POAG Pathophyiology& et cetra Glaucoma conference 2012.6.1 R3백지원/Ap.박혜영 Sheilds, Text book of Glaucoma, 6th edition

Introduction POAG? COAG Primary vs secondary : should be abandoned POAG : no longer valid term POAG -> COAG (=idiopathic OAG) COAG ; multifactorial optic neuropathy in which there is characteristic atrophy of the optic nerve open, normal-appearing AC angle c no apparent ocular or systemic abnormality that might account for eleveted IOP POAG 에서 secondary에 대비한 primary의 개념은 버려져야 되는 것으로 POAG는 더 이상 쓰지 않는 단어라고 shield 책에서 말하고 있습니다. 이제 chronic OAG나 idiopathic OAG로 불러야 합니다. COAG는 optic nerve 의 atrophy를 일으키는 multifactorial optic neuropathy 로 다음 특성으로 정의 됩니다. AC angle이 열려있다, IOP 상승을 설명할 만한 다른 ocular abnormality가 없다. 특징적 Optic nerve head damange and /or 녹내장성 시야 변화가 있다. typical optic nerve head damage and/or glaucomatous visual field damage

Introduction Etiology Risk factors 0.28% of general population 40세 이상에서 73%의 glaucomatous change 는 COAG가 원인 40세 이상에서 유병율 1~2% In Korea, 0.23% Risk factors Others older age(>60, for black, >40) black race Hispanic ethnicity Family Hx of glaucoma pph vasospasm, HTN, CVD, DM,, migraine, 흡연, 갑상선 기능 저하 혹은 다른 갑상선 질환, long-term steroid use, heavy computer use with refractive errors Ocular IOP myopia large C/D ratio PPA disc hemorrhage thin central cornea thickness 유병율은 전체 인구에서 0.28%로 알려져 있고 40세 이상에서 73%의 glaucomatous change 는 COAG가 원인 40세 이상에서 유병율 1~2% 한국에서는 0.23%로 알려져 있습니다. Risk factor로 .. 등이 있습니다.

Significance of IOP Discrepancy of Glacomatous change & IOP IOP level of 21 mmHg 2SD above the mean within a Gaussian distribution for the white population Upper limit of “normal” Discrepancy of Glacomatous change & IOP Many eyes will not develop glaucomatous damage despite having IOP above 21 mmHg. Progressive glaucomatous damage is possible at pressures that are never observed to exceed 21 mmHg. IOP가 21은 전체 인구 분포의 mean값에서 상위 2SD 위 숫자를 말하며, normal 의 upper limit으로 생각 되어 지고 있습니다. 이것 보다 높은 IOP가 녹내장에 미치는 영향은 한마디로 정의 할 수 없고, 21이상이라도 녹내장성변화가 없는 눈도 많고, 21을 한번도 넘지 않아도 녹내장으로 진행하는 눈도 많습니다.

Central corneal thickness (CCT) Anterior chamber angle Clinical findings IOP Only one of several risk factors for COAG The single most important risk factor for COAG Central corneal thickness (CCT) In thin cornea, the “true’ IOP is higher than measured but that the risk for progression may or may not be higher. Anterior chamber angle AC angle is open and grossly normal on gonioscopic examination More iris processes, a higher insertion of the iris root, more trabecular meshwork pigmentation, and a greater-than-normal degree of segmentation in the pigmentation of the meshwork IOP는 많은 위험인자중 하나일 뿐이지만, 개중에 가장 중요한 factor입니다. CCT가 얇을 수록 true IOP는 측정된 값 보다 큰것으로 알려져 있으나 progression에 대한 risk 는 크지 않을 수 있습니다. AC angle은 열려는 있지만 잘보면 iris process가 많고, iris root insertion이 높고, TM pigment가 많고, meshwork pigmentation에 segmentation이 정상보다 훨씬 많습니다.

Clinical findings Visual abnormalities ONH A helpful early finding: defects in the RNFL Enlargement of the cup, thinning or saucerizing of the neural rim, disc hemorrhages, and peripapillary atrophy Visual abnormalities Central visual acuity typically remains normal until there is marked VF loss within the central visual field optic nerve head에서 가장 중요한 초기 finding은 RNFL defect입니다. 이외에 cup enlarging, thinning, saucerizing, disc hemorrhage, ppa 등의 소견이 있습니다. 시야검사상 central field 결손이 있기 전 까지는 환자는 증상을 못느끼기 때문에 asymptomatic disease라고 합니다.

