Sunken Eyes, Sagging Brain Syndrome:Bilateral Enophthalmos from ChronicIntracranial Hypotension

Thomas N. Hwang, MD, PhD,1 Soraya Rofagha, MD, MPH,2 Michael W. McDermott, MD,3

William F. Hoyt, MD,2,3 Jonathan C. Horton, MD, PhD,2,4,5 Timothy J. McCulley, MD6,7

Purpose: To explain the mechanism for acquired enophthalmos after ventriculoperitoneal shunting (VPS).Design: Case series and a case-control study.Participants and Controls: Four study patients with bilateral enophthalmos after VPS and 10 control

subjects.Methods: Case description of 4 study patients. Calculated orbital volumes for 2 study patients were

compared with controls using the Wilcoxon rank-sum test.Main Outcome Measures: Exophthalmometry measurements and total orbital and fat volumes.Results: Patient 1 is a 25-year-old man who presented with progressive enophthalmos 3 years after VPS for

traumatic intracranial bleeding. Imaging demonstrated upward expansion of the orbital roof and evidence ofintracranial hypotension. The intracranial pressure (ICP) was 20 mm H2O. The enophthalmos improved aftershunt revision. Patient 2 is a 19-year-old man who presented with progressive enophthalmos 18 months afterVPS for traumatic intracranial hemorrhage. Patient 3 is a 38-year-old woman who presented with bilateralenophthalmos 15 years after VPS after a ruptured aneurysm. Imaging showed orbital expansion. Patient 4 is a16-year-old man who presented with severe enophthalmos 5 years after a VPS for aneurysm-related hemor-rhage. Imaging demonstrated orbital enlargement and findings of intracranial hypotension. Intracranial pressureranged between �200 and 0 mm H2O. Shunt revision improved the enophthalmos. Total orbital volumes weresignificantly greater in the study patients than in the controls. Control subjects (5 male, 5 female, ages 23–45years) had an average right orbital volume of 24.6�3.3 cm3 (n � 10). In comparison, the right orbital volumes ofpatients 1 and 3 were 32.6 and 32.1 cm3. Similar results were found for the left orbits (23.9�2.7 cm3 [controlaverage] vs. 35.9 and 32.6 cm3). In patient 1, the post-shunt volumes increased 14% (right) and 23% (left) frompre-shunt volumes. In contrast, orbital fat volume was not statistically significantly different between the controlgroup and enophthalmic patients (right orbit control mean 7.94�3.1 cm3 [n � 10] vs. 7.9 and 9.8 cm3; left orbitcontrol mean 7.88�3.1 cm3 vs. 9.2 and 10.0 cm3).

Conclusions: Enophthalmos after VPS results primarily from chronic intracranial hypotension. Low ICPcauses expansion of orbital volume with no fat atrophy. In such patients, shunt revision with a pressure-regulating valve to correct intracranial hypotension should be considered.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed

in this article. Ophthalmology 2011;118:2286–2295 © 2011 by the American Academy of Ophthalmology.

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Enophthalmos is a term that describes posterior displace-ment of the eye within the orbital cavity. It occurs from 2 basicmechanisms. Either the bony volume of the orbit increases orthe volume of soft tissues in the orbit decreases.1–3 Examplesof conditions causing a decrease in soft tissue volume includemetastatic breast cancer,4–13 human immunodeficiency virusand age-related orbital lipoatrophy,14–17 and sclerosing orbitalinflammation, such as linear scleroderma,18–20 Wegener’sgranulomatosis,21 and sarcoidosis.22 An increase in bony vol-ume is seen most commonly with orbital fractures but alsoresults from more unusual causes, such as chronic maxillarysinusitis (silent sinus syndrome), where the roof of the sinus ispulled inferiorly with a consequent expansion of the orbitalfloor.23,24

In 1996, Meyer et al25 identified a novel syndrome

producing bilateral enophthalmos. The report described 3 w

2286 © 2011 by the American Academy of OphthalmologyPublished by Elsevier Inc.

atients with congenital hydrocephalus who developed bi-ateral enophthalmos after ventriculoperitoneal shuntingVPS). There have been 2 additional reports addressing thishenomenon, describing 3 patients who developed enoph-halmos after shunting for pediatric hydrocephalus.26,27 Theechanism of enophthalmos in these cases has never been

lucidated, but theories have included fat atrophy and ex-ansion of the bony orbit.25–27

The current article describes 4 patients with acquiredydrocephalus who developed enophthalmos after VPS. Onhe basis of analysis of these cases, we propose that therobable mechanism responsible for the enophthalmos in-olves intracranial hypotension–related skull remodeling.or this collection of findings, we propose the name sunkenyes, sagging brain syndrome. Armed with this knowledge,

e have successfully treated 2 of the 4 patients.

