A Natural History of Silent Brain Syndrome over 36 Years: A case report

Abstract

A 34-year old Caucasian male who underwent a ventricular shunt at age 21 presented with bilateral enophthalmos, poor eyelid-globe apposition and exposure keratopathy characteristic of silent brain syndrome. Progressive enophthalmos and corneal decompensation was documented in serial photographs and radiographic studies over 36 years. Over this period no sequelae of shunt over-drainage were observed. A lumbar puncture at last follow-up measured CSF opening pressure to be within normal range. Additional systemic findings included pneumosinus dilatans, loss of adipose tissue in the temporalis fossa and atrophy of the dorsal interossei of the hand. Surgical interventions to preserve ocular function included insertion of orbital floor wedge and sheet implants, sheet orbital roof implants, and retroplacement of canthal tendons. This report chronicles the long-term clinical course of a patient with silent brain syndrome. The systemic changes suggest factors beyond low intracranial pressure may contribute to the pathogenesis of the condition in our patient.

The causes of enophthalmos can be divided into three broad categories as proposed by Cline and Rootman: bony structural abnormality, fat atrophy or fibrosis.¹ While an association between cerebral shunting and enophthalmos has been reported since 1996, gaining the designation “silent brain syndrome,” its pathophysiology remains elusive.^{2, 3} As described, the syndrome is characterized by poor eyelid-globe apposition and superior bowing of the orbital roof. Bony changes are the predominant feature⁴ but may also be accompanied by loss of orbital fat.² In this report we present a case of silent brain syndrome that was followed for over thirty years undergoing multiple surgical procedures to correct the progressive enophthalmos and restore apposition of the eyelids to the corneal surface.

All medical records of a patient presenting with bilateral enophthalmos occurring in the setting of cerebral shunting were reviewed. All reported laboratory testing was performed at Labcorp and Quest Diagnostics. The patient was treated between January 1984 and October 2020. No data was analyzed to develop generalized knowledge. The authors have received a written exemption of IRB review from the University of Miami Institutional Review Board. Published case reports of “silent brain syndrome” and “sunken eyes, sunken brain syndrome” were summarized. A written informed consent for all medical photography was obtained from the patient after full explanation of the article. The report adhered to the tenets of the Declaration of Helsinki as amended in 2013 and complied with the Health Insurance Portability and Accountability Act (HIPAA).

Case Presentation

A 34-year-old Caucasian male presented to the Cornea Service in 1984 for evaluation of recurrent corneal ulcers of the right eye occurring over 3 years. At age 21, a benign cyst of the cerebellum causing hydrocephalus was surgically resected with concurrent placement of a ventricular-atrial shunt. He had no known complications from the surgery but reported a 20 lb. weight loss in the months immediately following the procedure. He otherwise had an unremarkable medical history. The patient had no history of orbital trauma or chronic sinusitis. Examination in 1984 documented a well-developed but thin-appearing man (height: 5 ft 9 in, weight: 138 lb., BMI: 20.4) with severe bilateral enophthalmos and a small angle exotropia (Figure 1A–B). There was notably poor apposition between the upper eyelids and globes. Best-corrected visual acuity was 20/50 OD and 20/20 OS. The patient reported no diplopia. Ocular motility was full. Slit-lamp examination revealed in the right eye a superior corneal pannus, superficial keratopathy and diffuse corneal haze. A mild superficial keratopathy was present in the left eye. An orbital CT scan disclosed marked enophthalmos in both eyes with apparent loss of extraconal orbital fat and deep superior sulcus with a large pocket of air noted between the eyelids and globes (Figure 1C–D). There was no upward bowing of the orbital roof at initial presentation.

Figure 1.

External photographs of the patient on initial presentation demonstrating (A) marked enophthalmos and a small angle exotropia, (B) severe superior sulcus deepening, and lid-globe separation OU (arrows). Computed tomography showing (C) both globes separated from eyelids (arrows) and (D) a large air pocket outlining the cavernous superior forniceal space without discernable vaulting of the orbital roof (arrowheads). Note the location of the shunt in the lateral ventricle (asterisk).

