, and that lacking this supporting structure resulted pituitary dysfunction was documented in retrospective in penetration of the chiasm by the third ventricle. This studies hampered by ascertainment bias.20,21 Other studies malformation of the chiasm then somehow led to optic refuted the association, even to the point of showing no nerve or ocular anomalies. association of any adverse outcome with agenesis of the septum pellucidum.22,23,24 Indeed, as with de Morsier’s

104 | North American Neuro-Ophthalmology Society experience, most cases of agenesis of the septum pellucidum of those have hypopituitarism.26,31 However, hypopituitarism are coincidentally detected and not associated with optic occurs in 75% of patients with ONH, the majority of whom nerve or hormone problems. The prevalence of absent have no pituitary abnormalities on neuroimaging. It is also septum pellucidum in the general population is unknown. In interesting that absence of the posterior pituitary bright spot the only prospective study of ONH, absence of the septum on T1-weighted MRI has been reported to be associated pellucidum was not associated with laterality of ONH, vision, with anterior pituitary function, 31 but most of those patients pituitary dysfunction, or developmental outcome.25,26 do not have , as would be expected if the granules that cause T1-weighted hyperintensity Nonetheless, the term, septo-optic dysplasia (SOD), has are actually missing.32 persisted and its definition has evolved to include midline brain abnormalities such as hypoplasia of the corpus Optic Nerve callosum or pituitary anomalies on magnetic resonance Attempts to diagnose ONH based on radiographic imaging (MRI), in addition to absent septum pellucidum. measurements of the optic nerve or chiasm have been This definition has served to focus investigators on promising.33,34 Such studies have been retrospective, lacked morphogenetic mechanisms for the condition. It disregards controls with normal and atrophic optic nerves, or failed the fact that a small corpus callosum frequently denotes to adjust for age in young patients. Nonetheless, it seems hemispheric disease, and that most neuroradiographic likely that high-resolution MRI could be used to distinguish abnormalities associated with ONH are not midline.26 These ONH from optic atrophy once the appropriately controlled include hydrocephalus, white matter hypoplasia, cortical studies are done. Assessment of the intracranial portion of heterotopia, , and arachnoid the optic nerves is more reliable for detecting ONH than cysts. Rather than reassessing the appropriateness of the assessment of the orbital component.35 nomenclature, investigators recognizing these non-midline findings simply expanded the terminology to include “SOD Clinical Diagnosis plus” as a more severe expression on the spectrum of ONH.27 The diagnosis of ONH is made by ophthalmoscopic confirmation of a small optic disc. Such confirmation may Corpus Callosum be difficult with the binocular indirect ophthalmoscope Corpus callosum hypoplasia is the most prevalent due to limited magnification. With inadequate resolution, neuroimaging abnormality associated with ONH. It small pale optic discs may be difficult to distinguish from a surrounding hypopigmented scleral canal, and therefore is commonly associated with absence of the septum misdiagnosed as normal size discs with optic atrophy. The pellucidum; however, absence of the septum pellucidum optimal method for diagnosing ONH in a young child is with cannot serve as a surrogate for corpus callosum hypoplasia, direct ophthalmoscopy, especially if the diagnosis is not clear as partial agenesis of the corpus callosum may not be by indirect ophthalmoscopy. Direct ophthalmoscopy is usually associated with absence of the septum pellucidum. Corpus not difficult in visually impaired children as they have minimal callosum hypoplasia has been associated with developmental objection to the light or to the proximity of the examiner, as delay, but not with hypopituitarism in children with ONH.26 long as the examiner does not touch the child’s face.

Corpus callosum hypoplasia is detected in 1.8-2.05/10,000 Many authors have suggested that ONH can be confirmed live births and in 2.3% of developmentally disabled with measurements of the optic disc from fundus individuals.28,29 Forty-nine percent of patients with corpus photographs. Most have relied on measurement of disc diameter or area relative to other retinal landmarks. In all callosum hypoplasia have other central nervous system series of normal children, the ratio of the horizontal disc abnormalities, including non-midline defects typically diameter (DD) to the distance between the macula and associated with ONH (cortical heterotopias, schizencephaly, the temporal edge of the disc (DM) has been greater than white matter hypoplasia, polymicrogyria).28 However, 0.35.25,36,37 DD/DM ratios less than 0.35 crudely correlate ONH occurs in less than 10% of children with corpus with vision outcomes.38 Although most patients with DD/ callosum hypoplasia.29 Corpus callosum hypoplasia is DM ratios less than 0.35 have generally been described as associated with a myriad of syndromic conditions and having ONH, some with DD/DM ratios of 0.30 to 0.35 also chromosomal abnormalities, but pituitary dysfunction in had normal vision. Some overlap in optic disc size between those without ONH is uncommon.30 Although both ONH normal and ONH is not surprising. Although the absolute and corpus callosum hypoplasia may be the consequence risk for systemic complications in these borderline cases has of more generalized problems with CNS development, the not been determined, it is clear that some have associated hypopituitarism, so they should not be dismissed as normal presence of ONH appears to be uniquely associated with without appropriate investigation. hypothalamic dysfunction. The average DD/DM ratio of preterm, but otherwise normal, Pituitary Gland infants was 0.26 at birth, according to De Silva et al.39 Pituitary abnormalities on neuroimaging include empty sella, Compared with measurements from adults made by other non-visualized infundibulum, ectopic posterior pituitary, researchers, they estimated that the DD increases 44% in and non-visualized posterior pituitary. These radiographic a lifetime, compared to increases in DM of only 11%. This findings occur in 13-34% of children with ONH, and nearly all

2012 Annual Meeting Syllabus | 105 results in increased DD/DM ratio with age, which presumably Finally, a unique congenital disc anomaly known as superior occurs in the first 2 years of life, concomitant with maximal segmental optic nerve hypoplasia or “topless disc syndrome” growth of the eye. Therefore, the age of the patient may presents as an incidental finding on routine eye examination need to be considered when measuring DD/DM ratios. in children or adults. This is nearly always associated with a history of maternal diabetes during gestation. Such optic Thus far attempts to diagnose ONH or predict vision outcomes discs appear to have the top one-third of the disc missing from other imaging modalities such as optical coherence resulting in inferior visual field defects, but normal visual tomography (OCT) have not been reported. Eyes with ONH acuity. Affected individuals do not have increased risk for may have a poorly developed foveal umbo on OCT in spite any of the neurologic or systemic consequences of ONH, and of otherwise normal appearing foveae on ophthalmoscopic should not be considered to be the same condition. examination.40 The foveolar thickness is normal, but absence of the ganglion cell and nerve fiber layers results in a retina of Vision uniform thickness in which the umbo cannot be distinguished Most children with ONH initially present with vision with OCT. Presumably eyes with ONH and a visible foveal problems. Nystagmus usually develops at 1 to 3 months of umbo could be anticipated to have good vision. age followed by strabismus, typically esotropia, in the first year of life. Children with markedly asymmetric or unilateral ONH may present primarily with strabismus rather than For practical purposes, fundus imaging is not necessary to nystagmus. Patients with relatively symmetric hypoplasia diagnose ONH. An experienced clinician should be able to may have asymmetric vision from superimposed amblyopia assess the area of the disc relative to the area of the central due to strabismus or . retinal vessels overlying it. Approximately 80% of children with ONH are bilaterally In cases of ONH, a ring of hypo- or hyperpigmentation often affected and two-thirds of those are asymmetrically surrounds the disc defining the area of the putative scleral affected.26 The unilateral cases are usually detected at a canal. This is presumably caused by migration of sensory later age than those bilaterally affected. Children with retina and pigment epithelium from their original margin at unilateral ONH are at risk for hypothalamic/pituitary the edge of the optic stalk to a new position at the border dysfunction (69%) and developmental delay (39%), of the optic nerve that failed to fill, or regressed from, this although that risk is significantly lower than those 41 area. This “double ring” sign does not define ONH, as bilaterally affected (81% and 78%, respectively).25,26 a similar appearance may be present in or other common conditions. Visual acuity ranges from no light perception to near normal. More than 80% of bilateral cases are legally blind.45 Most Tortuous retinal arterioles, venules, or both, may affected children enjoy some improvement in their vision in accompany ONH. Alternatively, the vessels may be the first few years of life. It is possible that improved axonal uncommonly straight with decreased branching. Such a function due to optic nerve myelination that occurs in the nonbranching vessel pattern has also been recognized in first 4 years of life is responsible for this benefit.46 Although 42 children with primary growth hormone (GH) deficiency. subjective improvement in visual behavior is common, it is It is not known if the anomalous vascular patterns in ONH difficult to quantify vision improvement in this age group. correlate with the endocrine dysfunction. However, improvement from only light perception behavior to quantifiably functional vision is not rare. ONH has been broadly defined by some to include any optic disc with congenitally decreased neuronal area.43 Hypothalamic dysfunction As such, those eyes with a normal sized optic discs, but Hypothalamic dysfunction is the most common non- with enlarged cups, would qualify as having ONH. Such visual problem in patients with ONH, and results in loss of an appearance typically occurs in premature infants with regulation of homeostatic mechanisms controlling behavior 44 periventricular leukomalacia. Although such optic nerves and pituitary gland function. may have fewer than the normal number of axons and be technically hypoplastic, these children are not at risk for the Hypopituitarism same developmental and endocrinological consequences as In most cases of ONH, hypopituitarism is believed due to children with more typical of ONH. They should, therefore, hypothalamic dysfunction rather than pituitary dysgenesis. not be considered in the same diagnostic category. Thus children with ONH and hypopituitarism usually have moderately elevated serum prolactin levels, as this hormone Similarly, eyes with major congenital malformations such as is normally suppressed by the hypothalamus. Hypopituitarism microphthalmous, large , or persistent hyperplastic was notably uncorrelated with laterality of ONH in a primary vitreous might be expected to have small optic nerves. prospective study from which only 7% of subjects were referred by endocrinologists; thus with limited ascertainment Although occasional patients with bilateral ONH have been bias for hypopituitarism.25 Growth hormone (GH) deficiency seen with major malformations in one eye, a diagnosis of ONH was the most common endocrinopathy (70%), followed by should not be made on the basis of small optic nerves in eyes (43%), adrenocorticotropic hormone (ACTH) affected with other major malformations.

