Retinal and Optic Nerve Deformations Due to Orbital Versus Intracranial Venous Hypertension

Introduction: Abnormal forces around the optic nerve head (ONH) due to orbital diseases, intracranial hypertension (IH), glaucoma, and space travel, are associated with alterations of the ONH shape. Elevated cerebral and ophthalmic venous pressure can contribute to stress and strain on the ONH and peripapillary retina. We hypothesize that IH and elevated ophthalmic venous pressure without IH cause different ONH and retinal changes. Methods: We compared MRI and spectral domain optical coherence tomography (SDOCT) findings in patients with cavernous sinus arteriovenous shunts (CSAVSs), where orbital venous pressure is known to be elevated, with patients with intracranial dural venous sinus thrombosis and secondary IH. We also compared the results to those obtained in the Idiopathic IH (IIH) Treatment Trial. Results: Among 18 patients with dural venous sinus thrombosis, the MRI/magnetic resonance venography displayed partial empty sella (61%) and optic nerve sheath distension (67%). None exhibited ophthalmic vein dilation or signs of orbital congestion. SDOCT of these eyes and IIH eyes showed a similar frequency of abnormal thickening of the mean retinal nerve fiber layer, anterior displacement of the basement membrane opening, peripapillary wrinkles, retinal folds (RF), and choroidal folds (CF). Among 21 patients with CSAVSs, MRI showed ipsilateral dilated superior ophthalmic vein (76%) and orbital congestion (52%) without distension of the optic nerve sheath or globe distortion. SDOCT showed CF (19%), one with overlying RF, and no ONH deformations. Conclusions: SDOCT findings for dural venous sinus thrombosis are similar to those seen with IIH but distinct from changes due to local ophthalmic venous hypertension. These data support the concept that IH even if due to a vascular cause and local orbital venous hypertension cause different stresses and strains on the ONH.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Retinal and Optic Nerve Deformations Due to Orbital Versus Intracranial Venous Hypertension Mark J. Kupersmith, MD, Patrick A. Sibony, MD Introduction: Abnormal forces around the optic nerve head (ONH) due to orbital diseases, intracranial hypertension (IH), glaucoma, and space travel, are associated with alterations of the ONH shape. Elevated cerebral and ophthalmic venous pressure can contribute to stress and strain on the ONH and peripapillary retina. We hypothesize that IH and elevated ophthalmic venous pressure without IH cause different ONH and retinal changes. Methods: We compared MRI and spectral domain optical coherence tomography (SDOCT) findings in patients with cavernous sinus arteriovenous shunts (CSAVSs), where orbital venous pressure is known to be elevated, with patients with intracranial dural venous sinus thrombosis and secondary IH. We also compared the results to those obtained in the Idiopathic IH (IIH) Treatment Trial. Results: Among 18 patients with dural venous sinus thrombosis, the MRI/magnetic resonance venography displayed partial empty sella (61%) and optic nerve sheath distension (67%). None exhibited ophthalmic vein dilation or signs of orbital congestion. SDOCT of these eyes and IIH eyes showed a similar frequency of abnormal thickening of the mean retinal nerve fiber layer, anterior displacement of the basement membrane opening, peripapillary wrinkles, retinal folds (RF), and choroidal folds (CF). Among 21 patients with CSAVSs, MRI showed ipsilateral dilated superior ophthalmic vein (76%) and orbital congestion (52%) without distension of the optic nerve sheath or globe distortion. SDOCT showed CF (19%), one with overlying RF, and no ONH deformations. Conclusions: SDOCT findings for dural venous sinus thrombosis are similar to those seen with IIH but distinct from changes due to local ophthalmic venous hypertension. These data support the concept that IH even if due to a vascular cause and local orbital venous Departments of Neurology, Ophthalmology, and Neurosurgery (MJK), New York Eye and Ear Infirmary and Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Ophthalmology (PSS), State University of New York at Stony Brook, Stony Brook, New York. The authors report no conflicts of interest. Address correspondence to Mark J. Kupersmith, MD, Departments of Neurology, Ophthalmology, and Neurosurgery, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029; E-mail: [e-mail] Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 hypertension cause different stresses and strains on the ONH. Journal of Neuro-Ophthalmology 2021;41:321–328 doi: 10.1097/WNO.0000000000001074 © 2020 by North American Neuro-Ophthalmology Society T he relationship between the changes in the optic nerve head (ONH) and biomechanical factors