Cerebral Venous Sinus Thrombosis and Stenosis in Pseudotumor Cerebri Syndrome Prem S. Subramanian, MD, PhD Adnaan Haq, MBBS (Cand.) Obstruction of cerebral venous outflow and a resulting impairment of cerebrospinal fluid (CSF) resorption have been postulated for many years to be a cause of idiopathic intracranial hypertension (IIH). Cerebral venous outflow influences intracranial pressure (ICP) directly because of the hydrodynamics of CSF reabsorption into the cerebral venous sinus system. When structural venous outflow is seen, it is inappropriate to state that patients have IIH, but they may be categorized as pseudotumor cerebri (PTC) syndrome. Patients with tumor encroaching on the venous sinuses, often the posterior aspect of the superior sagittal sinus, may develop increased ICP.1 Meningioma is the most common lesion to narrow and even infiltrate the superior sagittal sinus, and these tumors present a significant surgical challenge because sacrifice of the venous sinus can be catastrophic, and reconstruction may be difficult. Cerebral venous sinus thrombosis (CVST) can occur with tumor infiltration and also in isolation, and CVST should be considered in all patients presenting with signs and symptoms of elevated ICP, especially when the onset of symptoms is quite rapid. Risk factors for CVST are described below; endothelial changes do not typically occur with local tumor compression, and turbulent flow as well as physical obstruction of flow rather than intraluminal factors are the major contributors to the disease state.
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CVST
Risk factors for CVST include dehydration, oral contraceptive use (especially associated with cigarette smoking), pregnancy/postpartum state, and coagulopathies (often associated with autoimmune disease in women).2 Septic venous thrombosis occurs much more rarely in the modern era with use of antibiotics. Prior hypercoagulable events such as deep INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 1, 61–71 r 2014, Lippincott Williams & Wilkins
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venous thrombosis and/or pulmonary embolism may not occur before CVST, but a history of >3 spontaneous abortions in an affected woman heightens suspicion for the presence of antiphospholipid antibody syndrome.3 The prevalence of CVST as a cause of PTC is extremely difficult to determine; although the diagnosis of PTC requires neuroimaging, cases of CVST are excluded from many clinical studies because they are not idiopathic. Thus, the appropriate denominator of all cases of elevated ICP both with and without CVST cannot be calculated. Contrastenhanced brain MR and MRV imaging techniques are used for diagnosis,4 and although numerous studies have suggested an incidence figure, numbers have varied greatly among them. In a study conducted by Leker and Steiner,5 46 patients with PTC symptoms and a negative initial CT scan were imaged with MRV to demonstrate any possible thrombosis. Twelve of the 46 patients had findings consistent with CVST, indicating that in this small study, sinus thrombosis can be identified as a cause of PTC in 26% of patients. Other studies have shown a far higher percentage of patients being diagnosed with sinus thrombosis, especially in a pediatric population. In a review of MRV data from 145 pediatric patients with potentially elevated ICP, 76 cases of venous outflow obstruction were seen, with 45 (59%) subjects having multiple sites of obstruction.6 Unlike the venous sinus stenoses discussed below, these potential thromboses were located throughout the transverse and sigmoid sinuses and not at the distal transverse sinus only. The retrospective nature of the study and the lack of CSF pressure data in the majority of patients (only 34 underwent lumbar puncture) limit the interpretation of these imaging findings, but they emphasize the need to exclude CVST in all cases of suspected PTC. Researchers have attempted to determine whether patients with PTC from CVST will have a clinical presentation that differs from more typical PTC. As the ICP may rise more rapidly with thrombosis, increased severity of headache or vision loss has been predicted. Small case series of postsurgical patients do report severe and rapid onset of symptoms, but these data may not apply to spontaneous cases. Other studies have also been conducted which have assessed the incidence of sinus thrombosis in other conditions not too dissimilar from PTC. In a series of 160 adult patients with venous sinus thrombosis, 59 (37%) presented with symptoms of isolated intracranial hypertension indistinguishable from typical PTC.7 Similar findings were found in a Saudi Arabian cohort of 40 patients with CVST. Of the 32 patients who had signs and symptoms of elevated ICP, 19 (47%) had no other clinical findings.8 Given the absence of reliable noninvasive neuroimaging to detect CVST in many historic studies, the true incidence of CVST in PTC will require larger prospective studies with standardized imaging protocols and interpretation. In contrast, Leker and colleagues evaluated patients with CVST and compared them to other patients with PTC of unknown cause. They reported that transient visual obscuration occurred in fewer patients www.internat-ophthalmology.com
