Septic cavernous sinus thrombosis

INTRODUCTION — Septic cavernous sinus thrombosis is an uncommon condition with only several hundred cases reported in the English medical literature during the antibiotic era. Since this disorder is rare, each clinician is likely to encounter only one or a few cases during his or her career. The combination of lack of familiarity and the myriad of potential symptoms and signs often leads to misinterpretation of the clinical manifestations.

The cavernous sinus is the most frequent dural venous sinus to become infected and thrombosed, producing headache along with swelling around the eye and cranial nerve deficits [1-3].

This topic discusses septic cavernous sinus thrombosis. Septic dural sinus thrombosis affecting other sites and aseptic dural sinus thrombosis are discussed separately:

●(See "Septic lateral sinus thrombosis".)

●(See "Neurologic complications of bacterial meningitis in adults", section on 'Cerebrovascular complications'.)

●(See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

●(See "Cerebral venous thrombosis: Treatment and prognosis".)

ANATOMY — The intracranial venous system includes a number of dural venous sinuses which are found between the endosteal and meningeal layers of the dura. They receive blood from the cerebral veins and ultimately empty into the internal jugular vein.

The cavernous sinuses are the most centrally located of the dural venous sinuses, positioned just lateral to the base of the sella turcica and to the sphenoid paranasal sinuses. These irregularly shaped sinuses contain multiple trabeculae that act as sieves to trap bacteria; this characteristic explains the higher risk of infection of the cavernous sinuses as compared with the other dural venous sinuses. The cavernous sinuses are connected by two intercavernous sinuses that pass anteriorly and posteriorly to the sella turcica and the pituitary gland; thus bilateral infection may occur, particularly if treatment is delayed.

A number of cranial nerves are located within a dural sleeve, lateral to the cavernous sinus: oculomotor nerve (cranial nerve III), trochlear nerve (cranial nerve IV), and ophthalmic (V₁) and maxillary branches (V₂) of the trigeminal nerve (figure 1). The abducens nerve (cranial nerve VI) is located more medially within the cavernous sinus and abuts the cavernous segment of the internal carotid artery [4].

PATHOGENESIS — The cavernous sinuses receive blood from the facial veins and pterygoid plexus via the inferior and superior ophthalmic veins. Infections of the face, including the nose, orbits, tonsils, and soft palate, can spread to the cavernous sinus by this route. These underlying infections contribute to the clinical presentation. (See 'Clinical manifestations' below.)

Three sites of primary infection are the most likely to lead to septic cavernous sinus thrombosis:

●Sphenoid and/or ethmoid sinus infections have increasingly been reported with cavernous sinus thrombosis [5,6]. Sphenoid and/or ethmoid sinusitis is the most common predisposing factor for cavernous sinus thrombosis [7]. Infection can arise via the emissary veins or, in the case of sphenoid sinusitis, can spread by breaking through the porous lateral air sinus wall [2,8,9]. Sphenoid sinus infection is particularly difficult to diagnose, and treatment is often delayed, providing time for the infection to spread to the cavernous sinus [8]. (See "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis".)

Ethmoid sinus infection can extend laterally to the orbit and subsequently spread to the cavernous sinus via the superior ophthalmic vein.

●Facial infections are implicated in septic cavernous sinus thrombosis, especially those that involve the so-called danger zone (medial third of the face [ie, the areas around the nose]) that drains into the ophthalmic veins (figure 2). Nasal furuncles are the most common facial infection to produce this complication, particularly if the furuncle is squeezed or drained in the absence of antibiotic coverage [5].

●Dental infection less commonly results in this complication; infection spreads to the cavernous sinus via the pterygoid venous plexus [10] or from septic thrombosis of the internal jugular vein (Lemièrre syndrome), presumably as a result of retrograde extension [11]. (See "Lemierre syndrome: Septic thrombophlebitis of the internal jugular vein" and "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections".)

●Otitis media and mastoiditis – Otitis media and its related complication, mastoiditis, rarely result in cavernous sinus disease despite the frequency of these infections as a cause in the pre-antibiotic era [5,12,13]. Mastoid infection can spread first to the lateral and sigmoid sinuses before reaching the cavernous sinuses via the inferior and superior petrosal sinuses. Infection can spread in a retrograde direction in this manner, depending upon the pressure gradients, because the dural venous sinuses contain no valves.

Conditions that cause immunosuppression (eg, diabetes, chronic alcohol abuse, long-term glucocorticoid therapy) may be risk factors for septic cavernous sinus thrombosis [5,11].

