Blood-Cell Velocity in the Nailfold Capillaries of Patients With Normal-Tension and High-Tension Glaucoma
Paul Gasser, M . D . , and Josef Flammer, M . D .
We c o m p a r e d t h e c a p i l l a r y b l o o d - c e l l v e l o c i t y in t h e fingertips o f 30 p a t i e n t s w i t h h i g h t e n s i o n g l a u c o m a , 30 p a t i e n t s w i t h n o r m a l t e n s i o n g l a u c o m a , a n d 30 c o n t r o l s u b j e c t s b y nailfold capillaroscopy. T h e r e were no m e a s u r a b l e d i f f e r e n c e s i n t h e m o r p h o l o g i c find ings. T h e blood-flow velocity, however, was reduced significantly in t h e p a t i e n t s w i t h n o r mal-tension glaucoma compared with the con t r o l s u b j e c t s (P < .05). T h i s d i f f e r e n c e w a s especially p r o n o u n c e d after cold provocation (P < .0005). A f t e r c o o l i n g , 25 of 30 p a t i e n t s with normal-tension glaucoma had a blood s t a n d s t i l l o f 12 s e c o n d s o r m o r e , w h e r e a s o n l y t h r e e o f 30 c o n t r o l s u b j e c t s a n d f o u r o f 30 patients with high-tension glaucoma had a measurable blood standstill.
G L A U C O M A is p h e n o m e n o l o g i c a l l y c h a r a c t e r ized by progressive excavation of the optic n e r v e h e a d a n d v i s u a l field d e f e c t s . T h e m e c h a n i s m s that l e a d to t h e d a m a g e o f t h e o p t i c n e r v e h e a d are n o t w e l l u n d e r s t o o d . C l i n i c a l s t u d i e s indicate that besides increased intraocular p r e s s u r e , o t h e r f a c t o r s m i g h t b e i n v o l v e d . In a d d i t i o n to a g e , d e m o g r a p h i c , a n d g e n e t i c f a c tors, m a i n l y v a s c u l a r a n d r h e o l o g i c f a c t o r s h a v e been d e s c r i b e d . ' ' A n association between glau c o m a a n d migraine* as w e l l a s b e t w e e n g l a u c o ma and peripheral c i r c u l a t i o n " ' has b e e n re p o r t e d . We c o m p a r e d t h e n a i l f o l d c a p i l l a r y b l o o d flow u n d e r b a s e l i n e c o n d i t i o n s as w e l l as after l o c a l w a r m i n g a n d c o o l i n g in p a t i e n t s
Accepted for publication Feb. 11, 1991. From the Department of Internal Medicine, St. Claraspital, Basel, Switzerland-(Dr. Gasser); and Department of Ophthalmology, University of Basel, Basel, Switzer land (Dr. Flammer). This study was supported by the Swiss National Science Foundation, grant No. 32-936787. Reprint requests to Josef Flammer, M.D., Department of Ophthalmology, University of Basel, Mittlere Strasse 91, CH-4056 Basel, Switzerland.
with normal-tension glaucoma, patients with high-tension glaucoma, and control subjects.
Patients and Methods We s t u d i e d 3 0 p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a , 30 p a t i e n t s w i t h h i g h - t e n s i o n g l a u c o m a , a n d 30 c o n t r o l s u b j e c t s ( T a b l e 1 ) . N o r m a l - t e n s i o n g l a u c o m a was defined as typical o p t i c n e r v e h e a d e x c a v a t i o n a n d v i s u a l field d e f e c t s w i t h an u n t r e a t e d m e a n i n t r a o c u l a r pressure of less than 21 m m Hg and a peak i n t r a o c u l a r p r e s s u r e o f l e s s t h a n 2 5 m m Hg based on several diurnal pressure curves. Hightension g l a u c o m a was defined as optic nerve h e a d e x c a v a t i o n a n d v i s u a l field d e f e c t s w i t h an untreated mean intraocular pressure greater t h a n 2 4 m m H g at r e p e a t e d m e a s u r e m e n t s . We i n c l u d e d p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a r e f e r r e d b y o t h e r o p h t h a l m o l o g i s t s to t h e U n i v e r s i t y E y e C l i n i c d u r i n g 1 9 8 9 for c l i n i -
TABLE 1
DEMOGRAPHIC DATA AND CLINICAL BACKGROUND OF CONTROL SUBJECTS AND PATIENTS*
CONTROL SUBJECTS (N = 30)
PAnENTS WITH PATIENTS WITH HIGH-TENSION NORMAL-TENSION GLAUCOMA GLAUCOMA (N = 30) (N = 30)
18:12 17:13 Sex (female: male) Age (years) 59.2 ± 12.7 58.6 ± 11.9 Pulse rate, 74.0 ± 14.5 73.0 ± 12.6 sitting (per minute) Systolic blood 132.8 ± 20.4 127.1 ± 15.5 pressure, sitting (mm Hg) Diastolic blood 82.8 ± 9.2 82.3 ± 9.7 pressure, sitting (mm Hg)
16:14 60.6 ± 11.7 74.2 ± 10.1 131.6 ± 23.9 82.5 ±13.1
•Values given are mean ± standard deviation.
