NANOS 1990

DIAGNOSIS & MANAGEMENT OF CAVERNOUS SINUS THROMBOSIS AND INFECTION

INTRODUCTION Thrombosis of the cavernous sinus is one of the most dramatic of neuro-ophthalmic conditions. Within a short period, a swollen orbit, limited ocular motility and impaired vision develop, and life is threatened, Rapid diagnosis and therapeutic action are required, Morbidity is high, and outcome cannot be certain, Therefore, this striking syndrome, first pathologically recognized by Duncan in 1821 and later clinically defined by Bright in 1831 and especially the eye findings by Knapp in 1868 (Clifford-Jones et al., 1982), is very pertinent to all physicians engaged in the care of patients who present with acute complaints of periocular pain, orbital congestion and double vision. The following review includes the anatomy, pathology, presentation, differential diagnosis, diagnostic approaches and management of cavernous sinus thrombosis, and is obtained from selected references and especially from the literature of the past decade,

JohnB. Selhorst, M.D. S. Louis, Missouri

ous sinus, however, is multi-directional and depends mainly on pressure gradients in neighboring sinuses, but tends to be posterior into the petrous sinuses. The lateral wall of the cavernous sinus is composed of both superficial and deep layers of the dura (Umansky and Nathan, 1982). The superficial layer is formed by the dura mater on the medial side of the middle cranial fossa, The deep layer is formed by the sheaths of the oculomotor, trochlear, ophthalmic and maxillary nerves. These layers are easily separated from one another. The sympathetic nerves course about the wall of the internal carotid artery and may leave it as it emerges from the foramen lacerum. These nerves briefly pass with the sixth nerve in the posterior cavernous sinus before jumping to the ophthalmic nerve with which they enter the orbit. The sixth nerve runs entirely within the cavernous sinus lateral to the carotid artery and often is divided into several filaments. Posteriorly, the forward reflection of the cavum trigeminale extends into the lateral wall of the sinus.

ANATOMY In 1732, to describe the anatomic space adjacent to the PATHOLOGY sella turcica, Winslow coined the term, cavernous sinus. Aseptic thrombosis of the cavernous sinus occurs with Containing a varied array Of blood vessels and nerves, trauma, tumor invasion, aneurysmal expansion, dehydraDwight Parkinson has referred to this space as a veritable tion, emaciation and hypercoagulable states, Septic thromanatomic jewel box. Shaped like an envelope, the cavern- bosis is much more common and occurs according to ous sinus lies between the dura on the medial edge of the Shaw (1952) from the spread of infection through various middle cranial fossa and the periosteum of the sella turroutes: 1,) from the face via the angular and ophthalmic cica. It extends over 2,0-2.5 cm from the superior orbital veins, 2.) from the middle ear via the superior petrous fissure to the petrus apex and is about 1.0 cm in width. sinus, 3.) from the teeth, maxillary sinus and cervical Often thought to consist entirely of a trabeculated venous vertebrae via the pterygoid plexus which empties into the canal, microscopic dissection and anatomic casts in reinferior ophthalmic vein, 4.) from the sphenoid sinus by cent years have suggested that a portion of the cavernous direct extension or draining emissary veins, 5,) by extensinus is composed of a network of extradural veins that sion from an infected Internal jugular vein, lateral sinus or surround the internal carotid artery. As a result, dissection petrosal sinus, or 6.) from the plexus of veins surrounding within this parasellar space is possible, especially in its the internal carotid artery. Often there is a latency of 5-6 posterior aspect. Nonetheless, Harris and Rhoton (1976) days between the initial infection and the subsequent have identified three main venous spaces within the cav- signs of cavernous sinusthrombosis. The extension of an ernous sinus, one medially, anteroinferior^ and posteroInfection into the cavernous sinus is explained by several superiorly. The cavernous sinus receives venous flow mechanisms: 1.) a continuous, infected clot bridges the from many regions which explains its susceptibility to initial infected site to the cavernous sinus; 2.) a septic Infection. It receives venous flow from the face by way of embolus lodges in the cavernous sinus; or 3.) bacterial connections through the superior orbital vein with the toxins induce endothelial changes and thrombosis of the facial vein and from the pterygoid plexus. Anteriorly, It also cavernous sinus which subsequently becomes infected. receives the sphenoparietal and superficial middle cereComplications include thrombosis of the veins which drain bral veins. Posteriorly, the superior petrosal and inferior into the cavernous sinus resulting in increased intracranial petrosal sinuses are connected to the cavernous sinus. pressure or venous infarction, septicemia, brain abscess, The paired cavernous sinuses are interconnected by small subdural empyema, pituitary insufficiency, orbital abscess anterior and posterior intercavernous channels. Pulsaand pulmonary embolism. If the carotid artery becomes tions of the internal carotid artery may aid in expelling inflamed, it may thrombose, form an embolus or fistula or blood from the cavernous sinus. Flow through the cavern- seed a mycotic aneurysm in distal branches of the middle