Given the prior medical history and unusual constellation of clinical findings, the patient was referred to neurosurgery and endocrinology for evaluation. The consulting neurosurgeon found no indication of shunt failure or over-drainage based on clinical exam and therefore did not recommend shunt revision or removal. A review of the patient’s neurosurgical records revealed that one year after shunt placement the patient had undergone a pneumoencephalogram to determine shunt patency and identify any obstructions in the ventricular system. No abnormalities were noted in this report. An endocrinological evaluation, which included an assessment of adrenocortical, thyroid and insulin function, was normal except for a low leptin hormone level (0.6 ng/mL, reference: 1.2–9.5 ng/mL BMI-adjusted). On physical exam, he was noted to have significant loss of subcutaneous adipose tissue on the face and neck, temporalis fossa, and moderately diminished fat on the chest, abdomen and extremities. Atrophy of the dorsal interossei of the hand was a prominent feature (Figure 2A). The consulting endocrinologist described the patient’s appearance as “gaunt” owing to the sunken cheeks and hollowed temples, in addition to the enophthalmos. The patient was started on pioglitazone, a diabetes drug aimed to promote subcutaneous fat deposition by restoring the body’s proper response to insulin. The treatment had no beneficial effect and was discontinued. No further systemic workups or treatments were recommended.

Figure 2.

(A) External photograph of the right hand demonstrating atrophy in the first dorsal interosseous space (arrowhead). (B) A customized silicone orbital floor wedge implant was inserted under the right eye through an inferior fornix incision along with right medial canthal tendon retroplacement. Note the improved contact between the eyelid and globe. The left side has not had the floor augmentation. Note the lid-globe disparity (arrow). The same procedure was repeated on the left side a few months later.

To address eyelid-globe disparity of the right eye, the patient underwent placement of a silicone wedge orbital floor implant with concurrent retroplacement of the medial canthal tendon anchored to a titanium T-plate in 1987 (Figure 2B). The improved corneal lubrication prompted the implementation of the same procedures for the left eye a few months later. Over the ensuing 22 years, the patient continued to develop a slow progressive worsening of enophthalmos with recurrence of poor eyelid-globe apposition. The patient was reluctant to pursue additional surgical intervention, but opted for medical management that included moisture chambers and lubrication with viscoelastics. The medical therapy was inadequate to manage the worsening exposure keratopathy due to lack of lid-cornea contact and suboptimal dynamic eyelid blinking to lubricate the corneal surface (Figure 3A–B). To address the physical gap between the eyelid and cornea, a second orbital floor implant (Medpor) to augment the wedge implant along with retroplacement of the lateral canthal tendon with a titanium T plate were performed in 2009. The combination of additional volume augmentation to displace the globe forward and retroplacement of the lateral canthal tendon restored the eyelid-globe apposition and improved corneal surface lubrication (Figure 3C–D). A CT scan confirmed the globes were displaced forward and there was significant reduction in the air pocket in the superior fornices (Figure 4).

Figure 3.

Slit lamp photographs from 2009 of the right (A) and left eye (B) demonstrating poor eyelid-globe apposition, irregular corneal epithelium, haze and pannus 22 years after the first surgical interventions to correct enophthalmos. (C) External photographs of the patient after floor augmentation with silastic sheet implant and retroplacement of the lateral canthal tendon demonstrating resolution of conjunctival injection and improvement in corneal clarity. (D) Restored lid-globe apposition OU (arrows).

Figure 4.

(A) Computed tomography showing both globes displaced forward to establish eyelid contact and collapse of the air pocket. (B) Reduction of air pocket in superior forniceal space (arrowheads). Note the bilateral floor implants displacing the globes upward to reduce superior sulcus deepening (arrows).

Following these surgeries, his eyes were no longer red and painful, and visual acuity improved. The patient was not seen again in our clinic until 10 years later in 2019 when he presented with onset of ocular pain, copious mucoid discharge, and progression of the enophthalmos causing recurrent lid-globe disparity (Figure 5). Visual acuity had deteriorated to 20/100 OD and 20/400 OS from worsening corneal surface desiccation. There was noticeable collection of thick mucus in the cavernous superior fornix. A repeat CT scan in 2019 revealed extensive remodeling of the frontal bone that included a marked increase in upward bowing of the orbital roof seen across multiple coronal slices as well as hyperaeration of the frontal sinuses (Figure 6A–C). There were no other changes to the orbital dimensions, and no neuroimaging findings on CT or MRI to suggest shunt malfunction (Supplemental Figure). The patient was referred to a new neurosurgeon for further evaluation, and this consulting provider again advised against shunt removal. However, given the progressive bony expansion of the orbit and prior reports attributing similar changes to low intracranial pressure, a diagnostic lumbar puncture was performed. The opening CSF pressure was found to be 110 mmH₂O (normal range: 82–242 mmH₂O).⁵ An analysis of the CSF revealed a glucose of 54 mg/dL (40–75 mg/dL), a total protein of 134 mg/dL (15–45 mg/dL), leptin of 0.3 ng/mL (0.05–0.4 ng/mL)⁶ and somatostatin of 66 pg/mL (55–76 pg/mL).⁷

Figure 5.

