Venous Thrombosis in Unusual Sites

Victor J. Marder

Hylton V. Joffe

Sam Schulman

Venous thromboembolism (VTE) typically presents with lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE).¹^,² Upper extremity deep vein thrombosis (UEDVT), which usually refers to thrombosis of the brachial, axillary, or subclavian veins, has become increasingly common with widespread use of central venous catheters for chemotherapy and parenteral nutrition.³^,⁴^,⁵ Thrombosis in other deep veins, such as the cerebral or mesenteric, may be a clue to an underlying thrombophilia.⁶^,⁷^,⁸ Patients with VTE in these unusual sites have distinct risk factors, signs and symptoms, diagnostic evaluations, and treatment considerations compared to patients with traditional lower extremity DVT or PE and should alert the physician to the need for specialized diagnostic tests, therapeutic approaches, and family studies.

UPPER EXTREMITY DEEP VEIN THROMBOSIS

Historically, UEDVT was considered a benign and self-limited condition.⁹^,¹⁰^,¹¹ However, recent studies have demonstrated that UEDVT may have significant complications, including PE, loss of vascular access, the superior vena cava (SVC) syndrome, and long-term arm pain and swelling.¹²^,¹³

Anatomy

The deep venous system of the upper extremity begins at the brachial vein, which becomes the axillary vein (AV) at the lower edge of the major pectoral muscle. The superficial basilic vein joins either of these deep veins (FIGURE 84.1). The AV extends to the outer border of the first rib where it becomes the subclavian vein. The subclavian vein joins the internal jugular vein (IJV) at the inner end of the clavicle to form the brachiocephalic vein (BCV), which merges with the contralateral BCV to form the SVC.¹⁴ The subclavian artery and vein pass under the clavicle and subclavius muscle and over the first rib. The subclavian artery travels between the anterior and middle scalene muscles, whereas the subclavian vein passes in front of the anterior scalene muscle. The brachial plexus is superior and posterior to the subclavian artery and anterior to the middle scalene muscle. The brachial plexus, subclavian artery, and subclavian vein comprise the neurovascular bundle. Compression of any component of this bundle as it exits the thoracic cavity can cause the thoracic outlet syndrome and involvement of the subclavian vein predisposes to UEDVT.¹⁵

Etiology

Primary UEDVT refers either to idiopathic disease or to Paget-Schroetter syndrome⁷^,¹⁶^,¹⁷ and occurs in approximately two cases per 100,000 persons per year.¹⁸^,¹⁹ Idiopathic UEDVT has no identifiable precipitant but may be associated with occult neoplasms, especially lung cancer and lymphomas.²⁰^,²¹ Paget-Schroetter syndrome refers to spontaneous UEDVT following strenuous activity, such as pole vaulting, boxing, baseball pitching, weight lifting, or rowing in young and otherwise healthy individuals.¹⁹^,²²^,²³ In this setting, repeated injury to the intimal lining of the upper extremity veins activates prothrombotic mechanisms, eventually causing clinical thrombosis.²² These patients sometimes have coexisting conditions that cause mechanical compression of the vasculature, including the thoracic outlet syndrome, rib anomalies, long transverse processes of the cervical spine, or musculofascial bands.¹⁵^,¹⁶^,²⁴^,²⁵

Secondary UEDVT develops in patients with underlying comorbidities, including cancer,²⁰^,²⁶^,²⁷ pacemakers,²⁸^,²⁹ and central venous catheters,⁴^,³⁰^,³¹^,³²^,³³^,³⁴ and accounts for most cases of UEDVT (Table 84.1). Other conditions associated with UEDVT include intravenous cocaine use,³⁵^,³⁶ artificial reproductive technology (e.g., in vitro fertilization) especially with ovarian hyperstimulation syndrome,³⁷ and upper extremity surgery or plaster cast.³⁸ The association of oral contraceptives with UEDVT has in different studies varied from none to a 5.7-fold (95% confidence interval [CI] 2.1 to 15.7) increase of the risk.³⁹