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with CVST (2 of 17) compared with 15 of 44 patients with PTC as did diplopia (5 of the 15 with PTC compared with 1 of the 8 patients with CVST).5 Neither finding was statistically significant, however, given the relatively small sample size. The modified Dandy criteria for PTC diagnosis allow sixth nerve palsy but not other cranial nerve deficits to be present. In a series of 9 patients with elevated ICP and normal CSF contents who had atypical patterns of ophthalmoplegia (ie, third and fourth cranial nerve palsy, internuclear ophthalmoplegia, skew deviation, and diffuse bilateral ophthalmoplegia), CVST was present in 4. All experienced an acute rise in ICP and rapid onset of symptoms.9 Nonetheless, the presentation of PTC from venous sinus thrombosis is extremely difficult to distinguish from ‘‘classical PTC’’ based on clinical findings alone due to the similarity in presentation of symptoms and signs. Most, if not all, venous sinus thrombosis patients will have visual symptoms and headache. Proper diagnosis, hematological workup, and anticoagulant therapy in addition to ICP lowering are required.10,11 ’
Other Disorders of Venous Return
Extracranial impairment of venous return also may be a cause of elevated ICP. Cardiac filling pressures have been reported to be markedly increased (eg, to levels above what is seen in congestive heart failure) in obese women with PTC,12 with improvement in these parameters after gastric bypass surgery and substantial weight loss.13–15 Researchers postulated that high intra-abdominal pressure would increase jugular venous pressure and thus reduce CSF resorption and raise ICP. A series of 7 obese PTC patients was subsequently treated with nightly wear of a suction device that lowered intra-abdominal pressure; symptoms of headache and pulsatile tinnitus improved during device application, although visual outcomes were not reported.16 Although gastric bypass surgery or other means of significant weight loss may work in part by relieving this venous hypertension, routine application of techniques to lower this pressure has not occurred. Impaired venous return also may be involved in the pathogenesis of papilledema and potentially elevated ICP during long-term space flight.17,18 In low or zero gravity conditions, there is a cephalad pooling of blood that is not easily reversed until the individual returns to a normal gravity environment. If elevated ICP is present under these conditions, then methods to mitigate these effects must be developed to prevent potential visual loss and disabling headaches that could compromise the health and safety of long-term flight personnel. Congenital and acquired abnormalities of the venous sinus system other than thrombosis have been identified in an increasing number of patients with PTC and have been implicated in the development of the www.internat-ophthalmology.com
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disease. In contrast to venous sinus thrombosis, stenosis of the cerebral venous sinuses is not distributed evenly through the venous system. Rather, there is a predilection for a stenosis to occur at the distal transverse sinus, near its junction with the sigmoid sinus. Cadaveric studies have shown that septations may form within the venous sinus system, but it is not known if these septae are involved in the development of hemodynamically significant stenoses.19 Similarly, large arachnoid granulations have been seen just distal to the entry of the vein of Galen to the transverse sinus, and the role of such changes in changing venous flow also is not certain.20 Dominance of 1 transverse venous sinus (usually the right) is not uncommon, and a hypoplastic nondominant transverse sinus should not be considered pathologic.19 Large population-based studies of the incidence of asymptomatic cerebral venous sinus stenoses have not been performed, as MRV sequences are not routinely obtained in patients presenting with common indications for MRI, such as headache or history of recent minor closed head trauma. ’
Cerebral Venous Sinus Stenosis and PTC
Nonetheless, a growing body of evidence has revealed that the majority of obese patients with PTC have bilateral transverse sinus stenoses that may be hemodynamically significant. King et al21 observed that superior sagittal and proximal transverse sinus pressures were elevated during cerebral venous manometry in obese PTC patients; they found a sharp pressure decline in the distal third of the transverse sinuses and documented varying degrees of luminal narrowing and/or obstruction. The precise anatomy was difficult to define by venography, and they postulated that mural thrombus caused partial transverse sinus occlusion. On the basis of this observation and the data of Sugerman and colleagues, Higgins et al22 were the first to report venous sinus stenting for the treatment of refractory PTC; a 30-year-old woman who had failed attempted weight loss and treatment with ICPlowering medications (acetazolamide, furosemide) but showed headache improvement with serial lumbar punctures was found to