Department of Ophthalmology, Amrita Institute of Medical Sciences, Kochi, Kerala, IndiaIndia
1 Department of Ophthalmology, Amrita Institute of Medical Sciences, Kochi, Kerala, IndiaIndia
Department of Ophthalmology and Vitreoretinal Surgery, Amrita Institute of Medical Sciences, Kochi, Kerala, IndiaIndia
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Background: Retinal haemorrhage is a recognised ocular manifestation of bone marrow failure, but bilateral macula-involving subhyaloid haemorrhage and its visual course are rarely documented with serial fundus photography. Case presentation: A 37-year-old male presented with blurred vision in both eyes for 10 days. An outside hospital had found multiple retinal haemorrhages and pancytopenia, and he was admitted for evaluation of the pancytopenia. At presentation, visual acuity was 6/9 in the right eye and 6/6p in the left eye, near vision was N6 in both eyes, and intraocular pressures were 15 and 16 mmHg. Fundus examination showed bilateral boat-shaped macular subhyaloid haemorrhages, dense haemorrhages along the superotemporal arcade adjacent to the optic disc, and scattered intraretinal haemorrhages. Haemoglobin was 8.0 g/dL, platelet count 15 × 10³/µL, white cell count 2.7 × 10³/µL (calculated absolute neutrophil count ≈0.62 × 10³/µL) and absolute reticulocyte count 15.6 × 10³/µL, with erythropoietin 326.8 mIU/mL; PT/INR was normal. He was treated with eltrombopag, tranexamic acid and cyclosporin. Visual acuity then fell to 6/60 in the right eye and 6/24 in the left eye as the haemorrhage involved the fovea. Nd:YAG laser hyaloidotomy was considered, but because blood counts remained low he was observed closely. On serial examination the haemorrhages contracted progressively and cleared from the macula, and visual acuity recovered to 6/6 in both eyes. Conclusion: Severe pancytopenia can produce bilateral macular subhyaloid haemorrhage with transient, marked visual loss when the fovea is involved. Even so, close observation without hyaloidotomy, while blood counts remained low, was followed by spontaneous resolution and full visual recovery. A dilated fundus examination should form part of the work-up of severe cytopenia, and retinal intervention should be approached conservatively while thrombocytopenia persists.
Keywords: pancytopenia; thrombocytopenia; aplastic anaemia; subhyaloid haemorrhage; eltrombopag; aplasticanaemia; subhyaloidhaemorrhage; eltrombopag subhyaloidhaemorrhageinvolvingthemaculainboth 1.Introduction eyes
subhyaloidhaemorrhageinvolvingthemaculainboth 1.Introduction eyes.
Bone marrow failure states, including aplastic anaemia, myelodysplasia, leukaemia and drug- or Colourfundusphotographsatpresentation(Figure1) immune-related cytopenias, may be complicated showedawell-demarcated,boat-shapedsubhyaloid byahaemorrhagicretinopathy. Lowplateletcounts haemorrhagewithahorizontalsedimentationlevelin andanaemiaacttogetherontheretinalvasculature, themacularregionofeacheye. Dense,dark,dome- and bleeding is more likely when both are present shapedhaemorrhageslayalongthesuperotemporal thanwheneitheroccursalone[1][2][3].Inpublished arcadeadjacenttotheopticdisc,togetherwithperi- seriesofaplasticanaemia,retinopathyaffectsroughly papillary haemorrhages and scattered dot-blot and one fifth to one quarter of patients, and retinal flame-shapedintraretinalhaemorrhagesintheposte- haemorrhage is its commonest sign [4]. The blood riorpole.Opticalcoherencetomography(OCT)showed mayliewithintheretina,beneaththeinternallimiting thehaemorrhagetobesubhyaloidinbotheyes(Figure membrane (sub-ILM), in the subhyaloid space or in 1Cand1D).
thevitreous.Retinalhaemorrhagewasalsofoundin about29%ofpatientswithseverethrombocytopenia 1.3 Investigations due to haematological or oncological malignancy LaboratoryresultsaresummarisedinTable1. There whounderwentfundoscopy,whichsupportsroutine waspancytopeniawithseverethrombocytopenia(15× fundusexaminationinthisgroup[5].