and forces, including the intracranial pressure, has been an area of keen interest in the study of the pathophysiology of glaucoma, papilledema, optic nerve sheath meningioma, and other causes of ONH swelling. Factors affecting the induced stresses and strains on the ONH and peripapillary retina might include potentially modifiable features that could be considered in treating these disorders (e.g., venous stenting for some forms of venous hypertension associated papilledema). Elevated venous pressure in the ophthalmic venous system was previously suggested as a contributing component in the development of papilledema (1,2), but later, this mechanism was found not to be clinically significant (3,4). Although increased resistance in the central retina vein outflow has been correlated with disc excavation due to glaucoma (5), the literature is unclear. A recent study reported low venous pressure, rather than elevated, in the central vein in eyes with normal tension glaucoma and optic disc hemorrhages (6). Increased venous pressure intracranially and in the orbit have been advanced as a contributory processes in the development of ONH swelling and choroidal folds (CF) in astronauts who remain in space for weeks or longer. After long duration (.6 months) space flight missions, astronauts can develop a space-associated “neuro-ocular syndrome” characterized by a hyperopic shift, flattening of the globe, distension of the optic nerve sheath, swollen optic disc, and CF, suggestive of papilledema. Some cases have mild elevation of cerebrospinal fluid (CSF) pressure post-flight (7–9). Although these findings were ostensibly caused by the microgravity environment, the precise mechanisms remain 321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution unknown. One hypothesis suggests a cephalad redistribution of fluids and resistance in the dural venous system induced venous hypertension that increased intracranial pressure. However, it was later proposed that the ocular changes could be due in part to increased orbital fluid content or a compartment syndrome in the perioptic intraorbital space, which causes persistent elevation limited to the retrobulbar subarachnoid space (7,10). Congestion in the choroidal vasculature was also considered to be a contributory factor for the CF in 60% of astronauts in space for more than 6 months (10). Occlusion or significant stenosis of major intracranial dural venous sinuses can cause symptoms and findings similar to other causes of intracranial hypertension (IH), such as idiopathic IH (IIH). And, disorders that slow or block outflow from the ophthalmic venous system can cause orbital, retinal, choroidal, and episcleral congestion (11–13). To address the effects of increased venous pressure on the eye, we investigated both disorders to determine whether there was an overlap in the findings due to local orbital venous hypertension and intracranial venous hypertension. Although choroidal effusion and retinal venous dilation and hemorrhages have been described in eyes affected by the orbital venous hypertension due to arteriovenous shunting of blood in the cavernous sinus region (CSAVS) (11), CF, similar to what has been described with IIH and in astronauts, have been infrequently found with CSAVSs (14). However, given reports of a mass effect caused by orbital masses on the globe, we anticipated, but did not find, that we might see CF due to globe compression by dilated ophthalmic veins (15). We further suggest that any swelling of the ONH due to CSAVSs results from retinal vein dilation and thus appearance of the ONH will differ between the 2 disorders. As models are developed for the many disorders of the ONH and peripapillary retina, human data are needed to provide context for considering pathophysiological changes in the venous circulation and intracranial pressure. We designed this study to further the understanding of the role of elevated intracranial and orbital venous pressure on the orbit and the eye. We explored the following 2 hypotheses: 1) Intracranial dural venous sinus obstruction induces orbital and ocular findings similar to those caused by IIH and 2) venous hypertension in the ophthalmic venous system due to partial thrombosis in the cavernous sinus and arterial shunting in the cavernous sinus(CSAVS), from dural arteriovenous malformation supplied by arteries from the external and internal carotid systems, causes ocular changes distinct from those caused by IIH. We hoped these results could enhance the understanding of the mechanisms that cause ONH and retinal changes in multiple local eye and systemic disorders. METHODS AND SUBJECTS Patients with diagnosed dural venous sinus thrombosis (excluding cavernous sinus) or a CSAVS who had both 322 spectral domain optical coherence tomography (SDOCT) imaging