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Sinovenous Thrombosis in Infants and Children
110 Sinovenous Thrombosis in Infants and Children Lori Billinghurst and Mahendranath Moharir
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.
INTRODUCTION Cerebral sinovenous thrombosis (CSVT) is included under the “ischemic stroke” category in children. In CSVT, brain dysfunction occurs due to thrombotic occlusion of cerebral veins and/ or dural venous sinuses. CSVT is rare but remains underrecognised children due to nonspecific presentation, resulting in delayed or missed diagnosis. CSVT is distinct from arterial ischemic stroke (AIS) even though there is an overlap in predisposing conditions. Although randomized controlled trials (RCTs) have established the usefulness of anticoagulation therapy (ACT) in adults, pediatric data are limited to observational and cohort studies. Timely diagnosis and management is essential as CSVT is a potentially life-threatening condition. This chapter will focus on CSVT in infants (older than 28 days) and older children. Neonatal CSVT is comprehensively reviewed in Chapter 20.
EPIDEMIOLOGY CSVT includes all children with thrombosis of the structures of the intracranial venous system with or without radiologically evident parenchymal lesions. Isolated thrombosis of the internal jugular vein (IJV) is not included under CSVT. Published epidemiologic studies suggest an incidence of 0.25 to 0.67 per 100,000 children per year. The ratio of pediatric CSVT to AIS cases is estimated at 1:4 annually. Like AIS, CSVT occurs more frequently in neonates and in males. Awareness of CSVT has increased in the last decade after the seminal populationbased study of pediatric CSVT from Canada (deVeber and Andrew, 2001). Several large case series, cohort studies (Moharir et al., 2010; Grunt et al., 2010), and multicenter registry studies (Ichord et al., 2015) have now been published.
PATHOGENESIS Sinovenous Circulation: Anatomy and Vascular Patterns Cerebral venous drainage occurs through a network of veins and sinuses that comprise broadly the superficial and deep venous systems (Fig. 110-1). In the superficial venous system (SVS), cortical veins drain cortical and subcortical white matter (WM) from both hemispheres medially toward the superior sagittal sinus (SSS), which remains the largest conduit for venous drainage. The deep venous system (DVS) includes internal cerebral (ICV), medullary, thalamic, and choroidal veins that converge centrally at the vein of Galen (VOG), which drains into straight sinus (STRS). The DVS predominantly drains basal ganglia, thalami, and deep WM. The SVS and DVS unite posteriorly at the torcula. Bilateral, often asymmetric, transverse sinuses (TS) then drain laterally into sigmoid sinus (SIGS), which connects to the IJVs. The SVS usually drains into larger right TS whereas DVS drains into the smaller left TS. Additional venous drainage pathways connect with this system at recognizable locations including the cavernous and petrosal
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sinuses and large superficial cerebral veins (e.g. Trolard, Labbé). Although the IJVs are the major exit for cerebral venous drainage, extrajugular pathways such as vertebral venous plexus (VVP) appear to be active, but poorly understood. Adult and more recent pediatric data suggest that patterns of parenchymal brain lesions following CSVT may have some predictability (Fig. 110-2). Bilateral, parasagittal lesions, with or without hemorrhage are associated with SSS thrombosis. DVS thrombosis involving ICV, STRS and/or VOG produces lesions of deep WM, basal ganglia, and thalamus. Hemorrhagic lesions close to the ventricles can result in intraventricular hemorrhage (IVH) in young infants.
Intracranial Venous Physiology The cerebral sinovenous system lacks valves and is a lowpressure, slow-velocity circuit. The dura of venous sinuses is rigid and noncollapsible, resulting in passive drainage of blood to the heart. The flow in sinuses is gravity- and respiration-dependent and can be bidirectional depending on the venous pressure gradient. The IJV appears to drain blood primarily in the supine position whereas the VVP appears to drain blood mainly in the upright position in humans. Reduction in systemic blood pressure can lead to stasis or reversal of blood flow. Venous sinus caliber is probably unresponsive to changes in systemic blood pressure. As the SSS and TS are main sites for CSF reabsorption through arachnoid granulations into the venous circulation, thrombosis or hypertension of these structures can cause communicating hydrocephalus. In supine infants with open fontanelles, mechanical compression of SSS by occipital bone may compromise venous drainage causing stasis and increased thrombosis risk.
Mechanisms of Thrombosis CSVT essentially results from a “hypercoagulable” state secondary to Virchow’s triad: abnormalities of blood (prothrombotic state), blood flow (stasis), and blood vessel (veins/ sinuses). As in systemic venous thrombosis, but in contrast to most AIS, the role of the coagulation cascade and thrombinrich thrombosis predominates. Platelets appear to play a minor role, hence antiplatelet therapy like aspirin is not considered in CSVT treatment. Inherited/acquired coagulation abnormalities play a prominent role in pathogenesis. A relative thrombomodulin deficiency in the cerebral venous endothelium may increase thrombotic tendency. In septic CSVT, infection within or immediately adjacent to venous structures directly provokes thrombophlebitis. In many cases, the exact mechanism of thrombosis is not evident. Slower, passive venous flow may favor initial formation and subsequent propagation of thrombosis. Dehydration, a potent risk factor for CSVT, may result in hemoconcentration and impaired laminar flow. Mechanical compression or injury (trauma, neurosurgery, venous catheter insertion, compressive masses, and occipital bone compression in supine infants) of venous structures may result in both venous stasis and/or endothelial
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Superior sagittal sinus
Frontal cerebral vein
Rolandic vein of Trolard
Parietal ascending vein
Inferior sagittal sinus
Straight sinus
Thalamostriate veins
Internal cerebral vein
Descending temporal occipital vein
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Vein of Galen
Basal vein of Rosenthal Communicating vein of Labbé Transverse sinus
Figure 110-1. Cerebral venous anatomy.
A
B
C
D
Figure 110-2. Intracranial venous drainage patterns. Diagram of cerebral venous drainage territories. Axial section at the level of the basal ganglia (A) and corona radiata (B). Coronal section at the level of the basal ganglia (C) and thalamus (D). The venous drainage of the intracranial venous structures is depicted; superior sagittal sinus (SSS), transverse sinus (TS), cavernous sinus (CS), and galenic venous system (GVS). (With permission from Teksam, M., Moharir, M., deVeber, G., Shroff, M., 2008. Frequency and topographic distribution of brain lesions in pediatric cerebral venous thrombosis. Am J Neuroradiol 29, 1961–1965.)
damage. In essence, CSVT results from a net imbalance between “procoagulant” forces (excess) and intrinsic “fibrinolytic” mechanisms (relative deficiency).
Mechanisms of Brain Injury Thrombosis within the venous system results in outflow obstruction and decreased venous drainage. This causes retrograde venous pressure elevation. It may occur locally in a single venous territory resulting in local/regional effect or globally when major venous sinuses are involved resulting in diffusely elevated intracranial pressure (ICP). This in turn causes elevated local capillary hydrostatic pressure resulting in
fluid transudation across capillary channels. Hemorrhage can result from diapedesis of red cells through leaky capillaries. This explains the high rate of spontaneous hemorrhage in CSVT. Hemorrhage occurs mainly in intraparenchymal and intraventricular (IVH) compartments and more frequently in younger infants. Initially, the increased hydrostatic pressure may produce only parenchymal edema and neuronal dysfunction resulting in symptoms without infarction. Further rise in regional tissue pressure may eventually exceed the arterial inflow pressure causing critically low cerebral perfusion and permanent infarction. Alternative venous drainage can develop but this may require time. Therefore total and rapid thrombotic occlusion carries the highest risk of infarction and
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permanent damage. The severity and duration of clinical symptoms associated with CSVT depend on the involved anatomic site(s), thrombosis acuity and collateral drainage. If collateral venous circulation develops adequately and rapidly, significant venous obstruction is tolerable without decompensation. Embryonic venous collaterals can sometimes develop even in older children as a compensatory mechanism.