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cal e x a m i n a t i o n . T h e c o n d i t i o n s w e r e e i t h e r newly diagnosed ( 2 0 of 3 0 patients) or the p a t i e n t s h a d p r o g r e s s i v e v i s u a l field l o s s ( t e n of 3 0 ) . Five p a t i e n t s w e r e t a k i n g b e t a - b l o c k e r s , even though their intraocular pressure had nev er b e e n i n c r e a s e d . For e a c h p a t i e n t w i t h n o r m a l - t e n s i o n g l a u c o ma included, a patient with high-tension glau coma and a control subject of the same age were selected. The patients with high-tension glau c o m a w e r e a l s o r e f e r r e d to us b y o t h e r o p h t h a l m o l o g i s t s for e x a m i n a t i o n b e c a u s e o f i n c r e a s e d intraocular pressure despite treatment, pro g r e s s i n g v i s u a l field l o s s , or b o t h . All p a t i e n t s were taking antiglaucoma medication, includ ing b e t a - b l o c k e r s ( 2 5 o f 3 0 ) , m i o t i c s ( 1 7 of 3 0 ) , or e p i n e p h r i n e d e r i v a t i v e s (five o f 3 0 ) . T h e systemic carbonic anhydrase-inhibitor therapy (four o f 3 0 ) was d i s c o n t i n u e d for at l e a s t 1 4 days b e f o r e t h e test. T h e c o n t r o l g r o u p c o n s i s t e d o f 11 staff m e m b e r s of t h e h o s p i t a l a n d 19 p a t i e n t s r e f e r r e d to us for c a t a r a c t s u r g e r y . T h e y all h a d n o r m a l intraocular pressure and normal-appearing op tic n e r v e h e a d s . E x c l u s i o n criteria for all g r o u p s w e r e m i graine, anemia, cardiovascular diseases, sys temic hypertension and hypotension, diabetes m e l l i t u s , a n d c o l l a g e n or v a s c u l a r d i s o r d e r s . The three groups were matched by age. Blood pressure and pulse rate were influenced by the exclusion criteria. The three groups, however, r e s e m b l e d e a c h o t h e r in t h i s r e s p e c t m e r e l y b y c h a n c e . N o n e o f the s u b j e c t s h a d b e e n t a k i n g any s y s t e m i c m e d i c a t i o n for at l e a s t t w o w e e k s b e f o r e the e x a m i n a t i o n . The nailfold capillaries were studied with the h e l p of an i n c i d e n t - l i g h t m i c r o s c o p e a t t a c h e d
to a t e l e v i s i o n m o n i t o r . " ' ^ To m e a s u r e t h e di ameter of the capillaries, p h o t o g r a p h s were t a k e n from t h e m o n i t o r . To m e a s u r e t h e c a p i l lary b l o o d - c e l l v e l o c i t y , t h e t e l e v i s i o n p i c t u r e s were videotaped and analyzed during playback b y t h e flying-spot t e c h n i q u e as p r e v i o u s l y d e scribed."'* T h e e x a m i n a t i o n s w e r e p e r f o r m e d in a r o o m w i t h a c o n s t a n t t e m p e r a t u r e o f 2 3 C. B e f o r e p a r t i c i p a t i n g in t h e i n v e s t i g a t i o n , t h e s u b j e c t s w e r e a c c l i m a t i z e d in t h i s r o o m for 3 0 m i n u t e s . T h e r e a f t e r , t h e v i d e o t a p e p i c t u r e s w e r e m a d e to measure the morphologic variables. T h e n , the b a s e l i n e b l o o d - c e l l v e l o c i t y w a s m e a s u r e d . Af ter i m m e r s i o n o f t h e fingertip in a w a r m - w a t e r b a t h o f 4 0 C for t h r e e m i n u t e s , t h e s e c o n d reading was performed. T h e third m e a s u r e m e n t w a s m a d e after c o o l i n g t h e o b s e r v e d s k i n a r e a for 6 0 s e c o n d s b y b l o w i n g d e c o m p r e s s e d c a r bon dioxide of approximately - 1 5 C over the n a i l f o l d . T h e f o u r t h a n d t h e fifth m e a s u r e m e n t s w e r e m a d e after s p o n t a n e o u s r e c o v e r y p e r i o d s of o n e a n d two m i n u t e s , r e s p e c t i v e l y . ' ^ In c a s e s w h e r e t h e b l o o d flow c e a s e d d u r i n g l o c a l c o o l ing, the duration of the blood-flow standstill w a s m e a s u r e d in s e c o n d s . S u c h c a s e s a r e c a l l e d vasospastic."
Results To i l l u s t r a t e e x a m p l e s o f t h e effect o f c o o l i n g , p h o t o g r a p h s w e r e t a k e n from t h e v i d e o m o n i t o r (Fig. 1 ) . T h e m o r p h o l o g i c c h a r a c t e r i s t i c s o f t h e i n d i v i d u a l c a p i l l a r i e s w e r e s i m i l a r in t h e t h r e e groups. The arterial, venous, and crest diame ters as w e l l a s t h e w i d t h o f t h e l o o p w e r e n o t
Fig. 1 (Gasser and Flammer). Photographs taken from the videomonitor demonstrating the nailfold capillaries after cold provocation. Left, A control subject with normal circulating erythrocytes. Right, Blood standstill and segmentation of the blood-cell column caused by flow stop after cooling (cold-induced vasospasm) in a patient with normal-tension glaucoma.
