Optic nerve inflammation and demyelination in a
viral-induced model of multiple sclerosis.
Pseudotumor Cerebri Syndrome
Optic Nerve Cell Survival
Optic Pathway Gliomas
Optic Nerve Degeneration and Regeneration
Pseudotumor Cerebri Syndrome
Pseudotumor Cerebri Syndrome (PTCS) is a condition in which high pressure in the head can lead to headaches and vision loss. Faculty and fellows in the Neuro-ophthalmology Division are investigating characteristics, risk factors, and potential treatments for PTCS and primary PTCS (Idiopathic Intracranial Hypertension (IIH)). Past studies have focused on patterns of weight-gain, visual function, and quality of life.
At the Children's Hospital of Philadelphia, Dr. Liu is interested in improving the diagnosis and management of children with pseudotumor cerebri syndrome. His clinical research interests have included those involving risk factors and neuroimaging in children with the disorder, classification criteria for the pseudotumor cerebri syndrome, and pathophysiologic mechanisms.
- Daniels AB, Liu GT, Volpe NJ, Galetta SL, Moster ML, Newman NJ, Biousse V, Lee AG, Wall M, Kardon R, Acierno MD, Corbett JJ, Maguire MG, Balcer LJ. Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri). Am J Ophthalmol 2007;143:635-641.
- Rangwala L, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol 2007;52:597-617.
- Avery RA, Shah SS, Licht DJ, Seiden JA, Huh JW, Boswinkel J, Ruppe MD, Chew A, Mistry RD, Liu GT. Reference range of cerebrospinal fluid opening pressure in children undergoing diagnostic lumbar puncture. N Engl J Med 2010;363:891-893.
- Ko MW, Liu GT. Pediatric idiopathic intracranial hypertension (pseudotumor cerebri). Hormone Research in Pediatrics 2010;74:381-389.
- Ko MW, Chang SC, Ridha MA, Ney JJ, Ali TF, Friedman DI, Mejico LJ, Volpe NJ, Galetta SL, Balcer LJ, Liu GT. Weight gain and recurrence in idiopathic intracranial hypertension: a case control study. Neurology 2011;76:1564-1567.
- Renuart AJ, Mistry RD, Avery RA, Licht DJ, Seiden JA, Huh JW, Boswinkel JP, Liu GT, Shah SS. Reference range for cerebrospinal fluid protein concentration in children and adolescents. Arch Pediatr Adolesc Med 2011;165:671-673.
- Avery R, Licht DJ, Shah S, Huh H, Seiden J, Boswinkel J, Ruppe M, Mistry R, Liu GT. Cerebrospinal fluid opening pressure in children with optic nerve head edema. Neurology 2011; 76: 1658-1661.
- Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology 2013:81:1-7.
- Sheldon CA, Paley GL, Xiao R, Kesler A, Eyal O, Ko MW, Boisvert CJ, Avery RA, Salpietro V, Phillips PH, Heidary G, McCormack SE, Liu GT. Pediatric idiopathic intracranial hypertension: age, gender, and anthropometric features at diagnosis in a large, retrospective, multisite cohort. Ophthalmology 2016;123:2424-2431.
- Mallery RM, Rehmani OF, Woo JH, Chen YJ, Reddi S, Slazman KL, Pinho MC, Ledbetter L, Tamhankar MA, Shindler, KS, Digre KB, Friedman Di, Liu GT. Utility of magnetic resonance imaging features for improving the diagnosis of IIH without papilledema. J Neuro-ophthalmol 2019;39:299-307.
Optic Nerve Cell Survival
Dr. Kenneth Shindler is conducting basic research on mechanisms of neuronal damage and neuroprotection in optic nerve diseases in the F. M. Kirby Center for Molecular Ophthalmology. Dr. Shindler's laboratory focuses on retinal ganglion cell damage during optic neuritis, an inflammatory disease of the optic nerve which commonly affects patients with multiple sclerosis. This damage can lead to permanent visual loss in patients with repeat episodes of optic neuritis. Potential neuroprotective therapies to prevent damage to the optic nerve cells are being evaluated in an experimental model to identify novel ways to treat optic neuritis. In addition, any therapies that are developed may have broader application for other neurologic deficits induced by multiple sclerosis, and other causes of optic neuropathy. Dr. Shindler's work has received support from the National Eye Institute of the National Institutes of Health (RO1), the National Multiple Sclerosis Society, Research to Prevent Blindness, the F.M. Kirby Foundation, Noveome Biotherapeutics, and Sirtris Pharmaceuticals, a GSK company.
