Graefe's Arch Clin Exp Ophthalmol (1990) 228:407 409
Graefe's Archive Ophthalmology for Clinical and Experimental
© Springer-Verlag 1990
Intraocular pressure in patients with Cushing's disease Jost B. Jonas 1, Oliver Huschle ~, Gerhard Koniszewski ~, Michael Buchfelder 2, and Rudolf Fahlbusch 2 1 Universit/its-Augenklinik and 2 Neurochirurgische Universit/itsklinik, Universitfit Erlangen-N/irnberg, Schwabachanlage 6, D-8520 Erlangen, Federal Republic of Germany Received December 30, 1989 / Accepted May 2, 1990
Abstract. E x t e r n a l l y a p p l i e d c o r t i c o s t e r o i d s increase the i n t r a o c u l a r p r e s s u r e in o n e - t h i r d o f the g e n e r a l p o p u l a tion. We e v a l u a t e d the i n t r a o c u l a r p r e s s u r e in 62 p a t i e n t s w i t h e n d o g e n o u s l y e l e v a t e d s e r u m c o r t i s o l levels d u e to h y p o t h a l a m i c p i t u i t a r y - d e p e n d e n t C u s h i n g ' s disease. A l l p a t i e n t s u n d e r w e n t t r a n s p h e n o i d a l m i c r o s u r g i c a l sella e x p l o r a t i o n w i t h i n 4 y e a r s a f t e r the o n s e t o f subjective symptoms. The intraocular pressure (preoperative mean, 14.9_+ 3.5 m m H g ) e x c e e d e d 21 m m H g in f o u r eyes before s u r g e r y a n d in one eye after s u r g e r y ( p o s t o p e r a t i v e m e a n , 14.3 _+ 2.8 m m Hg). I n p a t i e n t s a t t a i n i n g p o s t o p e r ative r e m i s s i o n a n d w h o s e p r e s s u r e r e a d i n g s were t a k e n at least 3 m o n t h s after surgery, the p o s t o p e r a t i v e i n t r a o c u l a r p r e s s u r e was significantly ( P = 0 . 0 4 ) l o w e r t h a n t h a t m e a s u r e d p r e o p e r a t i v e l y (14.2___2.7 vs 13.0_+ 2.0 m m Hg). B i o m o r p h o m e t r y o f the o p t i c disc t o p o g r a p h y a n d the r e t i n a l n e r v e - f i b e r l a y e r in 19 p a t i e n t s rev e a l e d n o g l a u c o m a t o u s changes. In c o n t r a s t to t o p i c a l l y applied corticosteroids, endogenously elevated serum c o r t i s o l levels in p a t i e n t s w i t h h y p o t h a l a m i c p i t u i t a r y d e p e n d e n t C u s h i n g ' s disease i n c r e a s e d i n t r a o c u l a r pressure o n l y slightly, w i t h no g r e a t risk o f g l a u c o m a t o u s o p t i c nerve d a m a g e .
Introduction O n e - t h i r d o f a g e n e r a l p o p u l a t i o n has been r e p o r t e d to r e s p o n d to local a d m i n i s t r a t i o n o f 0 . 1 % b e t a m e t h a s o n e w i t h a n increase in i n t r a o c u l a r p r e s s u r e [3, 5, 6]. We e v a l u a t e d p a t i e n t s w i t h C u s h i n g ' s disease a s s o c i a t e d w i t h e n d o g e n o u s l y e l e v a t e d s e r u m c o r t i c o s t e r o i d levels w i t h r e s p e c t to their i n t r a o c u l a r pressure, visual f u n c t i o n a n d e n d o c r i n e status.
