Cavernous Sinus Thrombosis

Etiology

Cavernous sinus thrombosis usually occurs with sepsis, but can also arise in aseptic conditions. Septic cases can result from facial infections primarily within the nasolabial triangle of the face that extends from the corners of the mouth to the bridge of the nose. These infections can include abscess formation, cellulitis, sphenoid or ethmoid sinusitis, otitis media, mastoiditis, and dental procedures, eg, maxillofacial surgery and tooth extractions, as well as a posterior superior alveolar nerve block where the nerve enters the pterygoid plexus. Aseptic causes of cavernous sinus thrombosis are less common than septic causes and include trauma, surgery, or pregnancy.[6]

A variety of infectious organisms can cause cavernous sinus thrombosis, with the majority being bacterial in origin. Staphylococcus aureus is responsible for approximately two-thirds of cases, with some organisms being resistant to methicillin. Other common organisms include Streptococcus species in approximately 20% of cases, pneumococcus in 5%, and gram-negative species, eg, Proteus, Haemophilus, Pseudomonas, Fusobacterium, and Bacteroides, as well as gram-positive species like Corynebacterium and Actinomyces. Several of these bacteria are anaerobic, including Bacteroides, Actinomyces, and Fusobacterium. Fungal infection in cavernous sinus thrombosis is less common than a bacterial infection, but can include, most commonly, Aspergillosis, Mucormycosis, and Coccidiomycosis in immunocompromised individuals. Rare causes of cavernous sinus thrombosis include parasites, eg, toxoplasmosis, malaria, and trichinosis, as well as viral causes like herpes simplex, cytomegalovirus, measles, hepatitis, and the human immunodeficiency virus (HIV).

Cavernous Sinus Thrombosis Risk Factors

Immunosuppression is associated with uncontrolled diabetes mellitus, steroid use, cancer, and chemotherapy administration, and represents a risk for developing cavernous sinus thrombosis and other medical complications.

However, the most significant risk factors for cavernous sinus thrombosis are facial infections, acute sinusitis, and periorbital infections, although thrombophilia is also a significant risk factor. Women who are pregnant, postpartum, or are receiving oral contraceptives or hormone replacement therapy may be at increased risk for developing cavernous sinus thrombosis. A variety of thrombophilic genetic disorders can cause cavernous sinus thrombosis, including the factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III deficiency, protein C or S deficiency, and elevated factor VIII levels.

Acquired disorders, eg, antiphospholipid antibody syndrome, hyperhomocysteinemia, heparin-induced thrombocytopenia, and obesity, may also contribute to the risk of cavernous sinus thrombosis. Other causes of cavernous sinus thrombosis include severe dehydration that occurs in a hyperosmolar nonketotic state, nephrotic syndrome, and sickle cell disease.[7][8][9][10]

Epidemiology

Cavernous sinus thrombosis is so rare that its incidence is difficult to determine. Since cavernous sinus thrombosis comprises approximately 1% to 4% of cerebral venous and sinus thrombosis (CVST), with an annual incidence of approximately 2 to 4 per million people per year and a higher incidence in children, the estimated annual incidence of cavernous sinus thrombosis may be approximately 0.2 to 1.6 per 100,000 per year.[11]

No male or female predominance in cavernous sinus thrombosis has been demonstrated. Despite a 3:1 female predominance in cerebral venous thrombosis, this may not be the case for cavernous sinus thrombosis. Weerasinghe and Lueck reported a 2:1 male-to-female ratio in 88 septic adult cases of cavernous sinus thrombosis.[12] Similarly, Thatai et al and Smith et al report a slight male preponderance in 35 and 12 cases, respectively.

Historically, cerebral venous thrombosis has been reported to be more common in children and neonates than in adults. However, the effects of routine vaccination and frequent antibiotic use in children on this occurrence are uncertain. The incidence and mortality of cavernous sinus thrombosis may be decreasing due to the availability and widespread use of antibiotics.

Pathophysiology

Anatomic Structures

The cavernous sinuses, located on each side of the sella turcica, are above and lateral to the sphenoid sinus. The cavernous sinus is demarcated anteriorly by the superior orbital fissure and posteriorly by the petrous apex of the temporal bone. The sinus is comprised of trabeculated cavernous spaces created by the layers of dura mater and filled with venous blood. This venous blood drains into the sinus from the superior and inferior ophthalmic veins and anteriorly from the superficial cortical veins. The sinus then drains into the basilar plexus posteriorly via the superior and inferior petrosal sinuses.

