1. Unusual anterior Uveitis in a Child

2. Ocular History  10 year old boy  1/2001: OD>OS  red eyes  iris thickening,  endothelial precipitates, hyphema  topical corticosteroids  IOP: OD: 40mmHg  YAG-iridotomy: unsuccessfull

3. First Diagnosis Anterior uveitis of unknown origin Anterior uveitis of unknown origin

4. Treatment topical corticosteroids every hour topical corticosteroids every hour

5. Ocular History at Presentation  6 weeks after first symptoms  VA OD 8/20; OS 12/20  IOP: 18/16mmHg  slitlamp OD:  iris thickening,  endothelial precipitates, hyphema  Fundus: unremarkable

6. First Presentation - OD

7.  massive granulomatous precipitates

8. Ocular History at Presentation  slitlamp OS  iris prominence at 11 o´clock  mild anterior chamber cells 1+  fundus: unremarkable

9. First Presentation - OS

10. General History unclassified malformation syndrome with anal atresia, insufficiency of the pituitary gland unclassified malformation syndrome with anal atresia, insufficiency of the pituitary gland heart transplantation at the age of 3 due to dilative cardiomyopathy with endocardial fibrosis heart transplantation at the age of 3 due to dilative cardiomyopathy with endocardial fibrosis several transplant rejections (2000) several transplant rejections (2000) Immunosuppression at the moment Immunosuppression at the moment Cyclosporin A, Azathioprin Cyclosporin A, Azathioprin

11. Second Diagnosis  CMV induced uveitis  based on:  CMV mismatch at transplantation  leading to high IgG- and IgM- antibody titers against CMV

12. Change of Treatment systemic ganciclovir in addition systemic ganciclovir in addition repeated negative PCR and PP-65 ruled out active CMV, leading to repeated negative PCR and PP-65 ruled out active CMV, leading to stop of ganciclovir stop of ganciclovir clinically and serologically no evidence for sarcoidosis, toxoplasmosis, toxocara or HIV-infection clinically and serologically no evidence for sarcoidosis, toxoplasmosis, toxocara or HIV-infection

13. Follow up – After 3 Months  angle closure - peripheral iridectomy  severe hyphema  systemic corticosteroids

14. Histology of Irisbiopsy  first view  lymphocytes  no lymphoma  severe inflammation  second view:  very few mitotic cells  probably low malignant non Hodgkin-lymphoma

15. Irisbiopsy – HE-Staining  polymorphic lymphocytic infiltration (brown) Rohrbach et al. Graefe´s Arch Clin Exp Ophthalmol 2004

16. Immunohistology of Irisbiopsy CD 20 +/ CD3 - lymphocytes CD 20 +/ CD3 - lymphocytes

17. Irisbiopsy- Immunostainig Rohrbach et al. Graefe´s Arch Clin Exp Ophthalmol 2004

18. Irisbiopsy - EBV irisbiopsy: positive PCR for EBNA-1 irisbiopsy: positive PCR for EBNA-1 EBV-load: 5,6 x 10 -3 (20 x elevated) EBV-load: 5,6 x 10 -3 (20 x elevated) monoclonal rearrangement in the CD2 region of Ig heavy chain gene in cells of the tumour (IgH-gene) monoclonal rearrangement in the CD2 region of Ig heavy chain gene in cells of the tumour (IgH-gene)

19. Gel-Electrophoresis  PCR with primers for the Ig heavy chain gene, hypervariable region  A,B: tumour  L: length marker  P: pos. control  lane 5, 6: neg. control Rohrbach et al. Graefe´s Arch Clin Exp Ophthalmol 2004 Rohrbach et al. Graefe´s Arch Clin Exp Ophthalmol 2004

20. Diagnosis  Posttransplantation-Lymphoproliferative Disease (PTLD)  localized NH-lymphoma in children after severe immunosuppression  nearly exclusively associated to EBV  interpretation of histology known to be difficult

21. Follow up – After 5 Months  low dose CsA, azathioprine stopped  ganciclovir orally  OS: iris tumor regressed slightly  OD: iris tumor progressed  high EBV-replication rate in mononuclear blood cells

22. Follow Up – After 6 Months

23.  radiation (5 x 2.0 Gy/week)  well tolerated  at the end of the radiation  mild conjunctivitis  partial remission of the tumor Follow up - After 6 Months

24. complete remission of the ocular tumor complete remission of the ocular tumor hypotonic situation hypotonic situation cataract with convergent squint cataract with convergent squint still very high EBV titers still very high EBV titers Follow up - After 8-12 Months

25. Follow Up- After 8 Months OD

26.  viral load half of the beginning  still consistant with persistant active EBV- infection  foscarnet started  after a few weeks:  viral load even higher than before begin of the foscarnet therapy  probably high risk for more lymphoma Follow Up – After 13 Months

27. Follow Up – After 17 Months  collection of EBV-infected B-cells from the patient  generation of patients own specific cytotoxic anti-EBV T-cells  Center for Gene and Cell Therapy Houston TX, USA

28. Follow Up – After 22 Months  anti-EBV Treatment  reinfusion of the T-cells in 3 portions  reduction of the EBV load  free of cells in the anterior chamber

29. Last Control – After 32 Months  VA: OD: hand movements, OS: 16/20  OU:  clear cornea, no AC cells  no iris tumors  IOP 5 and 10 mmHg  OD: dense cataract, surgery planned  then lost for follow-up

30. Posttransplantation Lymphoproliferative Disorder all age groups all age groups after transplantation of kidney, liver, heart, lung or bone marrow after transplantation of kidney, liver, heart, lung or bone marrow incidence ca. 2-3 % incidence ca. 2-3 % latency few weeks to 3 years latency few weeks to 3 years highest incidence probably in the first year after transplantation highest incidence probably in the first year after transplantation

31. Posttransplantation Lymphoproliferative Disorder  special entity, no simple lymphoma  3 variants  circumscribed lesion, typically later than 1 year after tranplantation, often localized in the CNS, gastrointestinal tract or salivary glands  benign, selflimiting disease resembling mononucleosis  malignant widespread lymphoproliferation with high mortality

32. Ocular PTLD  Brodsky et al 1991  until now 14 cases (50% with syst. disease)  7 with iris nodules  2 with iris nodules and subretinal mass  1 with widespread disease (uvea, retina, optic nerve,orbit)  1 vitritis,1chorioretinitis,1 anterior uveitis  1 orbital mass

33. Histology of Ocular PTLD proliferation of B-cells and/or plasma cells proliferation of B-cells and/or plasma cells proliferation of T-cells in 10% proliferation of T-cells in 10% polyclonal or monoclonal polyclonal or monoclonal

34. Role of EBV most PTLD caused by a chronic EBV-infection most PTLD caused by a chronic EBV-infection EBV negativ recipients are at higher risk than positive EBV negativ recipients are at higher risk than positive detectable in the tumor and blood monocytes detectable in the tumor and blood monocytes anti-T-cell treatment especially dangerous anti-T-cell treatment especially dangerous CMV-infection elevates risk for PTLD CMV-infection elevates risk for PTLD therapy: reduction of IS, increase antivirals therapy: reduction of IS, increase antivirals

35. Conclusion  PTLD incidence ca. 2-3%  diagnosis: history of solid organ transplantation  can affect the eye  iris nodules  uveitis  therapy:  reduction of immunosuppresion  virustatics  generation of own anti-EBV cytotoxic T-cells