Case Conference Pf.김만수/R3 정병주 Let us begin the case conference

Case 2010.4.19(OPD) F/42 Chief complaint : Dec. VA & ocular discomfort(OD) onset) 4 months ago 상환 제주도에 거주하는 분으로, 4개월 전 부터 피곤하면서 우안 불편감으로 local에서 헤르페스 각막염 의심 하에 치료 받음. 2달 후 호전되어 치료 중단. 본원 내원 1주전부터 우안 시력 급격히 저하되어 큰병원 권유받고 내원 A 42 year-old female visited our clininc on April 19th, 2010. The chief complaint was Decreased visual acuity and ocular discomfort for 4 months. She lives in Jeju island, and there, she was treated as herpes kerititis, After taking treatments for 2months, her symptoms was improved, but aggravated 1 week ago.

Past history DM/HBP (-/-) Ocular op/trauma(-/-) Gls (+) Eye drop (+ ): O-LON x 3-4 , O-MOX x 3-4 O-GC x 3-4(OD) SCL for about 10yrs, intermittently She had no specific past history, and no other ocular operation or trauma. And she have used eyedrops such as prednisolone, moxifloxacin, and gancyclovir about 3 or 4 times.

Ocular exam VA OD HM(n-c) OS 0.16(0.8) IOP OD 10 mmHg OS 13 mmHg EOM straight at 1 position by ACT, no LOM Orbit OU no exophthalmos Lid OU no swelling Conj. OD mod. Injected state c follicles(+), discharge(-) OS not injected Cornea OD 6.0x5.0mm ovoid epidefect c diffuse stromal opacity Stromal infiltration around epidefect(ring-shape) OS clear AC OD deep & blurry visible OS deep & cell(-) Pupil OD round & nl. sized, LR(+) OS round & nl sized, LR(+), RAPD(-/-), NVI(-/-) Lens OD blurry visible d/t corneal state OS clear Corneal sensitivity test : decreased KOH (-) Her visual acuity was just hand movement. Slit lamp examination of the anterior segment showed some inflammation signs. Conjunctiva was moderate injected and had some follicles, but there was no discharge. Corneal sensitivity was decreased KOH showed negative findings.

2010.4.19 (OPD) 6.0x5.0mm ovoid epidefect c diffuse stromal opacity Stromal infiltration around epidefect (ring-shape) This is the corneal photo of initial visit. We can find 6x5 mm sized epidefect and diffuse stromal opacities. And Ring shaped stromal infiltration was developed around epidefect.

Cue list Slow and long acting progress No Severe pain SCL for about 10yrs, intermittently Conjunctival injection & follicle Definite discharge(-), not supprurative Decreased corneal sensitivity Epidefect with surrounding stromal infiltration(Ring shaped)

Ring infiltration Fungus Acanthamoeba Herpes Pseudomonas Toxic keratopathy (Anesthetics) Acanthamoeba Herpes On the basis of cue list, specific findings is ring- infiltration, and this sign can be seen in like these disease.

Ring infiltration Rapid progression Pseudomonas Dense stromal infiltration Marked suppuration Liquefactive necrosis Similar to Acanthamoeba Pseudomonas Toxic keratopathy (Anesthetics) In some cases, the Characteristics of pseudomonas keratitis are rapid progression, dense stromal infiltration, marked suppuration, liquefactive necrosis, But, in our case, symptoms and signs are not similar.

Ring infiltration Pseudomonas Anesthetics abuse Toxic keratopathy Corneal epidefects Often with a ring infiltration C iridocyclitis, hypopyon, hyphema Like Acanthamoeba Toxic keratopathy (Anesthetics) Repeated use or abuse of topical anesthetics may present with the same sign and symptome like acanthamoeba, but she didn’t overuse

Ring infiltration Fungal keratitis Slow progression c gradually increasing pain Suppuration(+-) Nonspecific Conjunctival injection Epithelial defect Anterior chamber reaction Specific Infiltrate : Feathery margins Gray/brown pigmentation Elevated edges Rough texture Satellite lesions Fungal keratitis also can show ring infiltration, but fungus culture & KOH was negative, and our case was not corresponded to this.

