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Home , Confluence of sinuses, Deep cerebral veins, Occipital emissary vein

Cerebral Venous Thrombosis Yadollahikhales G GMJ.2016;5(Supp.1):48-61 www.gmj.ir

Cerebral Venous Sinus Thrombosis

Golnaz Yadollahikhales1, Afshin Borhani-Haghighi1, 2, Anahid Safari1 , Mohammad Wasay3,Randall Edgell4

1Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 2Department of Neurology, Shiraz University of Medical sciences, Shiraz, Iran. 3Division of Neurology, Department of Medicine, The Aga Khan University, Karachi, Pakistan. 4Departments of Neurology and Psychiatry, Saint Louis University, Saint Louis, USA.

Abstract

Cerebral venous thrombosis (CVT) is occlusion of dural sinuses and/or cortical due to clot formation. It is a potentially life-threatening condition that requires rapid diagnosis and urgent treatment. Cerebral venous thrombosis is more common in females and young peo- ple. Pregnancy, postpartum state, contraceptive pills, infection, malignancy, hyper-coagulable state, rheumatological disorders, trauma are among the major etiologies of cerebral venous thrombosis. Headache, focal neurologic deficits and seizure were the most common clinical presentations. Different techniques of unenhanced and contrast enhanced brain computerized tomography (CT scan) and, magnetic resonance imaging (MRI) are the most helpful ancillary investigations for diagnosis of Cerebral venous thrombosis. Specific treatment of the underly- ing cause of cerebral venous thrombosis should be considered as the mainstay of the treatment. Anticoagulation with heparin or low molecular weight heparinoids is the most accepted treat- ment. In acute phase, medical or surgical management to decrease intracranial pressure (ICP) is also recommended. If the patient’s clinical condition aggravates despite adequate anticoag- ulation, thrombolysis or mechanical thrombectomy can be an additive option. [GMJ.2016;5(- Supp.1):48-61]

Keywords: Cerebral venous thrombosis; Stroke; Hypercoagulable disorders; Virchow’s triad

Introduction hospitalized patients was reported by Daif in Saudi Arabia [3]. Number of Indian studies erebral venous thrombosis (CVT) is a have reported a very high frequency of CVT Cform of cerebrovascular disease primari- among young stroke patients ranging from ly affecting cerebral venous sinuses. Although 10-20% [4]. Pungayara et al [5] reported that considered to be more common in Asia and CVT accounts for half of all young strokes central/ south America most of the published and 40% of strokes in women. data is reported from Europe or North Amer- A study of young women from Asian coun- ica. It affects about 5 people per million tries reported a frequency of 20% CVT cases and accounts of 0.5% of all strokes [1]. The among all stroke [6]. The age of the patients largest reported series of CVT patients were of a cumulative data of published Iranian published by ISCVT (International study on studies were between 29.5-43.8 [7]. CVT) investigators; reporting 630 patients CVT in children and neonates is increasingly predominantly from European countries [2]. recognized. A Canadian study reported annu- A frequency of 7 CVT patients per 100,000 al incidence of 6.7 cases per million popula-

 Correspondence to: GMJ Afshin Borhani-Haghighi, Neurology department, ©2015 Galen Medical Journal Namazi hospital, Zand St. 71937-11351, Shiraz, Fars, Fax: +98 731 2227091 Iran PO Box 7461686688 Telephone Number: +98-718-8768543 Email:[email protected] E-mail: [email protected] Cerebral Venous Sinus Thrombosis Yadollahikhales G