MICROBIOLOGY — The organisms associated with septic cavernous sinus thrombosis reflect the primary sites of infection as outlined above [2,14-16]:

●Staphylococcus aureus accounts for 70 percent of all infections and is the etiologic pathogen in nearly all cases associated with facial infection or sphenoid sinusitis.

Community-acquired methicillin-resistant S. aureus (MRSA) is reported with increasing frequency [17,18].

●Streptococci (including S. pneumoniae, S. milleri, and viridans group streptococci) are less commonly found.

●Anaerobes are occasionally cultured, including Bacteroides spp and Fusobacterium spp, and are most often found with accompanying sinus, dental, or tonsillar infections.

●Fungal pathogens are less commonly reported and include Rhizopus spp [2,19,20] and other agents of mucormycosis [21], Aspergillus spp [22], and Schizophyllum commune [23]. In one reported outbreak of mucromycosis in patients with COVID-19 in India, a number of cases were complicated by septic cavernous sinus thrombosis [24]. (See "Mucormycosis (zygomycosis)", section on 'Coronavirus disease 2019-associated'.)

CLINICAL MANIFESTATIONS — Headache is the most common early symptom and generally precedes fever and periorbital edema by several days. The character of the headache is generally sharp; the pain progressively increases in severity, interferes with sleep, and is not relieved by pain medications. The pain is usually unilateral, involving the retro-orbital and frontal areas with occasional radiation to the occipital region [2]. The severe nature of the headache is the most common reason for patients to seek medical attention. Clinicians frequently misdiagnose the pain as migraine headache when the patient presents early in the course of the disorder, before the onset of neurologic deficits.

Patients often develop symptoms in addition to headache, including:

●Fever is present in most patients (64 to 94 percent) [2,7].

●Eye swelling that begins as a unilateral process but within 24 to 48 hours spreads via the intercavernous sinuses to produce swelling in the other eye; in one series, this was reported in 73 percent of patients [2].

●Diplopia is a presenting complaint in some patients but is less common than documented oculomotor deficits on examination [2].

●Alterations in mental status such as drowsiness, confusion, and coma can rapidly follow eye complaints, reflecting spread to the meninges. A depressed mental status occurs more commonly in older adult patients and in fatal cases [2].

In typical patients, symptoms progress over a few to several days. Rarely, cavernous sinus infection can be a subacute or chronic process, in which headache can be present for several months prior to the onset of eye findings [8].

Less common complaints include photophobia and eye tearing [2]. Rare complications include seizures, stroke, and hypopituitarism [25]. Loss of visual acuity can arise from optic nerve involvement. Blindness caused by compression of the optic nerve by a mycotic aneurysm of the intercavernous segment of the internal carotid/ophthalmic artery has been reported [26]. These uncommon complications are more common when treatment is delayed but can occur on antimicrobial therapy.

EVALUATION AND DIAGNOSIS — The early symptoms of septic cavernous sinus thrombosis are not specific, but the presence of cranial nerve signs (particularly lateral gaze palsy) on physical examination in a patient with headache should alert the clinician to the possibility of cavernous sinus involvement and prompt imaging studies, which are in most cases diagnostic. The evaluation should proceed promptly, as delays to treatment may be associated with morbidity and mortality.

Physical examination — When cavernous sinus septic thrombosis is fully manifest, the majority of patients present with fever and the classic constellation of bilateral ptosis, proptosis, chemosis, and ocular muscle paralysis. However, the physical findings may be considerably subtler when patients present earlier in the disease course. A careful eye and neurologic examination, with particular attention to the cranial nerves, is necessary in order to make a diagnosis at an earlier stage.

Periorbital edema may be the earliest physical finding and should prompt a more detailed neurologic examination in patients with headache:

●Funduscopic exam is abnormal in two-thirds of patients. Papilledema or dilated tortuous retinal veins are noted in almost two-thirds of patients [2].

●Extraocular muscle weakness is an important finding present in 50 to 88 percent of cases [2,3] and results from dysfunction of cranial nerves III, IV, and VI. The following signs should be sought:

•Lateral gaze palsy (isolated cranial nerve VI [abducens] dysfunction) may precede full-blown ophthalmoplegia, particularly in cases of chronic sphenoid sinusitis.

•Drooping of the eyelid (ptosis), dilation of the pupil (mydriasis), and eye muscle weakness result from cranial nerve III dysfunction. Total palsy of the nerve leads to an eye that is facing down and lateral.