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Blood-Cell Velocity and Glaucoma
TABLE 2 MORPHOLOGIC FINDINGS ON NAILFOLD CAPILLARIES*
Diameter (/tm) Arteriolar Venular Crest WIdtti Capillary density (numt>er of nallfold capillary loops per mmY
PATIENTS W I T H
PATIENTS W I T H
CONTROL
HIGH-TENSION
NORMAL-TENSION
SUBJECTS
GLAUCOMA
GLAUCOMA
11.1 2.1 13.0 ± 2.5 16.0 3.4 34.3 5.8
11.0 ± 1.8 13.3 2.3 16.3 ± 3.5 33.9 ± 6.3
10.6 1.8 12.7 ± 2.0 16.5 ± 2.9 32.8 ± 5.1
6.8
1.2
6.0
7.1
1.5
1.8
glaucoma had on the average a slightly slower capillary blood-cell velocity, although these differences were not statistically significant. The reduction of the capillary blood-cell ve l o c i t y , h o w e v e r , w a s m o r e p r o n o u n c e d in t h e normal-tension glaucoma group. T h e differenc es from t h e c o n t r o l s u b j e c t s w e r e s t a t i s t i c a l l y s i g n i f i c a n t in all i n s t a n c e s (P < . 0 5 ) , e s p e c i a l l y after c o l d p r o v o c a t i o n (P < . 0 0 0 5 ) . T h r e e c o n t r o l s u b j e c t s a n d four p a t i e n t s w i t h h i g h - t e n sion glaucoma had a measurable blood-flow standstill (Fig. 3 ) . O f the 3 0 patients with nor m a l - t e n s i o n g l a u c o m a , h o w e v e r , o n l y five p a tients had no blood-flow stop and 25 patients had a clear blood-flow standstill, the duration of which ranged b e t w e e n ten and 9 5 seconds.
'Values given are mean ± standard deviation. •Significance level between control subjects and patients with high-tension glaucoma, Ρ = .026. s i g n i f i c a n t l y different ( T a b l e 2 ) . T h e c a p i l l a r y d e n s i t y w a s s l i g h t l y s m a l l e r in t h e h i g h - t e n s i o n g l a u c o m a g r o u p t h a n in t h e c o n t r o l g r o u p , w h i c h w a s s t a t i s t i c a l l y s i g n i f i c a n t (P = . 0 2 6 ) . T h e c a p i l l a r y d e n s i t y in t h e n o r m a l - t e n s i o n glaucoma group, however, was not significantly different from t h a t in t h e c o n t r o l g r o u p . The control group showed the w e l l - k n o w n i n c r e a s e in t h e m e a n c a p i l l a r y b l o o d - c e l l v e l o c ity after w a r m i n g a n d a d e c r e a s e after c o o l i n g t h e fingertip a n d d u r i n g t h e r e c o v e r y ( F i g . 2 ) . The patients with high-tension glaucoma s h o w e d t h e s a m e b a s i c d y n a m i c s (Fig. 2 ) . In most instances, the patients with high-tension
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Discussion T h e p e r i p h e r a l b l o o d flow in p a t i e n t s w i t h high-tension and normal-tension glaucoma m i g h t b e different from t h a t in n o r m a l s u b j e c t s . The capillary blood-cell velocity was on the
••oonda
90 8070-
60 60-
mm/s
X 40-
0.« 0.6
30-
0.4
20-
0.2
Η
10V2 •
CONTROLS
V3 CDHTe
V4
V5
0-
ίΝτα
Fig. 2 (Gasser and Flammer). Blood-flow velocities of control subjects, patients with high-tension glau coma (HTG), and patients with normal-tension glau coma (NTG) at baseline ( V I ) , after the warm-water bath (V2), after cooling (V3), and after recovery (V4 and V5).
CONTROL*
HTQ
NTQ
Fig. 3 (Gasser and Flammer). Duration (in seconds) of cold-induced blood-flow standstill in the control subjects, patients with high-tension glaucoma (HTG), and patients with normal-tension glaucoma (NTG).