External photographs of the patient 35 years after his initial presentation demonstrating severe bilateral enophthalmos, deepening of the superior sulcus and loss of subcutaneous fat. Note the contrast with Figure 1A.

Figure 6.

(A) Computed tomography of the orbits 35 years after his initial presentation demonstrating an increase in air spaces in the superior orbit and a vaulted appearance of the orbital roof, (B) poor eyelid-globe apposition, and (C) hyperaeration of the frontal sinus. The asterisk identifies the area of pneumosinus dilatans. (D) The patient 6 months following placement of an orbital roof implant on the left and 3 months following orbital roof implant on the right. Note the apposition of the lid and cornea (arrows).

To address the ocular symptoms and recrudescence of the lid-globe disparity problem, the patient underwent additional orbital volume augmentation with placement of a Medpor barrier implant under the orbital roof through a sub-brow incision. The superior orbital volume augmentation procedure improved corneal lubrication by displacing the globe and orbital contents forward to restore eyelid-globe contact, and simultaneously reduced the mucus accumulation by collapsing the giant superior fornix. At last follow up the patient was noted to have normalization of eyelid-globe contact, total resolution of ocular irritation symptoms, absence of mucus accumulation and improved visual acuity (Figure 6D).

Discussion

Fourteen cases of bilateral enophthalmos presenting in the context of cerebral shunting have been reported in the literature (Table 1). In 1996, Meyer described three patients with congenital hydrocephalus who underwent ventricular shunt placement.² (The patient described herein was also known to those authors through personal communication and referenced in the article as a fourth similar case.) Bernardini later coined the term “silent brain syndrome” to describe the insidious progression of bony changes analogous to the more commonly described silent sinus syndrome.³ Across all published studies, the average age of shunting was 12 years and ranged from infancy to age 25.^{2–4, 8–12} There was a slight male predominance with a male-to-female ratio of 3:2. The most common indication for shunting was congenital hydrocephalus followed by elevated intracranial pressure (ICP) secondary to tumor and trauma. The average age at presentation was 26 and ranged from 16 to 37. Patients presented with ocular symptoms that varied from ocular irritation to diplopia and corneal ulcers. All articles reported visual acuity, ocular findings, characteristic facial features and radiographic imaging. Only two articles commented on body weight, body habitus or facial atrophy, and in the five cases described, the physical exam was noted to be grossly normal.^{2, 3}

Table 1.

Demographics and clinical history of reported patients with silent brain syndrome.

Author	Year	No. Cases	Age at Shunt Placement	Age at First Ocular Symptom	Sex	Indication
Meyer	1996	3	8	32	F	congenital hydrocephalus
			5mo	24	M	congenital hydrocephalus
			14	37	M	congenital hydrocephalus
Cruz	2008	1	13	22	F	anterior cranial fossa arachnoid cyst
Bernadini	2009	2	14	22	F	congenital hydrocephalus
			12	21	M	third ventricle tumor
Hwang	2011	4	21	25	M	trauma
			18	19	M	trauma
			22	38	F	ruptured aneurysm
			12	16	M	ruptured aneurysm
Chen	2012	1	infant	31	M	encephalocele
McCulley	2013	1	25	26	F	pituitary tumor
Yoon	2013	1	9	29	M	trauma
Pargament	2017	1	infant	21	F	congenital hydrocephalus
Pirakitikulr	2020	1	21	31	M	cerebellar cyst

There are gaps in the current understanding of the pathophysiology of silent brain syndrome. The prevailing hypothesis is that CSF shunting can lead to intracranial hypotension that induces compensatory bony remodeling of the skull base akin to what is seen in silent sinus syndrome. Cruz was the first to document radiographically that the clinically observed enophthalmos is primarily the result of bony expansion of the orbital roof.⁴ Subsequently, Bernardini proposed that low ICP allows the skull base to undergo centrifugal convex deformation of the thin frontal bone that forms the orbital roof.³ Even under physiologic conditions, it has been shown that ICP can intermittently drop below atmospheric pressure (e.g. when moving from a sit to stand position) and that the manifested differential gradient is most pronounced in the anterior cranial fossa above the orbit.^{13, 14}

Hwang provided evidence in support of the ICP hypothesis in describing two patients with markedly low pressures (0–20 mmH₂O, reference: 100–200 mmH₂O) and severe enophthalmos on presentation, reporting that after placement of programmable shunts calibrated to normal physiologic ICP,⁹ a 3 mm reversal in enophthalmos was documented. Notably, the reversal in enophthalmos was seen as early as 48 hours after shunt revision, suggesting that contracted orbital soft tissue volume can rapidly be normalized with restoration of physiologic ICP. The authors postulated that this normalization is theoretically possible because of direct CSF communication from the intracranial compartment to the orbit via the optic canal, which allows the optic nerve sheath and retroorbital space to expand or contract in response to ICP.^{15, 16} We infer based on this argument that bony changes would follow the changes to soft tissue volume.

