Cerebral Sinovenous Thrombosis

Cerebral Sinovenous Thrombosis – 10 Interesting Facts

Cerebral sinovenous thrombosis is the presence of a blood clot in the dural sinuses and/or cerebral veins. Cerebral venous thrombosis is an umbrella term used to encompass both entities; it is considered a type of stroke
Highest prevalence risk factors are use of oral contraception, underlying prothrombotic conditions, and pregnancy or puerperium¹
High level of suspicion is essential to diagnosis
Presentation can be variable, and patients can present with symptoms to a variety of physician subspecialties
Acute/subacute severe headache, either isolated or accompanied by sensory or motor deficit, seizure, cranial nerve palsy, or vision impairment, should trigger consideration of diagnosis, especially in patients with risk factors for thrombosis
Neuroimaging with head CT scan with contrast material, CT venography, or MR venography can confirm or exclude diagnosis¹⁸
Cerebral venous thrombus warrants emergent treatment; early and appropriate treatment can affect overall outcome
Treatment of choice is immediate anticoagulation with unfractionated or low-molecular-weight heparin, even if there is presence of intraparenchymal hemorrhage. Exception is cerebral venous thrombosis in setting of vaccine-induced immune thrombotic thrombocytopenia after recent adenovirus-vector coronavirus vaccine, in which case nonheparin anticoagulants are required
In some cases, neurosurgical or endovascular intervention may be warranted
Generally has favorable prognosis with early diagnosis and treatment but can be disabling or life-threatening in some patients

Alarm Signs and Symptoms

Signs of elevated intracranial pressure and risk for brain herniation include:
- Papilledema
- Large, unreactive pupil(s)
- Massive intracranial hemorrhage with mass effect and midline shift on neuroimaging

Introduction

Figure 1. Cerebral venous system and frequency of involvement.1,4

Cerebral sinovenous thrombosis is the presence of a blood clot in the dural sinuses and/or cerebral veins. Cerebral venous thrombosis is an umbrella term used to encompass both entities
Superior sagittal sinus is most frequently affected (62%), followed by transverse sinuses (41%-45%), straight sinus (18%), and deep venous system (11%).¹ Cavernous sinus thrombosis is less common (1%)² (Figure 1)
Classified as a type of stroke
- Accounts for about 0.5% of strokes³ and usually affects individuals younger than 50 years, especially females⁴
In 2021, cerebral venous thrombosis has been reported as a manifestation of vaccine-induced immune thrombotic thrombocytopenia, a condition rarely associated with adenovirus-vector coronavirus vaccines and mediated by platelet-activating antibodies to platelet factor 4⁵

Epidemiology

Relatively rare condition, although incidence is probably higher than previously thought²
- Recent studies reported overall incidence of 1.32⁶ to 1.57² per 100,000 person-years
Most common in females of reproductive age
- Among females between ages 31 and 50 years, incidence is 2.78 per 100,000 person-years (compared with 0.64 in males of this age)⁶
Males, however, are 2 times more likely to suffer from coma secondary to cerebral sinus or venous thrombosis, as compared to females⁷

Etiology

Underlying prothrombotic states, intracranial infection, and craniofacial trauma are frequent causes⁸
Similar to venous thrombosis in other sites, Virchow triad of stasis of blood, changes in vessel wall, and changes in composition of blood plays a role in development of cerebral sinovenous thrombosis regardless of specific associated risk factors
- Pathophysiology
  - Increased coagulability and/or reduced venous flow in a cerebral vein or dural sinus lead to development of a blood clot, resulting in increased venous pressure and reduced capillary perfusion
  - Once capacity of cerebral collateral network is exceeded, there is onset of venous stasis, increased intramural pressure, and damage to veins and blood-brain barrier. This leads to increased vasogenic edema and hemorrhagic infarcts
  - Reduction in cerebral perfusion can lead to cytotoxic edema and increase in intracranial pressure; cerebrospinal fluid reabsorption failure can follow obstruction of cerebral sinuses, which can increase intracranial pressure further

