Retinal and optic nerve head pathology in Susac's syndrome.

PURPOSE: This article describes the first retinal histopathologic findings in a patient with Susac's syndrome (SS). DESIGN: Observational case report. PARTICIPANT: A 51-year-old white woman diagnosed with SS. METHODS: Eyes from a 51-year-old white woman diagnosed with SS were obtained at autopsy. One retina was dissected and processed for adenosine diphosphatase (ADPase) flat embedding. Selected areas were processed further for transmission electron microscopy. MAIN OUTCOME MEASURES: Histopathologic examination using ADPase flat-embedding technique. RESULTS: There were vaso-occlusive changes in the retinal periphery resulting in small areas of capillary dropout. Cross-sections demonstrated serous filled spaces between the retinal blood vessels and the internal limiting membrane. Lumens adjacent to these spaces appeared compressed and sometimes closed, but without thrombosis. Decreased ADPase activity in some peripheral blood vessels suggested endothelial cell dysfunction and vaso-occlusion. In the optic nerve head, numerous corpora amylacea were observed in the vicinity of capillaries with thickened walls and narrow lumens. Transmission electron microscopy demonstrated thickened and amorphous vascular basal lamina and open endothelial cell junctions in some retinal blood vessels. CONCLUSIONS: The serous deposits with compression of retinal vessel lumens observed histologically probably represent the so-called string of pearls described clinically in SS. Chronic extension of these serous deposits along the vessel wall possibly are the cause of retinal arterial wall plaques as described by Gass and other investigators. In the optic nerve head, corpora amylacea are probably a result of microinfarcts resulting from optic nerve head capillary angiopathy. Accumulation of amorphous material in the basal lamina, loss of viable endothelial cells, and capillary dropout suggest that SS may be an endotheliopathy.

Endoscopic orbital roof fenestration as an alternative treatment option for idiopathic intracranial hypertension: a cadaveric anatomical study.

BACKGROUND: We investigated a new minimally invasive surgical technique for the treatment of idiopathic intracranial hypertension in a cadaveric model. This technique aims at establishing a communication between the intraorbital and intracranial compartments by creating a bone, dural, and periorbital window in the anterior cranial fossa. This procedure is predicated on intraorbital absorptive capability that has been demonstrated in animals and discussed in humans. METHODS: Three fresh cadaver heads were fixed in a head holder so as to mimic the hyperextended supine position. The procedure was conducted bilaterally in each specimen. Our technique is as follows: 1) An incision is made in the eyebrow medial to the supraorbital notch; 2) using an endoscope and a periosteal elevator, the intraorbital surface of the orbital roof is separated from the periorbita in an anteroposterior direction for a length of 1.5-2.5 cm; 3) a 1 cm of the exposed orbital roof is removed, and the dura and arachnoid are opened; and 4) slits are made in the exposed periorbita. RESULTS: We were able to create a communication between the intracranial and the intraorbital compartments in all specimens. CONCLUSION: Our technique is new and does not require any foreign body implantation. Its applicability in humans needs to be evaluated in a clinical context.

Susac's syndrome: 1975-2005 microangiopathy/autoimmune endotheliopathy.

Susac's syndrome (SS) consists of the clinical triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss. It is due to a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear (cochlea and semicircular canals). Women are more commonly affected than men (3:1); the age of onset ranges from 9 to 58 years; but young women between the ages of 20 and 40 are most vulnerable. The encephalopathy is almost always accompanied by headache which may be the presenting feature. Multifocal neurological signs and symptoms, psychiatric disturbances, cognitive changes, memory loss, and confusion may rapidly progress to dementia. The MRI shows a distinctive white matter disturbance that always affects the corpus callosum. The central callosal fibers are particularly vulnerable and central callosal holes develop as the active lesions resolve. Linear defects (spokes) and rather large round lesions (snowballs) sometime dominate the MRI findings, which include cortical, deep gray (70%) and leptomeningeal involvement (33%). Frequently, the lesions enhance and may be evident on diffusion weighted imaging (DWI). The BRAO are best evaluated with fluorescein angiography, which may show the pathognomonic multifocal fluorescence. Gass plaques are frequently present and reflect endothelial damage. Brain biopsy shows microinfarction to be the basic pathology, but more recent pathological studies have shown endothelial changes that are typical for an antiendothelial cell injury syndrome. Elevated levels of Factor VIII and von Willebrand Factor Antigen reflect the endothelial perturbation. Despite extensive evaluations, a procoagulant state has never been demonstrated. SS is an autoimmune endotheliopathy that requires treatment with immunosuppressants: steroids, cyclophosphamide, and intravenous immunoglobulin, usually in combination. Aspirin is a useful adjunct.