tion [8]. It is more common in women which cipital, transverse and sigmoid sinuses. is probably related to women specific risk drains blood from sphe- factors for CVT especially pregnancy, puer- noparietal sinus, and superior and inferior perium and use of oral contraceptives. In the . Two cavernous sinuses con- last three decades advances in neuroimaging nect via a circular (intercavernous) sinus in a and neurointerventions have completely rev- butterfly appearance. Cavernous sinus com- olutionized the diagnosis and management of municates with the transverse sinus and in- CVT. More cases are being diagnosed with up ternal jugular via to 85% patients in whom risk factors could be and , respectively. Oc- identified. Outcome is favorable with mortal- culomotor(III), trochlear(IV), abducent(VI) , ity less than 8-10%. ophthalmic(V1) and maxillary branches(V2) of trigeminal nerves and the syphon of the This chapter intends to cover anatomy of cere- internal carotid artery are located within the bral venous system, etiologies, pathophysiol- cavernous sinus. ogy, clinical and radiological manifestations, travels from anterior to medical and interventional management and posterior in a groove between falx cerebri and prognosis of CVT. dura of inner table and terminates to torchular herophili ().Occipital si- Anatomy nus, located in the margin of falx cerebelli, run Venous drainage of and brain is done into confluence as well. It is absent in about of by a network of extracranial veins, diploic one third of persons. Inferior sagittal sinus and veins, , and superficial vein of Galen unite to form the , and deep . External which runs posteriorly to the confluence of si- drains retromandibular venous plexus, poste- nuses. The venous blood drained from superi- rior auricular, transverse cervical, suprascap- or sagittal, occipital and straight sinuses goes ular and anterior jugular veins and ends in the into through transverse subclavian vein. Internal jugular vein orig- and sigmoid sinuses. Each Transverse sinus inates from jugular bulb and takes branches begins from internal occipital protuberance from common facial, lingual, pharyngeal, su- and run to petrous bone. It receives superior perior thyroidal and middle thyroidal veins. petrosal sinus and then forms . , suboccipital venous are asymmetric in most of plexus, and deep cervical veins go to the ver- the individuals and one of them can be aplas- tebral vein, which ends in the suclavian vein. tic or hypolplatic. The right one is the larger in Internal jugular vein unites with the subcla- the majority of the individuals. Sigmoid sinus vian vein to form the . is a S-shaped structure turn into jugular bulb. Inferior thyroidal vein directly pours to bra- Cerebral veins can be categorized to superfi- chiocephalic vein. Diploic veins are valveless cial, deep and posterior fossa veins. Super- veins course through the calvarium and con- ficial cerebral vein courses along sulci and nect with meningeal veins and dural sinuses to drain cortical gray matter and subcortical pericranial veins. Diploic veins are not usual- white matter. Of the numerous superficial ly seen in conventional angiography. cerebral veins, vein of Labbe and vein of Tro- Cerebral venous sinuses are pockets of blood lard worth mentioning. Superior anastomotic between two layers of dura. They drain the ve- vein of Trolard travels posterosuperiorly and nous blood from superficial and deep cerebral connects superior middle cerebral vein into veins and communicate with extracranial ve- the superior sagittal sinus. Inferior anastomot- nous system through diploic veins. For better ic vein of Labbe courses along the occipito- understanding, it is better to divide the cere- temporal sulcus and connects superior middle bral dural sinuses to anterior and posterior cerebral vein and the transverse sinus. systems. The main sinus of the anterior system drain venous blood from is cavernous sinus. Posterior system includes deep white matter and basal ganglia through superior sagittal, inferior sagittal, straight, oc- subependymal veins and from superficial

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white matter through medullary veins. An- Etiologies terior caudate vein and terminal vein form the thalamostriate vein. Thalamostriate vein More than one hundred risk factors have been unites to septal vein to form the internal cere- reported in published literature. About 50% bral vein. Internal cerebral vein and basal vein patients have multiple risk factors. A rational of Rosental form the short U-shaped greater approach to identify risk factors is warranted vein of Galen. after confirmation of diagnosis. A comprehen- Posterior fossa veins include superior (Galen- sive list of established risk factors is provided ic), anterior (petrosal) and posterior (tentorial) in table 1. groups of veins with numerous small veins [9- 11].