106 | North American Neuro-Ophthalmology Society deficiency (27%), and diabetes insipidus (5%). This high (44%). Independent risk factors for significantly delayed prevalence of endocrinopathy is consistent with previous cognitive and overall development included hypoplasia of retrospective studies.47,48 Delayed or is the corpus callosum and hypothyroidism, but not absence common, but the incidence is unknown. of the septum pellucidum. Developmental delay occurred in unilateral (39%) as well as bilateral (78%) cases of ONH. The incidence of evolving pituitary dysfunction in children with ONH is not currently known, but cases of acquired Autism spectrum disorders are over-represented in the hypopituitarism have been reported.48,49 Thus, the absence visually impaired population, with prevalence estimates of a particular pituitary endocrinopathy does not imply up to 25% in children with severe vision impairment.64 The absence of future pathology. prevalence of autism appears even higher children with ONH. In a group of thirteen Swedish children with ONH Thirst/Hunger and blindness, six had autism and three had an “autistic- Ventromedial nuclei within the hypothalamus suppress like” condition.65 Parr et al. reported that, in a sample hunger and eating in response to leptin, whereas lateral of 83 children with ONH and moderate to severe vision hypothalamic nuclei stimulate feeding behavior and impairment (worse than 6/30), 37% (31/83) had social, 50 regulate metabolism. Thus, children afflicted with communicative and repetitive or restricted behavioral ONH frequently exhibit hyperphagia with obesity or difficulties and the majority of those (26/31) had a clinical hypophagia, with or without wasting. Some children also diagnosis of autism spectrum disorder.66 Precise prevalence have an aversion to certain textures of food. Water-seeking estimates of autism require modifications of the autism behavior (and consequent enuresis) is also common and may be mistakenly attributed to diabetes insipidus. diagnostic instruments for visually impaired subjects. Such modifications have not yet been validated. Sleep The biological clock is generated within the suprachiasmatic Pathogenesis and genetics nuclei of the anterior hypothalamus above the optic chiasm. The presumed association of midline cerebral defects with They receive photic information via the optic nerves to ONH has led to a focus on the genetic mechanisms involved synchronize the clock to the 24-hour light-dark cycle. It is in division of the prosencephalon into cerebral hemispheres necessary to reset the circadian pacemaker each day with and in formation of the pituitary gland. Thus, several visual stimulation.51,52,53 Disturbance of the circadian system candidate genes have been identified as responsible for can have significant, pernicious effects on physiology and cases of “SOD.” These include mutations of HESX1 associated behavior.54,55 Many children with ONH have primary clock with and SOX2 associated with anterior lesions with loss of rhythmicity and sleep or wakefulness pituitary hypoplasia and hypogonadism. Only five cases of distributed over the 24-hour day.56,57 Alternatively, they may ONH in humans have ever been associated with the HESX1 67,68 have inadequate retinohypothalamic input to daily entrain mutation. Some of these were seen in cases of severe 69 the circadian clock, resulting in free-running sleep-wake forebrain malformation, such as alobar holoprosencephaly. cycles asynchronous with other family members. In either Such major malformations would be expected to impact case, such sleep irregularities commonly result in behavioral the development of subsequent structures such as the optic difficulties and disruption to family life. nerves, corpus callosum and septum pellucidum. However, the vast majority of cases of ONH cannot be attributed to Temperature regulation specific mutations. In fact, less than 1% of cases of ONH in The medial preoptic region of the hypothalamus is large series were found to have an HESX 1 mutation and 70,71 involved in fine body temperature regulation and, through none were found to have SOX2 mutations. communication with the paraventricular nucleus, regulates fever response.58 It is therefore not surprising that many The dearth of families with more than one affected infants and children with ONH have problems with body child and the lack of substantiated reports of trans- temperature regulation and may be frequently hospitalized generational transmission argue against a hereditable to rule out sepsis.59 cause for most cases of ONH. Fundus photographs from the only multigenerational report are not convincingly Developmental outcomes representative of ONH.72 There have been no reports of Margalith et al. in 1984 were the first to report affected identical twins. developmental delays in ONH, estimating neuropsychological handicaps in nearly three-fourths of cases of ONH.60 Burke Prenatal risk factors et al estimated delayed development, based on neurologic Lack of definitive genetic associations has led to a search examination, at a similar frequency.61 Observations of for prenatal environmental or biological risk factors for developmental delay in association with ONH range from development of ONH. Nearly all prenatal associations with 62,63 isolated focal defects to global delay. Garcia-Filion et ONH originate from retrospective review of records or al. found developmental delays in 71% of ONH patients anecdotal reports. The most commonly reported associations using standardized neuropsychological instruments in a 60,68,70,73,74 26 include young maternal age and/or primiparity, prospective study. Motor delays were the most common 3,45,60,75,76 (75%) and communication delays were the least common maternal use of recreational drugs (eight total cases),

2012 Annual Meeting Syllabus | 107 anticonvulsants (nine total cases),59,75,77 antidepressants (three Endocrinologic work-up should include fasting morning total cases),20,73,78 and viral infections during pregnancy (four and glucose, thyroid stimulating hormone, free T4, total cases).60,61,79 In small case series, ONH has been reported and the growth hormone surrogates - insulin-like growth in 25-48% of children with fetal alcohol syndrome,80,81 but in factor 1 (IGF-1) and insulin-like growth factor binding protein 3 large series of near-consecutive cases of ONH, any prenatal (IGFBP-3). If the child is less than 6 months of age, leuteinizing alcohol exposure was reported in 6-33%, and there were no hormone, follicle-stimulating hormone, and/or testosterone reports of excessive prenatal alcohol consumption.82,83 levels should be checked in order to anticipate delayed sexual development. Beyond 6 months of age, sex hormones are Only two studies have systematically and sequentially not normally produced until puberty, and thus cannot be investigated prenatal correlates in large cohorts of tested. Micropenis, also a harbinger of delayed puberty, can be patients with ONH. The first was a case-control study treated with testosterone injections during infancy. of 100 severe bilateral cases in Sweden, and data were obtained from interviews conducted in the first trimester Children should be monitored at least semi-annually for of pregnancy by a variety of midwives.73 That data has growth. With growth deceleration, thyroid function tests the advantage of being relatively unbiased by recall should be repeated and provocative GH testing should be or pregnancy outcomes, but the disadvantage of not performed. These should also be done if IGF-1 or IGFBP-3 is capturing associations that may have occurred after the low, even if the child is growing normally. Free T4 should be interview. That study found increased risk with young rechecked at least semi-annually until two years of age and maternal age, primiparity, and early prenatal smoking annually thereafter until at least four years of age. exposure, but not with drug or alcohol exposure. If fasting morning cortisol is low, it should be repeated The second study used a post-natal questionnaire and or provocative testing for cortisol should be done. This compared exposures with national registry data from can often be done simultaneously with GH testing, pregnant women during the same period of time. 83 This using glucagon as the provocative agent. Children with study confirmed that young maternal age and primiparity inadequate cortisol response to provocative tests should were independent risk factors, but refuted an association be given both oral and injectable forms of glucorticoids for with tobacco, alcohol, or drug exposure. In addition, it administration during illness or physical stress. suggested pre-natal maternal weight loss or poor weight gain, and premature labor (without premature birth) as Occupational, physical, and/or speech therapy are additional risk factors. There was no association with frequently needed by children with ONH. Attention should gestational diabetes mellitus, as has been reported for the especially be given to early development of oral motor “topless disc syndrome. skills and acclimation to textured foods for those children resistant to eating. Incorporating dialogue into song can Management sometimes ameliorate delayed verbal communication. Since ONH is particularly associated with abnormal hypothalamic function, physicians should be vigilant for signs Children with autistic behaviors should be evaluated by of hypothalamic dysfunction along with any vision problems in a neuropsychologist skilled in autism assessment as well children and vice-versa. Therefore, all neonates with jaundice as experienced in dealing with visually impaired children. and recurrent hypoglycemia should have ophthalmoscopic Lacking such experience, the autism expert should enlist evaluation, especially if associated temperature instability. Similarly, all infants with poor visual behavior, strabismus, assistance from a teacher for the visually impaired to or nystagmus by three months of age should have an appropriately modify the testing instruments. ophthalmoscopic examination to rule out ONH. Sleep dysregulation can sometimes be alleviated by Once ONH is confirmed ophthalmoscopically, MRI of the entraining the circadian clock with low doses (0.1–0.5 mg) brain should be obtained. The MRI can rule out treatable of melatonin in the evening or, alternatively, with soporific conditions such as hydrocephalus but can also be used to doses (3–5 mg) at bedtime.56 anticipate developmental delay associated with corpus callosum hypoplasia or other major malformations. Major The vision of young children with ONH should be monitored malformations such as schizencephaly or polymicrogyria at least annually, and any refractive errors should be treated should prompt neurologic examination in anticipation of when the visual acuity reaches a functional level. Patching focal deficits or seizures. In the past MRI of the brain was of the better eye can result in improvement of vision in the used to identify absence of the septum pellucidum in order worse eye. However, if the ONH is asymmetric, maintenance to determine the need for endocrinologic evaluation. This of improved vision requires prolonged patching that can feature can now be disregarded, as all children with ONH be disruptive to development in a child with many other regardless of the septum pellucidum status need pituitary handicaps. Thus, amblyopia therapy should be reserved function evaluated. 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.