Vision loss after spine surgery: review of the literature and recommendations.

In recent studies spinal surgery has replaced cardiac surgery as a leading cause of postoperative vision loss (POVL). Estimates of the incidence of POVL after spinal surgery range from 0.028 to 0.2%, but with advances in complex spinal instrumentation and the rise in annual spinal operations, POVL may see an ominous increase in its incidence. Postoperative vision loss is an uncommon but devastating complication, with unknown origin and pathogenesis. The authors undertook a literature review and summarize the current understanding of its pathophysiology, highlight the limitations of existing knowledge, and recommend practical guidelines for avoiding this devastating outcome.

In vitro model of cerebrospinal fluid outflow through human arachnoid granulations.

PURPOSE: To describe and validate an in vitro model of the arachnoid granulation (AG) outflow pathway for cerebrospinal fluid (CSF), by using human AG cells grown on a filter membrane support and perfused in a modified Ussing chamber at pressures analogous to normal human intracranial pressures. METHODS: Human AG cells were grown, characterized, seeded onto filter membranes, and perfused in the physiologic (basal to apical, B-->A) or nonphysiologic (apical to basal, A-->B) directions. Cells were fixed under pressure after perfusion and prepared for electron microscopy (EM). RESULTS: The average cellular hydraulic conductivity in the B-->A direction (10 total) was 4.52 +/- 0.43 microL/min per mm Hg/cm(2) with an average transcellular pressure decrease of 3.13 +/- 0.09 mm Hg. The average cellular hydraulic conductivity in the A-->B direction (six total) was 0.29 +/- 0.16 microL/min per mm Hg/cm(2) with an average transcellular decrease in pressure of 3.33 +/- 0.16 mm Hg. Cells perfused nonphysiologically showed a large number of dead and dying cells. EM postperfusion analysis showed that AG cells were integrally attached to the underlying filter membrane. Large extracellular cisternal spaces were visible between overlapping AG cells and vacuoles within the cytoplasm. It is possible that these spaces within and between cells represent pathways for transcellular and paracellular transport of fluid. CONCLUSIONS: The results demonstrate that AG cells in vitro show a statistically significant greater flow rate and cellular hydraulic conductivity when perfused in the physiologic versus the nonphysiologic direction under normal intracranial pressures. These results suggest that this in vitro model of the AGs can accurately replicate the unidirectional flow of CSF in vivo.

Characterization of cytoskeletal and junctional proteins expressed by cells cultured from human arachnoid granulation tissue.