ISSN 0161-6420/11/$–see front matterdoi:10.1016/j.ophtha.2011.04.031

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Hwang et al � Sunken Eyes, Sagging Brain Syndrome

Materials and Methods

Institutional review board/ethics committee approval was ob-tained, and the research adhered to the tenets of the Declaration ofHelsinki. From 1991 to 2010, 4 patients were identified at theUniversity of California San Francisco with progressive enoph-thalmos after VPS. They are described in detail, with focus onneuro-ophthalmologic, orbital, and radiographic evaluations.

Orbital volumetric analysis was performed on 2 enophthalmicpatients (patients 1 and 3) who had adequate imaging studies.Patient 1 also had a pre-shunt computed tomography (CT) scanavailable for comparison. Patient 2 did not undergo imaging afterthe development of enophthalmos and therefore could not beincluded in the volumetric analysis. Patient 4, although imagedwith CT, lacked the specific sequences required for volumetricanalysis. A control group (5 male and 5 female patients, mean age35.6 years, range 23–45 years) without orbital pathology was usedfor comparison. The control group was selected using a reversechronologic search starting from December 2008 through theradiology database at the University of California San Francisco.Patients with any intracranial or orbital pathology were excluded.

ImageJ software (v 140g, National Institutes of Health, http://rsbweb.nih.gov/ij, accessed July 2009) was used to analyze orbitalCT axial images by measuring the orbital area in each slice andmultiplying by the slice thickness. Total orbital volume, soft-tissue volume, fat volume, and air volume were all assessed. “Totalvolume” refers to the volume of the bony orbit. “Soft tissuevolume” refers to the volume of all soft tissues: This includes fat,muscles, and the eye itself, as well as numerous smaller structures.“Fat volume” refers to the amount of fat contained within theconfines of the bony orbit. In patients with severe enophthalmos,the anterior bony orbit is devoid of soft tissue; the size of thisair-filled space is referred to as “air volume.” The total orbital areain each axial slice was bounded on each side by the medial andlateral orbital walls. Anteriorly, if the slice did not have a bonyboundary because of the orbital opening, a line was drawn betweenthe inner aspects of the orbital rim on each side. In the slices at the

Figure 1. Patient 1. External photographs with close-up view of themedial lower eyelids show loss of apposition of the lower eyelid to theglobe, mucous strands, and injection due to enophthalmos.

level of the medial canthi, the anterior line was drawn between the o

ateral orbital rim and the anterior lacrimal crest. Posteriorly, atraight line was drawn across the openings of the superior andnferior orbital fissures and the optic canal. By using thresholdingnd windowing techniques included with the ImageJ software, theotal orbital volume could be divided into fat, soft tissue, and airolume. The 2-tailed Wilcoxon rank-sum test was used to assessifferences between study and control patients. Right and left eyesere assessed separately so that the tendency of each individual toave symmetric orbital volumes would not inappropriately de-rease the standard deviation.

igure 2. Patient 1. Axial computed tomography scans show the nor-al position of the right globe before ventriculoperitoneal shunting

A) and severe enophthalmos �5 years later (B) with short straight

ptic nerves (C).

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Results

Case Descriptions

Patient 1 is a 25-year-old man who was referred for evaluation ofdisconjugate gaze in September 2004. He was involved in a motorvehicle accident in November 2000 that resulted in extensivehemorrhagic brain contusions, frontotemporal epidural hematoma,and intraventricular hemorrhage. There were several skull frac-tures identified on CT, but none involved the orbits. In January2001, the patient had a sudden decrease in mental status. A CTscan revealed new ventriculomegaly from presumed elevated in-tracranial pressure (ICP). A VPS without a valve was placed,which restored his baseline mental status. Long-term sequelaeincluded muscular spasticity, neurogenic bowel and bladder, bra-dyphonia, hypophonia, and disconjugate gaze.