●Exophthalmos (anterior bulging of the eye) and chemosis (conjunctival edema) are thought to result from occlusion of the ophthalmic veins and generally occur just before or at the same time as ophthalmoplegia. One or both of these findings is present in most patients [2].

●Hypo- or hyperesthesia in the dermatomes served by the ophthalmic (V₁) and maxillary (V₂) branches of the fifth cranial nerve (trigeminal nerve) can be subtle [2].

In addition, it is important to evaluate for the source of the underlying infection, including a thorough physical examination of the head, neck, and scalp for a source of facial cellulitis as well as an examination of the oral and nasal cavities.

Imaging — In patients presenting with headache and cranial nerve signs localized to the cavernous sinus, a diagnostic neuroimaging study is urgent. Contrast-enhanced magnetic resonance imaging (MRI) and magnetic resonance venography are the imaging tests of choice and have been reported to be superior to computed tomography (CT) in some respects, because MRI can detect all stages of thrombus in septic cavernous sinus thrombosis (image 1) [7]. If MRI is not readily available, high-resolution orbital CT with contrast can also demonstrate septic cavernous thrombosis [27,28]. The early venous phase following administration of contrast demonstrates thickened cavernous sinus walls and decreased or irregular intrasinus enhancement (image 2) [29,30].

MRI and/or CT are also important to identify an associated paranasal sinus infection. The presence of paranasal sinus infection should prompt consultation for possible surgical intervention. (See 'Surgery' below.)

Blood cultures and other studies — Two sets of blood cultures should be sent prior to initiation of antibiotics, and they are positive in approximately 70 percent of cases [3].

The peripheral white blood cell count (WBC) is commonly elevated, suggesting an acute bacterial infection.

Lumbar puncture — A lumbar puncture is typically not performed unless there is concern that the patient has developed a complicating meningitis. (See 'Clinical manifestations' above.)

When performed, lumbar puncture reveals inflammatory cells in 75 percent of cases. In half of these cases, the cerebrospinal fluid (CSF) profile is most suggestive of a parameningeal focus (elevated WBC with a predominance of polymorphonuclear neutrophils [PMNs] and/or mononuclear cells, normal glucose, elevated or occasionally normal protein, and negative culture). In one-third of patients, the CSF profile is identical to that found in bacterial meningitis (elevated WBC with a predominance of PMN, low glucose, high protein, culture positive) [2,19]. In rare patients, the CSF profile is normal.

If a lumbar puncture is performed, Gram stain and culture should be performed; however, the CSF culture is rarely positive [7].

DIFFERENTIAL DIAGNOSIS — A number of conditions are considered in the differential diagnosis of septic cavernous sinus thrombosis, including those that are considered in the differential diagnosis of painful ophthalmoplegia (table 1). Signs of orbital congestion (proptosis, conjunctival injection, and chemosis) usually accompany diseases involving the orbit. Most of these can be distinguished by neuroimaging evaluation and/or clinical symptoms. Among the more common conditions to consider are:

●Orbital cellulitis – Orbital cellulitis and septic cavernous sinus thrombosis have overlapping symptoms including periorbital eye swelling, chemosis, and ophthalmoplegia. Also, in rare cases, septic cavernous sinus thrombosis is a complication of orbital cellulitis (see "Orbital cellulitis", section on 'Clinical manifestations'). Clinical characteristics that increase the probability of involvement of the cavernous sinus include:

•Dilated pupil or pupils

•Visual loss

•Papilledema

•Fifth cranial nerve dysfunction

•Bilateral eye involvement

•Inflammatory cells in the CSF

High-resolution CT or MRI can readily differentiate between the two diseases by demonstrating involvement of the cavernous sinus. (See 'Imaging' above.)

●Intraorbital abscess – This typically presents acutely with periorbital swelling, proptosis, chemosis, ophthalmoplegia, fever, decreased vision, and pain; however, it usually has an absence of papilledema and papillary involvement. Imaging studies are able to differentiate abscess from cavernous sinus thrombosis.

●Intracavernous carotid artery aneurysm or arteriovenous fistula – These entities are often accompanied by proptosis, pain with a pulsatile feeling, bruit, and engorgement of blood vessels. Patients do not have fever or other signs of infection. Neuroimaging findings are distinctive. (See "Carotid-cavernous fistulas", section on 'Diagnosis and imaging findings'.)