Patients with central venous catheters constitute up to one-fourth of cases of UEDVT.⁴^,³⁰^,⁴⁰ Thrombotic risk may be higher with polyvinyl chloride catheters compared to silicone catheters.³¹ Central venous catheters also predispose to UEDVT in patients with heparin-induced thrombocytopenia.³⁴ Likely, explanations for catheter-associated UEDVT include venous stasis and vessel wall injury³⁰^,⁴¹ and the toxic effect of infusate on the vein.²⁷^,⁴²^,⁴³ Catheter tips should be positioned in the proximal SVC or at the junction between the SVC and right atrium, where blood flow is most rapid.⁴^,³⁰^,³²^,⁴⁴^,⁴⁵ Venous thrombosis and stenosis probably develop in approximately 15% of patients with a permanent transvenous pacemaker, although most of these patients are asymptomatic.²⁸^,²⁹^,⁴⁶^,⁴⁷ Independent predictors of these venous lesions include previous transvenous temporary leads, the number of leads, and a left ventricular ejection fraction of 40% or less.²⁹

Thrombophilia

Several studies have evaluated the prevalence of inherited and acquired thrombophilia in patients with UEDVT (Table 84.2).³⁹^,⁴⁵^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ Antithrombin, protein C, and protein S deficiencies are seldom present in these patients, and the prevalence of factor V_Leiden, antiphospholipid antibodies, and anticardiolipin antibodies varies widely so their role in UEDVT is unclear, although several studies have shown an increased prevalence of these antibodies in UEDVT.⁷^,¹³ The
inconsistency between studies may be partially attributed to small sample sizes, different time points of blood collection, different types of coagulation tests used, and different patient populations.

FIGURE 84.1 Veins of the upper extremity. The axillary vein (AV) extends to the outer border of the first rib where it becomes the subclavian vein (SV). The subclavian vein joins the internal jugular vein (IJV) at the inner end of the clavicle to form the brachiocephalic vein (BCV), which merges with the contralateral BCV to form the superior vena cava (SVC). RV, right ventricle. (Copyright protected material from Anatomy Atlases used with permission of the authors and Dr. Michael P. D’Alessandro, http://www.anatomyatlases.org/atlasofanatomy/plate19/04overview.shtml.)

Table 84.1 Risk factors for UEDVT

Primary UEDVT

Strenuous activity of the upper extremity (Paget-Schroetter syndrome)

Thoracic outlet syndrome

Idiopathic

Secondary UEDVT

Central venous catheters, including the Swan-Ganz catheter

Cancer (perhaps more prevalent in lung neoplasms and lymphoma)

Pacemakers

Implantable cardioverter-defibrillator

Upper extremity surgery or plaster cast

Fibrosing mediastinitis

Heparin-induced thrombocytopenia

Artificial reproductive technology especially with ovarian hyperstimulation syndrome

Intravenous cocaine use

Amyloidosis

Table 84.2 Prevalence (%) of acquired and inherited thrombophilia in patients with UEDVT

Study	Factor V_Leiden	Prothrombin Gene Mutation	Antiphospholipid	Antithrombin Deficiency	Protein S Deficiency	Protein C Deficiency
*Primary UEDVT*
Heron et al.⁵²	10.6	0	22	0	4.3	0
Martinelli et al.⁵³	8.3	—	0	0	0	0
Martinelli et al.⁵¹	8.7	9.6	7.0	—	—	—
*Primary or Secondary UEDVT*
Bombeli et al.⁶	25.3	7.3	—	1.0	2.0	2.0
Ellis et al.⁵⁴	50	—	11.1	—	—	—
Leebeek et al.⁵⁵	4.9	0	26.8	2.4	0	0
Linnemann et al.⁵⁶	15.8	4.9	7.7	0.7	0.8	3.3
Prandoni et al.¹³	7.4	—	3.7	3.7	3.7	7.4
Ruggeri et al.⁵⁷	3.7	—	14.8	0	0	3.7
Mayo⁵⁸	3.8	11.4	7.6	0	0	0