through the ONH and macula regions and high resolution (1.5 T) brain and orbit MRI available for review were included in the study. We used MRI performed with and without intravenous gadolinium. Sequences included T1, T2, and fluid attenuation inversion-recovery for the brain and h axial and coronal postcontrast fat-suppressed T1 images and short tau inversion recovery coronal images for the orbit. All cases with a CSAVS had either MRA or intraarterial angiography confirmation. We used 3D time-offlight MRA of the intracranial arterial circulation, performed with a GE 1.5 T MRI. Multioblique maximum intensity projection reformatted images were reviewed as well as the source images. All included cases with dural venous sinus thrombosis had magnetic resonance venography (MRV) confirmation. The intracranial MRV was performed using 2D time-of-flight and 3D phase contrast MRV with a GE 1.5 T MRI. Multioblique maximum intensity projection reformatted images were obtained and reviewed as well as the source images. Using these inclusion parameters, 18 of 22 patients with intracranial dural venous thrombosis (4 without SDOCT images were excluded), and 21 of 21 patients with a CSAVS, evaluated from 2010 to 2016, were included in this study. The reviewers of the MRI, MRV, and SDOCT images were not masked to the diagnosis. One unmasked author (M.J.K.) reviewed all radiographic studies without referring to the SDOCT images. The review included MRA and MRV source images and assessed the presence of globe/scleral flattening, optic nerve sheath dilation in the orbit, enlarged extraocular muscles, edema of orbital tissue, ophthalmic vein dilation or thrombosis, abnormal flow voids in the region of the cavernous sinus, partial empty sella, stenosis, or obstruction or hypoplasia of the transverse or sigmoid sinuses or jugular vein or the posterior superior sagittal sinus or straight sinus. Cirrus (Zeiss Meditec, Inc, Dublin, CA) SDOCT scans were performed using the following: 1) a 9-mm horizontal high-definition (HD) 5-line raster scan at 0.5 mm intervals across the central surface of the optic disc and peripapillary retina; 2) ONH-centered volume scans; 3) macula-centered volume SDOCT images; and 4) a HD 5-line raster scan at 0.25 mm across the macula. Images were evaluated for folds using the 5-line raster and macula and optic nerve volume scans. Volume scans were also evaluated with en face imaging with the Advanced Visualization Analysis program visualizing the retina layers and folds. The ONH shape was analyzed with 5-line raster images. The average peripapillary retinal nerve fiber layer (RNFL) was measured in each eye using the SDOCT machine algorithm. We evaluated the ONH and peripapillary tissues for folds and shape previously defined in IIH (Fig. 1A–G) (16– 19). Peripapillary wrinkles (PPW) are closely spaced circumferential folds in the RNFL on the disc surface or juxtapapillary retina within half a disc diameter from the disc Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. A. En face view, at level of the RNFL, of the swollen ONH shows circumferential PPW (black arrows). B. Transaxial view shows corresponding PPW in the RNFL layer (black arrow). C. En face view, at level of RPE, of the swollen ONH shows a line circumferentially around the optic disc (black arrow). D. Transaxial view shows the line to be a folding of the RPE layer. E. En face view, at the level of the RNFL, of the papillomacula retina shows radial RF (white arrows). F. Transaxial view of the same shows the RF (black arrows) across multiple retinal layers. G. En face view, at the level of the RPE, shows horizontal large amplitude CF superior to the dark shadow of the ONH. H. Transaxial view (taken vertically) shows the CF (white undulating line). CF, choroidal folds; ONH, optic nerve head; PPW, peripapillary wrinkles; RF, retinal folds; RNFL, retinal nerve fiber layer; RPE, retinal pigment epithelium. border. Retinal folds (RF) are radial or horizontal undulations confined to the middle and inner layers of the retina greater than half a disc diameter from the disc. CF are wider spaced undulations in the retinal pigment epithelium/Bruch membrane (RPE/BM) of retinal layer. In IIH, CF almost always have associated overlying RF. An uncommon finding with IIH is a peripapillary crease, presumably due to folding of the RPE (20). For evaluating the ONH shape, we used the simple determination previously described. The 5-line raster image was used to determine the position of a line drawn tangential to the curve of the unaltered RPE/BM in the peripapillary retina furthest from the ONH and the altered border adjacent to the neural canal opening on both the nasal and temporal sides of the optic nerve. The direction of the RPE/BM position was measured as displaced anteriorly (toward the