What are the main goals of management during the subacute phase of cerebral venous thrombosis (CVT)?

The primary goals include preventing thrombus extension, managing complications such as seizures or intracranial hemorrhage, and initiating anticoagulation therapy to prevent recurrence.

How long should anticoagulation therapy be continued in patients with CVT during the subacute phase?

Anticoagulation therapy is usually continued for a minimum of three to six months, depending on individual factors such as the extent of thrombosis and the presence of underlying conditions.

CEREBRAL VENOUS SINUS THROMBOSIS

Management in the subacute phase of cerebral venous thrombosis

David Goldemund M.D.
Updated on 15/05/2024, published on 08/03/2023

Anticoagulant therapy

Drug choice

acute parenteral therapy (usually using LMWH) is switched to oral anticoagulant therapy after 5-15 days (AHA guidelines, 2024)
WARFARIN with a target INR 2-3 → see here
DOACs seem to have similar efficacy and better safety profiles [Geisbüsch, 2014]
- positive results of the RE-SPECT CVT trial
  - n=120 (dabigatran 2x150mg vs. warfarin with INR 2-3), treatment duration 24 weeks
  - 5-15 days pretreatment with parenteral heparin, major bleeding 1 vs. 2 (warfarin), no thrombotic events
- ACTION-CVT (2022) trial showed equal efficacy of DOACs and warfarin, with DOACs having a lower risk of major bleeding (HR 0.35)
- DOACs are not recommended:
  - in women who are pregnant or breastfeeding (contraindication)
  - in individuals with antiphospholipid syndrome (higher risks of recurrent thromboembolic events)

therapy of CVST provoked by VITT (Vaccine-induced Immune Thrombotic Thrombocytopenia)
- DOACs are preferred (American Society of Hematology guidelines for HIT therapy – 2018)
- switch to oral anticoagulation is advised only after normalization of platelet count

warfarin	LMWH	DOAC
antiphospholipid syndrome (APL) hypercoagulable states (Leiden, etc.)	pregnancy active cancer	active cancer VITT (Vaccine-induced Immune Thrombotic Thrombocytopenia) other causes of CSVT

Duration of the anticoagulant therapy

the duration of anticoagulant therapy should be decided based on individual hereditary and provoking factors, along with the potential bleeding risks associated with long-term treatment (Einhäupl, 2006]
sinus recanalization most commonly occurs within the first 3-4 months; the rate of rethrombosis is low
regular follow-up visits should be conducted after discontinuing anticoagulant therapy
patients should be educated about early signs of potential relapse (most commonly headache)

3-6 months	transient/reversible risk factors (e.g., oral contraceptives, puerperium, infection)
6-12 months	idiopathic (unprovoked) thrombosis mild thrombophilia (e.g., heterozygous Leiden V or MTHFR), then switch to aspirin (AHA/ASA 2014 IIa/C) some clinicians use repeated venous imaging to guide the duration of therapy
long-term anticoagulation	recurrent venous thrombosis severe thrombophilia (e.g., Leiden homozygote, prothrombin G20210A mutation, protein C and S deficiency, antiphospholipid antibodies)

Antiplatelet agents after discontinuation of oral anticoagulation

studies focused on secondary prevention of VTE showed that aspirin was more effective than placebo
potential benefits should be carefully considered (based on risk factors); optimal duration of therapy is unknown ⇒ temporary antiplatelet therapy may be considered

Hormonal contraceptives and pregnancy

avoid estrogen-containing contraceptives (ESO guidelines 2017)
- an intrauterine contraceptive device (IUD) is advised
in the absence of a hypercoagulable state or a history of previous thromboembolism, recurrent venous thrombotic events during subsequent pregnancy are rare [Sousa, 2017]
- educate patients about the increased risk of CVST and/or VTE
- reviews indicate no increased incidence of miscarriage after the previous CVST
no clear consensus exists on the prophylactic administration of LMWH during pregnancy and puerperium; data are weak and mostly from observational studies
- prophylactic LMWH seems appropriate (unless contraindicated or full anticoagulation is indicated) (ESO guidelines 2017)
- in the U.S., LMWH is administered from the 3rd trimester to the 8th week postpartum
patients on warfarin should plan pregnancy with a switch to LMWH (due to warfarin´s teratogenicity)

Antiseizure medication

optimal duration of antiseizure medication (ASM) is unknown
risk of epilepsy is ~ 5-11% (higher in patients with parenchymal hemorrhages and focal neurological deficits)
- most late-onset seizures occur within the first year
- late-onset seizures are more common in patients with early symptomatic seizures
duration should be guided by the presence and extent of parenchymal lesions, EEG findings, and the timing of epileptic seizures (early x late) → stroke-related epilepsy and seizures

Levetiracetam

Parameter	Details
Initial dosing (PO)	start with 500 mg twice daily can be rapidly titrated up; typical increments are 500 mg every 1-2 days, depending on seizure control and tolerability
Initial dosing (IV)	20-30 mg/kg + 100 mL of NS infused over 15 minutes (< 150 mg/minute) SE: 30-60 mg/kg + 100 mL of NS infused over 10 minutes
Maintenance dose	500-1500 mg twice daily, adjusted based on response, tolerance, and renal function
Notes	adjust dose for renal impairment monitor for psychiatric symptoms such as depression or agitation
Main contraindications	hypersensitivity to levetiracetam or any component of the formulation