blurred for near if the parasympathetic fibers of the third cranial nerve for accommodation are involved. Vision is also limited by arterial insufficiency, venous stasis with engorged retinal veins, retinal hemorrhages, papilledema and keratitis from loss of corneal sensation. Friberg and Sogg (1978) have provided evidence that elevated intraocular pressure and increased resistance to flow from high intraorbital pressure may contribute to ischemic changes in the optic nerve. Not infrequently the media is clouded, and visualization of the fundus is impeded. These ocular signs generally progress either acutely or subacutely, and occasionally chronically. Not infrequently, spread through an intercavernous sinus to the opposite cavernous sinus occurs over several days and is marked by contralateral chemosis, edema of the eyelids and lateral rectus paresis. In persistent cases, the failure of involvement of the opposite cavernous sinus should give pause toward the correctness of the diagnosis. Signs of a thrombotic facial or mastoid vein, although infrequent, or infected furuncle should also be sought. Invasion of the meninges is indicated by a stiff neck, generalized headache and altered mental status. Venous Infarcts or carotid arterial emboli are heralded by focal neurologic signs, Variation in the rapidity of the symptom complex has been commented upon by a number of observers. The more acute forms of cavernous sinus thrombosis appear to occur in patients with facial infections. This may be due to the virulence of staphylococcal or streptococcal organPRESENTATION isms, More subacute or chronic evolutions tend to deIn patients with cavernous sinus thrombosisj^fever, che^hvelop in patients with paranasal sinus, middle ear or dental almost invariably present (DiNubile, 1988). occurs in half of the patients and is much more common in-^ infections. those patients with facial Infections. Typically, both the headache or periorbital pain worsen overtime. Paresthe-* DIAGNOSIS ' sias or pain over the face, in the distribution of the first ancj Clinical Features s i x > often-quoted, points as ^ff^gpifiihaT"clKtel?ns, may occur, A very early r1 ocular sign is swelling of the eyelids andchemosis. This is guides to the diagnosis of cavernous sinus thrombosis: 1,) ih followed by piroptosis'andswelling oTthilace. Ophthala known site of infection, 2.) septicemia, 3.) early signs of moplegia is ofterTpifesent soon after and results from venous^or^estlon"such vWsT4ll>c"uTar orbital 'ffiOs^^filS "{W^Hr*~ nerve~ ophthalmic or maxillary nerve deficits, 5.) abscess 1937)" or inactivat'ion ofocufar nervegrThrsfxtfmanial y Phlebitis contiguous tolFS'c^ernous'sihus^"and 67) nerve is commonly the first ocular nerve affected because signs of an intracranial infection (e.gThei^Tfe, stiffrfeck, of its course directly throughthe cavernous sinus, involve- obfuniJation). Whereas not all of these points must be ment of the third, fourth and first two divisions of the cranial present to Initiate expectant management, they should be nerve soon follows and usually indicates more extensive sought. disease because these nerves are more protected in their The differential diagnosis of cavernous sinus thrombocourse in the lateral wall of the cavernous sinus. With sis includes a variety of acute and subacute infections of involvement of the oculomotor nerve the pupil is dilated ) jthe orbit. Orbital vein thrombosis is occasionally a complir_, and fixed to light unless the sympathetic plexus about the i ' cation of a hypercoagulable state or embolization of a carotid artery is disrupted in which event the pupil remains fistulous i n t e r f e ^ m painful orbital swelfixed but in a mid-position. Rarely, patients with a sixth ling differs from a cavernous sinus thrombosis with its nerve paresis and a post-gangtionic Homer's syndrome dramatic suddenness. The conjunctival and orbital swelhave been described who have selective lesions in the ling and ophthalmoplegia of orbital cellulitis makes disposterior cavernous sinus or distal portion of the petrous tinction from cavernous sinuswBffitxijSlS1 blttlfcult. Tenpart of the carotid canal (Parkinson and Mitchell, 1979), In derness to retropulsion of the globe and spread of infecthose patients who are not obtunded, loss of sensation of tion from an adjacent ethmoidal sinus Is common in orbital the cornea and forehead and the cheek and palate in the cellulitis (Haynes and Cramblett, 1967; Goodwin, 19B5), respective first and second branches of the trigeminal Pseudotumor of the orbit and the superior orbital fissure nerve may be demonstrated. Although initially alert, obsyndrome oLlotosal-Hunt both present with painful ophtundation and lapses into a delirium develop in a majority IhalmopI^l^llWlf&^fmilarly difficult to separate from of patients. In those patients with an impaired sensorium, the early stages of a cavernous sinus thrombosis. Posonly a depressed corneal reflex may be found. Vision is sible distinction between the entities is made by the patcerebral artery. In 1952 Shaw reported lung Infection in 17 of 50 cases which he thought were invariably a result of septic emboli. Pulmonary emboli probably are derived from a thrombus that has extended from the cavernous sinus into the inferior petrous sinus and its draining jugular vein. Abscesses of the orbit were also found by Shaw in 9 of 50 patients. In this report, infection originated in 61% from furuncles of the nose and face, 15% from the paranasal sinuses, 8% from the middle ear, 7% from dental infections (usually from the maxillary area) and 9% from miscellaneous sources. The high incidence of furuncle infection of the face or "muzzle area" is reflected in the isolation of 70% staphylococcus aureus and 22% strept<> coecal organisms in this series. Staphylococcus aureus is also a common pathogen in acute sphenoidal sinusitis, a predisposing condition to thrombosis of the cavernous sinus (Lew eta!., 1983). Anerobic streptococcal infections are less commonly encountered in cavernoussinus thrombosis, but Important pathogens to consider when selecting antibiotics. In patients with a history of chronic sinusitis that exceeds one month, often with proceeding antibiotic coverage, anerobes, coagulase-negatrve staphylocei, gram negative organisms and fungi, particularly species of Aspergillus (Sekar et al., 1980), should be considered. The frequency of primary middle ear infections appears to be less than that noted earlier In this century.

