Cerebral venous thrombosis

Cerebral venous thrombosis (CVT) is a thrombotic obstruction of the cerebral venous system that can lead to ischemic lesions (or hemorrhages) in the brain. The condition can occur at any age and is often associated with a hypercoagulable state, a trigger (e.g., delivery, head injury, CNS instrumentation) or an infection (i.e., as in septic CVT). Women are affected more frequently than men, possibly as a result of the additional risk factors of pregnancy and oral contraceptive use. Cavernous sinus thrombosis is a rare subset of CVT that is most often due to infections in the paranasal region. Headache is the most common symptom of CVT and, depending on the size and location of the clot, may be accompanied by visual impairment, focal neurological deficits, seizures, or signs of raised intracranial pressure. Neuroimaging (MRI or CT venography) of the cerebral veins and dural sinus is used to establish the diagnosis. The mainstay of management is anticoagulation alongside the treatment of any potential underlying cause (e.g., antibiotics for septic CVT). Surgical intervention (e.g., endovascular thrombolysis or decompressive craniectomy) may be necessary in patients with significant symptoms who do not respond to anticoagulation.

• Cerebral venous thrombosis (CVT) or cerebral venous sinus thrombosis (CVST): a thrombotic obstruction of the cerebral veins and/or related anatomical structures (dural sinuses) which drain blood from the brain. Common subtypes include transverse sinus thrombosis and superior sagittal sinus thrombosis. ^[1]
• Septic cerebral venous thrombosis: a subtype of CVT of infectious origin (see “Etiology”).
• Cavernous sinus thrombosis: a rare subtype of CVT, typically septic in origin, that is associated with cavernous sinus syndrome.

• Sex: ♀ > ♂; 3:1 ^[2][3][4]
• Age: any age group (average age ∼ 40 years)
• Incidence: 3–4 cases per million in adults; approx. 7 cases per million in children ^[1]

References:^[1][3][5]

Epidemiological data refers to the US, unless otherwise specified.

Noninfectious ^[2][5][6][7]

• Hypercoagulable states
  • Oral contraceptives, pregnancy, and postpartum period
  • Blood clotting disorders (e.g., factor V Leiden, protein C deficiency, protein S deficiency, antiphospholipid syndrome)
  • Hematologic diseases (e.g., polycythemia, sickle-cell anemia)
  • Malignancies
• Head trauma
• Neurosurgical procedures (e.g., lumbar puncture)
• Additional associated systemic conditions
  • Inflammatory bowel disease (e.g., Crohn's disease)
  • Collagen vascular diseases and blood vessel disorders (e.g., lupus erythematosus, granulomatosis with polyangiitis, temporal arteritis)
  • Hyperhomocysteinemia
  • Hematologic conditions (e.g., paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, sickle cell disease)
  • Nephrotic syndrome
  • Dehydration

Infectious ^[2][7][8]

• Rhinogenic (e.g., after sinusitis - paranasal, sphenoid, maxillary, and ethmoid)
• Mid-facial infections (cellulitis or abscess)
• Dental infections
• Otogenic (e.g., after acute otitis media) → generally infection of the lateral sinuses (transverse/sigmoid sinuses) or mastoiditis
• Meningitis
• Pharyngitis
• Tonsillitis
• Orbital and periorbital cellulitis

References:^{[2][5][6][7][8]}

• Thrombogenesis occurs in the cerebral venous system, including the dural sinuses → ↓ cerebral drainage → ↑ intracranial pressure → clinical features; ; (see below) ^[5][7]
• Additionally, thrombus formation → congestion within the venous system of the brain → blood stasis → ↓ oxygenated blood in brain tissue → cerebral edema and/or infarcts/stroke ^[7]

Symptoms vary depending on the size and location of the thrombosis. They are often nonspecific and may be masked by the underlying disorder(s), necessitating a high degree of clinical suspicion. Patients may have any symptoms of increased ICP or cerebral ischemia. ^[2][9][10]

