2. Acute Treatment of Symptomatic Cerebral Venous Thrombosis

Notes

These recommendations refer to initial acute management of CVT. Outpatient management of CVT in the post-acute phase is discussed in Section 3.

Anticoagulation treatment: Anticoagulation management for CVT can be categorized in 3 phases: (1) acute management, which is immediately around the initial diagnosis; 2) "primary" management, which is the period of time when a person is treated with therapeutic anticoagulation for their initial CVT; (3) "secondary prevention," which is any further antithrombotic therapy after the primary phase aimed at preventing VTE recurrence (ASH Guideline 2020).(Ortel et al. 2020).

Symptomatic CVT – where the diagnosis is associated with neurological symptoms such as headache, focal neurological symptoms, seizure, or signs of increased intracranial pressure.

Recommendations and/or Clinical Considerations

2.0 Stroke Unit Management

Individuals with a diagnosis of CVT requiring inpatient management should receive routine stroke unit care [Strong recommendation; High quality of evidence]. Refer to CSBPR Acute Stroke Management module, Section 8 for additional information.
Individuals with CVT should receive supportive care with hydration, management of intracranial pressure, headache, nausea and vomiting, and seizures [Strong recommendations; Low quality of evidence]. Refer to Section 3 for additional information on late seizures and epilepsy and post-acute headaches. Refer to CSBPR Acute Stroke Management module, Section 9 for additional information on post stroke complications and management.

2.1 Antithrombotic Management

Therapeutic-dose subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin (UFH) should be initiated as soon as possible following diagnosis of symptomatic CVT [Strong recommendation; Moderate quality of evidence].
1. Subcutaneous LMWH is preferred over intravenous UFH infusion for most individuals with CVT due to more reliable and longer duration of anticoagulant effect, predictable pharmacokinetics enabling administration of fixed doses without laboratory monitoring, and lower risk of heparin-induced thrombocytopenia [Conditional recommendation; Moderate quality of evidence].
2. Intravenous UFH is typically reserved for individuals with CVT who have severely impaired renal function or require a surgical or invasive procedure [Conditional recommendation; Low quality of evidence].
3. If using intravenous UFH, it should be administered as a bolus followed by infusion and adjusted based on institutional protocols [Conditional recommendation; Low quality of evidence].
4. Heparin should be avoided in individuals with CVT with a history of heparin-induced thrombocytopenia (HIT) [Strong recommendation; Moderate quality of evidence].
5. For any individuals with CVT with a history of HIT consider consulting hematology to discuss anticoagulant management [Strong recommendation; Low quality of evidence].
There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOACs) as the initial antithrombotic of choice (i.e., without parenteral lead-in anticoagulation) in the acute management of CVT [Conditional recommendation; Low quality of evidence].
The presence of intracranial or subarachnoid blood is not a contraindication to anticoagulation [Strong recommendation; Moderate quality of evidence].
Systemic intravenous thrombolysis is not recommended in the acute treatment of CVT [Strong recommendation; Low quality of evidence].

Section 2.1 Clinical Considerations

There may be rare cases where there are concerns regarding the safety of anticoagulation (e.g. large or rapidly expanding intracranial hemorrhage, anticipated emergency surgical intervention, meningitis/encephalitis with cortical venous hemorrhage) that will require case-by-case collaborative decision-making by neurology, neurosurgery and hematology/thrombosis. The benefits of anticoagulation should be weighed against the risks of symptomatic hemorrhage and should be regularly re-evaluated based on clinical and neuroimaging reassessment. If experts are not available on site, arrangements should be in place to contact the nearest centre providing these services. Refer to Section 2.7 on “Surgical Management, Clinical Considerations 2” for additional information.
The presence of concurrent head or neck infection is not an absolute contraindication to anticoagulation.
There is insufficient evidence to support routine use of DOACs as first-line anticoagulation for CVT, although first-line DOAC may be considered on a case-by-case basis.

2.2 Inpatient Seizure Management

In individuals with CVT who have not had clinical seizures, use of prophylactic antiseizure medications is not recommended [Strong recommendation; Low quality of evidence].
Acute symptomatic seizure(s) (occurring within 7 days of presentation) requires management with anti-seizure medications (ASM) per local protocols to prevent further acute symptomatic seizures [Strong recommendation; Low quality of evidence].
Late seizures (occurring after 7 days of presentation), regardless of the presence or absence of acute symptomatic seizures, may require long-term management with anti-seizure medications [Strong recommendation; Moderate quality of evidence].
Status epilepticus should be treated as per accepted local protocols [Strong recommendation; High quality of evidence].
Electroencephalography (EEG) should be considered for individuals with episodic or prolonged unexpected alterations in level of consciousness to rule out non-convulsive seizures or status epilepticus [Strong recommendation; Low quality of evidence].

