Secondary Ocular Hypertension with Exophthalmos as the First Presentation of Endogenous Cushing’s Syndrome

Abstract

Introduction

Cushing’s syndrome results from excessive exposure to exogenous or endogenous steroid, while cushing’s disease is hypercortisolism from an adrenocorticotropic hormone-secreting pituitary adenoma. Secondary ocular hypertension (OHT) accompanied by exophthalmos as the initial presentation of endogenous Cushing’s syndrome has rarely been reported.

Case Presentation

A 46-year-old Thai woman was referred for OHT treatment despite maximum tolerance to medication. Intraocular pressure (IOP) was 21 mm Hg (right eye) and 25 mm Hg (left eye). Visual acuity was 20/20 in both eyes. Bilateral eyelids were swollen without any palpable masses. Exophthalmometer measurements were 24 mm (right eye) and 23 mm (left eye). Extraocular muscle movements, anterior segment, gonioscopy, and dilated fundoscopic exams were normal bilaterally. Optic nerve head was unremarkable in both eyes. Optical coherence tomography showed marginal inferior thinning of the retinal nerve fiber layer and ganglion cell layer in left eye. Computerized visual field 24-2 was normal bilaterally. She was diagnosed with secondary OHT with exophthalmos in both eyes. Thyroid function and thyroid antibody tests were unremarkable. Orbital and brain computed tomography revealed exophthalmos with an increase of retrobulbar fat bilaterally and a hypodense pituitary lesion. She was diagnosed with Cushing’s disease and underwent endoscopic transsphenoidal adenectomy. At 6-month postoperatively, IOP decreased to 16 mm Hg (right eye) and 17 mm Hg (left eye), without any IOP-lowering medications. Exophthalmos also improved as exophthalmometer measurements were 20 mm (right eye) and 19 mm (left eye).

Conclusions

Endogenous Cushing’s syndrome should be included in the differential diagnosis of secondary OHT with exophthalmos.

Introduction

Cushing’s syndrome is a type of hypercortisolism caused by excessive exposure to either exogenous or endogenous steroids. Cushing’s disease is a hypercortisolism resulting from pituitary adenoma-secreting adrenocorticotropic hormone [1]. Clinical presentations of Cushing’s syndrome include weight gain, hirsutism, menstrual irregularity, proximal muscle weakness, easy bruising, abdominal striae, and an increased risk of metabolic syndrome. Ocular manifestations of patients diagnosed with Cushing’s syndrome including secondary ocular hypertension (OHT), exophthalmos, cataract, and central serous chorioretinopathy have been reported [2–4]. Secondary OHT accompanied by exophthalmos as the initial presentation of endogenous Cushing’s syndrome has rarely been reported. Herein, we describe a case of secondary OHT with exophthalmos as the first presentation of the aforementioned syndrome.

Case Report

Patient’s Information

A 46-year-old Thai woman was referred to the glaucoma clinic for further treatment of OHT in both eyes despite maximum tolerance to medication. Her underlying diseases were diabetes mellitus, systemic hypertension, hyperlipidemia. She was diagnosed with OHT in both eyes 5 years ago and was initially treated with topical timolol 0.5% in each eye. Subsequently, the treatment regimen was expanded to include brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005%, all administered bilaterally. However, intraocular pressure (IOP) remained elevated at 21 mm Hg (right eye) and 25 mm Hg (left eye).

Clinical Findings

Her visual acuity was 20/20 in both eyes, pupils were 3 mm reactive to light in both eyes, with no relative afferent pupillary defect. Her eyelids were significantly swelling and puffy without any palpable masses on both sides. The Hertel exophthalmometer (base: 110 mm) measurements were 24 mm in the right eye and 23 mm in the left eye. Full range of extraocular muscle movements were observed in all directions in both eyes. The ophthalmic, maxillary, and mandibular branches of the trigeminal cranial nerve dermatome showed equal sensation of the pinprick and cold temperatures on both sides. On slit lamp examination, there was no chemosis observed in both eyes. The anterior chamber depth appeared normal and no cellular reactions were detected in both eyes. On gonioscopy, the iris insertion was deep into the ciliary body face, the angular width was approximately 35° with a flat iris configuration, and the trabecular meshwork (TM) pigmentation was grade 1 in both eyes. The gonioscopy also revealed the absence of blood in Schlemm’s canal, as well as the absence of peripheral anterior synechiae, angle recession, and angle neovascularization in both eyes. The lens appeared clear in both eyes. On dilated fundoscopic examination (shown in Fig. 1), the vitreous appeared clear without cellularity in both eyes. The retinal background and vessels were normal in both eyes. Cup-to-disc ratio of the optic nerve head was 0.3 without notching, vertical elongation, pallor, neuro-retinal rim thinning, or optic disc hemorrhage in both eyes. Optical coherence tomography of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) (shown in Fig. 2) appeared normal in the right eye. However, there was marginal inferior thinning of both RNFL and GCL in the left eye. The computerized visual field 24-2 was normal in both eyes.

