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Bascom Palmer Eye Institute Grand Rounds

Bascom Palmer Eye Institute Grand Rounds. Yousuf Qureshi, M.D. Discussant: Kristen Hartley, M.D. 1. 1. Patient Presentation. CC: 22 yo African American female with c/o floaters x 5yrs HPI: Pt presents to clinic with non-resolving floaters OD ever since being hit with a ball in 2001

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Bascom Palmer Eye Institute Grand Rounds

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  1. Bascom Palmer Eye InstituteGrand Rounds Yousuf Qureshi, M.D. Discussant: Kristen Hartley, M.D. 1

  2. 1

  3. Patient Presentation CC: 22 yo African American female with c/o floaters x 5yrs HPI: Pt presents to clinic with non-resolving floaters OD ever since being hit with a ball in 2001 Pt relates that she has had poor vision since birth and that her eyes have always been unsteady 2

  4. More Medical History • Past Medical Hx: deferred for now • Past Surgical Hx: none • Allergies: NKDA • Current Medications: none • Family Hx: Mother - Hypertension Maternal Aunt - Liver Cancer • Social Hx: unemployed, o/w non- contributory 2

  5. BCVA OD: 20/200 OS: 20/100 IOP OD: 17 OS: 15 Pupils: OD: 6mm  3.5mm OS: 6mm  3.5mm No APD OU Confrontational Fields: full ou Motility: Full Ductions Intermittent Esotropia OS Primary pendular slow horizontal nystagmus SLE Lids: see picture Conj: wnl K: clear AC: D/Q Iris: see picture Lens: clear Ant Vit: clear Exam 3

  6. DFE…. 3

  7. Dilated Fundus Exam 4

  8. Dilated Fundus Exam 4

  9. 5

  10. 5

  11. Differential Diagnosis Albinism Choroideremia Blond fundus Gyrate atrophy (late) Central Areolar Choroidal Dystrophy Diffuse Choroidal Atrophy Isolated Foveal Hypoplasia Aniridia 6

  12. Skin hypopigmentation: Albinism Piebaldism Waardenburg syndrome Vitiligo Nystagmus: Aniridia Albinism Achromatopsia Bilateral Macular toxoplasmosis Optic nerve disease/hypoplasia Visual pathway NOS Differential Diagnosis 6

  13. Slit Lamp Exam 7

  14. Slit Lamp Exam 7

  15. Albinism • 1st described in book of Enoch (1 to 2 BC): • “(Noah)..born to Lamech, but “resembles not him. His color is whiter than snow; he is redder than rose; the hair on his head is whiter than white wool; his eyes are like rays of the sun.” • The first scientific description of albinism was in 1895, Kaposi described Leukoderma congenitale: • “.. absence of pigment from the epidermis causes a lustrous or dull white appearance…The iris and pupil appear red, and there is extreme photophobia with nystagmus …” 9

  16. Albinism • Heterogeneous group of inherited abnormalities in melanin metabolism • Ocular features are the primary morbidity in this disease • Three subtypes: • Oculocutaneous (mostly AR) • Ocular (X-linked or AR) • OCA associated with systemic disorder • HPS • CHS 9

  17. Epidemiology of Albinism • 1:16,000 in the US • OCA1: 1:40,000 • OCA2: 1:10,000 African Americans and 1:36,000 Caucasians • OA1: 1:50,000 • Highest prevalence of albinism is in Cuña Indians of the San Blas Islands of Panama - 63:100,000 • HPS is seen in 1:2700 in Puerto Rico • Affects all races 10

  18. Biochemistry • Ultimate products include eumelanin (black-brown) and phaeomelanin (red-yellow) 10 Jeffery G. The albino retina: an abnormality that provides insight into normal retinal development. Trends Neurosci 1997;20:165-169