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lv M-iJw-ivj V|S, iOSS ;]- V>Sl Of V i c h lA^.lJi^k* / Neuroradiology tern of ocular muscle weakness, orbital tenderness and CT may show signs of orbital involvement similar to degree of orbital swelling. In general, patients with orbital orbital cellulitis, i.e., scleral thickening, swollen ocular cellulitis, pseudotumor of the orbit and the superior orbital muscles and retrobulbar densities. It may also show a fissure syndrome are not as ill. Inflammation of the spinal fluid or bilateral orbital involvement definitively favors throm- dilated superior orbital vein, orbital abscess or cortical vein infarct, but it rarely shows a thrombus in the cavernbosis of the cavernous sinus. If modern imaging studies ous sinus. Thin transverse and coronal sections through exclude mass lesions within the orbit or cavernous sinus, a prompt response to a course of glucocorticoids is highly the orbits and parasellar region with bone windows are indicated In all patients suspected of a cavernous sinus consistent with pseudotumor of the orbit or the superior process. Dynamic or slow infusion of a large volume of orbital fissure syndrome (Hunt, 1976). Acute infections of the orbital apex, which are typified by the spread of Mucor contrast accompanied by coronal sections may reveal organisms from the ethmoid sinus, are marked not onlyby" impaired filling of the involved cavernous sinus. Magnetic resonance scanning is perhaps now the procedure of profound orbital swelling and ophthalmoplegia, but also choice to show altered flow or a thrombus in the cavernous severe loss of vision. Additional clues to mucormycosis sinus as well as most of the soft tissue abnormalities Include the presence of diabetes mellitus, roentgenogradisclosed by CT scanning (Savino et al., 1986). With the ph^ signs of ethmoidal infection and a blackish eschar in availability of these non-invasive studies, cerebral angii v the nose or over the face. As previously mentioned, ography, orbital or juguiar venography are no longer '^S^spergillus infection should be considered in patients with needed to confirm the diagnosis of cavernous sinus throm^ a chronic history of sinus infection. Because of their bosis. tendency to invade blood vessels, both mucormycosis | and aspergillosis are known to cause thrombosis of either /O the cavernous sinus or the internal carotid artery. Lateral MANAGEMENT ^ expansion of the cavernous carotid artery in the form of an In 1936 Grove reported more than 400 cases of cavern^ aneurysm causes a painful acute ophthalmoplegia with ous sinus thrombosis; the mortality approximated 100%. partial facial anesthesia due to compression of the cranial The high mortality rate prompted Eagleton to suggest ^ nerves in the lateral wall of the cavernous sinus. This ligation of the internal carotid artery, evisceration of the condition usually differs from cavernous sinus thrombosis orbit and drainage of the cavernous sinus through a in the lack of orbital swelling, antecedent infection and sphenoidal fistula. The availability of antibiotics has sigfever. Its diagnosis is readily confirmed by modern imagnificantly changedtfleippfSacTTTmi^^ ing studies of the cavernous sinus region. Recognition of heufo^opFvtiRalmic conditions, _Hrst, widespread use ot the painful ophthalmoplegia of an acute or subacute " orat antibiotics for infections about the face, in the sinuses carotid-cavernous sinus fistula is assisted by the presand the ear has greatly reduced the incidence of cavern'eoce of prominently tortuous, arteriafeed conjunctival vessels ous sinus thrombosis. Secondly, the mortality of cavernand auscultation of a bruit over the eye. Subperiosteal ous sinus thrombosis is much diminished, Shaw in 1952 mucoceles cause an indolent pain, low-grade orbital swelling reported recovery In 52 of 60 patients, and Yarington in and ophthalmoparesis that may mimic a chronic cavern1977_confirmed that the mortality had fallen to 12-14%. ous sinus thrombosis. Fine serial sections of the sinuses "DiNubile (1988) contends that mortality remains closer to adjacent to the orbit and cavernous sinus with modern " 30%. Morbidity, however, remains a very serious concern. imagers are currently able to identify these lesions. Trichinel- Ophthalmic or neurologic deficits are found in over half of losis is now rare, but Barr (1966) has reported the sudden the survivors (DiNubile, 1988L, Shaw (1952) reported appearance of fever, bilateral orbital edema, ophthaicranial nerve deficits to persist In 40%. In addition, blindmoparesis and subsequent altered mental status as facness occurred in 5 of 60 patients and another 4 of 60 tors giving consideration to thrombosis of the cavernous patients had limited vision. Considerations for further sinus. Diffuse myalgia, lack of chemosis and eosinophil lowering the mortality and morbidity rates should focus on are the usual indications for trichinlasis that lead to further rapidity of diagnosis and Institution of treatment, selection serologic study or muscle biopsy. of antibiotics, use of corticosteroids and decision for anticoagulant and thrombolytic therapy.