CLINICAL FEATURES Clinical diagnosis of childhood CSVT is challenging due to the nonspecific nature of presenting neurologic symptoms and signs that can develop gradually over many hours, days, or even weeks. Abrupt onset can also occur. Diffuse neurologic signs and seizures are more common. Headache, lethargy, nausea and vomiting, and signs of raised ICP including papilledema and sixth nerve palsy are seen frequently. These are clinically indistinguishable from idiopathic intracranial hypertension (IIH); hence, CSVT must be ruled out in all children with suspected IIH. Acute symptomatic seizures are more common than in AIS ranging from 23% to 90%. Altered mental status ranging from isolated lethargy and irritability on the milder end of the spectrum, to frank coma on the severe end, may occur. However, frank coma can also occur. The clinical features of associated risk factors (see following section) are usually present at diagnosis. Given the nonspecific clinical manifestations of childhood CSVT, a low index of suspicion is essential in any child with unexplained raised ICP, seizures and encephalopathy.
RISK FACTORS Risk factors readily are identifiable in most children. Multiple risk factors may co-exist in the same child and a broad range of investigations should be considered. Head and neck infections occur in nearly one in every three preschool children whereas other associations like systemic disease and trauma are clustered in older children.
Infection Infection is a major risk factor for childhood CSVT reported in 24% to 62% of published cohorts. “Septic” CSVT is defined as thrombosis of venous sinuses associated with head and neck infections like otitis media, mastoiditis, sinusitis, meningitis, and, less frequently, intracranial abscess. Although the relative proportion of septic to nonseptic CSVT has decreased in general, infection remains an important and treatable cause of CSVT. Mechanisms include direct extension of infection from structures adjacent to venous sinuses causing thrombophlebitis. The infectious state per se also increases the risk of dehydration and a transient systemic prothrombotic state. Given the frequency of septic CSVT, thorough infectious disease history, physical examination, and diagnostic investigations must be sought in childhood CSVT.
Anemia Anemia is reported in 10% to 20% of children with CSVT, though the pathophysiologic mechanism of CSVT is unclear. Iron-deficiency anemia (IDA) (Fig. 110-3) is most commonly reported in pediatric cohorts, though chronic anemias secondary to hemolysis, thalassemia, and sickle cell disease, have also been reported. Screening for anemia in CSVT is recommended though diagnosis may be difficult due to hemoconcentration in dehydrated children and the dilutional effect of parenteral rehydration.
Prothrombotic Disorders Prothrombotic disorders are reported in 20% to 80% of children with CSVT; their pathogenic role remains uncertain. These figures exceed adult CSVT estimates (15% to 20%). Several case-control studies have reviewed the role of prothrombotic risk factors in CSVT. In a recent pediatric meta-analysis, thrombophilia increased the risk of AIS or CSVT, particularly when more than one abnormality was detected (Kenet et al., 2010). The detection of specific prothrombotic disorders has varied across studies due to lack of systematic and variable testing methods and normative ranges across different laboratories. These include genetic thrombophilias such as mutations in Factor V Leiden and Prothrombin G20210A genes, and deficiencies of protein C, protein S, and antithrombin. Prothrombin gene mutation significantly increases recurrent thromboembolism risk in children older than 2 years, especially in the setting of additional risk factors. Other disorders include anticardiolipin antibodies, elevated lipoprotein (a), hyperhomocysteinemia, and MTHFR homozygosity. Elevated D-dimer may be present in CSVT, but its clinical utility in children has not been determined. Most children with CSVT undergo prothrombotic testing, but the cost-effectiveness and yield of comprehensive testing is unknown.
Acute Systemic Conditions Dehydration is the most common acute risk factor for CSVT. History and physical examination should screen for decreased fluid intake, excessive sensible and insensible volume losses, potential fluid shifts and third-spacing in systemic disease, urinary output, and physical signs of dehydration. Isolated emesis without diarrhea should not be presumed to be secondary to gastroenteritis. It may, especially when accompanied by headache, be one of the first clinical indicators of increased ICP. Nausea and emesis from increased ICP can compound preexistent dehydration and place the child at higher risk of thrombus propagation and venous infarction. Head trauma or cranial surgery may also lead to CSVT. Head injury-associated CSVT may result from a mechanical shearing injury of the venous endothelium and extrinsic compression of dural sinuses causing stasis. Head injury, as an associated risk factor in pediatric CSVT cohorts, ranges from 6% to 9% (Xavier et al., 2014). It is also important to consider CSVT in the differential diagnosis of infants with suspected nonaccidental head trauma due to overlapping radiologic features.
Chronic Systemic Conditions Several chronic systemic diseases increase CSVT risk. Childhood cancers and their treatments carry potential risks including chemotherapy-related hypercoagulable states (Lasparaginase), antithrombin deficiency, infections secondary to compromised immunity, direct CNS involvement of cancer, cranial surgery, and neck venous catheters. CSVT occurs at a rate of 1 in 50 to 200 cases of acute lymphoblastic leuke mia. In inflammatory bowel disease (IBD), systemic inflammation may combine with gastrointestinal disease factors such as dehydration, medications, and IDA. Conditions that lose protein (enteropathies, nephropathies, liver failure) may lead to relative deficiencies in antithrombin-III. Systemic lupus erythematosus is associated with procoagulants like lupus anticoagulant and antiphospholipid antibodies. Cardiac disease increases CSVT risk probably due to decreased venous return (cerebral venous hypertension) or treatments (jugular lines, ECMO, etc.). CSVT is also reported in association with steroid and estrogen-containing contraceptive use in teenagers (Fig. 110-3).
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A
B
C
D
Figure 110-3. Iron deficiency anemia and birth control pill related CSVT in a teenager. A 14-year-old girl presented with increasing headache and new-onset focal seizures. She was being treated with iron supplements for iron deficiency anemia secondary to heavy menstrual bleeding. She was also on the birth control pill to regulate her periods. A, Axial plain head CT scan showing area of bilateral frontal parenchymal hypodensities. B, Sagittal CT venogram. C, Axial Diffusion-weighted imaging showing diffusion restriction of the frontal parenchymal lesions that eventually completely reversed on follow-up imaging. She was treated with low-molecular-weight heparin for 6 months with full recanalization of the thrombus. D, Sagittal T1-weighted MRI showing an occlusive thrombus in the anterior half of superior sagittal sinus. CT, computed tomography. MRI, magnetic resonance imaging.
DIAGNOSIS: NEUROIMAGING Radiologic diagnosis of childhood CSVT poses some challenges. Awareness of pitfalls and limitations of imaging modalities and knowledge of variations in intracranial venous anatomy is needed to prevent misdiagnosis. The goals of imaging include direct visualization of the thrombus and parenchymal brain injury. Noninvasive modalities include cranial ultrasound (cUS) (applicable in newborns), computed tomography (CT), and magnetic resonance imaging (MRI). Each imaging modality has its own advantages and disadvantages. Imaging in pediatric CSVT has been extensively reviewed (Shroff and deVeber, 2003).