Section 2.2 Clinical Considerations

The choice of antiseizure medications will be dependent on individual factors including co-morbidities and interactions with other treatments including anticoagulation. The duration of treatment with antiseizure medications will be person dependent. Long-term management with antiseizure medications (greater than 3 months) may not be required.

2.3 Acute Headache Management

Note, no evidence-based recommendations included for this section.

Section 2.3 Clinical Considerations:

Headache from CVT is most commonly secondary to increased intracranial pressure or intracranial hemorrhage. Early treatment with anticoagulation to reduce venous hypertension may help with headache management.
It is reasonable to treat headache secondary to increased intracranial pressure with acetazolamide.
The use of prolonged nonsteroidal anti-inflammatory drugs (NSAIDs) for headache management while taking concurrent anticoagulation should be avoided given the risk of bleeding.

Refer to Section 3 for additional information on longer term management of chronic headaches.

2.4 Vision

Section 2.4 Vision

Individuals with visual symptoms or signs of increased intracranial pressure (ICP) on the initial treating physician’s bedside examination should have an urgent ophthalmologic assessment, ideally within 24-48 hours of CVT diagnosis [Strong recommendation; Low quality of evidence].

Section 2.4 Clinical Considerations:

All individuals with a new diagnosis of CVT should have an initial ophthalmological assessment including fundus examination and assessment for papilledema, visual fields and enlarged blind spots at the time of their diagnosis.

Individuals with evidence of visual abnormalities or severe papilledema should receive an urgent ophthalmology assessment and be started on acetazolamide.

Individuals without visual symptoms or signs of increased ICP should have an ophthalmologic assessment, ideally within 7 days of CVT diagnosis.
Individuals without ophthalmic abnormalities related to the CVT on initial assessment should have a subsequent ophthalmologic assessment to rule out development of later-onset papilledema (as outlined above).
The initial formal ophthalmological assessment should be performed by a neuro-ophthalmologist or ophthalmologist.

If there are no ophthalmologists locally accessible, then an optometrist capable of performing a dilated fundus examination can perform the initial assessment with an ophthalmologist or neuro-ophthalmologist consulted remotely for advice.

Ophthalmologic assessment should include:

Best-corrected visual acuity and color vision.
Dilated fundus examination with stereoscopic viewing of the fundus.
If papilledema is present, there should be automated threshold visual field testing with standard automated perimetry with white-on-white stimuli, which has the best evidence base for reliable, operator-independent longitudinal assessment of vision changes secondary to increased ICP. Papilledema can be graded using the modified Frisén scale for longitudinal follow-up.

In the case of ophthalmologic diagnostic uncertainty as to whether there is papilledema secondary to increased intracranial pressure (vs. drusen, crowded discs, hyperopia), lumbar puncture with opening pressure and cerebrospinal fluid analysis should only be undertaken to clarify the presence of increased intracranial pressure if the benefits are deemed to outweigh the potential risks related to herniation and/or disrupting anticoagulation.
Optimal timing for ophthalmologic reassessment is unclear; follow up can be considered at 4 weeks and 3-6 months following diagnosis to exclude later-onset papilledema or vision loss.

2.4.1 Management of Papilledema

Acetazolamide may be initiated with dose escalation depending on the response of the papilledema to therapy. The risks of acetazolamide therapy, including fluid loss, metabolic acidosis, and hypokalemia, should be monitored, and individuals with CVT should be counselled to be aware of paresthesia as a common side effect with higher doses [Strong recommendation; Low quality of evidence].
If, despite optimal medical management with anticoagulation and acetazolamide, there are either (1) worsening of visual field deficits, acuity, or color vision; or (2) severe visual field loss or abnormal acuity; then surgical intervention should be considered. The optimal approach (i.e. optic nerve sheath fenestration or CSF diversion with shunting) can be considered as a shared decision with relevant experts (i.e. ophthalmologists, neurosurgeons) [Strong recommendation; Low quality of evidence].

Section 2.4.1 Clinical Considerations:

Individuals with papilledema or visual symptoms that could be attributed to increased intracranial pressure should be managed by a neuro-ophthalmologist or ophthalmologist.

