Martin Lubow

Susac's syndrome: 1975–2005 microangiopathy/autoimmune endotheliopathy

Susacs 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.

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.

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.

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.

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 patients 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.

Retinal and optic nerve head pathology in Susac's Syndrome

PURPOSE This article describes the first retinal histopathologic findings in a patient with Susacs 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.

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 Susacs 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 patients outcome provides evidence for the importance of prompt, aggressive, and sustained immunosuppressive treatment of encephalopathic SS.

Red-green mixture thresholds in congenital and acquired color defects

A color television display was used to measure thresholds for mixtures of red and green on a white background; red and green components could be either incremental, decremental or zero. Ellipses are fitted to a plot of green contrast as a function of red contrast, and it is argued that the length of the ellipse is a measure of red-green color discrimination and the width of the ellipse is a measure of luminance discrimination. It is shown that the technique reliably distinguishes normals from congenital color defectives and also protan from deutan subjects. For some cases of acquired color defects (e.g. optic neuritis), there is a roughly equal loss of color and luminance discrimination whereas, in other cases (e.g., hereditary optic atrophies), the loss of color discrimination is much greater than the loss of luminance discrimination.

Ex Vivo Model of Cerebrospinal Fluid Outflow across Human Arachnoid Granulations

PURPOSE The brains 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.

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

BackgroundThe 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.MethodsHuman 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.ResultsConfluent 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.ConclusionTo 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.