David J. Browning - Hydroxychloroquine and Chloroquine Retinopathy

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David J. Browning Hydroxychloroquine and Chloroquine Retinopathy 2014 10.1007/978-1-4939-0597-3_1

Springer Science+Business Media New York 2014

1. Preclinical Foundations: Relevant Anatomy and Physiology

David J. Browning 1

(1)

Charlotte Eye Ear Nose & Throat Associates, Charlotte, NC, USA

Abstract

Reviewing the preclinical science relevant to the mechanisms and risk factors for chloroquine and hydroxychloroquine retinopathy can solidify clinical understanding of that condition. This chapter gathers the scattered and often difficult-to-access pertinent facts and concepts.

Abbreviations

4AQs

4-Aminoquinolines (chloroquine and hydroxychloroquine)

APC

Antigen presenting cell

4AQR

4-Aminoquinoline retinopathy

BM

Bruchs membrane

BRB

Bloodretina barrier

C

Concentration

CpG ODN

CpG oligodeoxynucleotide

CD

CD number

CD3

Cluster of differentiation T3 cell co-receptor

CD74 gene

Cluster of differentiation 74 gene

D

Daily dose in mg/kg

DN cells

Double negative cells

DP cells

Double positive cells

EC50

Effective concentration 50 %

ELM

External limiting membrane

FAZ

Foveal avascular zone

GCL

Ganglion cell layer

HLA

Human leukocyte antigen

IFN

Interferon alpha

Ii

Invariant chain

IK complex

Inhibitor of kappa B kinase complex

IL

Interleukin

ILM

Internal limiting membrane

INL

Inner nuclear layer

IPL

Inner plexiform layer

IRAK

Interleukin-1 receptor-associated kinase

IS/OS

Inner segment/outer segment

K

Rate constant for elimination

m

Micrometer

MHC

Major histocompatibility complex

miRNA

MicroRNA

nm

Nanometer

NEMO

Nuclear factor- essential modifier regulatory subunit

NF-

Nuclear factor-

NFL

Nerve fiber layer

NLRs

Nucleotide-binding and oligomerizing domain-like receptors

OCT

Optical coherence tomography

OPL

Outer plexiform layer

ONL

Outer nuclear layer

PAMP

Pathogen-associated molecular pattern

RA

Rheumatoid arthritis

RCS

Royal College of Surgeons

RPC

Radial peripapillary capillary

RPE

Retinal pigment epithelium

SD-OCT

Spectral domain optical coherence tomography

SLE

Systemic lupus erythematosus

SP cells

Single positive cells

TCR

T cell receptor

TCRCD3

T cell receptorcluster of differentiation 3T cell co-receptor complex

TD-OCT

Time domain optical coherence tomography

Th cells

Helper T cells

Treg cells

Regulatory T cells

V

Volume of distribution

VEGF

Vascular endothelial growth factor

Concepts and facts in this chapter are drawn from ocular anatomy, physiology, immunology, and pharmacology that are important in understanding the cause, progression, and ways to prevent chloroquine and hydroxychloroquine retinopathy. Because chloroquine and hydroxychloroquine are 4-aminoquinolines (4AQs), the retinopathy that they cause is referred to as 4-aminoquinoline retinopathy (4AQR). It is assumed that the reader has a medical-school background but needs to be refreshed about the relevant topics. Where possible, the particular structures and physiologic steps influenced by 4AQs will be noted. Looking ahead, Chap. their toxicology and the pathologic ocular changes they can cause. Commonly used abbreviations in this chapter are collected in Abbreviations for reference. Each term will be first used in its full form, along with its abbreviation.

1.1 Anatomy and Histology

Histologically, the retina is a multilayered sheet of neuronal, glial, and vascular tissue that lines the inside posterior two-thirds of the eye. It is bounded anteriorly by the vitreous humor and posteriorly by the retinal pigment epithelium (RPE), Bruchs membrane (BM), and choroid. The macula is a circular area of the retina 5.25.5 mm in diameter with a center located 17, or 4.05.0 mm temporal, and 0.530.8 mm inferior to the center of the optic disc (Fig. ].

Fig. 1.1

Fundus photograph from a normal eye showing the macula ( green circle ) and fovea ( black circle ). The normal central retinal artery ( black arrow ) is located nasal to the central retinal vein ( green arrow ) in the optic disc. The luteal pigment gives the region encircled in black its darker pigmentation relative to the surrounding retina

Xanthophylls are not synthesized by the body, but must come from the diet [].

The central 1.5 mm circular area of the macula is called the fovea, denoted by a gently curved depression in the retinal surface. Within the fovea is a roughly circular avascular area, the foveal avascular zone (FAZ), approximately 400500 m in diameter which contains only cones, present at a density of approximately 125,500140,000/mm2 [].

Deriving the Conversion from Degrees to Micrometers

Without derivation, it has been asserted that 1280 m [):

Fig. 1.2

Diagram of schematic eye used in deriving the conversion factor for transforming arc length on the retina to subtended angle

360 (5.5/circumference of eye)=26.18.

One half the straightened image height ( i /2) can be calculated noting the geometrical relationship:

Solving for i ,

and therefore i /2=2.78 mm.

The simplified version of the eye is that of a single lens 17 mm in front of the retina (the eyes nodal point). Ray tracing shows the relationship between object and image in Fig.. One half the angle subtended by the image from the eyes nodal point can be calculated from the geometrical relationship

where

The conclusion, then, is that 18.57=5.5 mm, or 1=0.296 mm=296 m, which is in fair agreement with the published figure.

A cross section through the retina just outside the area centralis shows ten layers (Figs. ].

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