Normal tension glaucoma 2010 Glaucoma conference Normal tension glaucoma Pf.안명덕 / R2 이지명 2010.10.08

1. Defenition Glaucoma Close angle glaucoma Open angle glaucoma Normal tension glaucoma 1. Defenition Glaucoma Close angle glaucoma Open angle glaucoma POAG - 안압상승이 주요한 risk factor NTG – IOP independent factor ( Cur opin opthalmology 2008 Mar:19(2):85-2, ‘Normal tension glaucoma : Is it different from POAG? )

1. Defenition 전방각은 개방 안압 21mmHg이하 특징적인 녹내장성 시신경 유두함몰, 시야결손 Normal tension glaucoma 1. Defenition 전방각은 개방 안압 21mmHg이하 특징적인 녹내장성 시신경 유두함몰, 시야결손 시야결손의 원인이 될 만한 안질환이나 전신질환이 없는 상태

2. Epidemilology 1) 유병율 : 실제임상에서 보는 것보다 유병율이 높다. Normal tension glaucoma 2. Epidemilology 1) 유병율 : 실제임상에서 보는 것보다 유병율이 높다. 우리나라 1.71% 전체 개방각 녹내장의 20-50% 이상 차지 2) 나이 : 평균 연령 60대 (고령층에 많다) 50세 이하에서는 드물다 3) 성별 : 여성에게 많다 (고령층인구에는 여성이 더 많다는 점을 고려)

2. Epidemilology Normal tension glaucoma 4) 심혈관계 질환 NTG를 전신적 혈관질환의 안소견으로 보는 견해 심한출혈, 부정맥, 급성 저혈압과 같은 hemodynamic crisis의 과거력이 있는 경우 5) 편두통 정상 안압 녹내장에서 높은 유병율을 보고 (편두통이 뇌혈관의 국소적 혈관수축에 의해 유발되는 질환임을 고려할 때 국소적 혈관수축에 의한 정상 안압 녹내장 유발 가능성 제시 )

3. Etiolology Normal tension glaucoma 1) 안압 정상인구의 평균 안압에 비해 높은 안압 안압의 일차변동이 크다 양안 NTG환자의 경우 높은 안압을 가진 눈에서 녹내장 시야결손이 크다 2) 시신경유두의 혈관 관류압(vascular perfusion pressure)의 영향 관의 관류압이 감소되어 시신경유두에 허혈이 발생 비진행성 정상안압녹내장 : 일시적인 vascular shock에 의함 진행성의 정상안압녹내장: 만성적인 혈관부전에 의함 Hemodynamic crisis가 많이 동반 이완기 안동맥혈압의 감소 시신경유두 혈액순환의 자동조절능력 감소(autoregulation) Vasospastic event: 편두통이 많고, 추위에 노출 시 손톱바닥혈관의 혈류량이 비정상적으로 감소

4. 임상양상 ◎ Disc hemorrhage가 있는 부분에서 Normal tension glaucoma 4. 임상양상 1) 안압 정상범위에서 높은 수준 일차변동의 폭이 크고 , 자세에 따른 안압의 변동이 크다 2) 시신경유두 (원발 개방각 녹내장과 비교) 유두창백 심함 유두함몰의 경사가 완만(broadly sloping) 귀쪽과 아래 귀쪽의 시신경 유두테가 좁다 유두륜(Peripapillary halo)이 많다 Splinter hemorrhage 증가 ◎ Disc hemorrhage가 있는 부분에서 retinal nerve fiber defect 소견을 관찰 (Retinal Nerve Fiber Layer Thickness Evaluation Using Optical Coherence Tomography in Eyes With Optic Disc Hemorrhage, Ophthalmic Surgery, Lasers & Imaging · March/April 2007 · Vol 38, No 2)

4. 임상양상 Normal tension glaucoma 3)시야결손 : 원발 개방각 녹내장과 차이가 있는지에 논란 주시점과 가깝게 더 깊고, 경사가 가파르며 상반부시야에서 결손이 많이 발생

5. 진단 자세한 문진 : 과거의 안압상승,안외상,염증, 독극물에 대한노출 Normal tension glaucoma 자세한 문진 : 과거의 안압상승,안외상,염증, 독극물에 대한노출 Hemodynamic crisis에 대한 문진: 심한 출혈, 빈혈, 부정맥, 수혈, 급성 저혈압 안압측정: 새벽과 같은 늦은 밤을 포함하여 매 2시간마다 시행하여 일차변동곡선을 알아내야하며 선자세와 누운자세의 안압측정도 반드시 시행하여야 한다 자세한 시신경 유두검사 내과검사 전산화단층촬영 – 65세-70세미만 환자, 시야결손이 빠르고, 시신경 유두함몰에 비해 유두 창백이 심한경우 종양, 낭종 등에 의한 시신경 압박을 감별위해.