Risk Factors

Highest prevalence risk factors:¹
- Use of oral contraception (54.3%)
- Prothrombotic conditions (34.1%)
- Pregnancy/puerperium (21%)
Risk factors can be acquired or genetic⁹
- Acquired thrombophilia/thrombophilic states include:
  - Pregnancy
  - Puerperium
  - Nephrotic syndrome
  - Antiphospholipid syndrome
- Genetic thrombophilias include:
  - Protein C and S deficiency
  - Antithrombin deficiency
  - Prothrombin G20210A variant
  - Hyperhomocysteinemia
  - Factor V Leiden variant
- Drugs
  - Oral contraceptives
  - Hormone replacement therapy
  - Steroids
  - Asparaginase
- Hematologic conditions
  - Polycythemia
  - Thrombocythemia
  - Iron deficiency anemia
  - Paroxysmal hemoglobinuria
- Local infection
  - Ear and sinus infections
  - Infection of mouth, face, and neck
  - Meningitis
- Systemic disease
  - Malignancy
  - Systemic lupus erythematosus
  - Rheumatoid arthritis
  - Behçet disease
  - Granulomatosis with polyangiitis
  - Thromboangiitis obliterans
  - Inflammatory bowel disease
  - Sarcoidosis
  - Thyroid disease
  - COVID-19¹⁰
- Mechanical, procedural, and intracranial factors
  - Neurosurgical procedures
  - Cranial trauma
  - Lumbar puncture
  - Jugular vein catheterization
  - Dural arteriovenous fistula or intracranial arteriovenous malformation
- Miscellaneous factors
  - Dehydration
  - Obesity
  - Vaccine-induced thrombocytopenia¹⁰
Newly identified risk factors during COVID-19 pandemic
- Cerebral venous thrombosis has been associated with both SARS-CoV-2 infection and with adenovirus-vector coronavirus vaccines (vaccine-induced immune thrombotic thrombocytopenia); both associations appear to be rare¹¹¹²
  - ChAdOx1 nCoV-19 (AstraZeneca and others): incidence of vaccine-induced immune thrombotic thrombocytopenia is 1:150,000⁹
  - Ad26.COV2.S (Janssen; Johnson & Johnson): incidence of vaccine-induced immune thrombotic thrombocytopenia is 1:470,000⁹

Risk Models and Risk Scores

Risk model has been developed to predict outcome in patients with cerebral venous thrombosis (Table 1)¹³¹⁴
- Scores are classified into good outcome (less than 3 points) versus poor outcome (3 or more points), where poor outcome indicates higher risk of death or dependency at 6 months¹⁴
- Good sensitivity (96.1%) but poor specificity (13.6%)¹⁴
- May be useful aid to avoid unnecessary or aggressive interventions in low-risk patients and may help to identify high-risk patients
- Needs additional validation and is not yet in common use clinically
Another risk model using different scoring values incorporates ages less than 37 years and presence of central nervous system infection as risk factors for poor prognosis¹⁵ in addition to factors listed in Table 1

Table 1. Cerebral venous thrombosis risk score.¹³¹⁴

Associated signs or symptoms	Points
Malignancy	2
Coma	2
Deep vein thrombosis	2
Male	1
Decreased level of consciousness	1
Intracerebral hemorrhage	1
Add points for score. Scores range from 0 to 9. Scores are categorized into good outcome (<3 points) versus poor outcome (≥3 points), where poor outcome indicates higher risk of death or moderate disability (modified Rankin Scale score >2) at 6 months.¹⁴

Diagnosis

Approach to Diagnosis

Figure 2. Management of cerebral venous thrombosis. – CTV, CT venography; CVT, cerebral venous thrombosis; ICH, intracranial hemorrhage; MRV, MR venography; OAC, oral anticoagulant; VTE, venous thromboembolism.
Diagnosis of cerebral sinovenous thrombosis is based on high clinical suspicion and confirmation with imaging studies¹⁶ (Figure 2)
- Acute/subacute severe headache, either isolated or accompanied by sensory or motor deficit, seizure, cranial nerve palsy, or vision impairment, should trigger consideration of diagnosis, especially in patients with risk factors for thrombosis
- Can mimic other acute neurologic conditions; history and physical examination alone can suggest but not establish diagnosis
- D-dimer testing can be helpful, along with other clinical variables, before neuroimaging,¹⁷¹⁸ although it cannot be used in isolation to rule disease in or out
  - Clinical probability score that incorporates D-dimer results has been developed based on prospective multicenter study and may be useful as pretest score (Table 2)¹⁷
- Neuroimaging with head CT scan with contrast material, CT venography, or MR venography can confirm or exclude diagnosis¹⁸

Table 2. Cerebral venous thrombosis clinical probability score.¹⁷

Associated signs or symptoms	Points
Seizure at presentation	4
Known thrombophilia	4
Oral contraception use	2
Symptoms for >6 days	2
Worst headache ever experienced	1
Focal neurological deficit at presentation	1
Add points for score (14 points max score). Scoring:¹⁷6 = High probability3-5 = Moderate probability0-2 = Low probability
Scoring that includes D-dimer as an additional variable may be most helpful (17 points max score):¹⁷D-dimer ≥500 mcg/L adds 3 points to scoreBest cerebral venous thrombosis prediction model was with clinical score ≥6 plus D-dimer ≥500 mcg/L (sensitivity 83%; specificity 86.8%)

Caption: Data from Heldner MR et al. Prediction of cerebral venous thrombosis with a new clinical score and D-dimer levels. Neurology. 2020;95(7):e898-e909.