108 | North American Neuro-Ophthalmology Society Early surgical correction of strabismus should be reserved 11. Schwarz O. Ein Fall von mangelhafter Bildung beider Sehnerven. for children who have symmetrical functional vision in the Albrecth von Graefes Arch Klin Ophthalmol. 90:326, 1915. eyes, and thus some potential for binocularity. Otherwise, 12. Reeves D. Congenital absence of the septum pellucidum. Bull Johns correction of strabismus should be deferred until it is an Hopkins 69:61, 1941. impending psychosocial issue. 13. Straatsma BS: Irvine R., Trans Am Ophthalmol Soc. 98:9, 2000. 14. De Morsier G. Etudes sur les dysraphies cranio-encephaliques: Conclusion Agenesis du septum lucidum avec malformation du tractus optique. Optic nerve hypoplasia is an increasingly prevalent, La dysplasie septo-optique. Schweizer Archiv fur Neurologie und Psychiatrie 77:267, 1956. probably non-hereditary, cause of congenital blindness that 15. De Morsier G. Median cranioencephalic dysraphias and olfactogenital is the unifying feature of a syndrome that usually includes dysplasia. World Neurology 3:485 1962. developmental, hypothalamic and/or neuro-anatomical 16. Gross H, Hoff H. Sur les malformations ventruculaires dependantes abnormalities. The first recognized association was with des dysgenesies commisurales. In: Heuyer G, Feld M, Gruner J, eds. absence of the septum pellucidum. It is now recognized Malformations congentales du cerveau. Paris: Masson, 1959: 329-51. that this is the least significant, and least prognostic, of 17. Ellenberger C, Runyan TE. Holoprosencephaly with hypoplasia of the the associated abnormalities. The presence of ONH alone optic nerves, dwarfism, and agenesis of the septum pellucidum. Am J imparts risk for serious systemic and neurologic problems Ophthalmol. 70:960, 1970. that need to be carefully monitored. Focus on the septum 18. Hoyt WF, Kaplan SL, Grumbach MM, et al. Septo-optic dysplasia and pellucidum has distracted physicians from the serious pituitary dwarfism. Lancet. 1:893, 1970. and complicated nature of the syndrome. “Septo-optic 19. Hedges TR. Charles Bonnet, his life, and his syndrome. Surv dysplasia” and “de Morsier’s syndrome” are inappropriate Ophthalmol. 52:111, 2007. and historically inaccurate terms that should be abandoned. 20. Birkebaek N, Patel L, Wright NB, et al.: Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab.: CME Answers 88:5281, 2003. 1. false 21. Patel H, Tze WJ, Crichton JU, et al.: Optic nerve hypoplasia with hypopituitarism. Septo-optic dysplasia with hypopituitarism, Am J Dis 2. central hypothyroidism; Child. 129:175, 1975. 3. true, but at less risk than those with Bilateral ONH. 22. Williams J, Brodsky MC, Griebel M, et al.: Septo-optic dysplasia: the clinical insignificance of an absent septum pellucidum, Dev Med Child Neurol. 35:490, 1993. 23. Wilson DM, Enzmann DR, Hintz RL, et al. Computed tomographic References findings in septo-optic dysplasia: discordance between clinical and 1. Blohme J, Tornqvist K.: in Swedish children. III. radiological findings, Neuroradiology 26:279, 1984. Diagnoses. Acta Ophthalmol Scand. 75:681, 1997. 24. Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance 2. Blohme J, Bengtsson-Stigmar E, Tornqvist K. Visually impaired of associated central nervous system abnormalities on magnetic Swedish children. Longitudinal comparisons 1980-1999. Acta resonance imaging, Arch Ophthalmol. 111:66, 1993. Ophthalmol Scand. 78:416, 2000. 25. Ahmad T, Garcia-Filion P, Borchert M, et al. Endocrinological and 3. Patel L, McNally R, Harrison E, Lloyd IC, et al.: Geographical auxological abnormalities in young children with optic nerve distribution of optic nerve hypoplasia and septo-optic dysplasia in hypoplasia: a prospective study, J Pediatr. 148:78, 2006. Northwest England. J Pediatr.; 148:85, 2006. 26. Garcia-Filion P, Epport K, Nelson M, et al. Neuroradiographic, 4. Jan J, Robinson G, Kinnis C, McLeod PJ. Blindness due to optic-nerve endocrinologic, and ophthalmic correlates of adverse developmental atrophy and hypoplasia in children: an epidemiological study (1944- outcomes in children with optic nerve hypoplasia: a prospective 1974). Dev Med Child Neurol. 19:353,1977. study, Pediatrics 121:e653, 2008. 5. Acers TE. Optic nerve hypoplasia: septo-optic-pituitary dysplasia 27. Miller SP, Shevell MI, Patenaude Y, et al. Septo-optic dysplasia plus: syndrome. Trans Am Ophthalmol Soc.; 79:425, 1981. A spectrum of malformations of cortical development, Neurology 54:1701, 2000. 6. Williamson WD, Desmond MM, Andrew LP, et al. Visually impaired infants in the 1980s. A survey of etiologic factors and additional handicapping 28. Glass HC, Shaw GM, Ma C, et al. Agenesis of the corpus callosum in conditions in a school population. Clin Pediatr 26:241, 1987. California 1983-2003: a population-based study, Am J Med Genetics 146A:2495, 2008. 7. DeCarlo DK, Nowakowski R. Causes of visual impairment among students at the Alabama School for the Blind. J Am Optom Assoc. 29. Szabo N, Gergev G, Kobor J, et al. Corpus callosum anomalies: birth 70:647, 1999. prevalence and clinical spectrum in Hungary, Pediatr Neurol. 44:420, 2011. 8. Mets MB. Childhood blindness and visual loss: an assessment at 30. Schell-Apacik CC,1* Wagner K,1 Bihler M, et al.: Agenesis and dysgenesis two institutions including a “new” cause. Trans Am Ophthalmol Soc. of the corpus callosum: Clinical, genetic and neuroimaging findings in a 97:653, 1999. series of 41 patients. Am J Med Genet A. 146A:2501, 2008. 9. Hatton D, Schwietz E, Boyer B, et al. Babies Count: the national 31. Phillips PH, Spear C, Brodsky MC. Magnetic resonance diagnosis of registry for children with visual impairments, birth to 3 years. J congenital hypopituitarism in children with optic nerve hypoplasia, AAPOS 11:351, 2007. JAAPOS 5:275, 2001. 10. Magnus K. Clin Monatsbl Augenh 32:85, 1884. 32. Kucharczyk W, Lenkinski RE, Kucharczyk et al. The effect of phospholipid vesicles on the NMR relaxation of water: an explanation for the MR appearance of the neurohypophysis? AJNR 11:693, 1990.

2012 Annual Meeting Syllabus | 109 33. Birkebaek NH, Patel L, Wright NB, et al., Optic nerve size evaluated by 54. Edgar DM, Dement WC, Fuller CA.: Effect of SCN lesions on sleep in magnetic resonance imaging in children with optic nerve hypoplasia, squirrel monkeys: evidence for opponent processes in sleep-wake multiple pituitary hormone deficiency, isolated growth hormone regulation, J Neurosci. 13:1065, 1993. deficiency, and idiopathic short stature, J Pediatr 145:536, 2004. 55. Moore-Ede MC, Czeisler CA, Richardson GS.: Circadian timekeeping in 34. Hellstrom A, Wiklund LM, Svensson E: Diagnostic value of magnetic health and disease. Part 1. Basic properties of circadian pacemakers, resonance imaging and planimetric measurement of optic disc size N Engl J Med. 309:469, 1983. in confirming optic nerve hypoplasia, J Am Assoc Pediatr Ophthalmol 56. Rivkees SA.: Arrhythmicity in a child with septo-optic dysplasia and Strabismus 3:104, 1999. establishment of sleep-wake cyclicity with melatonin, J Pediatr. 35. Brodsky MC, Glasier CM, Pollock SC, et al.: Optic nerve hypoplasia: 139:463, 2001. Identification by magnetic resonance imagjng. Arch Ophthalmol, 57. Rivkees S, Fink C, Nelson M, et al.: Prevalence and risk factors 108:1562, 1990. for disrupted circadian rhythmicity in children with optic nerve 36. Borchert M, McCulloch D, Rother C, et al.: Clinical assessment, optic hypoplasia, Br. J. Ophthalmol. 94:1358, 2010. disk measurements, and visual-evoked potential in optic nerve 58. Scammell TE, Elmquist JK, Griffin JD, et al. Ventromedial preoptic hypoplasia, Am J Ophthalmol. 120:605, 1995. prostaglandin E2 activates fever-producing autonomic pathways, J 37. Zeki SM, Dudgeon J, Dutton GN.: Reappraisal of the ratio of disc to Neurosci. 16:6246, 1996. macula/disc diameter in optic nerve hypoplasia, Br J Ophthalmol. 59. McMahon C, Braddock S.: Septo-optic dysplasia as a manifestation of 75:538, 1991. valproic acid embryopathy, Teratology 64:83, 2001. 38. McCulloch DL, Garcia-Filion P, Fink C, et al. Clinical electrophysiology 60. Margalith D, Jan JE, McCormick AQ, et al.: Clinical spectrum of optic and visual outcome in optic nerve hypoplasia, Br J Ophthalmol. nerve hypoplasia: a review of 51 patients, Dev Med Child Neurol. 94:1017, 2010. 1984; 26:311–322. 39. De Silva DJ, Cocker KD, Lau G, et al.: Optic disk size and optic disk-to- 61. Burke J, O’Keefe M, Bowell R.: Optic nerve hypoplasia, fovea distance in preterm and full-term infants, Invest Ophthalmol encephalopathy, and neurodevelopmental handicap, Br J Vis Sci. 47:4683, 2006. Ophthalmol. 75:236, 1991. 40. Srinivasan G, Venkatesh P, Garg S.: Optic nerve head, retinal 62. Garcia ML, Ty EB, Taban M, et al.: Systemic and ocular findings in 100 nerve fiber layer, and macular thickness characteristics on optical patients with optic nerve hypoplasia, J Child Neurol. 21:949, 2006. coherence tomography in optic disk hypoplasia. J Ped Ophthalmol Strab. 2007; 44:140-141. 63. Griffiths P, Hunt S.: Specific spatial defect in a child with septo-optic dysplasia, Dev Med Child Neurol. 26:395, 1984. 41. Mosier MA, Lieberman MF, Green WR, et al. Hypoplasia of the optic nerve, Arch Ophthalmol. 96:1437, 1978. 64. Brown R, Hobson RP, Lee A, et al.: Are there “autistic-like” features in congenitally blind children? J. Child Psychol. Psychiat. 36:693, 1997. 42. Hellstrom A, Svensson E, Carlsson B, et al.: Reduced retinal vascularization in children with growth hormone deficiency, J Clin 65. Ek U, Fernell E, Jacobson L.: Cognitive and behavioural characteristics Endocrinol Metab. 84:795, 1999. in blind children with bilateral optic nerve hypoplasia, Acta Paediatrica. 94:1421, 2005. 43. Jacobson L, Hellstrom A, Flodmark O.: Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with 66. Parr JR, Dale NJ, Shaffer LM, et al.: Social communication difficulties periventricular leukomalacia, Arch Ophthalmol. 115:1263, 1997. and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia, Dev Med Child Neurol. 44. Brodsky MC.: Periventricular leukomalacia: an intracranial cause of 52:917, 2010. pseudoglaucomatous cupping, Arch Ophthalmol. 119:626, 2001. 67. Tajima T, Hattorri T, Nakajima T, et al.: Sporadic heterozygous 45. Siatkowski R, Sanchez J, Andrade R, et al.: The clinical, frameshift mutation of HESX1 causing pituitary and optic nerve neuroradiographic, and endocrinologic profile of patients with hypoplasia and combined pituitary hormone deficiency in a Japanese bilateral optic nerve hypoplasia, Ophthalmology 104:493, 1997. patient, J Clin Endocrinol Metab. 88:45, 2003. 46. Magoon EH, Robb RM.: Development of myelin in human optic nerve 68. Webb EA, Dattani MT.: Septo-optic dysplasia, Eur J Hum Genetics and tract. A light and electron microscopic study, Arch Ophthalmol. 18:393, 2010. 99:655, 1981. 69. Dattani MT, Martinez-Barbera JP, Thomas PQ, et al.: Mutations in the 47. Reidl S, Mullner-Eidenbock A, Prayer D, et al.: Auxological, homeobox gene HESX1/Hesx1 associate with septo-optic dysplasia in ophthalmological, neurological and MRI findings in 25 Austrian patients human and mouse, Nat Genet. 19:125, 1998. with septo-optic dysplasia (SOD), Horm Res. 58(Suppl. 3):16, 2002. 70. McNay DE, Turton JP, Kelberman D,et al.: Candidate gene sequencing 48. Haddad NG, Eugster EA.: Hypopituitarism and neurodevelopmental of LHX2, Hesx1, and SOX2 in a large schizencephaly cohort, Am J Med abnormalities in relation to central nervous system structural defects Genet A. 1562A:2736, 2010. in children with optic nerve hypoplasia, J Pediatr Endocrinol Metab. 18:853, 2005. 71. Mellado C, Poduri A, Gleason D, et al.: Candidate gene sequencing of LHX2, Hesx1, and SOX2 in a large schizencephaly cohort, Am J Med 49. Ma NS, Geffner ME, Borchert M. Evolving central hypothyroidism in Genet A. 1562A:2736, 2010. children with optic nerve hypoplasia, J Ped Endocrinol Metab. 23:53, 2010. 72. Hackenbruch, Y, Meerhoff E, Besio R, et al.: Familial bilateral optic 50. Elmquist JK.: Hypothalamic pathways underlying the endocrine, nerve hypoplasia, Am J Ophthalmol. 79:314, 1975. autonomic, and behavioral effects of leptin, Physiol Behav. 74:703, 2001. 73. Tornqvist K, Ericsson A, Kallen B.: Optic nerve hypoplasia: risk factors 51. Moore RY.: Circadian rhythms: basic neurobiology and clinical and epidemiology, Acta Ophthalmol Scand. 80:300, 2002. applications, Annu Rev Med. 48:253, 1997. 74. Murray PG, Paterson WF, Donaldson MD.: Maternal age in patients 52. Panda S, JB Hogenesch, Kay SA.: Circadian rhythms from flies to with septo-optic dysplasia, J Pediatr Endocrinol Metab. 18:471, 2005. human, Nature. 417:329, 2002. 75. Hoyt C, Billson F.: Maternal anti- convulsants and optic nerve 53. Weaver DR.: The suprachiasmatic nucleus: a 25-year retrospective, J hypoplasia, Br J Ophthalmol. 62:3, 1978. Biol Rhythms. 13:100, 1998. 76. Hotchkiss M, Green W.: Optic nerve aplasia and hypoplasia, J Pediatr Ophthalmol Strabismus 16:225, 1979.