On ophthalmic examination, the patient’s best-corrected vi-sual acuity was 20/70 oculus dexter (OD) and 20/50 oculus

Figure 3. Patient 1. Pre-shunt revision T1-weighted sagittal (A) and axipons against the clivus with decrease of the pontine cistern (open black archiasmic cistern also is diminished in size (open white arrow). Two-monthof the brainstem findings and dural enhancement.

sinister (OS). He did not have an afferent pupillary defect, and i

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isual fields were full to counting fingers. In primary gaze, head 20-prism diopters of right exotropia and 10-prism dioptersf right hypotropia. Supraduction was limited to 5% of normalD and 50% of normal OS. Infraduction was limited to 50% oformal OD and 10% of normal OS. Horizontal ductions werentact. Despite his disconjugate gaze, the patient did not reportiplopia.

His external examination (Fig 1) showed bilateral enophthal-os with exophthalmometry measurements of 9 mm oculus uter-

ue (OU). The enophthalmos was so severe that the ocular surfacead lost contact with the eyelids, especially along the medial onealf of each lower lid. The gap caused accumulation of debris inhe inferior fornix, inferior conjunctival injection, and recurrenteratoconjunctivitis. There was fluorescein staining of the inferiorornea. Fundus examination revealed bilateral optic nerve pallor,lightly worse on the right.

Comparison of orbital CT imaging obtained at the time of

magnetic resonance imaging (MRI) scans demonstrate flattening of theand diffuse gadolinium enhancement of the dura (thin white arrows). Theshunt revision sagittal (C) and axial (D) MRI scans show normalization

al (B)row)post-

njury (Fig 2A) and slightly �4 years later (Fig 2B) documented

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Hwang et al � Sunken Eyes, Sagging Brain Syndrome

acquired enophthalmos. The intracranial hypotension–related skullremodeling resulted in not only enophthalmos but also expansionof all adjacent sinuses. The optic nerves were short and straight(Fig 2C) with an intraorbital length of 18 mm bilaterally comparedwith a reported typical length of 25 mm.28 Magnetic resonanceimaging (MRI) obtained after the development of enophthalmos,showed classic signs of intracranial hypotension. There was flat-tening of the pons against the clivus, reduction of the interpedun-cular and pre-pontine cisterns, crowding of the optic chiasmagainst the pituitary gland, and thickening of the dura with gado-linium enhancement (Fig 3A, B).29–34 The ICP was measured at20 mm H2O (normal range 100–200 mm H2O), confirming lowcerebrospinal fluid (CSF) pressure.

To determine whether the ventriculoperitoneal shunt was stillnecessary, the intraventricular tube was connected directly to anexternal ventricular drain set to 200 mm H2O. The CSF continuedto drain at a high rate, proving that the patient’s ICP wouldincrease �200 mm H2O without a VPS. To address the high ICPand avoid over-shunting, a Medtronic Delta Valve PerformanceLevel 1.5 VPS was placed (Medtronic Inc., Minneapolis, MN).This pressure-controlled valve opens only when the ICP exceeds acertain threshold. The Performance Level 1.5 version is calibratedto maintain the ICP between 70 and 105 mm H2O (http://www.medtronic.com/neurosurgery/valves.htmldelta). As demon-strated by MRI 2 months later, the radiographic signs of intracra-nial hypotension resolved (Fig 3C, D).

In less than 48 hours after shunt revision, some improvement of

Figure 4. Patient 1. A, Post-shunt revision external photographs showforward movement of globe position, disappearance of the abnormal teartrough, and resolution of ocular inflammation. B, Comparison of the axialcomputed tomography scans before shunt revision (left) and 2 days after-ward (right) shows a 3-mm improvement of the enophthalmos bilaterally.

the enophthalmos was observed. Although the globes did not i

eturn to their pre-injury position, there was an increase in exoph-halmometry measurements from 9 to 12 mm bilaterally. Photo-raphs taken 2 months later showed that the ocular surface wasow in contact with the lower eyelids all the way to the medialanthi (compare Figs 1 and 4A). In addition, the patient’s chroniconjunctival injection had resolved. The anterior shift of the globesas also apparent in comparison of pre-shunt revision and post-perative CT scans (Fig 4B).

Patient 2 is a 19-year-old man who presented in December005 with a history of a motor vehicle accident in June 2004. Head traumatic brain injury with a hemorrhage in the left frontalobe, right internal capsule, midbrain, and fourth ventricle. Severalkull fractures were observed on CT. Several ethmoid air cellsere opacified bilaterally, suggesting medial wall fractures; how-

ver, no bone displacement was seen. Several weeks later, a CTcan showed new ventriculomegaly, so a right parietal ventriculo-eritoneal shunt was placed. Long-term neurologic sequelae in-luded severe spasticity and neurogenic bowel and bladder. Heas wheelchair-bound with severe hypophonia, preferring to com-unicate by pointing at letters on a letter board.