The degree or duration of intracranial hypotension necessary to manifest in physical findings seen in silent brain syndrome is not known and may vary widely. At least one study has shown that the orbital volume expands after shunting even when ICP is maintained between 60 and 100 mmH₂O.¹⁷ In our patient, there was no indication that ICP was profoundly reduced for a sustained period of time. A recent measurement of ICP by lumbar puncture was well within accepted normal ranges given the patient’s age and BMI, and notably above the 100 mmH₂O threshold.^{5, 18} Throughout the over thirty years of follow-up care the patient never reported postural headaches, nausea or vomiting. Neuroimaging did not demonstrate slit ventricles, brainstem slumping or tonsillar herniation to suggest chronic low ICP. We consulted several independent neurosurgeons at different institutions from the years 1984 to 2020; each advised against shunt removal or revision.

In the majority of reported cases of silent brain syndrome, patients underwent CSF shunting prior to adolescence. It is known that cranial bone growth in childhood depends on ICP, thus it is understandable that immature bone can be adversely affected by a sudden drop in ICP particularly across the malleable orbital roof bone.¹⁹ However, similar clinical findings have been reported in patients who, like our patient, underwent CSF shunt procedures in adulthood.^{9, 10} Our patient had the intracranial procedure performed at age 21, presumably an age at which his bony skull development had reached maturity. His age of onset, evident body fat atrophy, coupled with the progressive orbital bony changes into his 60’s, raised the possibility that other factors besides ICP may be at play. We therefore explored the possibility of neuroendocrine dysfunction in our patient noting his history of unintended weight loss and clinically apparent low body fat. We initially hypothesized that either removal of the cerebellar cyst or shunt placement had disrupted the hypothalamic-pituitary-adrenal (HPA) axis. However, the endocrine workup identified no alterations in cortisol, thyroid or growth hormones, suggesting the HPA axis was grossly intact. The sole laboratory abnormality from this initial workup was a persistently low leptin level. Leptin is a hormone produced by adipocytes that signals the hypothalamus to regulate hunger, bone metabolism and energy balance.^{20, 21} Leptin level directly correlates with body fat and is therefore generally normalized to BMI.

Interestingly, we found the level of leptin in the CSF to be higher than expected given the patient’s BMI, and the CSF:serum leptin ratio (calculated using a serum leptin of 0.5 ng/mL obtained immediately prior to lumbar puncture) was nearly five-fold higher than normal.⁶ It is unclear why this occurs, but it is known that leptin regulates bone formation²² and may also impact CSF formation and absorption.²³ For instance in patients with idiopathic intracranial hypertension (IIH) leptin is generally markedly elevated and in many cases far exceeds the levels expected given their BMI.^{24, 25}

We therefore propose that shunt-associated changes to CSF dynamics drive hormonal fluctuations that affect skull rigidity, bony remodeling, and maintenance of body fat. Perhaps the shunt provides a physical conduit for the diffusion of small proteins from blood into the CSF. The elevated CSF protein and the deviations in serum and CSF leptin seen in our patient may be an indirect marker for this process.²⁶ Our hypothesis attempts to explain two key findings that the ICP hypothesis alone does not address: how dramatic changes to the cranium can develop and progress even in mature adults, and why weight loss and orbital fat loss were observed in our patient. Because no other case of silent brain syndrome with a complete endocrinology evaluation has been reported, it is hard to assess how applicable our observations are to the 14 other known cases. Indeed, there is already considerable heterogeneity in the patients described with this syndrome with those showing clear signs of intracranial hypotension and rapid reversal of enophthalmos representing only a subset.