Patients and methods A total of 62 patients (12 men, 50 women) found to have adrenocorticotropic hormone (ACTH)-dependent hypothalamic pituitaryOffprint requests to: J. Jonas
dependent Cushing's disease [7] were studied. All patients showed typical clinical features of hypercortisolism such as rapidly acquired, sometimes painful adiposity confined to the face, neck and trunk, with the extremities being spared; amenorrhea in females and ultimate impotence in males; hirsutism; plethoric appearance of the face; purplish striae best seen on the abdomen; arterial hypertension; variable fatigability; and backache. The diagnosis was based on (1) elevated plasma cortisol levels without a marked circadian rhythm; (2) nonsuppressibility of serum cortisol or urine steroids after administration of low-dose (2 mg) dexamethasone overnight, but suppressibility by at least 50% of serum cortisol levels or urine steroids with high-dose dexamethasone (8 mg; in some cases, 16 mg); (3)normal or slightly elevated ACTH serum concentrations despite hypercortisolism; and (4)stimulation of cortisol and ACTH release by corticotropin-releasing hormone (CRH). All patients underwent transphenoidal microsurgical sella exploration. In 58 of 62 cases (93.5%) an adenoma of the pituitary gland was intraoperatively detected; in 4 patients sella exploration was negative. In 45 cases the surgical procedure was followed by clinical and endocrinological remission of the disease. Criteria for remission included normal suppressibility of serum cortisol levels to 2 gg/dl after low-dose dexamethasone administration (2 mg) or even lower cortisol levels without dexamethasone treatment in patients with postoperatively transient adrenocortical insufficiency. On plain skull X-rays, abnormalities were noted in 25 of 62 patients (40.3%). In 34 of 62 cases (54.8%) a tumor of the pituitary gland was directly observable by thin-collimation cranial computed tomography (CCT) [9] or magnetic resonance scanning (MR). In some cases diagnosis was confirmed by histological examination of the surgically excised specimen or by cell-culture studies. Patients had noticed the first subjective symptoms not more than 4 years before admission. Their mean age ( ± SD) was 40.3 ± 13.4years (minimum, 15 years; maximum, 64years) and their mean refractive error was -0.74 ± 2.57 diopters (range, - 1 3 . 0 - + 2.63 diopters). Preoperative visual acuity averaging 0.85±0.31 (metric system: minimum, 0.01; maximum, 1.25) in the right eye and 0.87±0.24 (range, 0.1-1.25) in the left eye was decreased in patients with suprasellar extension of the adenoma or those who had undergone previous transcranial neurosurgical intervention. Postoperative mean visual acuity was 0.88 ±0.29 (0.01 1.2) in the right eye and 0.92±0.17 (0.5-1.2) in the left eye. The increase in visual acuity in the left eye was significant (P=0.02; Wilcoxon test). There was no known glaucoma history prior to the onset of Cushing's disease. No ocular medication was used before hospital admission. The basal preoperative morning serum cortisol levels determined at 9 a.m. (29.9 ± 11.6 gg/100 ml) were significantly higher (P < 0.0001 ; Wilcoxon test) than those determined after surgery (15.3 ± 13 gg/100 ml). Intraocular pressure was measured by Goldmann applanation tonometry once or twice preoperatively
408 and between 6 days and 23 months after surgery (mean, 103.3_+ 118.2 days). In 19 patients with a mean age of 38.2-t- 10.2 years and a mean refractive error of 0_+ 0.76 diopters (range, -1.75-_+ 2.0 diopters), 15° color stereo optic disc diapositives were taken using a tetecentric fundus camera equipped with a stereo separator. The slides were projected at a magnification of 15. The outlines of the intraand parapapillary optic disc structures were plotted and analyzed planimetrically. The method for determination of the morphometry of the optic nerve head, including correction of the photographic magnification; partitioning of the optic disc into a temporal horizontal sector of 64 °, a right-angle superior temporal and a rightangle inferior temporal sector, and a nasal sector of 116°; definition of the intra- and parapapillary structures; and the method's reproducibility have recently been reported [11, 12]. As nonquantitative characteristics we evaluated the location of the smallest part of the neuroretinal rim, the occurrence of a discrepancy between areas with pallor and those with cupping, the number of bared circumlinear vessels, the frequency of optic disc hemorrhages, and the location of the widest extension of the parapapillary chorioretinal atrophy. The retinal nerve-fiber layer was examined using 60 ° red-free fundus photographs and a method previously described in detail [2, 13]. The photographs were evaluated in a masked fashion together with photographs of normal subjects and those of patients with glaucomatous and nonglaucomatous optic nerve damage.