Staging or Classification

Can be classified based on duration of headache:¹⁹
- Acute: 48 hours or less
- Subacute: more than 48 hours to 30 days
- Chronic: 1 month or more

Workup

History

Presentation is variable from patient to patient and depends on extent of thrombus, location, and physiologic sequelae
- Symptoms can be caused by obstruction of venous outflow with increased intracranial pressure, ischemia, or infarction of brain tissue with hemorrhagic changes
- Especially in young adult female patients, history of headache followed by seizure, symptoms of stroke, or altered mental status should always raise suspicion for cerebral venous thrombosis
Headache is most common presentation, with about 90% of patients with cerebral venous thrombosis reporting it²⁰
- Can be acute onset but commonly develops over period of days with increasing headache severity
- Variable in nature, intensity, and location; may be unilateral or bilateral²¹
Headache followed by sensory or motor deficit, cranial nerve palsy, and vision impairment is common
- Focal motor deficits can be present in about 40% of patients²⁰
Focal or generalized seizures can be present in about 40% of patients and can evolve into status epilepticus²⁰
Presentation without headache but with altered consciousness, diplopia, and visual loss is possible, but these symptoms rarely occur in absence of headache
Obtain additional relevant history to screen for potential prothrombotic conditions and risk factors
- Use of oral contraceptives
- Current or recent pregnancy
- Family history of blood clots
- Underlying inflammatory disease and infectious processes
- COVID-19 respiratory infection (cerebral venous thrombosis develops at a mean of 13 days, and most patients do not have additional thrombotic risk factors)¹¹
- Recent (within 1 month) adenovirus-vector coronavirus vaccine⁵⁹

Physical Examination

Common neurologic findings in patients with cerebral venous thrombosis include:
- Hemiplegia, hemiparesis
- Hemisensory loss
- Gaze palsy
- Seizures
- Aphasia
- Altered mental status
- Coma
Proptosis with or without cranial nerve III, IV, or VI palsy
Papilledema can be present in about 30% of patients and may indicate elevated intracranial pressure²⁰

Laboratory Tests

Cerebral venous thrombosis cannot be confirmed or ruled out on basis of specific laboratory tests
Obtain CBC, chemistry panel, sedimentation rate, and coagulation studies for patients with suspected cerebral venous thrombosis¹
Obtain D-dimer level before neuroimaging, except in those with isolated headache or prolonged duration of symptoms (ie, more than 1 week before test)²²
- D-dimer can be elevated in patients with cerebral venous thrombosis; however, sensitivity is 82% to 94%, with higher sensitivity in patients with acute, extensive disease and lower sensitivity in those with subacute or more focal thrombus¹⁸
In setting of recent COVID-19 vaccine:
- If platelet count is less than 150 × 10⁹ cells/L (and/or 50% drop from previous value) and D-dimer is elevated, obtain immunoassay for antiplatelet factor 4 antibodies (heparin-induced thrombocytopenia ELISA test), which suggests vaccine-induced immune thrombotic thrombocytopenia if thrombosis is identified on imaging⁵
Consider testing for underlying thrombophilia
- European guidelines recommend such testing for individuals with high pretest probability of having severe thrombophilia (ie, personal and/or family history of venous thrombosis, cerebral venous thrombosis without a transient or permanent risk factor)²²
- US guidelines recommend routine evaluation during initial clinical assessment¹
- Hematology consultation is helpful for determining specific testing strategy
Lumbar puncture is not diagnostic but may be helpful in ruling out meningitis and/or encephalitis as cause of symptoms, unless contraindications exist
- Contraindications include uncontrolled coagulopathy, skin infection over needle site, and patient at risk of brain herniation
- Cerebrospinal fluid sample may show elevated opening pressure, pleocytosis, and increased RBC count; however, these findings are nonspecific¹⁸