Table 1. Risk Factors for CVT Pregnancy Medications Related Puerperium Oral contraceptive pills Androgens Infection Related Anti estrogen therapy Direct septic trauma Anti-neoplastic agents: Cisplatin, L asparaginase Cerebral abscesss Sildenafil Subdural empyema Carbamazepine Meningitis Tuberculous meningitis Malignancy Otitis media Squamous cell metablastic cervical cancer Orbital cellulitis Non hodgkins lymphoma Tonsillitis Bilateral glomus tumors Dental infections Colorectal cancer Stomatitis Epidermoid carcinoma of tongue Cellulitis Dysgerminoma Septicemia Ewing’s sarcoma TB Allogenic transplant for acute lymphoblastic leuke- Endocarditis mia Measles Paraneoplastic syndrome Hepatitis Meningioma Herpes simplex Varicella Zoster Rheumatologic Diseases Cytomegalovirus Bachet’s disease HIV Antiphospholipid antibody syndrome Malaria Systemic Lupus erythematosus Trichinosis Wegeners granulomatosis Toxoplasmosis Churg-strauss syndrome Aspergillosis Cryptococcosis Nephrotic Syndrome Paroxysmal nocturnal hemoglobinuria Hypercoagulable Disorders Iron deficiency anemia Protein C deficiency Sickle cell anemia Protein S deficiency Inflammatory bowel diseases Anti thrombin III deficiency Trauma Factor V leiden mutation Lumbar puncture Prtothrombin gene mutation Endocrine disorders: Diabetes, thyroid disease Homocystinemia/ homocystinuria Renal allograft Essential thrombocythemia Dehydration Primary polycythemia Anemia Plasminogen deficiency Prolonged flights TPa deficiency Elevated plasminogen activator inhibitor-1 Idiopathic Dysfibrinogenemia Evans syndrome Heparin induced thrombocytopenia (HIT) Increased Factor VIIIc

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Pathophysiology Infarction and hemorrhage Thrombosis of dural sinus especially superi- Cerebral venous thrombosis refers to complete or sagittal sinus leads to a rise in dural sinus or partial occlusion of either the main sinus/ pressure. This pressure could range from mild sinuses or the feeding cortical veins leading to severe and is an important factor underly- to secondary effects of vascular congestion ing initial symptomatology of CVT. Presence and focal or generalized neurological deficits. of collateral channels and recanalization are Thrombosis in venous channels draining the important as all venous occlusions do not brain is a consequence of the characteristic necessarily end up in the neuronal injury or risk factors under the heading of Virchow’s infarction. Location of occlusion may be im- triad, which includes local trauma to vessel portant. One study showed that occlusion of wall, stasis and hypercoagulable state. posterior SSS leads to significantly reduced Predominant involvement of superior sagittal cerebral blood flow and hemoglobin oxygen sinus in large number of cases could be relat- saturation. It may lead to reduced capillary ed to the fact that the superficial cortical veins perfusion pressure and increased cerebral draining against the blood flow in the sinus. blood volume. Reduction of capillary perfu- Presence of fibrous septa present at inferior sion pressure and increased cerebral blood angle of the sinus causes turbulence hence volume may lead to neuronal injury at this making it more susceptible to thrombosis. A stage. thrombosed sagittal sinus leads to compres- When the veins get thrombosed, there is in- sion of the arachnoid villi, which drain CSF crease in backpressure, resulting in reversal from the ventricles, leading to raised intra- of flow direction (predominantly in setting of cranial pressure [12]. Hypercoagulable state transverse sinus and straight sinus thrombosis) has been attributed as one of the major risk and increased in flow velocity. In the setting factors in the development of CVT. Mutations of transverse sinus occlusion, compensatory in genes encoding for coagulation factors, in- increase in flow velocity in the contra later- creased basal production of these factors in al sinus is also documented. In sigmoid sinus certain physiological and pathological states thrombosis, increased flow velocity may lead and certain malignancies and autoimmune to enhanced drainage into cavernous sinus. disorders lead to an imbalance between pro- Venous flow obstruction leads to raised in- thrombic and antithrombotic factors. Preg- tracranial pressure (ICP) leading to blood nancy and puerperium is a state of compen- brain barrier (BBB) disruption, resulting in sated, accelerated intravascular coagulation, decreased cerebral blood flow. Declining which is necessary for maintenance of the consciousness level could be directly related uterine-placental interface and preparation for to the extent of venous flow velocity. Venous the haemostatic challenge of delivery. This is outflow obstruction leads to moderate en- achieved by a physiological increase in pro- largement of extracellular spaces. Blood brain duction of coagulation factors that induce a barrier is prone to get damaged in the setting prothrombotic state. This is considered to be of raised retrograde venous pressure. Hence, most likely explanation of its association with leakage of fluid (vasogenic edema) ensues CVT. with increase post capillary venules pressure and opening of tight junctions. Alternatively, Mechanism of Neuronal injury increased venous pressure leads to increased Mechanism of neuronal injury in CVT could intracranial pressure, decreased capillary per- be attributed to four pathophysiologic stages fusion pressure and remarkably decreased ce- of CVT [12]. rebral blood flow. This causes translocation Increased dural sinus pressure of water content from the extracellular to the Venous flow obstruction intracellular space (cytotoxic edema) where Development of cytotoxic and vasogenic ede- water movement is more restricted, a pattern ma observed in acute arterial infarction.

