PowerPoint-Präsentation€¦ · Uveitis" Bilateral 60-90% Epidemiology Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015) U N I V E R S I T Ä

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U N I V E R S I T Ä T S M E D I Z I N B E R L I NU N I V E R S I T Ä T S M E D I Z I N B E R L I N

Masquerades…

Uwe Pleyer

[email protected]

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Mimikry

Background


Background


Children > Adults!

Uveitis-masquerades…


Non-malignant clinical disease Coats' disease

Juvenile Xanthogranuloma

Persistent hyperplasia

Astrocytoma

Retinal hemangioma

Retinopathy of prematurity

Norrie's disease

Incontinentia pigmenti

Retinal choroidal coloboma

Malignant clinical disease Retinoblastoma

Leukemic uveal infiltrates

Uveitis-masquerade in childhood


Uveitis?

Masquerade syndrome?

Retinoblastoma

Leukemia

(M. Coats)


Differential diagnosis

https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjF-6q5wuPTAhULIlAKHeT_COoQjRwIBw&url=https%3A%2F%2Fangeloconcuore.wordpress.com%2Ftag%2Fmimikry%2F&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiG--7ZwuPTAhUSI1AKHZekCGUQjRwIBw&url=http%3A%2F%2Fwww.tierchenwelt.de%2Ftierleben%2F2880-meister-der-tarnung-wie-sich-tiere-unsichtbar-machen.html%3Fstart%3D3&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi7ss7gz-vaAhUFPFAKHRYHAzwQjRx6BAgBEAU&url=https%3A%2F%2Feyecancer.com%2Fpress%2Fdr-finger-spearheading-effort-create-vitreoretinal-lymphoma-registry%2F&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjF-6q5wuPTAhULIlAKHeT_COoQjRwIBw&url=https%3A%2F%2Fangeloconcuore.wordpress.com%2Ftag%2Fmimikry%2F&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiG--7ZwuPTAhUSI1AKHZekCGUQjRwIBw&url=http%3A%2F%2Fwww.tierchenwelt.de%2Ftierleben%2F2880-meister-der-tarnung-wie-sich-tiere-unsichtbar-machen.html%3Fstart%3D3&psig=AFQjCNEH0jbJA56OEHn9lk06XrPeGaPOdg&ust=1494437031989530

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Child 1: f/ 6 weeks

• FH: none

• RE Leukocoria, strabism



Dx. : Bilateral Retinoblastoma

RE LE



Epidemiology

• Incidence 5,000 per year worldwide

• 45 per year in Germany

• 50% lethality worldwide

• 2% in industrialized countries

• 25% bilateral/ 75% unilateral

• 100% bilateral RB – germline mutation

• 40% germline mutation

• 100% bilateral RB - multifokal


Shields et al. 2013


Initial clinical signs of Retinoblastoma

Abramson et al, 2002



Screening program for eye disorders in general

since 2016 in Germany


Any leukocoria = urgent clarification!No invasive diagnostic precedure in susp. child!


Uveitis?


Retinoblastoma

Leukemia

(M. Coats)



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Leukemia


• Uni- or bilateral

• Granulomatous precipitates

• Pseudohypopion

• Localized or diffuse iris lesions

• Intraretinal hemorrhages


• Retinopathy

children < adults

• Poor prognosis

• Mainly: choroid affected

• Retinal findings

• Perivascular infiltrates

• Microinfarction

• Hemorrages

– Flame shaped

– White centered

Chen J et al., Acute promyelocytic leukemia http://webeye.ophth.uiowa.edu/eyeforum