Phenytoin

Parameter	Details
Initial dosing (PO)	slow titration of 100 mg per week
Initial dosing (IV)	250 mg over 5 minutes, which can be repeated to a total dose of 750-1000 mg (especially in repeated seizures) SE: 15 mg/kg, administered at a rate < 50 mg/min, followed by 100mg every 6 hours
Maintenance dose	typically 300 mg/day (max dose 500mg/d) in adults divided into 2-3 doses
Notes	monitor for hypotension and arrhythmias during IV administration
Contraindications	sinus bradycardia, sinoatrial block, second-and third-degree AV block hypersensitivity to phenytoin

Valproate

Parameter	Details
Initial dosing (PO)	start with 400-600 mg, divided into 2 doses
Initial dosing (IV)	repeated seizures: bolus 10-15 mg/kg, administered over 5 minutes, followed by infusion SE: bolus 30 mg/kg, administered over 10 minutes (3-6 mg/kg/min), followed by infusion follow-up infusion: 1-2 mg/kg /h 1200 mg+50 ml NS (1mL=24mg) IV 0.042-0.083 mL/kg/h (1-2 mg/kg/h)
Maintenance dose	usual daily dose: 1000-2000 mg, divided into 2-3 doses, adjusted based on clinical response and tolerance target VPA levels: 300-700 µmol/L / 50-100 µg/mL
Notes	monitor liver function, blood counts, and serum ammonia levels be cautious of potential teratogenic effects
Contraindications	significant hepatic dysfunction urea cycle disorders porphyria hypersensitivity to valproate

Lacosamide

Parameter	Details
Initial Dosing (PO)	start with 50 mg twice daily
Initial Dosing (IV)	200 mg +100 mL NS infused over 20-40 minutes SE: 200-400 mg loading dose over 3-5 minutes, followed by a maintenance dose of 100 mg every 12 hours (then switch to PO)
Maintenance dose	100-200 mg twice daily, adjusted based on response and tolerance
Notes	monitor for PR interval prolongation; use caution in patients with cardiac conduction abnormalities adjust dose for renal and hepatic impairment (half dose for ClCr≤30 mL/min) monitor for dizziness, ataxia
Contraindications	hypersensitivity to lacosamide or any component of the formulation second- or third-degree AV block without an artificial pacemaker

Carbamazepine

Parameter	Details
Initial Dosing (PO)	start with 100-200 mg twice daily
Maintenance dose	800-1200 mg/day divided into 2 doses; adjust dose based on response and tolerance
Notes	monitor for blood dyscrasias, liver function, and dermatological reactions (such as signs of Stevens-Johnson syndrome) may cause dizziness and nausea
Contraindications	hypersensitivity to carbamazepine history of bone marrow depression use of MAO inhibitors within the last 14 days

Clonazepam

Parameter	Details
Initial Dosing (PO)	start with 0.5 mg twice daily
Dosing (IV)	1mg + 5 mL NS bolus injection over 5 minutes (max speed 0.25-0.5 mg/min) 1mg + 100 mL NS infusion over 5-10 minutes continuous infusion – 5mg/20mL NS (1ml=0.25 mg) 0-2 mL/h (0.25-0.5 mg/h) maximum daily dose is 10mg
Maintenance dose	1-4 mg/day in divided doses
Notes	titrate dose slowly to minimize sedation and dizziness; monitor for signs of dependency and withdrawal
Contraindications	significant liver disease, acute narrow-angle glaucoma, and hypersensitivity to clonazepam or benzodiazepines

Therapeutic levels of ASMs

*ASMs therapeutic levels* (values may differ in various labs)
carbamazepine (CBZ)	17-51 µmol/L (4-12 µg/mL) toxic level: >85 µmol/L (>20 µg/mL)
valproate (VPA)	350-700 µmol/L (50-100 µg/mL) toxic level: >1040 µmol/L (>150 µg/mL)
phenytoin (PHE)	40-80 µmol/L (10-20 µg/mL) toxic levels: >120 µmol/L (>30 µg/mL)
lamotrigine (LTG)	10-60 µmol/L (3-14 µg/mL) toxic levels: >70 µmol/L (>18 µg/mL)
levetiracetam (LEV)	35-217 µmol/L (5-25 µg/mL)
topiramate (TPM)	10-50 µmol/L (2-10 µg/mL)
lacosamide (LCM)	10-60 µmol/L (2.5-15 µg/mL)

Neuropsychiatric disorders

anxiety
depression (SSRI)
vascular cognitive deficit or impaired symbolic functions in patients with parenchymal lesions

Chronic headache

up to 14% of patients experience chronic headache
in cases of atypical presentation or intensity, thrombosis recurrence must be excluded (brain CT/MRI + venography + D-Dimer test)