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a v e r a g e s l i g h t l y s l o w e r in t h e p a t i e n t s w i t h h i g h - t e n s i o n g l a u c o m a t h a n in n o r m a l c o n t r o l subjects, although this difference was not sta tistically significant. The normal-tension glau coma group, however, had a more pronounced a n d s t a t i s t i c a l l y s i g n i f i c a n t d e c r e a s e in t h e c a p illary b l o o d - c e l l v e l o c i t y . T h e d i f f e r e n c e from the c o n t r o l s u b j e c t s w a s e s p e c i a l l y e v i d e n t after t h e c o l d p r o v o c a t i o n . T h e m o s t s t r i k i n g finding, h o w e v e r , w a s t h e d i f f e r e n c e in b l o o d - f l o w s t a n d s t i l l after c o o l i n g . In t h i s r e s p e c t , p a t i e n t s with high-tension glaucoma and control sub jects were essentially the same. The patients with n o r m a l - t e n s i o n g l a u c o m a , h o w e v e r , h a d a c l e a r a n d s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e in blood-flow standstill. It is difficult to k n o w h o w m u c h t h e p o p u l a t i o n t e s t e d is r e p r e s e n t a t i v e o f t h e t o t a l p o p u l a t i o n . All the p a t i e n t s s e l e c t e d from o u r c l i n i c were referred by other ophthalmologists. S o m e of t h e s e o p h t h a l m o l o g i s t s k n e w t h a t w e h a d a s p e c i a l i n t e r e s t in v a s o s p a s t i c d i s o r d e r s . T h e r e fore, we c a n n o t e x c l u d e t h e p o s s i b i l i t y that t h e p r o p o r t i o n o f v a s o s p a s t i c c a s e s in t h e p o p u l a t i o n t e s t e d w a s s l i g h t l y h i g h e r t h a n t h a t in an average population. N e v e r t h e l e s s , t h e s e findings i n d i c a t e t h a t a pathologic vascular reaction called a vasospas tic disorder'^ m o s t p r o b a b l y o c c u r s m o r e often in p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a t h a n in c o n t r o l s u b j e c t s or p a t i e n t s w i t h h i g h - t e n sion g l a u c o m a . T h i s s u p p o r t s t h e h y p o t h e s i s t h a t v a s o s p a s m m a y b e i n v o l v e d in t h e p a t h o genesis of normal-tension glaucoma.'*" These findings are in a g r e e m e n t w i t h t h e o b s e r v a t i o n s of D r a n c e a n d a s s o c i a t e s ' a n d m a y h a v e m a j o r t h e r a p e u t i c i m p l i c a t i o n s . It is p o s s i b l e t h a t treatment of this vasospastic disorder may be beneficial to p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a , as h a s b e e n p r e v i o u s l y reported.'*"^'
References 1. Demailly, P., Cambien, P., Plouin, P. P., Baron, P., and Chevallier, B.: Do patients with low-tension glaucoma have particular cardiovascular characteris tics? Ophthalmologica 188:65, 1 9 8 4 . 2. Carter, C. J . , Brooks, D. E., Doyle, D. L., and Drance, S. M.: Investigations into a vascular etiology for low-tension glaucoma. Ophthalmology 97:49, 1990. 3. Drance, 5. M., Sweeny, V. P., Morgan, R. W., and Feldman, F.: Studies of factors involved in the production of low-tension glaucoma. Arch. Ophthal mol. 89:457, 1973.
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4. Freyler, Η., and Menapace, R.: 1st die Erblindung an Glaukom vermeidbar? Spektrum Augenheilkd. 2:121, 1 9 8 8 . 5. Goldberg, I., Hollows, F. C , Kass, M. Α., and Becker, B.: Systemic factors in patients with lowtension glaucoma. Br. J. Ophthalmol. 65:56, 1 9 8 1 . 6. Trope, G. E., Salinas, S. Α., and Glynn, M.: Blood viscosity in primary open-angle glaucoma. Can. J. Ophthalmol. Vis. Sei. 22:202, 1987. 7. Worch, Α., and Kästner, R.: Das Glaukom ohne Hochdruck. Folia Ophthalmol. 10:221, 1 9 8 5 . 8. Phelps, D., and Corbett, J. J.: Migraine and lowtension glaucoma. A case-control study. Invest. Oph thalmol. Vis. Sei. 2 6 : 1 1 0 5 , 1 9 8 5 . 9. Drance, S. M., Douglas, G. R., Wijsman, K., Schulzer, M., and Britton, R. J . : Response of blood flow to warm and cold in normal and low-tension glaucoma patients. Am. J. Ophthalmol. 105:35, 1 9 8 8 . 10. Gasser, P., Flammer, J . , Guthauser, U., and Mahler, F.: Do vasospasms provoke ocular diseases? Angiology 4 1 : 2 1 3 , 1 9 9 0 . 11. Guthauser, U., Flammer, J . , and Mahler, F.: The relationship between digital and ocular vaso spasm. Graefes Arch. Clin. Exp. Ophthalmol. 226:224, 1988. 12. Bollinger, Α., and Fagrell, B.: Clinical Capillaroscopy. Toronto, Hogrefe-Huber, 1990, pp. 1-30. 13. Gasser, P.: Capillary blood cell velocity in finger nailfold, Characteristics and reproducibility oí the local cold response. Microvasc. Res. 40:29, 1990 14. Mahler, F., Saner, H., Würbel, Η., and Flam mer, J.: Local cooling test for clinical capillaroscopy in Raynaud's phenomenon, unstable angina, anc vasospastic visual disorders. Vasa 18:201, 1 9 8 9 . 15. Boss, C , Schneuwiy, P., and Mahler, F.: Evalu ation and clinical application of the flying-spot meth od in nailfold capillary TV-microscopy. Int. J. Micro circ. Clin. Exp. 6:15, 1987. 16. Flammer, J . , Guthauser, U., and Mahler, M. Do ocular vasospasms help cause low-tension glau coma? Doc. Ophthalmol. Proc. Ser. 49:397, 1987. 17. Gasser, P., and Flammer, J.: Influence of vaso spasm on visual function. Doc. Ophthalmol. 66:3 1987. 18. Flammer, ] . , and Guthauser, U.: Behandlun, chorioidaler Vasospasmen mit Kalziumantagonister Klin. Monatsbl. Augenheilkd. 190:299, 1987. 19. Gasser, P., and Flammer, J . : Short- and long term effect of nifedipine on the visual field in patient with presumed vasospasm. J. Int. Med. Res. 18:334 1990. 20. : Die dynamisch-video-kapillarmikro skopische Beeinflussung akraler und okulärer Vasos pasmen durch Kalzium- und Serotoninantagonisten Vasa 27:79, 1989. 21. Kitazawa, Y., Shirai, H., and Go, F. ] . : Th. effect of Ca^*-antagonist on visual field in low-ten sion glaucoma. Graefes Arch. Clin. Exp. Ophthalmol 227:408, 1989.