Clinical Presentation

Patients with UEDVT have a wide spectrum of presentation, ranging from no symptoms to the catastrophic SVC syndrome, characterized by facial edema, blurred vision, head fullness, vertigo, and dyspnea.¹³^,⁵⁸ A coexisting thoracic outlet syndrome may injure the brachial plexus and cause radiation of pain down the medial aspect of the arm into the fourth and fifth fingers.¹⁵ The
usual symptoms of UEDVT are extremity edema, discomfort, and erythema.¹³ Patients with coexisting PE may also have dyspnea, chest pain, or cough.³³

Table 84.3 Advantages and disadvantages of imaging modalities used to diagnose UEDVT

	Advantages	Disadvantages
Ultrasonography	• Inexpensive • Noninvasive • Reproducible	• May fail to detect central thrombus that is directly below the clavicle or sternum
Venography or CT scan	• May detect central thrombus • May detect the presence of extrinsic vessel compression	• Contrast dye • Not fully validated
Magnetic resonance angiography	• Accurately detects central thrombus • Provides detailed evaluation of collaterals and blood flow	• Limited availability • Claustrophobia • Not suitable for some patients with implanted metal

Findings on physical examination may include fever, sinus tachycardia, arm and hand edema, supraclavicular fullness, jugular venous distension, upper extremity cyanosis, a palpable tender cord, dilated cutaneous collateral veins over the chest or upper arm, and a completely or partially occluded central venous catheter.¹³^,⁵⁸^,⁵⁹^,⁶⁰ Low-grade fever may be present, but high fever is likely due to another cause, such as septic thrombophlebitis, coexisting infection, or underlying neoplasm.⁶¹^,⁶² Sinus tachycardia may reflect pain or anxiety but could also suggest compensation for reduced venous return to the heart and may occur in the setting of PE.⁶³ If thoracic outlet syndrome is suspected, the examiner should palpate the supraclavicular fossa for brachial plexus tenderness and perform provocative tests.¹⁵^,⁶⁴^,⁶⁵

Diagnosis

Muscle injury, superficial vein thrombosis (SVT), lymphedema, and neoplastic compression of the vasculature can mimic UEDVT.¹³ Therefore, the diagnosis of UEDVT cannot be made solely on the basis of the history and physical examination but must be confirmed with objective testing. D-dimer testing may have limited usefulness for excluding UEDVT because the negative predictive value is not reliably known in this setting and a majority of patients are expected to have high D-dimer concentrations because of concomitant disease.⁶⁶

Duplex ultrasonography (US) is recommended as the initial test for diagnosing UEDVT because it is noninvasive and appears to have good sensitivity and specificity for jugular, distal subclavian, and axillary UEDVT.¹³^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷² However, acoustic shadowing from the clavicle and sternum limits the reliability of this technique for assessing thrombosis in the brachiocephalic and proximal subclavian veins.⁶⁸^,⁶⁹ Based on a systematic review of published literature, compression US has a sensitivity of 97% and a specificity of 96% for UEDVT compared to venography.⁷³ Color Doppler does not seem to improve the test performance. However, additional studies are needed because these calculated performance characteristics of US are based on studies with important methodologic limitations such as small sample sizes and large between-study differences.

Contrast venography provides excellent characterization of the venous anatomy⁷⁴ but has several important drawbacks, including technical difficulty cannulating the vein in an edematous arm, use of an iodinated contrast agent, and radiation exposure (Table 84.3).⁷⁵ The contrast agent may cause renal injury; allergic reactions, including urticaria, bronchospasm, and anaphylaxis; or local extravasation and chemical phlebitis.⁷⁵^,⁷⁶ Acetylcysteine and adequate hydration may reduce contrast-induced nephrotoxicity in patients with abnormal renal function; a confirmatory large, randomized, controlled trial of acetylcysteine is underway.⁷⁷^,⁷⁸ Although iodinated contrast is rated pregnancy class B and radiation exposure from venography confers minimal risk to the fetus, concerns over teratogenicity limit the use of venography during pregnancy.⁷⁹ Despite these disadvantages, venography may be required to confirm or exclude the diagnosis of UEDVT when there is high suspicion for thrombosis despite a negative or inconclusive US study.⁶⁷ Venography is also required before interventions, including catheter-directed thrombolysis and angioplasty, and is used to assess the response to these treatments.⁷^,¹⁷^,⁸⁰^,⁸¹^,⁸²