• Headache ^[11]
  • Most common symptom (∼ 90% of patients)
  • Acute, subacute, or chronic
  • May progress in severity over days or weeks
• Signs associated with intracranial hypertension
  • Bilateral papilledema
  • Vision impairment (diplopia, vision loss)
  • Nausea and vomiting
  • Impaired level of consciousness
• Seizures (focal or generalized) ^[12]
• Signs of cranial nerve dysfunction, including: ^[9][10]
  • Diplopia, tinnitus, unilateral deafness, facial palsy
  • Cavernous sinus syndrome
• Other focal neurological symptoms
• Behavioral changes (e.g., delirium, amnesia)

Since the thrombus develops gradually, clinical symptoms usually appear progressively and vary in magnitude.

Diagnosis of CVT is based on neuroimaging with venography. Laboratory studies can help identify underlying conditions (e.g., infections) and to assess baseline organ function prior to therapy. ^[11]

Neuroimaging ^[11][13][14]

• Preferred modalities
  • MRI head with MR venography (MRV): modality of choice (highest sensitivity) ^[15][16]
  • CT head with CT venography (CTV): if MRI is unavailable or is contraindicated
  • Findings: Typically similar in CTV and MRV
    • Absence of flow in venography (Evidenced by filling defect in a vein or sinus)
    • Intraluminal venous thrombus
    • Focal edema secondary to ischemia
    • Intraparenchymal hemorrhage
    • Empty delta sign
      • A radiological finding in contrast-enhanced CT/MRI that resembles the Greek letter delta (Δ)
      • Consists of a central hypodensity (representing the thrombus) with a triangular outline of contrast enhancement
      • May be seen in cerebral venous thrombosis of the superior sagittal sinus.
• Additional modalities
  • Direct cerebral venography: if MRV/CTV are inconclusive or for procedural planning. Findings include filling defects and venous congestion
  • Noncontrast head CT
    • Normal in 70% of patients with CVT ^[11]
    • The thrombus may appear as a hyperdense vein or sinus.
    • Hypodense ischemic area of brain parenchyma with/without a hemorrhagic component

Additional evaluation ^[9][11][13]

• Routine laboratory studies
  • D-dimer
    • Typically elevated in acute disease
    • Normal levels indicate a lower probability for CVT but do not exclude the diagnosis. ^[11][17]
  • CBC ^[18]
  • Baseline renal function tests
  • Coagulation studies
• Additional studies to consider: to evaluate underlying etiology or complications
  • CRP and blood cultures ^[19]
  • Lumbar puncture ^[11]
  • ESR and antibody studies
  • Liver function tests ^[9]
  • Thrombophilia screening: see “Diagnostics” in hypercoagulable states ^[11][13]
    • Individual decision based on pretest probability (e.g., positive family history, young age)
    • Should be initiated 2–4 weeks after anticoagulation is discontinued, not during the acute phase
  • EEG: if seizures are present
    • Determines seizure focus
    • May show focal abnormalities if a unilateral infarct occurs

Posterior reversible encephalopathy syndrome (PRES) ^{[20][21][22][23]}

• Definition: a neurologic condition characterized by vasogenic edema in the subcortical white matter, especially in the posterior cerebral hemispheres
• Etiology
  • Increased blood pressure (severe hypertension, preeclampsia, eclampsia)
  • Renal failure
  • Sepsis
  • Certain autoimmune diseases (e.g., systemic lupus erythematosus)
  • Certain antineoplastic drugs and immunosuppressant drugs (e.g., cyclosporine, cisplatin, cyclophosphamide)
• Pathophysiology: The exact pathophysiology of PRES is not fully understood, but the following theories have been proposed.
  • ↑ Blood pressure → loss of cerebrovascular self-regulation → hyperperfusion with endothelial damage and vasogenic edema
  • Presence of endogenous or exogenous toxins → endothelial dysfunction
• Clinical features: severity of symptoms may vary
  • Seizures (most common)
  • Headache (constant, generalized, unresponsive to analgesics)
  • Visual disturbances
  • Nausea, vomiting
  • Altered mental status
• Diagnostics
  • MRI of the brain
    • Typically shows bilateral edema of the posterior cerebral hemispheres, especially the parietooccipital regions
  • Lumbar puncture
    • Used to exclude other causes of altered mental status
    • CSF analysis is normal or only shows a mildly elevated protein concentration
• Treatment
  • Treatment of the underlying cause (e.g., blood pressure monitoring and antihypertensives, dose modification or discontinuation of immunosuppressive therapy)
  • Seizure prophylaxis with anticonvulsants
• Prognosis
  • Complete recovery over days to weeks occurs in approx. 80% of cases