Computed Tomography Plain CT (noncontrast) with estimated sensitivity of only 40% to 60% is not adequate to exclude CSVT. It can miss early edema or infarction and may underestimate as well as overestimate thrombosis extent. Caution is required to avoid false positive results, particularly in young infants with higher hematocrit, slower venous flow, and unmyelinated brain that may create an illusion of sinus hyperdensity. Subdural hemorrhage layering along the tentorium can mimic TS thrombosis.
Plain CT may be quite sensitive for deep system CSVT where there is STRS hyperdensity along with thalamic hypodensity or hemorrhage into thalamus or ventricles. Contrast-enhanced CT venography (CTV) is highly sensitive and specific for childhood CSVT diagnosis. Thrombus is represented by a filling defect in the vein/sinus in which contrast flows through a narrowed channel or bypass via venous collaterals. The empty triangle or “empty delta” sign is an example, seen with occlusion of the larger dural sinuses like SSS and TS. The “empty delta” refers to the shape of the enhancing dura encompassing the nonenhancing intraluminal clot on axial CT slice. A multislice contrast-enhanced CT with submillimeter slices and multiplanar reformations for axial, coronal, and sagittal views have significantly improved yield of CSVT. As CTV requires additional radiation exposure and most children will require serial scanning, age-adjusted radiation dosages must be considered.
Magnetic Resonance Imaging MRI is the diagnostic modality of choice for pediatric CSVT. MRI lacks radiation and provides additional details of both brain parenchyma and the venous system. The need for sedation remains a drawback in young children. Combining MRI
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modalities sensitive to vasogenic edema (e.g., fluid-attenuated inversion recovery [FLAIR]), cytotoxic edema and infarction (e.g., diffusion-weighted imaging [DWI]) and blood products (e.g., susceptibility-weighted imaging [SWI]) can both confirm and characterize CSVT-related parenchymal changes. MRI can also image the thrombosis itself, providing more information on both the age and nature of the lesion. Subacute thrombus often appears hyperintense on T1/T2-weighted images. This can be helpful in cortical vein thrombosis in which filling defects are hard to visualize amid numerous artifactual mimics. Approximation of the age of the thrombus can be attempted on MR pulse sequences, but ultimately, this is difficult due to poor correlation between age of thrombus and its signal characteristics. Diffusion-weighted imaging (DWI) can be helpful in investigating the location and extent of associated parenchymal abnormalities, including edema and infarction. However, lesions with diffusion restriction must be interpreted with caution as many resolve on follow-up imaging. Restricted diffusion may also be directly observed within a thrombus and has been reported to predict incomplete recanalization in adults. An SWI is exquisitely sensitive to blood products and is very sensitive to detect hemorrhage and thrombus in smaller venous channels. MR-venography (MRV) can employ time-of-flight (TOFMRV), phase-contrast (PC-MRV) or contrast-enhanced meth ods to image the venous system in a comparable fashion to CTV. The TOF-MRV depends on flow signal characteristics and vessel orientation and is therefore subject to artifacts. As such, apparent “filling defects” on TOF-MRV are not equivalent to those observed with CTV and must be interpreted with caution. Expert interpretation is essential and confirmatory CTV may be required if abnormalities on TOF-MRV are equivocal. Contrast-enhanced MRV appears superior to TOF-MRV in adults but is less studied in children. The effects of flow turbulence are less than what is observed with TOF-MRV and contrast-enhanced MRV is better at delineating smaller veins and collaterals. The PC-MRV can overcome the limitations of TOF-MRV to a large extent, but has not been widely adopted yet in children.
Catheter Angiography CA is rarely employed for CSVT diagnosis nowadays due to vastly improved CT and MRI. CA is typically performed only when thrombolytic or endovascular intervention is being considered. It adds dynamic information regarding the presence of collateral veins, delayed venous emptying, reversal of normal venous flow, or anatomic venous abnormalities.
TREATMENT The three pillars of management of CSVT in children include: (1) antithrombotic therapy, and nonantithrombotic strategies such as (2) neuroprotection and (3) treatment of associated risk factor.
ANTITHROMBOTIC THERAPY Anticoagulation Therapy The role of anticoagulation therapy (ACT) in childhood CSVT is supported by adult clinical trials and pediatric cohort studies and ACT experience in systemic thrombosis. The goal of ACT is to maintain sinovenous system patency by preventing thrombus propagation and new thrombosis. The exact frequency with which children are anticoagulated is unknown as practice patterns vary even among pediatric stroke experts. Factors influencing treatment decisions include the child’s age,
thrombus extent/location, CSVT propagation, ICH, reversibility of associated risk factors, and capacity to monitor ACT. Randomized controlled trials in adults, although relatively small in sample-size, and large cohort studies have demonstrated improved survival and outcome in patients treated with ACT. Metaanalysis of adult data suggests good safety and a trend for efficacy, as well reduction in death and disability. In children, ACT safety is supported by recent cohort studies (Moharir et al., 2010; Grunt et al., 2010) though randomized controlled trials are lacking. In a single-center prospective study of 79 children, among 56 (71%) who received ACT only 3 (5%) had significant, but nonfatal, ICH due to ACT (Moharir et al., 2010). The study was underpowered to determine the effect of hemorrhagic complication on outcome. Two consensus-based pediatric-specific guidelines for AIS and CSVT management have been published by the American Heart Association (AHA) (Roach et al., 2008) and the American College of Chest Physicians (ACCP) (Monagle et al., 2012). These address the safety and efficacy of antithrombotic therapies in children and generally agree on the indications, contraindications, and duration of ACT for CSVT. More recently, specific guidelines for adult and pediatric CSVT have been published (Saposnik et al., 2011) that relatively contraindicate ACT only in the presence of “major” intracerebral/systemic bleeding. If ACT is not initiated at diagnosis, early repeat venous imaging (5 to 7 days) is indicated to exclude thrombus propagation and/or new venous infarction. It is important to note that one third of children with CSVT who are not treated with ACT will propagate their thrombus in the first week after diagnosis and 40% of these will develop additional parenchymal infarction and worse outcome (Moharir et al., 2010). A recent retrospective review of head injury-associated CSVT in 14 of 20 children anticoagulated in the subacute phase post-injury did not find any fatality or major hemorrhagic complication even with significant ICH (Xavier et al., 2014). ACT options include intravenous (IV) unfractionated heparin (UFH), subcutaneous low-molecular-weight heparin (LMWH), and oral warfarin. LMWH is considered first-line in many centers. Intravenous UFH may be used initially when there is concern for increased hemorrhage risk, as UFH may be more easily reversed than LMWH. Warfarin is a reasonable alternative although there are challenges to maintain a satisfactory international normalized ratio (INR), particularly in young children. ACT needs close monitoring by periodic assessment of activated partial thromboplastin time (APTT), anti-Xa level, and INR. The duration of ACT typically follows common adult practice and is planned for 3 to 6 months (Moharir et al., 2010). Repeat venous imaging is performed at 3 to 6 months. If complete recanalization has occurred and none of the provoking risk factors remain, ACT can be discontinued. Longer-term ACT is required only if there are persistent risk factors for CSVT is expected or severe inherited/ acquired prothrombotic states.