Paul Gasser, M . D . , and Josef Flammer, M . D .
We c o m p a r e d t h e c a p i l l a r y b l o o d - c e l l v e l o c i t y in t h e fingertips o f 30 p a t i e n t s w i t h h i g h t e n s i o n g l a u c o m a , 30 p a t i e n t s w i t h n o r m a l t e n s i o n g l a u c o m a , a n d 30 c o n t r o l s u b j e c t s b y nailfold capillaroscopy. T h e r e were no m e a s u r a b l e d i f f e r e n c e s i n t h e m o r p h o l o g i c find ings. T h e blood-flow velocity, however, was reduced significantly in t h e p a t i e n t s w i t h n o r mal-tension glaucoma compared with the con t r o l s u b j e c t s (P < .05). T h i s d i f f e r e n c e w a s especially p r o n o u n c e d after cold provocation (P < .0005). A f t e r c o o l i n g , 25 of 30 p a t i e n t s with normal-tension glaucoma had a blood s t a n d s t i l l o f 12 s e c o n d s o r m o r e , w h e r e a s o n l y t h r e e o f 30 c o n t r o l s u b j e c t s a n d f o u r o f 30 patients with high-tension glaucoma had a measurable blood standstill.
G L A U C O M A is p h e n o m e n o l o g i c a l l y c h a r a c t e r ized by progressive excavation of the optic n e r v e h e a d a n d v i s u a l field d e f e c t s . T h e m e c h a n i s m s that l e a d to t h e d a m a g e o f t h e o p t i c n e r v e h e a d are n o t w e l l u n d e r s t o o d . C l i n i c a l s t u d i e s indicate that besides increased intraocular p r e s s u r e , o t h e r f a c t o r s m i g h t b e i n v o l v e d . In a d d i t i o n to a g e , d e m o g r a p h i c , a n d g e n e t i c f a c tors, m a i n l y v a s c u l a r a n d r h e o l o g i c f a c t o r s h a v e been d e s c r i b e d . ' ' A n association between glau c o m a a n d migraine* as w e l l a s b e t w e e n g l a u c o ma and peripheral c i r c u l a t i o n " ' has b e e n re p o r t e d . We c o m p a r e d t h e n a i l f o l d c a p i l l a r y b l o o d flow u n d e r b a s e l i n e c o n d i t i o n s as w e l l as after l o c a l w a r m i n g a n d c o o l i n g in p a t i e n t s
Accepted for publication Feb. 11, 1991. From the Department of Internal Medicine, St. Claraspital, Basel, Switzerland-(Dr. Gasser); and Department of Ophthalmology, University of Basel, Basel, Switzer land (Dr. Flammer). This study was supported by the Swiss National Science Foundation, grant No. 32-936787. Reprint requests to Josef Flammer, M.D., Department of Ophthalmology, University of Basel, Mittlere Strasse 91, CH-4056 Basel, Switzerland.
with normal-tension glaucoma, patients with high-tension glaucoma, and control subjects.
Patients and Methods We s t u d i e d 3 0 p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a , 30 p a t i e n t s w i t h h i g h - t e n s i o n g l a u c o m a , a n d 30 c o n t r o l s u b j e c t s ( T a b l e 1 ) . N o r m a l - t e n s i o n g l a u c o m a was defined as typical o p t i c n e r v e h e a d e x c a v a t i o n a n d v i s u a l field d e f e c t s w i t h an u n t r e a t e d m e a n i n t r a o c u l a r pressure of less than 21 m m Hg and a peak i n t r a o c u l a r p r e s s u r e o f l e s s t h a n 2 5 m m Hg based on several diurnal pressure curves. Hightension g l a u c o m a was defined as optic nerve h e a d e x c a v a t i o n a n d v i s u a l field d e f e c t s w i t h an untreated mean intraocular pressure greater t h a n 2 4 m m H g at r e p e a t e d m e a s u r e m e n t s . We i n c l u d e d p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a r e f e r r e d b y o t h e r o p h t h a l m o l o g i s t s to t h e U n i v e r s i t y E y e C l i n i c d u r i n g 1 9 8 9 for c l i n i -
TABLE 1
DEMOGRAPHIC DATA AND CLINICAL BACKGROUND OF CONTROL SUBJECTS AND PATIENTS*
CONTROL SUBJECTS (N = 30)
PAnENTS WITH PATIENTS WITH HIGH-TENSION NORMAL-TENSION GLAUCOMA GLAUCOMA (N = 30) (N = 30)
18:12 17:13 Sex (female: male) Age (years) 59.2 ± 12.7 58.6 ± 11.9 Pulse rate, 74.0 ± 14.5 73.0 ± 12.6 sitting (per minute) Systolic blood 132.8 ± 20.4 127.1 ± 15.5 pressure, sitting (mm Hg) Diastolic blood 82.8 ± 9.2 82.3 ± 9.7 pressure, sitting (mm Hg)
16:14 60.6 ± 11.7 74.2 ± 10.1 131.6 ± 23.9 82.5 ±13.1
•Values given are mean ± standard deviation.