10³/µL),anaemia(haemoglobin8.0g/dL;normocytic, MCV97.2fL;raisedRDW19.8%)andleucopeniawith Severeaplasticanaemiaisdiagnosedwhenahypocel- neutropenia(whitecellcount2.7×10³/µL;calculated lular marrow is accompanied by at least two of the absoluteneutrophilcount ≈0.62×10³/µL).Theretic- following: an absolute neutrophil count below 0.5 9 9 ulocyte count was inappropriately low (0.615%; ab- × 10 /L, a platelet count below 20 × 10 /L and a 9 solutecount15.6×10³/µL)despiteamarkedlyraised reticulocytecountbelow20×10 /L[6][7].Treatment erythropoietinlevel(326.8mIU/mL).PTandINRwere restsonimmunosuppressionwithcyclosporin,with normalandtheAPTTwasnotprolonged,whichargues orwithoutantithymocyteglobulin,togetherwiththe against a coagulation factor defect. Renal and liver thrombopoietin-receptoragonisteltrombopag,oron function,calcium,electrolytesandbilirubinwerenor- haematopoieticstemcelltransplantation[7][8]. mal,andLDHwasmarginallyraised(263U/L).Thepe- We report a patient with bilateral subhyaloid haem- ripheralsmearwasconsistentwithaplasticanaemia. orrhages involving the macula in severe pancytope- nia.Visualacuityfellto6/60and6/24whenthefovea 1.4 Treatment wasinvolvedandthenrecoveredto6/6withcloseob- Systemicmanagementwasdirectedbythehaematol- servation,andserialfundusphotographsdocument ogyteam. Thepatientreceivedoraltranexamicacid thecourse.Thecaseillustratesthedilemmabetween 500mg,eltrombopag50mgandcyclosporincapsules. Nd:YAGhyaloidotomyandobservationinapatientwith Ophthalmicmanagementconsistedofcloseobserva- persistentseverethrombocytopenia.
1.1 CaseReport 1.5 Follow-upandoutcome A37-year-oldmalewasadmittedunderMedicalOncol- Duringfollow-upthehaemorrhageenlargedtoinvolve ogyandHaematologyforevaluationofpancytopenia. thefoveainbotheyes, andvisualacuityfellto6/60 Hehadnoticedblurringofvisioninbotheyesfor10 intherighteyeand6/24inthelefteye. Becausethe days and had consulted an outside hospital, where haemorrhagesweredenseandcentral,Nd:YAGlaser multipleretinalhaemorrhagesandpancytopeniawere hyaloidotomywasconsidered. Inviewofthepersis- diagnosed,beforebeingreferredforfurtherevaluation. tently low platelet and other blood counts and the bleedingriskofintervention,thedecisionwasmade 1.2 Clinicalfindings toobserveclosely.Bloodcountsremainedlowduring Anteriorsegmentexaminationwasnormalinbotheyes. thisperiod,andthepatientwasreviewedweekly.Fun- Visualacuitywas6/9intherighteyeand6/6pinthe dusevaluationshowedprogressivecontractionofthe lefteye,andnearvisionwasN6inbotheyes.Intraoc- macularsubhyaloidhaemorrhagesinbotheyes(Fig- ular pressure was 15 mmHg in the right eye and 16 ures2and3).Thesedimentationlevelwaslost,andthe mmHg in the left eye. Fundus examination showed peripapillaryhaemorrhagesshrankanddarkened.At normalopticdiscs,withmultipleintraretinalhaemor- thelatervisit(Figure3),therighteyeretainedasmall rhagespredominantlyintheperipapillaryareaanda pigmentedmacularhaemorrhageandasmallhaem-