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Development of cytotoxic and vasogenic ede- ing more common in children. This pattern of ma represent an important landmark in CVT neurological involvement is subacute in pre- cascade. Neuronal injury at this point is still sentation as compared to acute presentation reversible and has been shown by many stud- of arterial ischemic stroke. Majority of these ies especially Diffusion weighted Imaging patients have evidence of focal cerebral in- (DWI) [13]. volvement on imaging especially MRI includ- Infarctions and hemorrhage are endpoints of ing infarct, hemorrhagic infarct, hemorrhage, CVT cascade. Hemorrhagic tendency in ve- focal cerebral edema etc. nous thrombosis is more frequent as contrary 20-30% of patients with CVT with enceph- to arterial thrombosis, occurring approximate- alopathy or coma usually have involvement ly in 10-50% of cases. Hemorrhagic infarc- of deep venous system or large parenchymal tions principally affect the cortex and gray- lesions due to thrombosis of cortical veins. white matter junction. The bleeding in CVT is Mass effect, midline shift and hydroceph- attributable to increase venous and capillary alus may be identified on imaging of these pressure. patients. Encephalopathy could be related to There are anecdotal reports of association of seizures, post ictal state and status epilepticus CVT with accelerated myelination. It is pro- in some patients. posed that cerebral venous thrombosis with Unusual or rare presentation is not uncommon the consequent restriction of venous outflow in CVT (10-30%). These include thunderclap could be a possible key factor in the induction headache, tinnitus, transient ischemic attack, of accelerated myelination. The exact associ- cavernous sinus syndrome, isolated headache, ation of accelerated myelination and neuronal and migraine with aura, psychiatric symptoms injury in patients with CVT is not well under- and cranial nerve palsies. Those patients pose stood. a diagnostic dilemma for number of clinicians and high index of suspicion is needed to make Clinical Manifestations an early diagnosis.

Clinical manifestations of CVT are diverse Imaging but could be grouped under four patterns; iso- lated intracranial hypertension, focal cerebral Unenhanced brain CT scan is unremarkable signs (deficit/ seizures), encephalopathy and in most patients of acute CVST. In other pa- unusual presentations. Headache is by far the tients, hyperdensity of a cortical vein or dural most common presenting symptom. Number sinus can be seen in unenhanced brain CT of patients has normal neurological examina- scan [15]. If CVST is in subacute or chronic tion at presentation. In about 15% cases head- state, thrombosis may be isodense, hypodense, ache is the only abnormal finding. Headache or have mixed density. does not have any localizing value. One study Brain CT scan with contrast may show en- suggested that occipital headache was more hancement of the dural lining of the sinus with common in sigmoid sinus thrombosis [14]. a filling defect within the vein or sinus which Isolated intracranial hypertension may be called empty delta sign [16]. In unenhanced present in 10-15% cases with headache, pap- brain MRI, signal intensity of thrombosis can illedema and otherwise normal neurological be very different. Early signs of CVST in- examination. Course is sub-acute to chronic. clude absence of a fluid void signal in the si- Likely pathology is thrombosis of superior nus and/or T2 hypointensity suggestive of a sagittal sinus. It is recommended that CVT thrombus. In First week of evolution of CVST must be ruled out in patients diagnosed with thrombosis has deoxyhemoglobin and usu- isolated intracranial hypertension (pseudotu- ally presents as isointense to brain tissue on mor cerebri). T1-weighted images(T1-WI) and hypointense Focal cerebral signs are present in 20-50% of on T2-weighted images(T2-WI) . In second CVT cases. Focal neurological deficits are be- week thrombus has methemoglobin and pres- ing more common in adults while seizures be- ents in hyperintensity on bothT1-WI and T2-