Imaging Studies

In the setting of headache or other acute neurologic symptoms, head CT scan without contrast material is commonly the first neuroimaging test obtained to identify intracerebral hemorrhage and other life-threatening conditions
However, CT scan without contrast material has poor sensitivity for identifying cerebral venous thrombosis, and findings can be normal in 30% to 60% of cases¹⁸
- Positive findings include:
  - Acute thrombosis of cortical veins and dural sinuses appears as a homogenous hyperdensity that fills vein or sinus
  - Cord sign can be seen in acute thrombosis of cortical or deep veins⁴
  - Filled delta or dense triangle sign can be seen if posterior portion of superior sagittal sinus is acutely thrombosed⁴
  - Bilateral intracerebral hemorrhages, hemorrhagic conversion of ischemic stroke, or an infarction beyond boundaries for an arterial territory should raise suspicion for cerebral venous sinus thrombosis
  - Deep vein thrombosis can lead to bilateral thalamic infarction and/or hemorrhage and can be seen on head CT scan without contrast material
Perform imaging of cerebral venous system when:¹
- Cerebral venous thrombosis is suspected but is not identified on initial CT imaging
- There is lobar intracerebral hemorrhage of unclear cause or cerebral infarction crossing arterial territories on initial CT neuroimaging
- Recommended imaging modalities include either:¹²²
  - Brain MRI with contrast-enhanced venography:
    - Thrombus can be visualized in T1-weighted images or as loss of signal in venous system on MR venogram
    - Signal from thrombosed veins and hemorrhage (if any) can change over time on different MRI sequences and may warrant discussion with radiologist, keeping the clinical history in perspective
    - Gradient echo sequence or susceptibility-weighted imaging may be useful in identifying hemorrhagic lesions.²³
  - Head CT scan with contrast-enhanced venography (with or without 3D reconstruction):
    - Reasonable alternative¹⁰
      - Centers in which MRI/MR venography unavailable
      - Low pretest probability
    - Can directly visualize thrombus, which appears as absence of contrast agent filling in thrombosed vein.
    - Delta sign can also be present on contrast-enhanced study and represents thrombosis of posterior portion of superior sagittal sinus or transverse sinus
  - For thrombosis of smaller veins, MRI contrast-enhanced venography is more sensitive than non–contrast-enhanced time-of-flight MRI, although time-of-flight sequences have excellent sensitivity for slow flow.¹

Diagnostic Procedures

Cerebral angiography with venography may be needed in patients with high suspicion for cerebral venous thrombosis in whom initial radiographic studies such as CT scan, CT venography, or MR venography have been inconclusive
- Venous phase of angiogram will show partial or complete filling defect in thrombosed vein.

Differential Diagnosis

Table 3. Differential Diagnosis: Cerebral sinovenous thrombosis.

Condition	Description	Differentiated by
Meningitis	Classically presents as headache, fever, and neck stiffness	Meningeal signs are absent in cerebral venous thrombosis. Cerebrospinal fluid analysis confirms diagnosis
Subarachnoid hemorrhage from ruptured cerebral aneurysm	Classically presents as worst headache of life	Headache reaches maximal intensity at onset versus gradual worsening of headache in cerebral venous thrombosis. Head CT scan, MRI, and/or xanthochromic cerebrospinal fluid confirms diagnosis
Idiopathic intracranial hypertension	Classically presents as sixth nerve palsy, papilledema, and visual field deficits	Diagnosis of idiopathic intracranial hypertension can be made using modified Dandy criteria:Signs or symptoms of elevated intracranial pressure (eg, transient visual loss, tinnitus, headache, papilledema) without any other neurologic deficitNormal cerebrospinal fluid analysisNo apparent cause for elevated intracranial pressure discernable
Preeclampsia or eclampsia	Classically presents with headache, nausea, and visual symptoms	Presents in pregnancy or postpartum state. Elevated blood pressure is hallmark of preeclampsia or eclampsia
Posterior reversible encephalopathy syndrome	Classically presents with headache and altered mentation with elevated blood pressure	Posterior reversible encephalopathy syndrome typically occurs in patients with immunosuppression, hypertension, and end-stage renal disease. Focal deficits are rare. MRI scan characteristically shows white matter edema
Reversible cerebral vasoconstriction syndrome	Classically presents as recurrent thunderclap headache	Reversible cerebral vasoconstriction syndrome typically presents in peripartum state with hypertension and with intake of certain medications. Arterial imaging demonstrates narrowing of 2 or more intracranial arteries
Intracranial arterial dissection	Usually presents with headache, neck pain, and focal neurologic deficits	History of neck manipulation, trauma, or injury raises suspicion for dissection. Arterial imaging confirms diagnosis
Giant cell arteritis (temporal arteritis)	Usually presents with headache, visual symptoms, and jaw pain with or without fever	Typically presents in patients older than 50 years and in patients with history of polymyalgia rheumatica. Diagnose in presence of symptoms of jaw claudication, tender temporal artery, or elevated erythrocyte sedimentation rate/C-reactive protein
Acute angle-closure glaucoma	Usually presents with headache, nausea/vomiting, and visual symptoms	Typically abrupt and has associated eye injection and blurry vision. May have decreased pupillary reactivity

