Cerebral venous sinus thrombosis, paediatrics (1231)

History and examination

Treatment

Recurrence

Teams responsible for care

Follow up

Important clues in the history and examination:

Past Medical History: meningitis, chicken pox, COVID19 infection and/or vaccination, congenital heart disease, systemic lupus erythematosus, inflammatory bowel disease, lymphoproliferative disease, diarrhoea and vomiting or fluid loss, sickle cell anaemia, nephrotic syndrome, malignancy, head injury, iron deficiency anaemia, protein C and S deficiency, homocystinuria, obesity, central venous catheter.

Drug history: Asparaginase, exogenous oestrogens.

General Paediatric Examination:

CNS: Perform GCS/AVPU and PEWS and continue to document these observations.

Signs of raised intracranial hypertension (sunsetting, raised anterior fontanelle, scalp vein distension; the triad of bradycardia, hypertension, and altered breathing pattern indicates a pre-terminal emergency).

Growth: BMI

ENT: infection (otitis media, sinusitis, mastoiditis, oropharyngeal), rash (chicken pox, lupus).

Eyes: Visual acuity, direct fundoscopy for disc swelling. Proptosis and ophthalmoplegia may suggest a cavernous sinus thrombosis

Systemic: anaemia, cardiovascular disease, rash

Radiological diagnosis:

Discussions about imaging should occur early on with the duty radiologist.  Magnetic resonance imaging (MRI) with venography (MRV) is the preferred imaging examination. If MR is not available acutely or CT is preferred due to the presenting aetiology, then high resolution CT venography with contrast is an appropriate alternative modality.  Non-contrast CT may be useful in the most general setting but can be normal initially. Mimics and pitfalls can occur with both MR and CT techniques, especially in younger children/infants thus radiological expertise is required in interpretation of the imaging.  MR and CT complement each other but undertaking both is not indicated if there is a confirmed diagnosis of thrombosis. Radiation exposure and requirements for anaesthesia are always a consideration for any imaging.

Investigations seeking risk factors:

Haematology: FBC, ferritin, ESR, coagulation.

A thrombophilia screen (Protein C and S, antithrombin III) may be indicated for spontaneous, unprovoked CVSTE (without obvious cause) and/or strong family history of venous thromboembolism. Similarly, in unprovoked events, consider sending Prothrombin gene mutation (G20210A) and Factor V Leiden.  Discuss with haematology about the appropriate timings for undertaking the above testing as different anticoagulants may affect levels of the above proteins.

Biochemistry: Fasting homocysteine, renal profile

Ophthalmic examination:

Clinic setting assessment including – visual acuity, colour vision, contrast, pupils, ocular motility, disc clinical and OCT assessment +/- fields (per presenting age group and generalised clinical condition) when reliable clinical assessment is hindered by compliance issues, invasive ICP monitoring may have to be considered / discussed.

Treatment:

Firstly, acute care and neuroprotection are essential. Adequate hydration and management of any source of infection are required.

Anticoagulation:

Please see NHS GGC Paediatric Haematology guidelines on anticoagulation (Anti-Thrombotic therapy, Haematology)

1. Firstly, treatment with heparin for at least 5 days is recommended. A longer duration may be appropriate dependent on the clinical picture. Low molecular weight heparin (LMWH) is typically used, unless there are concerns regarding bleeding or the likelihood of urgent surgery. This should be optimised with Anti-Xa levels if LMWH heparin is used, aiming for an anti-Xa level of 0.5-1.0 (0.3-0.7 if UFH used). Once five days of therapeutic anticoagulation with LMWH have been achieved, alternative anticoagulants may be considered - this includes continuation on LMWH, warfarin or rivaroxaban. The haematology service can help guide this decision as to the most appropriate anticoagulant.
2. Patients should be referred and seen in the thrombosis clinic following discharge to discuss optimal length and type of anticoagulant. This will likely include repeat imaging. Broadly, continuation of anticoagulation will be advised) for;
3. Most patients for 3-6 months. A shorter duration may be appropriate for neonates where the risk/benefit may be different.
4. Longer term/lifelong anticoagulation would likely be suggested for patients with recurrent episodes of CVSTE, no evidence of a provoking event or evidence of a thrombophilic tendency. Patients with evidence of an inherited thrombophilia should have detailed discussion within the thrombosis clinic with regards to the risk/balance of remaining on therapeutic anticoagulation – this will depend on condition/mutation identified.
5. All patient on anticoagulation should be followed up within the anticoagulation service (in addition to referral to the thrombosis clinic), regardless of anticoagulation used. The haematology team should be contacted, if possible 24-48 hours prior to planned discharge to ensure appropriate follow up is in place (e.g. if further Anti-Xa levels are required for patients on LMWH)

Contra-indications to anticoagulation:

• Major cerebral or systemic haemorrhage

Note that intracerebral haemorrhage which can be due to cortical vein congestion is not an absolute contraindication to starting anticoagulant treatment (provided other factors do not favour bleeding) but the decision should be consultant led.