Leukemia



https://www.everydayhealth.com/leukemia/what-are-common-symptoms/


Diagnosis: Leukemia


Child 2: f, 2 yrs

PH: Strabism for 6 months/ Leukocoria LE

FH: none

U N I V E R S I T Ä T S M E D I Z I N B E R L I N U N I V E R S I T Ä T S M E D I Z I N B E R L I N

M. Coats Yellowish / white cholestrol crystals Viscous subretinal exudation

with sluggish flow B-Scan

Occ. subretinal gliotic nodule

Irregular dilatation

of retinal vessels

with teleangiectasia

retinal aneurysms

avascular retinal periphery


• Mainly unilateral

• Young males 1/100,000

• Breakdown-blood-retinal barrier

• Slowly progressive

• Cataract, Glaucoma, Ablatio

https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjhvenow8bdAhXNyKQKHQ2hDk8QjRx6BAgBEAU&url=https%3A%2F%2Fwww.everydayhealth.com%2Fleukemia%2Fwhat-are-common-symptoms%2F&psig=AOvVaw0t7eKytKE-Yv2xuh7l1-Ch&ust=1537427961889368

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Retinoblastoma M. Coats

BE AWARE: Exudative Retinal Detachment*

* FEVR – similar/ bilateral/ FA



Uveitis-masquerade…?


Uveitis?


Melanoma

Metastasis

Leukemia

Lymphoma

Uveitis-masquerade: Adults



Uveitis?


Melanoma

Metastasis

Leukemia

Lymphoma

Uveitis-masquerade



Metastasis

Uveitis-masquerade


Ocular history: unremarkable

General history:

Arterial hypertension, 30 Nicotine years

Ø B symptoms, Ø rheumatic disease

Visual Acuity:

OD: cc = 20/25 OS: cc = 20/20

IOP: 14 mm Hg

Anterior Segment

OD: from 6-11 o'clock Iris irregular bulging

with multiple graywhite nodular changes

Rubeosis iridis, posterior synechiae

Lens with pigmentation

Anterior chamber cells 1+

OS: unremarkable

High suspicion of iris tumor / metastasis

Uveitis-masquerade - f, 68 yrs

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X Ray: Distention of the Hilum formation

lymph node enlargement

chronic obstructive pulmonary disease?

=> Thorax-CT recommended

CBC: slight leukocytosis with left shift

ACE + IL 2 receptor: normal

Work-up….

Uveitis-masquerade


Diagnostic iridectomy

Uveitis-masquerade


https://doi.org/10.1016/j.sjopt.2019.07.006 - (2019)

Uveitis-masquerade


Shields CL et al. Indian J Ophthalmol. (2015)

• Search for primary tumor and

staging CT / MRI / PET scan

• Fluorescein and indocyanine

angiography

• OCT-EDI

• Biopsy (selected)

- cytological, genetic,

immunocytochemical and

immunohistochemical

Uveitis-masquerade - work-up


Uveitis?


Melanoma

Metastasis

Leukemia

Lymphoma

Uveitis-masquerade



Primary CNS lymphoma

Rare CNS tumor (4%) but incidence is increasing!

1973 2.5 / 10 million?

2012 30/10 million

Risk factors: HIV, EBV

Histology: mostly diffuse large B-cell lymphoma

Prognosis: worse than with other nodal lymphomas (survival time - median: 33 months)

Epidemiology

Jaehne D, Coupland SE. Primary vitreoretinal lymphoma. Ophthalmologe 115: 343-356 (2018)

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Intraocular lymphoma will develop in 15-25% of patients with

primary CNS lymphoma

Primary intraocular lymphoma (PIOL) may present independently

BUT

90% of PIOL patients develop intracranial lymphoma

"Masquerade syndrome"!

Median age: 63 years

Men > Women

History: „interm. Uveitis"

Bilateral 60-90%

Epidemiology

Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015) U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Clinical presentation

30% without any

ophthalmological symptoms!