Other differential diagnoses

• Primary headaches
• Subarachnoid hemorrhage
• Idiopathic intracranial hypertension

The differential diagnoses listed here are not exhaustive.

Initial management consists of general stabilization procedures (control of seizures, administration of fluids, treatment of intracranial hypertension) and treatment of the underlying cause. All patients require anticoagulation, and those with underlying infection require antimicrobial therapy. Surgical intervention should be considered if there is no improvement with medical therapy.

Medical management ^[11][13]

• Anticoagulation: indicated for all patients with CVT (intracerebral hemorrhage and underlying infection are not absolute contraindications) ^{[8][11][13][24]}
  • Acute phase
    • First line: low molecular weight heparin (LMWH): e.g., Enoxaparin
    • Second-line: unfractionated heparin
  • Long-term anticoagulation: Transition to vitamin K antagonists, e.g., warfarin , while in-hospital. ^[11][13][25]
    • Duration of treatment: 3–12 months ^[15]
• Empiric antibiotic therapy: only indicated for suspected septic CVT (see also empiric antibiotic therapy for bacterial meningitis).
  • Sample regimen: combination therapy including an antistaphylococcal agent ^[26]
    • Vancomycin ^[27]
    • PLUS a third- or fourth-generation cephalosporin, e.g., ceftriaxone
    • PLUS metronidazole for anaerobic coverage
  • Duration of treatment: 3–4 weeks (tailored to clinical response) ^[26]
• Antifungals
  • CVT is rarely caused by fungal infection.
  • Immunosuppression (e.g., neutropenia, diabetes mellitus) is the most important risk factor. ^[28][29]
  • Initial treatment option: amphotericin B ^[8][30]
• Supportive care
  • Fluid resuscitation
  • Neuroprotective measures
  • ICP management
  • Consider anticonvulsants: Indicated in patients with a seizure and supratentorial lesions on imaging, otherwise not routinely recommended. ^[11][13]
  • Consider corticosteroids in the following:
    • Treating other complications, e.g., hypopituitarism
    • Treating underlying conditions: e.g., corticosteroids for or Behcet disease.
    • Highly controversial: reducing vasogenic edema ^[11][13]

Invasive procedures ^[11][13]

• Endovascular interventions
  • Indications
    • Absolute contraindications to anticoagulation
    • Significant symptoms despite anticoagulation
  • Procedures
    • Endovascular thrombolysis
    • Catheter thrombectomy
• Surgery
  • Indications
    • Progressive neurological worsening (despite adequate anticoagulation), e.g., visual loss, signs of ↑ ICP or cerebral herniation syndrome
    • Purulent collections requiring drainage
  • Procedures ^[31]
    • Decompressive craniectomy
    • Hematoma evacuation
    • Shunt placement
    • Abscess drainage

• Identify and treat any life-threatening complications.
• Obtain MRI/MRV to confirm the diagnosis (CT venography if MRV unavailable)
• Emergency neurology consult
• Start anticoagulation (e.g., heparin).
• Identify and treat underlying etiology, e.g., empiric IV antibiotics for septic CVT
• Begin neuroprotective measures and ICP management as needed.
• Monitor with serial neurological examination (e.g., GCS, visual field examination).
• If neurological deterioration despite therapeutic anticoagulation , urgent interventional radiology and/or neurosurgery consult for invasive treatment
• Consider ICU/stroke unit admission