vitreous), displaced posteriorly (away from the vitreous), or neutral (18). We compared the clinical findings and the frequency of SDOCT-determined anterior displacement of the RPE/BM neural canal borders, PPW, RF, and CF between both groups. We also compared these results for the group with intracranial venous sinus occlusive disease with the findings of study eyes with IIH from 125 of the 165 participants of the IIH Treatment Trial (IIHTT) who were part of a substudy (16). However, MRIs and MRV were not available for the IIHTT participants. RESULTS There were 21 patients (12 women and 9 men) with CSAVSs, with a mean age of 68 ± 16 years. There were 18 patients (10 women and 8 men) with intracranial dural venous sinus obstructive disease with a mean age of 46 ± 17 years. In the patients with CSAVSs, the eye ipsilateral to the shunt (Table 2) showed proptosis in the clinical examinaKupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 tion (19), elevated intraocular pressure .22 mm Hg (7) and $4 mm Hg than the contralateral eye (11), and dilated vessels in the conjunctiva and sclera (18). There were clinical signs of retinal venous occlusion (1), macula edema (2), optic nerve swelling (2, one with the central retinal vein occlusion and one with mild venous dilation), and associated visual acuity reduction in 3 eyes (2 from macula edema and one from CF). MR (Table 1) showed superior ophthalmic vein dilation in 16, one with thrombosis of the ophthalmic venous system and extraocular muscle swelling or orbital fat congestion in 11. There were no MRI findings suggestive of IH, including no dilated optic nerve sheaths or flattening of the globe. By SDOCT (Table 2), there was no thickening of the RNFL beyond the 95th percentile, but 5 affected eyes had a 10-mm thicker RNFL than the unaffected contralateral eye. The SDOCT showed no eyes with anterior displacement of the RPE/BM at the neural canal borders, PPW, or RF. Two patients had one eye that had no CF at presentation (Fig. 2A) but developed low amplitude and low periodicity CF (Fig. 2B), one with overlying RF; in one of the 2 eyes, the CF persisted as the CSAVS never resolved. At presentation, 2 eyes had CF with low amplitude and low periodicity, one with macula edema that resolved with resolution of the CSAVS (Fig. 3A, B). None of the 18 patients with intracranial dural venous sinus obstruction had clinical findings (Table 2) of orbital venous congestion, including proptosis, dilated conjunctival vessels, chemosis, lid edema, or elevated intraocular pressure. Papilledema was seen on ophthalmoscopy in one or both eyes in 15 patients. On MR (Table 1), there was no engorgement of the ophthalmic veins or swelling of the extraocular muscles, and no suggestion of edema in the orbital fat. On MRI, distension of the optic sheath in the orbit occurred in 11 patients and flattening of the globe occurred in 8 patients. The SDOCT showed swelling of 323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. MRI/magnetic resonance venography findings Diagnosis (No. of Patients) Dilated Intraorbital Ophthalmic Vein Increased Vasculature Cavernous Sinus CSAVS 76% (16/21) 100% (21/21) Intracranial 0 0 venous sinus obstruction Bilateral Transverse or Unilateral Transverse or Sigmoid Sinus or Sigmoid Sinus or Jugular Vein or Combination Jugular Vein or Obstruction/ Combination Stenosis/ Obstruction/ Hypoplasia Stenosis 0 56% (10/18) 0 44% (8/18) Optic Nerve Sheath Partial Empty Orbital Dilation Sella Congestion Globe Flattening 0 0 0 52% (11/21) 56% (10/18) 67% (12/18) 61% (11/18) 0 CSAVS—arteriovenous shunts involving the cavernous sinus; for this study, dural arteriovenous malformations alone. Findings expressed as percentage of the number of cases per diagnostic group. CSAVS, cavernous sinus arteriovenous shunts. quencies for SDOCT demonstrated retinal and neural canal abnormalities were similar to those seen in study eyes of the IIHTT (Table 2). The CF in eyes of one patient with dural venous sinus outflow restriction resolved completely after resolution of the papilledema (Fig. 5B). the RNFL beyond the 95th percentile in at least one eye in 12 patients (Table 2). The SDOCT image of the RPE/BM borders revealed a neutral or posterior positioned in both eyes of 7 patients (2 of whom had Grade I papilledema and one of whom had atrophic papilledema on clinical examination at the time of SDOCT study). We observed anterior deformation bilaterally in 10 patients and in one eye of one patient (all of these eyes had papilledema seen clinically). The SDOCT showed PPW in 5 patients, RF in 10 patients, and CF (with higher periodicity than associated with CSAVSs) in 2 patients (Figs. 4, 5A). The frequency of these SDOCT findings increased if only eyes with clinically apparent papilledema were considered (Table 2). The fre- DISCUSSION