The cavernous sinus has been called the “anatomic jewel box” because it shares an intimate relationship with several important anatomic structures. Within the lumen of the cavernous sinuses pass the horizontal segment of the internal carotid artery, the sympathetic plexus, and cranial nerve VI (abducens) medially. Whereas the outer layers of the lateral wall of the cavernous sinus are traversed by cranial nerves III (oculomotor), V (the first ophthalmic and second maxillary branches of the trigeminal nerve), and IV (trochlear).

Pathophysiologic Mechanisms of Thrombosis

Septic cavernous sinus thrombosis may occur from any of the following:

• Local spread from the valveless facial and ophthalmic veins
• Adjacent infections, eg, sinusitis (possibly the most common cause), sphenoiditis, and ethmoiditis
• Facial cellulitis or abscess within the nasolabial triangle of the face, formed by the corners of the mouth and the bridge of the nose
• Periorbital and orbital cellulitis
• Pharyngitis
• Tonsillitis
• Otitis media
• Mastoiditis
• Dental infections [13]

A pathophysiologic mechanism of thrombosis is the embolization of bacteria and other infectious organisms, which can cause thrombosis and subsequently trap infection within the cavernous sinus. Another cause of cavernous sinus thrombosis is decreased drainage from the facial vein and superior and inferior ophthalmic veins, resulting in facial and periorbital edema, ptosis, proptosis, chemosis, discomfort, and pain with eye muscle movement, as well as papilledema, retinal venous distension, and loss of vision. The lack of valves in the dural sinus system allows for blood flow through the emissary veins into and out of the cavernous sinus, and thrombus can propagate into the dural system. Communication between the right and left cavernous sinuses via the intercavernous sinuses located anterior and posterior to the sella will allow for the spread of thrombus and infection from one side to the other.

Local compression and inflammation of cranial nerves can lead to several partial or complete cranial neuropathies that include:

• Diplopia from partial or complete external ophthalmoplegia due to compression of the sixth (abducens), third (oculomotor), and fourth (trochlear) cranial nerves. Limited eye abduction from abducens palsy is the most common early finding, often progressing to inability to move the eye in any direction when III, IV, and VI are involved.
• Internal ophthalmoplegia (nonreactive pupil) occurs from loss of sympathetic fibers from the short ciliary nerves, resulting in miosis, or from loss of parasympathetic fibers from cranial nerve III, resulting in mydriasis.
• Numbness or paresthesias may develop around the eyes, nose, and forehead due to loss of the corneal blink reflex from the ophthalmic nerve, which is a branch of the trigeminal nerve (V)
• Facial pain, paresthesias, or numbness secondary to compression of the maxillary branch of the trigeminal nerve.

Septic cavernous venous sinus thrombosis can result in infectious central nervous system or pulmonary complications. Because the dural venous and cavernous system is valveless, this venous blood can communicate with the dural sinuses and cerebral and emissary veins, leading to meningitis, subdural empyema, or brain abscess. Infection can spread via the jugular vein to the pulmonary vasculature, resulting in septic emboli or pulmonary abscess, pneumonia, or pleural empyema.

Furthermore, stroke can occur following carotid artery narrowing, vasculitis, or hemorrhagic infarction of brain parenchyma due to cortical vein thrombosis. Hypopituitarism can occur due to ischemia of or the direct spread of infection to the pituitary gland.

History and Physical

Clinical History

Patients with cavernous sinus thrombosis most commonly complain of fever, headache in 50% to 90% of patients, periorbital swelling, ocular pain, and visual changes, eg, photophobia, diplopia, and loss of vision. Symptoms may be present at onset or progress subacutely over days. Typically, symptoms begin in 1 eye and then progress to the other eye. Less common symptoms may include rigors, stiff neck, facial numbness, confusion, seizures, stroke-like symptoms, or coma.

Physical Examination Findings

Vital signs may reveal fever, tachycardia, or hypotension. A "picket fence" fever pattern indicates a rapid rise in temperature followed by the temperature decreasing back to normal. This pattern occurs with involvement of the lateral wall of the cavernous sinus.