6. 감별진단 - 시신경유두소(pit)와 시신경 결손증(coloboma)과 같은 시신경의 선천적 결함 - 허혈시신경증 Normal tension glaucoma 6. 감별진단 - 시신경유두소(pit)와 시신경 결손증(coloboma)과 같은 시신경의 선천적 결함 - 허혈시신경증 - 종양, 동맥류, 낭종 등에 의한 시신경의 압박성 병증 - 망막색소변성과 망막분지혈관 폐쇄와 같은 망막질환

7. 치료 Normal tension glaucoma 병변이 진행하지 않을 경우 - 정기적으로 추적관찰하면서 시신경유두와 시야에 변화가 나타날 때까지 치료를 하지 않는다 - 빈혈,부정맥,울혈성 심부전이 있는 경우는 반드시 이에 대한 치료해야함 병변이 진행하고 있거나 시신경유두함몰과 시야결손이 매우 심한 경우 - 심혈관계 치료와 함께 안압 하강

(Collaborative Normal Tension Glaucoma Study) CTNGS (Collaborative Normal Tension Glaucoma Study) 1) 안압을 조절하는 것이 치료에 도움 2) High risk of diz. Progression - 여자, 편두통 환자, Disc hemorrhage ( Age, Baseline median IOP level, Field defect는 포함되지 않음.) 3) High risk 하지 않는 경우 대부분이 Nonprogressive하다. 따라서, 관찰하다가 치료하는 것도 도움이 된다. 1) IOP가 NTG의 Pathogenesis에 영향을 끼치기 때문에 안압을 조절하는 것이 치료에 도움이 된다. 2) 여자, 편두통 환자, Disc hemorrhage가 있는 환자는 high risk이므로 NTG의 Progression이 빠르다. ( Age, Baseline median IOP level, Field defect는 포함되지 않음.) 3) 대부분이 Nonprogressive하다. 따라서 관찰하다가 치료하는것도 도움이 된다.

7. 치료 2) 레이져 섬유주성형술 현저한 안압하강 효과를 얻기는 어려움 병변의 진행을 막아주지는 못함 Normal tension glaucoma 7. 치료 2) 레이져 섬유주성형술 현저한 안압하강 효과를 얻기는 어려움 병변의 진행을 막아주지는 못함 3) 여과수술 : NTG의 진행을 막을 수 있는지에 대해 논란 - 전층여과수술 열응고공막절개술(thermal sclerostomy) 공막천공술(scleral trephination) 공막절제술(sclerectomy) - Mitomycin C or 5-FU를 사용한 섬유주절제술 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

Review articles

PERSPECTIVE Blood Pressure, Perfusion Pressure, and Glaucoma Normal tension glaucoma PERSPECTIVE Blood Pressure, Perfusion Pressure, and Glaucoma JOSEPH CAPRIOLI AND ANNE L. COLEMAN, ON BEHALF OF THE BLOOD FLOW IN GLAUCOMA DISCUSSION GROUP 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다. ( Am J Ophthalmol 2010;149:704–712 )

Clinical measurements of ocular blood flow Ophthalmic a. , and its tributaries the post. Ciliary artery, and central retianl a. -> post. Segment Short post. Ciliary a. from the choroid -> prelaminar portion of the optic head

Clinical measurements of ocular blood flow FAG : estimate the AV transit time Mircosphere technique ; regional optic nerve head blood flow ; need to euthanize the animal Laser Doppler velocimetry(LDV) ; determines the velocity of blood cells in the larger blood vessel ; cannot be used to measure optic nerve head blood flow

Clinical measurements of ocular blood flow Laser Dopler flowmetry(LDF) or Laser speckle flowgraphy(LSFG) ; Based on Doppler shift imparted to light scattered by Blood cells ; measure flux ( mean velocity x number of moving cells) ; measure microcirculatory perfusion in the optic nerve head ; cannot be used to measure flow in large vessel ; cannot provide measurements in absolute units ; differences in tissue light scattering elements between tissues