40.0–50.0 RBCcount 2.50×106/µL 4.5–5.5 MCV/MCH/MCHC 97.2fL/32.0pg/32.9g/dL 83–101/27–32/31.5–34.5 RDW 19.8% 11.6–14.8 Plateletcount 15×10³/µL 150–400 Meanplateletvolume 9.89fL 6.8–10 Whitecellcount 2.7×10³/µL 4.0–10.0 Neutrophils/lymphocytes 22.9%/70.1% 60–80/20–40 Absoluteneutrophilcount(calculated) – Reticulocytes(%/absolute) 0.615%/15.6×10³/µL 0.5–1.0/26–126 Erythropoietin 326.8mIU/mL 3.22–31.9 PT/INR 14.4s/0.98 12.8–16.6s APTT 26.8s 28.1–33.9s LDH 263U/L 0–248 Creatinine/urea 0.90/33.6mg/dL 0.7–1.2/19–44 AST/ALT/ALP 19.9/25.5/64.5IU/L 0–50/0–40/0–130 Totalbilirubin 0.49mg/dL 0–1.1 Sodium/potassium 139.1/3.9mmol/L 136–145/3.5–5.1 HIV-1/2(p24AgandAb) Non-reactive(index0.07) – Bloodgroup ARhDpositive – Abbreviations:ALP,alkalinephosphatase;ALT,alanineaminotransferase;APTT,activatedpartialthromboplastintime;AST, aspartateaminotransferase;INR,internationalnormalisedratio;LDH,lactatedehydrogenase;MCH/MCHC/MCV,mean corpuscularhaemoglobin/haemoglobinconcentration/volume;PT,prothrombintime;RDW,redcelldistributionwidth. orrhageadjacenttothedisc,andthelefteyeasmall 2.Discussion residualdarkhaemorrhageatthemacula. Thefinal Thispatienthadextensivebilateralhaemorrhagesin photographs(Figure4)showclearanceofthehaemor- thepremacularandperipapillaryregionsduringevalu- rhagesinbotheyes,andvisualacuityrecoveredto6/6 ationforpancytopenia.Themainclinicalpointisthe althoughthebloodcountsremainedlowthroughout linkbetweenaseriousunderlyinghaematologicaldis- thecourse.
orderandhaemorrhagicretinalchange, whichhere causedamarkedbutreversiblefallinvision. Bleedingintotheretinaincytopenicstatesresultsfrom ries,bilateralhaemorrhagepredominatedamongthe retinalfindingsandthemeanplateletcountofaffected patientswaslow,closetothevalueseenhere[4]. A Valsalva-typeriseinvenouspressurecanalsoprovoke sub-ILMbleedinginathrombocytopeniceye[9],sothe historyshouldbeexploredforcoughing,vomitingor straining.
The macular lesions were boat-shaped with a hor- izontal level, reflecting layering of red cells under gravityinthesubhyaloidspace.OCThelpstoseparate subhyaloidfromsub-ILMhaemorrhage:sub-ILMblood lies under a thin, taut, hyper-reflective membrane, whereas subhyaloid blood lies beneath a detached posteriorhyaloid.Thedistinctionaffectsmanagement, because Nd:YAG hyaloidotomy releases the blood into the vitreous cavity and has given good visual results in dense premacular haemorrhage [10][11], butitcarriesrisksthatincludemacularhole,retinal detachmentandpersistentvitreousopacity[10].The choiceoftreatmentdependsontheinitialacuity,the sizeandlocationofthehaemorrhageandthepatient’s generalhealth[12].Inourpatienttheindicationwas debatable. Vision had fallen to 6/60 and 6/24 with fovealinvolvement,whichwouldusuallyfavourearly hyaloidotomy to shorten the period of visual loss andlimittoxicityofbloodonthemacula. However, both eyes were affected, platelet and other counts remained low, and any laser-induced bleeding or vitreous haemorrhage would have been difficult to manage. We therefore observed closely, and the haemorrhages cleared spontaneously. One series reservedlaserforhaemorrhagesthathadnotresolved ontheirown[11],andconservativemanagementhas beenchosenforapatientonanticoagulanttherapy [12].Ouroutcomesupportsobservationasareason- able first approach in selected thrombocytopenic patients,providedfollow-upiscloseandintervention remainsavailableifthehaemorrhagepersistsorclot organisationthreatensthefovea.