Ring infiltration Fungus Acanthamoeba Herpes Pseudomonas Toxic keratopathy (Anesthetics) Acanthamoeba Herpes So, our impressions were R/O Herpes keratitis, R/O Fungal keratitis, R/O Acanthamoeba keratitis(OD) This patient’s signs and symptoms were compatible with herpetic keratitis or Acanthamoeba keratitis. It’s difficult to distinguish herpetic keratitis and Acanthamoeba keratitis, especially advanced stage. And Frankly, Her contact lens use history was missed, because she was from the contryside.

Ring infiltration Herpes stromal keratitis Immune ring(Wessely) Deposition of viral antigen and host antibody complexes 사진 넣기

Impression Treatment plan R/O Herpes keratitis R/O Acanthamoeba keratitis R/O Fungal keratitis Treatment plan O-GC X 3-4 O-LON X 2 O-MOX X 3-4 O-1AT X 2 Acyclovir 1000mg H-TRI 1T So, first impression, was chronic herpes keratitis, We prescribe ~~ eyedrops and planned FU ocular exam after 2 wks based on herpetic keratitis.

2010.5.10(OPD & adm) 6x5mm sized ovoid epidefect c diffuse stromal opacity Stromal infiltration around epidefect (ring-shape) :Stationary: This is the f/u photo after 2wks from initial visit. Corneal state shows no definite change , so we decided to take her to receive hospital treatment.

2010.5.10(Adm) Impression Treatment plan R/O Herpes keratitis : Neurotrophic keratitis : Herpes stromal keratitis R/O Acanthamoeba keratitis R/O Fungal keratitis Treatment plan Minimize eyedrops CUT O-GC CUT O-MOX O-LON x 4 O-1AT X 2 H-LON 30mg Acyclovir 2000mg 상태 호전 없어 입원하여, 경과 관찰하기로 하고, 약제를 변경함 (스테로이드 증량, eyedrop 최소화)

lab HSV IgG positive HSV IgM negative VZV IgG positive VZV IgM negative CMV IgG positive CMV IgM negative Viral marker 는 특이 소견 관찰되지 않음.

Flow sheet 6x5mm sized ovoid epidefect c diffuse stromal opacity Stromal infiltration (ring-shape) Slightly improved Slightly increased infiltration 2010.5.10 O-LON x 4 O-1AT X 2 H-LON 30mg Acyclovir 2000mg 2010.5.15 O-LON tapering O-1AT X 2 H-LON tapering Acyclovir 2000mg 2010.5.20 ADD O-GC X 5 ADD TFT O-1AT X 2 Acyclovir 2000mg HD 5일째, 증상 및 상태 호전 있어, 퇴원함.

Newly developed Suppurative lesion 2010.6.3 (OPD) Newly developed Suppurative lesion Treatment plan ADD O-MOX q1hr O-GC x 5-6 O-1AT x2 Cut TFT d/t pain Acyclovir 2000mg 외래 내원, After 2 weeks, she visited clinic, and newly suppurative lesion was developed. 2’ infection was Suspected, so moxifloxacin was applied q1h. But she came back to Jeju island, so her f/u was loser for 6 months. Culture : (-) F/U loss for 6 months

c stromal thinning (inf. 3/4) 2010.12.6 2.5x2.5mm epidefect c stromal opacity c stromal thinning (inf. 3/4) c ring infiltration Treatment plan <Keep local medication> O-MOX x 3 O-GC x 5 AMT failed d/t poor compliance * Culture : all (-) * HSV type 1 & 2 PCR (-) 6개월만에 환자가 내원함. 각막 병변 상태는 stromal thinning 소견이 진행된 상태로 내원, AC reaction 이 악화됨. Dec. 6th, the patient visited d/t increased ocular pain. On slit lamp exam, epidefect and stromal infiltration was ramained, but stromal thinning was aggravated. All culture and HSV PCR were negative findings.