Clinical measurements of ocular blood flow Color Doppler imaging(CDI) ; evaluates erythrocytes velocity in the large ophthalmic vessel ; Provides the peak systolic velocity(PSV) end diastolic velocity(EDV) mean velocity the resistive index ([PSV-EDV]/PSV) ; but for CRA , correlates poorly with direct measures of retinal vascular resistance ; Interpret of ophthalmic a. is difficulty (much of blood flow in ophthalmic a. does not penetrate eyeball) ; Large variation among individuals

Clinical measurements of ocular blood flow The Limitations of these techniques ; Difficult to determine the fundamental characteristics of ocular blood flow in glaucoma and in normal controls ; No widely accepted consensus regarding which technique should be used how the results should be interpreted ; None of the methods have veen standardized or validated for humans ->Ocular blood flow measurements are not currently used in the Dx or Mx.

Physiology and autoregulation of ocular blood flow Designed to math the metabolic need despite changes in the OPP High flow bed, smallest AV oxygen difference in the choroidal vasculature ; metabolic autoregulation of choroidal blood flow is not clear Marked difference in autoregulatory capacity between the choroid and retinal vasculature Autoregluation of ocular(retina & choroid) blood flow make it difficult to modify ocular circulation for therapeutic benefit and unforseen adverse consequences (administration of vasodilator in rabbit  large transient IOP spike)

Ischemia and Glaucoma Glaucomatous damage does not resemble ischemic damage (initial pallor rather than cupping in ischemic damage) Elevated IOP could cause microangiopathy and decreased blood flow Blood velocity measurement shown difference between POAG and normal control Whether decreased blood flow is etiology of glaucoma or secondary from a loss of retinal ganglion cells and decrease in metabolic demand  is it cause or the effect?

Ischemia and Glaucoma Elevated concentrations of endothelin-1(ET-1) in Aqueus humor in glaucoma pt.  support ischemic theroy Chronic administration of ET-1 in rat, rabbit, primates Rat model : retinal ggl. Cell axonal loss but no optic nerve head cupping wheter ischemia might increase susceptibility to pr. Mediated damage? The loss of retinal ggl. Cells in ET-1 animal models  ischemia may be involved in glaucoma But no change in blood flow was measured.(non-vascular effect of ET-1?) ; astrocytes proliferation and effects from changes in enothelin B R expression

Clinical evidence of ischemic pathophysiology in glaucoma Early case series study of 29 NTG pt 10 had a history of hemodynamic crissis. 9 of them did not progress (Drance SM. Some factors in the production of low tension glaucoma. Br J Ophthalmol 1972;56:229 –242.) Subsequent studies have found little or no relationship between glaucoma and either symptomatic hypotensive episodes or systemic antihypertensive treatment Higher occurrence of migraine in NTG patients Percentage of pt. with history of migraine is low. No significant association between migraine and glaucoma However migraine was as an independent risk factor for progression in CNTGS

Clinical evidence of ischemic pathophysiology in glaucoma No significant association between Raynaud’s synd and glaucoma But in the Canadian glaucoma study, trend toward more VF progression in patients with vasospasm ; Overall effect was small but in some pt., vasospasm may be important risk factor for progression Typically no significant relationship between migraine, Raynaud’s synd and glaucoma Subtype of glaucoma with a vascular component?

Clinical evidence of ischemic pathophysiology in glaucoma In Epidemiologic data, high IOP is the major strong risk factor , low OPP is also a strong risk factor for glaucoma In the Early Manifest Glaucoma Trial ;pt. with systolic OPP< 125mmHg increased risk of progression ;higher systolic BP show protective effect against progression ; Greater incidence of progression in pt. with low BP, with lower IOP  suggest vascular risk factor independent of IOP

Systemic cardiovascular considerations Protective effect of High BP, but long-term hypertension can produce microangiopathy on the retina, optic nerve -> Systemic effect of Hyper- or hypotension have to be considered.