●Neoplastic or inflammatory infiltration of the cavernous sinus from meningioma or metastasis, as well as neurosarcoid, IgG4-related disease, idiopathic pachymeningitis or granulomatosis with polyangiitis, and Tolosa-Hunt syndrome. These can present with headache, periorbital pain and external ophthalmoplegia; however, fever is usually mild or absent. (See "Tolosa-Hunt syndrome", section on 'Differential diagnosis'.)

●Aseptic cavernous sinus thrombosis – Septic cavernous sinus thrombosis is typically distinguished from aseptic disease by the presence of fever on examination as well as associated finding of infection in the sinus, mastoid, or face on imaging and/or examination. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Syndromes associated with isolated sinus or vein thrombosis'.)

TREATMENT — The mainstay of therapy for septic cavernous sinus thrombosis is antibiotics; anticoagulation and surgery are appropriate adjunctive treatments in selected cases. Treatment should be started urgently as delays to treatment may be associated with morbidity and mortality.

Antibiotics — Intravenous (IV) antibiotics should be instituted emergently and directed at the probable organisms causing this type of infection. (See 'Microbiology' above.)

The regimens listed below are for patients with normal renal function. Dose adjustments for patients with reduced kidney function can be found in the drug information topics within UpToDate.

●Empiric and directed regimens – Empiric therapy should include coverage for community-acquired MRSA. Appropriate empiric parenteral regimens include:

•Vancomycin (table 2);

PLUS EITHER:

•Ceftriaxone (2 g IV every 12 hours); OR

•Cefepime (2 g IV every 8 to 12 hours). Cefepime (2 g IV every eight hours) should be used if Pseudomonas coverage is desired (eg, in patients with chronic sinusitis and known colonization of the sinus with pseudomonas).

Anaerobic coverage should be added if a dental or sinus infection is suspected. IV metronidazole (500 mg every six to eight hours) is highly effective for this purpose.

If a cephalosporin or metronidazole (if indicated) cannot be used, the combination of vancomycin (table 2) and meropenem (2 g IV every eight hours) is a reasonable empiric regimen for most patients. If meropenem is not available, imipenem (1 g IV every six hours) can be used; however, we prefer meropenem since imipenem may increase the risk of seizures. Patients with severe beta-lactam allergies (eg, Stevens Johnson syndrome) may require a different regimen. (See "Penicillin allergy: Delayed hypersensitivity reactions" and "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics" and "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics" and "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".)

Antifungal therapy is rarely required and should only be utilized if invasive fungal infection is proven by biopsy. Patients prone to such infections include those who are immunosuppressed.

If susceptibility testing reveals methicillin-susceptible S. aureus, therapy should be changed to nafcillin (2 g IV every four hours) or oxacillin (2 g IV every four hours). First-generation cephalosporins (eg, cefazolin) should be avoided for treatment of central nervous system infections because of poor CSF penetration.

If the organism is methicillin resistant S. aureus, vancomycin should be continued (table 2) [31-33]. If vancomycin cannot be used or is ineffective based on a lack of improvement of clinical manifestations (eg, fever, bacteremia, changes in mental status) over the course of seven days, reasonable alternatives include ceftaroline (600 mg IV every 8 to 12 hours) [34], daptomycin (6 to 10 mg/kg IV once daily), linezolid (600 mg IV or orally twice daily) [17,35-37], and trimethoprim-sulfamethoxazole (5 mg/kg [based on the trimethoprim component] IV every 8 to 12 hours) [38-40].

●Duration – Because thrombus may limit the penetration of antibiotics, prolonged IV antibiotics are recommended. A minimum of three weeks of treatment is generally required to assure sterilization. The duration may need to be extended longer based upon the presence of other factors, such as bacteremia with S. aureus (see "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Completing antibiotic therapy') or if significant ophthalmoplegia or edema of the eye remains at the end of planned therapy. We use clinical rather than imaging parameters to guide this decision, as improvement in imaging is often delayed.

Anticoagulation — We suggest immediate anticoagulation in patients with unilateral cavernous sinus thrombosis in order to prevent bilateral extension. This practice is based on limited and conflicting data. For patients with bilateral disease, we do not use anticoagulation.