2010.12.06 (OPD & Adm) Local medication O-MOX x 3 Tobramycin eyedropx 3 Trifluridine x 4 O-GC x 5 ~6 Neomycin ointment x hs /OD O-1AT - intermmitent Steroid IV injection (12.1 ~12.5) vacrax-> 제주도에 없어서 zovirax po.medi. 하다 한달 전 stop. Local medication 은 여전히 herpes keratitis에 준해서 사용하던 상태임.

c stromal thinning (inf. 3/4) 2010.12.14 (OPD) Enlarged epidefect c stromal opacity c stromal thinning (inf. 3/4) c ring infiltration Treatment plan Conjunctival Flap After 1 week, epidefect size was enlarged and stromal thinning was aggravated, so conjunctival flap was done.

Soft contact lens Hx. was notified !! 2010.12.16 (OPD) Soft contact lens Hx. was notified !! Impression R/O Acanthamoeba keratitis R/O Herpes keratitis Treatment plan Start O-chlorhexidine x q1h O-PHMP x q1h After taking history examnination, repeatedly, we finally found out she was soft contact lens user. So, in conclusion, our impression was changed to acanthamoeba keratitis, and changed our regimen. We started chlohexidine, & polyhexamethylene biguanide q1h.

2010.12.24 (OPD & adm) After 5 days later, Evisceration was done. Inoculated pus underneath the conjunctival flap & aggravated thinning & Impending perforation Treatment plan After 5 days later, Evisceration was done. After 1 week, She visited with increased ocular pain, and like this photo, inocularated pus was developed underneath the conjunctival flap. And stromal thinning was aggravated. After 5days later, the patient had a evisceration.

Pathology & Final diagnosis Acute and chronic inflammation with few (two) parasite eggs Final diagnosis Acanthamoeba keratitis When we took a evisceartion, corneal excision biopsy was done, and on pathologic exam, two parasite egg was discovered. So final diagnosis was confirmed as Acanthamoeba keratitis.

Flow sheet 10.4.19 10.5.10 10.6.3 10.12.6 10.12.14 10.12.21 10.12.24 11.1.13

Acanthamoeba Keratitis Cornea, 3rd edition 각막, 2nd edition

Introduction Related to the CL wear ( more than 90% ) Found Ubiquitously in water and soil Healthy people Severe chronic keratitis Immunosuppressed individuals Chronic granulomatous amoebic encephalitis Cutaneous amoebiasis Related to the CL wear ( more than 90% ) Extended usage of CL !! -> increased incidence !! 우리 주변에서 흔히 볼수 있는 아메바로, 수돗물이나, 수영장, 흙, 컨택트 렌즈, 렌즈 케이스 에서도 발견됩니다.

Life cycle Cyst는 포낭형으로 비활동성이고 생활환경과 여건에 따라 활동성인 영양형 trophozoite로 변하게 되고 환경이 좋지 않을때 다시 cyst가 됩니다. Cyst나 trophozoite가 눈이나, 폐, 피부를 통해서 인체에 들어오게 되고 눈으로 들어온것은 keratitis를 일으키고 폐나, 피부를 통해 들어온 것은 immune compromised 환자에서 systemic infection인 granulomatous amoebic encephalitis나 cutaneous amoebiasis를 일으킵니다.

in unfavorable condition Introduction Trophozoites Cyst infective type 1 nucleolus cytoplasmic vacuoles acanthopodia-motile 생활환경과 여건에 따라 활동성인 영양형 trophozoites와 비활동성인 포낭형 cyst으로 변형 주변환경의 습도, 온도, 영양분이 좋지 않을 경우 cyst로 존재. 65도의 높은 온도에서 5분 간 생존 생존하고 -20도의 냉동된 상태에서도 생존. Irradiation에도 resistant하다고 최근 보고 in unfavorable condition double wall resistant to extreme conditions ( osm. pH, freezing, chemical antimicrobial agents)

Risk factors Occurs in immunocompetent, healthy young individuals (CL wearers) Men & women are equally affected most frequently unilat. but bilat. Exposure to contaminated water or CL solution (오염된 수돗물, 오염된 렌즈 용기, 렌즈 착용하고 수영하기 ) Contact lens wear ( Trophozoites가 렌즈에 부착) (1 Day SCL 40%> 38% SCL > 22% RGP) Corneal trauma-damage to the corneal epithelium ( poorly fitting CL나 착용하면서 생긴 손상) : 실질 내로 침투 1 Day SCL 40%> 38% SCL >22% RGP Acanthamoeba keratitis 환자들ㅔ게 다음과 같은 세가지 risk factor가 있었다고 합니다. 첫째는 최근에는 acanthamoeba keratitis 환자들의 눈물에 anti acanthamoeba IgA antibody가 정상인보다 유의하게 낮음이 밝혀져서 IgA level 도 risk factor로 떠오르고 있습니다. Lack or low level of anti-Acanthamoeba Ig A in the tears