On ophthalmologic evaluation, his best-corrected vision wasifficult to assess because of his inability to communicate whichetters he could see on the vision chart, but he did foveate well onargets. His pupils were minimally reactive, but his visual fieldsere full to confrontation. In primary gaze, he was orthotropic by

orneal light reflex, and his eye movements were full except for

igure 5. Patient 3. A, Pre-incident external photograph shows normaleriocular appearance before the rupture of the aneurysm. B, Fifteen-yearost-shunt external photographs demonstrate the severe enophthalmosausing a large gap between the globe and the eyelids with resultingxposure keratopathy and associated corneal scarring and conjunctival

njection.

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poor supraduction bilaterally with some beats of convergenceretraction nystagmus. He also had synchronous downbeating nys-tagmus in primary gaze, a combined downbeating and clockwiserotary nystagmus in left gaze, and a left-beating nystagmus in rightgaze.

On external examination, he had enophthalmos with exophthal-mometry measurements of 12 mm bilaterally. Loss of appositionbetween the globe and the eyelids was seen at the medial andlateral canthal angles. There was mild exposure with conjunctivalinjection, but no fluorescein staining of the corneas. Fundus ex-amination revealed a normal optic nerve, macula, and periphery in

Figure 6. Patient 3. A, Axial computed tomography (CT) scan showsbilateral enophthalmos with both globes posterior to the anterior bound-ary of the orbits. Sagittal (B) and axial (C) CT scans localize the variousabnormal air spaces, deepened upper and lower eyelid sulci pulled into theexpanded orbits (white arrows), expanded superior fornices (single whiteasterisks), abnormally large and aerated sinuses (double white asterisks), andlarge pneumatized anterior clinoid processes (black arrow). The images arealso oriented to show the entire orbital and part of the intracanalicularsegment of the optic nerves to show the lack of redundant optic nervelength.

each eye. r

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The only available imaging studies were a maxillofacial CTcan done at the time of the accident, a brain CT scan at 1 monthhowing the development of ventriculomegaly, and a brain CT atmonths after the accident showing the VPS and reduced ventricle

ize. Volumetric orbital analysis could not be performed becausehe brain scans did not include the entire orbits. There was neitherir in the superior orbit nor radiographic evidence of enophthalmosn the head CT 1 month after VPS. No orbital or brain imagingas performed after enophthalmos was detected. The patient diedyears after his initial evaluation from positional asphyxia. Shunt

evision had not been performed.Patient 3 is a 38-year-old woman who was referred for evalu-

tion and management of progressive bilateral exposure keratopa-hy in 2006. She had a ruptured left basilar artery aneurysm in991 and underwent VPS for ventriculomegaly. Although notertain of the exact onset, her mother reported subsequent progres-ive sinking in of the patient’s eyes (Fig 5A, B). She had under-one small bilateral permanent lateral tarsorrhaphies in the past butad begun to show recurrent signs of exposure. Persistent neuro-ogic deficits included an expressive aphasia, ataxia, and a seizureisorder well controlled with carbamazepine.

On ophthalmic examination, the visual acuity was 20/50 ODnd 20/200 OS. The pupils were symmetric and reactive with nofferent pupillary defect. Her visual fields were full to confronta-ion. She had a small exotropia in primary gaze, and her ocularotility was limited in all directions, vertically more than hori-

ontally. Supra- and infraduction were approximately decreased to5% of normal, and horizontal ductions were decreased to 50% oformal in both directions.

Her external examination (Fig 5B) showed severe enophthal-os with exophthalmometry measurements of 6 mm OU. The

nophthalmos was so dramatic that there was no contact betweenhe ocular surface and the lower eyelid margins across their entireength, and the upper eyelids wrapped around the superior orbitalim into the intraorbital space (Fig 6B). Severe ocular exposuread resulted in bilateral corneal scarring and vascularization, asell as significant conjunctival injection. The posterior segment

xamination showed a normal optic nerve, macula, and peripheryn each eye.

