Continuing Education Activity

Cavernous sinus thrombosis (CST) is a rare, life-threatening disorder that can complicate facial infection, sinusitis, orbital cellulitis, pharyngitis, or otitis or following traumatic injury or surgery, especially in the setting of a thrombophilic disorder. Early recognition of cavernous sinus thrombosis which, often presents with fever, headache, eye findings such as periorbital swelling, and ophthalmoplegia, is critical for a good outcome. Despite modern treatment with antibiotics and anticoagulation, the risk of long-term sequelae, such as vision, diplopia, and stroke, remains significant. This activity examines when cavernous sinus thrombosis should be considered, how to properly evaluate this condition and the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Review the causes of cavernous sinus thrombosis.
• Describe the presentation of a patient with cavernous sinus thrombosis.
• Outline the treatment options for cavernous sinus thrombosis.
• Explain when cavernous sinus thrombosis should be considered, how to properly evaluate this condition and the role of the interprofessional team in caring for patients with this condition.

Introduction

Cavernous sinus thrombosis (CST) is a rare, life-threatening disorder that can complicate facial infection, sinusitis, orbital cellulitis, pharyngitis, or otitis or following traumatic injury or surgery, especially in the setting of a thrombophilic disorder. Early recognition of cavernous sinus thrombosis which, often presents with fever, headache, eye findings such as periorbital swelling, and ophthalmoplegia, is critical for a good outcome. Despite modern treatment with antibiotics and anticoagulation, the risk of long-term sequelae, such as vision, diplopia, and stroke, remains significant.[1][2][3][4][5]

Etiology

Cavernous sinus thrombosis is usually septic, but can also be aseptic. Septic cases can follow central facial infections, especially within the danger triangle of the face (from the corners of the mouth to the bridge of the nose). These include abscess or cellulitis, sinusitis (especially sphenoiditis and ethmoiditis), dental infections, extractions or procedures (even a posterior superior alveolar nerve block entering the pterygoid plexus), maxillofacial surgery, otitis media, and mastoiditis. Aseptic causes are less common than septic causes. These include trauma, surgery, or pregnancy.[6]

A variety of infectious organisms can cause cavernous sinus thrombosis although the majority are bacterial. Staphylococcus aureus may account for two-thirds of cases, and methicillin resistance should be considered. Other typical organisms include Streptococcus species (approximately 20% of cases), pneumococcus (5%), gram-negative species such as Proteus, Hemophilus, Pseudomonas, Fusobacterium, Bacteroides, as well as gram-positive species such as Corynebacterium and Actinomyces. Several of these (Bacteroides, Actinomyces, Fusobacterium) are anaerobic.  Fungal infection in cavernous sinus thrombosis is less common but can include Aspergillosis (most common), Zygomycosis (such as Mucormycosis) or Coccidiomycosis in immunocompromised individuals. Rare precipitants of cavernous sinus thrombosis can include parasites, such as toxoplasmosis, malaria, and trichinosis, as well as viral causes such as herpes simplex, cytomegalovirus, measles, hepatitis, and human immunodeficiency virus (HIV).

Immunosuppression, such as uncontrolled diabetes, steroid use, cancer, or chemotherapy, maybe a risk for not only developing cavernous sinus thrombosis but also developing complications.

The biggest risk factors are facial infections, acute sinusitis, and periorbital infections. Thrombophilia is a significant risk factor for cavernous sinus thrombosis. Women who are pregnant, post-partum, or receiving oral contraceptives or hormone replacement therapy may be at increased risk. A variety of thrombophilic genetic disorders may lead to cavernous sinus thromboses. These include factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III, protein C or S deficiency, or increased factor VIII. Acquired disorders such as antiphospholipid antibody syndrome, hyperhomocysteinemia, heparin-induced thrombocytopenia, and obesity could also contribute to cavernous sinus thrombosis risk. Other risk factors for thrombosis include severe dehydration, such as in the hyperosmolar non-ketotic state, nephrotic syndrome, and sickle cell disease.[7][8][9][10]

Epidemiology

Cavernous sinus thrombosis is so rare that incidence data is difficult to estimate. Since cavernous sinus thrombosis comprises approximately 1% to 4% of cerebral venous and sinus thrombosis (CVST), which has an annual incidence of approximately two to four per million people per year, with a higher incidence in children, one can estimate that the annual incidence of cavernous sinus thrombosis might be approximately 0.2 to 1.6 per 100,000 per year.