  19. OCA-1A OCA-1B OCA-1MP OCA-1-ts Tyrosinase gene (Chromosome 11) Inactive enzyme Partially active (Amish) Minimal pigment Thermolabile enzyme OCA-2 “Brown Albinism” P gene (Chromosome 15) “Tyrosinase-positive” P gene codes for melanosomal protein OCA-3 TRP1 gene (Chromosome 9) DHICA oxidase is responsible for Eumelanin formation; as is TRP2 gene product X-linked ocular albinism OA1 gene (X chromosome) Unknown protein affected Autosomal Recessive Ocular Albinism (AROA) No specific gene Varied enzymes affected (including tyrosinase or P protein) Albinism 11

  20. OCA • OCA1a • Null mutation of tyrosinase • Marked hypopigmentation throughout life • OCA1b • “Leaky” tyrosinase protein • Slow accumulation of pigment • OCA2 • VA may improve as they accumulate pigmentation • OCA3 • Not all patients have ocular findings www.visionsupport.com 11

  21. OA • OA1 (X-linked): • Posterior embryotoxon in 30% of patients • Female carriers may have “mud splattered” fundi • AROA: • Distinct entity or a presentation of OCA2, OCA1? www.mrcophth.com 12

  22. Carrier state of OA1 Mud splattered fundus of X-limked OA in a carrier female. COSTA et al. Retina. 23(3):410-411, June 2003 12

  23. Ocular Associations of Albinism… 13

  24. Refractive Error • Significant refractive error • 14% have refractive errors greater than 10D • <40% of OCA1 better than 20/200 BCVA • VA ranges from near normal to 20/400 • Frequently high “with the rule” (vertical) astigmatism OD: -20.00 +3.50 x177 OS: -20.00 +3.75 x097 13

  25. Iris translucency • The lens edge may be visible on iris retroillumination • Increases intraocular light scatter and photophobia • No correlation of iris translucency with visual acuity • Normal VA in OA1 carriers and fair-complexioned individuals 14

  26. Iris translucency Infrared light source is not blocked due to lack of pigment in iris Baikoff, et al. An in vivo OCT study of human natural accommodation in a 19-year-old albino. Source Journal Francais d Opthalmologie. 28(5):514-9, 2005 May. 14

  27. Retinal Features • None to rudimentary foveal reflex • Paucity of macular luteal pigment • Vessels may cross the central macular area and often do not “wreathe” the fovea • Lack of RPE pigmentation lead to poor laser uptake www.optos.com 15 Journal of AAPOS. 10(3): 237-242. June 2006

  28. Retinal Features • OCT • Foveal hypoplasia and high inner retinal reflectivity (believed to be multiple ganglion cell layers) in a 10 year old with OCA • (Meyer et al. Observational case report; AJO 3/02) • Foveal depression • In a group of 11 albino patients with >20/60BCVA, 4/22 eyes were noted to have a foveal depression • (Patti et al. Observational case series. J of AAPOS; 6/06) 15

  29. mfERG in Albinism • mfERG of 2 OCA patients revealed lower amplitude at the central 5 to 10 degrees of the macula when compared with adult norms • This is consistent with macular hypoplasia and the lack of an increase in cone density in the central retina see in the normal Case series; n=2; mfERG with 103 hexagon array centered on macula assessing cone function; pts were under general anesthesia • Kelly et al. Topographical retinal function in oculocutaneous albinism.American Journal of Ophthalmology. 141(6):1156-8, 2006 Jun. 16

  30. OD stimulus Anomalous Visual Pathways C1 C3 C2 C2 O2 O1 OZ • In albinism, the majority of the ganglion cell axons cross at the optic chiasm • This is seen as asymmetrical occipital responses on VEP with monocular stimulation • This is most useful in equivocal cases of ocular albinism 3 lead normal pattern onset/offset VEP OS stimulus C1 C3 O1 O2 OZ C2 Smith: J Clin Neurophysiol, Volume 15(2).March 1998.146-149 16

  31. hrMRI differences in the normal and albino chiasm Albino Group mean image Normal Group mean image Schmitz et al; Blinded standardized morphologic evaluation; 17 pts with albinism; 15 normal controls