Orbital CT scan showed extreme enophthalmos (Fig 6A) andhort, straight optic nerves (Fig 6B, C) with an intraorbital lengthf 19 mm bilaterally. Again, the bony orbits were expanded, andhe sinuses also were abnormally large. Before recognizing thessociation with VPS, surgical exploration with biopsies of theeriorbita and orbital fat was performed to investigate possibleeoplastic and inflammatory processes. Not surprisingly, in retro-pect, no histologic abnormality was seen. In particular, the orbitalat cells were normal in size and morphology and had no evidencef inflammation or atrophy. The patient declined shunt revision.he exposure keratopathy resolved with larger permanent lateral

arsorrhaphies, fusing 25% of the eyelid margin.Patient 4 is a 16-year-old male who presented in May 2010 for

valuation of progressive bilateral enophthalmos. His medicalistory included an in utero right hemispheric stroke resulting in aeft hemiplegia. In July 2005, he underwent clipping of 2 intracra-ial aneurysms, complicated by intracranial hemorrhage and ele-ated ICP, necessitating VPS placement. Visual acuity was 20/25nd 20/20 in the right and left eyes, respectively. An incompleteeft homonymous hemianopia was found on confrontation visualeld testing. He had full extraocular motility and was orthophoric

n all fields of gaze. He was markedly enophthalmic with loss ofontact between the globes and eyelids medially (Fig 7A). Exoph-halmometry measurements were 10 and 9 in the right and leftyes, respectively. Magnetic resonance imaging showed charac-eristic findings of intracranial hypotension (Fig 7B). The ICP

anged between negative 200 and 0 mm H2O while monitored with

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a ventricular drain over the course of 3 days. The existing VPS wasreplaced with a pressure-controlled model. Some “filling in” of theorbits was observed within 1 day of ICP normalization. Long-termfollow-up is not yet available.

Volumetric Analysis

The coronal CT scans of the enophthalmic orbits in patients 1 and3 (Fig 8A, B) show a vaulting of the orbital roof with associatedexpansion of the total orbital volume. To test the hypothesis oforbital expansion, we calculated the orbital volumes of 10 controlpatients as described in the “Materials and Methods” for compar-

Figure 7. Patient 4. A, Three-year post-shunt external photographs demeyelids causing corneal scarring and conjunctival injection from exposuflattening of the pons against the clivus (open black arrow), reduction of thof the dura with gadolinium-enhancement (thin white arrow) indicative o

Figure 8. Coronal computed tomography images from enophthalmic pa-tient 1 (A) and patient 3 (B) reveal the abnormal upward expansion and

oconcave configuration of the orbital roof.

son with 2 enophthalmic patients. In addition, we compare there-shunt and post-shunt volumes of patient 1, directly showing anncrease after VPS.

Table 1 summarizes the results comparing the right and leftrbits of the control group and the 2 study patients (numbers 1 and) who had CT scans available documenting their enophthalmos.ean right orbital volume of the control group was 24.6�3.3 cm3.

otal volume of the right orbits in the study patients was 32.6 cm3

patient 1) and 32.1 cm3 (patient 3). These volumes are �2tandard deviations above the mean of the control group. Theifference was statistically significant by the Wilcoxon rank-sumest (P � 0.03). The mean left orbital volume of the control groupas 23.9�2.7 cm3. The left orbital volumes of the patients were5.9 cm3 (patient 1) and 32.6 cm3 (patient 3). Again, there was atatistically significant difference (P � 0.03, Wilcoxon rank-sumest).

The pre-shunt total orbital volumes of patient 1 were 28.5 cm3

right) and 29.3 cm3 (left), which was not statistically differentrom the controls. The post-shunt volumes increased by 4.1 cm3

14%) on the right and 6.6 cm3 (23%) on the left.The other notable feature was the presence of air within the

rbital boundary. The air was not post-septal, but rather, wasocated mostly in the expanded conjunctival fornices and partiallyn the deep eyelid sulci caused by the severe globe retraction (FigB, C). None of the control patients had any air within their orbits,hereas the enophthalmic patients had 1 and 3.5 cm3 on the right

nd 4.7 and 3.4 cm3 on the left.No significant difference was seen between fat volumes in the

ight orbits of the control group (7.9�3.1 cm3) compared with thetudy patients (7.9 and 9.8 cm3) (P � 0.75, Wilcoxon rank-sumest). Similar results were found for the left orbits (control 7.9�3.1m3 vs. study patients 9.2 and 10 cm3, P � 0.60 Wilcoxonank-sum test). However, there was a trend for more total softissue within the orbits of the enophthalmic patients. Because theontrol group did not have any orbital air, the soft tissue volume ishe same as the total volume (i.e., 24.6�3.3 [right] and 23.9�2.7 cm3

left]). The enophthalmic patients had soft tissue volumes of 31.6 and8.6 cm3 on the right (P � 0.12, Wilcoxon rank-sum test) and 31.2nd 29.2 cm3 on the left (P � 0.06, Wilcoxon rank-sum test).