Optic disc degeneration AAO’s Guideline Screening and Testing People with risk factors People without risk factors 40-54 yrs every 1-3 yrs 55-64 yrs every 1-2 yrs ≥ 65 yrs every 6 to 12 mo 40-54 yrs every 2-4 yrs 55-64 yrs every 1-3 yrs ≥ 65 yrs every 1-2 yrs POAG ! Optic disc degeneration Elevated IOP VF loss POAG Dx pupil Ant. segment IOP CCT AC angle Optic N head and RNFL VF Fundus AAO 에서 제시한 screening guideline은 다음과 같습니다. If, two of these signs(+)

Mechanism : histopathology The greatest concentration of mucopolysaccharides The greates phagocytic activity Trabeculo canalicular outflow TM Schlemm’s canal 집결로 Episcleral vein Conjunctival vein Uveoscleral outflow 홍채 뿌리와 섬모체를 통하여 공막 바깥으로 유출 (5-15%) Obstruction & aqueous outflow Influence of aqueous humor ↑TGFβ2 →TM cellularity ↓ → buildup extracellular matrix→ ↑aqueous outflow R Alterations of the trabecular meshwork Obstruction of TM with plaque material Insufficient catabolism or Excessive production of normal constituent Collagen deposits : curly, coiling collagen ↑with age loss of trabecular endothelial cells TM 기능저하 : phagocytosis and synthesis and degradation of macromolecules 병인 방수 유출 경로는 다음과 같습니다. 85%이상이 –TM -- -- 통하여 배출되고 5-15% 가 uveoscleral outflow를 통해 나갑니다 TM 중에서도 juxtacanalicular area가 mucopolysaccharide의 concentration 이 많고, phacocytic activity가 많아 가장 중요한 부위입니다. 이 경로중 어디가 막혀 outflow가 제대로 안될 때 안압이 높아 질 수 있는에 이에 관련하여 먼저 Aqeous humor내의 변화로 ↑TGFβ2 로 TM cellularity ↓ , buildup extracellular matrix→ ↑aqueous outflow R는 것으로 알려 져 있습니다. TM의 변화로는 plaque material로 TM 막힐 수 있고 이는 normal constituent 너무 과다 생성 ㅎ혹은 제거 되지 않을때 발생하는 일로, 나이들면 curly coiling collagen이 많이 생기는데 이로인해서도 발생 할 수 있다고 합니다. 또한 trabecular endothelial cell이 없어지면서 phagocytosis, macromolecule의 synthesis및 degeneration기능이 저하되어 outflow에 저해가 옵니다.

Mechanism : histopathology Disturbance of neurologic feedback mechanisms Nerves in TM : function to speed outflow when IOP is elevated Schlemm’s canal ↓pore density and size in the inner wall of endothelium of Schlemm’s canal A loss of giant vacuoles in the inner wall of endothelium of Schlemm’s canal Collapse of Schlemm’s canal Bulge of TM into canal, relaxation of ciliary m Schlemm’s canal only collapses at very high levels of IOP. 25-35mmHg에서는 collapse 되지 않는다 Alterations of the intrascleral channels Swelling of glycosaminoglycans TM에 있는 nerve가 IOP가 상승하면 자극받아 outflow를 증가 시키는데 nuerolotic feedback이 망가져 이 작용을 못하는 것도 병인으로 제시되고 있습니다. 다음 shlemm canal의 문제로는 endothelium inner wall의 pore density 가 줄고, giant vacuole이 없어지는 변화가 관찰 되며, schlemm canal이 collapse가 되는 것이 병인중 하나로 제시 되기도 합니다. 하지만 schlemm canal은 IOP 가 아주 높지 않으면 collapse되지 않는 것으로 알려져있습니다. intrascleral channel의 glycosaminoglycan이 부어서 막히는 바람에 outflow가 줄어든다고도 합니다.

Histopathology Alterations in the trabecular beams, including fragmentation of collagen, increased curly and long-spacing collagen, and coiling of fiber bundles Thickened basement membranes Narrowed intertrabecular spaces Fused trabecular beams Decreased number of giant vacuoles Reduced actin filaments Accumulation of foreign material Narrowing of collector channels Closure of Schlemm’s canal Thickened scleral spur histopathology를 정리해서 보며 TM 의 변화, BM이 두꺼워짐, intertrabecular space가 좁아짐, trabecular beam이 fusion됨, giant vacuole이 줄어듬, actic filament 감소, foreign material이 쌓임, collectoro channel 좁아짐, schlemm canal closure, scleral spur thicknening. <Sagittal section through TM in COAG> Basement membrane are thickened, trabecular sheets are widened, and curly collagen has accumulated (arrows).