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cal e x a m i n a t i o n . T h e c o n d i t i o n s w e r e e i t h e r newly diagnosed ( 2 0 of 3 0 patients) or the p a t i e n t s h a d p r o g r e s s i v e v i s u a l field l o s s ( t e n of 3 0 ) . Five p a t i e n t s w e r e t a k i n g b e t a - b l o c k e r s , even though their intraocular pressure had nev er b e e n i n c r e a s e d . For e a c h p a t i e n t w i t h n o r m a l - t e n s i o n g l a u c o ma included, a patient with high-tension glau coma and a control subject of the same age were selected. The patients with high-tension glau c o m a w e r e a l s o r e f e r r e d to us b y o t h e r o p h t h a l m o l o g i s t s for e x a m i n a t i o n b e c a u s e o f i n c r e a s e d intraocular pressure despite treatment, pro g r e s s i n g v i s u a l field l o s s , or b o t h . All p a t i e n t s were taking antiglaucoma medication, includ ing b e t a - b l o c k e r s ( 2 5 o f 3 0 ) , m i o t i c s ( 1 7 of 3 0 ) , or e p i n e p h r i n e d e r i v a t i v e s (five o f 3 0 ) . T h e systemic carbonic anhydrase-inhibitor therapy (four o f 3 0 ) was d i s c o n t i n u e d for at l e a s t 1 4 days b e f o r e t h e test. T h e c o n t r o l g r o u p c o n s i s t e d o f 11 staff m e m b e r s of t h e h o s p i t a l a n d 19 p a t i e n t s r e f e r r e d to us for c a t a r a c t s u r g e r y . T h e y all h a d n o r m a l intraocular pressure and normal-appearing op tic n e r v e h e a d s . E x c l u s i o n criteria for all g r o u p s w e r e m i graine, anemia, cardiovascular diseases, sys temic hypertension and hypotension, diabetes m e l l i t u s , a n d c o l l a g e n or v a s c u l a r d i s o r d e r s . The three groups were matched by age. Blood pressure and pulse rate were influenced by the exclusion criteria. The three groups, however, r e s e m b l e d e a c h o t h e r in t h i s r e s p e c t m e r e l y b y c h a n c e . N o n e o f the s u b j e c t s h a d b e e n t a k i n g any s y s t e m i c m e d i c a t i o n for at l e a s t t w o w e e k s b e f o r e the e x a m i n a t i o n . The nailfold capillaries were studied with the h e l p of an i n c i d e n t - l i g h t m i c r o s c o p e a t t a c h e d
to a t e l e v i s i o n m o n i t o r . " ' ^ To m e a s u r e t h e di ameter of the capillaries, p h o t o g r a p h s were t a k e n from t h e m o n i t o r . To m e a s u r e t h e c a p i l lary b l o o d - c e l l v e l o c i t y , t h e t e l e v i s i o n p i c t u r e s were videotaped and analyzed during playback b y t h e flying-spot t e c h n i q u e as p r e v i o u s l y d e scribed."'* T h e e x a m i n a t i o n s w e r e p e r f o r m e d in a r o o m w i t h a c o n s t a n t t e m p e r a t u r e o f 2 3 C. B e f o r e p a r t i c i p a t i n g in t h e i n v e s t i g a t i o n , t h e s u b j e c t s w e r e a c c l i m a t i z e d in t h i s r o o m for 3 0 m i n u t e s . T h e r e a f t e r , t h e v i d e o t a p e p i c t u r e s w e r e m a d e to measure the morphologic variables. T h e n , the b a s e l i n e b l o o d - c e l l v e l o c i t y w a s m e a s u r e d . Af ter i m m e r s i o n o f t h e fingertip in a w a r m - w a t e r b a t h o f 4 0 C for t h r e e m i n u t e s , t h e s e c o n d reading was performed. T h e third m e a s u r e m e n t w a s m a d e after c o o l i n g t h e o b s e r v e d s k i n a r e a for 6 0 s e c o n d s b y b l o w i n g d e c o m p r e s s e d c a r bon dioxide of approximately - 1 5 C over the n a i l f o l d . T h e f o u r t h a n d t h e fifth m e a s u r e m e n t s w e r e m a d e after s p o n t a n e o u s r e c o v e r y p e r i o d s of o n e a n d two m i n u t e s , r e s p e c t i v e l y . ' ^ In c a s e s w h e r e t h e b l o o d flow c e a s e d d u r i n g l o c a l c o o l ing, the duration of the blood-flow standstill w a s m e a s u r e d in s e c o n d s . S u c h c a s e s a r e c a l l e d vasospastic."
Results To i l l u s t r a t e e x a m p l e s o f t h e effect o f c o o l i n g , p h o t o g r a p h s w e r e t a k e n from t h e v i d e o m o n i t o r (Fig. 1 ) . T h e m o r p h o l o g i c c h a r a c t e r i s t i c s o f t h e i n d i v i d u a l c a p i l l a r i e s w e r e s i m i l a r in t h e t h r e e groups. The arterial, venous, and crest diame ters as w e l l a s t h e w i d t h o f t h e l o o p w e r e n o t
Fig. 1 (Gasser and Flammer). Photographs taken from the videomonitor demonstrating the nailfold capillaries after cold provocation. Left, A control subject with normal circulating erythrocytes. Right, Blood standstill and segmentation of the blood-cell column caused by flow stop after cooling (cold-induced vasospasm) in a patient with normal-tension glaucoma.