Endovascular Treatment and Thrombolysis Neither the AHA nor ACCP guidelines endorse use of recombinant tissue plasminogen activator (tPA) or other thrombolytic therapies for pediatric CSVT given the lack of safety and efficacy data. Thrombolysis is usually reserved for cases in which there is a high risk of mortality (extensive CSVT, multifocal/ diffuse infarction) or clinical deterioration despite adequate ACT during acute/subacute stage of CSVT. The decision to initiate this therapy must be carefully weighed using a multi disciplinary consensus approach. There is some adult data suggesting possible efficacy of thrombolytics/endovascular interventions in select circumstances. Publications in children
are even more limited and include small case series only. Success has been reported with local catheter-mediated thrombolysis tissue plasminogen activator (tPA), mechanical thrombectomy, and agents like abciximab.
Nonantithrombotic Therapies In addition to ACT, supportive and neuroprotective care is vital in CSVT treatment. Simple measures, such as maintenance of normal blood pressure, blood volume, glucose, and temperature, have been shown in adults to limit the extent of brain injury and are recommended in infants and children with CSVT (AHA Class 1, level of evidence C) (Roach et al., 2008; Saposnik et al., 2011). Head elevation to 30 degrees is also suggested.
Increased Intracranial Pressure Screening, recognition, surveillance, and management of raised ICP are of paramount importance. Malignant ICP and resulting ischemic optic neuropathy can occur acutely or over the long term and be secondary to thrombosis, narrowed venous sinuses, or communicating hydrocephalus. Baseline fundoscopy at diagnosis and regular follow-up are required given that many children are not able to reliably report changes in vision. At-risk patients require repeat visual field testing and imaging. Treatment options include the temporary use of carbonic anhydrase inhibitors (acetazolamide, topiramate) or furosemide to lower CSF production, serial lumbar punctures, and, in resistant cases, lumboperitoneal shunting or optic nerve fenestration. Decompressive craniectomy in children with severely raised ICP secondary to ICH and impending herniation has been employed on a case by case basis, but there is no published data to guide the clinician at the bedside.
Seizures Given the high incidence of acute symptomatic seizures during presentation, particularly in presence of parenchymal lesions (deVeber and Andrew, 2001), a low threshold for anticonvulsants is necessary. Timely recognition and treatment of seizures with standard anticonvulsants is warranted to prevent added brain injury. Consideration may be given for routine and/or continuous electroencephalogram (EEG) monitoring in selected cases. There is no evidence to support prophylactic use of anticonvulsants.
Steroids Adult evidence suggests that steroids are not beneficial and may be harmful and/or a risk factor for CSVT. Therefore, routine pediatric use is not supported. However, this needs to be balanced for children with systemic inflammatory diseases such as irritable bowel syndrome (IBD), nephropathy, or malignancy.
Risk Factor Management Judicious treatment of CSVT-associated infection in consultation with an infectious disease expert is essential. Surgical approaches may be necessary for localized infections in selected patients. Dehydration should be corrected and iron replacement considered in patients with IDA. Treatment of other systemic diseases that provoked CSVT is important. Other modifiable risk factors include removing jugular venous lines, altering chemotherapy protocols, or possibly replacing depleted anticoagulation factors.
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OUTCOME Outcome data are available in pediatric CSVT, although few studies have employed standardized outcome measures. Long-term follow-up is required to account for the full spectrum of morbidity after childhood brain injury. Consistent with this, 25% of children with CSVT followed in the CPISR showed increased severity of their neurologic deficits over time (deVeber and Andrew, 2001). Several large studies have shown that only 10% to 15% of adult CSVT patients have adverse neurologic outcomes. By contrast, the range of adverse outcomes reported in children ranges from 25% to 74%, implying heterogeneity in outcome measures and worse prognosis. Neurologic deficits range from mild to severe sensorimotor impairments, developmental delay, cognitive and behavioral difficulties as well as remote symptomatic seizures and epilepsy. The largest population-based, prospective cohort study of childhood CSVT (mean follow-up: 1.6 years) reported favorable outcomes in 48% only, including 35% with neurologic deficit and 20% with epilepsy (deVeber and Andrew, 2001). Mortality rates (comparatively higher in neonates) range from 4% to 25%, though the primary causes of death are often not described (deVeber and Andrew, 2001). Adult predictors of poor outcome include presentation with coma, ICH, and DVS involvement. Predictors of poor outcome in children include comorbid neurologic conditions, ICH, and longer follow-up duration (Moharir et al., 2010). Of note, radiologic recanalization beyond the acute period after diagnosis does not seem to have any effect on the clinical outcome, but recanalization rate in the acute period may influence prognosis and thrombus propagation may potentially affect it adversely (Moharir et al., 2010). In adults, recanalization rates appear maximal after 4 months of ACT, whereas in children maximal recanalization is achieved by 6 months (Moharir et al., 2010). Persistent intracranial hypertension, communicating hy drocephalus, and visual sequelae have been reported in one of every three children. Twenty percent develop recurrent cerebral or systemic thrombosis (deVeber and Andrew, 2001). Fifty percent of these recurrences are systemic. These rates are comparable to adults (CSVT—12%; pulmonary embolism— 11%). Recurrences are less common in children younger than 2 years of age at diagnosis. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES deVeber, G., Andrew, M., Adams, C., et al., 2001. Canadian Pediatric Ischemic Stroke Study Group. Cerebral sinovenous thrombosis in children. N. Engl. J. Med. 345 (6), 417–423. Grunt, S., Wingeier, K., Wehrli, E., et al., 2010. Swiss Neuropaediatric Stroke Registry. Cerebral sinus venous thrombosis in Swiss children. Dev. Med. Child Neurol. 52 (12), 1145–1150. Ichord, R.N., Benedict, S.L., Chan, A.K., et al. for the International Paediatric Stroke Study Group, 2015. Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study. Arch. Dis. Child. 100 (2), 174–179. Kenet, G., Lutkhoff, L.K., Albisetti, M., et al., 2010. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 121 (16), 1838– 1847. Moharir, M.D., Shroff, M., Stephens, D., et al., 2010. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann. Neurol. 67 (5), 590–599.
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Monagle, P., Chan, A., Goldenberg, N., et al., 2012. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 141 (2 Suppl.), e737s–801s. Roach, E.S., Golomb, M.R., Adams, R., et al., 2008. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 39, 2644–2691. Saposnik, G., Barinagarrementeria, F., Brown, R.D., et al., 2011. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 42, 1158–1192. Shroff, M., deVeber, G., 2003. Sinovenous thrombosis in children. Neuroimaging Clin. N. Am. 13, 115–138. Xavier, F., Komvilaisak, P., Williams, S., et al., 2014. Anticoagulation therapy in head injury-associated cerebral sinovenous thrombosis in children. Pediatr. Blood Cancer 61 (11), 2037–2042.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 110-4 Anatomic variations in Intracranial Venous System. Fig. 110-5 Otitis Media/Mastoiditis and CSVT. Fig. 110-6 CSVT due to dehydration and iron deficiency anemia. Fig. 110-7 Head injury associated CSVT. Fig. 110-8 CSVT in association with neurosurgical intervention. Fig. 110-9 CSVT due to L-Asparaginase. Fig. 110-10 Diffusion Positivity of the thrombus in CSVT.