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WI.In chronic stages thrombus present iso- to ity for detecting CVST. Due to dense cortical hyperintense both in T1-WI and T2-WI. In bone neighboring to venous sinuses, bone ar- MRI with gadolinium central isodense lesion tifact may interfere with the visualization of in a venous sinus with surrounding enhance- enhanced dural sinus [21]. ment is counterpart of empty delta sign in The most commonly used MRV techniques are CT[17].(Figure-1) time-of-flight (TOF) MRV and contrast-en- Susceptibility-weighted images can be a help hanced magnetic resonance. The 2-dimen- with revealing thrombosis as a low signal sional TOF technique is the most commonly lesion in the area of dural sinuses. used method currently for the diagnosis of The T2*-weighted conventional GRE se- CVT, because 2-dimensional TOF has excel- quences may be the best method for detecting lent sensitivity to slow flow compared with of cerebral venous thrombosis [18]. (Figure-2) 3-dimensional TOF (Figure-3). Contrast-en- If CVST cause venous infarction CT or MRI hanced MRV improved visualization of ce- can show infarction with or without hemor- rebral venous structures. Some authorities rhagic transformations. Diffusion-weight- believe drawbacks to CTV include concerns ed images (DWI) may show high signal about radiation exposure, potential for iodine intensities as restricted diffusion and perfu- contrast material allergy, and issues related sion-weighted MRI may reveal prolonged to use of contrast in the setting of poor renal transit time. Venous infarcts do not respect ar- function [17, 21]. terial territories and usually are seen in higher As noninvasive vascular imaging methods brain cuts [19]. Deep cerebral vein thrombo- MRV and CTV have their own advantages sis may cause bilateral thalamic and/or basal and drawbacks. CTV is a rapid and available ganglionic infarctions. Isolated cortical vein method with less motion artifacts, which can thrombosis may induce small cortical infarc- be done in patients with metal pieces or de- tions [20]. vices in their body or brain. MRI plus MRV. Vascular imaging studies for CVST include Issues related to CTV include radiation ex- computerized tomographic venography posure, contrast allergy, and contrast induced (CTV), magnetic resonance venography and nephropathy [17]. digital subtraction angiography (DSA). CTV can provide a rapid and reliable modal-

Figure 1. Contrast enhanced T1- images showing Figure 2. T2*-weighted image showing clot in filling defect in torcular herophili right transverse sinus

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Figure 3. Time of flight (TOF) magnetic resonance venography (MRV) showing clot in transverse and straight sinuses