Primary intraocular lymphoma


Symptoms Total (%)

Ataxia 10 (4,6)

"Dizziness" 4 (1,8)

Headache 4 (1,8)

Disorientation 3 (1,4)

Others 6 (2,8)

Subjective ocular

complaints

Subjective extraocular

complaints

Initial complaints (n=217)

The Japanese Intraocular Lymphoma Study Group, Jpn J Ophthalmol. 56:383-9; 2012


Symptoms Total (%)

Visual loss 157 (72,4)

"Floater" 48 (22,1)

"Visual Field..." 5 (2,3)

Incidental finding 3 (1,4)

Others 4 (1,8)


Initial eye findings n=217 (%)

Vitreous opacity 197 (90.8)

Subretinal infiltration 124 (57.1)

Iritis 68 (31.3)

Corneal precipitates 54 (24.9)

Retinal vasculitis 21 (9.7)

Secondary glaucoma 9 (4.1)

Retinal bleeding 5 (2.3)

Papilledema 4 (1.8)

Vitreous hemorrhage 3 (1.4)

Retinal exudates 3 (1.4)

Retinal detachment 2 (0.9)

Subconjunctival tumor 1 (0.5)

Scleritis 1 (0.5)

Hypopyon 1 (0.5)

The Japanese Intraocular Lymphoma Study Group, Jpn J Ophthalmol. 56:383-9; 2012



• Fluffy sub-retinal and

sub-RPE infiltrates

• "Vasculitis"

• "Retinitis"

• Uveal "tumor" (rare)

Findings

Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015)



PIOL - Presentation

Imaging


https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi7ss7gz-vaAhUFPFAKHRYHAzwQjRx6BAgBEAU&url=https%3A%2F%2Feyecancer.com%2Fpress%2Fdr-finger-spearheading-effort-create-vitreoretinal-lymphoma-registry%2F&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811

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Primary school teacher

for weeks “visual field changes”

LE: "Micropsia"

"Had a lot of stress" ....

Visual acuity: 0.6

(external) DX: RCS, Drusen

"Chorioretinitis work-up"

"all OK"

Holger Hermsdorf – m, 52 yrs


Follow-up

- Edema decreased under acetazolamide

- Visual acuity increased to 20/20

- 2 months later edema regression, no complaints

- New: "Cotton-wool“- like spot LE (ischemic?)

- Cardiovascular consultation, incl. Carotid duplex


Follow-up

6 months later

subj. "Deterioration"

Visual acuity both eyes cc. 20/20

worse contrast vision

multiple diffuse whitish-yellow, partly confluent?

bilateral: subretinal infiltrates!


Diagnostic work-up

Invasive diagnostics

Aqueous humor: IL-10 >>> IL-6 (> 500pg / ml)

PPV + Retinal biopsy?

"B-cell dominant lymphocytic infiltrate"

Neurological work-up

cMRT: Intrabulbar lesion

No intracerebral involvement

Lumbar and BM puncture: unremarkable

Diagnosis: „Primary“ intraocular lymphoma



U N I V E R S I T Ä T S M E D I Z I N B E R L I N Williams BK, et al. Graefes Arch Clin Exp Ophthalmol. 248:1837-42, 2010


https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiw4u28zOvaAhVHK1AKHXmMDgIQjRx6BAgBEAU&url=https%3A%2F%2Fwww.researchgate.net%2Ffigure%2FAutofluorescence-and-optical-coherence-tomography-OCT-imaging-in-the-left-eye-of-the_fig2_318789923&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiX7IvNzOvaAhVIEVAKHTX1DrYQjRx6BAgBEAU&url=https%3A%2F%2Fwww.researchgate.net%2Ffigure%2FOptical-coherent-tomography-OCT-of-the-patient-in-Figure-1-A-Cross-sectional-images_fig2_51763468&psig=AOvVaw1YwZjzodinQZo2O8JMAqFw&ust=1525507438913811http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click on image to zoom&p=PMC3&id=2974205_417_2010_1427_Fig1_HTML.jpg

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Diagnosis



Cytology

Immunocytology

Molecular pathology

Biopsy

Aqueous humor

analysis

Diagnostics



Biopsy

Aqueous humor

analysis

Significance of aqueous

humor analysis

Interleukin-10 as an

"index" cytokine

vs. interleukin-6

(inflammation)


Dunn JP. Retina. 38:647-649 (2018)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Fisson S, et al., PLoS One; 2013