Treatment

Approach to Treatment

Anticoagulation is cornerstone of treatment, even with evidence of intracranial hemorrhage
- Start immediately when diagnosis is confirmed²²²⁴
If elevated intracranial pressure is suspected, transfer to appropriate level of care (eg, ICU) and immediately begin measures to reduce intracranial pressure³
- Osmotic therapy (hypertonic saline and/or mannitol)
- Sedation
- Hyperventilation
- Consider decompressive hemicraniectomy
- If loss of vision is ongoing concern, consider:
  - Acetazolamide
  - Surgical approaches such as cerebrospinal diversional shunts or optic nerve sheath fenestration
Begin antiepileptic treatment in patients who present with focal or generalized seizure in setting of cerebral venous thrombosis¹²²
- Antiepileptic medication can be continued until outpatient follow-up or may be discontinued sooner if recommended by appropriate consultant
Treat headache symptomatically
Treat associated and underlying conditions, if present⁴
- If bacterial infection is suspected, begin appropriate antibiotics promptly
Management of cerebral venous thrombosis differs if it occurs in setting of suspected vaccine-induced immune thrombotic thrombocytopenia
- Multiple specialty organizations recommend immediate treatment with nonheparin anticoagulant and IV immunoglobulin to competitively inhibit binding of vaccine-induced immune thrombotic thrombocytopenia antibodies to platelets¹²
- Specific anticoagulant and IV immunoglobulin recommendations are available in guidelines from American Heart Association/American Stroke Association,²⁵ American Society of Hematology,²⁶ International Society on Thrombosis and Haemostasis,²⁷ and British Society of Haematology²⁸
- Additional potential treatments for this syndrome include high-dose corticosteroids, plasma exchange, and fibrinogen substitution⁹
Follow-up neuroimaging to assess clot burden is performed on case-by-case basis based on clinical expertise⁴
In patients in whom anticoagulant therapy is not effective or clot burden remains high, endovascular removal of clot or endovascular thrombolysis can be considered using multidisciplinary team approach to consider risks and benefits²²
- However, limited evidence does not show improved functional outcomes²⁹

Drug Therapy

Anticoagulation is indicated, even in presence of intracranial hemorrhage¹²²
- Acute treatment is with heparin
  - Subcutaneous low-molecular-weight heparin is preferred over unfractionated IV heparin¹⁰
  - Pregnant patients should be treated with therapeutic dose low-molecular-weight heparin throughout pregnancy¹
- In setting of cerebral venous thrombosis with suspected vaccine-induced immune thrombotic thrombocytopenia (thrombocytopenia and positive antiplatelet factor 4 antibodies), immediate initiation of nonheparin anticoagulant (ie, IV direct thrombin inhibitors, fondaparinux, direct oral anticoagulants) is recommended because of overlap in mechanism of vaccine-induced immune thrombotic thrombocytopenia with that of heparin-induced thrombocytopenia¹²
  - Consult relevant specialty society guidelines for specific treatment recommendations²⁵²⁶²⁷²⁸
- Transition to oral anticoagulant once acute condition is stable
  - In patients with provoked cerebral venous thrombosis (eg, caused by infections or medications), oral anticoagulant is recommended for 3 to 6 months²²
    - If using vitamin K antagonist (eg, warfarin), target INR goal is 2 to 3
  - The most recent American Heart Association guidelines state that direct oral anticoagulants appear to be a safe and effective alternative option to vitamin K antagonists¹⁰
  - In patients with unprovoked cerebral venous thrombosis, oral anticoagulation is recommended for 3 to 12 months¹⁰²² or longer depending on opinion of physician with expertise in cerebral venous thrombosis or primary disease process (if applicable)
  - In patients with recurrent unprovoked cerebral venous thrombosis, indefinite oral anticoagulation is recommended²² depending on opinion of physician with expertise in cerebral venous thrombosis or primary disease process (if applicable

Table 4. Drug Therapy: Cerebral sinovenous thrombosis.