The retinal and ONH changes in eyes with ophthalmic venous outflow restriction associated with CSAVSs differ from those due to intracranial dural venous sinus outflow restriction or occlusion. Eyes affected by CSAVSs did not show SDOCT-demonstrated or MRI-demonstrated ONH TABLE 2. Clinical and SDOCT findings (for eye ipsilateral to cavernous sinus arteriovenous shunts and bilateral for intracranial venous sinus thrombosis) Diagnosis (No. of Patients) CSAVS Intracranial venous sinus obstruction (all cases) Intracranial venous sinus obstruction (with papilledema) Study eyes from IIHTT Orbital Congestion Clinically Seen Clinically Unilateral Seen Swollen Neural Canal Retinal Vein ONH at Time RNFL .95th Borders Thrombosis of SDOCT Percentile Anterior 95% (20/21) 5% (1/21) 0 0 10% (2/21) 83% (15/18) 0 67% (12/18) 100% (15/15) 80% (12/15) 95% (119/125) 0 61% (11/18) 73% (11/15) RF PPW 5% (1/21) 56% (10/18) 0 19% 0 (4/21) 28% 11% 11% (2/18)* (5/18)* (2/18)* 67% (10/15) 33% (5/15) 63% 47% (79/125) (59/125) CF 13% (2/15) Creases 13% (2/15) 46% 10% 20% (25/125) (57/125) (12/125) *Only seen in eyes with papilledema. CF, choroidal fold; CSAVS, cavernous sinus arteriovenous shunts; IIHTT, idiopathic intracranial hypertension treatment trial; ONH, optic nerve head; PPW, peripapillary wrinkles; RF, retinal fold; RNFL, retinal nerve fiber layer; RPE, retinal pigment epithelium; SDOCT, spectral domain optical coherence tomography. 324 Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Eye affected by cavernous sinus arteriovenous shunts shows no retinal/choroidal deformations at presentation by high-definition raster scans through the posterior pole retina. B. At follow-up evaluation, the same eye shows low spatial frequency subtle choroidal and retinal folds. changes or deformations nor peripapillary retinal deformations similar to those seen with papilledema due to IIH. By contrast, the patients with intracranial dural venous sinus obstructive disease had clinical and imaging signs of papilledema, peripapillary retinal deformations, and CF bilaterally. Although the intracranial venous hypertension induced increased intracranial pressure, there was no evidence of ophthalmic venous system hypertension and MR signs of orbital congestion or ophthalmic vein dilation. In addition, none of these cases with raised intracranial pressure had clinical signs of orbital congestion. Retinal vein congestion and retinal edema were seen on ophthalmoscopy in both groups. Although not found in this case series, in children with extensive maldevelopment of the posterior dural venous sinus system, the principal drainage of the brain can be through the orbital and facial veins, resulting in dilated ophthalmic vein and clinical signs of orbital congestion. Thrombosis in the cavernous sinus that directly affects the ophthalmic venous system, without arteriovenous shunting, also causes orbital congestion and retinal abnormalities (11). The results of our study suggest that CSAVSs and intracranial venous obstructive disease cause dissimilar changes in the orbit and eye suggesting different biodynamic pathophysiologic mechanisms. Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 FIG. 3. A. Eye affected by cavernous sinus arteriovenous shunts shows “cystic” macula edema and low spatial frequency CF (white arrows) on a high-definition raster scan. B. At follow-up evaluation, the same eye show resolution of the macula edema and CF. CF, choroidal fold. Cavernous Sinus Arteriovenous Shunt Effects No patients with a CSAVS had anterior displacement of the basement membrane opening of the ONH or retinal deformations except for macula edema and CF. These retinal changes seemed to be due to local ophthalmic venous congestion. Although ophthalmic vein enlargement was common, none had evidence on MRI of ophthalmic vein distortion of the globe or optic nerve sheath dilation or scleral deformation suggestive of increased pressure within the subarachnoid space behind the globe. Given the rarity of articles describing CF with a CSAVS, we were surprised at the frequency of 19%. In 2 of the 4 eyes, the CF were not clinically apparent because they were seen only with properly oriented HD raster scans on SDOCT. One explanation may be that most previous large case series on a CSAVS emphasized diagnosis and management (11) and were conducted long before SDOCT was available. The CF were possibly due to the known choroidal congestion resulting from the ophthalmic venous system hypertension. Unfortunately, the SDOCT method we used to image these cases could not provide enhanced depth imaging needed to accurately assess the presence of choroidal congestion. The 3 eyes with a CSAVS had CF that seemed wider than those seen with IH, and only one 325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Right