Laboratory Tests Medical Treatment

In a prospective, multicenter study of 343 pa- Extent of neurological damage in CVT de- tients, D-dimer for CVST had sensitivity of pends on the rate at which occlusion occurs 97.1%, specificity of 91.2%, negative predic- and collaterals are formed. Occlusion of ce- tive value of 99.6%, and positive predictive rebral venous sinuses leads to acute raise in value of 55.7%. Consequently, a normal D-di- intracranial pressure. In this acute phase, mer level can’t rule out the diagnosis of CVST medical management to decrease intracranial [22]. pressure (ICP) is recommended. This includes head elevation, hyperventilation to a target Prognosis PaCO2 of 30-35 mmHg and use of manni- tol. Carbonic anhydrase inhibitors such as The overall prognosis of CVST is better than acetazolmide or topiramate is recommended outcome of the arterial stroke [22]. for acute to subacute phases. Steroids have no Multivariate logistic regression showed old- proven benefit in this condition. er age [1-4,23-26], stupor or coma[3-5,25,26], Specific treatment must address underlying intracerebral hemorrhage at time of presen- cause of cerebral venous thrombosis. For drug tation [1,4,6,23,26,27], and underlying he- induced CVT, the drug has to be discontinued matological disorders [1,23] ، malignancy [1- while malignancy requires its own specific 3,5,7,23,24,28] or infection [1,6,7,23,27,28] therapy besides treatment for CVT. For in- as independent predictors of mortality in fections related CVT especially mastoiditis or studies. middle ear infections high dose antibiotics are Venous infarcts and hyperintensity on DWI the mainstay of treatment. Additionally local were associated with clinical deterioration collections of pus at these sites may have to in patients with CVT [8, 29]. In addition, be drained. Patients with nephrotic syndrome prognosis of CVST is overall good in women related CVT should be treated with steroids. with hormonal-dysregulation [9, 22]. Those patients who achieve remission of ne-

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phrotic syndrome may discontinue anticoag- significant. Anticoagulation proved to be safe, ulation after six months following remission even in patients with cerebral hemorrhage. if there is no other indication for anticoagu- A recently published Cochrane review used lation. these two trials for meta-analysis and con- Role of anticoagulation in management of cluded that based upon the limited evidence CVT has long been debated [30]. Lyons and available, anticoagulant treatment for cerebral colleagues reported two cases of infective cav- sinus thrombosis appeared to be safe and was ernous sinus thrombosis that greatly benefited associated with a potentially important reduc- from a combination of antibiotics and heparin tion in the risk of death or dependency which [31]. In 1991, the first randomized controlled did not reach statistical significance [34]. trial on anticoagulation in CVT was published Endovascular treatment [32]. Twenty patients with CVT were random- ized into a placebo arm (n=10 patients) and Indications for Endovascular Treatment heparin arm (n=10 patients). Patients in the heparin arm showed a clear improvement at Intrasinus thrombolysis and/or mechanical day 3 (p<0.05) and the difference remained thrombectomy should be only considered for significant after 8 days of treatment (p<0.01). a limited number of the patients with defined After 3 months, 8 of the heparin-treated pa- critheria: tients had a complete clinical recovery and 2 had slight residual neurological deficits. In the Refractory to medical regimen placebo group, only 1 patient had a complete Refractoriness to non-invasive treatments is recovery, 6 patients had neurological deficits, the most agreed indication of thrombolysis. and 3 patients died (P < 0.01). (Class IIb, level of evidence C). Refractori- The authors concluded that anticoagulation ness could be defined in clinical and radio- with dose-adjusted intravenous heparin is an logical aspects. Clinical failure can be defined effective treatment in patients with CVT and as progression of focal or generalized neuro- that ICH is not a contraindication to heparin logic deficits, and/or unresponsive high intra- treatment in these patients. The study was cranial pressure (ICP). Persistent headache, criticized for its small sample size, use of an deepening coma, progressive weakness or outcome measure that was not previously val- uncontrolled seizures can be examples. Ra- idated and a significant delay from symptom diological refractoriness can be defined as ex- onset to the initiation of therapy. This was fol- pansion of infarcts in CTs or MRIs, and/or ab- lowed by another double blind, placebo-con- sence of signs of recanalization in CTA, MRA trolled multicenter trial. Patients (n=59) were or DSA. Obviously, this indication should be randomized to subcutaneous nadroparin considered at least afew days after initiation (n=30) and matching placebo (n=29) for 3 of anti-coagulations [21, 35]. weeks (double-blind part of trial), followed by 3 months of oral anticoagulants for patients al- Early Poor Prognostic Factors located nadroparin (open part). After 3 weeks, Although pharmacological or mechanical 6 of 30 patients (20%) in the nadroparin group thrombolysis were advocated mostly in pa- and 7 of 29 patients (24%) in the placebo tients with progressive course despite ade- group had a poor outcome, defined as death or quate anti-coagulation, there have been some Barthel Index score of <15. After 12 weeks, 4 arguments that adopting this policy may de- of 30 patients (13%) in the nadroparin group prive some patient s from potentially life-sav- and 6 of 29 (21%) in the placebo group had ing therapeutic modalities. Some researchers a poor outcome [33]. Authors concluded that proposed some early poor prognostic factors patients with cerebral sinus thrombosis treat- such as coma at the time of admission or pre- ed with anticoagulants (low-molecular-weight dominant involvement of deep cerebral veins heparin followed by oral anticoagulation) had can be used for indications of the early endo- a favorable outcome more often than con- vascular interventions [21, 35]. trols, but the difference was not statistically