A male or female predominance in cavernous sinus thrombosis is uncertain. Despite a 3:1 female predominance in cerebral venous thrombosis, this may not be the case for cavernous sinus thrombosis.  Weerasinghe reported a 2:1 male to female ratio in 88 septic adult cases. 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, although the effects of routine vaccination and frequent use of antibiotics (such as for otitis) on this relationship are uncertain. 

The incidence and mortality may be decreasing likely due to the availability and use of antibiotics.

Pathophysiology

The cavernous sinuses (one on each side of the sella turcica, above and lateral to the sphenoid sinuses, anteriorly superior orbital fissure and posteriorly petrous part of the temporal lobe) are trabeculated cavernous spaces created by the layers of dura mater and filled with venous blood. This blood drains the superior and inferior ophthalmic veins and superficial cortical veins anteriorly and then drains into the basilar plexus posteriorly via the superior and inferior petrosal sinuses.

The cavernous sinus has been coined the “anatomic jewel box” because it shares an intimate relationship with several important 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 carotid sinus are traversed by cranial nerves III (oculomotor), V (the first and second branches, ophthalmic and maxillary, of the trigeminal) and IV (trochlear).

Septic cavernous sinus thrombosis occurs from the following:

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

The mechanism is due to

1. Embolization of bacteria and other infectious organisms which trigger thrombosis which then can trap infection within the cavernous sinus.

2. Cavernous sinus thrombosis leads to 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, papilledema, retinal venous distention, and loss of vision. Lack of valves in the dural sinus system allows flow through the emissary veins into and out of the cavernous sinus and thrombus can propagate into the dural system. Also, communication between the right and left cavernous sinuses via the intercavernous sinuses, anterior and posterior to the sella, allows 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 including:

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

Septic cavernous venous thrombosis can result in the central nervous system or infectious 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, dural empyema or brain abscess. Infection can spread via the jugular vein to the pulmonary vasculature resulting in septic emboli or abscess, pneumonia or empyema.

Stroke can occur following carotid artery narrowing, vasculitis, or hemorrhagic infarction following progression to cortical vein thrombosis.

Hypopituitarism can occur due to ischemia or the direct spread of infection.

History and Physical

History:

Patients with cavernous sinus thrombosis most commonly complain of fever, headache (50% to 90%), periorbital swelling and pain, vision changes, such as photophobia, diplopia, loss of vision. Symptoms may be present at onset or progress subacutely over days. Usually, it starts with one eye and then progresses to another eye. Less common symptoms may include rigors, stiff neck, facial numbness, confusion, seizures, stroke symptoms, or coma.

Physical Exam:

Vital signs may reveal fever (sometimes in a “picket fence” pattern characteristic for septic thrombophlebitis), tachycardia, or hypotension.

Neurologic findings such as altered mentation, lethargy, or obtundation, are not unusual. Seizures or stroke syndromes (such as hemiparesis) are rare.

Eye findings are nearly universal (90%). 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 (7% to 22%), photophobia, diminished pupillary reflex, and pulsating conjunctiva. Blindness can result in 8% to 15% of cases.

Individually, a sixth cranial neuropathy is the most common neuropathy, resulting in partial ophthalmoplegia with limited eye abduction. Most cases, however, progress rapidly to complete external ophthalmoplegia from third, fourth and sixth cranial neuropathy.

Internal ophthalmoplegia results in a nonreactive pupil, from paralysis of the iris and ciliary body, either constricted (miosis) from loss of sympathetic fibers from the short ciliary nerves or dilated (mydriasis) from loss of parasympathetic fibers from cranial nerve III.

Horner syndrome (ptosis, miosis, and anhidrosis) may be present.

The sensory exam might reveal diminished sensation to face (due to compression of the ophthalmic and maxillary branches of the fifth cranial nerve) and an impaired corneal reflex.

Evaluation

The optimal diagnostic test is neuroimaging with either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). CT venogram (CTV) and contrast-enhanced MR venogram (MRV) are highly sensitive, whereas non-contrast CT and time-of-flight MRV may miss the diagnosis. Non-contrast CT of the head, although not ideal for a cavernous sinus thrombosis diagnosis, may reveal several subtle abnormalities such as engorgement or dilation of the superior and/or inferior ophthalmic veins, bulging of the lateral margins of the cavernous sinus, exophthalmos, and possibly the presence of sphenoid or ethmoid sinusitis, or mass lesions near the sphenoid or pituitary gland. Contrast-enhanced MRI brain shows bulging of the cavernous sinus, increased dural enhancement, and absent flow void is seen. [11]

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 in the superior ophthalmic vein or veins and tributaries leading to the cavernous sinus. Additionally, carotid artery narrowing, carotid arterial wall enhancement, cerebral infarcts, intraparenchymal hemorrhages, empyema, meningitis, cerebritis or abscess may be noted.[12][13][14][15] As multiple thromboses are common with this condition, dural venous sinuses and cerebral veins are to be evaluated carefully. [16]

Blood 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.