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.
INTRODUCTION Cerebral sinovenous thrombosis (CSVT) is included under the “ischemic stroke” category in children. In CSVT, brain dysfunction occurs due to thrombotic occlusion of cerebral veins and/ or dural venous sinuses. CSVT is rare but remains underrecognised children due to nonspecific presentation, resulting in delayed or missed diagnosis. CSVT is distinct from arterial ischemic stroke (AIS) even though there is an overlap in predisposing conditions. Although randomized controlled trials (RCTs) have established the usefulness of anticoagulation therapy (ACT) in adults, pediatric data are limited to observational and cohort studies. Timely diagnosis and management is essential as CSVT is a potentially life-threatening condition. This chapter will focus on CSVT in infants (older than 28 days) and older children. Neonatal CSVT is comprehensively reviewed in Chapter 20.
EPIDEMIOLOGY CSVT includes all children with thrombosis of the structures of the intracranial venous system with or without radiologically evident parenchymal lesions. Isolated thrombosis of the internal jugular vein (IJV) is not included under CSVT. Published epidemiologic studies suggest an incidence of 0.25 to 0.67 per 100,000 children per year. The ratio of pediatric CSVT to AIS cases is estimated at 1:4 annually. Like AIS, CSVT occurs more frequently in neonates and in males. Awareness of CSVT has increased in the last decade after the seminal populationbased study of pediatric CSVT from Canada (deVeber and Andrew, 2001). Several large case series, cohort studies (Moharir et al., 2010; Grunt et al., 2010), and multicenter registry studies (Ichord et al., 2015) have now been published.
PATHOGENESIS Sinovenous Circulation: Anatomy and Vascular Patterns Cerebral venous drainage occurs through a network of veins and sinuses that comprise broadly the superficial and deep venous systems (Fig. 110-1). In the superficial venous system (SVS), cortical veins drain cortical and subcortical white matter (WM) from both hemispheres medially toward the superior sagittal sinus (SSS), which remains the largest conduit for venous drainage. The deep venous system (DVS) includes internal cerebral (ICV), medullary, thalamic, and choroidal veins that converge centrally at the vein of Galen (VOG), which drains into straight sinus (STRS). The DVS predominantly drains basal ganglia, thalami, and deep WM. The SVS and DVS unite posteriorly at the torcula. Bilateral, often asymmetric, transverse sinuses (TS) then drain laterally into sigmoid sinus (SIGS), which connects to the IJVs. The SVS usually drains into larger right TS whereas DVS drains into the smaller left TS. Additional venous drainage pathways connect with this system at recognizable locations including the cavernous and petrosal
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sinuses and large superficial cerebral veins (e.g. Trolard, Labbé). Although the IJVs are the major exit for cerebral venous drainage, extrajugular pathways such as vertebral venous plexus (VVP) appear to be active, but poorly understood. Adult and more recent pediatric data suggest that patterns of parenchymal brain lesions following CSVT may have some predictability (Fig. 110-2). Bilateral, parasagittal lesions, with or without hemorrhage are associated with SSS thrombosis. DVS thrombosis involving ICV, STRS and/or VOG produces lesions of deep WM, basal ganglia, and thalamus. Hemorrhagic lesions close to the ventricles can result in intraventricular hemorrhage (IVH) in young infants.
Intracranial Venous Physiology The cerebral sinovenous system lacks valves and is a lowpressure, slow-velocity circuit. The dura of venous sinuses is rigid and noncollapsible, resulting in passive drainage of blood to the heart. The flow in sinuses is gravity- and respiration-dependent and can be bidirectional depending on the venous pressure gradient. The IJV appears to drain blood primarily in the supine position whereas the VVP appears to drain blood mainly in the upright position in humans. Reduction in systemic blood pressure can lead to stasis or reversal of blood flow. Venous sinus caliber is probably unresponsive to changes in systemic blood pressure. As the SSS and TS are main sites for CSF reabsorption through arachnoid granulations into the venous circulation, thrombosis or hypertension of these structures can cause communicating hydrocephalus. In supine infants with open fontanelles, mechanical compression of SSS by occipital bone may compromise venous drainage causing stasis and increased thrombosis risk.
Mechanisms of Thrombosis CSVT essentially results from a “hypercoagulable” state secondary to Virchow’s triad: abnormalities of blood (prothrombotic state), blood flow (stasis), and blood vessel (veins/ sinuses). As in systemic venous thrombosis, but in contrast to most AIS, the role of the coagulation cascade and thrombinrich thrombosis predominates. Platelets appear to play a minor role, hence antiplatelet therapy like aspirin is not considered in CSVT treatment. Inherited/acquired coagulation abnormalities play a prominent role in pathogenesis. A relative thrombomodulin deficiency in the cerebral venous endothelium may increase thrombotic tendency. In septic CSVT, infection within or immediately adjacent to venous structures directly provokes thrombophlebitis. In many cases, the exact mechanism of thrombosis is not evident. Slower, passive venous flow may favor initial formation and subsequent propagation of thrombosis. Dehydration, a potent risk factor for CSVT, may result in hemoconcentration and impaired laminar flow. Mechanical compression or injury (trauma, neurosurgery, venous catheter insertion, compressive masses, and occipital bone compression in supine infants) of venous structures may result in both venous stasis and/or endothelial
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Superior sagittal sinus
Frontal cerebral vein
Rolandic vein of Trolard
Parietal ascending vein
Inferior sagittal sinus
Straight sinus
Thalamostriate veins
Internal cerebral vein
Descending temporal occipital vein
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Vein of Galen
Basal vein of Rosenthal Communicating vein of Labbé Transverse sinus
Figure 110-1. Cerebral venous anatomy.
A
B
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D
Figure 110-2. Intracranial venous drainage patterns. Diagram of cerebral venous drainage territories. Axial section at the level of the basal ganglia (A) and corona radiata (B). Coronal section at the level of the basal ganglia (C) and thalamus (D). The venous drainage of the intracranial venous structures is depicted; superior sagittal sinus (SSS), transverse sinus (TS), cavernous sinus (CS), and galenic venous system (GVS). (With permission from Teksam, M., Moharir, M., deVeber, G., Shroff, M., 2008. Frequency and topographic distribution of brain lesions in pediatric cerebral venous thrombosis. Am J Neuroradiol 29, 1961–1965.)
damage. In essence, CSVT results from a net imbalance between “procoagulant” forces (excess) and intrinsic “fibrinolytic” mechanisms (relative deficiency).
Mechanisms of Brain Injury Thrombosis within the venous system results in outflow obstruction and decreased venous drainage. This causes retrograde venous pressure elevation. It may occur locally in a single venous territory resulting in local/regional effect or globally when major venous sinuses are involved resulting in diffusely elevated intracranial pressure (ICP). This in turn causes elevated local capillary hydrostatic pressure resulting in
fluid transudation across capillary channels. Hemorrhage can result from diapedesis of red cells through leaky capillaries. This explains the high rate of spontaneous hemorrhage in CSVT. Hemorrhage occurs mainly in intraparenchymal and intraventricular (IVH) compartments and more frequently in younger infants. Initially, the increased hydrostatic pressure may produce only parenchymal edema and neuronal dysfunction resulting in symptoms without infarction. Further rise in regional tissue pressure may eventually exceed the arterial inflow pressure causing critically low cerebral perfusion and permanent infarction. Alternative venous drainage can develop but this may require time. Therefore total and rapid thrombotic occlusion carries the highest risk of infarction and
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permanent damage. The severity and duration of clinical symptoms associated with CSVT depend on the involved anatomic site(s), thrombosis acuity and collateral drainage. If collateral venous circulation develops adequately and rapidly, significant venous obstruction is tolerable without decompensation. Embryonic venous collaterals can sometimes develop even in older children as a compensatory mechanism.