Magnetic resonance angiography (MRA) correlates well with venography and provides a more complete evaluation of blood flow, contralateral vessels, and the SVC and the brachiocephalic vessels.⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸ Therefore, MRA is a reasonable noninvasive alternative when venography is contraindicated or technically impossible (FIGURE 84.2).

Treatment

There are no randomized, controlled trials evaluating the optimal treatment of patients with UEDVT; the general approach used today is based on case series, retrospective reviews, and expert opinion.

Anticoagulation is the cornerstone of therapy for DVT at any site,⁸⁹^,⁹⁰ reducing thrombus propagation and maintaining patency of venous collaterals.⁴ Usually, intravenous unfractionated heparin (UFH) is promptly started at the time of diagnosis unless there is an absolute contraindication to anticoagulation.
Low-molecular-weight heparin (LMWH) is a safe and effective alternative and may reduce the duration of hospitalization.⁹¹ Typically, heparin is used as a “bridge” to warfarin therapy, which is continued for a minimum of 3 months with an international normalized ratio of 2.0 to 3.0.⁹^,⁵⁹^,⁹² A longer duration of anticoagulation may be appropriate if there is an underlying hypercoagulable state.⁶³^,⁹³^,⁹⁴

FIGURE 84.2 MRA demonstrating left BCV (arrow). (Adapted from Joffe HV, Goldhaber SZ. Upper-extremity deep vein thrombosis. Circulation 2002;106(14):1874-1880.)

Thrombolysis. Several case series of UEDVT catheter-directed thrombolysis in carefully selected patients have reported excellent outcomes with only minor bleeding complications, such as occasional hematomas or oozing at catheter sites.¹⁷^,⁸⁰^,⁸¹^,⁸³ Although these small studies are underpowered to assess the risk of intracranial or gastrointestinal hemorrhage, the frequency of these serious events is expected to be similar to that of catheter-directed thrombolysis of lower extremity DVT.⁹⁵^,⁹⁶^,⁹⁷

FIGURE 84.3 Multimodal therapy for UEDVT: 51-year-old weight lifter complaining of right arm pain. Initial venogram (A) shows occluded right axillary and subclavian veins with flow through collateral vessels (arrow). After percutaneous thrombectomy (B), there is persistent occlusion of the proximal subclavian vein (arrow). After thrombolysis (C), the subclavian vein (SV) is fully patent with flow into the brachiocephalic vein (BCV). (Adapted from Joffe HV, Goldhaber SZ. Upper-extremity deep vein thrombosis. Circulation 2002;106(14):1874-1880.)

The best thrombolysis candidates are young, otherwise healthy patients with acute, primary UEDVT because these individuals may have significant long-term morbidity if treated only with conventional anticoagulation.⁷^,⁹⁸^,⁹⁹^,¹⁰⁰ Other appropriate candidates for thrombolysis include patients with symptomatic SVC syndrome and those who require preservation of a mandatory central venous catheter.⁸¹^,¹⁰¹^,¹⁰²^,¹⁰³ Catheter-directed recombinant tissue-type plasminogen activator (tPA) may be administered as a continuous infusion of 1 to 2 mg/h, for at least 8 hours with serial venography used to assess treatment response (FIGURE 84.3). Percutaneous mechanical thrombectomy with devices such as the AngioJet (MEDRAD Interventional/Possis; Minneapolis, Minnesota) can be used to rapidly extract large quantities of thrombus with the goal of reducing the dose and duration of thrombolytic therapy.¹⁰⁴ Unlike conventional anticoagulation, thrombolysis restores venous patency early, which may minimize injury to the vessel endothelium and potentially reduce the risk of long-term complications, including the morbid postthrombotic syndrome.⁵⁹^,⁹⁸