Nocturnal dips and glaucoma progression Physiolgic increase in OPP when lie down

Nocturnal dips and glaucoma progression In the normal dipping pattern, 10-20% decrease of BP during night In some studies NTF and POAG with VF progression ; lower nocturnal BP and greater nocturnal dip compared to stable pts. Magnitude of nocturnal dip in glaucoma pts. Correlates with VF progression NTG pts had greater variability of nighttime BP compared with controls Variation in circadian mean OPP was related to the severity of VF loss

Blood pressure measurements in Glaucoma Still controversial Is it necessary to take blood pr. Along with IOP measurements? Are office measurements of BP sufficient, or Home monitoring or amblatory monitoring required?

Prospects for drug development Optic n. perfusion may be reduced in glaucoma But all of the technique used to evaluate blood flow have significant limitations which extent? Accurate identification of vascular beds? reduced blood supply is whether etiology or results of tissue loss? Treatment aimed specifically at increasing ocular blood flow does not seem to be promising strategy for glaucoma management Future drugs : Calcium channel blockers? (increased ocular blood flow) But possibility that improving optic nerve perfusion by diverting blood flow from elsewhere(such as retinal cpll. Beds) may have unoreseen adverse effects.

Conclusion Significant challenges remain in the measurement and intepretation of ocular blood flow. Low OPP is a risk factor for glaucoma progression But no evidence that BP control improves outcomes in glaucoma Glaucoma is a heterogenous group. There may be subgroups of pt. in whom vascular factors are important (have not been identified)

Conclusion Difficult to use a strategy to increase OPP by increasing BP. Eliminating the nocturnal dip in BP can be harmful Increasing blood flow could also be dangerous if it were not specifically targetted at correct capillary beds ( For a small subgroup of pt. who are hypotensive use a volume expander(salt) may be beneficial. but no evidence to support this approach. and this treatment would be contraindicated in many pt.

PURPOSE To provide a critical review of the relationships Normal tension glaucoma PURPOSE To provide a critical review of the relationships between blood pressure, ocular blood flow, and glaucoma and the potential for glaucoma treatment through modulation of ocular perfusion. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

DESIGN Summaries of the pertinent literature and Normal tension glaucoma DESIGN Summaries of the pertinent literature and input from glaucoma researchers and specialists with relevant experience. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

METHODS Review and interpretation of selected literature Normal tension glaucoma METHODS Review and interpretation of selected literature and the results of a 1-day group discussion involving glaucoma researchers and specialists with expertise in epidemiology, blood flow measurements, and cardiovascular physiology. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

Normal tension glaucoma RESULTS - 1 Accurate, reproducible, and clinically relevant measurements of blood flow within the optic nerve head and associated capillary beds are not fully achievable with current methodology. Autoregulation of blood flow in the retina and optic nerve head occurs over a large range of intraocular pressures and blood pressures. Regulation of choroidal blood flow is provided by a mix of neurohumoral and local mechanisms. Vascular factors may be important in a subgroup of patients with primary open-angle glaucoma, and particularly in patients with patients with normal-tension glaucoma and evidence of vasospasm. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

Normal tension glaucoma RESULTS - 2 Low ocular perfusion pressure and low blood pressure are associated with an increased risk of glaucoma in population based studies. The physiologic nocturnal dip in blood pressure is protective against systemic end-organ damage, but its effects on glaucoma are not well elaborated or understood. Large-scale longitudinal studies would be required to evaluate the risk of glaucomatous progression in non-dippers, dippers, and extreme nocturnal blood pressure dippers. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

Normal tension glaucoma CONCLUSIONS Decreases in perfusion pressure and blood pressure have been associated with glaucoma. However,there is no evidence to support the value of increasing a patient’s blood pressure as therapy for glaucoma. Such recommendations are not currently warranted, since we lack crucial information about the microvascular beds in which perfusion is important in glaucoma, and the appropriate methods to evaluate their blood flow. There are also cardiovascular safety concerns associated with treatments designed to increase ocular perfusion pressure and blood flow by increasing blood pressure, especially in elderly patients. For these reasons and with present evidence it is unlikely that safe and effective glaucoma treatments based on altering optic nerve perfusion will soon be available. 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

Summary paucity of evidence of ischemic damage Normal tension glaucoma Summary paucity of evidence of ischemic damage Lack of knowledge about which vascular beds are important Lack of measurements to measure blood flow Safety concerns Treatments aiming at altering blood flow and pressure are not useful options at this time Need more research! 전층여과수술이 정상안압녹내자오아자에서 가장 적합한 수술방법으로 알려져있고 최근에는 MMC 또는 5-FU를 사용한 섬유주절제술이 선호된다.

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