- Shindler KS, Ventura E, Rex, TS, Elliott P, Rostami A: SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest. Ophthalmol. Vis. Sci. 48(8): 3602-3609, August 2007. PMCID: PMC1964753
- Shindler KS, Kenyon LC, Dutt M, Hingley ST, Das Sarma J: Experimental optic neuritis induced by a demyelinating strain of mouse hepatitis virus. J. Virol. 82(17): 8882-8886, Sept 2008. PMCID: PMC2519666
- Das Sarma J, Kenyon LC, Hingley ST, Shindler KS: Mechanisms of primary axonal damage in a viral model of multiple sclerosis J. Neurosci. 29(33): 10272-10280, Aug 2009. PMCID: PMC2747667
- Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A: Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J. of Neuro-Ophthalmol. 30(4): 328-39, Dec 2010. PMCID: PMC3312784
- Shindler KS, Chatterjee D, Biswas K, Goyal A, Dutt M, Nassrallah M, Khan RS, Das Sarma J: Macrophage-mediated optic neuritis induced by retrograde axonal transport of spike gene recombinant mouse hepatitis virus. J. Neuropathol. Exp. Neurol. 70(6): 470-80, June 2011. PMCID: PMC3110774
- Fonseca-Kelly Z, Nassrallah M, Uribe J, Khan RS, Dine K,Dutt M, Shindler KS: Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front. Neurol. 3: 84, May 2012. PMCID: PMC3359579
- Zuo L, Khan RS, Lee V, Dine K, Wu W, Shindler KS: SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest. Ophthalmol. Vis. Sci. 54(7): 5097-102, Jul 2013. PMCID: PMC3726244
- Khan RS, Dine K, Das Sarma J, Shindler KS: SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease. Acta Neuropathol. Commun. 2(1): 3, Jan 2014. PMCID: PMC3892130
- Khan RS, Dine K, Bauman B, Lorentsen M, Lin L, Brown H, Hanson LR, Svitak AL, Wessel H, Brown L, Shindler KS: Intranasal delivery of a novel amnion cell secretome prevents neuronal damage and preserves function in a mouse multiple sclerosis model. Sci. Rep. 7: 41768, Jan 2017. PMCID: PMC5282572
- Khan RS, Dine K, Geisler JG, Shindler KS: Mitochondrial Uncoupler Prodrug of 2, 4-Dinitrophenol (DNP), MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxid. Med. Cell. Longev. 2017: 7180632, 2017. PMCID: PMC5478871
- McDougald DS, Dine KE, Zezulin AU, Bennett J, Shindler KS: SIRT1 and NRF2 gene transfer mediate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis. Invest. Ophthalmol. Vis. Sci. 59:1212-1220, Mar 2018. PMCID: PMC5839257
- Grinblat GA, Khan RS, Dine K, Wessel H, Brown L, Shindler KS: RGC neuroprotection following optic nerve trauma mediated by intranasal delivery of amnion cell secretome. Invest. Ophthalmol. Vis. Sci. 59: 2470-2477, May 2018. PMCID: PMC5959511
Optic Pathway Gliomas
At the Children's Hospital of Philadelphia, Drs. Avery and Liu, in collaboration with Dr. Michael Fisher of the Division of Oncology, are investigating the optimal methods for assessing the visual pathways of children with optic pathway gliomas. They serve as study chairs for the multi-center international study of optic pathway gliomas secondary to Neurofibromatosis type 1. Although visual acuity remains the best method today, other potential modalities are being explored and include neuroimaging techniques and optical coherence tomography (OCT). Dr. Avery is the ophthalmology lead for three Phase 3 clinical trials testing new therapies for children with optic pathway gliomas. He was awarded an R01 from the National Eye Institute: "Biomarkers of Vision Loss in Children with Optic Pathway Gliomas" and an Investigator Initiated Award from the Department of Defense: "MRI Volumetrics for Risk Stratification of Vision Loss in Optic Pathway Gliomas Secondary to NF1."
- Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007;61:189-198.
- Avery RA, Liu GT, Fisher MJ, Quinn GE, Belasco JB, Phillips PC, Maguire MG, Balcer LJ. Retinal nerve fiber layer thickness in children with optic pathway gliomas. Am J Ophthalmol 2011;151:542-549.
- Avery RA, Fisher MJ, Liu GT. Optic pathway gliomas. J Neuro-ophthalmology 2011;31:269-278.
- Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, Packer RJ, Tabori U, Hoffman RO, Ardern-Holmes SL, Hummel TR, Hargrave DR, Bouffet E, Charrow J, Bilaniuk LT, Balcer LJ, Liu GT. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro-oncology 2012;12:790-797.
- Avery RA, Ferner RE, Listernick R, Fisher MJ, Gutmann DH, Liu GT. Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research. J Neuro-oncology 2012;110:1-7.
- Avery RA, Bouffet E, Packer RJ, Reginald A. Feasibility and comparison of visual acuity testing methods in children with Neurofibromatosis type 1 and or optic pathway gliomas. Invest Ophthalmol Vis Sci 2013;54:1034-1038.