eye (left eye similar) in a patient with venous sinus thrombosis shows retinal folds affecting all layers and medium spatial frequency choroidal folds on the high-definition raster scan. had overlying RF, possibly due to the CF distortion of the retina. It is possible that we missed subtle or low periodicity folds in the retina or choroid (in this study and in the IIHTT) because these images were collected using horizontal raster imaging, which was before we were aware of the predisposition of CF to be oriented horizontally, in patients with IH (16). However, given that en face image analysis should have shown any significant CF, the frequency of CF is likely accurate. Most importantly, in the 3 patients with CF that had treatment or spontaneous resolution of CSAVS findings and MRA verification of no arteriovenous shunting, the retinal abnormalities including the CF resolved. By contrast, the CF typically persisted in patients with dural venous sinus obstruction and IIH even when papilledema resolved (19). Intracranial Hypertension Effects The patients with dural venous sinus obstructive disease showed the same changes in the ONH and retina as seen with IIH (16). The prevalence of PPW, RF, and CF in eyes with papilledema due to venous sinus obstruction was comparable to eyes with IIH. Any differences in the frequency of the deformations might have been due to the case selection for the IIHTT which required that subjects have clinically determined papilledema while the patients in this study had no such requirement. Also, the speed of developing increased intracranial pressure with acute venous sinus obstruction might differ from IIH. We suggest the CF resulted from the increased retrolaminar subarachnoid pressure changes around the scleral flange as in IIH and not due to ophthalmic venous hypertension–associated choroidal congestion. A rapid resolution of the increased intracranial pressure in one patient with venous sinus obstruction resulted in the complete resolution of the CF, possibly suggesting that CF can resolve when the IH and papilledema are not prolonged. Relevant Intracranial Venous System Details FIG. 5. A. Right eye (left eye similar) in a patient with venous sinus thrombosis shows anterior displacement of the BM/RPE nasal neural canal border (large arrows), peripapillary wrinkles (arrowhead), retinal folds of all layers, and choroidal folds (large arrows) on a high-definition raster scan through the ONH and peripapillary retina. B. At followup evaluation, the right eye (left eye similar) showed normalization of the ONH, retina, and choroid. The BM/RPE nasal neural canal borders have the normal posterior position. BM, Bruch membrane; ONH, optic nerve head; RPE, retinal pigment epithelium. 326 Technical difficulties have limited accurate measurement of venous blood flow in the cavernous sinus, ophthalmic veins, and transverse and sigmoid sinuses in normal humans (21– 23). Based on clinical cases studies with dural venous sinus stenosis and obstruction, most normal intracranial venous outflow is through the transverse sinus/sigmoid sinus/ internal jugular vein components. Unless there are underlying collaterals or large contralateral venous structures, blocking these channels can result in major clinically apparent symptoms and neurological dysfunction, in addition to IH. The cavernous sinus essentially serves as a collecting system for some of the anterior fossa venous system through the small sphenoparietal sinus and some part of the middle cerebral veins, as well as the orbit through the ophthalmic veins (11). Most of the venous blood in the cavernous sinus passes through the superior and inferior petrosal sinuses into the much larger transverse and sigmoid sinuses. Although there are emissary veins draining through the various skull Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution base foramen, the amount of blood exiting is negligible compared with the posterior dural venous system (11). The ophthalmic venous system is not normally an important route of intracranial venous drainage. Blocking the cavernous sinus generally causes focal orbital problems because of local congestion and does not typically cause raised intracranial pressure. Debate on Ophthalmic Venous System Changes and Intracranial Hypertension Acquired ONH swelling from all causes can congest and impede retinal venous drainage from the eye, and dilated retina veins are a secondary, not a causal, phenomenon. The edema and swelling of the anterior optic disc due to reduced retinal venous outflow with CSAVSs may be difficult to differentiate from papilledema. However, the anterior displacement of the neural borders in eyes with intracranial venous sinus thrombosis due to the effects of the increased pressure in the retrolaminar subarachnoid space on the