Lumbar puncture is important to exclude meningitis and may show elevated opening pressure and pleocytosis even in culture-negative samples.

Screening for thrombophilia may give false results during anticoagulation therapy and should be delayed until after treatment is completed.

Treatment / Management

Because of the rarity of diagnosis, no randomized controlled trials are available, and expert opinion guides treatment. In general, antimicrobial and antithrombotic therapies are primary considerations.

Antimicrobial therapy includes an anti-staphylococcal agent (vancomycin if methicillin resistance is high, or nafcillin), a third-generation cephalosporin, and metronidazole (for anaerobic coverage) as well as antifungal therapy with amphotericin B. A prolonged duration of parenteral therapy, typically three to four weeks or at least two weeks beyond clinical resolution is suggested.

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. Though not supported by prospective clinical trials in cavernous sinus thrombosis, retrospective reviews suggest a possible decrease in mortality from 40% to 14% with UFH and reduction in neurologic morbidity, from 61% to 31% when anticoagulation is combined with antibiotics for septic cavernous sinus thrombosis. There does remain controversy with anticoagulation. The advantage would be to halt the progression of thrombosis, prevent clot propagation, and possibly allow penetration of antibiotics, whereas the risk would be systemic or intracranial bleeding or 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 mortality reduction (though not statistically significant).  The European Federation of Neurological Societies (EFNS) recommends three months of anticoagulation in secondary cerebral venous and sinus thrombosis with a transient risk factor, six to 12 months for idiopathic cerebral venous and sinus thrombosis and those with mild thrombophilia and indefinitely if subsequent cerebral venous and sinus thrombosis or severe thrombophilia.

As in cerebral venous and sinus thrombosis, there is inadequate evidence to support thrombolysis in cavernous sinus thrombosis.

Corticosteroids are often given but without demonstrated efficacy. The potential benefit would be decreased inflammation and vasogenic edema surrounding cranial nerves and orbital structures.  Steroids are necessary, however, for 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.

No surgical interventions are recommended for the cavernous sinuses themselves. However, some patients might require sphenoidectomy, ethmoidectomy, maxillary antrostomy, mastoidectomy, abscess drainage, craniotomy (subdural empyema), orbital decompression, or ventricular shunt placement.

Patients should be followed closely even after the discontinuation of the antibiotics. 

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 non-thrombotic lesions, 30% of which are tumors:

• 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 (such as 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 into the cavernous sinus, manifesting as retro-orbital pain, ophthalmoplegia, cranial nerve palsy, and clinical response 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 more vision loss than cavernous sinus thrombosis)
• Orbital cellulitis
• Sarcoidosis
• Syphilis
• Tuberculosis

Enhancing Healthcare Team Outcomes

Cavernous sinus thrombosis (CST) is a rare, life-threatening disorder that can complicate facial infection, sinusitis, orbital cellulitis, pharyngitis, or otitis or following traumatic injury or surgery, especially in the setting of a thrombophilic disorder. The disorder is best managed by an interprofessional team that includes a primary care provider (nurse practitioner, physician assistant, family physician) ophthalmologist, neurosurgeon, neurologist, infectious disease expert, hematologist, and an emergency department physician.

Early recognition of cavernous sinus thrombosis which, often presents with fever, headache, eye findings such as periorbital swelling, and ophthalmoplegia, is critical for a good outcome. Despite modern treatment with antibiotics and anticoagulation, the risk of long-term sequelae, such as vision, diplopia, and stroke, remains significant.

As many as 50% of survivors might have sequelae, most commonly third or sixth nerve palsy.  Other complications can include sepsis, meningitis, subdural empyema, brain abscess, blindness, panhypopituitarism, intracranial hypertension, infectious arteritis or mycotic aneurysm of the internal carotid artery, vasospasm, septic emboli, stroke from carotid narrowing, cortical vein thrombosis or hemorrhagic infarction, coma, and death. Mortality rates as high as 80% in the era before antibiotics have diminished to below 8% to 13%.[17][18]