Neurological findings, eg, altered mentation, lethargy, or obtundation, are not unusual. Seizures or stroke-like syndromes (eg, hemiparesis) are rare. Ocular findings are nearly universal and occur in 90% of patients. These include periorbital edema initially unilateral but typically bilateral, lid erythema, chemosis, ptosis, proptosis due to impaired venous drainage of the orbit, restricted or painful eye movement, and less commonly papilledema, retinal hemorrhages, decreased visual acuity in 7% to 22%, photophobia, decreased pupillary reflex, and conjunctiva pulsation. Blindness can result in 8% to 15% of cases.

A sixth cranial neuropathy is the most common neuropathy, resulting in partial ophthalmoplegia with limited eye abduction. However, most cases progress rapidly to complete external ophthalmoplegia due to third, fourth, and sixth cranial neuropathies. Internal ophthalmoplegia results in a nonreactive pupil, from paralysis of the iris and ciliary body, either constricted, causing miosis from loss of sympathetic fibers from the short ciliary nerves, or dilation and resulting mydriasis from loss of parasympathetic fibers from cranial nerve III.[14] Additionally, Horner syndrome, associated with ptosis, miosis, and anhidrosis, may develop. The sensory exam might reveal diminished sensation to the face due to compression of the ophthalmic (V1) and maxillary (V2) branches of the fifth cranial nerve and a decreased corneal reflex.

Evaluation

Imaging Studies

The optimal diagnostic test is neuroimaging, which can be performed using either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). CT venogram (CTV) and contrast-enhanced MR venogram (MRV) are highly sensitive, whereas noncontrast CT and time-of-flight MRV may not yield a diagnosis. Noncontrast CT of the head, although not ideal for the diagnosis of cavernous sinus thrombosis may demonstrate several subtle abnormalities, eg, engorgement or dilation of the superior and inferior ophthalmic veins, bulging of the lateral margins of the cavernous sinus, exophthalmos, the presence of sphenoid or ethmoid sinusitis, or a mass lesion near the sphenoid sinus or pituitary gland. Contrast-enhanced MRI of the brain can show widening of the cavernous sinus, increased dural enhancement, and an absent flow void.[15]

CTV and enhanced-MRV can detect dilation of the cavernous sinus, enhancement, and convexity of the lateral wall, which is normally concave on coronal views, heterogeneous and asymmetric filling defects after contrast, increased density of orbital fat, thrombosis of the superior ophthalmic vein or veins, and tributaries leading to the cavernous sinus. Additionally, carotid artery narrowing, carotid arterial wall enhancement, cerebral infarction, intraparenchymal hemorrhages, subdural empyema, meningitis, cerebritis, or brain abscess may be apparent.[16][17][18][19] As multiple thromboses are common with this condition, dural venous sinuses and cerebral veins need to be evaluated carefully.[20]

Laboratory Studies

Blood laboratory studies may reveal elevations in the white blood cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and D-dimer. Blood cultures should be obtained routinely and are frequently positive. Screening for thrombophilia may give false results during anticoagulation therapy and should be delayed until after treatment is completed.

Lumbar puncture is important for excluding meningitis and may reveal an elevated opening pressure and pleocytosis, even in culture-negative samples. The presence of an intracranial mass should be excluded with imaging before considering a lumbar puncture to prevent a herniation syndrome.

Treatment / Management

Due to the rarity of the diagnosis, no randomized controlled trial results or expert opinion treatment guidelines are available. In general, antimicrobial and antithrombotic therapies are the necessary primary treatment modalities.[21](A1)

Antimicrobial Therapy

Antimicrobial therapy includes an anti-staphylococcal agent (vancomycin if methicillin resistance is present), a third-generation cephalosporin, and metronidazole (for anaerobic coverage) as well as antifungal treatment with amphotericin B. A prolonged duration of parenteral therapy, typically 3 to 4 weeks or at least 2 weeks beyond clinical resolution, is suggested. Patients should be closely followed even after antibiotics are discontinued. 

Anticoagulation Therapy

Most experts recommend anticoagulation, in the absence of strong contraindications, with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for several weeks to several months. Although this practice is not supported by prospective clinical trials for cavernous sinus thrombosis, retrospective reviews suggest a potential decrease in mortality from 40% to 14% with UFH and a reduction in neurologic morbidity, from 61% to 31% when anticoagulation is combined with antibiotics for septic cavernous sinus thrombosis.