The increase in total soft tissue and air volumes in the enoph-halmic patients was due to the increase in the total volume of theony orbit. The extra space was partially taken up by a volume ofoft tissue (e.g., eyelids and globe), which would normally lie

te the severe enophthalmos with a large gap between the globe and theratopathy. B, Sagittal magnetic resonance imaging scan demonstratesrpeduncular and pre-pontine cisterns (open white arrows), and thickeningcranial hypotension.

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posteriorly into the orbital space as the enophthalmos develops.The remaining volume was taken up by air spaces within theorbital boundary that reside in the expanded conjunctival fornicesand the deepened eyelid sulci created by the enophthalmos (Fig6B, C).

Additional volumetric analysis was performed to compare theCT scans of patient 1 before and after shunt revision. The totalpostoperative orbital volumes (33.5 and 36.6 cm3, right and leftrespectively) were similar to the preoperative measurements (32.6and 35.9 cm3, right and left respectively). The slight differencelikely represents variations in measurements.

Discussion

Shunting of CSF is a well-established surgical approach fortreatment of increased ICP. Over-shunting is a known com-plication of this procedure. In pediatric patients when theskull is still developing, over-shunting inhibits normal ex-pansion of the cranial vault and can lead to premature suturefusion and secondary craniosynostoses.35,36 In contrast, ourdata support the hypothesis that over-shunting and intracra-nial hypotension in adult patients can present with a differ-ent type of bony change: intracranial hypotension–relatedskull remodeling with expansion of the orbits, sinuses, andmastoid air cells. This is to such a dramatic degree that evenaeration of the clinoid processes was seen. In previousreports, bilateral enophthalmos was associated with pediat-ric shunting for congenital or childhood hydrocephalus.25–27

Our cases show that CSF shunts placed during adulthood foracquired ventriculomegaly can cause remodeling of fullymature orbital bone. In patients 1 and 4, our findingsstrongly support the hypothesis that intracranial hypoten-sion from over-shunting is likely the cause for this change.We propose the term sunken eyes, sagging brain syndrometo describe the enophthalmos seen with intracranialhypotension–related skull remodeling.

Previously suggested mechanisms for enophthalmos af-ter VPS include fat atrophy25 and orbital bony expan-sion.26,27 Our findings are sufficient to exclude fat atrophyas a contributing factor. When the volume of orbital fat wascalculated in enophthalmic patients, no significant differ-ence was seen compared with a control group. In addition,a biopsy of the orbital fat was performed on 1 patient before

Table 1. Orbital

Total Volume (cm3)So

OD OS O

Control group 24.6�3.3 23.9�2.7 24.Patient 1 (pre-shunt) 28.5 29.3 2Patient 1 (post-shunt) 32.6* 35.9* 3Patient 3 32.1* 32.6* 2

OD � oculus dexter; OS � oculus sinister.*P � 0.05.†Unable to change window level on scan to differentiatavailable only in a hard copy.

the diagnosis was established. Histologically, the adipose r

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ells were normal in size and structure, and there was novidence of inflammation, fibrosis, or atrophy. Orbital bi-psy is not necessary when the history and radiologic find-ngs are consistent with sunken eyes, sagging brainyndrome.

Volumetric analysis of our patients supports the theoryf orbital expansion. Our study is the first to compareirectly the orbital volumes in an enophthalmic patientefore and after VPS. Measurement of the bony orbitalpace confirmed that the orbital volumes in the study pa-ients were greater than the control average by �30%. Theeasured mean volume of our control patients (24.3 cm3) is

imilar to previously published data, which range from 17.8o 28.4 cm3,37–41 supporting the accuracy of the techniquessed in this study.

The orbital volume expansion stems mostly from upwardaulting of the roof the orbit, which is apparent on CT.here may also be more subtle remodeling of the medialnd inferior orbital walls. We postulate that this syndromeesults from chronic intracranial hypotension, which wasonfirmed directly in patients 1 and 4. It represents a rarexample of skull bone remodeling resulting from an alteredressure gradient across the orbital walls.

