modulo 3 lezione 2 degenerazione maculare senile...

MODULO 3 | Lezione 2DEGENERAZIONE MACULARE SENILEGiovanni Staurenghi, Alessandro Invernizzi, Marco Pellegrini, Andrea Giani Clinica Oculistica Ospedale SaccoDipartimento di Scienze Biomediche e Cliniche “Luigi Sacco” Università degli Studi di Milano

ARGOMENTI DI QUESTA LEZIONE :EpidemiologiaEzio-patogenesiDiagnosiTrattamento

martedì 1 aprile 14

© Giovanni Staurenghi 2014 - Tutti i diritti riservati

Heidelberg Engineering1,2, OD-OS1,2, Optos1,2, Ocular Instruments4, Quantel Medical1,2, Carl Zeiss

Meditec1, Alcon1,3, Allergan1,3, Bayer1,3, Boheringer1, Genentech1, GSK1,3, QLT1, Novartis1,3,

Roche1,3

Conflitti di interesse:

1 consulente, 2 finanziamenti per ricerca, 3 rimborsi per letture, 4 brevetti


Definizione



Nomenclatura1. druplets: depositi inferiori a 63 µm2. drusen: depositi sotto l’epèitelio pigmentato retinico superiori ai 63 µm (drusen hard) e superiori ai 125µm (drusen soft)3. pseudodrusen reticolari (drusen reticolari - subretinal drusenoid deposits): depositi al di sopra dell’epitelio pigmentato4. lesione neovascolare (forma umida): complicanza5. atrofia geografica (forma secca): complicanzaN.B.: si usa il termine secca solo per indicare la complicanza.

1 2

3

N.B: per immagini delle singole drusen riferire alla lezione 1



Non evidenti alterazioni correlate all’età

No drusenNo anomalie pigmentarie

Normali alterazioni correlate all’età

Druplets (drusen ≤ 63µm)No anomalie pigmentarie

Iniziale DMS

Drusen > 63 µm e ≤ 125 µmNo anomalie pigmentarie

DMS intermedia

Drusen > 125 µmQualsiasi anomalia pigmentaria

DMS avanzata

DMS Neovascolare e/oAtrofia Geografica

Clinical Classification of Age-Related Macular Degeneration Ophthalmology April 2013

Clinical Classification of Age-Related Macular Degeneration


Epidemiologia


© Giovanni Staurenghi 2014 - Tutti i diritti riservati modified from Delori FC

Data from:*The Eye Diseases Prevalence Research Group. Arch Ophthalmol. 2004;122:564-572**The European Eye Study. Arch Ophthalmol . 2006;124:529-535

Prevalenza della DMS nel mondo occidentale

0

3,75

7,50

11,25

15,00

65-69 70-74 75-79 ≥80

11,77

3,24

1,660,91

6,94

4,07

1,970,90

anni

prev

alen

za d

ella

DM

SEurope USA



Data from:The Eye Diseases Prevalence Research Group. Arch Ophthalmol. 2004;122:564-572The European Eye Study. Arch Ophthalmol . 2006;124:529-535The Greenland Inuit Eye Study Ophthalmology 2008;115:700–707The Rotterdam Eye Study Arch Ophthalmol . 2003;121:519-526The Reykjavik Eye Study Arch Ophthalmol. 2003;121:379-385

0

3

6

9

12

15

Europe USA Greenland Rotterdam Iceland

2,30

1,10

6,10

0,65

2,30

9,20

0,70

2,30

1,201,20

Goegraphic atrophy Neovascular ARMD

prev

alen

ce o

f ARM

D

Prevalence of ARMD in western countries



Age category

(yrs)Person n Incidence

rate 95% CI2-yrs

cumulative Incidence

(%)

55-64

65-74

Total

85+

75-84

3546

4011

1952

340

9849

0

3

6

3

12 0.6-2.1

1.8-25.8

1.1-6.7

0.15-2.2

0-1.00

0.75

3.07

8.80

1.22

0

0.15

0.61

1.75

0.24

Rotterdam Eye Study 2001

Incidenza per 1000 persone/anno e Incidenza cumulativa a 2 anni



Fumo di sigaretta

R: Rotterdam Eye Study; BM: Blue Mountain Eye Study; BM: Beaver Dam Eye study

Neovascular ARMD

Early ARMD

Odds Ratio 95% I.C.