2.5 Neurocritical Care Management for CVT

Individuals with CVT should be routinely and regularly monitored clinically for signs or symptoms of increased intracranial pressure [Strong recommendation; Low quality of evidence].
Individuals with CVT identified to have elevated ICP should be treated emergently based on the severity of signs and symptoms using standard protocols [Strong recommendation; Low quality of evidence].
1. Those who fail medical management for elevated ICP and are at risk of life-threatening increased ICP should be considered for surgical and/or endovascular management, as appropriate [Strong recommendation; Low quality of evidence]. Please refer to Endovascular (Section 2.6) and Surgical management (Section 2.7) sections for additional information.

Section 2.5 Clinical Considerations:

For signs and symptoms of ICP elevation, acetazolamide could be considered.
Appropriate referrals to critical care and neurosurgical services should be considered for management of worsening ICP.
Non-invasive or invasive ICP monitoring technologies can be considered in comatose patients.

2.6 Endovascular Management

Endovascular therapy should not be routinely used as first-line therapy for the acute treatment of cerebral venous thrombosis [Conditional recommendation; Moderate quality of evidence].

Section 2.6 Clinical Considerations

The optimal candidates for endovascular therapy (EVT) for CVT are not known.
The optimal technical approaches for endovascular therapy for CVT, if any, are not known, and the procedure should be performed by an experienced neurointerventionalist.
The optimal timing for EVT, if any, is not known.

Endovascular therapy (EVT) may be considered for treatment of cerebral venous thrombosis in cases where there is clinical deterioration despite optimal medical therapy and mechanical recanalization is considered to be of potential benefit.
In select cases where the treating physician and neurointerventionalist agree that the benefits of early intervention are highly likely to exceed potential risks, EVT may be considered alongside anticoagulation as first-line therapy for the acute treatment of CVT.

EVT should be considered as a complement, and not a substitute, to anticoagulation unless anticoagulation is otherwise contraindicated (e.g., active and uncontrolled bleeding).

2.7 Surgical Management

Decompressive hemicraniectomy should be considered in cases of life-threatening malignant mass effect due to venous infarction and/or hemorrhage [Strong recommendation; Moderate quality of evidence].

Section 2.7 Clinical Considerations:

Insertion of an external ventricular drain can be considered as a treatment and/or monitoring option for elevated ICP and/or hydrocephalus.
If anticoagulation must be disrupted for a neurosurgical procedure, the approach to restarting anticoagulation should be made on a case-by-case basis in discussion with a neurosurgeon and with review of repeat neuroimaging with relevant specialists involved (e.g., stroke neurology, hematology).
Long term management of chronically elevated ICP may require surgical management including insertion of a shunt (ventriculoperitoneal or lumboperitoneal); or optic nerve sheath fenestration.

Rationale +-

In the acute phase of CVT, potential causes of clinical deterioration and death include thrombus extension, venous edema or intracranial hemorrhage causing mass effect, status epilepticus, and other post-stroke complications including pulmonary embolism and sepsis. Therefore, early therapeutic interventions to address these issues are critical to ensure the best opportunity for a good outcome. Anticoagulation using subcutaneous low molecular weight heparin (LMWH), or intravenous unfractionated heparin (UFH) is the mainstay of acute treatment for CVT, with the aims of preventing clot extension, facilitating recanalization and treating the systemic hypercoagulable state. The incidence of early seizure associated with CVT is high (24-40%) (Duman et al. 2017; Ferro et al. 2004). Intracranial hypertension (IH) is a potential complication of CVT, which can cause both headache and vision loss, due to altered venous drainage. The incidence of IH in one small study was estimated to be 10% within a 6-month follow-up period, with a higher risk in patients who did not recanalize (Geisbüsch et al. 2021).

The use of endovascular thrombectomy (EVT) for the treatment of patients with CVT has been studied in one randomized trial. The recent TO-ACT trial was halted after the first interim analysis for reasons of futility (Coutinho et al. 2020). There were no significant differences between EVT or medical management groups in either 6-month or one-year mortality. Issues persist regarding patient selection, imaging, technique and lack of devices specific to treatment of the cerebral venous system (Goyal et al. 2022).

Hemicraniectomy is a life-saving measure that is performed in cases of CVT complicated by malignant mass effect. DECOMPRESS-2, the largest prospective study to date of over 180 CVT patients receiving hemicraniectomy, is not yet published. Results presented at the European Stroke Organization Conference 2021 suggested that rates of death and functional dependence were higher that what was reported in previous retrospective series (Alimohammadi et al. 2022).

People with lived experience (PWLE) highlighted the importance of person-centred care, being actively involved in their treatment plan, and ongoing communication with their healthcare team. They emphasized the value of receiving specific information on what CVT is, how their brain was affected, the impact the stroke may have on their everyday tasks and functions, and CVT risk factors and risk of recurrence. Individuals with CVT also valued receiving information and feedback following tests, assessments and screenings. Doing so contributed towards an early understanding of CVT and the residual impairments that may be experienced. Information on early or late-onset seizures was also highly valued by PWLE.