BACKGROUND: The arachnoid granulations (AGs) are projections of the arachnoid membrane into the dural venous sinuses. They function, along with the extracranial lymphatics, to circulate the cerebrospinal fluid (CSF) to the systemic venous circulation. Disruption of normal CSF dynamics may result in increased intracranial pressures causing many problems including headaches and visual loss, as in idiopathic intracranial hypertension and hydrocephalus. To study the role of AGs in CSF egress, we have grown cells from human AG tissue in vitro and have characterized their expression of those cytoskeletal and junctional proteins that may function in the regulation of CSF outflow. METHODS: Human AG tissue was obtained at autopsy, and explanted to cell culture dishes coated with fibronectin. Typically, cells migrated from the explanted tissue after 7-10 days in vitro. Second or third passage cells were seeded onto fibronectin-coated coverslips at confluent densities and grown to confluency for 7-10 days. Arachnoidal cells were tested using immunocytochemical methods for the expression of several common cytoskeletal and junctional proteins. Second and third passage cultures were also labeled with the common endothelial markers CD-31 or VE-cadherin (CD144) and their expression was quantified using flow cytometry analysis. RESULTS: Confluent cultures of arachnoidal cells expressed the intermediate filament protein vimentin. Cytokeratin intermediate filaments were expressed variably in a subpopulation of cells. The cultures also expressed the junctional proteins connexin43, desmoplakin 1 and 2, E-cadherin, and zonula occludens-1. Flow cytometry analysis indicated that second and third passage cultures failed to express the endothelial cell markers CD31 or VE-cadherin in significant quantities, thereby showing that these cultures did not consist of endothelial cells from the venous sinus wall. CONCLUSION: To our knowledge, this is the first report of the in vitro culture of arachnoidal cells grown from human AG tissue. We demonstrated that these cells in vitro continue to express some of the cytoskeletal and junctional proteins characterized previously in human AG tissue, such as proteins involved in the formation of gap junctions, desmosomes, epithelial specific adherens junctions, as well as tight junctions. These junctional proteins in particular may be important in allowing these arachnoidal cells to regulate CSF outflow.

Visual loss with West Nile virus infection: a wider spectrum of a "new" disease.

We describe a case of severe visual loss as a result of West Nile virus (WNV) infection. Associated headache and fever led to the proper diagnosis and management, but the findings of optic neuritis, retinitis, and uveitis were a surprising and prominent component of the patient's meningitis syndrome. Physicians diagnosing and treating patients with WNV infection should be alerted to the possibility of ocular and optic nerve involvement, which may leave permanent neuropathic residua.

Expression of somatostatin receptors 1 and 2 in human choroid plexus and arachnoid granulations: implications for idiopathic intracranial hypertension.

OBJECTIVE: To investigate the localization of somatostatin receptor types 1 and 2 in human choroid plexus (CP) and arachnoid granulations (AGs) by immunohistochemistry. METHODS: A prospective study was performed in an institutional setting. Immunohistochemistry was performed on 15 samples of CP and 12 samples of AGs from 15 patients who died with no signs or symptoms of intracranial disease (age range, 52-81 years). The CP samples were dissected from the lateral ventricles and AG samples were dissected from the superior sagittal sinus. RESULTS: We demonstrated the presence of both somatostatin receptor types 1 and 2 in all samples of normal human CP and AGs. CONCLUSIONS: Analogous to their demonstration and to their function in kidney and ocular tissues, these receptors may be involved in the processes of cerebrospinal fluid production and absorption, and may play a role in the increased intracranial pressure of idiopathic intracranial hypertension. CLINICAL RELEVANCE: Somatostatin analogues have been used to treat idiopathic intracranial hypertension, a disorder of cerebrospinal fluid homeostasis. Data are scarce regarding the cell-specific distribution of somatostatin receptors in normal human CP and AGs, the sites of cerebrospinal fluid production and egress.

West Nile virus-associated optic neuritis and chorioretinitis.

PURPOSE: To report the new ocular and neurologic features of West Nile virus (WNV) meningoencephalitis. DESIGN: Observational case report. METHODS: A 55-year-old woman presented with headache, stiff neck, visual loss, and fever 10 days after a weekend camping trip. Examination revealed vitritis, creamy yellow circular chorioretinal lesions, and peripheral visual field loss. RESULTS: Laboratory investigation indicated the patient was suffering from WNV meningoencephalitis with neuro-ocular involvement. CONCLUSION: Ophthalmologists and infectious disease specialists should recognize that the WNV infection spectrum may include ophthalmic findings, specifically optic neuritis and multifocal chorioretinitis.

Orbital "shanking": a unique prison injury.