Pathogenesis

decreased vision(vary) Clinical symptoms Early Stage - Disproportionately severe pain (1 week) d/t radial keratoneuritis - Epithelial irregularity & dendriform pattern epithelial haze c elevated line, epithelial defect, microcysts, pseudodendrites , punctate epithelial erosion Symptoms … Severe~ mod. pain decreased vision(vary) redness irritation FBS photophobia mucous discharge tearing Late Stage Dense single or multiple stromal infiltrates Ring infiltration → loss of stroma c formation descemetocele → possible perforation Radial keratoneuritis는 병변에서부터 limbus까지 각막신경 주행을 따라 신경의 비후와 침윤을 나타냄.

특징적인 임상양상 각막염에 비해 심한 PAIN, perineuritis, ring infiltration Radial keratoneuritis는 병변에서부터 limbus까지 각막신경주행을 따라 신경의 비후와 침윤을 나타냄. 왜 심한 pain? 염증반응에 의해 각막의 삼차신경염이 발병하기 때문

Early isolated epithelitis Epithelitis with radial neuritis Ant. stromal disease Deep stromal keratitis Ring infiltration

Lab diagnosis • early diagnosis is better 도말 표본 염색 검사(scraping and biopsy of epithelial or subepithelial abnormality) - Gram / Giemsa-Wright / Wheatly trichrome / Acridine orange stains 배양검사 - non-nutrient agar (c lawn of E.coli.), after 24 hrs-48hrs 관찰->7-10 days - CL wearer : corneal scraping+corneal smear+CL+CL solutions+CL case if, corneal smear & culture(-), but CL & case(+) : 진단적 가치 높음. Therapy most effective when initiated early and requires prolonged treatment

Lab diagnosis 생검 : Epithelium is intact, but stromal lesion is active. Restriction enzyme analysis of DNA ( 검출된 아메바의 종 동정) PCR Confocal microscopy : in vivo에서 가능. but 정확한 Dx.어려움(낮은 해상도)

Differential diagnosis Misdiagnosed as viral, bacterial, fungal keratitis Fungal and mycobacterial infection : slowly progressive and suppurative , Satellite lesion (+) Bacterial infection : suppurative, may be accompanied with anterior chamber reaction, develop more rapidly Severe pain radial keratoneuritis ring infiltrates Acanthamoeba Keratitis HSV keratitis ( CL wear x ) early stage Pseudodendritic lesion - elevated Dendritic lesion - ulcerated advanced ulcerated , stromal tissue loss – resemble HSV keratitis

Treatment - Medical (200-600mg / day po) Chlorhexidine, PHMB 복합/단독+ 점안 항생제+systemic imidazole +2% homatropine + NSAID Chrorhexidine은 점안시 심한 자극감과 통증이 있는 것이 단점. Combination of antibiotic, antifungal, antiviral, antiparasitic, antiprotozoal drug 단독 또는 병합투여, 점안항생제, 전신 imidazole Antiprotozoal 항원충제

Treatment Role of corticosteroid Unclear In animal study, induces chronic keratitis & increases severity of deep stromal keratitis 아메바의 대사와 증식을 촉진하는 효과가 있어 일단은 금기

Treatment - Surgical Epithelial debridement - effective in the early phase - improve the penetration of the drug Paritial tarsorrhaphy or AMT Helpful to not respond to topical medication Cryotherapy Maybe reduce the number of organisms Conjunctival flap Uncertain benefits

Treatment - Surgical Corneal transplantation Controversial Infection을 먼저 control하지 않으면 재발 Ix) 충분한 약물 치료 후에 하는 것이 원칙 각막병변이 중심부에 국한, 주변부각막에서 아메바가 살충 되었다고 판단되는 경우 각막이식으로 병변을 제거할 수있는 경우 천공 등의 휴유증 예방하고 안구를 보존하기 위해