have bilateral venous sinus stenoses with an accompanying pressure gradient across each one. A self-expanding stent was placed across the R-sided lesion, and in follow-up the patient had resolution of papilledema with improved headache. This result suggested that the stenosis was causative, and that treatment of such lesions could be therapeutic. However, King and colleagues also investigated the correlation between ICP and venous stenosis because of concerns that increased ICP itself could compress the venous sinuses as a secondary effect. Indeed, 8 patients with documented high ICP and a venous pressure gradient across the distal transverse sinus (unilateral or bilateral) had resolution or marked diminution of this gradient immediately upon cervical puncture and drainage of CSF to a normal closing pressure (
’
CVST
Risk factors for CVST include dehydration, oral contraceptive use (especially associated with cigarette smoking), pregnancy/postpartum state, and coagulopathies (often associated with autoimmune disease in women).2 Septic venous thrombosis occurs much more rarely in the modern era with use of antibiotics. Prior hypercoagulable events such as deep INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 1, 61–71 r 2014, Lippincott Williams & Wilkins
www.internat-ophthalmology.com | 61
62
’
Subramanian and Haq
venous thrombosis and/or pulmonary embolism may not occur before CVST, but a history of >3 spontaneous abortions in an affected woman heightens suspicion for the presence of antiphospholipid antibody syndrome.3 The prevalence of CVST as a cause of PTC is extremely difficult to determine; although the diagnosis of PTC requires neuroimaging, cases of CVST are excluded from many clinical studies because they are not idiopathic. Thus, the appropriate denominator of all cases of elevated ICP both with and without CVST cannot be calculated. Contrastenhanced brain MR and MRV imaging techniques are used for diagnosis,4 and although numerous studies have suggested an incidence figure, numbers have varied greatly among them. In a study conducted by Leker and Steiner,5 46 patients with PTC symptoms and a negative initial CT scan were imaged with MRV to demonstrate any possible thrombosis. Twelve of the 46 patients had findings consistent with CVST, indicating that in this small study, sinus thrombosis can be identified as a cause of PTC in 26% of patients. Other studies have shown a far higher percentage of patients being diagnosed with sinus thrombosis, especially in a pediatric population. In a review of MRV data from 145 pediatric patients with potentially elevated ICP, 76 cases of venous outflow obstruction were seen, with 45 (59%) subjects having multiple sites of obstruction.6 Unlike the venous sinus stenoses discussed below, these potential thromboses were located throughout the transverse and sigmoid sinuses and not at the distal transverse sinus only. The retrospective nature of the study and the lack of CSF pressure data in the majority of patients (only 34 underwent lumbar puncture) limit the interpretation of these imaging findings, but they emphasize the need to exclude CVST in all cases of suspected PTC. Researchers have attempted to determine whether patients with PTC from CVST will have a clinical presentation that differs from more typical PTC. As the ICP may rise more rapidly with thrombosis, increased severity of headache or vision loss has been predicted. Small case series of postsurgical patients do report severe and rapid onset of symptoms, but these data may not apply to spontaneous cases. Other studies have also been conducted which have assessed the incidence of sinus thrombosis in other conditions not too dissimilar from PTC. In a series of 160 adult patients with venous sinus thrombosis, 59 (37%) presented with symptoms of isolated intracranial hypertension indistinguishable from typical PTC.7 Similar findings were found in a Saudi Arabian cohort of 40 patients with CVST. Of the 32 patients who had signs and symptoms of elevated ICP, 19 (47%) had no other clinical findings.8 Given the absence of reliable noninvasive neuroimaging to detect CVST in many historic studies, the true incidence of CVST in PTC will require larger prospective studies with standardized imaging protocols and interpretation. In contrast, Leker and colleagues evaluated patients with CVST and compared them to other patients with PTC of unknown cause. They reported that transient visual obscuration occurred in fewer patients www.internat-ophthalmology.com
Venous Sinus Disease and PTC
’
63
with CVST (2 of 17) compared with 15 of 44 patients with PTC as did diplopia (5 of the 15 with PTC compared with 1 of the 8 patients with CVST).5 Neither finding was statistically significant, however, given the relatively small sample size. The modified Dandy criteria for PTC diagnosis allow sixth nerve palsy but not other cranial nerve deficits to be present. In a series of 9 patients with elevated ICP and normal CSF contents who had atypical patterns of ophthalmoplegia (ie, third and fourth cranial nerve palsy, internuclear ophthalmoplegia, skew deviation, and diffuse bilateral ophthalmoplegia), CVST was present in 4. All experienced an acute rise in ICP and rapid onset of symptoms.9 Nonetheless, the presentation of PTC from venous sinus thrombosis is extremely difficult to distinguish from ‘‘classical PTC’’ based on clinical findings alone due to the similarity in presentation of symptoms and signs. Most, if not all, venous sinus thrombosis patients will have visual symptoms and headache. Proper diagnosis, hematological workup, and anticoagulant therapy in addition to ICP lowering are required.10,11 ’