The purpose of this paper is to describe orbitocranial penetration due to "shanking", a common mode of assault in prison facilities. We report the case of a prisoner who presented with orbital apex syndrome 5 days after an assault. He died 9 days after surgical removal of the "shank" due to a presumed ruptured traumatic aneurysm. Physicians who evaluate prisoners must maintain a high index of suspicion for penetrating injuries. The entrance site is often inconspicuous and the history may be limited in this unique population.

A chick model of retinal detachment: cone rich and novel.

BACKGROUND: Development of retinal detachment models in small animals can be difficult and expensive. Here we create and characterize a novel, cone-rich retinal detachment (RD) model in the chick. METHODOLOGY/PRINCIPAL FINDINGS: Retinal detachments were created in chicks between postnatal days 7 and 21 by subretinal injections of either saline (SA) or hyaluronic acid (HA). Injections were performed through a dilated pupil with observation via surgical microscope, using the fellow eye as a control. Immunohistochemical analyses were performed at days 1, 3, 7, 10 and 14 after retinal detachment to evaluate the cellular responses of photoreceptors, Müller glia, microglia and nonastrocytic inner retinal glia (NIRG). Cell proliferation was detected with bromodeoxyuridine (BrdU)-incorporation and by the expression of proliferating cell nuclear antigen (PCNA). Cell death was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). As in mammalian models of RD, there is shortening of photoreceptor outer segments and mis-trafficking of photoreceptor opsins in areas of RD. Photoreceptor cell death was maximal 1 day after RD, but continued until 14 days after RD. Müller glia up-regulated glial fibriliary acidic protein (GFAP), proliferated, showed interkinetic nuclear migration, and migrated to the subretinal space in areas of detachment. Microglia became reactive; they up-regulated CD45, acquired amoeboid morphology, and migrated toward outer retina in areas of RD. Reactive NIRG cells accumulated in detached areas. CONCLUSIONS/SIGNIFICANCE: Subretinal injections of SA or HA in the chick eye successfully produced retinal detachments and cellular responses similar to those seen in standard mammalian models. Given the relatively large eye size, and considering the low cost, the chick model of RD offers advantages for high-throughput studies.

Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies.

Susac syndrome (SS) is the triad of encephalopathy, branch retinal artery occlusions (BRAOs), and hearing loss. Migraines may herald and accompany encephalopathy. Little is known about pathogenesis. Based on light microscopic findings in brain biopsy material analogous to anti-endothelial cell antibody (AECA)-mediated microvascular injury, we postulated that SS microangiopathy was attributable to AECAs. We examined serum samples from 11 patients with SS for AECAs; 9 were positive by indirect immunofluorescence and Western blot studies. A highly distinctive band on Western blots corresponding to a 50-kDa protein was observed in 8 positive SS samples; the other positive case exhibited specific reactivity with a protein band at 40 kDa. Of the 2 negative cases, 1 had been inactive since 1988; the other was an abortive variant characterized solely by BRAOs. There was enhanced surface binding of SS serum using live endothelial cell substrates compared with samples from healthy subjects. Additional serum samples from apparently healthy patients, 2 with atypical migraines, and patients with other forms of autoinflammatory disease did not show the distinctive band of immunoreactivity. SS is a distinct autoimmune endotheliopathy syndrome associated with AECAs; the antibody target seems specific in many cases and may be a disease biomarker. The exact role of AECAs in disease propagation remains unanswered.

Endoscopic transconjunctival surgical approach to the optic nerve and medial intraconal space: a cadaver study.