The combination of severe thrombocytopenia, neu- tropeniabelow1.0×109/L,aninadequatereticulocyte responseandamarkedlyraisederythropoietinlevel pointstohypoproliferativemarrowfailure,andtreat- mentwithcyclosporinandeltrombopagfollowsstan- fragilecapillariesanddefectiveprimaryhaemostasis dardpracticeforaplasticanaemia[7][8].Spontaneous whenplateletsarelow, andanaemichypoxiaaggra- resolutionofaplasticanaemiaretinopathyhasbeen vatesthisbyincreasingvesselpermeability. Throm- described,withnear-completeclearingandvisualim- bocytopeniaandanaemiaacttogether[1],andwhite- provementoverabout16weeksafterstemcelltrans- centredhaemorrhagesareseeninmanyhaematolog- plantation[13],andocularlesionshavebeenreported icalconditions[2]. Ourpatienthadaplateletcount toevolveinstepwithsystemicimprovement[14].Reti- of15×10³/µLtogetherwithhaemoglobinof8.0g/dL, nalhaemorrhageshavelikewiseregressedasplatelet andthenormalPT/INRandnon-prolongedAPTTargue countsroseinimmunethrombocytopenia[15].Inour againstacoagulopathy.Inalargeaplasticanaemiase- patientthehaemorrhagesclearedwhilebloodcounts
remainedlow,sofullhaematologicalrecoverymaynot ColourphotographyandOCTdocumentmorphology beaprerequisiteforresolution,althoughasinglecase andmonitorresolution. (3)Hyaloidotomyshouldbe cannotestablishthis.Thecontributionofhaematologi- balancedagainstbleedingrisk;wherecountsremain caltreatmentrelativetonaturalresolutionalsocannot low,closeobservationcanbeeffective,withlaserre- beseparated.Ophthalmicsurveillanceisreasonable servedfornon-resolvingcollectionsandideallyper- during long-term eltrombopag, and blood pressure formedwithplateletsupport.(4)Theretinalfindings shouldbemonitoredduringcyclosporintherapy. reinforcetheimportanceofcorrectingthrombocytope- nia.
Clinicalimplications: (1)Patientsadmittedwithse- verecytopeniashouldundergoadilatedfundusexam- Limitations: Thisisasinglecase.Thenaturalhistory ination,sinceretinalhaemorrhageiscommoninthis ofsuchhaemorrhagesisgenerallyfavourable,sothe settingandmaygounnoticedorpresentlate[4,5].(2) roleofobservationintherecoverycannotbeseparated
fromthatofhaematologicaltreatment,andwecannot American journal of ophthalmology. 1968 compareouroutcomewiththatofhyaloidotomy. Mar;65(3):435-9.
2. DuaneTD,OsherRH,GreenWR.Whitecentered hemorrhages: their significance. Ophthalmol- 3.Conclusion ogy.1980Jan1;87(1):66-9 Bilateralmacula-involvingsubhyaloidhaemorrhagein 3. Kincaid MM, Green MR. Ocular and orbital severepancytopeniacanreducevisionto6/60and6/24 involvementinleukemia.Surveyofophthalmol- yetresolvewithcloseobservation,withrecoveryto6/6, ogy.1983Jan1;27(4):211-32.
evenwhilebloodcountsremainlow.Earlydilatedfun- 4. MansourAM,LeeJW,YahngSA,KimKS,Shahin dusexamination,multimodalimagingandclosecol- M,HamerschlakN,BelfortRN,KurupSK.Ocular laborationbetweenretinaandhaematologyservices manifestationsofidiopathicaplasticanemia:ret- arecentraltoprotectingvision,anddecisionsabout rospectivestudyandliteraturereview. Clinical hyaloidotomyshouldbeindividualisedtoplateletsta- ophthalmology.2014Apr17:777-87.
5. SaadéMC,HaddadFG,SukkariehG,MechlebN, WakedN.Theroleoffunduscopyinseverethrom- 4.Declarations bocytopenia:Aprospectivestudy. Transfusion Ethicalapproval CliniqueetBiologique.2022May1;29(2):138-40. 6. CamittaBM,RappeportJM,ParkmanR,Nathan Thecasewasmanagedinaccordancewiththeprinci- DG.Selectionofpatientsforbonemarrowtrans- plesoftheDeclarationofHelsinki. Writteninformed plantationinsevereaplasticanemia.
consentforpublicationoftheclinicaldetailsandim- 7. Marsh JC, Ball SE, Cavenagh J, Darbyshire P, ageswasobtainedfromthepatient.
Dokal I, Gordon-Smith EC, Keidan J, Laurie A, Martin A, Mercieca J, Killick SB. Guidelines 5.Conflictsofinterest: forthediagnosisandmanagementofaplastic Nil anaemia.Britishjournalofhaematology.2009 Oct1;147(1):43.
6.Financialsupport: 8. TownsleyDM,ScheinbergP,WinklerT,Desmond Nil R,DumitriuB,RiosO,WeinsteinB,ValdezJ,Lot- terJ,FengX,DesiertoM.Eltrombopagaddedto standardimmunosuppressionforaplasticane-