Vol. I l l , No. 5
Blood-Cell Velocity and Glaucoma
TABLE 2 MORPHOLOGIC FINDINGS ON NAILFOLD CAPILLARIES*
Diameter (/tm) Arteriolar Venular Crest WIdtti Capillary density (numt>er of nallfold capillary loops per mmY
PATIENTS W I T H
PATIENTS W I T H
CONTROL
HIGH-TENSION
NORMAL-TENSION
SUBJECTS
GLAUCOMA
GLAUCOMA
11.1 2.1 13.0 ± 2.5 16.0 3.4 34.3 5.8
11.0 ± 1.8 13.3 2.3 16.3 ± 3.5 33.9 ± 6.3
10.6 1.8 12.7 ± 2.0 16.5 ± 2.9 32.8 ± 5.1
6.8
1.2
6.0
7.1
1.5
1.8
glaucoma had on the average a slightly slower capillary blood-cell velocity, although these differences were not statistically significant. The reduction of the capillary blood-cell ve l o c i t y , h o w e v e r , w a s m o r e p r o n o u n c e d in t h e normal-tension glaucoma group. T h e differenc es from t h e c o n t r o l s u b j e c t s w e r e s t a t i s t i c a l l y s i g n i f i c a n t in all i n s t a n c e s (P < . 0 5 ) , e s p e c i a l l y after c o l d p r o v o c a t i o n (P < . 0 0 0 5 ) . T h r e e c o n t r o l s u b j e c t s a n d four p a t i e n t s w i t h h i g h - t e n sion glaucoma had a measurable blood-flow standstill (Fig. 3 ) . O f the 3 0 patients with nor m a l - t e n s i o n g l a u c o m a , h o w e v e r , o n l y five p a tients had no blood-flow stop and 25 patients had a clear blood-flow standstill, the duration of which ranged b e t w e e n ten and 9 5 seconds.
'Values given are mean ± standard deviation. •Significance level between control subjects and patients with high-tension glaucoma, Ρ = .026. s i g n i f i c a n t l y different ( T a b l e 2 ) . T h e c a p i l l a r y d e n s i t y w a s s l i g h t l y s m a l l e r in t h e h i g h - t e n s i o n g l a u c o m a g r o u p t h a n in t h e c o n t r o l g r o u p , w h i c h w a s s t a t i s t i c a l l y s i g n i f i c a n t (P = . 0 2 6 ) . T h e c a p i l l a r y d e n s i t y in t h e n o r m a l - t e n s i o n glaucoma group, however, was not significantly different from t h a t in t h e c o n t r o l g r o u p . The control group showed the w e l l - k n o w n i n c r e a s e in t h e m e a n c a p i l l a r y b l o o d - c e l l v e l o c ity after w a r m i n g a n d a d e c r e a s e after c o o l i n g t h e fingertip a n d d u r i n g t h e r e c o v e r y ( F i g . 2 ) . The patients with high-tension glaucoma s h o w e d t h e s a m e b a s i c d y n a m i c s (Fig. 2 ) . In most instances, the patients with high-tension
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Discussion T h e p e r i p h e r a l b l o o d flow in p a t i e n t s w i t h high-tension and normal-tension glaucoma m i g h t b e different from t h a t in n o r m a l s u b j e c t s . The capillary blood-cell velocity was on the
••oonda
90 8070-
60 60-
mm/s
X 40-
0.« 0.6
30-
0.4
20-
0.2
Η
10V2 •
CONTROLS
V3 CDHTe
V4
V5
0-
ίΝτα
Fig. 2 (Gasser and Flammer). Blood-flow velocities of control subjects, patients with high-tension glau coma (HTG), and patients with normal-tension glau coma (NTG) at baseline ( V I ) , after the warm-water bath (V2), after cooling (V3), and after recovery (V4 and V5).
CONTROL*
HTQ
NTQ
Fig. 3 (Gasser and Flammer). Duration (in seconds) of cold-induced blood-flow standstill in the control subjects, patients with high-tension glaucoma (HTG), and patients with normal-tension glaucoma (NTG).
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a v e r a g e s l i g h t l y s l o w e r in t h e p a t i e n t s w i t h h i g h - t e n s i o n g l a u c o m a t h a n in n o r m a l c o n t r o l subjects, although this difference was not sta tistically significant. The normal-tension glau coma group, however, had a more pronounced a n d s t a t i s t i c a l l y s i g n i f i c a n t d e c r e a s e in t h e c a p illary b l o o d - c e l l v e l o c i t y . T h e d i f f e r e n c e from the c o n t r o l s u b j e c t s w a s e s p e c i a l l y e v i d e n t after t h e c o l d p r o v o c a t i o n . T h e m o s t s t r i k i n g finding, h o w e v e r , w a s t h e d i f f e r e n c e in b l o o d - f l o w s t a n d s t i l l after c o o l i n g . In t h i s r e s p e c t , p a t i e n t s with high-tension glaucoma and control sub jects were essentially the same. The patients with n o r m a l - t e n s i o n g l a u c o m a , h o w e v e r , h a d a c l e a r a n d s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e in blood-flow standstill. It is difficult to k n o w h o w m u c h t h e p o p u l a t i o n t e s t e d is r e p r e s e n t a t i v e o f t h e t o t a l p o p u l a t i o n . All the p a t i e n t s s e l e c t e d from o u r c l i n i c were referred by