There remains controversy regarding anticoagulation. The advantage would be to halt the progression of thrombosis, prevent clot propagation, and possibly allow increased penetration of antibiotics, whereas the risk would be systemic or intracranial bleeding or possibly even dissemination of septic emboli. Although cavernous sinus thrombosis differs from cerebral venous and sinus thrombosis, the Cochrane Collaboration (Coutinho) suggests that anticoagulation for cerebral venous and sinus thrombosis appears safe, even in the presence of intracranial hemorrhage, and demonstrates a potentially important reduction in mortality, though not statistically significant. The European Federation of Neurological Societies (EFNS) recommends 3 months of anticoagulation in secondary cerebral venous and sinus thrombosis with a transient risk factor, 6 to 12 months for idiopathic cerebral venous and sinus thrombosis and in those with mild thrombophilia and indefinitely if subsequent cerebral venous and sinus thrombosis or severe thrombophilia is present. As with cerebral venous and sinus thrombosis, inadequate evidence supports thrombolysis in cavernous sinus thrombosis.

Corticosteroids

Corticosteroids are often given in the absence of demonstrated efficacy. The potential benefit of steroids would be to decrease inflammation and vasogenic edema surrounding cranial nerves and orbital structures. However, steroids are required in cases of hypopituitarism. The International Study on Cerebral Veins and Dural Sinus Thrombosis (ISCVT) reported steroid use in 24% of cerebral thrombosis, with no evidence of improvement.

Surgical interventions

No direct surgical interventions are recommended for the cavernous sinuses. However, some patients may require sphenoidectomy, ethmoidectomy, maxillary antrostomy, mastoidectomy, abscess drainage, craniotomy for subdural empyema or brain abscess, orbital decompression, or ventricular shunt placement. Extensive sinus debridement may be necessary in patients with CTS due to mucormycosis.

Differential Diagnosis

The differential diagnosis includes other causes of cavernous sinus syndrome and painful ophthalmoplegia.

Cavernous sinus syndrome can also be caused by local compression of the cavernous sinus from noninfectious and nonthrombotic lesions, 30% of which are tumors, including:

• Carotid cavernous fistula with enhanced CT or MRI showing proptosis, enlarged superior ophthalmic vein, “dirty” appearance of retro-orbital fat, and enlarged extraocular muscles
• Lytic bone lesions near the sphenoid sinus or sella turcica, tumors (eg, metastatic cancer, meningioma, schwannoma, plexiform neurofibroma, pituitary adenoma, chordoma, chondrosarcoma, melanocytoma, or nasopharyngeal carcinoma (the most common primary malignant tumor), or a cavernous hemangioma
• Meningioma
• Sino-orbital aspergillosis
• Superior orbital fissure syndrome
• Tolosa-Hunt syndrome involving a retro-orbital granulomatous pseudotumor extending into the cavernous sinus, manifesting as retro-orbital pain, ophthalmoplegia, cranial nerve palsy, and clinically responsive to systemic steroids

Other causes of painful ophthalmoplegia include:

• Orbital apex syndrome (inflammation of the posterior orbit, including the superior orbital fissure through which cranial nerves III, IV, V, and VI and the superior ophthalmic vein traverse, as well as the optic canal involving the ophthalmic artery and optic nerve and characterized by less edema and proptosis but with more vision loss than cavernous sinus thrombosis)
• Orbital cellulitis
• Sarcoidosis
• Syphilis
• Tuberculosis

Prognosis

The prognosis for cavernous sinus thrombosis has improved significantly with early diagnosis and treatment. Early diagnosis requires the prompt detection of presenting signs and symptoms, which include fever, headache, periorbital swelling, and ophthalmoplegia involving cranial nerves III, IV, and VI. Even though mortality rates were high in the past, approaching 80% to 100%, the availability of effective antibiotics and prompt diagnosis has now reduced the mortality rate to approximately 8% to 13%.[22][23][24] However, even with treatment, significant morbidity is present, with <20% having some degree of visual impairment and approximately 50% having persistent cranial nerve deficits, most commonly of cranial nerves III and VI. 

Complications

Other complications that can develop despite appropriate treatment with antibiotics and anticoagulation for cavernous sinus thrombosis include seizures, meningitis, sepsis, subdural empyema, brain abscess, blindness, panhypopituitarism, elevated intracranial pressure, infectious arteritis, mycotic aneurysm, vasospasm, septic emboli, stroke from carotid narrowing, cortical vein thrombosis, hemorrhagic infarction, coma and death.