The maintenance of bone involves a dynamic processediated by continual absorption by osteoclasts and cre-

tion of new bone by osteoblasts. The balance of bonebsorption and formation is mediated in part by mechanicaltress on the bone regulated by strain-sensitive cells, whichre thought to be osteocytes. Although this process is morective during childhood, even mature bone has the potentialf remodeling. For example, under circumstances of disuser zero-gravity, long bones will resorb because of the lackf mechanical loading required to maintain the bone.42 Inddition, previous work has shown that during prolongeded rest, the skull will increase in mass, which is believed toesult from a net bone formation from the increased ICProm a chronic caudal shift in fluid.43 We propose that thepposite process occurs in our enophthalmic patients. Es-entially, with chronic intracranial hypotension, the pressureradient across the bone of the orbital roof is altered fromecreased force from the intracranial side. This effect wouldheoretically cause not only a net resorption of bone becausef decreased stress but also an effective intracranially di-

metric Analysis

sue Volumecm3) Fat Volume (cm3) Air (cm3)

OS OD OS OD OS

23.9�2.7 7.94�3.1 7.88�3.1 0 028.1 † † 0 031.2 7.9 9.2 1.0 4.729.2 9.8 10 3.5 3.4

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process occurs progressively over months but, as demon-strated by patient 2, can be clinically apparent in as little as18 months after shunt placement.

Comparison can be made with the “silent sinus syn-drome.” In this entity, downward bowing of the orbital floorinto an imploding maxillary sinus results in enophthalmos.Previous reports on “silent sinus syndrome” identified analtered pressure gradient across the bone of the orbital floorfrom a decrease in the intramaxillary sinus pressure,44 justas described previously for the orbital roof from a decreasein ICP in our patients. In addition, demineralization of theorbital floor consistent with bony remodeling has beenidentified in “silent sinus syndrome.”45 This is consistentwith our proposed mechanism for enophthalmos resultingfrom intracranial hypotension–related skull remodeling.

Although intracranial hypotension–related skull remod-eling seems to be the major contributor to enophthalmos,other factors also contribute as illustrated by patients 1 and4. In patient 1, ICP was extremely low at 20 mm H2O. Aftercorrection of intracranial hypotension, a small but rapidimprovement in enophthalmos was seen within 48 hours.This was also observed in patient 4, in whom negative ICPwas measured, and again partial improvement was seenwithin days of ICP normalization. It seems improbable thata change in the orbital wall could occur this quickly. Thissuggests that additional factors, other than bone remodeling,are involved. First, forward movement of the globe aftershunt revision may result from increased hydraulic forcegenerated by the increased CSF pressure in the subarach-noid space of the optic nerve just as increased pressures canflatten the globe in cases of intracranial hypertension.46–49

Second, an increase in ICP causes an elevation in venouspressure within the cavernous sinus and thus the orbitalvenous pressure, which would cause orbital soft tissue ex-pansion just as pressure from a carotid-cavernous fistula cancause proptosis.50,51 Finally, the cuff of CSF around theoptic nerve would also expand with normalization of theICP. It has been shown that an increase in optic nervediameter of up to 1 mm is seen with elevation in ICP.52 Byassuming a cylindrical optic nerve with a diameter of 5 mmand an intraorbital optic nerve length of 25 mm,27 the addedvolume would be on the order of 0.86 cm3.

A notable finding in the enophthalmic patients is shortstraight optic nerves. This was seen in our cases withimaging (Fig 2C and Fig 6B, C). On review of the orbitalimaging shown in the figures by Meyer at al25 and Bernar-dini et al,27 at least 1 in each series had a short taut opticnerve. This gives the impression that the nerves might bepulling on globes, causing posterior displacement. Our find-ings suggest that this is occurring secondarily to the devel-opment of enophthalmos, as opposed to being causative.Perhaps the combination of chronic enophthalmos and ab-normally low pressure within the subarachnoid space of theoptic nerves allows this configuration to develop. Admit-tedly, this is speculative, and further study is needed todetermine the true significance of this finding.