Mechanism : histopathology Stress response markers Myocilin↑during stress : 1st gene identified as mutated in G Heat shock proteins (αB-crystallin) : Increased in TM in G Endothelial cells lining the TM more active in COAG, BM ↑… Cross-linked actin network ↑ : TM Fx alteration Na-K-Cl cotransport Fx and regulation are altered in G Intertrabecular spaces : narrowed c RBC, pigment, ↓hyaluronic acid → influence aqueous outflow resistance JCT : just beneath inner wall endothelium of Shlemm’s canal hyaluronic acid,↑chondroitin sulfate →↑aqueous outflow R 또한 stress response marker 가 증가하는 것을 histopathologic study를 통하여 확인 하였습니다. COAG에서 처음으로 알려진 gene mutation은 myocilin gene으로 stress 동안 증가합니다,. Heatshock protein aB-crystallin은 stress 반응시 glaucoma환자의 TM에서 증가합니다. Stress 시 endothelial cell lining의 변화는 다음과 같습니다.

Mechanism : Corticosteroid Corticosteroid sensitivity Topical corticosteroid response – COAG 환자에게 사용시 IOP ↑ Some researchers proposed that the IOP response to topical corticosteroids was inherited and that this inheritance was either the same as or closely linked to, the inheritance of POAG. Plasma cortisol studies Relationship of IOP to corticosteroid sensitivity – H-P-A axis.. Etc Mutations of GLC1A (trabecular meshwork-inducible glucocorticoid response (TIGR)) Associated with the production of an abnormal glucocorticoid-inducible stress-response protein(myocilin) in the TM Associated with JOAG and a small fraction of adult-onset POAG 또한 corticosteroid에 대한 sensitivity도 변하는 것으로 알려 져 있습니다. Topical corticosteroid response – COAG 환자에게 사용시 IOP ↑ GLC1A 의 mutation은 myocilin과 연관 있으며 JOAG 및 adult onset POAG와의 연관성이 밝혀져 있습니다. topical corticosteroids에 대한 반응은 유전이며, 아마 POAG에 대한 유전성과 연관이 있을거다… 이것을 더 확실히 하기 위해 plasma cortisol study, HPA axis등을 연구하는 조상 등이 시행.

Mechanism of Optic Neuropathy Abnormal immunologic process γ-globulin, plasma cell ↑in TM ANA (+) in COAG ↑ Blood flow ↑ plasma viscosity and clotting system Altered autoregulation in the optic nerve and retinal circulation Similar to age-related alterations Choroidal circulation is compromised in COAG Histopathology of Optic nerve The total number of capillaries and the density of capillaries decreased with loss of axons. Increased connective tissue in the septa and surrounding the central retinal vessels, including increased amounts of types IV and IV collagen 또한 γ-globulin, plasma cell ↑in TM ANA (+) in COAG ↑ blood flow에서도 변화 optic nerve는 수가 줄고 axon도 줄어듬, septa의 connective tissue가 늘어나며, type IV collagen 늘어남.

Possible Infectious Susceptibility ↑ anticardiolipin antibody progression of COAG 과 관계 있다 H.pylori infection 88% of the patients with COAG. (control: 47%) CSF Pressure Translaminar pressure! : the pressure difference between intraocular space and the subarachnoid space A reduced CSF pressure = an increase in IOP : same effect ↓ CSF pressure In COAG In NTG, lower than COAG. ↑ anticardiolipin antibody 및 H.pylori infection 와의 연관성도 언급되고 있음. ↓ CSF pressure In COAG & In NTG, lower than COAG.

Apoptosis of Ganglion Cells 여러 요소들이 RGC cell apoptosis 를 유발

Management General principles good visual function + prevent interference c the quality of life pressure lowering : slowing or stopping the progression Set target IOP IOP level before treatment Stage of glaucoma Rate of progression during follow-up Age and life expectancy Presence of other risk factors Other aggravating conditions (eg. DM or vascular dz) The family history of glaucoma 치료 원칙은.. targe IOP를 정할 때에는..

Management The first-line approach in COAG The relative safety Medical therapy The first-line approach in COAG The relative safety Argon or selective laser therapy As effective as timolol IOP rises again months to years after laser treatment Surgery Filtering surgery Glaucoma drainage-device surgery 먼저 약물치료 이후 argon or selective laser 그후 surgery

Prognosis Prognosis <The Early Manifest Glaucoma Trial Study > The degree of optic nerve damage The height of the IOP The vulnerability of the disc tissue The presence of systemic vascular disease The compliance with treatment The timeliness and appropriateness of treatment prognosis는 - - - - - 에 관계가 있으며 <The Early Manifest Glaucoma Trial Study > 에서 6년동안 53% 가 진행하였고, 1mmHg안압 낮추면 10% progression rate가 줄어든다.. <The Early Manifest Glaucoma Trial Study > 53% progressed in 6 years 1mmHg IOP lowering = 10% reduction in the rate of progression