110 | North American Neuro-Ophthalmology Society 77. West J, Burke J, Strachan I.: Carbamazepine, epilepsy, and optic nerve 81. Ribeiro IM, Vale PJ, Tenedorio PA, et al. Ocular manifestations in fetal hypoplasia, Br J Ophthalmol. 74:511, 1990. alcohol syndrome, Eur J Ophthalmol. 17:104, 2007. 78. Hellstrom A, Wiklund L, Svensson E.: The clinical and morphological 82. Roberts-Harry J, Green S, Willshaw H.: Optic nerve hypoplasia: spectrum of optic nerve hypoplasia, JAAPOS 3:212, 1999. associations and management, Arch Dis Child. 65:103, 1990. 79. Hittner H, Desmond M, Montgomery J.: Optic nerve manifestations 83. Garcia-Filion P, Fink C, Geffner M, et al.: Optic nerve hypoplasia of cyto- megalovirus infection, Am J Ophthalmol. 81:661, 1976. in North America: a re-appraisal of perinatal risk factors, Acta Ophthalmol Scand. 88:527, 2010. 80. Stromland K.: Ocular involvement in the fetal alcohol syndrome, Surv Ophthalmol. 31:277, 1987.

2012 Annual Meeting Syllabus | 111 112 | North American Neuro-Ophthalmology Society Why Juvenile Pilocytic Astrocytoma Optic Pathway Gliomas Are Hamartomas

Cameron F. Parsa, MD University of Wisconsin Madison, WI

Learning Objectives This presentation, however, shall only specifically address 1. That Grade I juvenile pilocytic astrocytomas (optic the behavior of Grade I juvenile pilocytic astrocytomas, gliomas) are self-limited growths which meet all criteria those more commonly referred to as optic gliomas. for designation as hamartomas. Grade II and higher malignant gliomas of the anterior visual pathway that behave more aggressively, including 2. Anti-mitotic regimens, both ionizing radiation therapy glioblastoma multiforme, are recognized in adults 1,2 and and genotoxic chemotherapy have failed to show any may occasionally also occur in children; 3,4,5,6 their diagnosis efficacy. By failing to stratify “optic pathway gliomas and treatment, altogether different, is not discussed here. (OPG)” or “low-grade gliomas (LGG)” into Grade I and Grade II tumors, and by assuming that an initial decline Optic gliomas (World Health Organization grade I pilocytic in visual acuity is indicative of an enlarging tumor astrocytomas) do, of course, represent tumors.7 Such necessitating treatment when the opposite may be the terminology, however, while technically correct, remains case, published results have had little relevance. imprecise and can be misleading. The normal crystalline of the eye, for example, also represents a tumor, yet Intracranial and intraorbital optic gliomas should be treated 3. to call it so with patients would unquestionably lead to in much the same way as those which occur intraocularly. irresponsible and inappropriate interventions.8

The situation with juvenile pilocytic gliomas is not entirely CME Questions dissimilar. By alluding to these masses simply as tumors, or 1. Are optic pathway gliomas or low grade gliomas by including them within categories such as “OPG” (optic synonymous with Grade I, juvenile pilocytic pathway gliomas) or “LGG” (low-grade gliomas) which astrocytomas, commonly referred to as optic gliomas? are inclusive of frank neoplasms such as Grade II fibrillary gliomas, one leads both family members and physicians 2. Does the term hamartoma indicate stability and lack of alike toward antimitotic and genotoxic therapies that, to growth during development? date, have had no proven efficacy.8, 9, 10, 11,12,13, 14, 15, 16, 17, 18 The 3. Does a decline in visual acuity indicate that an optic term neoplasm, which commonly implies a more general glioma is growing? and uncontrolled status of cellular proliferation, with active mitoses, does not apply to these developmental lesions, many of which remain stable and asymptomatic, or regress Keywords (when they ever do actually grow, it is only during the period of development, hence the adjective “juvenile”). Whether 1. Hamartoma benign or malignant, the word neoplasm literally means a 2. Non-Stratified Data new growth, from the Greek neo-, new + plasma, that which is formed, or a growth = a new growth. Most optic gliomas, 3. Collins’ Law on the other hand, represent congenital lesions that remain 4. Mucosubstance stable; i.e., they are not new and do not grow.

