Cavernous sinus thrombosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The overall mortality and morbidity associated with cavernous sinus thrombosis (CST) continues to be high.[15] Consequently, institution of intensive treatment at the earliest suspicion of disease should be emphasised. Antibiotics are the mainstay of CST therapy. Anticoagulation, corticosteroids, and surgery are adjunctive treatment in appropriately selected patients. Because it is often difficult to distinguish between septic and non-septic causes of CST, the initial management is the same. Only when a septic aetiology is ruled out definitively can antibiotics be withdrawn. In practice, therefore, the treatments are the same for both aseptic and septic disease.[Figure caption and citation for the preceding image starts]: Treatment of aseptic cavernous sinus thrombosis (CST)From the collection of Dr Jayant Pinto, University of Chicago [Citation ends]. com.bmj.content.model.Caption@4c60779b [Figure caption and citation for the preceding image starts]: Treatment of septic cavernous sinus thrombosis (CST)From the collection of Dr Jayant Pinto, University of Chicago [Citation ends].

Initial therapy in all patients

Based on case reports and expert opinion, antibiotics are recommended as the mainstay of therapy. They have the greatest impact on the prognosis of septic CST.[2] High-dose intravenous antibiotics should be instituted at the earliest suspicion of this diagnosis.[2] Appropriate selection of empiric antibiotic regimens should be directed at the probable organisms implicated as the primary source of infection. It is necessary to take into account possible complications, such as brain or orbital abscesses, meningitis, or subdural empyema.[1][50]

Staphylococcus aureus is the most common pathogen, identified in approximately 70% of cases and is the pathogen implicated in nearly all cases of facial infections.[1] Bacteria associated with sinusitis include Fusobacterium necrophorum and Streptococci (including S pneumoniae, S milleri, and S viridans group).[13] Anaerobes are found occasionally, especially with sinus, dental, or tonsillar infections. Rarely, fungal infection from Aspergillus fumigatus or mucormycosis have been implicated in CST.[73][74]

For empirical antibiotic therapy, the Infectious Diseases Society of America (IDSA) guideline recommends vancomycin for 4-6 weeks with or without rifampicin.[75] Alternative options may include linezolid or trimethoprim/sulfamethoxazole.[75] However, these guidelines were published in 2011 and no evidence-based guidelines on empirical antibiotics for this indication have been published since. Some experts do not recommend vancomycin unless the patient is known to be colonised with MRSA. Other options, based on expert opinion, may include amoxicillin/clavulanate plus gentamicin, a third-generation cephalosporin, a fluoroquinolone, and the addition of metronidazole if brain abscess or dental or sinus infection is suspected.[6][76][77][78] Consult your local guidelines or infectious disease consultant for more information as this is a very specialised area with little evidence available to guide treatment decisions.

Antifungal therapy has been advocated only in cases of biopsy-confirmed invasive fungal infection. However, in at-risk patients, antifungal treatment should be considered as fungi may cause devastating neurological complications beyond cerebral venous thrombosis.[79]

As soon as the laboratory has reported sensitivities, empiric antibiotics can be switched to specific antibiotic therapy.

High doses of intravenous antibiotics are required because thrombus may limit penetration of antibiotics. Bacteria, sequestered within the thrombus, may not be killed until the dural sinuses have started to re-canalise. Antibiotics also need to be administered over an extended period, for at least 3-4 weeks.[41] This aims to insure complete sterilisation and prevent relapses.

Concurrent supportive therapy is necessary alongside antibiotic treatment, and includes resuscitation, oxygen support, and local eye care.[4]

Adjunctive therapy: anticoagulation

Considerable controversy exists concerning the efficacy of anticoagulation in the treatment of CST.[41] [ ] Prospective trials to establish any benefit from anticoagulation have never been (and are unlikely to be) performed owing to the rarity of the condition.[41] Anticoagulation carries the risk of haemorrhage, especially in patients with concomitant complications (e.g., cortical venous infarction, necrosis of intra-cavernous portions of the carotid artery, and cerebral or intra-orbital haemorrhages).[50] However, there is some evidence that the use of anticoagulation prevents propagation and contributes to re-canalisation of the thrombus. These are potentially beneficial effects, partly because the thrombus itself can harbour bacteria and sustain their growth.[2] Two retrospective reviews examining the use of anticoagulation for septic CST produced varying results.[15][22]