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Contraindication for Endovascular Inter- 10 minutes, then by a continuous infusion of vention 50 mg in 3 hours, and finally a continuous in- fusion at 5 mg per hour until complete throm- Most authorities are against administration of bolysis or a total dose of 100 mg per day had pharmacological and mechanical intervention been reached. Repeat thrombolysis was tried in the patients with impending cerebral her- the following day if complete recanalization niation. For the patients with very high ICP did not occur at 100 mg per day [38]. Moham- presented with unequal pupils, abnormal pos- madian et al. advocated rTPA injection with tures or breathing rhythms, bilateral Babins- 30 mg/3o minutes single infusion schedule ki’s sign and other signs of herniation, urgent [39].In Sood et al. case successful throm- action to decrease ICP rather than thrombo- bolysis with a bolus of 10 mg rt-PA injection lytic measures should be carried out [21,35]. followed by 1 mg/hr infusion was performed Hyperventilation, Intravenous mannitol or 3% [40]. saline and Hemicraniectomy could be used sequentially [36]. Urokinase dose Li G et al, 2013 underwent urokinase 100 Technique to 1500 × 10 IU intravenous sinus injection via a jugular catheter [41]. In Kothur K, Both common femoral vein and internal jugu- case thrombolysis was performed by bolus lar vein can be used as access site, but common 100,000 units urokinase injection followed by femoral vein seems to be more convenient for continuous 70,000 units/hour urokinase infu- both patient and neuro-interventionist. Intro- sion [42] .In Guo XB et al.[43] 2012, series A ducer sheath (6 or 7 F) is inserted to common microcatheter was put in the superior sagittal femoral vein and then guide catheter (5 or sinus or straight sinus and thrombolysis was 6F) advanced into inferior vena cava. Cath- performed with continuous urokinase (42,000 eter can be navigated from inferior vena cava U/h, total 1,000,000 U/day) infusion. to superior vena cava by a rotation maneuver In Xia ZK, series the initial dose of urokinase in right atrium. Guide catheter then advance was 2000 - 4000 U/kg/24 hour: the bolus dose to internal jugular vein and parked in jugu- was 20 000 - 40 000 U (given in 15 - 30 min- lar bulb. A retrograde venogram is obtained. utes), and the remainder was infused through A microcatheter is loaded with micro-guide the first day. Thereafter, urokinase 2000 U/kg/ wire (0.014 inch) and advanced to thrombus 24 hour was infused for 3 to 7 days [44]. site. Thrombus is gently tried to be mechani- To sum up, it has been accepted that if the pa- cally disrupted and then micro-guidewire is tient’s clinical condition aggravates despite withdrawn and thrombolytic administration is adequate anticoagulation, thrombolysis can started [37]. be a good therapeutic option. But the optimal Both Urokinase and recombinant tissue plas- administration route (local or intravenous), minogen activator (rTPA) have been used. In thrombolytic agent (urokinase or alteplase) most reports a bolus dose of thrombolytic and their dose are remained to be elucidated agent was injected and then thrombolytic [48]. agents was infused through the catheter for Administered bolus doses were 80000- hours or even days. 250000 IU Urokinase or 10-25 mg rTPA and infusion rates were 20000-150000 IU/hour for rTPA Dose urokinase and 1-5 mg/hour for rTPA [37, 45] Frey et al.[37] advocated a loading dose of rtPA into the clot at 1 mg/cm, followed by Complication continuous intrathrombus infusion at 1 to 2 The risk of significant bleeding is increased mg/h, simultaneous with intravenous heparin by thrombolysis in comparison to heparin. infusion. Mortality for cerebral bleeding is about 0.5% In Kim and Suh series, thrombolysis was [46]. Evolution or aggravation of intracere- started with injection of 10 mg of rTPA over bral hemorrhage after thrombolysis was re-