CLINICAL FEATURES Clinical diagnosis of childhood CSVT is challenging due to the nonspecific nature of presenting neurologic symptoms and signs that can develop gradually over many hours, days, or even weeks. Abrupt onset can also occur. Diffuse neurologic signs and seizures are more common. Headache, lethargy, nausea and vomiting, and signs of raised ICP including papilledema and sixth nerve palsy are seen frequently. These are clinically indistinguishable from idiopathic intracranial hypertension (IIH); hence, CSVT must be ruled out in all children with suspected IIH. Acute symptomatic seizures are more common than in AIS ranging from 23% to 90%. Altered mental status ranging from isolated lethargy and irritability on the milder end of the spectrum, to frank coma on the severe end, may occur. However, frank coma can also occur. The clinical features of associated risk factors (see following section) are usually present at diagnosis. Given the nonspecific clinical manifestations of childhood CSVT, a low index of suspicion is essential in any child with unexplained raised ICP, seizures and encephalopathy.
RISK FACTORS Risk factors readily are identifiable in most children. Multiple risk factors may co-exist in the same child and a broad range of investigations should be considered. Head and neck infections occur in nearly one in every three preschool children whereas other associations like systemic disease and trauma are clustered in older children.
Infection Infection is a major risk factor for childhood CSVT reported in 24% to 62% of published cohorts. “Septic” CSVT is defined as thrombosis of venous sinuses associated with head and neck infections like otitis media, mastoiditis, sinusitis, meningitis, and, less frequently, intracranial abscess. Although the relative proportion of septic to nonseptic CSVT has decreased in general, infection remains an important and treatable cause of CSVT. Mechanisms include direct extension of infection from structures adjacent to venous sinuses causing thrombophlebitis. The infectious state per se also increases the risk of dehydration and a transient systemic prothrombotic state. Given the frequency of septic CSVT, thorough infectious disease history, physical examination, and diagnostic investigations must be sought in childhood CSVT.
Anemia Anemia is reported in 10% to 20% of children with CSVT, though the pathophysiologic mechanism of CSVT is unclear. Iron-deficiency anemia (IDA) (Fig. 110-3) is most commonly reported in pediatric cohorts, though chronic anemias secondary to hemolysis, thalassemia, and sickle cell disease, have also been reported. Screening for anemia in CSVT is recommended though diagnosis may be difficult due to hemoconcentration in dehydrated children and the dilutional effect of parenteral rehydration.
Prothrombotic Disorders Prothrombotic disorders are reported in 20% to 80% of children with CSVT; their pathogenic role remains uncertain. These figures exceed adult CSVT estimates (15% to 20%). Several case-control studies have reviewed the role of prothrombotic risk factors in CSVT. In a recent pediatric meta-analysis, thrombophilia increased the risk of AIS or CSVT, particularly when more than one abnormality was detected (Kenet et al., 2010). The detection of specific prothrombotic disorders has varied across studies due to lack of systematic and variable testing methods and normative ranges across different laboratories. These include genetic thrombophilias such as mutations in Factor V Leiden and Prothrombin G20210A genes, and deficiencies of protein C, protein S, and antithrombin. Prothrombin gene mutation significantly increases recurrent thromboembolism risk in children older than 2 years, especially in the setting of additional risk factors. Other disorders include anticardiolipin antibodies, elevated lipoprotein (a), hyperhomocysteinemia, and MTHFR homozygosity. Elevated D-dimer may be present in CSVT, but its clinical utility in children has not been determined. Most children with CSVT undergo prothrombotic testing, but the cost-effectiveness and yield of comprehensive testing is unknown.
Acute Systemic Conditions Dehydration is the most common acute risk factor for CSVT. History and physical examination should screen for decreased fluid intake, excessive sensible and insensible volume losses, potential fluid shifts and third-spacing in systemic disease, urinary output, and physical signs of dehydration. Isolated emesis without diarrhea should not be presumed to be secondary to gastroenteritis. It may, especially when accompanied by headache, be one of the first clinical indicators of increased ICP. Nausea and emesis from increased ICP can compound preexistent dehydration and place the child at higher risk of thrombus propagation and venous infarction. Head trauma or cranial surgery may also lead to CSVT. Head injury-associated CSVT may result from a mechanical shearing injury of the venous endothelium and extrinsic compression of dural sinuses causing stasis. Head injury, as an associated risk factor in pediatric CSVT cohorts, ranges from 6% to 9% (Xavier et al., 2014). It is also important to consider CSVT in the differential diagnosis of infants with suspected nonaccidental head trauma due to overlapping radiologic features.
Chronic Systemic Conditions Several chronic systemic diseases increase CSVT risk. Childhood cancers and their treatments carry potential risks including chemotherapy-related hypercoagulable states (Lasparaginase), antithrombin deficiency, infections secondary to compromised immunity, direct CNS involvement of cancer, cranial surgery, and neck venous catheters. CSVT occurs at a rate of 1 in 50 to 200 cases of acute lymphoblastic leuke mia. In inflammatory bowel disease (IBD), systemic inflammation may combine with gastrointestinal disease factors such as dehydration, medications, and IDA. Conditions that lose protein (enteropathies, nephropathies, liver failure) may lead to relative deficiencies in antithrombin-III. Systemic lupus erythematosus is associated with procoagulants like lupus anticoagulant and antiphospholipid antibodies. Cardiac disease increases CSVT risk probably due to decreased venous return (cerebral venous hypertension) or treatments (jugular lines, ECMO, etc.). CSVT is also reported in association with steroid and estrogen-containing contraceptive use in teenagers (Fig. 110-3).
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A
B
C
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Figure 110-3. Iron deficiency anemia and birth control pill related CSVT in a teenager. A 14-year-old girl presented with increasing headache and new-onset focal seizures. She was being treated with iron supplements for iron deficiency anemia secondary to heavy menstrual bleeding. She was also on the birth control pill to regulate her periods. A, Axial plain head CT scan showing area of bilateral frontal parenchymal hypodensities. B, Sagittal CT venogram. C, Axial Diffusion-weighted imaging showing diffusion restriction of the frontal parenchymal lesions that eventually completely reversed on follow-up imaging. She was treated with low-molecular-weight heparin for 6 months with full recanalization of the thrombus. D, Sagittal T1-weighted MRI showing an occlusive thrombus in the anterior half of superior sagittal sinus. CT, computed tomography. MRI, magnetic resonance imaging.
DIAGNOSIS: NEUROIMAGING Radiologic diagnosis of childhood CSVT poses some challenges. Awareness of pitfalls and limitations of imaging modalities and knowledge of variations in intracranial venous anatomy is needed to prevent misdiagnosis. The goals of imaging include direct visualization of the thrombus and parenchymal brain injury. Noninvasive modalities include cranial ultrasound (cUS) (applicable in newborns), computed tomography (CT), and magnetic resonance imaging (MRI). Each imaging modality has its own advantages and disadvantages. Imaging in pediatric CSVT has been extensively reviewed (Shroff and deVeber, 2003).