other ophthalmologists. S o m e of t h e s e o p h t h a l m o l o g i s t s k n e w t h a t w e h a d a s p e c i a l i n t e r e s t in v a s o s p a s t i c d i s o r d e r s . T h e r e fore, we c a n n o t e x c l u d e t h e p o s s i b i l i t y that t h e p r o p o r t i o n o f v a s o s p a s t i c c a s e s in t h e p o p u l a t i o n t e s t e d w a s s l i g h t l y h i g h e r t h a n t h a t in an average population. N e v e r t h e l e s s , t h e s e findings i n d i c a t e t h a t a pathologic vascular reaction called a vasospas tic disorder'^ m o s t p r o b a b l y o c c u r s m o r e often in p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a t h a n in c o n t r o l s u b j e c t s or p a t i e n t s w i t h h i g h - t e n sion g l a u c o m a . T h i s s u p p o r t s t h e h y p o t h e s i s t h a t v a s o s p a s m m a y b e i n v o l v e d in t h e p a t h o genesis of normal-tension glaucoma.'*" These findings are in a g r e e m e n t w i t h t h e o b s e r v a t i o n s of D r a n c e a n d a s s o c i a t e s ' a n d m a y h a v e m a j o r t h e r a p e u t i c i m p l i c a t i o n s . It is p o s s i b l e t h a t treatment of this vasospastic disorder may be beneficial to p a t i e n t s w i t h n o r m a l - t e n s i o n g l a u c o m a , as h a s b e e n p r e v i o u s l y reported.'*"^'
References 1. Demailly, P., Cambien, P., Plouin, P. P., Baron, P., and Chevallier, B.: Do patients with low-tension glaucoma have particular cardiovascular characteris tics? Ophthalmologica 188:65, 1 9 8 4 . 2. Carter, C. J . , Brooks, D. E., Doyle, D. L., and Drance, S. M.: Investigations into a vascular etiology for low-tension glaucoma. Ophthalmology 97:49, 1990. 3. Drance, 5. M., Sweeny, V. P., Morgan, R. W., and Feldman, F.: Studies of factors involved in the production of low-tension glaucoma. Arch. Ophthal mol. 89:457, 1973.
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4. Freyler, Η., and Menapace, R.: 1st die Erblindung an Glaukom vermeidbar? Spektrum Augenheilkd. 2:121, 1 9 8 8 . 5. Goldberg, I., Hollows, F. C , Kass, M. Α., and Becker, B.: Systemic factors in patients with lowtension glaucoma. Br. J. Ophthalmol. 65:56, 1 9 8 1 . 6. Trope, G. E., Salinas, S. Α., and Glynn, M.: Blood viscosity in primary open-angle glaucoma. Can. J. Ophthalmol. Vis. Sei. 22:202, 1987. 7. Worch, Α., and Kästner, R.: Das Glaukom ohne Hochdruck. Folia Ophthalmol. 10:221, 1 9 8 5 . 8. Phelps, D., and Corbett, J. J.: Migraine and lowtension glaucoma. A case-control study. Invest. Oph thalmol. Vis. Sei. 2 6 : 1 1 0 5 , 1 9 8 5 . 9. Drance, S. M., Douglas, G. R., Wijsman, K., Schulzer, M., and Britton, R. J . : Response of blood flow to warm and cold in normal and low-tension glaucoma patients. Am. J. Ophthalmol. 105:35, 1 9 8 8 . 10. Gasser, P., Flammer, J . , Guthauser, U., and Mahler, F.: Do vasospasms provoke ocular diseases? Angiology 4 1 : 2 1 3 , 1 9 9 0 . 11. Guthauser, U., Flammer, J . , and Mahler, F.: The relationship between digital and ocular vaso spasm. Graefes Arch. Clin. Exp. Ophthalmol. 226:224, 1988. 12. Bollinger, Α., and Fagrell, B.: Clinical Capillaroscopy. Toronto, Hogrefe-Huber, 1990, pp. 1-30. 13. Gasser, P.: Capillary blood cell velocity in finger nailfold, Characteristics and reproducibility oí the local cold response. Microvasc. Res. 40:29, 1990 14. Mahler, F., Saner, H., Würbel, Η., and Flam mer, J.: Local cooling test for clinical capillaroscopy in Raynaud's phenomenon, unstable angina, anc vasospastic visual disorders. Vasa 18:201, 1 9 8 9 . 15. Boss, C , Schneuwiy, P., and Mahler, F.: Evalu ation and clinical application of the flying-spot meth od in nailfold capillary TV-microscopy. Int. J. Micro circ. Clin. Exp. 6:15, 1987. 16. Flammer, J . , Guthauser, U., and Mahler, M. Do ocular vasospasms help cause low-tension glau coma? Doc. Ophthalmol. Proc. Ser. 49:397, 1987. 17. Gasser, P., and Flammer, J.: Influence of vaso spasm on visual function. Doc. Ophthalmol. 66:3 1987. 18. Flammer, ] . , and Guthauser, U.: Behandlun, chorioidaler Vasospasmen mit Kalziumantagonister Klin. Monatsbl. Augenheilkd. 190:299, 1987. 19. Gasser, P., and Flammer, J . : Short- and long term effect of nifedipine on the visual field in patient with presumed vasospasm. J. Int. Med. Res. 18:334 1990. 20. : Die dynamisch-video-kapillarmikro skopische Beeinflussung akraler und okulärer Vasos pasmen durch Kalzium- und Serotoninantagonisten Vasa 27:79, 1989. 21. Kitazawa, Y., Shirai, H., and Go, F. ] . : Th. effect of Ca^*-antagonist on visual field in low-ten sion glaucoma. Graefes Arch. Clin. Exp. Ophthalmol 227:408, 1989.