R - smokers

R - Past smokers

BM - smokers

BM - Past smokers

BD - smokers

BD - Past smokers

0 1 2 3 4 5 6 7 8

R - smokers

R - Past smokers

BM - smokers

BM - Past smokers

BD - smokers

BD - Past smokers

0 1 2 3 4 5 6 7 8

12



Clinical Classification of Age-Related Macular Degeneration Ophthalmology April 2013

0 1 2 3 40

102030405060

%%%%

%%%

Rischio a 5 aa di sviluppare DMS avanzata

AREDS Clinical Severity Scale for AMD

Patients severity score

Rischio di sviluppare DMS avanzata

Two risk factors

No drusen

Small drusen

Medium drusen

anni

0

20

40

60

80

0 1 2 3 4 5 6 7 8 9 10

Occhi con occhio allelo con DMS avanzata%

%

%

%

%

0

20

40

60

80

0 1 2 3 4 5 6 7 8 9 10

Occhi senza drusen grandi al baseline%

%

%

%

%anni

anni

Rischio di sviluppare drusen grandi

0

5

10

15

20

0 1 2 3 4 5 6 7 8 9 10

Drusen medie in entrambi gli occhi

No drusen

Drusen piccole

Drusen medie in un occhio

%

%

%

%

%

anni

Occhi senza drusen al baseline

Rischio di sviluppare DMS avanzata


Ezio-patogenesi



1a teoria: Lipofuscina 2a teoria: Vascolare 3a teoria: Lipidica

•Accumulo dal metabolismo del ciclo visivo

•Formazione di A2E (sostanza tossica)

•Dorey, Sparrow, Delori(Invest. Ophthalmol. Vis. Sci. 2001 ; 42:1855-66)

•prima alterazione a carico della coriocapillare

•Sarks (Br J Ophthal. 1999;83:358-68)

•Accumulo di materiale lipidico

•Curcio, Spaide (RETINA 2013 33:265-276)



Lesioni Neovascolari

- forma umida -



Polipoidali

RCARetinal Choroidal Anastomois

RAPRetinal Angiomatous Lesion

RLARetinal Lesion in Anastomosis

Occult RCAOccult Retinal Choroidal

Anastomosis

D-RVACDeep retinal Vascular Anomalous

Complex



Lesione Atrofica

(Atrofia Geografica)

- forma secca -

lettura suggerita: F. Holz et al. Ophthalmology 2014;-:1e13 a 2014



hyperpigmentation, as compared with 2.5 years in thepresence of hypopigmentation.3,4

The biology of neovascular AMD is better understood thanthe atrophic form of the disease. This may be because of theavailability of better predictive preclinical modelsfor neovascular AMD, although more recently rodent modelsof atrophic AMD have shown some promise.5 Because mostpathways identified by genetics seem to predispose to bothforms of AMD, the current thinking is that both advancedstages are initiated by common pathways that culminate instress and damage to the RPE, Bruch’s membrane, andchoroid, and can result in either photoreceptor degenerationor choroidal neovascularization with subsequentdegeneration. Based on this principle, early treatment ofAMD at the high-risk intermediate AMD stage would berequired to prevent both forms of advanced AMD.

Currently, there is no approved or effective treatment toprevent either onset or progression of GA. However, inrecent years, significant progress has been made in under-standing the pathogenesis of GA, which has led to a numberof new potential therapies currently undergoing clinical trialevaluation (Table 1, available at http://aaojournal.org).

Clinical Background on GA

Epidemiology and Risk Factors

In the industrially developed world, AMD is the primarycause of blindness for adults >55 years of age. Patients inthe early and intermediate stages of dry AMD generally donot lose central vision, but instead have other functionalimpairments, such as difficulty reading and limited vision at

night or with reduced light.6 Risk factors for AMD includeadvanced age, race, smoking, and diet.