Computed Tomography Plain CT (noncontrast) with estimated sensitivity of only 40% to 60% is not adequate to exclude CSVT. It can miss early edema or infarction and may underestimate as well as overestimate thrombosis extent. Caution is required to avoid false positive results, particularly in young infants with higher hematocrit, slower venous flow, and unmyelinated brain that may create an illusion of sinus hyperdensity. Subdural hemorrhage layering along the tentorium can mimic TS thrombosis.
Plain CT may be quite sensitive for deep system CSVT where there is STRS hyperdensity along with thalamic hypodensity or hemorrhage into thalamus or ventricles. Contrast-enhanced CT venography (CTV) is highly sensitive and specific for childhood CSVT diagnosis. Thrombus is represented by a filling defect in the vein/sinus in which contrast flows through a narrowed channel or bypass via venous collaterals. The empty triangle or “empty delta” sign is an example, seen with occlusion of the larger dural sinuses like SSS and TS. The “empty delta” refers to the shape of the enhancing dura encompassing the nonenhancing intraluminal clot on axial CT slice. A multislice contrast-enhanced CT with submillimeter slices and multiplanar reformations for axial, coronal, and sagittal views have significantly improved yield of CSVT. As CTV requires additional radiation exposure and most children will require serial scanning, age-adjusted radiation dosages must be considered.
Magnetic Resonance Imaging MRI is the diagnostic modality of choice for pediatric CSVT. MRI lacks radiation and provides additional details of both brain parenchyma and the venous system. The need for sedation remains a drawback in young children. Combining MRI
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modalities sensitive to vasogenic edema (e.g., fluid-attenuated inversion recovery [FLAIR]), cytotoxic edema and infarction (e.g., diffusion-weighted imaging [DWI]) and blood products (e.g., susceptibility-weighted imaging [SWI]) can both confirm and characterize CSVT-related parenchymal changes. MRI can also image the thrombosis itself, providing more information on both the age and nature of the lesion. Subacute thrombus often appears hyperintense on T1/T2-weighted images. This can be helpful in cortical vein thrombosis in which filling defects are hard to visualize amid numerous artifactual mimics. Approximation of the age of the thrombus can be attempted on MR pulse sequences, but ultimately, this is difficult due to poor correlation between age of thrombus and its signal characteristics. Diffusion-weighted imaging (DWI) can be helpful in investigating the location and extent of associated parenchymal abnormalities, including edema and infarction. However, lesions with diffusion restriction must be interpreted with caution as many resolve on follow-up imaging. Restricted diffusion may also be directly observed within a thrombus and has been reported to predict incomplete recanalization in adults. An SWI is exquisitely sensitive to blood products and is very sensitive to detect hemorrhage and thrombus in smaller venous channels. MR-venography (MRV) can employ time-of-flight (TOFMRV), phase-contrast (PC-MRV) or contrast-enhanced meth ods to image the venous system in a comparable fashion to CTV. The TOF-MRV depends on flow signal characteristics and vessel orientation and is therefore subject to artifacts. As such, apparent “filling defects” on TOF-MRV are not equivalent to those observed with CTV and must be interpreted with caution. Expert interpretation is essential and confirmatory CTV may be required if abnormalities on TOF-MRV are equivocal. Contrast-enhanced MRV appears superior to TOF-MRV in adults but is less studied in children. The effects of flow turbulence are less than what is observed with TOF-MRV and contrast-enhanced MRV is better at delineating smaller veins and collaterals. The PC-MRV can overcome the limitations of TOF-MRV to a large extent, but has not been widely adopted yet in children.
Catheter Angiography CA is rarely employed for CSVT diagnosis nowadays due to vastly improved CT and MRI. CA is typically performed only when thrombolytic or endovascular intervention is being considered. It adds dynamic information regarding the presence of collateral veins, delayed venous emptying, reversal of normal venous flow, or anatomic venous abnormalities.
TREATMENT The three pillars of management of CSVT in children include: (1) antithrombotic therapy, and nonantithrombotic strategies such as (2) neuroprotection and (3) treatment of associated risk factor.
ANTITHROMBOTIC THERAPY Anticoagulation Therapy The role of anticoagulation therapy (ACT) in childhood CSVT is supported by adult clinical trials and pediatric cohort studies and ACT experience in systemic thrombosis. The goal of ACT is to maintain sinovenous system patency by preventing thrombus propagation and new thrombosis. The exact frequency with which children are anticoagulated is unknown as practice patterns vary even among pediatric stroke experts. Factors influencing treatment decisions include the child’s age,
thrombus extent/location, CSVT propagation, ICH, reversibility of associated risk factors, and capacity to monitor ACT. Randomized controlled trials in adults, although relatively small in sample-size, and large cohort studies have demonstrated improved survival and outcome in patients treated with ACT. Metaanalysis of adult data suggests good safety and a trend for efficacy, as well reduction in death and disability. In children, ACT safety is supported by recent cohort studies (Moharir et al., 2010; Grunt et al., 2010) though randomized controlled trials are lacking. In a single-center prospective study of 79 children, among 56 (71%) who received ACT only 3 (5%) had significant, but nonfatal, ICH due to ACT (Moharir et al., 2010). The study was underpowered to determine the effect of hemorrhagic complication on outcome. Two consensus-based pediatric-specific guidelines for AIS and CSVT management have been published by the American Heart Association (AHA) (Roach et al., 2008) and the American College of Chest Physicians (ACCP) (Monagle et al., 2012). These address the safety and efficacy of antithrombotic therapies in children and generally agree on the indications, contraindications, and duration of ACT for CSVT. More recently, specific guidelines for adult and pediatric CSVT have been published (Saposnik et al., 2011) that relatively contraindicate ACT only in the presence of “major” intracerebral/systemic bleeding. If ACT is not initiated at diagnosis, early repeat venous imaging (5 to 7 days) is indicated to exclude thrombus propagation and/or new venous infarction. It is important to note that one third of children with CSVT who are not treated with ACT will propagate their thrombus in the first week after diagnosis and 40% of these will develop additional parenchymal infarction and worse outcome (Moharir et al., 2010). A recent retrospective review of head injury-associated CSVT in 14 of 20 children anticoagulated in the subacute phase post-injury did not find any fatality or major hemorrhagic complication even with significant ICH (Xavier et al., 2014). ACT options include intravenous (IV) unfractionated heparin (UFH), subcutaneous low-molecular-weight heparin (LMWH), and oral warfarin. LMWH is considered first-line in many centers. Intravenous UFH may be used initially when there is concern for increased hemorrhage risk, as UFH may be more easily reversed than LMWH. Warfarin is a reasonable alternative although there are challenges to maintain a satisfactory international normalized ratio (INR), particularly in young children. ACT needs close monitoring by periodic assessment of activated partial thromboplastin time (APTT), anti-Xa level, and INR. The duration of ACT typically follows common adult practice and is planned for 3 to 6 months (Moharir et al., 2010). Repeat venous imaging is performed at 3 to 6 months. If complete recanalization has occurred and none of the provoking risk factors remain, ACT can be discontinued. Longer-term ACT is required only if there are persistent risk factors for CSVT is expected or severe inherited/ acquired prothrombotic states.