System Implications +-

To ensure people experiencing CVT receive timely assessments, interventions and management, interdisciplinary teams need to have the infrastructure and resources required. These may include the following components established at a systems level.

Organized systems of stroke care including stroke units with a critical mass of trained staff (interdisciplinary team). Availability of Health Human Resources to appropriately staff stroke units and provide recommended best practice service (e.g., 7 days/week) and promote optimal outcomes.
Comprehensive and advanced stroke care centres with leadership roles within their geographic regions, to ensure specialized stroke care access is available to individuals with CVT who may first appear at general healthcare facilities (usually remote or rural centres) and facilities with basic stroke services only.
Protocols and mechanisms to enable the rapid transfer of individuals with CVT requiring admission from the emergency department to a specialized stroke unit as soon as possible after arrival in hospital.
Standardized evidence-based protocols instituted for optimal inpatient care of all individuals with CVT, regardless of where they are treated in the healthcare facility (stroke unit or other ward), and across the regional stroke system of care.
Efforts to facilitate building and maintaining of stroke expertise among staff to provide appropriate and evidence-based best practice care to individuals with CVT. The interprofessional healthcare team members should have stroke-specific knowledge, skills, and expertise, and access regular education to maintain competency.
Referral systems to ensure rapid access to specialty care such as ophthalmology and hematology.
Telestroke service infrastructure and utilization optimized to ensure access to specialized stroke care across the continuum to meet individual needs (including access to rehabilitation and stroke specialists) including the needs of northern, rural, and remote residents in Canada.
Information on geographic location of stroke units, rehabilitation, and home care services, and other specialized stroke care models available to community service providers, to facilitate navigation to appropriate resources and to strengthen relationships between each sector along the stroke continuum of care.
Ongoing professional development and educational opportunities for all healthcare professionals who care for individuals with CVT.

Performance Measures +-

System Indicators:

Median length of stay for during acute phase of care for all individuals with acute symptomatic CVT admitted to hospital (core).
Proportion of individuals with acute symptomatic CVT who experience prolonged length of stay beyond expected length of stay as a result of experiencing one or more complications.

Process Indicators:

Number of individuals with symptomatic CVT who are admitted to hospital and treated on a specialized stroke unit at any time during their inpatient hospital stay for CVT (numerator) as a percentage of total number of individuals with acute symptomatic CVT admitted to hospital.
Median length of stay, stratified by complication type, during acute phase of care for all individuals with CVT admitted to hospital who experience one or more complications during hospitalization (core).
Proportion of individuals discharged with CVT who are readmitted within 30 days (or 90 days) for any cause.

Patient-oriented outcome and experience indicators:

Proportion of individuals admitted to hospital with a diagnosis of acute symptomatic CVT who experience one or more complications during hospitalization (e.g., deep venous thrombosis, pulmonary embolus, secondary intracranial hemorrhage, gastrointestinal bleeding, pressure ulcers, UTI, pneumonia, seizures) during inpatient stay.
Proportion of individuals who have experienced multiple visits to acute medical care prior to having a definitive diagnosis of CVT.
Proportion of individuals with CVT who experience neuroradiological worsening (new or worsening edema or ICH, or new/extension of venous thrombus).
Quality of life rating at 30 and 90 days for people who experience complications during acute inpatient admission following CVT, using a validated tool.
In-hospital mortality rates (overall, 7 and 30-day) for patients with CVT.

Measurement Notes

For Indicator #1: CVT with deficits or stroke/ich should definitely be on a stroke unit. Uncomplicated CVT may reasonably be under neurology or medicine, and traumatic CVT under trauma so at the local level clarify which subpopulation to apply this to as denominator.
For Indicator #3: ‘Expected length of stay’ refers to the standard length of stay based on Canadian Institute for Health Information algorithms.
For Indicator #5: Due to the smaller incidence rates of CVT compared to other stroke types, numerators and denominators may become very small when looking at multiple sub-categories of complications and stratifying by age and sex. Larger grouping variables may be required.

Implementation Resources and Knowledge Transfer Tools +-

Resources and tools listed below that are external to Heart & Stroke and the Canadian Stroke Best Practice Recommendations may be useful resources for stroke care. However, their inclusion is not an actual or implied endorsement by the Canadian Stroke Best Practices team or Heart & Stroke. The reader is encouraged to review these resources and tools critically and implement them into practice at their discretion.