Results
In all 62 patients the intraocular pressure readings were preoperatively (mean+S.D." 14.9_+3.5mm Hg" minimum, 7 mm Hg; maximum, 24 mm Hg) and postoperatively (14.3_+3.1 mm Hg; range, 9-22 mm Hg) not significantly different ( P = 0.98; Wilcoxon test). Before surgery the readings were 3 months after surgery, the correlation was not significant. In patients achieving remission whose postoperative intraocular pressure readings were taken at least 3 months after surgery, the difference between preand postoperative intraocular pressure readings was significant (14.2 + 2.7 vs 13 ± 2 mm Hg; P = 0.04; Wilcoxon test). In patients who did not experience remission, the intraocular pressure readings were not significantly correlated with the time between surgery and the pressure measurement; the difference between intraocular pressure before (15.6 _+4.1 mm Hg) and after surgery (15.5 _ 3.1 man Hg) was not significant (P=0.98; Wilcoxon test). The topographic data of the intra- and parapapillary region and the nonquantitative optic disc characteristics were not significantly different between the eyes of 19patients undergoing photography of the posterior fundus and 571 normal eyes [12]. Retinal nerve-fiber
layer photography and perimetry revealed no defects typical for glaucoma. Corneal aesthesiometry and ocular motility were normal in all cases, Slit-lamp biomicroscopy showed a subcapsular posterior cataract in 5 of 124 eyes (4.0%) in 3 of 62 patients (4.8%). Nuclear and cortical lens opacities were detected in 6 of 124 eyes (4.8%) in 3 of 62 patients (4.8%).
Discussion
In the 1960s Becker and Hahn [5], Becker and Mills [6] and Armaly [3] showed that local administration of 0.1% betamethasone increased intraocular pressure to levels between 20 and 30 mm Hg in about 30% of a general population and to values exceeding 30 mm Hg in 4% of the same population. Numerous studies [1, 4, 14, 15, 19, 22] have since evaluated the responsiveness of intraocular pressure to externally applied corticosteroids in regard to its importance for pathogenesis, diagnosis and therapy of glaucoma. Intraocular pressure has been investigated by few authors in patients with endogenously high serum cortisol concentrations. D6rer and Kopf [8], Tatfir [24], Radn6t [17] and Schmelzer [21] reported on the occurrence of glaucoma in patients with mostly Cushing's syndrome. Neuner and Dardenne [16] examined nine patients aged 18-35 years who suffered from bilateral adrenal hyperplasia; seven had increased intraocular pressure readings that returned to normal values after hypercortisolism had been normalized by surgical adrenalectomy. One eye of this series showed glaucomatous cupping of the optic disc, and static manual perimetry revealed a Bjerrum scotom in the visual field. Haas and Nootens [10] and Robbin and Haas [18] reported on a patient with Cushing's syndrome caused by a benign adrenal adenoma and presenting with uncontrollable, elevated intraocular pressure that could not be regulated before adrenalectomy. Under local application of 0.1% betamethasone, the patient redeveloped high ocular pressures. The authors concluded that "ocular corticosteroid sensitivity" was the reason for the high intraocular pressure before tumor removal. They argued that this also explained why not all patients with Cushing's syndrome had elevated pressure measurements. In 1975, Sayegh and Weigelin [20] examined 70 patients suffering from hyperplasia, adenoma or carcinoma of the adrenal cortex. Intraocular pressure before adrenalectomy (mean, 19 mm Hg) was significantly (P