Endovascular Treatment and Thrombolysis Neither the AHA nor ACCP guidelines endorse use of recombinant tissue plasminogen activator (tPA) or other thrombolytic therapies for pediatric CSVT given the lack of safety and efficacy data. Thrombolysis is usually reserved for cases in which there is a high risk of mortality (extensive CSVT, multifocal/ diffuse infarction) or clinical deterioration despite adequate ACT during acute/subacute stage of CSVT. The decision to initiate this therapy must be carefully weighed using a multi disciplinary consensus approach. There is some adult data suggesting possible efficacy of thrombolytics/endovascular interventions in select circumstances. Publications in children
are even more limited and include small case series only. Success has been reported with local catheter-mediated thrombolysis tissue plasminogen activator (tPA), mechanical thrombectomy, and agents like abciximab.
Nonantithrombotic Therapies In addition to ACT, supportive and neuroprotective care is vital in CSVT treatment. Simple measures, such as maintenance of normal blood pressure, blood volume, glucose, and temperature, have been shown in adults to limit the extent of brain injury and are recommended in infants and children with CSVT (AHA Class 1, level of evidence C) (Roach et al., 2008; Saposnik et al., 2011). Head elevation to 30 degrees is also suggested.
Increased Intracranial Pressure Screening, recognition, surveillance, and management of raised ICP are of paramount importance. Malignant ICP and resulting ischemic optic neuropathy can occur acutely or over the long term and be secondary to thrombosis, narrowed venous sinuses, or communicating hydrocephalus. Baseline fundoscopy at diagnosis and regular follow-up are required given that many children are not able to reliably report changes in vision. At-risk patients require repeat visual field testing and imaging. Treatment options include the temporary use of carbonic anhydrase inhibitors (acetazolamide, topiramate) or furosemide to lower CSF production, serial lumbar punctures, and, in resistant cases, lumboperitoneal shunting or optic nerve fenestration. Decompressive craniectomy in children with severely raised ICP secondary to ICH and impending herniation has been employed on a case by case basis, but there is no published data to guide the clinician at the bedside.
Seizures Given the high incidence of acute symptomatic seizures during presentation, particularly in presence of parenchymal lesions (deVeber and Andrew, 2001), a low threshold for anticonvulsants is necessary. Timely recognition and treatment of seizures with standard anticonvulsants is warranted to prevent added brain injury. Consideration may be given for routine and/or continuous electroencephalogram (EEG) monitoring in selected cases. There is no evidence to support prophylactic use of anticonvulsants.
Steroids Adult evidence suggests that steroids are not beneficial and may be harmful and/or a risk factor for CSVT. Therefore, routine pediatric use is not supported. However, this needs to be balanced for children with systemic inflammatory diseases such as irritable bowel syndrome (IBD), nephropathy, or malignancy.
Risk Factor Management Judicious treatment of CSVT-associated infection in consultation with an infectious disease expert is essential. Surgical approaches may be necessary for localized infections in selected patients. Dehydration should be corrected and iron replacement considered in patients with IDA. Treatment of other systemic diseases that provoked CSVT is important. Other modifiable risk factors include removing jugular venous lines, altering chemotherapy protocols, or possibly replacing depleted anticoagulation factors.
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OUTCOME Outcome data are available in pediatric CSVT, although few studies have employed standardized outcome measures. Long-term follow-up is required to account for the full spectrum of morbidity after childhood brain injury. Consistent with this, 25% of children with CSVT followed in the CPISR showed increased severity of their neurologic deficits over time (deVeber and Andrew, 2001). Several large studies have shown that only 10% to 15% of adult CSVT patients have adverse neurologic outcomes. By contrast, the range of adverse outcomes reported in children ranges from 25% to 74%, implying heterogeneity in outcome measures and worse prognosis. Neurologic deficits range from mild to severe sensorimotor impairments, developmental delay, cognitive and behavioral difficulties as well as remote symptomatic seizures and epilepsy. The largest population-based, prospective cohort study of childhood CSVT (mean follow-up: 1.6 years) reported favorable outcomes in 48% only, including 35% with neurologic deficit and 20% with epilepsy (deVeber and Andrew, 2001). Mortality rates (comparatively higher in neonates) range from 4% to 25%, though the primary causes of death are often not described (deVeber and Andrew, 2001). Adult predictors of poor outcome include presentation with coma, ICH, and DVS involvement. Predictors of poor outcome in children include comorbid neurologic conditions, ICH, and longer follow-up duration (Moharir et al., 2010). Of note, radiologic recanalization beyond the acute period after diagnosis does not seem to have any effect on the clinical outcome, but recanalization rate in the acute period may influence prognosis and thrombus propagation may potentially affect it adversely (Moharir et al., 2010). In adults, recanalization rates appear maximal after 4 months of ACT, whereas in children maximal recanalization is achieved by 6 months (Moharir et al., 2010). Persistent intracranial hypertension, communicating hy drocephalus, and visual sequelae have been reported in one of every three children. Twenty percent develop recurrent cerebral or systemic thrombosis (deVeber and Andrew, 2001). Fifty percent of these recurrences are systemic. These rates are comparable to adults (CSVT—12%; pulmonary embolism— 11%). Recurrences are less common in children younger than 2 years of age at diagnosis. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES deVeber, G., Andrew, M., Adams, C., et al., 2001. Canadian Pediatric Ischemic Stroke Study Group. Cerebral sinovenous thrombosis in children. N. Engl. J. Med. 345 (6), 417–423. Grunt, S., Wingeier, K., Wehrli, E., et al., 2010. Swiss Neuropaediatric Stroke Registry. Cerebral sinus venous thrombosis in Swiss children. Dev. Med. Child Neurol. 52 (12), 1145–1150. Ichord, R.N., Benedict, S.L., Chan, A.K., et al. for the International Paediatric Stroke Study Group, 2015. Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study. Arch. Dis. Child. 100 (2), 174–179. Kenet, G., Lutkhoff, L.K., Albisetti, M., et al., 2010. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 121 (16), 1838– 1847. Moharir, M.D., Shroff, M., Stephens, D., et al., 2010. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann. Neurol. 67 (5), 590–599.
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Monagle, P., Chan, A., Goldenberg, N., et al., 2012. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 141 (2 Suppl.), e737s–801s. Roach, E.S., Golomb, M.R., Adams, R., et al., 2008. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 39, 2644–2691. Saposnik, G., Barinagarrementeria, F., Brown, R.D., et al., 2011. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 42, 1158–1192. Shroff, M., deVeber, G., 2003. Sinovenous thrombosis in children. Neuroimaging Clin. N. Am. 13, 115–138. Xavier, F., Komvilaisak, P., Williams, S., et al., 2014. Anticoagulation therapy in head injury-associated cerebral sinovenous thrombosis in children. Pediatr. Blood Cancer 61 (11), 2037–2042.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 110-4 Anatomic variations in Intracranial Venous System. Fig. 110-5 Otitis Media/Mastoiditis and CSVT. Fig. 110-6 CSVT due to dehydration and iron deficiency anemia. Fig. 110-7 Head injury associated CSVT. Fig. 110-8 CSVT in association with neurosurgical intervention. Fig. 110-9 CSVT due to L-Asparaginase. Fig. 110-10 Diffusion Positivity of the thrombus in CSVT.