Healthcare provider information

Information for individuals with lived experience of stroke, including family, friends and caregivers

Summary of the Evidence +-

Evidence Table and Reference List

Stroke unit management

Evidence summarizing the benefits of stroke unit care in a general post-stroke population can be found in the Canadian Best Practice Guidelines for Acute Stroke Management, 2022 Seventh Edition (Heran et al. 2022). The historical proportion of individuals with CVT comprising all patients admitted to stroke units is approximately 0.5-1%.

Systemic thrombolysis

A previous review of case reports and case series describing systemic thrombolysis for management of CVT (n=26 patients) reported high rates of intracranial (12%) and extracranial hemorrhage (19%), with an 8% rate of fatal hemorrhage. In those who survived, available information regarding rates of recanalization (n=16, 62%) and functional independence (n=26, 88%) were not out of keeping from other series of individuals with CVT with usual management (Duman et al. 2017; Ferro et al. 2004; Kim et al. 2023). Systemic thrombolysis is therefore not recommended.

Antithrombotic management

Anticoagulation is the mainstay of acute treatment for CVT, with the objectives of facilitating venous recanalization, preventing thrombus extension and treating the overall hypercoagulable state. Unlike with primary intracranial hemorrhage, the presence of intracranial bleeding in the context of CVT should not delay initiation of anticoagulation. Approximately 30-40% of individuals with CVT may have some type of intracranial bleeding on their initial scans (Afifi et al. 2020; Girot et al. 2007). A review of 260 patients from an international cohort found that 39% had hemorrhage at baseline, with 63% having intraparenchymal bleeding (29% with small juxtacortical hemorrhages) with subarachnoid blood and subdural blood in 24% and 11%, respectively. Approximately one-quarter had multiple hemorrhage types (Afifi et al. 2020). Approximately 5-10% of patients will go on to develop new intracranial bleeding (either expansion of pre-existing bleeding or a de novo hemorrhage in a separate anatomical location) following diagnosis (Busch et al. 2016; Girot et al. 2007). Baseline ICH is associated with a higher risk of delayed ICH (Busch et al. 2016); however, there is no evidence from the observational literature suggesting that anticoagulation increases the risk of delayed intracranial hemorrhage (Girot et al. 2007; Shakibajahromi et al. 2019). We note that the available literature in this regard is limited in defining symptomatic versus asymptomatic delayed ICH and may be biased by a lack of timed prospective follow-up early neuroimaging.

Despite its central role in the management of CVT, the quality of evidence comparing anticoagulation to placebo is based on small underpowered studies that are heterogenous with respect to populations, interventions and outcomes. Further, duration of follow-up is brief, with one randomized trial reporting outcomes at approximately one month and another at 13 weeks (Al Rawahi et al. 2018; Coutinho et al. 2011a).

The evidence supporting low-molecular weight heparin over unfractionated heparin as the initial therapy for CVT is based on observational and small randomized studies, that demonstrate non-significant trends in favour of LWMH for better functional outcomes and less intracranial bleeding (Al Rawahi et al. 2018) and reduced mortality (Al Rawahi et al. 2018; Coutinho et al. 2010). Comparisons between treatments in the non-randomized literature may be confounded by indication. The benefits of low molecular-weight heparin over unfractionated heparin for treatment of acute venous thromboembolism in general include more predictable pharmacokinetics without laboratory monitoring and more reliable anticoagulant effect in addition to lower rates of heparin-induced thrombocytopenia (HIT).

The overall rate of heparin-induced thrombocytopenia (HIT) is approximately 1 per 1500 hospitalizations in US-based data, with increased risks with major surgery and longer durations of heparin exposure (Dhakal et al. 2018; May et al. 2023). Indefinite avoidance of heparin anticoagulation is recommended in individuals with a history of HIT (Cuker et al. 2018; May et al. 2023). CVT secondary to HIT is a very rare occurrence, estimated to affect less than 2% of those with HIT (Aguiar de Sousa et al. 2022).

Clinical trials comparing DOACs to warfarin have mostly included participants who had an initial lead-in with parenteral anticoagulation. The RE-SPECT CVT trial, which compared dabigatran against vitamin K antagonist anticoagulation, required 5-15 days of lead-in parenteral anticoagulation prior to initiation of therapy (Ferro et al. 2019). The EINSTEIN-Jr pediatric thromboembolism trial, which included 117 children with CVT, also required 5-15 days of parenteral lead-in therapy (prior to randomization to rivaroxaban 20 mg daily equivalent dosing versus control (VKA or LWMH) (Connor et al. 2020). The SECRET trial, which compared rivaroxaban to standard-of-care anticoagulation (warfarin or ongoing LWMH) did not have any requirement for lead-in parenteral therapy. One of 26 participants randomized to rivaroxaban received no lead-in therapy, and the median time to initiation of rivaroxaban was 3 days (IQR 2 - 6), with 46% of patients initiated on rivaroxaban within 48 hours of diagnosis and 73% prior to day 5. There were no complications related to symptomatic intracranial bleeding or early (day 30) symptomatic extension of CVT or early recurrent VTE in either group (Field et al. 2023). There is insufficient evidence to support routine use of DOACs as first-line anticoagulation for CVT, although first-line DOAC may considered on a case-by-case basis (Carrion et al. 2024).