  32. MRI differences in the normal and albino chiasm Difference of the Group Mean between the albino and normal subjects reveals a significant decrease in the width of the chiasm Smaller size and a different configuration of the optic chiasm in albinism revealed by high resolution MRI are distinctly different from those in normal control subjects and may reflect the atypical crossing of optic fibers (paucity of lateral chiasmal fibers – ipsilateral projections) 17

  33. Strabismus and Stereoacuity • Strabismus is associated with 27-53% of albinism cases and high grade stereoacuity is unlikely • Gross binocular function • Facilitated by corpus collosum projections from the temporal retinal periphery • Refractive correction was noted to have significant improvement in strabismic alignment • If surgical treatment for strabismus is considered, presence of a positive angle kappa must be determined since it may be a clinical feature of albinism • (Brodsky et al; Observational case series; 95% of tested albino patients had at least one affected eye; n=21; p=0.0003) 18

  34. Nystagmus • Majority of albino individuals develop nystagmus several weeks after birth • Degree of nystagmus is correlated to the VA • (Wolf et al., RCR, n=38, p=0.0003) • May worsen with fatigue, stress, and bright lighting • Convergence dampening leads to improved acuity with near vision • Hertle et al showed that there was a statistically significant improvement in VA in 14/15 patients with OCA after Horizontal EOM surgery • (Interventional, prospective, non comparative case series; p<0.01; n=15;  0.1 LogMAR BBOCA (-log10Snellen equivalent)) 18

  35. Chediak-Higashi syndrome • AR • Deficiency in NK cell activity • Frequent pyogenic infections • Progressive neurologic defects • Accelerated lymphoproliferation in major organs • Tx: BMT Shiflett et al. Chediak-Higashi Syndrome: a rare disorder of lysosomes and lysosome related organelles. Pigment Cell Research. 15(4):251-7, 2002 Aug. 19

  36. Hermansky Pudlak Syndrome • AR • Platelet granule deficiency • Bleeding diathesis • Excessive lysosomal ceroid storage • interstitial pulmonary fibrosis • granulomatous colitis • renal failure • cardiomyopathy 19 Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Research. 19(1):19-42, 2006 Feb.

  37. Diagnosis • Clinical • Cutaneous and ocular findings? • Hair bulb test • Tyrosinase activity Negative = OCA1A Positive = OCA1B, OCA2, OCA3, OA1 • Molecular methods (PCR) • if hair bulb test + • prenatal sample (14 weeks GA) • Shave biopsy and melanocyte culture • can assess for Tyrosinase, P protein, and TRP1 function; also macromelanosomes (OA1) • Blood tests: large inclusions in PMNs (CHS), decreased blood clotting (HPS) • Electrophysiologic testing • mfERG • VEP 20

  38. Management • Currently no curative treatment • UV protection and annual physician exams • Refractive correction and low vision aids • Strabismus treatment • patching • surgery • Nystagmus treatment • surgery • Education/societal awareness/support groups • The ophthalmologist often initially diagnoses albinism and therefore can initiate the appropriate education and management 20

  39. Back to our patient… Reassured that the persistent floaters she has is the result of a well documented PVD, and that otherwise her retina appears stable compared to her last exam. Follow up in 6 months to refine her refractive correction 21

  40. Back to our patient… 21

  41. Siamese cats? 22

  42. OCA-1A OCA-1B OCA-1MP OCA-1-ts Tyrosinase gene (Chromosome 11) Inactive enzyme Partially active (Amish) Minimal pigment Thermolabile enzyme OCA-2 “Brown Albinism” P gene (Chromosome 15) “Tyrosinase-positive” P gene codes for melanosomal protein OCA-3 TRP1 gene (Chromosome 9) DHICA oxidase is responsible for Eumelanin formation; as is TRP2 gene product X-linked ocular albinism OA1 gene (X chromosome) Unknown protein affected Autosomal Recessive Ocular Albinism (AROA) No specific gene Varied enzymes affected (including tyrosinase or P protein) Albinism 22