Several thrombolytic agents have been used to treat DVT. Urokinase is effective⁸⁰^,⁸¹^,¹⁰³^,¹⁰⁵^,¹⁰⁶ but is now only approved by the Food and Drug Administration for lysis of pulmonary emboli that are massive or accompanied by unstable hemodynamics. Streptokinase has also been used successfully¹⁰⁷^,¹⁰⁸^,¹⁰⁹^,¹¹⁰ but may be ineffective if previously administered. tPA is a popular choice in the United States.¹¹¹ Catheter-directed thrombolysis is preferred over systemic thrombolysis because local delivery of therapy achieves higher rates of complete clot resolution with lower doses of medication.⁸¹^,⁸²^,¹¹²^,¹¹³ Heparin is usually given concurrently to prevent pericatheter thrombus formation.⁵⁹ Thrombolysis is most effective when used within several weeks of the onset of symptoms before progressive thrombus organization has occurred.⁸¹^,⁸²^,¹⁰¹^,¹⁰⁶

Surgery. Although thrombolysis may successfully restore vessel patency, persistent vein compression may predispose to recurrent thrombosis and long-term morbidity.¹⁷^,⁵⁹ Therefore, after successful thrombolysis for primary UEDVT, vascular surgeons may recommend early assessment for vein compression
followed by prompt surgical correction, such as resection of bone or lysis of dense, perivascular adhesions.¹²^,¹⁷^,⁵⁹^,¹⁰⁴^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸ Persistent strictures after surgery could be treated with venoplasty and possibly vein stenting.¹¹⁹^,¹²⁰ This multimodal approach can successfully achieve long-term vessel patency.⁷^,¹⁶^,¹⁷^,⁹⁹^,¹²⁰^,¹²¹^,¹²²^,¹²³ Although surgical thrombectomy restores venous patency, this approach is considered as a last resort because it is invasive, requires general anesthesia, and may be complicated by pneumothorax and brachial plexus damage.⁵⁹ Conservative therapy rather than prompt surgical intervention may be preferable for selected patients with the thoracic outlet syndrome because physical therapy, weight loss, and nonsteroidal anti-inflammatory medications may avert the need for surgery.¹⁵

SVC filters may protect against clinical PE, but there are limited data supporting their safety and efficacy.¹²⁴^,¹²⁵ There is concern that the benefits of SVC filters may be outweighed by their risks, including filter migration, dislodgment, fracture, and precipitation of the SVC syndrome. Potential candidates for SVC filter placement include patients with UEDVT who have an absolute contraindication to anticoagulation or those who develop PE despite adequate anticoagulation.

Prophylaxis. Early small trials suggested that the incidence of UEDVT can be reduced in patients with cancer and an inserted central venous catheter by using pharmacologic prophylaxis with either minidose warfarin (1 mg daily) or the LMWH dalteparin.¹²⁶^,¹²⁷^,¹²⁸ However, several subsequent trials have failed to show a benefit of pharmacologic prophylaxis in this patient population.⁴⁴^,⁴⁷^,⁴⁸^,⁴⁹^,¹²⁹ Similarly, it is unclear whether pharmacologic prophylaxis protects against catheter-associated UEDVT in patients without cancer.¹³⁰^,¹³¹ Adding heparin to parenteral nutrition does not significantly reduce the risk of catheter-associated UEDVT, but these studies are small and underpowered.¹³⁰ These limited data may explain why pharmacologic prophylaxis of catheter-associated UEDVT is not commonly used in the United States. In a DVT registry,³³ less than one-fourth of patients with catheter-associated UEDVT and no obvious contraindication to anticoagulation were receiving prophylaxis at the time of diagnosis.

FIGURE 84.4 Venous phase of carotid angiography in the anteroposterior (left panel) and lateral (right panel) projections. The superior sagittal sinus (21), confluence of sinuses (5), transverse sinus (23), sigmoid sinus (16), and IJV (11) are as indicated. (Reproduced from the Encyclopedia of Medical Imaging [Medcyclopaedia], with permission.)