5. Natural History Optic Glioma The terms hamartoma and choristoma were created by Albrecht 19, 20 in 1904, to designate tumors that had the potential to grow in self-limited form during the period of It is important to recognize that many optic pathway development. Hamartoma signifies a disorganized overgrowth gliomas (OPG) do represent neoplasms, since OPGs are of differentiated tissue normal to a site, while choristoma defined as a collection of both pilocytic WHO Grade I as indicates such growth when it is ectopic to the organ location. well as fibrillary WHO Grade II and higher tumors. Bill Hoyt This terminology has been used, without controversy, to along with Leroy Meshel, Simmons Lessell, Norman Schatz, describe the evident growth of optic disk and retinal glial and Rod Suckling were among the first, in 1973, to define hamartomas in tuberous sclerosis, or of the melanocytic such neoplasms affecting the visual pathways.1 iris hamartomas known as Sakurai-Lisch nodules in NF1. 2012 Annual Meeting Syllabus | 113 Choristomas, such as dermoids, may certainly also enlarge, both T1- and T2-weighted MRI signal abnormalities in NF-1 often via the accumulation of mucosubstance or glandular patients disappear later in life is indicative that a process secretions. The notion that gliomas represent relatively of spontaneous glial regression must be widespread.40, 44, stable congenital growths was first hinted by Hudson in 45 Spontaneous regression is often overlooked in patients 1912.21 Histopathologists, notably Davis 22 and to some extent known to harbor an optic glioma whose clinical condition Zimmerman 23 described the essentially hamartoma-like has remained stable for many months or years and for whom qualities of these tumors in their written correspondence. repeat scans are not performed, or for whom the older scans These gliomas were openly declared to have the features of are no longer available for comparison. Since first reported congenital hamartomata by Hoyt and Baghdassarian in 1969,24 by Brzowski and colleagues in 1992, 46 it is being noted with and later by Borit and Richardson 25 who also espoused this increasing frequency. The personal experience of virtually opinion. The previous inability to monitor juvenile pilocytic all those who have reported instances of MRI-documented astrocytomas intracranially, however, and the more serious spontaneous regression has been to subsequently identify consequences that could entail from enlargement within further cases in their practices. the limited cavitary space of the skull, understandably led to difficulties in ascertaining their self-limited growth Mechanisms, such as programmed cell death (apoptosis) pattern and hesitancy amongst some to call them outpacing proliferation of cells may be involved. Given hamartomas. Subsequent rare descriptions, beginning only that the proliferation of juvenile pilocytic astrocytoma cells in the 1970s, of apparent anaplastic transformations also slows down with age,47 it is plausible to think that given served to undermine these notions. enough time, and the patient ability to endure its presence, most such tumors would eventually regress. The well- The more recent advent of neuroimaging has, however, established fact that recurrences following surgery of these confirmed only occasional growth during the period of Grade I masses, unlike that for Grade II and higher tumors, development, along with the possibility for spontaneous do not follow Collins’ law of exponential growth patterns as regression. Most growth, furthermore, has been related to a function of patient age, is also indicative of this. 11, 48 microcystic collections of mucosubstance and hydration, 9, 26 not proliferation of a solid tumor component.27 No consensus exists regarding the criteria for classifying pilocytic astrocytomas with atypical features. However, Growth of the solid tumor portion of gliomas is a function of many features indicated by some authors, such as both cellular proliferative and apoptotic activity; both may hyperchromasia, multinucleated cells, microvascular be high, or both low, reflecting a steady-state function within proliferation, necrosis, increased cellularity, and even at a tumor that demonstrates clinical stability. 28, 29 For these times a higher than usual rate of mitosis, in general, are reasons, histopathological examinations assessing proliferative not accepted by histopathologists to be associated with activity alone using immunohistochemical labeling indices, anaplasia or malignancy. Some of these features merely such as MIB-1 to detect Ki-67 protein associated with represent degenerative atypia seen more often with aging, cells during their proliferative phase, 5,6, 7, 30 without also while other features have no proven relationship with ascertaining the rate of apoptosis, cannot provide information malignant behavior or survival. 23, 25, 49-52 of prognostic utility. 8, 31 Inherently limited biopsy sampling sizes for tumors that are known to be heterogenous both in Misleading terminology is also sometimes used to describe their composition and in their growth patterns and phases, mostly adult and Grade II and higher gliomas as “pilocytic- further limits the prognostic potential for such approaches. like”, “atypical pilocytic”, or “pilocytic with anaplastic features” 5, 53 causing many to erroneously believe an By definition, Grade 1 pilocytic gliomas possess only rare, if anaplastic transformation of Grade I tumors into a higher any, mitotic figures and the majority of tumors demonstrate grade neoplasm occurred. overall stability 9, 24, 32 with only limited growth potential during development. Unlike higher grade gliomas, they do A recent review of the literature, however, revealed that all not show p53 mutations.28 and no genetic changes typically individuals who suffered actual anaplastic transformation associated with the more clinically aggressive fibrillar all had had tumors that had been irradiated years before. astrocytomas have been found in these masses.33, 34 53,54 Such anaplastic degenerations of Grade I pilocytic astrocytomas, the first cases reported in the 1970s, On the other hand, spontaneous regression may also occur, were therefore all iatrogenic in origin while spontaneous 31 and once a tumor is discovered, it is as likely to shrink given anaplastic degeneration does not occur.53 As early as enough time, as it is to grow initially. 13, 16, 17, 18, 31,35 Although 1937, the possibility of radiotherapy inducing malignant as many as 25% of children with NF1 have gliomas, 36, 37, 38, transformation of astrocytomas had been raised by Tarlov,55 39 such incidences have not been noted in adults with NF1, with others later also voicing similar concerns.56-58 and virtually no new cases present in adults with, or without, NF1. These studies and others 36, 37, 40-43 have also indicated Gliomas also do not metastasize in the usual sense; or shown T2-weighted signal abnormalities at some point during infancy, rarely, “drop metastases,” often in as many as 80% of patients with NF-1. The fact that asymptomatic in nature, may occur to the leptomeninges

114 | North American Neuro-Ophthalmology Society via the cerebrospinal fluid passageways after surgical More recent surveys and other studies, particularly manipulations during ventricular shunt placement, or from the neurosurgical literature, with some specifically less commonly, after hemorrhagic cystic degeneration addressing in part some of these concerns have confirmed and rupture, 59-62 much as occurs with such acknowledged the lack of beneficial treatment effects in the face of intraocular hamartomas such as astrocytic or glial tumors demonstrated toxicities. 12,17,18 of the optic disc or retina 63-66 both when isolated or in the setting of tuberous sclerosis, and for hamartomas in other Optic nerve gliomas situated anterior to the chiasm may sites and settings. 67-70 appear as threatening to involve this structure and affect contralateral vision. 31 Despite radiological appearances, Given these above characteristics, these tumors indeed such reports are rare 79, 80 and evidence is lacking to show fulfill the criteria for, and are best described as, glial such evolution often occurs 77, 79, 80 or that surgical excision hamartomas. 8, 19, 20, 24, 53, 71 of such tumors 81 would prevent anticipated contralateral eye involvement; one may instead be witnessing instead Since mitoses, by definition, are very rare, if at all present multicentric nests of cells within different phases of in these lesions, no clinically significant benefit should be growth rather than a true progression and invasion of cells expected from anti-mitotic ionizing radiation beyond that moving forward. 26, 82 expected from background spontaneous regression as part of the natural evolution of these tumors. 9, 10, 13, 14, 16 Multifocal growth, as well as regression, may occur contemporaneously or at different times with either or both Due to the severe adverse effects, moreover, of radiation optic nerves affected, sparing chiasm, or vice-versa. 31, 82 on incompletely myelinated and still developing Hence surgical resection of a distal optic nerve tumor may not brain—including severe mental and growth retardation, necessarily prevent later growth more proximally. 26, 83, 77, 82 psychiatric problems, vascular occlusions and the induction of second tumors—attempts at treatment via Resection of the intracranial portion of an optic nerve ionizing radiation are now universally contraindicated in near the chiasm, furthermore, can endanger chiasmal young children. blood supply, with spreading necrosis. However, surgical decompression of an expanded nerve sheath, with For similar reasons, anti-mitotic chemotherapy can also aspiration of perineural mucoid contents can be considered offer no benefits. In previous studies reporting minor if visual obscurations are due to mucoid accumulation and treatment effects, investigators failed to stratify results hydration. If disfiguring proptosis is present and there is for those with “low-grade gliomas (LGG)” or “optic evidence of steady tumoral enlargement on sequential pathway gliomas (OPG)” into those with Grade I pilocytic MRI scans, with total absence of the intraocular nerve fiber gliomas versus those with Grade II fibrillary astrocytomas. layer, it is certainly reasonable to surgically remove the As with initial reports ascribing benefits to radiation intraorbital portion of the nerve, preserving posterior ciliary therapy, these studies also did not factor for the fact of blood supply and for cosmetic purposes. 24, 21, 84, 85 spontaneous regression acknowledged by their authors 31, 53, 72 and often include instances of tumor regression Though some have believed that gliomas occurring in the long after the cessation of therapy as a treatment effect. presence of NF1 have a better visual prognosis compared 73 Whenever recurrences and regressions do occur, again, to those occurring sporadically, such impressions are due they often violate the timeframes set by Collins’ law for to selection biases; since most NF1-associated gliomas are neoplastic growth.11, 48 detected by surveillance MRI scans ordered for asyptomatic NF1 patients, many clinically insignificant tumors are Declining acuity has long been well-known and thus detected. Individuals without NF1, on the other documented not to correlate with tumor size or with tumor hand, present to the physician only when they have large, enlargement. 9, 31, 74, 75, 76, 77 Even the spontaneous regression symptomatic masses. Overall survival for those with NF1- of tumors can reduce visual acuity and function by associated gliomas, moreover, is worse; since these patients distorting nerve axons. 31, 74 For reasons unjustified, a loss of have an underlying mutation in the NF1 tumor suppressor vision is nonetheless used in many treatment protocols as gene, they tend to develop, for reasons not well understood, a triggering measure to initiate chemotherapy, or, in older 86 other, non-neural crest derived, tumors, particularly soft- children, radiotherapy. 7, 77, 78 tissue sarcomas,32, 82, 87 and myelogenous disorders.

Ignoring the fact that even a spontaneously shrinking tumor With a lack of beneficial radiative or antimitotic intrinsic to the visual pathways can reduce visual acuity, chemotherapeutic effects, and with limited indications it should be of no surprise then if subsequent immediate for surgical intervention of optic gliomas, the emphasis radiographic evidence demonstrates a reduction in tumor of management for the moment must therefore be size, with the temporal correlation held to support an effect conservative. A reasonable approach is to follow clinical of the “treatment,” rather than a process already in . 74 symptomatology, addressing secondary issues as they may arise, i.e., placing a shunt to deal with an obstructive