Graefe's Archive Ophthalmology for Clinical and Experimental
© Springer-Verlag 1990
Intraocular pressure in patients with Cushing's disease Jost B. Jonas 1, Oliver Huschle ~, Gerhard Koniszewski ~, Michael Buchfelder 2, and Rudolf Fahlbusch 2 1 Universit/its-Augenklinik and 2 Neurochirurgische Universit/itsklinik, Universitfit Erlangen-N/irnberg, Schwabachanlage 6, D-8520 Erlangen, Federal Republic of Germany Received December 30, 1989 / Accepted May 2, 1990
Abstract. E x t e r n a l l y a p p l i e d c o r t i c o s t e r o i d s increase the i n t r a o c u l a r p r e s s u r e in o n e - t h i r d o f the g e n e r a l p o p u l a tion. We e v a l u a t e d the i n t r a o c u l a r p r e s s u r e in 62 p a t i e n t s w i t h e n d o g e n o u s l y e l e v a t e d s e r u m c o r t i s o l levels d u e to h y p o t h a l a m i c p i t u i t a r y - d e p e n d e n t C u s h i n g ' s disease. A l l p a t i e n t s u n d e r w e n t t r a n s p h e n o i d a l m i c r o s u r g i c a l sella e x p l o r a t i o n w i t h i n 4 y e a r s a f t e r the o n s e t o f subjective symptoms. The intraocular pressure (preoperative mean, 14.9_+ 3.5 m m H g ) e x c e e d e d 21 m m H g in f o u r eyes before s u r g e r y a n d in one eye after s u r g e r y ( p o s t o p e r a t i v e m e a n , 14.3 _+ 2.8 m m Hg). I n p a t i e n t s a t t a i n i n g p o s t o p e r ative r e m i s s i o n a n d w h o s e p r e s s u r e r e a d i n g s were t a k e n at least 3 m o n t h s after surgery, the p o s t o p e r a t i v e i n t r a o c u l a r p r e s s u r e was significantly ( P = 0 . 0 4 ) l o w e r t h a n t h a t m e a s u r e d p r e o p e r a t i v e l y (14.2___2.7 vs 13.0_+ 2.0 m m Hg). B i o m o r p h o m e t r y o f the o p t i c disc t o p o g r a p h y a n d the r e t i n a l n e r v e - f i b e r l a y e r in 19 p a t i e n t s rev e a l e d n o g l a u c o m a t o u s changes. In c o n t r a s t to t o p i c a l l y applied corticosteroids, endogenously elevated serum c o r t i s o l levels in p a t i e n t s w i t h h y p o t h a l a m i c p i t u i t a r y d e p e n d e n t C u s h i n g ' s disease i n c r e a s e d i n t r a o c u l a r pressure o n l y slightly, w i t h no g r e a t risk o f g l a u c o m a t o u s o p t i c nerve d a m a g e .
Introduction O n e - t h i r d o f a g e n e r a l p o p u l a t i o n has been r e p o r t e d to r e s p o n d to local a d m i n i s t r a t i o n o f 0 . 1 % b e t a m e t h a s o n e w i t h a n increase in i n t r a o c u l a r p r e s s u r e [3, 5, 6]. We e v a l u a t e d p a t i e n t s w i t h C u s h i n g ' s disease a s s o c i a t e d w i t h e n d o g e n o u s l y e l e v a t e d s e r u m c o r t i c o s t e r o i d levels w i t h r e s p e c t to their i n t r a o c u l a r pressure, visual f u n c t i o n a n d e n d o c r i n e status.