Medication	Therapeutic use	Dosage	Safety concerns	Notable adverse reactions	Special considerations
Parenteral anticoagulation
Low-molecular-weight heparin (LMWH)
Dalteparin	Prevent thrombus extension, facilitate recanalization, and prevent DVT/PE regardless of presence of ICH^D1^D2 LMWH is preferable to UFH when there are no contraindications for use; data trend favors LMWH in mortality and functional outcomes with similar rates of systemic bleeding^D2^D3	100 units/kg subcutaneously twice daily^D4 Adjust dose to target anti-Xa concentration of 0.5-1.5 International Units/mL for patients with CrCl <30 mL/minute^D5	BOXED WARNING: risk of hematoma with spinal/epidural anesthesia or puncture^D5 Contraindicated in patients with major bleeding, history of HIT or HITT, porcine hypersensitivity, or those undergoing epidural/neuraxial anesthesia^D5 Use with caution in patients with renal impairment or at high bleeding risk^D5	Bleeding Hepatic enzymes, increased HIT or HITT Injection site pain Thrombocytopenia^D5	Coagulation labs: anti-Xa^D5 Reversal strategies: protamine (partial)^D6
Enoxaparin	Prevent thrombus extension, facilitate recanalization, and prevent DVT/PE regardless of presence of ICH^D1^D2 LMWH is preferable to UFH when there are no contraindications for use; data trend favors LMWH in mortality and functional outcomes with similar rates of systemic bleeding^D2^D3	1 mg/kg subcutaneously every 12 hours^D7 Adjust dose for CrCl <30 mL/minute^D7	BOXED WARNING: risk of hematoma with spinal/epidural anesthesia or puncture^D7 Contraindicated in patients with major bleeding, history of HIT within past 100 days or circulating antibodies, or porcine hypersensitivity^D7 Use with caution in patients with renal impairment or at high bleeding risk^D7	Bleeding Hepatic enzymes, increased HIT or HITT Injection site pain Thrombocytopenia^D7	Coagulation labs: anti-Xa^D7 Reversal strategies: protamine (partial)^D6
Unfractionated heparin (UFH)
Heparin, unfractionated	Prevent thrombus extension, facilitate recanalization, and prevent DVT/PE regardless of presence of ICH^D1^D2	80 units/kg IV bolus then 18 units/kg/hour continuous IV infusion; titrate to maintain aPTT 1.5-2.5 times the control value^D6^D8 Heparin may be administered without a bolus at discretion of neurologist/neurosurgeon	Contraindicated in patients with uncontrollable bleeding, history of HIT/HITT, history of thrombocytopenia with pentosan, or porcine hypersensitivity^D9 Use with caution in patients at high bleeding risk^D9	Bleeding Hepatic enzymes, increased HIT or HITT Thrombocytopenia^D9	Coagulation labs: aPTT or anti-Xa^D9 Reversal strategies: protamine^D9
Vitamin K antagonist
Warfarin	Prevent recurrent CVT and other VTE^D1^D2	Usual dose: 2-10 mg PO once daily*^D10 Titrate dose to maintain target INR of 2-3^D1^D2 Treatment duration: 3-12 months; consider indefinite anticoagulation in recurrent CVT, VTE after CVT, or first CVT with severe thrombophilia^D1^D2	BOXED WARNING: bleeding risk^D10 Contraindicated in patients with bleeding disorders; recent CNS, eye, or traumatic surgery; active ulceration or bleeding; cerebral aneurysm; dissecting aorta; pericarditis; pericardial effusions; bacterial endocarditis; spinal puncture; major regional or lumbar block anesthesia; malignant hypertension; or high potential for noncompliance^D10 Do not use as initial therapy in patients with HIT or HITT^D10 Use with caution in patients with disturbance of intestinal flora, indwelling catheters, moderate to severe hypertension, protein C deficiency, polycythemia vera, vasculitis, diabetes, renal impairment, or hepatic impairment^D10 Drug interactions: may need to avoid or adjust dosage of certain drugs^D10	Bleeding Calciphylaxis Kidney injury, acute Skin necrosis Systemic atheroemboli^D10	Monitor INR daily until INR is therapeutic, then every 1-4 weeks^D10 Genetic polymorphisms and changes in diet affect therapeutic efficacy and safety^D10 Reversal strategies: vitamin K, PCC, FFP^D5^D11
Direct oral anticoagulant (DOAC)
Rivaroxaban^D12	Prevent recurrent CVT and other VTE^D1^D2 Higher risk of recurrent thromboembolic events compared to warfarin in patients with antiphospholipid antibody syndrome¹⁰	Usual dose: 20 mg PO once daily Treatment duration: 3-12 months; consider indefinite anticoagulation in recurrent CVT, VTE after CVT, or first CVT with severe thrombophilia¹⁰	BOXED WARNING:³⁰ increased risk of thrombotic events with premature discontinuation, risk of hematoma with spinal/epidural anesthesia or puncture Contraindicated in patients with active pathologic bleeding,³⁰ pregnancy or while breastfeeding¹⁰ Avoid use in patients with CrCl <15 mL/minute or moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment³⁰	Bleeding	Monitor anti-Xa or aPTT for efficacy is not recommended³⁰ Reversal strategies: andexanet alfa, PCC, aPCC^D11