Our hormone hypothesis also offers a plausible explanation for the observation that silent brain syndrome is only seen in a small subset of patients with ventricular shunts. Approximately 30,000 ventricular shunts are placed each year in the United States with the vast majority performed in patients under the age of 30.²⁷ Over-drainage is a recognized complication²⁸, serving as the primary indication for shunt revision in 3.4–16.7% of cases in a European study.²⁹ These statistics suggest that the incidence of silent brain syndrome should be higher if low ICP is sufficient to cause acquired enophthalmos. It is likely that other confounding factors, such as a hormonal predisposition, could be involved in the pathogenesis of this perplexing condition. The wide population variation and variation in how the body responds to leptin may help explain why only some patients develop silent sinus syndrome.^30–32

Concurrent with the orbital changes in our patient, progressive hyperaeration of the frontal sinuses was observed. This specific finding, termed pneumosinus dilatans, has not been previously associated with silent brain syndrome and was only detected in our patient because of the long follow-up period. In contrast to what we observe in our patient, pneumosinus dilatans generally does not cause bowing of the orbital roof, but can cause rather marked hyperaeration of the supraorbital frontal bone.^{33, 34} Pneumosinus dilatans has been described since 1898, but the cause remains unknown.³⁵ It can occur spontaneously, most commonly in men between the ages of 20 and 30. Rarely, it can be associated with other conditions such as meningiomas, arachnoid cysts or intracranial tumors.^{33, 36} Because of the age and sex distribution of affected patients and measured changes to osteogenic activity³⁷ it has been proposed that there is a hormonal trigger.^{37, 38} If true, this lends support to our hypothesis.

The principal goal in managing ophthalmic manifestations of silent brain syndrome is to address the anatomical sequelae of enophthalmos due to orbital bony volume expansion. The orbital volume disparity in this condition is the converse of Graves orbitopathy in which too much orbital tissue and not enough volume causes proptosis. In silent brain syndrome, analogous to silent sinus syndrome, the bony volume expansion due to bone deformation leads to shifting of the orbital soft tissue volume posteriorly to create enophthalmos. With the vertical plane of the eyelids remaining constant, progressive enophthalmos contributes to altered lid-globe apposition to affect the physiology of corneal lubrication. The surgical principle is to restore the lid-globe relationship to optimize corneal lubrication by either moving the eye forward to contact the eyelids or moving the eyelids backward to contact the eye. Numerous surgical procedures have been described in the literature. Notably, adequate correction and good cosmetic outcomes have been reported after orbital roof implants.^{3, 4, 11} This approach is anatomically sound as it narrows the space within the superior orbit where bowing of the orbital roof has created extra volume, thus addressing the volume disparity to improve hypoglobus and enophthalmos. This is the converse of Graves orbitopathy management – rather than expand orbital volume through bony decompression, we fill the orbital volume to displace the globe and orbital contents forward. In our patient, this was the third and final implant placed around each eye. When the patient first came to our attention, no other cases of silent brain syndrome had been described. We were uncertain whether a roof implant would be appropriate, and therefore proceeded with the more established floor implants to move the globe forward to reestablish eyelid-globe apposition. Although this surgical maneuver was effective in restoring and maintaining the lid-globe relationship in our patient for 14 years, it presents a theoretical risk of magnifying the forces responsible for expansive bowing of the orbital roof. The radiographic studies did not show the globes pushing on the orbital roof, but the patient did develop progressive enophthalmos likely from the natural course of his disease. To address this the medial and lateral canthal tendons were retroplaced with titanium T-plates serving as fixation anchors to establish contact with the cornea. The reported case of orbital roof implant placement for a patient with silent brain syndrome similarly had a floor implant initially for volume augmentation.³ Lateral tarsorrhaphies have also been described to achieve satisfactory results in patients unwilling to undergo orbital surgery.⁹

This is the first and only study to report on the long-term follow up of a patient with silent brain syndrome. Our patient was followed for over three decades. His clinical course was documented in serial photographs and radiographic studies of the orbit. Assessment of body habitus and endocrine function revealed new systemic features of this syndrome. Despite multiple surgical procedures aimed at augmenting orbital volume to reduce lid-globe disparity and alleviate the deleterious effects of severe enophthalmos, our patient continued to exhibit progressive upward bowing of the orbital roof, loss of orbital and subcutaneous adipose tissue, and corneal decompensation. With intracranial pressure remaining at near-physiologic levels over the last 36 years, additional factors must be playing a role in the progressive structural remodeling of the orbital roof, expansion of orbital volume, loss of body mass and depressed leptin levels observed in the patient. We posit that altered regulation of hormones including leptin that occur following CSF shunting may be contributory to the pathogenesis of this enigmatic condition, and that the high degree of population variation in leptin response provides plausible explanation for the rarity of this condition among patients with shunts.