scleral flange, as occurs in IIH, is not found with CSAVSs. Most studies on papilledema in people are in IIH, where the intracranial pressure elevation likely develops over months and is chronic. This is contrasted to the experimental models where induced intracranial pressure elevation occurs over a short time interval even if the animals are observed over the course of time (3,24). In animal investigations, the orbital veins dilate and orbital tissues appear swollen from acute pressure rise (by 600 mm H2O) that is massive compared with the cerebral spinal fluid pressure in most human disorders. Our case series suggests that in patients with intracranial venous sinus thrombosis, venous hypertension in the ophthalmic venous system in the orbit is unlikely to be a clinically significant factor of the changes seen in the ONH. Intracranial pressure elevation due to venous hypertension does not cause MRI or clinical signs of congestion of the orbit. Investigators should be aware of the complexity of the intracranial venous and CSF circulations and the intricacy of measuring them under the wide range of normal physiological (21,22) and pathological conditions. We note, there are small case series that describe measuring elevated ophthalmodynamometry-determined raised central retina vein pressure associated with increased elevated CSF pressure (25). Increased intracranial venous pressure proximal to secondary transverse sinus narrowing in IIH has been noted but it is not the cause of IIH. Small increases in ophthalmic venous system pressure would seem plausible but published articles using ophthalmodynamometry provide limited details such as whether the patient actually had papilledema at the time of the measurement (26). Except in glaucoma secondary to raised episcleral/orbital venous pressure (as is seen with arteriovenous shunting in the orbit and cavernous sinus), it is unlikely that small changes in the orbital or retinal venous system is a significant risk factor in causing glaucoma or other disorders of the ONH. Kupersmith and Sibony: J Neuro-Ophthalmol 2021; 41: 321-328 Choroidal Folds Different types and orientation of CF may reflect different mechanisms and pathological processes. For example, CF associated with choroidal neovascularization (27) have a radial appearance around the macula lesion, whereas CF due to choroidal congestion from ophthalmic vein hypertension show a low spatial frequency. By contrast, CF due to IH, , either intracranial venous hypertension or IIH, have an intermediate spatial frequency and can extend outside the posterior pole and have a more horizontal orientation. Idiopathic folds have an intermediate spatial frequency and can extend across the entire posterior pole retina (28). The CF after space flight have a high spatial frequency, have horizontal orientation, and affect the peripapillary retina (9). And, wider CF with almost any orientation have been described with an orbital mass effect on the globe due to orbital cavernoma or thyroid eye disease (29). Limitations and Conclusions This study has limitations, which include the retrospective evaluations, one reviewer of MR studies, neither reviewer of the SDOCT images was masked, and the significant difference in age between each disease group. Nevertheless, the difference in MR and SDOCT findings between the 2 groups is robust and cannot be accounted for by any of the limitations. Furthermore, the SDOCT findings in the intracranial dural venous sinus obstruction patients were very similar to those reported for the prospectively collected IIHTT patients. The results of this study should provide context for understanding the ocular effects of pathological increase of the venous and intracranial pressures. When intracranial venous sinus occlusion impairs cerebrospinal fluid absorption, IH develops. The elevated pressure in the CSF spaces is transmitted into the retrobulbar subarachnoid space inducing papilledema and the associated shape changes in the ONH, peripapillary retina, and choroid. By contrast, CSAVS-associated increased orbital venous pressure, without IH, causes elevated choroidal and retinal vein and episcleral venous pressure that secondarily affect the ONH and peripapillary retina. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. J. Kupersmith and P. S. Sibony; b. Acquisition of data: M. J. Kupersmith; c. Analysis and interpretation of data: M. J. Kupersmith and P. S. Sibony. Category 2: a. Drafting the manuscript: M. J. Kupersmith and P. S. Sibony; b. Revising it for intellectual content: M. J. Kupersmith. Category 3: a. Final approval of the completed manuscript: M. J. Kupersmith. REFERENCES 1. Hedges TR. A correlative study of orbital vascular and intracranial pressure in the rhesus monkey. 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