Caption: aPCC = activated prothrombin complex concentrate, aPTT = activated partial thromboplastin time, CNS = central nervous system, CrCl = creatinine clearance, CVT = cerebral venous thrombosis, DVT = deep venous thrombosis, FFP = fresh frozen plasma, HIT = heparin-induced thrombocytopenia, HITT = heparin-induced thrombocytopenia and thrombosis, ICH = intracerebral hemorrhage, LMWH = low-molecular-weight heparin, PCC = prothrombin complex concentrate, PE = pulmonary embolism, UFH = unfractionated heparin, VTE = venous thromboembolism.

*Individualize initial dose based on clinical (eg, age, weight, comorbidities) and genetic (CYP2C9 and VKORC1 genotypes) factors, taking into consideration expected maintenance dose.D10

Treatment Procedures

Consider endovascular interventions in patients who have:
- Evidence of thrombus propagation
- Neurologic deterioration while on medical therapy
- Contraindications to anticoagulation¹⁰
Endovascular interventions can include clot removal or thrombolysis endovascularly²²
- No high-quality evidence to support this procedure, although it is widely performed in high-volume centers
- TO-ACT trial, a multicenter, open-label, blinded end point, randomized clinical trial, demonstrated that endovascular therapy with standard medical care did not appear to improve functional outcome of patients with cerebral venous thrombosis when compared with treatment with unfractionated or low-molecular-weight heparin infusion alone. There was no statistically significant difference in either mortality or frequency of symptomatic intracerebral hemorrhage²⁹
- A multidisciplinary team approach considering risks and benefits of this therapeutic decision process is recommended
Some patients may benefit from surgical decompression, including patients with midline shift and mass effect who are at risk of brain herniation²⁵
- Surgical decompression may improve clinical outcomes especially if done early in patients with massive venous infarction or hemorrhage
- Neurologic and neurosurgical consultation is recommended

Persistent or Recurrent Disease

Indefinite anticoagulation is recommended in patients with persistent or recurrent cerebral venous thrombosis²²
Referral to physician with expertise in this condition is highly recommended

Admission Criteria

Patients with cerebral venous thrombosis must be admitted to hospital for treatment and monitoring
- Initial admission to ICU should be considered

Special Considerations

Pregnancy

Incidence for cerebral venous thrombosis during pregnancy and puerperium ranges from 1 in 2500 deliveries to 1 in 10,000 deliveries in Western countries. Odds ratio ranges from 1.3 to 13¹
Highest risk for complications of hypercoagulability in last trimester and 4 weeks postpartum
- Initial treatment with therapeutic low-molecular-weight heparin dose should be continued throughout pregnancy¹
  - Subsequently, low-molecular-weight heparin or vitamin K antagonist (target INR of 2-3) should be continued for at least 6 weeks postpartum (for total minimum duration of therapy of 6 months)
- Reasonable to advise that future pregnancies are not contraindicated
  - Recommend prophylaxis with low-molecular-weight heparin during subsequent pregnancies and through the postpartum period¹⁰
- Consultation with hematologist for appropriate laboratory workup is recommended

Pediatric Population

Incidence of pediatric cerebral venous thrombosis is 0.67 per 100,000 children per year¹
- Neonatal risk factors appear to be maternal hypertension, preeclampsia, and exclampsia³
- Additional risk factors include
  - Infections
  - Dehydration
  - Anemia
  - Head trauma
- In older children, cerebral venous thrombosis has similarities with adult cerebral venous thrombosis; however, a slight male preponderance, increased chance of infective causes, and worse functional prognosis is observed³
Clinical presentation depends on age of presentation¹
- Neonates constitute 43% of pediatric patients with cerebral venous thrombosis; may present with seizures or lethargy
- Older infants and children tend to present with symptoms and signs similar to those of adults
Approach to diagnosis is similar to that in adults
Treatment is also similar to that in adults
- First line is parenteral anticoagulation¹⁰
- Transition to low-molecular-weight heparin, vitamin K antagonist, or rivaroxaban¹⁰
- Repeated neuroimaging within 1 week is recommended to monitor for worsening of initial thrombus or hemorrhage even if anticoagulation is withheld
Periodic assessment of visual fields and visual acuity is highly recommended