Patients and methods A total of 62 patients (12 men, 50 women) found to have adrenocorticotropic hormone (ACTH)-dependent hypothalamic pituitaryOffprint requests to: J. Jonas
dependent Cushing's disease [7] were studied. All patients showed typical clinical features of hypercortisolism such as rapidly acquired, sometimes painful adiposity confined to the face, neck and trunk, with the extremities being spared; amenorrhea in females and ultimate impotence in males; hirsutism; plethoric appearance of the face; purplish striae best seen on the abdomen; arterial hypertension; variable fatigability; and backache. The diagnosis was based on (1) elevated plasma cortisol levels without a marked circadian rhythm; (2) nonsuppressibility of serum cortisol or urine steroids after administration of low-dose (2 mg) dexamethasone overnight, but suppressibility by at least 50% of serum cortisol levels or urine steroids with high-dose dexamethasone (8 mg; in some cases, 16 mg); (3)normal or slightly elevated ACTH serum concentrations despite hypercortisolism; and (4)stimulation of cortisol and ACTH release by corticotropin-releasing hormone (CRH). All patients underwent transphenoidal microsurgical sella exploration. In 58 of 62 cases (93.5%) an adenoma of the pituitary gland was intraoperatively detected; in 4 patients sella exploration was negative. In 45 cases the surgical procedure was followed by clinical and endocrinological remission of the disease. Criteria for remission included normal suppressibility of serum cortisol levels to 2 gg/dl after low-dose dexamethasone administration (2 mg) or even lower cortisol levels without dexamethasone treatment in patients with postoperatively transient adrenocortical insufficiency. On plain skull X-rays, abnormalities were noted in 25 of 62 patients (40.3%). In 34 of 62 cases (54.8%) a tumor of the pituitary gland was directly observable by thin-collimation cranial computed tomography (CCT) [9] or magnetic resonance scanning (MR). In some cases diagnosis was confirmed by histological examination of the surgically excised specimen or by cell-culture studies. Patients had noticed the first subjective symptoms not more than 4 years before admission. Their mean age ( ± SD) was 40.3 ± 13.4years (minimum, 15 years; maximum, 64years) and their mean refractive error was -0.74 ± 2.57 diopters (range, - 1 3 . 0 - + 2.63 diopters). Preoperative visual acuity averaging 0.85±0.31 (metric system: minimum, 0.01; maximum, 1.25) in the right eye and 0.87±0.24 (range, 0.1-1.25) in the left eye was decreased in patients with suprasellar extension of the adenoma or those who had undergone previous transcranial neurosurgical intervention. Postoperative mean visual acuity was 0.88 ±0.29 (0.01 1.2) in the right eye and 0.92±0.17 (0.5-1.2) in the left eye. The increase in visual acuity in the left eye was significant (P=0.02; Wilcoxon test). There was no known glaucoma history prior to the onset of Cushing's disease. No ocular medication was used before hospital admission. The basal preoperative morning serum cortisol levels determined at 9 a.m. (29.9 ± 11.6 gg/100 ml) were significantly higher (P < 0.0001 ; Wilcoxon test) than those determined after surgery (15.3 ± 13 gg/100 ml). Intraocular pressure was measured by Goldmann applanation tonometry once or twice preoperatively
408 and between 6 days and 23 months after surgery (mean, 103.3_+ 118.2 days). In 19 patients with a mean age of 38.2-t- 10.2 years and a mean refractive error of 0_+ 0.76 diopters (range, -1.75-_+ 2.0 diopters), 15° color stereo optic disc diapositives were taken using a tetecentric fundus camera equipped with a stereo separator. The slides were projected at a magnification of 15. The outlines of the intraand parapapillary optic disc structures were plotted and analyzed planimetrically. The method for determination of the morphometry of the optic nerve head, including correction of the photographic magnification; partitioning of the optic disc into a temporal horizontal sector of 64 °, a right-angle superior temporal and a rightangle inferior temporal sector, and a nasal sector of 116°; definition of the intra- and parapapillary structures; and the method's reproducibility have recently been reported [11, 12]. As nonquantitative characteristics we evaluated the location of the smallest part of the neuroretinal rim, the occurrence of a discrepancy between areas with pallor and those with cupping, the number of bared circumlinear vessels, the frequency of optic disc hemorrhages, and the location of the widest extension of the parapapillary chorioretinal atrophy. The retinal nerve-fiber layer was examined using 60 ° red-free fundus photographs and a method previously described in detail [2, 13]. The photographs were evaluated in a masked fashion together with photographs of normal subjects and those of patients with glaucomatous and nonglaucomatous optic nerve damage.