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  44. Oculocutaneous Albinism Summary: Albinism is a genetic melanin synthesis abnormality characterized by multiple ocular findings and decreased visual acuity as the result of multiple factors; no current curative treatment exists but prevention of sequelae from the lack of UV protection, screening for potentially lethal variants, and techniques to maximize visual acuity are paramount in these patients. 23

  45. References • Journal of the European Academy of Dermatology & Venereology. Volume 17 Page 251  - May 2003. Oulocutaneous albinism. • Kelly, John P. Weiss, Avery H, University of Washington Medical Center. Topographical retinal function in oculocutaneous albinism.American Journal of Ophthalmology. 141(6):1156-8, 2006 Jun. • Brodsky, Michael C. Fray, Katherine J. University of Arkansas for Medical Sciences. Positive angle kappa: a sign of albinism in patients with congenital nystagmus. American Journal of Ophthalmology. 137(4):625-629, 2004 Apr. • Schmitz, Bernd. Schaefer, Torsten. Krick, Christoph M. Reith, Wolfgang. Backens, Martin. Kasmann-Kellner, Saarland University Hospital. Configuration of the optic chiasm in humans with albinism as revealed by magnetic resonance imaging.Investigative Ophthalmology & Visual Science. 44(1):16-21, 2003 Jan. • Morland, A B. Hoffmann, M B. Neveu, M. Holder, G E. University of London. Abnormal visual projection in a human albino studied with functional magnetic resonance imaging and visual evoked potentials..Journal of Neurology, Neurosurgery & Psychiatry. 72(4):523-6, 2002 Apr. • Meyer, Carsten H. Lapolice, Deborah J. Freedman, Sharon F. Duke University Medical Center. Foveal hypoplasia in oculocutaneous albinism demonstrated by optical coherence tomography.American Journal of Ophthalmology. 133(3):409-10, 2002 Mar. • Smith, Sherry A., Wong, Peter K., Jan, James E. Unilateral Alpha Reactivity: An Electroencephalographic Finding in Albinism. Journal of Clinical Neurophysiology. Volume 15(2), March 1998, pp 146-149. 24

  46. References • Lee, K A. King, R A. Summers, C G. University of Minnesota Medical School. Stereopsis in patients with albinism: clinical correlates.Journal of Aapos: American Association for Pediatric Ophthalmology & Strabismus. 5(2):98-104, 2001 Apr. • Merrill, Kimberly S. Lavoie, Jane D. King, Richard A. Summers, C Gail. University of Minnesota Medical School. Positive angle kappa in albinism.Journal of Aapos: American Association for Pediatric Ophthalmology & Strabismus. 8(3):237-9, 2004 Jun. • Oetting, William S. Richard A. King, M.D. The Clinical Spectrum of Albinism in Humans. Department of Medicine, University of Minnesota Murray H. Brilliant, Ph.D. • Baikoff, et al. An in vivo OCT study of human natural accommodation in a 19-year-old albino. Source Journal Francais d Opthalmologie. 28(5):514-9, 2005 May. • Patti et al. Spectrum of Foveal Development in Albinism Detected with Optical Coherence Tomography. Journal of AAPOS. 10(3): 237-242. June 2006. • Hertle et al. Effects of Extraocular Muscle Surgery on 15 Patients With Oculocutaneous Albinism and Infantile Nystagmus Syndrome. AJO. 138(6): 978-987. Dec. 2004. • Wolf et al. Comparison of Clinical Findings in Pediatric Patients with Albinism and Different Amplitudes of Nystagmus. Journal of AAPOS. 9(4): 363-368 24

  47. Possibilities for treatment? • Foveal development continues several months after birth and occurs much slower in albinism. This opens the possibility of future therapies which may be applied after birth to assist in maturing the retina16 • Gene therapy may be able to replace the missing components of the melanin synthetic pathway (already performed in albino rats) 1

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