- Fisher MJ, Avery R, Allen J, Ardern-Holmes A, Bilaniuk L, Ferner R, Gutmann D, Listernick R, Martin S, Ullrich N, Liu GT. Functional outcomes for neurofibromatosis type 1-associated optic pathway glioma clinical trials. Neurology 2013;81 (Suppl):S15-S24.
- Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol 2014;132:111-114.
- Avery RA, Hardy KK. Vision specific quality of life in children with optic pathway gliomas. J Neuro-Oncol 2014;116:341-347.
- Avery RA, Hwang EI, Ishikawa H, Acosta MT, Hutcheson KA, Santos D, Zand DJ, Kilburn LB, Rosenbaum KN, Rood BR, Schuman JS, Packer RJ. Handheld optical coherence tomography during sedation in young children with optic pathway gliomas. JAMA Ophthalmol 2014;132:265-271.
- Gu S, Glaug NC, Cnaan A, Packer RJ, Avery RA. Retinal ganglion cell layer thickness in children with vision loss from optic pathway gliomas. Invest Ophthalmol Vis Sci 2014;55:1402-1408.
- Avery RA, Cnaan A, Schuman JS, Chen C-L, Glaug NC, Packer RJ, Quinn GE, Ishikawa H. Reproducibility of circumpapillary retinal nerve fiber layer measurements using hand-held optical coherence tomography in sedated children with optic pathway gliomas. Am J Ophthalmol 2014;158:780-787.
- Avery RA, Cnaan A, Schuman JS, Chen C-L, Glaug NC, Packer RJ, Quinn GE, Ishikawa H. Intra- and inter-visit reproducibility of ganglion cell inner plexiform layer measurements using handheld optical coherence tomography in children with optic pathway gliomas. Am J Ophthalmol 2014;158:916-923.
- Rajjoub RD, Trimboli-Heidler C, Packer RJ, Avery RA. Reproducibility of retinal nerve fiber layer thickness measures using eye tracking in children with nonglaucomatous optic neuropathy. Am J Ophthalmol 2015;159:7177.
- Avery RA, Cnaan A, Schuman JS, Trimboli-Heidler C, Chen C-L, Packer RJ, Ishikawa H. Longitudinal change of circumpapillary retinal nerve fiber layer thickness in children with optic pathway gliomas. Am J Ophthalmol 2015;160:944-952.
- de Blank PMK, Fisher MJ, Liu GT, Gutmann DH, Listernick R, Ferner RE, Avery RA. Optic pathway gliomas in neurofibromatosis type 1: an update: surveillance, treatment indications, and biomarkers of vision. J Neuro-ophthalmol 2017;37 Suppl 1:S23-S32.
Optic Nerve Degeneration and Regeneration
Dr. Ahmara Ross is in the initial stages of researching mechanisms of neurological degeneration and regeneration using experimental models of glaucoma at the F.M. Kirby Center for Molecular Ophthalmology. Dr. Ross’s studies focus on retinal ganglion cell damage and mechanisms of cell death that occur during optic nerve damage from stretch and elevated intraocular pressure conditions that occur in glaucoma. This damage leads to irreversible vision loss associated with glaucoma, one of the leading causes of blindness in the United States. This disease disproportionality effects African Americans, the aging population, and people with diabetes and hypertension. At present, the only treatment modalities, including medications, laser, and incisional surgery are aimed at lowering intraocular pressure. Dr. Ross has an NIH K08 Career Development award to investigate the neuroprotective potential of gene therapy directed at retinal ganglion and neighboring support cells to treat glaucoma.
Neurodegenerative diseases such as Parkinson's disease are a growing public health problem, and there is increasing recognition of visual symptoms caused by these diseases as well as the role that vision plays in patient outcomes such as hallucinations and falls. Dr. Hamedani's early career research interests center around the intersection between neuro-ophthalmology and neurodegenerative disease, and he is using a combination of epidemiologic methods including national health survey data, administrative health claims, and patient surveys to measure the prevalence, determinants, and health outcomes associated with visual symptoms in Parkinson s disease. He is also interested in contrast acuity, OCT, and other neuro-ophthalmic biomarkers of degeneration in inherited movement disorders.
- Hamedani AG, Hauser LA, Perlman S, Mathews K, Wilmot GR, Zesiewicz T, Subramony SH, Ashizawa T, Delatycki MB, Brocht A, Lynch DR. Longitudinal analysis of contrast acuity in Friedreich ataxia. Neurol Genet 2018 Jul 23;4(4):e250.
- Hamedani AG, Gold DR. Eyelid dysfunction in neurodegenerative, neurogenetic, and neurometabolic disease. Front Neurol 2017 Jul 18;8:329.