Fig. 1.

On dilated fundoscopic examination, the vitreous appears clear without cellularity in both eyes. The retinal background and vessels are normal in both eyes. Cup-to-disc ratio of the ONH is 0.3 without notching, vertical elongation, pallor, neuro-retinal rim thinning, or optic disc hemorrhage in both eyes.

Fig. 2.

Optical coherence tomography of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) appears normal in the right eye. However, there is marginal inferior thinning of both RNFL and GCL in the left eye.

Diagnostic Assessment

The patient was diagnosed with secondary OHT with clinically significant exophthalmos in both eyes. Therefore, bilateral thyroid eye disease was initially suspected. However, the thyroid function test and thyroid antibody test (thyroid-stimulating hormone receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody) were unremarkable. Contrast-enhanced computed tomography (CT) of the orbit and brain (shown in Fig. 3) revealed bilateral exophthalmos (24.52 mm [right eye] and 23.90 mm [left eye] measured by the distance from the anterior surface of the eyeball to the interzygomatic line). The extraocular muscles and tendons were of normal size bilaterally, with no evidence of an orbital mass. Moreover, an increase of retrobulbar fat in both orbits was observed. Interestingly, a hypodense pituitary lesion was identified, measuring 11.51 × 9.83 mm² in the coronal plane and 10.44 × 11.17 mm² in the sagittal plane. Pituitary macroadenoma causing Cushing’s disease was suspected. The patient was referred to an endocrinologist and Cushing’s disease was definitively diagnosed.

Fig. 3.

Contrast-enhanced computed tomography of the orbit and brain. a Bilateral exophthalmos (24.52 mm [right eye] and 23.90 mm [left eye] measured by the distance from the anterior surface of the eyeball to the interzygomatic line [yellow thick line]). The extraocular muscles and tendons are of normal size bilaterally, with no evidence of an orbital mass. A hypodense pituitary lesion measuring 11.51 × 9.83 mm² in the coronal plane (b) and 10.44 × 11.17 mm² in the sagittal plane (c).

Therapeutic Intervention

The patient subsequently underwent endoscopic transsphenoidal adenectomy. Histopathological analysis of the resected lesion confirmed the diagnosis of a pituitary adenoma.

Follow-Up and Ophthalmic Outcomes

At 6-month postoperatively, IOP decreased to 16 and 17 mm Hg in the right eye and the left eye, respectively, without any IOP-lowering medications. Moreover, exophthalmos also improved bilaterally as the Hertel exophthalmometer (base: 110 mm) measurements were 20 mm in the right eye and 19 mm in the left eye.

Discussion

Steroids have consequences on TM replication, migration, activation, organelle activity, and biosynthesis [5]. It also affects the extracellular matrix, cytoskeleton formation, and gene expression [6]. Glucocorticoids activates myocilin expression through the MYOC gene [7] and an increased mRNA transcription, causing increased expression of collagen IV and elastin in the TM [6]. Dexamethasone causes upregulation of genes encoding prostaglandin D2 synthase, alpha-1-antichymotrypsin, cornea-derived transcription factor 6, and pigment epithelium-derived factor in the TM [8]. Although secondary OHT and glaucoma caused by excessive exogenous steroids are evident, the effects of excessive endogenous steroids on IOP have not been well described. Our case highlighted the coexistence of secondary OHT and excessive endogenous steroids. We speculate that increased IOP in our patient was secondary to steroid-induced OHT. However, the precise mechanisms of elevated IOP in endogenous Cushing’s syndrome should be further investigated.