OBJECTIVE: Surgical approaches to the orbit require great precision and care because of the functional and aesthetic importance of this region. Conventional approaches to the posterior orbit often require bone removal, may disrupt extraocular muscles, and may create external surgical scars. We conceived a transconjunctival surgical approach to the medial intraconal space that is aided by a minimally invasive endoscopic technique and avoids muscle transection. METHODS: Assisted by a rigid endoscope measuring 2.7 mm in diameter, with 0- and 30-degree lenses, we made a medial conjunctival incision along the limbus to approach the medial intraconal space and optic nerve in 7 fresh cadaver heads (a total of 9 procedures). RESULTS: This approach provided direct and quick access to the medial intraconal space and intraorbital optic nerve with the use of endoscopes via an aesthetically acceptable conjunctival incision, and it provided an excellent view of the operative area. Unlike conventional techniques, this approach left the anatomy relatively undisturbed and did not require detachment of the medial rectus muscle. CONCLUSION: The endoscopic medial transconjunctival surgical approach provides minimally invasive direct access to the medial intraconal space and the intraorbital optic nerve. The approach is easy; minimally disturbs structures; and lends itself to biopsy, drainage, and even excision of selected lesions in this region without muscle transection and with aesthetically acceptable anatomic closure.

Ex vivo model of cerebrospinal fluid outflow across human arachnoid granulations.

PURPOSE: The brain's arachnoid membrane with granulations is an important biological barrier whose responsibilities include the transmission of cerebrospinal fluid (CSF) and the regulation of pressure. Membrane disturbance may cause changes that are difficult to replicate with animal models, suggesting the need for a model using human arachnoid membrane with granulations for the study of conditions such as Alzheimer disease, hydrocephalus, and pseudotumor cerebri. The authors detail the development and validation of an ex vivo model of CSF outflow across human arachnoid granulations (AGs) as an approximation of in vivo conditions. METHODS: Human AGs were perfused at normal physiological pressure in physiological and nonphysiological directions for permeability data. Fluorescent particle perfusion with electron microscopy identified outflow pathways through the AGs. RESULTS: This human ex vivo model demonstrated in vivo properties of unidirectionality, particle transport, and ultrastructure, similar to our 2005 in vitro model. The average baseline hydraulic conductivity in the physiological direction (n = 20) was 1.05 +/- 0.15 microL/min/mm Hg/cm(2) compared with 0.11 +/- 0.03 microL/min/mm Hg/cm(2) in the nonphysiological direction (n = 3) under statistically equivalent (P = 0.46) average normal physiological pressures (5.88 +/- 0.22 mm Hg and 6.14 +/- 0.23 mm Hg, respectively). CONCLUSIONS: The ex vivo model is feasible and herein demonstrated. These findings agree with in vivo CSF outflow. This model increases understanding of the clearance not only of CSF but also of metabolites through the arachnoid membrane. Additional evidence suggests, but does not yet prove, that CSF outflow may occur in a similar manner in the arachnoid membrane adjacent to the granulations, in addition to the flow through the AGs. This is a topic for further investigation.

Cerebrospinal fluid outflow: an evolving perspective.

Cerebrospinal fluid (CSF) serves numerous important functions in the central nervous system. Despite numerous reports characterizing CSF and its circulation in the subarachnoid space, our understanding of CSF outflow remains limited. Although initial work suggested that both arachnoid granulations and lymphatic capillaries shared in the role of CSF outflow, predominant work since then has focused on the arachnoid granulations. A growing body of recent evidence not only suggests the importance of both arachnoid granulations and lymphatic capillaries, but also additional contributions through transependymal passage likely share in the role of CSF outflow. Consideration of all mechanisms and pathways will help us to better understand the significance of CSF outflow, in health and disease. Here we review how the present concept of CSF outflow has evolved, including a historical review of significant findings and a discussion of the latest innovative developments.

Aggressive immunosuppressive treatment of Susac's syndrome in an adolescent: using treatment of dermatomyositis as a model.

We describe aggressive immunosuppressive treatment of an adolescent with Susac's syndrome (SS), a disease of the microvasculature in the brain, retina, and inner ear. Because the immunopathogenesis of SS appears to have much in common with that of juvenile dermatomyositis (JDM), the patient was treated with an approach that has been effective for severe JDM. The patient's outcome provides evidence for the importance of prompt, aggressive, and sustained immunosuppressive treatment of encephalopathic SS.