Other Disorders of Venous Return
Extracranial impairment of venous return also may be a cause of elevated ICP. Cardiac filling pressures have been reported to be markedly increased (eg, to levels above what is seen in congestive heart failure) in obese women with PTC,12 with improvement in these parameters after gastric bypass surgery and substantial weight loss.13–15 Researchers postulated that high intra-abdominal pressure would increase jugular venous pressure and thus reduce CSF resorption and raise ICP. A series of 7 obese PTC patients was subsequently treated with nightly wear of a suction device that lowered intra-abdominal pressure; symptoms of headache and pulsatile tinnitus improved during device application, although visual outcomes were not reported.16 Although gastric bypass surgery or other means of significant weight loss may work in part by relieving this venous hypertension, routine application of techniques to lower this pressure has not occurred. Impaired venous return also may be involved in the pathogenesis of papilledema and potentially elevated ICP during long-term space flight.17,18 In low or zero gravity conditions, there is a cephalad pooling of blood that is not easily reversed until the individual returns to a normal gravity environment. If elevated ICP is present under these conditions, then methods to mitigate these effects must be developed to prevent potential visual loss and disabling headaches that could compromise the health and safety of long-term flight personnel. Congenital and acquired abnormalities of the venous sinus system other than thrombosis have been identified in an increasing number of patients with PTC and have been implicated in the development of the www.internat-ophthalmology.com
64
’
Subramanian and Haq
disease. In contrast to venous sinus thrombosis, stenosis of the cerebral venous sinuses is not distributed evenly through the venous system. Rather, there is a predilection for a stenosis to occur at the distal transverse sinus, near its junction with the sigmoid sinus. Cadaveric studies have shown that septations may form within the venous sinus system, but it is not known if these septae are involved in the development of hemodynamically significant stenoses.19 Similarly, large arachnoid granulations have been seen just distal to the entry of the vein of Galen to the transverse sinus, and the role of such changes in changing venous flow also is not certain.20 Dominance of 1 transverse venous sinus (usually the right) is not uncommon, and a hypoplastic nondominant transverse sinus should not be considered pathologic.19 Large population-based studies of the incidence of asymptomatic cerebral venous sinus stenoses have not been performed, as MRV sequences are not routinely obtained in patients presenting with common indications for MRI, such as headache or history of recent minor closed head trauma. ’
Cerebral Venous Sinus Stenosis and PTC
Nonetheless, a growing body of evidence has revealed that the majority of obese patients with PTC have bilateral transverse sinus stenoses that may be hemodynamically significant. King et al21 observed that superior sagittal and proximal transverse sinus pressures were elevated during cerebral venous manometry in obese PTC patients; they found a sharp pressure decline in the distal third of the transverse sinuses and documented varying degrees of luminal narrowing and/or obstruction. The precise anatomy was difficult to define by venography, and they postulated that mural thrombus caused partial transverse sinus occlusion. On the basis of this observation and the data of Sugerman and colleagues, Higgins et al22 were the first to report venous sinus stenting for the treatment of refractory PTC; a 30-year-old woman who had failed attempted weight loss and treatment with ICPlowering medications (acetazolamide, furosemide) but showed headache improvement with serial lumbar punctures was found to have bilateral venous sinus stenoses with an accompanying pressure gradient across each one. A self-expanding stent was placed across the R-sided lesion, and in follow-up the patient had resolution of papilledema with improved headache. This result suggested that the stenosis was causative, and that treatment of such lesions could be therapeutic. However, King and colleagues also investigated the correlation between ICP and venous stenosis because of concerns that increased ICP itself could compress the venous sinuses as a secondary effect. Indeed, 8 patients with documented high ICP and a venous pressure gradient across the distal transverse sinus (unilateral or bilateral) had resolution or marked diminution of this gradient immediately upon cervical puncture and drainage of CSF to a normal closing pressure (