The role of anticoagulation for CVT secondary to head or neck infection is less well-characterized in the literature. A sub study of the prospective observational International Study on Cerebral Venous and Dural Sinus Thrombosis (ISCVT) had 57 (9%) participants with CVT secondary to head or neck infection. Of those, 83% were treated with therapeutic anticoagulation, without notable differences distinguishing those with versus without anticoagulation. Rates of new intracranial hemorrhage were high overall (6/23 in anticoagulated patients and 1/10 non-anticoagulated patients) but small numbers and low event rates precluded specific recommendations. In the CVT sub study of the EINSTEIN-Jr trial comparing rivaroxaban versus standard-of-care anticoagulation in a pediatric cohort of 117 children, 63% had infection-related CVT (80% otomastoiditis, 28% CNS infection 24% sinusitis, 12% upper respiratory tract infection and 39% with multiple infection sites. Anticoagulation was held for lumbar puncture (30%) and surgical interventions (55%). There were no major or clinically relevant nonmajor bleeding events in the surgical group. One patient in the standard treatment group with meningitis developed a subdural hemorrhage. No other patients had symptomatic intracranial bleeding, nor was there any bleeding on repeat neuroimaging performed in 69/74 by the three-month mark.

Seizure management

Rates of seizure complicating CVT are high. Over one-quarter will have seizures at the time of their presentation (Duman et al. 2017; Ferro et al. 2004). A recent study using retrospective and prospective data including 1,281 adults CVT reported that one-third had a symptomatic seizure within 7 days of admission to hospital and 6% had status epilepticus. However, only 7% of patients with seizures post-admission did not have a seizure preceding their admission to hospital. Predictors of early seizures included presence of hemorrhagic or non-hemorrhagic parenchymal lesions or subarachnoid blood, cortical vein or sagittal sinus involvement, focal deficits and OCP- or pregnancy/puerperial CVT. The authors concluded that prophylactic antiseizure therapy was not warranted in individuals presenting without seizure (Lindgren et al. 2020). In a substudy of the ISCVT (n=624), 39% presented with seizures. Of those who did not present with seizures, 3% had a new seizure within the first two weeks of diagnosis. Two-hundred and thirty-one were prescribed antiseizure medication, 75% of whom had seizures at presentation. Overall, use of antiseizure medications (ASM) was associated with a reduced risk of seizure, but rates of new seizures in those without seizures at presentation were low.

Rates of later seizures (i.e. after one week following diagnosis)(Beghi et al. 2010) were 11% over a median follow-up of 2 years in a large cohort including retrospective and prospective data (n=1127). Median time to late seizure was 5 months. Predictors of late seizures included history of status epilepticus within the first week of admission, decompressive hemicraniectomy, subdural hematoma and intracerebral hemorrhage. Although 70% with late seizures experienced subsequent recurrence and 94% were initially prescribed antiseizure medication (Sánchez van Kammen et al. 2020), the study did not distinguish whether those with recurrences were still taking anti-seizure medication at the time. A recent meta-analysis including four studies also explored prevalence and risk factors for late seizures, although the previously discussed cohort of 1127 accounted for 86% of the 1309 patients in the analysis and findings were similar (Gasparini et al. 2022).

Headache management

Headache is a presenting feature in approximately 90% of individuals with CVT and is presumed to be due to increased intracranial pressure in most cases. Management principles of CVT-related headache include appropriate management with anticoagulation to facilitate recanalization, management of increased intracranial pressure, and appropriate analgesia. Beyond its role in the management of increased intracranial pressure, the role of acetazolamide in headache management for CVT is not known. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), which enrolled individuals with idiopathic intracranial hypertension, not CVT, found no reduction in headache-related disability, measured by the Headache Impact Test (HIT-6) at six months between individuals randomized to acetazolamide (maximum 4g/day) versus placebo (Wall et al. 2014).