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ported in 2 out of 12 in Frey et al series [37] Craniotomy but none of patients in Mohammadian et al. series [39]. Decompressive surgery may be life sav- ing also in patients with lesions producing Mechanical thrombectomy mass-effect and clinical deterioration. Until recently, the information on decom- Mechanical thrombectomy for CVST has pressive surgery in CVT was limited to case been conducted by different types of cathe- reports and results from small series from re- ters, balloons, stents or snares [1-18, 47-63]. ferral centres, which are difficult to generalise [36, 65-69]. Rheolytic thrombectomy Conclusion Rheolytic thrombectomy is based upon Ber- noulli’s principle stating an increase the ve- The variable natural history of the CVT is locity of fluid in a vessel cause a decrease in a great obstacle to consider straightforward pressure. This principle was applied in Angio- directions for initiating of intrasinus throm- jet Rheolytic catheter by induction of vacuum bolysis or mechanical clot disruption. The with infusion of very high-speed saline. The diameter of the cerebral dural sinuses are AngioJet catheter is an over-the-wire catheter larger and consequently venous thrombi are with multiple outflow pores for about 2500- bigger [1].Accordingly intrasinus thrombol- 9000 psi saline jet and one-inflow lumina for ysis needs a considerable amount of time in aspiration of the thrombus [47, 48]. Clot dis- comparison to intraarterial thrombolysis. In ruption can be performed by micro-guidewire contrast, mechanical thrombectomy has an movements and suction caused by rheolytic immediate effect and can decrease the intra- catheter. Several case reports [1-3, 47-49] and cranial pressure much more promptly [9].The case series [51, 52] have be [4, 5] en attest to rate of hemorrhagic transformation is higher efficacy of rheolytic thrombectomy. in cerebral venous thrombosis in comparison to arterial stroke. Meanwhile, the thicker du- Balloon Angioplasty and/or Stenting ral wall of the sinuses decreases the risk of vessel dissection. All of the above-mentioned Balloon catheter can be dexpanded to mac- rationalization favors the mechanical throm- erate the clot [6, 53] or be inflated distal to betomy in comparison to intrasinus thrombol- the clot and pulled back to aspirate it [7, 54]. ysis alone. In combined pharmacological and Angioplasty can also dilate the stenotic le- mechanical thrombectomy the dose of throm- sions which predispose venous thrombosis bolytic drug and the duration of infusion can [1]. Using compliant microballoon catheters, be decreased due to increased surface area of undersizing of the balloon and low-pressure thrombus exposed to the drug [8, 11]. High- inflation is recommended for decreasing the er cost of devices is against the mechanical risk of vascular injury [8, 9, 55, 56]. Stenting thrombectomy. of the site of clot formation can be performed To sum up, it has been accepted that if the pa- after angioplasty [10, 57]. tient’s clinical condition aggravates despite adequate anticoagulation, thrombolysis can Manual Aspiration be a good therapeutic option. But the optimal administration route (local or intravenous), Instead of using mechanical devices, there is a thrombolytic agent (urokinase or alteplase) report of manual aspiration of thrombus with and their dose are remained to be elucidated. relatively large catheters in addition to intrasi- To best of our knowledge, there has been no nus infusion of tPA. Manual aspiration was clinical randomized trial comparing the effect safe and efficacious in a small group of pa- of intrasinus thrombolysis and/or mechanical tients with CVST who had progressive deteri- thromectomy to standard-of-care anticoagula- oration despite early anticoagulation [18, 64]. tion.

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