Complications

UEDVT may cause significant morbidity.¹⁰^,¹¹^,¹³ PE is present in up to one-third of patients with UEDVT, although fatal PE arising from UEDVT is uncommon.¹³^,¹³²^,¹³³^,¹³⁴ PE may occur during removal of a central venous catheter because fibrin sheaths may peel off, break loose, and embolize.⁵⁸ Therapeutic heparinization for at least 24 hours before removal of the catheter may be a reasonable approach.

Other complications include loss of vascular access, the SVC syndrome, septic thrombophlebitis, brachial plexopathy, thoracic duct obstruction, and recurrent UEDVT.¹²^,⁵⁰^,¹³⁵ The postthrombotic syndrome, secondary to venous hypertension from outflow obstruction and valvular injury, can lead to incapacitating limb pain and swelling.¹³⁶ This syndrome occurs in 7% to 44% of patients treated only with conventional anticoagulation⁵ and may be less likely to occur following multimodal therapy.⁷^,⁹⁸^,¹⁰⁰^,¹³⁷^,¹³⁸ Therefore, aggressive treatment, including thrombolysis, may be most suitable for patients with primary UEDVT who are young and otherwise healthy and more likely to be bothered by the postthrombotic syndrome than are patients with chronic medical conditions. Patients with secondary UEDVT have high short-term mortality rates compared with patients with lower extremity DVT,¹³⁹ most of them dying from underlying medical problems.

CEREBRAL VEIN AND SINUS THROMBOSIS

Anatomy and Pathogenesis

Cerebral vein and sinus thrombosis (CVST) includes thrombosis of the veins and dural sinuses of the brain.¹⁴⁰^,¹⁴¹ Most often, thrombosis involves the superior sagittal sinus (FIGURE 84.4), which occupies the superior border of the falx cerebri, draining posteriorly into a “confluence of sinuses,” then coursing mostly into one of the transverse sinuses, following the sigmoid sinus as it becomes continuous with the IJV. In the preantibiotic era, CVST was associated with chronic suppurant infections of the inner ear and skull, but most cases today
have no identifiable cause or are associated with head trauma, oral contraceptive (OC) usage, pregnancy or the puerperium, cachexia, dehydration, local malignancy, arteriovenous malformations, or other causes of generalized hypercoagulability. CVST is a well-recognized manifestation of the inherited and acquired thrombophilias, complicating virtually all of the known causes.¹⁴²^,¹⁴³^,¹⁴⁴^,¹⁴⁵^,¹⁴⁶ Of note is the danger of cerebral vein thrombosis in patients with a hereditary predisposition who have been prescribed OC agents⁸ and in patients with paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, and myeloproliferative disorders.¹⁴⁷^,¹⁴⁸^,¹⁴⁹^,¹⁵⁰ Following thrombus formation in a venous sinus, increased venous pressure leads to cerebral edema and even hemorrhage (FIGURE 84.5), a process that may progress to the development of large and/or multiple venous infarctions, which cross the normal boundaries of arterial supply.¹⁵¹

FIGURE 84.5 Intracerebral venous sinus thrombosis. A: Shows an axial CT scan with hemorrhagic infarction of the left temporal lobe. B: Shows the MR, T2-weighted axial image, with an isointense area of recent hemorrhage and a hyperintense area surrounding the infarcted edematous zone. C: Shows an angiographic MR study with occlusion of the left transverse sinus, the sigmoid sinus, and the internal jugular vein. (Reproduced from the Encyclopedia of Medical Imaging [Medcyclopaedia], with permission.)