Older Adult Population

Depressed consciousness may be the more frequent presenting symptom³
Prognosis may be worse in comparison with younger patients

Associated With COVID-19

Infection with SARS-CoV-2 predisposes to thrombosis, both venous and arterial, and increases risk of cerebral venous thrombosis by more than 40-fold³¹
An early 2021 systematic review identified 57 cases of cerebral venous thrombosis from 28 reports¹¹
- Estimated frequency among patients hospitalized for SARS-CoV-2 infection was 0.08%¹¹
- Cerebral venous thrombosis accounted for 4.2% of cerebrovascular disorders in individuals with COVID-19 (in cohort of 406 patients)¹¹
- Signs and symptoms developed within 1 to 8 weeks of respiratory or systemic symptoms of COVID-19¹¹
Majority of cases in patients with COVID-19 do not have additional risk factors for cerebral venous thrombosis¹¹
Mechanism does not appear to be mediated by antiplatelet factor 4 antibodies

Associated With COVID-19 Vaccines

Vaccine-induced immune thrombotic thrombocytopenia has been rarely reported within about 4 weeks of receipt of adenovirus-based coronavirus vaccine
- ChAdOx1 nCoV-19 (AstraZeneca and others): incidence is 1:150,000⁹
- Ad26.COV2.S (Janssen; Johnson & Johnson): incidence is 1:470,000⁹
Thrombocytopenia and thromboses of multiple vascular beds (both venous and arterial circulation) occur with vaccine-induced immune thrombotic thrombocytopenia, with cerebral venous thrombosis the predominant presentation⁵
- 17 patients out of 7.98 million recipients of Ad26.COV2.S vaccine with reported cerebral venous thrombosis or splanchnic vein thrombosis⁹
- 169 patients out of 35 million recipients of ChAdOx1 nCoV-19 vaccine with reported cerebral venous thrombosis⁹
In UK cohort with vaccine-induced immune thrombotic thrombocytopenia that received ChAdOx1 nCoV-19 vaccine:⁵
- Usually manifested 5 to 30 days after first vaccine
- 85% of patients were younger than 60 years
Pathophysiology involves platelet-activating antibodies to platelet factor 4 (90% of patients)⁵

Follow-Up

Monitoring

New, severe, or persisting headache in patients with history of cerebral venous thrombosis necessitates neurologic evaluation for recurrence or intracranial hypertension
Ongoing follow-up with neurologist is recommended for decision about duration of antiepileptic drug therapy
Follow-up with either vascular neurologist, neurologist, neurosurgeon, or interventional neuroradiologist is recommended:
- To establish resolution of thrombus and patency of affected sinus
- When there is concern for development of dural arteriovenous fistula
Frequent monitoring of INR is recommended in patients on oral vitamin K antagonists

Complications

Headache can be present as chronic complaint in up to 50% of patients with cerebral venous thrombosis¹
Remote seizures (occurring more than 2 weeks after initial diagnosis) can occur in between 5% to 32% of patients¹
Visual loss due to papilledema is rare but occurs in 2% to 4% of patients
Dural arteriovenous fistulas can rarely develop in patients with cavernous, lateral, or sagittal sinus thrombosis

Prognosis

Generally has favorable prognosis with early diagnosis and treatment, but can be disabling or life-threatening in some patients
- About 85% of patients have either no or mild long-term symptoms¹³
- 15% death or dependency rate is associated with cerebral venous thrombosis¹³¹³
Case fatality in acute phase is 4%³
- Early mortality can be associated with brain herniation, hemorrhage with or without cerebral edema, multifocal lesions, and status epilepticus¹³¹³
Recanalization rates at 1 year is about 85%, although in adults this is not related to outcomes¹
The incidence of recurrent venous thromboembolism after an initial episode ranges from 1% to 4% per year¹⁰

Referral

Initial presentation
- Patients may initially present with symptoms related to a variety of physician subspecialties
- If diagnosis of cerebral venous thrombosis is suspected, patient must be sent to emergency room for emergent head CT scan
- At time of initial diagnosis, consultation with neurologist and neurosurgeon is highly recommended
- Hematology consultation can also be made at time of admission to assist with decision-making about laboratory evaluation of hypercoagulability
Follow up with ophthalmologist or neuro-ophthalmologist if there is concern for visual loss

Author Affiliations

Atul Kalanuria, MD
Associate Professor
Neurology
Neurocritical Care
University of Pennsylvania