Currently, evidence is accumulating for the efficacy of anticoagulation in other forms of dural venous thrombosis. There have been two controlled trials comparing the use of placebo to anticoagulants in patients with cerebral sinus venous thrombosis.[80][81] European Federation of Neurological Societies (EFNS) guidelines recommend either subcutaneous low molecular weight heparin or intravenous heparin for aseptic dural venous thrombosis.[82] Similarly, guidelines published by the European Paediatric Neurology Society (EPNS) in 2012 recommend the use of anticoagulants for dural venous thrombosis to lessen the risk of death and other sequelae.[83] However, it should be noted that septic CST and aseptic dural venous thrombosis differ in many respects and that anticoagulation may be more hazardous in patients with septic CST.[50] The differences include the presence of infective aetiology, the site of the thrombosis, the acuteness of the process, and the presence of associated haemorrhagic complications.[50]

Based on limited observation, anticoagulation may be beneficial after exclusion of haemorrhagic complications by CT scan.[2][15][22] Anticoagulation is thought by some to be dangerous in patients with bilateral CST and/or concurrent intracranial haemorrhage.

The types and protocols for anticoagulation have varied considerably in research protocols. Intravenous and intramuscular unfractionated heparin, subcutaneous low molecular-weight heparin, and oral anticoagulation have all been used. However, the use of a rapidly reversible agent, such as intravenous unfractionated heparin has been advocated in the early stages of disease, followed by conversion to longer-acting agents, such as warfarin, when the patient's condition has stabilised.[50] One systematic review and meta-analysis suggested that in patients with cerebral venous thrombosis, direct oral anticoagulants (DOACs), and warfarin may have comparable efficacy and safety.[84] The evidence for the use of DOACs for CVT is limited.[85]

Newer anticoagulants, including direct thrombin inhibitors and factor Xa inhibitors, offer many advantages over heparin, including a more predictable anticoagulant effect and an absence of induction of immune-mediated heparin-induced thrombocytopenia (HIT).[86] However, there is a lack of reported cases of CST or other forms of dural sinus thrombosis that have been treated with these agents. The use of direct thrombin inhibitors, such as argatroban, can be considered as an alternate form of anticoagulation to heparin in patients with HIT or those at risk of HIT.

The duration of anticoagulation has not been determined and varies in reports from a few weeks to several months.[4][6] Some authors have suggested that anticoagulation should be continued until clinical or radiological evidence of complete resolution is present, or until there is significant improvement of the infection and thrombus.

Patients commenced on anticoagulants are usually still in an unstable clinical condition and are therefore not candidates for surgical management. However, if the patient's condition stabilises and surgical management is indicated, rapidly reversible anticoagulants can be discontinued to allow surgery.

If a patient is considered suitable for anticoagulation but deteriorates despite this therapy, they may be considered for endovascular therapy.[87][88][89] Although endovascular treatment is increasingly being used to treat patients with cerebral venous thrombosis, this treatment is not routinely recommended in all patients.[90] This therapy is usually reserved for progressive, aseptic CST and carries with it the risks of intracranial haemorrhage, stroke, and the inability to recanalise. It does not preclude corticosteroids.

Adjunctive therapy: corticosteroids

The role of corticosteroids is controversial in many cases of CST. They are potentially harmful because of their immunosuppressive effects. However, corticosteroids are absolutely indicated in cases of pituitary insufficiency. Corticosteroid use may have a critical role in patients with Addisonian crisis secondary to ischaemia or necrosis of the pituitary that complicates CST.[91][92]

Although there would seem to be only empiric support for their anti-inflammatory properties, with a real fear of progression to generalised sepsis, corticosteroids may also be beneficial for:[4]

Reducing intra-orbital congestion in patients with orbital oedema
Reducing cranial nerve inflammation in patients with cranial nerve dysfunction.

There are only a few anecdotal reports concerning the use of corticosteroids in CST in general and their efficacy has not been proved by these reports. In the studies in which the use of corticosteroids has been reported, other treatments have been used concurrently.[15][39][93][94] In one case, reported in 1962, cranial nerve dysfunction and orbital oedema failed to improve after 37 days of antibiotic and anticoagulant therapy but regressed dramatically 2 days after the addition of corticosteroid therapy, with eventual complete resolution in eye signs and symptoms.[95]

Surgical drainage post-stabilisation

Finally, as soon as the patient's condition permits, prompt drainage of the primary site of infection (such as the para-nasal sinusitis, dental abscess) or other concurrent closed-space infection is advisable.[7][15][96]

Surgical drainage of the cavernous sinus is almost never performed.[1]

In sinogenic CST, surgical drainage of the sinuses for all cases has been advocated.[11][12][13] Different operations have been performed to decompress the sinuses, including trans-septal sphenoidectomy, endoscopic sphenoidectomy and ethmoidectomy and external fronto-ethmoidal-sphenoidectomy. In cases of otogenic CST, mastoidectomy has been performed, with decompression of sigmoid sinus thrombophlebitis.[42]

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