Cytokine Pattern (n=49)



Cytokine Pattern: Therapy Course

Fisson S, et al., PLoS One; 2013


U N I V E R S I T Ä T S M E D I Z I N B E R L I N Dunn JP. Retina. 38:647-649 (2018)


IL-10/IL-6 ratio > 1 Vitreous Sensitivity= 93% Specificity= 100%Cut off 65/30pg ml Aqueous humor Sensitivity= 78% Specificity= 97%

http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=3566156_pone.0052385.g004.jpg

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U N I V E R S I T Ä T S M E D I Z I N B E R L I N Gonzales J et al., Br J Ophthalmol.; 102: 6–8. (2018)


Metagenomic

deep sequencing


PPV/Biopsy

Anterior chamber

paracentesis

Indication: Aqueous humor analysis/ppV/Biopsy

Chronic "therapy-resistant"

uveitis

Suspicious sub-retinal /

sub-RPE lesions

Clinical suspicion

of lymphoma

Elderly patients with initial Dx of

intermediate "uveitis"

Immunocompromised

individuals

Chemotherapy

Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015)



Treatment options



IntravitrealChemotherapy

Radiotherapy(Eyes)

SystemicChemotherapy

Radiotherapy(CNS)

Intraocular relapseor after CNS

Radiation

Only intraocular(untreated)

Intraocular andCNS lymphoma

(untreated)

one eye both eyes both eyesboth eyes one eye one eye


Treatment options


• The therapy recommendations

of the International Primary

Central Nervous System

Lymphoma Collaborative

Group from 2011

• Unilateral PIOL: local

intravitreal therapy

• Bilateral PIOLs: systemic

chemotherapy in combination

with intravitreal therapyChan CC et al. Primary vitreoretinal lymphoma. Oncologist 16:1589-99 (2011)P. Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B‐cell lymphoma.Br J Hematology, 2018

Treatment recommendation



P. Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B‐cell lymphoma. Br J Hematology, 2018


https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5754869_bjophthalmol-2017-311151f01.jpg

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• 8/2008 – 8/2017

• 11 centers (Berlin, Bonn, Düsseldorf, Würzburg, Münster, Heidelberg, Lübeck)

• 43 Patients

• Age: median 75 years [41-90]

PIOL in newly diagnosed lymphoma:

32/43 (74%)

PIOL in case of relapse: 11/43 (26%)

PIOL isolated : 5

PIOL + CNS involvement 6

PIOL: German registry study


Results: therapy (n=43)

Systemic only 13

HD-MTX/Ifosfamide+Rituximab 21

CHOP 3

Others 4

Local + systemic 18

Radiation 2

Intraocular therapy 24Rituximab 13

Rituximab + Methotrexate 2

Methotrexate 1

other / unknown 8



Progression-free survival (n=35)

Relapse (n=19 Patienten)

-Only CNS 8

-Only Eye 6

-CNS+Eye 1

-Others (jaw) 1

-Unknown 3

Median 26 months


U N I V E R S I T Ä T S M E D I Z I N B E R L I N Akiyama H et al., Japanese PIOL Study Group Cancer Sci. 107:1458-1464 (2016)

Weekly intravitreal MTX

+

5 Cycles systemic

High-Dosis MTX (3.5 g/m2 )

biweekly

5 - Annual survival rate

61 % (n=195)

Prognosis – Follow-up (n=195)



Important, vital differential

diagnosis in “intraocular

inflammation“

Initial diagnosis: still late…!

Invasive diagnostics!

Clear trend from purely local

therapy to systemic therapy

Further data with longer follow-

ups is necessary

Summary


Augenwerkstatt

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Mange

for din opmærksomhed!

Documents

PowerPoint-Präsentation€¦ · Uveitis" Bilateral 60-90% Epidemiology Stübiger N, Kakkassery V, Gundlach E, Winterhalter S, Pleyer U. Ophthalmologe (2015) U N I V E R S I T Ä