Results
In all 62 patients the intraocular pressure readings were preoperatively (mean+S.D." 14.9_+3.5mm Hg" minimum, 7 mm Hg; maximum, 24 mm Hg) and postoperatively (14.3_+3.1 mm Hg; range, 9-22 mm Hg) not significantly different ( P = 0.98; Wilcoxon test). Before surgery the readings were 3 months after surgery, the correlation was not significant. In patients achieving remission whose postoperative intraocular pressure readings were taken at least 3 months after surgery, the difference between preand postoperative intraocular pressure readings was significant (14.2 + 2.7 vs 13 ± 2 mm Hg; P = 0.04; Wilcoxon test). In patients who did not experience remission, the intraocular pressure readings were not significantly correlated with the time between surgery and the pressure measurement; the difference between intraocular pressure before (15.6 _+4.1 mm Hg) and after surgery (15.5 _ 3.1 man Hg) was not significant (P=0.98; Wilcoxon test). The topographic data of the intra- and parapapillary region and the nonquantitative optic disc characteristics were not significantly different between the eyes of 19patients undergoing photography of the posterior fundus and 571 normal eyes [12]. Retinal nerve-fiber
layer photography and perimetry revealed no defects typical for glaucoma. Corneal aesthesiometry and ocular motility were normal in all cases, Slit-lamp biomicroscopy showed a subcapsular posterior cataract in 5 of 124 eyes (4.0%) in 3 of 62 patients (4.8%). Nuclear and cortical lens opacities were detected in 6 of 124 eyes (4.8%) in 3 of 62 patients (4.8%).
Discussion
In the 1960s Becker and Hahn [5], Becker and Mills [6] and Armaly [3] showed that local administration of 0.1% betamethasone increased intraocular pressure to levels between 20 and 30 mm Hg in about 30% of a general population and to values exceeding 30 mm Hg in 4% of the same population. Numerous studies [1, 4, 14, 15, 19, 22] have since evaluated the responsiveness of intraocular pressure to externally applied corticosteroids in regard to its importance for pathogenesis, diagnosis and therapy of glaucoma. Intraocular pressure has been investigated by few authors in patients with endogenously high serum cortisol concentrations. D6rer and Kopf [8], Tatfir [24], Radn6t [17] and Schmelzer [21] reported on the occurrence of glaucoma in patients with mostly Cushing's syndrome. Neuner and Dardenne [16] examined nine patients aged 18-35 years who suffered from bilateral adrenal hyperplasia; seven had increased intraocular pressure readings that returned to normal values after hypercortisolism had been normalized by surgical adrenalectomy. One eye of this series showed glaucomatous cupping of the optic disc, and static manual perimetry revealed a Bjerrum scotom in the visual field. Haas and Nootens [10] and Robbin and Haas [18] reported on a patient with Cushing's syndrome caused by a benign adrenal adenoma and presenting with uncontrollable, elevated intraocular pressure that could not be regulated before adrenalectomy. Under local application of 0.1% betamethasone, the patient redeveloped high ocular pressures. The authors concluded that "ocular corticosteroid sensitivity" was the reason for the high intraocular pressure before tumor removal. They argued that this also explained why not all patients with Cushing's syndrome had elevated pressure measurements. In 1975, Sayegh and Weigelin [20] examined 70 patients suffering from hyperplasia, adenoma or carcinoma of the adrenal cortex. Intraocular pressure before adrenalectomy (mean, 19 mm Hg) was significantly (P