2012 Annual Meeting Syllabus | 115 hydrocephalus, addressing endocrine abnormalities It will be very useful to stratify and separate the radiologically- associated with a hypothalmic/chiasmal gliomas, or defined behavior of Grade I juvenile pilocytic astrocytoma instituting penalization therapy if a strabismus is present. hamartomas from Grade II astrocytoma neoplasms in ongoing In rare settings where exophytic growth is noted, when studies of antimitotic chemotherapeutic regimens. If the draining symptomatic cysts or mucinoid accummulations non-stratified radiologic data can ultimately be stratified may be possible, or whenever there is no hope for visual and published, current multicenter trials using anti-mitotic recovery due to total absence of intraocular nerve fiber regimens ineffective against such optic glioma hamartomas layer, excisional surgery can be considered. A comprehensive which, by definition have little to no mitoses, could be put to discussion should take place with the family to ensure good use and serve as effective surrogates to delineate the their understanding of the lack of efficacy of anti-mitotic natural history of these tumors. These studies could then regimens and of the not-inconsequential adverse effects be used in a most constructive manner to determine the they induce. It follows that frequent neuroimaging in those effectiveness of novel and more appropriately targeted non- known to harbor a tumor may not be warranted. Use of the antimitotic treatments such as, for example, ripamycin for more precise term “hamartoma,” rather than the broader inhibition of mTOR, or bevacizumab to inhibit angiogenesis71, 93, 94 designation of “tumor,” which is psychologically more and for other yet untested pharmacologic agents that will offer threatening and evocative of neoplasms, can be helpful. 8, 71 better potential in years to come. In children who also have NF1, pointing out the melanocytic hamartoma Sakurai-Lisch nodules that grow post-natally on The use of these and other newer agents in patients with the irides can serve as a helpful educational analogy. More large intraocular hamartomas threatening ocular structures often than not, parents are relieved to hear that their child and integrity, 88, 89 can also afford unique opportunities to may not need as many repeated examinations, including observe drug effects on these lesions directly, using the eye MRIs under sedation, and that they need not agree to some as a transparent laboratory to investigate treatments more recommendations for current antimitotic treatments that, often needed within the and skull. Perhaps such directly even by reports of their proponents, provide mediocre observable responses to non-mutagenic pharmacologic results with non-negligible adverse effects, in order to agents may help guide us toward more efficacious therapies be considered responsible parents. Despite the relatively for juvenile pilocytic astrocytoma optic pathway gliomas. decreased cavitary space available for the expansion of intracranial masses, until efficacious treatment modalities become available, glial hamartomas which occur either CME Answers intracranially or intraorbitally should be approached in much 1. No. The terminology “optic pathway gliomas” and the same conservative way that ophthalmologists have to 8, 24, 71, 82 “low-grade gliomas” is also inclusive WHO Grade II date managed those which occur intraocularly. astrocytomas. Indeed, to imply that patients with such bona fide tumors, 2. No. Hamartomas may grow in self-limited form during enlarging or otherwise, could benefit from antimitotic the period of development. treatments, such as radiation or current genotoxic 3. No. A decline in visual acuity indicates a distortion of chemotherapy, as a means to avoid “nihilistic” attitudes axons which may also occur during tumor shrinkage. towards disease is akin to proposing such therapies to thwart the sometimes undesirable growth of retinal and optic disk hamartomas,88, 89 or of limbal dermoids. In face References of our current-day knowledge, persisting on applying such antimitotic and genotoxic regimens for tumors such as 1. Hoyt WF, Meshel LG, Lessell S, Schatz NJ, Suckling RD. Malignant optic glioma of adulthood. Brain 96, 121-132, 1973. juvenile pilocytic astrocytomas that more specifically are hamartomas, like so many other so-called “controversies,” 2. Spoor TC, Kennerdell JS, Martinez AJ, et al. Malignant gliomas of the optic pathways. Am J Ophthalmol 89: 284–92, 1980. would represent an example of faith-based, rather than evidence-based, medicine. 3. Moseley IF, Sanders MD. Computerized Tomography in Neuro- ophthalmology. London: Chapman and Hall; 1982. As is often the case, the physician’s dictum first to do 4. Rush JA, Younge BR, Campbell RJ, et al. Optic glioma: long-term follow-up of 85 histopathologically verified cases. Ophthalmology 89: no harm comes to mind. With genotoxic properties and 1213–9, 1982. systemic diffusion, antimitotic chemotherapy now being 90 5. Rodriguez FJ, Scheithauer BW, Burger PC, Jenkins S, Giannini C. promoted may be predicted to cause secondary tumors Anaplasia in pilocytic astrocytoma predicts aggressive behavior. Am J developing elsewhere within the body and become Surg Pathol 43(2):147-160, 2010. 91, 92 increasingly evident many years following treatment. 6. Rodriguez EF, Scheithauer BW, Giannini C, Rynearson A, Cen L, as for radiation therapy by now already well-established. Hoesley B, Gilmer-Flynn H, Sarkaria JN, Jenkins S, Long J, Rodriguez FJ. Such effects would be even more likely in patients PI3K/AKT pathway alterations are associated with clinically aggressive treated at a young age, and in those already harboring and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol Mar;121(3):407-20, 2011. Epub 2010 Nov 28. germline mutations in tumor suppressor genes such as for neurofibromatosis or tuberous sclerosis.

116 | North American Neuro-Ophthalmology Society 7. Miller NR. Optic pathway gliomas are tumors! Ophthal Plast Reconstr 29. Takeuchi H, Kabuto M, Sato K, Kubota T. Chiasmal gliomas with Surg Nov-Dec;24(6):433, 2008. spontaneous regression: proliferation and apoptosis. Childs Nerv Syst 13:229-233, 1997. 8. Parsa CF. Why optic gliomas should be called hamartomas. Ophthal Plast Reconstr Surg Nov-Dec;26(6):497, 2010. 30. Walrath JD, Engelbert M, Kazim M. Magnetic resonance imaging evidence of optic nerve glioma progression into and beyond the optic 9. Glaser JS, Hoyt WF, Corbett J. Visual morbidity with chiasmal glioma. chiasm. Ophthal Plast Reconstr Surg Nov-Dec;24(6):473-5, 2008. Long-term studies of visual fields in untreated and irradiated cases. Arch Ophthalmol 85: 3–12, 1971. 31. Parsa CF, Hoyt CS, Lesser RL, et al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch 10. Packer RJ, Savino PJ, Bilaniuk LT, et al. Chiasmatic gliomas of Ophthalmol 119: 516–29, 2001. childhood. A reappraisal of natural history and effectiveness of cranial irradiation. Childs Brain 10: 393–403, 1983. 32. Imes RK, Hoyt WF. Childhood chiasmal gliomas: update on the fate of patients in the 1969 San Francisco study. Br J Ophthalmol 70: 11. Austin EJ, Alvord EC Jr. Recurrences of cerebellar astrocytomas: 179–82, 1986. a violation of Collins’ randomized trial of radiotherapy versus radiotherapy plus CCNU for incompletely resected low-grade gliomas: 33. Haapasalo H, Sallinen SL, Sallinen P, et al. Clinicopathological a Southwest Oncology Group study. J Neurosurg 78:909-914, 1993. correlation of cell proliferation, apoptosis and p53 in cerebellar pilocytic astrocytomas. Neuropathol Appl Neurobiol 25:134-42, 1999. 12. Eyre HJ, Crowley JJ, Townsend JJ, Eltringham JR, Morantz RA, Schulman SF, Quagliana JM, Al-Sarraf M. A randomized trial of 34. Li J, Perry A, James CD, Gutmann DH. Cancer-related gene expression radiotherapy versus radiotherapy plus CCNU for incompletely profiles in NF1-associated pilocytic astrocytomas. Neurology 56:885- resected low-grade gliomas: a Southwest Oncology Group study. J 90, 2001. Neurosurg 78:909-914, 1993. 35. Palma L, Celli P, Mariottini A. Long-term follow-up of childhood 13. Smoots DW, Geyer JR, Lieberman DM, Berger MS. Predicting disease cerebellar astrocytomas after incomplete resection with particular progression in childhood cerebellar astrocytoma. Child’s Nerv Syst reference to arrested growth of spontaneous tumour regression. 14:636-48, 1998. Acta Neurochir (Wien) 146:581-88, 2004. 14. Kaye AH, Walker DG. Low grade astrocytomas: controversies in 36. Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM. Associations management. J Clin Neurosci 7(6):475-83, 2000. of clinical features in neurofibromatosis 1 (NF1). Genet Epidemiol Dec;19(4):429-39, 2000. 15. Grill J, Laithier V, Rodriguez D. When do children with optic pathway tumors need tx? Eur J Pediatr 159:692-6, 2000. 37. Listernick R, Charrow J, Greenwald M, et al. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a 16. Due-Tønnessen BJ, Helseth E, Scheie D, Skullerud K, Aamodt G, longitudinal study. J Pediatr 125: 63–6, 1994. Lundar T. Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0-19 years): report of 110 38. Rossi LN, Pastorino G, Scotti G, et al. Early diagnosis of optic glioma consecutive cases. Pediatr Neursurg 37:71-80, 2002. in children with neurofibromatosis type 1. Childs Nerv Syst 10:426- 429, 1994. 17. Dalla Via P, Opocher E, Pinello ML, Calderone M, Viscardi E, Clementi M, Battistella PA, Laverda AM, Da Dalt L, Perilongo G. Visual outcome 39. DiMario FJ, Jr, Ramsby G, Greenstein R, Langshur S, Dunham B. of a cohort of children with neurofibromatosis type 1 and optic Neurofibromatosis type 1: magnetic resonance imaging findings. J pathway glioma followed by a pediatric neuro-oncology program. Child Neurol 8:32-39, 1993. Neuro Oncol Oct;9(4):430-7, 2007. Epub 2007 Aug 17. 40. Sevick RJ, Barkovich AJ, Edwards MS, Koch T, Berg B, Lempert T. 18. Moreno L, Bautista F, Ashley S, Duncan C, Zacharoulis S. Does Evolution of white matter lesions in neurofibromatosis type 1: MR chemotherapy affect the visual outcome in children with optic path findings. AJR Am J Roentgenol 159:171-175, 1992. glioma? A systematic review of the evidence. Eur J Cancer 46:2253- 41. Brown EW, Riccardi VM, Mawad M, Handel S, Goldman A, Bryan RN. 2259, 2010. MR imaging of optic pathways in patients with neurofibromatosis. 19. Albrecht E. Ueber Hamartome. Verh Dtsch Ges Pathol 7:153–7, 1904. AJNR Am J Neuroradiol 8:1031-1036, 1987. 20. Albrecht E. Die Grundprobleme der Geschwulstlehre. I. Teil. Frankf Z 42. Goldstein SM, Curless RG, Donovan Post MJ, Quencer RM. A new sign Pathol 1:221–47, 1907. of neurofibromatosis on magnetic resonance imaging of children. Arch Neurol 46:1222-1224, 1989. 21. Hudson AC. Primary tumours of optic nerve. Roy Lond Ophthalmol Hosp Rep 18:317–439, 1912. 43. Duffner PK, Cohen ME, Seidel FG, Shucard DW. The significance of MRI abnormalities in children with neurofibromatosis. Neurology 22. Davis RL. Written communication to William H. Spencer, April 17, 1968. 39:373-378, 1989. 23. Zimmerman LE. Written communication to William F. Hoyt, M.D., 44. Aoki S, Barkovich AJ, Nishimura K, et al. Neurofibromatosis types 1 April 1, 1969. and 2: cranial MR findings. Radiology 172:527-534, 1989. 24. Hoyt WF, Baghdassarian SA. Optic glioma of childhood. Natural 45. Curless RG, Siatkowski M, Glaser JS, Schatz NJ. MRI diagnosis of NF-1 history and rationale for conservative management. Br J Ophthalmol in children without cafe´-au-lait skin lesions. Pediatr Neurol 18:269- 53:793– 8, 1969. 271, 1998. 25. Borit A, Richardson EP Jr. The biological and clinical behavior of 46. Brzowski AE, Bazan C III, Mumma JV, Ryan SG. Spontaneous pilocytic astrocytomas of the optic pathways. Brain 105:161-87, 1982. regression of optic glioma in a patient with neurofibromatosis. 26. Anderson DR, Spencer WH. Ultra structural and histochemical Neurology 42:679-681, 1992. observations of optic nerve gliomas. Arch Ophthalmol 83: 324-35, 1970. 47. Ito S, Hoshino T, Shibuya M, Prados MD, Edwards MS, Davis RL. 27. Burger PC, Scheithauer BW, Paulus W, et al. Pilocytic astrocytoma. In: Proliferative characteristics of juvenile pilocytic astrocytomas Kleihues P, Cavenee WK, eds. World Health Organization classification determined by bromodeoxyuridine labeling. Neurosurgery 31:413- of tumours. Pathology and genetics of tumours of the nervous 418, 1992. system. Lyon: IARC Press:45–51, 2000. 48. Collins VP, Loeffler RK, Tivey H. Observations on growth rates of human 28. Facoetti A, Ranza E, Nano R. Proliferation and programmed cell tumors. Am J Roentgenol Radiat Ther Nucl Med 76:988-1000, 1956. death: role of p53 protein in high and low grade astrocytoma. 49. Burger PC, Scheithauer BW, Vogel FS. Surgical pathology of the Anticancer Res Jan-Feb;28(1A):15-9, 2008. nervous system and its coverings, 4th edn. New York: Churchill Livingstone pp:203–15, 2002.