There were several studies of the secondary OHT in endogenous Cushing’s syndrome which aligned with our case [9–13]. Khaw et al. [9] reported an 11-year-old boy with endogenous Cushing’s syndrome and an IOP of 50 mm Hg in both eyes caused by an ectopic adrenocorticotropic hormone producing tumor. Tsushima et al. [10] reported a case of glaucoma as the initial presentation of endogenous Cushing’s syndrome caused by pituitary adenoma. Griffin et al. [11] also reported a case series in which a 65-year-old man and a 21-year-old woman were found to have endogenous Cushing’s syndrome caused by adrenal adenoma and pituitary adenoma, respectively, following the presentation of secondary OHT. Moreover, a retrospective matched-cohort study found that patients with endogenous Cushing’s syndrome, caused by pituitary or adrenal adenomas, were associated with an increased risk for glaucoma compared to the general population [12]. Furthermore, a prospective study documented that patients with Cushing’s disease had an increased risk of secondary OHT compared to patients with growth hormone-secreting pituitary adenomas and patients with nonfunctioning pituitary adenomas [13].

Our case presented with secondary OHT in both eyes, accompanied by marginal inferior thinning of both RNFL and GCL in the left eye. Despite these findings in the left eye, secondary OHT in both eyes was the definite diagnosis according to normal optic nerve head appearance and visual field. However, longitudinal follow-up is necessary to assess further anatomical and functional glaucomatous damage and to monitor disease progression.

Apart from bilateral secondary OHT, our case also demonstrated exophthalmos in both eyes. Exophthalmos in Cushing’s syndrome can result from either endogenous [14, 15] or exogenous [4] steroids. Exophthalmos has been reported in 0%–33% of patients with Cushing’s syndrome [16]. Our contrast-enhanced CT of the orbit and brain also revealed that bilateral exophthalmos was related to an increase of retrobulbar fat in both orbits. Furthermore, the extraocular muscles and tendons were of normal size bilaterally, with no evidence of an orbital mass. Not only in Cushing’s syndrome, increased retrobulbar fat can be observed in conditions such as Graves’ disease and in patients with obesity [17, 18]. Graves’ disease is often characterized by an increase of retrobulbar fat and tendon-sparing extraocular muscle enlargement. However, in type I (lipogenic) Graves’ orbitopathy, in which only the retrobulbar fat volume is increased, distinguishing it from other etiologies can be challenging. Regensburg et al. [19] demonstrated that in Graves’ orbitopathy, retrobulbar fat density shifts closer to water density, suggesting the presence of edema. To date, there are no distinct imaging characteristics that differentiate Cushing’s syndrome from other conditions associated with increased retrobulbar fat, such as type I (lipogenic) Graves’ orbitopathy and obesity [17]. Clinical signs and hormonal testing are essential for the differential diagnosis of these disease entities.

Several theories have been proposed regarding the cause of retrobulbar fat expansion, including its involvement in central fat redistribution. Excessive corticosteroid exposure modulates both adipogenesis and lipogenesis through glucocorticoid receptors in adipocytes, with depot-specific effects driven by differential gene expression [20]. For instance, omental fat expresses a higher level of glucocorticoid receptor alpha (GR_α) than subcutaneous fat, making it more sensitive to glucocorticoids and promoting adipogenesis in omental fat during Cushing’s syndrome [21]. Comparative studies have shown that retrobulbar fat exhibits a higher expression of the GR_α than both omental and subcutaneous fat likely as a compensation for markedly lower levels of 11-beta hydroxysteroid dehydrogenase type 1 (11_β-HSD1) which is the enzyme responsible for the local conversion of cortisone to cortisol [22].

In addition to steroid-induced OHT, we hypothesize that elevated IOP may be partially attributed to increased orbital pressure resulting from an increase in retrobulbar fat. The increased orbital pressure may indirectly compromise orbital venous drainage, leading to elevated episcleral venous pressure. However, the precise mechanisms of elevated IOP with exophthalmos in endogenous Cushing’s syndrome should be further investigated. The CARE Checklist has been completed by the authors for this case report, is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546434).

Conclusions

Endogenous Cushing’s syndrome should be included in the differential diagnosis of a patient who presented with secondary OHT with exophthalmos.

Statement of Ethics

This study was reviewed and approved by the Burapha University Institutional Review Board, Ethics Approval No. 136/2567. Written informed consent was obtained from the participant for publication of the details of her medical case and accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funding.

Author Contributions

Thanatporn Threetong, MD and Sasikant Leelawongs, MD: conceptualization, data curation, methodology, writing – original draft, and writing – review and editing.

Funding Statement

This study was not supported by any sponsor or funding.

Data Availability Statement

The data supporting this study’s findings are not publicly available due to privacy and security reasons but can be obtained from the corresponding author upon reasonable request.