With aging, gradual and cumulative damage to the retinaoccurs through various factors, including oxidative stress. Inaddition, impairment of normal physiologic function in RPEcells, including the constant degradation of lipid-rich outerphotoreceptor discs, can lead to formation of intracellular(lipofuscin) and extracellular debris (drusen). The advancedformof dryAMD,orGA, is responsible for approximately 20%of all legal cases of blindness in North America with increasingincidence and prevalence owing to a higher life expectancy.

Overall, AMD is more common in white patients than inindividuals of other ethnic origins. Although drusen are seenwith similar frequency in non-white and white people, thelatter have been shown to have an increased prevalence ofadvanced AMD, perhaps a consequence of lower melaninlevels. In the Multi-ethnic Study of Atherosclerosis, theprevalence of AMD was 2.4% in blacks, 4.2% in Hispanics,4.6% in Chinese, and 5.4% in whites.7

Cigarette smoking is another risk factor for AMD inmany clinical trials. A direct correlation has been reportedbetween the risk of developing the disease and number ofcigarettes smoked. In a case-control study of 715 whitepatients, smoking >40 pack-years of cigarettes wasassociated with a 3.5-fold higher risk for GA.8 Themechanisms by which smoking increases the risk forAMD include the reduced generation of antioxidants,induction of hypoxia, generation of reactive oxygenspecies, and impaired choroidal blood flow.

Finally, there is some evidence for an association be-tween diet, specifically fat intake, and obesity and anincreased risk of AMD. Moreover, several studies havedemonstrated the protective effect of antioxidants, nuts, fish,

Figure 1. Simplified diagram showing changes in the macula during evolution of geographic atrophy (GA). Three manifestations of retina failure arerepresented. The course of the disease can vary from case to case. (Modified from Sarks et al., Eye 1988.) A2E ¼ N-retinyl-N-retinylidene ethanolamine;ATR ¼ all-trans retinal; GCL ¼ ganglion cell layer; INL ¼ inner nuclear layer, ONL ¼ outer nuclear layer; RPE ¼ retinal pigment epithelium.

Ophthalmology Volume -, Number -, Month 2014

2

da: F. Holz et al. Ophthalmology 2014;-:1e13 a 2014


Diagnosi



confronta capitolo 1 e appendice


Trattamento



Laser photocoagulation

1968

Wet AMD TreatmentsPhotodynamic

therapy

2005

Pegaptanib

Bevacizumab (off-label)

2006

Ranibizumab

2007

Aflibercept(Eylea)

2012-2013

FVT

TTT

1991-2005



Pegilazione Aptamero Inibitore

Pegaptan ib



umanizzato anticorpo monoclonale

zuBeva mabcircolo ematico

ci



umanizzato anticorpo monoclonale

occhio

zuRani mabbi



target recettoreVEGF

berAfli cept

proteina di fusione da anticorpi che mima immunoglobulina



* Tre trattamenti poi trattamenti ad intervalli aumentati di 2 settimane fino ad un massimo di 10 settimane. Nel caso di ricomparsa di liquido l’intervallo viene ridotto a 4 settimane per poi continuare con l’aumento degli intervalli

Ranibizumabnegli studi di registrazione: mensile

0 4 8 12 16 20 24 28 32Settimane 36-48 secondo anno

Ranibizumablabel Europeo: PRN

Eylealabel Europeo

14 22 32Ranibizumab“treat and extend” *

*

* Il trattamento deve essere continuato fino a quando non si raggiunge la stabilità del visus per almeno tre visite. Nel caso di riattivazione della lesione si segue la stessa procedura con trattamenti fino a raggiungere la stabilità del visus per almeno tre visite (due iniezioni almeno).Visite mensili per controllo visusSecondo label il ritrattamento deve essere eseguito solo in caso di calo del visus.



modificato da Br J Ophthalmol 2010;94:2–13

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