Vision

Increased intracranial pressure can be associated with visual disturbances due to increased pressure transmitted along the optic nerve sheath, causing papilledema (swelling at the optic nerve head due to increased pressure). These visual changes can include transient visual obscurations and blurred vision as well as visual field deficits or enlarged blind spots. Other visual disturbances in CVT can include diplopia (usually secondary to increased pressure transmitted along the intradural portions of the sixth cranial nerves, or, in the case of cavernous venous thrombosis, direct disturbances of the intrasinus portions of the cranial nerves), and binocular vision loss (usually from focal parenchymal brain involvement) or positive visual phenomena (usually from seizure activity).

Individuals with papilledema, however, may not be aware of any visual disturbances, and it is important to assess for, and identify, papilledema as early as possible to facilitate timely, appropriate management to reduce the likelihood of any permanent visual loss. In addition to the initial bedside neurologic assessment, including fundoscopy, routine early involvement of healthcare professionals with dedicated expertise in ophthalmology is of importance for several reasons. First, papilledema is better detected on dilated fundoscopic exam than at the bedside. Second, appropriate assessments, including stereoscopic fundoscopic assessment with papilledema grading, and automated perimetry, can detect subclinical visual abnormalities, and can assess response to therapy over time.

There is minimal literature related specifically to management of papilledema in CVT. The literature for management of papilledema with mild visual loss secondary to idiopathic intracranial hypertension (IIH) demonstrates a benefit for use of acetazolamide for individuals with mild visual loss due to IIH. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) randomized adults with a diagnosis of IIH meeting modified Dandy criteria for diagnosis (Wall et al. 2014). Participants were randomized to acetazolamide and dietary intervention versus placebo and dietary intervention. The acetazolamide treatment protocol was an initial dose of 500 mg bid, increasing by 250 mg every six days to a maximum tolerated dose of 2 g bid. The primary outcome was the perimetric mean deviation (PMD) in the worst affected eye at six-month follow-up. Eighty-six participants were randomized to active drug therapy, 44% of whom tolerated the maximum dose; 45% tolerated doses between 1 - 3.75 g/day. In the acetazolamide arm there was a modest statistically significant improvement in the primary outcome of average perimetric mean deviation in the more affected eye (0.71 light stimulus decibels [95% CI 0 to 1.43 dB; p=0.050). Although this did not meet the predetermined threshold for clinical significance (1.3 dB), treatment effects were greater in participants with higher-grade papilledema at baseline. There were also significant improvements in the acetazolamide arm compared to control for secondary outcomes including cerebrospinal fluid opening pressure, papilledema grade on fundus photography and optical coherence imaging, and quality of life in patients with mild visual field loss (Smith and Friedman 2017).

Interestingly, patients with CVT can also develop late intracranial hypertension/ papilledema, with or without venous recanalization, and for this reason it is important to have follow-up ophthalmological assessment, even if the initial evaluation is normal. In a retrospective cohort of 70 CVT patients with follow-up, 7 (10%) developed new (n=5) or worsening (n=2) symptomatic intracranial hypertension within a median follow-up of six months (Geisbüsch et al. 2021). Five of the 7 patients with late intracranial hypertension had achieved partial (n=3) or complete (n=2) recanalization. In the SECRET trial, 1/50 (2.5%) developed new persistent papilledema at 90 days despite complete recanalization. Anecdotal discussions with members of the International CVT Consortium also confirm a similar experience with late “idiopathic” intracranial hypertension in a minority of CVT patients who have achieved partial or complete recanalization. Although there is some overlap in predisposing features for CVT and IIH, including younger age, female sex, and increased body mass index, the mechanism for this phenomenon and associated risk factors are not currently known. The optimal timing for later reassessment is not known, but could be considered around the one-month mark (balancing timing at which some recanalization is expected to occur, (Aguiar de Sousa et al. 2020) but not waiting too long such that previously undetected papilledema would persist without management for a prolonged period of time) and again at the 3-6 month mark, to be reassessed alongside repeat vascular neuroimaging and usual clinical follow-up.

Endovascular management

The role of endovascular therapy (EVT) in the management of CVT is not well defined, and practices vary, including use of EVT as first-line versus rescue therapy, candidate selection, and approaches (Goyal et al. 2022). Assessment of the benefits of EVT in CVT may be further complicated by the challenges in defining an optimal outcome measure, as the modified Rankin Scale (mRS) may be insufficiently sensitive to measure outcomes after CVT, given high rates of functional independence amongst survivors.

The Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TO-ACT) trial randomized patients with CVT with one or more pre-defined risk factors for worse prognosis, including intracranial bleeding, GCS<9, “mental status disorder,” or deep venous involvement, to endovascular therapy as per local practices versus conservative therapy (Coutinho et al. 2020). Endovascular techniques included mechanical thrombectomy alone, intradural thrombolysis or both. The primary outcome was an mRS of 0-1 at 12 months. At enrollment, median GCS was 11 and median NIHSS was 12. The trial was stopped early for futility after 67 of a planned 164 patients were randomized. There was no difference between groups with respect to the primary outcome (67% vs. 68%, RR 0.99, 95% CI 0.71-1.38). One-quarter in the EVT group received intradural thrombolysis as part of therapy. Sinus perforation occurred in 3/33 in the EVT group.

Although systematic reviews of case series of CVT receiving EVT report high rates of favourable outcomes, (Goyal et al. 2022) studies comparing outcomes between patients undergoing EVT versus anticoagulation alone CVT report higher rates of mortality with EVT, likely suggesting that the procedure is being performed in participants with worse clinical presentations. One large single-centre prospective study of 546 CVT patients from India had 10% who went for EVT, most commonly for clinical deterioration. EVT was performed through retrograde venous access through the internal jugular using a Fogarty balloon. The only complication reported was an intrasinus fracture of the Fogarty balloon retrieved with snare. There were no clinical incidences suspicious for pulmonary embolism. At 12-month follow-up, 67% in the EVT group had an mRS of 0-2. Outcomes for the non-EVT group were not described (Alwan et al. 2023). A recent systematic review and network meta-analysis of clinical trials and observational series of patients with CVT treated with anticoagulation or EVT (n=17 studies) found an increased odds of death (OR 1.83, 95% 1.04 - 3.21) in those treated with EVT (Naik et al. 2022). A recent review of cases of CVT undergoing mechanical thrombectomy (MT) between 2005 and 2018 in the US-based National Inpatient Sample identified use of MT in 1.56% of 85,370 CVT cases, with an upward trend of 0.13% per year (Wahood et al. 2023). Mortality was 16.7% in the MT group compared with 3.8% in those not receiving MT. Individuals who had MT had a higher proportion of markers in line with more severe presentations, including a higher prevalence of coma, ICH, and intubation.

Surgical management

Decompressive hemicraniectomy for CVT has been described in retrospective case series and systematic reviews. The results of the prospective DECOMPRESS-2 study were previously presented at the 2021 European Stroke Organization Conference but are not yet published (Aaron et al., 2021). In 118 individuals receiving decompressive hemicraniectomy for CVT, 58% were characterized as comatose prior to surgery, with 23% having unilaterally absent and 8% with bilaterally absent pupillary responses. Thirty-five percent had an mRS of 0-2 at 12 months, which is lower than what is reported in previous systematic reviews (Ferro et al. 2011).

Sex and gender considerations

No sex-specific concerns related to acute medical antithrombotic therapy have been identified outside of scenarios related to pregnancy or breastfeeding, where DOACs are contraindicated. Warfarin is contraindicated in pregnancy.

Acetazolamide has been identified as a potential teratogen in the context of animal studies, although a retrospective series of 50 women treated before 13 weeks of gestation with acetazolamide for IIH did not report an increase in spontaneous abortion above controls with IIH not taking acetazolamide, and no congenital anomalies were reported (Falardeau et al. 2013). In cases of individuals who are pregnant and being considered for treatment with acetazolamide, an obstetric opinion is recommended (Mollan et al. 2018; Thaller et al. 2022).

There are multiple considerations related to the use of ASM in women who are pregnant or breastfeeding which have been well-summarized in guidelines by the International League Against Epilepsy. https://www.ilae.org/patient-care/epilepsy-and-pregnancy

Special considerations related to acute treatment in pregnancy:

There is a previous Canadian Stroke Best Practice Consensus Statement related to management of acute stroke in pregnancy (Ladhani et al. 2018). As with other stroke types, acute treatment principles represent the confluence of two clinical considerations: (1) appropriate treatment if the patient were not pregnant and (2) appropriate treatment if the patient were not experiencing a stroke. Management decisions should thus be based on symptom severity, clinical condition of the patient and, when available, personal values and wishes of the patient and next of kin. A systematic review of management of CVT in pregnancy identified 66 cases, with a high prevalence of EVT, including thrombolysis alone (26%) or thrombectomy (8%) (Kashkoush et al. 2017). Five patients (8%) underwent hemicraniectomy. Those receiving EVT had a higher prevalence of coma at presentation. Overall, 94% in the series had an mRS of 0-2; 91% in the EVT group had an mRS of 0-2. It should be noted that the review was mostly composed of case reports and thus reporting bias towards successful cases, with an overrepresentation of EVT cases, is expected.