Clinical Aspects

Clinical features of CVST may be nonspecific and are often insidious in onset.¹⁴⁰^,¹⁴¹^,¹⁵¹ In a series of 32 cases admitted to hospital, the most frequent presenting complaints were headache (81%) and “reduced consciousness” (72%).¹⁵² Among 17 cases initially seen in the emergency department, the presenting symptom was headache in 70% of cases; focal neurologic complaints such as weakness and aphasia were present in 29% and seizures in 24%.¹⁵³ In a large observational study, Ferro et al.¹⁵⁴ noted seizures in 39% of 624 cases; 6.9% of patients exhibited
seizure as an early manifestation, associated with supratentorial thrombotic lesions (OR = 3.0). Headache in combination with papilledema and absent focal neurologic signs can simulate brain tumor (“pseudotumor cerebri”).¹⁵⁵ Nausea, vomiting, and mental confusion develop over hours to days, followed in the most severe cases by stupor and coma, but focal sensory or motor losses are not dominant features, and the cerebrospinal fluid and the electroencephalogram may show only nonspecific findings. Fever will usually accompany sinusitis or other infection that leads to direct extension of the process into a contiguous (e.g., cavernous) sinus. Diagnosis is established by magnetic resonance (MR) or computerized tomography (CT) venography,¹⁴¹^,¹⁵⁶^,¹⁵⁷^,¹⁵⁸^,¹⁵⁹ which documents the important contribution of “cytotoxic edema” in the pathogenesis of cerebral venous infarction.¹⁶⁰ D-Dimer levels have been noted to be elevated, in correlation with the degree of thrombosis, and it is unlikely that an acute thrombotic event exists in the face of a normal D-dimer value.¹⁶¹ Predictors of adverse outcomes (death, dependency) are age >37 years, coma, intracranial hemorrhage, central nervous system infection, or malignant disease.¹⁶²

Pediatric and Elderly Patients

Neonates

A review of 52 neonates (median gestational age 39 weeks) in Amsterdam indicated an incidence of CVST of 1.4 to 12 cases per 100,000 births.¹⁶³ There was an association with assisted or complicated delivery in 62%, and seizures were the primary manifestation (56%), appearing at a median age of 1.5 days (0 to 28 day range). Anticoagulation was administered in 42% of cases, without hemorrhagic complications. Mortality was 19% and moderate to severe neurologic sequelae occurred in 38%. In a prospective study of 90 neonates followed at the Hospital for Sick Children in Toronto,¹⁶⁴ complete recanalization occurred in 90% by 3 months, but a “lack of anticoagulation” predicted thrombus propagation (P = 0.0007). Late outcomes at 2.5 years (median) included epilepsy in 17% and neurologic disability (language, sensorimotor, or cognitive/behavioral) in 56%. The importance of anticoagulation is highlighted by a retrospective study in which half of a cohort of 18 patients with CVST managed with hydration only had clot extension.¹⁶⁵

Children

Presentation of CVST in the postneonatal, pediatric population resembles that seen in adults, with local symptoms reflecting cerebral edema of headache, seizures, and emesis, plus focal neurologic signs or coma and generalized complaints of lethargy and anorexia.¹⁶⁶ Many patients (40%) had prior chronic conditions and the remainder usually had an acute illness (infection or dehydration). Interestingly, iron deficiency or hemolytic anemia was present in 62% of cases, as commonly as was a prothrombotic disorder, which was mostly an elevated factor VIII or homozygous methylene tetrahydrofolate reductase (MTHFR) mutation.¹⁶⁶ A systematic study of prothrombotic associations in neonates and children with CVST¹⁴⁶ noted significant values for hereditary predispositions such as deficiency of antithrombin and protein C (OR 7 to 8), or protein S; factor V_Leiden and the prothrombin G20210A mutation (OR 2.4 to 3.2), less so for the MTHFR mutation (OR 1.6); and acquired changes of antiphospholipid antibodies (OR 6.95) and increased lipoprotein (a) (OR 6.27). A separate study of 20 children emphasized the prior occurrence of minor head trauma preceding sigmoid or transverse sinus thrombosis.¹⁶⁷ Of 42 patients with CVST, only 18 were anticoagulated, and follow-up at a median of 1 year showed sequelae in 62%, including pseudotumor cerebri, cognitive disability, epilepsy, and hemiparesis.¹⁶⁶

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