For patients treated with anticoagulation, we suggest continuous-infusion heparin anticoagulation, adjusting the dose to maintain a partial thromboplastin time ratio of 1.5 to 2.5 [41]. There are no reports of low-molecular-weight heparin being used in this setting; however, hemorrhagic complications have been observed in two patients who were receiving low-molecular-weight heparin for septic lateral sinus thrombosis (see "Septic lateral sinus thrombosis", section on 'Anticoagulation'). Warfarin should be avoided in the acute phase of the illness because of the difficulty in rigorously maintaining safe anticoagulation levels.

The duration of anticoagulation has not been determined. We continue anticoagulation until the infection as well as the symptoms and signs of cavernous sinus thrombosis (eg, periorbital edema, fever, leukocytosis) have resolved or significantly improved.

Although the use of anticoagulants in septic cavernous sinus thrombosis is controversial and there are limited data on this issue, one retrospective study observed a reduction in mortality in patients with unilateral involvement who presented early and who received heparin (14 percent) compared with those who did not receive heparin (36 percent) [2]. In a second retrospective analysis, the addition of early anticoagulation to antibiotic treatment did not affect mortality but did decrease morbidity, including ophthalmoplegia, blindness, stroke, hypopituitarism, and seizures [25]. In another cohort of 57 patients who had central nervous system venous thrombosis associated with head or neck infections, use of heparin was not associated with an increase in intracranial hemorrhage in patients receiving heparin compared with patients not receiving heparin (26 versus 25 percent) [42].

Surgery — Surgical drainage of sphenoid sinus infection or soft tissue abscess that have been documented on imaging should be strongly considered and, if done, should be performed emergently [43]. Debridement of the infected sphenoid can be followed by rapid improvement. Although controlled studies are lacking, the improved mortality from this condition over the past decade is likely attributable in part to improved imaging and earlier surgical drainage [44].

Lack of role for glucocorticoids — We do not favor the use of glucocorticoids for septic cavernous sinus thrombosis.

There has been interest in using glucocorticoids in patients with septic cavernous sinus thrombosis to potentially reduce cranial nerve edema and orbital inflammation, but the limited data available suggest they are not useful [41,45,46]. In one prospective observational study of 624 patients with cerebral venous thrombosis, poor outcome defined as death or dependence at six months was similar in patients treated with steroids compared with patients not treated with steroids (odds ratio 1.7; 95% CI 0.9 to 3.3) [46].

OUTCOME — Older case series have reported a mortality rate as high as 30 percent [2]. An additional 30 percent of patients in that series suffered serious sequelae including persistent oculomotor weakness, blindness, hemiparesis, or pituitary insufficiency.

More recent case series and reviews provide a small number of patients for analysis, but the prognosis appears to be more favorable, with estimated mortality rates of 9 to 16 percent and morbidity rates of 15 to 38 percent [44,47].

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The cavernous sinus is the most frequent dural venous sinus to become infected and thrombosed. Septic cavernous sinus thrombosis typically arises from local infections such as sphenoid or ethmoid sinusitis, facial infections, and dental infections. (See 'Anatomy' above and 'Pathogenesis' above.)

●Microbiology – Staphylococcus aureus accounts for 70 percent of all infections and is the etiologic pathogen in nearly all cases associated with facial infection or sphenoid sinusitis. (See 'Microbiology' above.)

●Clinical features – Headache is the most common early symptom and generally precedes fever and periorbital edema by several days. Other common clinical manifestations include eye swelling and diplopia. (See 'Clinical manifestations' above.)

●Diagnosis – While the symptoms are not specific, the presence of cranial nerve signs (particularly lateral gaze palsy) on physical examination in a patient with headache should alert the clinician to the possibility of the diagnosis and prompt an urgent evaluation. Other entities in the differential diagnosis include infections and inflammatory processes involving the orbit and/or cavernous sinus. (See 'Differential diagnosis' above.)

Magnetic resonance imaging (MRI) with gadolinium is essential to investigate symptoms in this setting and typically establishes the diagnosis. (See 'Evaluation and diagnosis' above.)

●Management – Urgent empiric antibiotic therapy is required. For most patients, we suggest a regimen that includes vancomycin plus ceftriaxone or cefepime (Grade 2C). Metronidazole should be added if anaerobic coverage is required (eg, suspected dental or sinus infection). (See 'Antibiotics' above.)

We suggest early heparinization in patients with unilateral cavernous sinus thrombosis in order to prevent bilateral extension (Grade 2C). (See 'Anticoagulation' above.)

Surgical drainage of a sphenoid sinus infection that has been documented on imaging should be strongly considered and, if done, should be performed emergently. (See 'Surgery' above.)