Neurosurgical intervention:

The neurosurgical conditions, requiring treatment, that can follow CVST are hydrocephalus, intracerebral haematoma and diffuse brain swelling. All present with raised intracranial pressure and will be treated surgically.

Intracranial hypertension:

Visual loss:

Children are at risk of visual loss as a complication of raised intracranial pressure, thus require careful ophthalmological assessment and follow up. Management should be discussed with neurology and neurosurgery and be considered on a case-by-case basis.

Recurrence:

The rate of CVSTE recurrence rate is between 2 and 8%. In children with CVSTE, recurrence only occurred when CVSTE was diagnosed after 2 years of age and was more likely when there was persistent occlusion on repeat imaging and with a demonstrated thrombophilic tendency such as a Prothrombin gene mutation.  The risk of recurrent CVSTE in pregnancy appears to be low but it is unknown whether thromboprophylaxis in pregnancy is required.

Teams responsible for care

“Medical” CVSTE will be managed by the lead team for the patient which will most often be Medical Paediatrics, renal medicine, gastroenterology or neurology.

Haematology will advise on matters relating to anticoagulation.

Neurology will advise on medical management of intracranial hypertension and seizures.

Neurosurgery will advise on surgery for severe intractable intracranial hypertension where sight is at risk or brain herniation is likely.

Ophthalmology will monitor discs and visual function.

Follow up

Haematology - As detailed within the anticoagulation section, patients should be referred to the Thrombosis clinic on discharge for ongoing management of anticoagulation. In addition, please contact the haematology team 24-48 hours prior to planned discharge so appropriate follow up may be arranged with the outpatient anticoagulation service (prior to Thrombosis clinic appointment.  

Imaging follow-up should be based on clinic concern, primary aetiology, extent of thrombosis and secondary effects seen on initial imaging.  Routine follow-up imaging is not indicated if there are no clinical concerns and/or following treatment of a small thrombosis. MRV is the modality of choice. The risk-benefit of routine follow-up imaging requiring general anaesthetic must be considered.

Ophthalmology - Following initial assessment at diagnosis, further follow ups will be based on presenting visual function and degree of disc swelling. Ophthalmology follow ups will be deferred when disc oedema is in remission, 2 months following cessation of systemic treatment.

General paediatric medicine - If there are residual concerns and follow up is considered necessary then please discuss.  

Neurology - follow up is required for those with recurrent seizures (1 in 4 may develop late epilepsy) and those on drugs to control intracranial hypertension.

History and examination

Treatment

Team responsible for care

Follow up

History and examination

In children presenting with ear and sinus infections, it is important to be vigilant for signs of intracranial complications such as:

• Change in behaviour, lethargy, lack of usual interaction, impaired GCS.
• Signs of raised intracranial pressure (bradycardia, hypertension, altered breathing pattern, sunsetting, raised anterior fontanelle, scalp vein distension), papilloedema.
• Focal neurological signs

Diagnosis of CVSTE will usually be made on cross-sectional imaging which has been requested because of concerns about CNS symptoms, or because surgery is being considered for the primary site of infection (eg mastoidectomy for acute mastoiditis).

Radiological diagnosis:

Discussions about imaging should occur early on with the duty radiologist.  Given that the scan is being ordered primarily for surgical planning, it will usually be computed tomography (CT) with contrast.  Mimics and pitfalls can occur, thus radiological expertise is required in interpretation of the imaging.

Magnetic resonance imaging (MRI) with venography (MRV) is the most sensitive diagnostic test and could be considered if CT is negative or equivocal and the situation is strongly suggestive of CVSTE.

Treatment

Hydration, analgesia and careful neurological observations are essential. 

Adequate control of the source of infection is also essential and should include both intravenous antibiotic therapy and surgical control.  Anticoagulation should be considered on a case-by-case basis, depending on the child’s circumstances and the nature and timing of surgical interventions.

ENT surgical interventions

ENT surgical drainage should be performed promptly (under the same GA as a neurosurgical procedure if one is being performed).  Often this will be out of hours.  Drainage must be adequate for the circumstances:

• For acute otitis media without mastoiditis, examination of the ear and placement of a tympanostomy tube should be considered if the tympanic membrane has not spontaneously perforated.
• For acute mastoiditis, tympanostomy tube placement should be accompanied by incision and drainage of the mastoid subperiosteal abscess as a minimum. At the discretion of the operating surgeon, a cortical mastoidectomy should be considered.
• For acute ethmoid and maxillary sinusitis, endoscopic sinus surgery should be performed to remove the uncinate process, widen the maxillary sinus ostium and open the ethmoid bulla.
• For acute frontal sinusitis, endoscopic sinus surgery should be performed to ensure drainage of the maxillary sinus and ethmoids. If there is any doubt about the adequacy of drainage of the frontal recess that has been achieved, then an external frontal sinus trephine should be performed.
• For all acute sphenoid sinusitis, drainage should be performed via the posterior ethmoids or direct transnasal sphenoid puncture at the surgeon’s discretion.