2012 Annual Meeting Syllabus | 117 50. Russell DS, Rubinstein LJ. Astrocytomas. In: Pathology of tumours 73. Packer RJ, Sutton LN, Bilaniuk LT, Radcliffe J, Rosenstock JG, Siegel of the nervous system, 4th edn. Baltimore: Williams & Wilkins, KR, Bunin GR, Savino PJ, Bruce DA, Schut L. Treatment of chiasmatic/ pp:183–9, 1977. hypothalamic gliomas of childhood with chemotherapy: an update. Ann Neurol Jan;23(1):79-85, 1988. 51. Russell DS, Rubinstein LJ. Astrocytomas. In: Pathology of tumours of nervous system, 5th edn. London: Arnold, pp:95–160, 370–6, 1989. 74. Parsa CF. Why visual function does not correlate with glioma size or growth. Arch Ophthalmol (in press). 52. Burger PC, Scheithauer BW. Tumors of the central nervous system. AFIP atlas of tumor pathology. Fourth series. Fascicle 7. Washington, 75. Fletcher WA, Imes RK, Hoyt WF. Chiasmal gliomas: appearance and DC: American Registry of Pathology, pp:89–101, 2007. long-term changes demonstrated by computerized tomography. J Neurosurg 65(2):154-159, 1986. 53. Parsa CF, Givrad S. Juvenile pilocytic astrocytomas do not undergo spontaneous malignant transformation: grounds for designation as 76. Fisher MJ, Balcer L, Gutmann D, Listernick R, Ferner R, Packer R, hamartomas. Br J Ophthalmol Jan;92(1):40-6, 2008. Epub 2007 Oct Hoffman R, Tabori U, Ullrich N, Ardern-Holmes S, Hargrave D, Bouffet E, 25. Review. Loguidice M, Liu GT. Neurofibromatosis type 1 associated optic glioma visual outcomes following chemotherapy: an international multi- 54. Ellis JA, Waziri A, Balmaceda C, Canoll P, Bruce JN, Sisti MB. Rapid center retrospective analysis [abstract]. Neuro Oncology 12:ii19, 2010. recurrence and malignant transformation of pilocytic astrocytoma in adult patients. J. Neurooncol 95:377–382, 2009. 77. Avery RA, Fisher MJ, Liu GT. Optic pathway gliomas. J Neuro- Ophthalmol 31:269-278, 2011. 55. Tarlov IM. Effect of roentgenotherapy on gliomas. Arch Neurol Psychiatry 38:513–36, 1937. 78. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis 1: Controversies and recommendations. Ann 56. Evans DGR, Birch JM, Ramsden RT, et al. Malignant transformation Neurol 61:189-98, 2007. and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med 79. McDonnell P, Miller NR. Chiasmatic and hypothalamic extension of Genet 43:289–94, 2006. optic nerve glioma. Arch Ophthalmol Sep;101(9):1412-5, 1983. 57. Kortmann RD, Timmermann B, Taylor RE, et al. Current and future 80. Walrath JD, Engelbert M, Kazim M. Magnetic resonance imaging strategies in radiotherapy of childhood low-grade glioma of the evidence of optic nerve glioma progression into and beyond the optic brain. Part II: Treatment-related late toxicities. Strahlenther Onkol chiasm. Ophthal Plast Reconstr Surg 24:473–5, 2008. 179:585–97, 2003. 81. Wright JE, McNab AA, McDonald WI. Optic nerve glioma and the 58. Buyukpamukcu M, Varan A, Yazici N, et al. Second malignant management of optic nerve tumours in the young. Br J Ophthalmol neoplasms following the treatment of brain tumors in children. J 73: 967–74, 1989. Child Neurol 21:433–6, 2006. 82. Parsa CF. Neurogenic tumours. In: Hoyt CS, Taylor D (eds): Pediatric 59. Van der Hoeve J. Augengeschwülste bei der tuberösen hirnsklerose Ophthalmology and Strabismus, 4th edition. W.B. Saunders Ltd (Bourneville). Albrecht von Graefes Arch Ophthalmol 105:880–98, 1921. (scheduled for 2012). 60. Kocks W, Kalff R, Reinhardt V, et al. Spinal metastasis of pilocytic 83. Wright JE, McDonald WI, Call NB. Management of optic nerve astrocytoma of the chiasma opticum. Childs Nerv Syst 5:118–20, 1989. gliomas. Br J Ophthalmol 64: 545–52, 1980. 61. Pollack IF, Hurtt M, Pang D, et al. Dissemination of low grade 84. Wolter JR. Ten years without orbital optic nerve: late clinical results intracranial astrocytomas in children. Cancer 73:2869–78, 1994. after removal of retrobulbar gliomas with preservation of blind eyes. J Pediatr Ophthalmol Strabismus 25: 55–60, 1988. 62. Zorlu F, Selek U, Akyuz C, et al. Spinal seeding of a pilocytic astrocytoma following multiple subtotal resections. Pediatr 85. Rootman J. Diseases of the Orbit: a Multidisciplinary Approach. 2nd Neurosurg 41:248–52, 2005. ed. Philadelphia: Lippincott Williams & Wilkins; 2002. 63. De Juan E Jr, Green WR, Gupta PK, et al. Vitreous seeding by retinal 86. Ferrari A, Bisogno G, Macaluso A, Casanova M, D’Angelo P, Pierani astrocytic hamartoma in a patient with tuberous sclerosis. Retina P, Zanetti I, Alaggio R, Cecchetto G, Carli M. Soft-tissue sarcomas 4:100–2, 1984. in children and adolescents with neurofibromatosis type 1. Cancer 109(7), Apr 1, 1406-1412, 2007. 64. Song S, Seo MS. Spontaneous regression of a solitary astrocytoma of the optic disk. Retina 22:502–3, 2002. 87. Cecen E, Ince D, Uysal KM, Ozer E, Cetingoz R, Ozguven AA, Cakmakci H, Sarialioglu F, Olgun N. Soft tissue sarcomas and central nervous 65. Kiratli H, Bilgic S. Spontaneous regression of retinal astrocytic system tumors in children with neurofibromatosis type 1. Childs Nerv hamartoma in a patient with tuberous sclerosis. Am J Ophthalmol Syst Mar 26, 2011 [Epub ahead of print]. 133:715–6, 2002. 88. Gündüz K, Eagle RC Jr, Shields CL, et al. Invasive giant cell 66. Moschos MM, Chamot L, Schalenbourg A, et al. Spontaneous astrocytoma of the retina in a patient with tuberous sclerosis. regression of an isolated retinal astrocytic hamartoma. Retina Ophthalmology 106:639–42, 1999. 25:81–2, 2005. 89. Shields CL, Shields JA, Eagle RC Jr, et al. Progressive enlargement of acquired 67. Farooki ZQ, Ross RD, Paridon SM, et al. Spontaneous regression of retinal astrocytoma in 2 cases. Ophthalmology 111:363-368, 2004. cardiac rhabdomyoma. Am J Cardiol 67:897–9, 1991. 90. 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Br J Ophthalmol Jan;92(1):3-6, 2008. 72. Schmandt SM, Packer RJ, Vezina LG, Jane J. Spontaneous regression of low-grade astrocytomas in childhood. Pediatr Neurosurg Mar;32(3):132-6, 2000.

118 | North American Neuro-Ophthalmology Society OPTIC PATHWAY GLIOMAS ARE NEOPLASMS!

Grant T. Liu, MD University of Pennsylvania School of Medicine Philadelphia, PA

Learning Objectives Optic pathway gliomas do not satisfy the definition of hamartomas. Understand the differences and similarities between hamartomas and neoplasms, and that optic pathway A hamartoma is a “benign, focal malformation that gliomas are neoplasms. resembles a neoplasm in the tissue of its origin . . . it grows at the same rate as the surrounding tissues. It is composed of tissue elements normally found at that site, CME Questions: TRUE/FALSE but which are growing in a disorganized mass. They occur in many different parts of the body and are most often 1. Hamartomas do not in general cause symptoms asymptomatic and undetected unless seen on an image 7 2. Spontaneous regression does not occur with taken for another reason.” neoplasms. Opitz and Jorde8 wrote, “hamartomata are localized 3. There is no proof of the efficacy of chemotherapies in overgrowths of a single tissue or combination of tissues, optic pathway gliomas indigenous to the affected body part or organ, usually growing at the same rate as the normal components and causing little pain or functional impairment.” Keywords 1. Optic athwayP Glioma Optic gliomas on the other hand:

2. Neoplasm 1. Can demonstrate growth at rates more rapid than that of the visual pathways or brain. 3. Hamartoma 2. Can destroy the structures within and around which they are growing. Introduction 3. Are often symptomatic. While many are asymptomatic, Hoyt and Bagdassarian1 popularized the notion that optic up to 50% of patients with neurofibromatosis type pathway gliomas are hamartomas. Parsa has continued to 1 and optic gliomas exhibit vision loss to some argue extensively that optic pathway gliomas are congenital degree.9 Hypothalamic gliomas can cause diencephalic developmental lesions, not neoplastic, and therefore syndrome and obstructive hydrocephalus. should not be treated, even when there is evidence of 4. Can metastasize in the absence of shunt manipulation,10 clinical or radiographic progression.2-4 a behavior not characteristic of hamartomas.