Several other findings are worthy of mention. First, 3 ofthe patients had significant ocular motility problems, inparticular a marked reduction in supraduction. Potential

causes could be a mechanical abnormality stemming from t

lobe/muscle malposition versus neurologic from cranialerve or brainstem pathology. Because each patient had aignificant intracranial injury, and there is no documentationf the eye movements in the immediate period afterward, its unclear if the abnormalities were present because of thecute event or developed later as part of this syndrome.econd, in addition to the orbits being expanded, the frontal,phenoid, ethmoid, and maxillary sinuses also seemed en-arged, especially in patient 3, who also had pneumatizedlinoid processes (Fig 6A, B). This finding suggests thathere could be expansion of all the pericranial spaces. Fi-ally, in patient 1, bilateral optic nerve atrophy was noted,nd in 1 patient in the series by Meyer et al,25 progressiveision loss and optic atrophy to the point of no light per-eption in 1 eye were documented, suggesting that opticerve and chiasm damage occur within the spectrum ofndings in sunken eyes, sagging brain syndrome. This neu-opathy may be the result of intracranial hypotension34

ausing stretch injury from displacement of the chiasm.Several management options are available. If present,

orrection of cerebral hypotension should be considered.his will likely halt progression, and may result in an

mmediate partial improvement, as seen in patients 1 and 4.hether resolution of the intracranial hypotension will re-

ult in correction of the bony expansion remains unknownut may be revealed with longer-term follow-up. Surgicalugmentation is another reasonable option. Although noterformed in any of our patients, surgical augmentation haseen reported in the literature. Orbital floor implants werelaced in 1 of the patients included in the original series byeyer et al.25 This procedure resulted in partial correction

f the enophthalmos but also with unwanted superior dis-lacement of the globe. However, as described by Cruz etl26 and Bernardini et al,27 favorable results were achievedhen the implant was placed in the orbital roof. Given that

he abnormality lies in the roof and not the floor of the orbit,ne might expect better results with augmentation of theuperior orbit. Patient 3 of this series declined shunt revisionnd placement of an orbital implant. However, satisfactoryymptomatic relief of exposure-related symptoms waschieved with simple tarsorrhaphy. Of course, some patientsould consider this procedure cosmetically inferior to shunt

evision and orbital volume augmentation.This study is limited by its small size. Despite this,

onsistent findings in all patients and the significanteasured differences from a normal control group help to

ubstantiate our findings. Also, the control group waselected from patients aged 18 to 45 years, which over-aps but is not identical to our study subjects. Age-relatedhanges in skull anatomy might contribute in part toifferences seen between our study subjects and the con-rol group. However, our patients were of a wide ageange (16 –38 years), making age-related changes un-ikely to be a major contributor.

The sunken eyes, sagging brain syndrome develops pri-arily as the result of intracranial hypotension–related skull

emodeling. The prevalence of this disorder is unknown, butith increasing recognition, the number of reports will

ikely increase. Other causes of low CSF pressure could also

heoretically cause this syndrome, including over-shunting

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from lumboperitoneal shunting, a ruptured Tarlov’s cyst, oridiopathic spontaneous low ICP. Our data confirm that theprimary mechanism underlying this syndrome is bony ex-pansion from superior vaulting of the orbital roof likely dueto an abnormal pressure gradient across the bone because oflow ICP. Decreased orbital blood or CSF volume maycontribute to a lesser degree. To manage a patient post-VPSwith enophthalmos, consider the following options: (1) anMRI to screen for any inflammatory or neoplastic orbitalpathology and to check for any radiographic signs of intra-cranial hypotension and large orbital cavities, (2) a proce-dure to confirm low CSF pressure, (3) an assessment ofcontinued shunt dependence, and (4) either removal of theshunt if not shunt dependent or a revision with a valve-controlled shunt if still shunt dependent. Correction ofthe intracranial hypotension may result in partial imme-diate improvement and will presumably prevent furtherprogression. Other management options include surgicalaugmentation of the orbital volume and tarsorrhaphy.

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Footnotes and Financial Disclosures

Francisco, California.

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Originally received: March 9, 2010.Final revision: April 17, 2011.Accepted: April 26, 2011.Available online: July 23, 2011. Manuscript no. 2010-354.1 Department of Ophthalmology, The Permanente Medical Group, KaiserPermanente, Redwood City, California.2 Department of Ophthalmology, University of California San Francisco,San Francisco, California.3 Department of Neurological Surgery, University of California San Fran-cisco, San Francisco, California.4 Department of Neurology, University of California San Francisco, San

Department of Physiology, University of California San Francisco, Sanrancisco, California.

The Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore,aryland.

King Khaled Eye Specialist Hospital, Rihadh, Saudi Arabia.

inancial Disclosure(s):he author(s) have no proprietary or commercial interest in any materialsiscussed in this article.

orrespondence:imothy J. McCulley, MD, Department of Ophthalmology, The Wilmerye Institute, Johns Hopkins School of Medicine, 600 North Wolfe St.,

ilmer 110, Baltimore, MD 21287. E-mail: tmccull5@jhmi.edu.

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