Consideration should be given to the placement of a line under the same anaesthetic as the surgical drainage procedure if circumstances allow, as prolonged antibiotic therapy is likely (see below).  A PICC line is ideal but a midline is acceptable if that is all that is available out of hours.  This should be discussed with the anaesthetist responsible for the list.

Neurosurgical intervention may be required for any associated intracranial collections but not for the CVSTE itself. 

Management of surgical CVST associated infection

Initial investigation and management of surgical CVST associated infection is given below. 

Please refer all stable patients to the Paediatric Infectious Diseases (ID) team within daytime working hours (ID Registrar DECT 84939 or Consultant on call via switchboard). ID will consult on every stable patient with CVST associated infection within daytime working hours (including weekends). If advice is needed urgently or out of hours, then contact the on-call Consultant in Paediatric Infectious Diseases via switchboard. 

ID advice will include further antibiotic therapy, duration of antibiotics, monitoring of the infection and antibiotic therapy, IV to oral stepdown (IVOST) and suitability for outpatient parenteral antibiotic therapy (OPAT), in liaison with the primary team.

The overall clinical responsibility for the patient remains with their primary team at all times. This includes organising and reviewing the results of diagnostic and monitoring investigations, prescribing, and clinical decision making.

Empirical antibiotic therapy:

Intracranial infections are often polymicrobial, requiring empirical gram positive, gram negative, and anaerobic cover. 

• Initial antibiotic regimen: Cefotaxime, Metronidazole
• If known MRSA colonisation: Cefotaxime, Metronidazole, Vancomycin
• Penicillin allergy initial regimen: Metronidazole, Vancomycin, Ciprofloxacin

Doses and regimen of antibiotics are based on BNFc recommendations for severe infection, summarised in the table below:

¹ Metronidazole and Ciprofloxacin have similar bioavailability with Oral and IV routes. The 1st dose of metronidazole and ciprofloxacin may be given Oral or IV depending on the clinical assessment of the primary team. If the 1st dose is given IV, then Metronidazole and Ciprofloxacin should be switched to the Oral route for the 2nd dose provided that the patient is tolerating enteral medication. 

² See BNFc if dosing is required for premature infants 33 weeks corrected gestation or below.

³ Target a high Vancomycin trough (15-20 mg/L for intermittent infusion and 20-25 for continuous infusion) unless advised otherwise by ID.

Minimum duration of IV antibiotic therapy:

• Extradural infection only: 3 weeks
• Subdural infection: 6 weeks

Final decision on duration of antibiotics should be made on a case by case basis, after discussion with the ID team.

Microbiological investigations:

• Blood culture prior to starting antibiotics (unless this will cause an unacceptable delay in giving IV antibiotics).
• Pus and tissue from intra-operative sampling are the preferred samples (as assessed by the operating surgeon)
• Bacterial swabs from intra-operative sampling can also be sent for culture, particularly if pus or tissue is not available (as assessed by the operating surgeon)
• Please ensure adequate clinical details on the request form

Anticoagulation

Early treatment with anticoagulation is likely to be safe and beneficial, thus it is recommended for all CVSTE without contraindications to anticoagulant therapy. Anticoagulation is used to promote endogenous thrombolytic mechanisms, prevent thrombus propagation and promote recanalisation over the coming weeks-months. 

The decision of when to commence anticoagulation must be taken by the haematology team in conjunction with both neurosurgery and ENT surgical teams to ensure that all foreseeable surgical procedures have been completed and a suitable time window for likely surgical complications has passed.  The responsibility for supervising the outpatient anticoagulation therapy lies with the haematology team.

The regimen is the same as that described above (see Management of “medical” CVSTE).

Team responsible for care

For CVSTE secondary to acute infection in the ear or paranasal sinuses, the care will primarily be under the ENT team.  If there is also intracranial infection, care will be shared with the neurosurgical team.

Haematology will advise on matters relating to anticoagulation.

ID will advise as required on choice and duration of antibiotic therapy.

Ophthalmology will monitor visual function until resolution of disc oedema.

Neurology will advise on medical management of intracranial hypertension and seizures.

Follow up

ENT follow up will be arranged for 6 weeks post discharge for audiometric testing in cases of CVSTE complicating acute otitis media or mastoiditis.

Haematology: Patient should be seen in the haematology thrombosis clinic following discharge. Consideration may be given to further imaging dependent on clinical picture and anticoagulation duration at this time

ID follow up is not usually required.

Neurosurgery: If the patient has required neurosurgical intervention the neurosurgical team will arrange follow up including investigations.

Ophthalmology:  Following initial assessment at diagnosis, further follow ups will be based on presenting visual function and degree of disc swelling. Ophthalmology follow ups will be deferred when disc oedema is in remission, 2 months following cessation of systemic treatment following surgery.

Thrombosis UK. Venous Thromboembolism in Infants, Children & Young People.