However, more recently MRI techniques have provided clinicians a more detailed method for observing the natural Histopathologically, optic pathway history of optic pathway gliomas not available decades gliomas are neoplasms ago. Now most clinicians today dealing with optic pathway 1. Many are grade I juvenile pilocytic astrocytomas, just like gliomas have realized that the growth patterns are varied the childhood cerebellar juvenile pilocytic astrocytomas, and unpredictable.5 While most optic pathway gliomas are which are not hamartomas because they do not look at benign, some clearly act aggressively.6 all like normal cerebellum as a hamartoma would. 2. Some optic pathway gliomas are grade II fibrillary The question boils down to this: are optic pathway gliomas astrocytomas, and it is artificial to separate those which hamartomas or slowly-growing neoplasms? It is our might be predominantly grade I from those with grade II opinion that optic pathway gliomas are slowly-growing components, because many are not biopsied (due to the neoplasms and not hamartomas risk associated with biopsy) and sampling error may occur. 3. The fact that they, like subependymal giant cell tumors and craniopharyngiomas, do not generally undergo malignant transformation does not put them into the hamartoma category.

2012 Annual Meeting Syllabus | 119 4. As Walrath et al.6 and Miller11 have discussed, some Newer therapies are being explored.5 Our developing optic pathway gliomas may exhibit markers of understanding of the biology of these tumors carries the cellular proliferation identified by using MIB-1, an promise of improved outcomes for this tumor. Inhibitors antibody to the Ki-67 antigen,12 and AgNOR (silver of BRAF, MEK and mTOR are already in clinical trials. nuclear organizing region)13 techniques. Like pilocytic In addition, drugs targeting tumor angiogenesis, such astrocytomas in other brain locations,14-16 a portion as bevacuzimab, have been shown to yield objective of optic pathway gliomas have elevated proliferative responses in recurrent/refractory optic pathway gliomas29 activity (MIB-1 labeling index of 2-3%),12 and this is and are being evaluated in larger studies. associated with more aggressive tumor behavior.12,16 Implication of designating optic pathway Thus, optic pathway gliomas satisfy the gliomas as hamartomas definition of neoplasms It is a disservice to and potentially dangerous for patients A neoplasm is defined as an “abnormal mass of tissue as a with optic pathway gliomas and their families to call these result of . . . and abnormal proliferation of cells. The growth lesions hamartomas not requiring treatment.2-4 Families of neoplastic cells exceeds and is not coordinated with that may get the false impression that if treatments are of the normal tissue around it. . . . It usually causes a lump or ineffective or unnecessary, clinical follow-up and imaging tumor.”17 The growth characteristics and pathology of optic are also unnecessary. pathway gliomas would be more consistent with a neoplasm. Conclusion Spontaneous improvement and In summary, based upon their growth patterns and resolution can be seen in neoplasms histopathology, optic pathway gliomas are not hamartomas This behavior is not a characteristic of just hamartomas as it but truly are neoplasms. Spontaneous regression can be occurs in some neoplasms as well. For instance, neuroblastomas, seen in neoplasms. Chemotherapies should be used when the majority of which are neoplasms, may also demonstrate radiographic or clinical progression occurs. Other more spontaneous regression. In one study,18 of 53 of six month old directed therapies will certainly be used in the future. infants found to have neuroblastoma on screening, 17 (32%) exhibited complete spontaneous regression. In addition, cases Appendix of stage IV neuroblastoma, with metastases, later demonstrating Choristomas, “forms of heterotopia, are closely related spontaneous regression, have been observed. benign tumors. These tumors also contain normal tissues but are found in abnormal locations.”7 There is proof that anti-mitotic therapies are effective in optic pathway gliomas Chemotherapy is used when radiographic and/or clinical CME Answers progression are documented. 1. true Using radiologic data primarily as the outcome measure, the 2. false combination of carboplatin and vincristine, the most common 3. false regimen, was associated with a 3 year progression-free survival rate of 77%19 and 5 year progression-free survival rate of 69% in patients with NF1.20 Although allergies may occur, References this regimen in general is very well tolerated in children. 1. Hoyt WF, Baghdassarian SA: Optic glioma of childhood: natural history and rationale for conservative management. Br J Ophthalmol Data regarding visual outcomes following chemotherapy 1969;53:793-798. for optic pathway glioma now exists. In our retrospective 2. Parsa CF, Givrad S: Pilocytic astrocytomas as hamartomas: multi-center review of 115 patients treated with implications for treatment. Br J Ophthalmol 2008;92:3-6. chemotherapy over a ten year period at ten sites 3. Parsa CF, Givrad S: Juvenile pilocytic astrocytomas do not undergo throughout the world, at the completion of therapy, visual spontaneous malignant transformation: grounds for designation as acuity improved (32% of subjects), remained stable (40%), hamartomas. Br J Ophthalmol 2008;92:40-46. 21 or declined (28%). This rate of improvement (32%) 4. Parsa CF: Why optic gliomas should be called hamartomas [letter]. can not be explained by the occasional phenomena of Ophthal Plast Reconstr Surg 2010;26:497. 22,23 spontaneous regression. 5. Avery RA, Fisher MJ, Liu GT: Optic pathway gliomas [review]. J Neuro-Ophthalmol 2011;31:269-278. Radiation therapy, again using radiologic data, has been 6. Walrath JD, Engelbert M, Kazim M: Magnetic resonance imaging shown to be efficacious for optic pathway gliomas with evidence of optic nerve glioma progression into and beyond the optic reported 10 year progression-free survival (PFS) rates of chiasm. Ophthal Plast Reconstr Surg 2008;24:473-475. 66-90%.24-28 However, radiation is no longer used first-line 7. http://en.wikipedia.org/wiki/hamartoma (accessed 10/12/11). because of the risk of cognitive decline, endocrinopathies, 8. Opitz JM, Jorde LB: Hamartoma syndromes, exome sequencing, and cerebrovascular disease, and secondary malignancies.5 a protean puzzle [editorial]. N Engl J Med 2011;365:661-663.

120 | North American Neuro-Ophthalmology Society 9. Balcer LJ, Liu GT, Heller G, et al.: Visual loss in children with 20. Ater J, Holmes E, Zhou T, et al.: Abstracts from the thirteenth neurofibromatosis type 1 and optic pathway gliomas: relation to international symposium on pediatric neuro-oncology: Results tumor location by magnetic resonance imaging. Am J Ophthalmol of COG protocol A9952- a randomized phase 3 study of two 2001;131:442-445. chemotherapy regimens for incompletely resected low-grade glioma in young children. Neuro-Oncology 2008;10:451. 10. Civitello LA, Packer RJ, Rorke LB, et al.: Leptomeningeal dissemination of low-grade gliomas in childhood. Neurology 21. Fisher M, Loguidice M, Gutmann D, et al.: Visual outcomes in 1988;38:562-566. children with neurofibromatosis type 1 associated optic pathway glioma following chemotherapy: a multi-center retrospective 11. Miller NR: Optic pathway gliomas are tumors! Ophthal Plast analysis. NANOS 2010. Reconstr Surg 2008;24:433. 22. Liu GT, Lessell S: Spontaneous visual improvement in chiasmal 12. Cummings TJ, Provenzale JM, Hunter SB, et al.: Gliomas of the optic gliomas. Am J Ophthalmol 1992;114:193-201. nerve: histological, immunohistochemical (MIB-1 and p53), and MRI analysis. Acta Neuropathol 2000;99:563-570. 23. Parsa CF, Hoyt CS, Lesser RL, et al.: Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch 13. Burnstine MA, Levin LA, Louis DN, et al.: Nucleolar organizer regions Ophthalmol 2001;119:516-529. in optic gliomas. Brain 1993;116:1465-1476. 24. Horwich A, Bloom HJG: Optic gliomas: radiation therapy and 14. Giannini C, Scheithauer BW, Burger PC, et al.: Cellular proliferation prognosis. Int J Radiat Oncol Biol Phys 1985;11:1067-1079. in pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol 1999;58:46-53. 25. Bataini JP, Delanian S, Ponvert D: Chiasmal gliomas: results of irradiation management in 57 patients and review of literature. Int J 15. Haapasalo H, Sallinen S, Sallinen P, et al.: Clinicopathological Radiat Oncol Biol Phys 1991;21:615-623. correlation of cell proliferation, apoptosis and p53 in cerebellar pilocytic astrocytomas. Neuropathol Appl Neurobiol 1999;25:134-142. 26. Jenkin D, Angyalfi S, Becker L, et al.: Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 16. Bowers DC, Gargan L, Kapur P, et al.: Study of the MIB-1 labeling 1993;25:215-225. index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol 2003;21:2968-2973. 27. Cappelli C, Grill J, Raquin M, et al.: Long-term follow up of 69 patients treated for optic pathway tumours before the chemotherapy 17. http://en.wikipedia.org/wiki/neoplasm (accessed 11/7/11). era. Arch Dis Child 1998;79:334-338. 18. Tanaka M, Kigasawa H, Kato K, et al.: A prospective study of a long- 28. Grabenbauer GG, Schuchardt U, Buchfelder M, et al.: Radiation term follow-up of an observational program for neuroblastoma therapy of optico-hypothalamic gliomas (OHG)--radiographic detected by mass screening. Pediatr Blood Cancer 2010;54:573-578. response, vision and late toxicity. Radiother Oncol 2000;54:239-245. 19. Packer RJ, Ater J, Allen J, et al.: Carboplatin and vincristine 29. Packer RJ, Jakacki R, Horn M, et al.: Objective response of multiply chemotherapy for children with newly diagnosed progressive low- recurrent low-grade gliomas to bevacizumab and irinotecan. Pediatr grade gliomas. J Neurosurg 1997;86:747-754. Blood Cancer 2009;52:791-795.

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