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Laboratory Data pi^a^ f* ^ Usually patients with cavernous sinus thrombosis have a leucocytosis. _B[ood cultures are posjyg,iri..QvaLtWfr... thirds of patienuTlfavior, 1957), especially if antibiotics have not been given previously. In over half of the patients, the spinal fluid reflects a parameningeal infection with a mixed pleocvtosls of mononuclear and polymorphonuclear cells, raised proteinand normal sugar, In another ~25%of patients therelie^enceoTa concurrent bacterial meningitis with a predominance of polymorphonuclear cells, raised protein and low glucose; in these patients cultures of the spinal fluid may grow out the offending organism. The meningeal inflammation often coincides with alterations in the mental status. j , ^

Yarington (1977) has argued that because the morbidity of cavernous sinus thrombosis is so high, Intravenous antibiotics should be begun immediately in all individuals suspected of having cavernous sinus thrombosis. No delay In treatment should be permitted for confirmatory studies. After blood cultures have been drawn, the institution of intravenous antibiotics is perfectly reasonable. CT scanning with bone windows, a dynamic CT scan or MR study and a spinal fluid analysis should follow soon after in order to confirm or reconsider the diagnosis. The choice of the antibiotic depends on the availability of a Gram stain of infected material, but in general should Include coverage against a penicillinase-resistant organism, such as nafcillin, and a third-generation cephalosporin, such as

ceftazidime. If the source of infection is from the teeth, ear or sinus, metronidazole or chloramphenicol should be given for protection against anerobic pathogens. In patients with a methiciliin-resistant staphylococcal Infection or serious penicillin allergy, vancomycin in combination with either sulfamethoxazole and trimethoprim or metronidazole may be used. Broad spectrum, intravenous antibiotics often leads to clinical improvement within several days, but overall recovery is generally slow. There is no proven benefit to corticosteroids in patients with cavernous sinus thrombosis, but their recently shown efficacy in reducing the morbidity of bacterial meningitis in children would argue in favor of their use (Lebel et al., 1988). If there is any reason to suspect Involvement of the pituitary gland, replacement corticosteroid therapy is also advisable. The benefit of anticoagulants remains unproven and is controversial. One argument often advanced in theirfavor is that impeding thrombosis improvesthe access of antibioticsto the infection, In 1988, Levine and associates reviewed their experience in seven patients and the literature perSELECTED REFERENCES

taining to cavernous sinus thrombosis since the advent of the antibiotic era. They concluded that morbidity was reduced when anticoagulation was used early in the course of this disease, but was of no benefit in reducing mortality or morbidity in a well-established thrombosis of the cavernous sinus, Pertinently, there were few complications of hepatization. Southwick (1986) has also suggested that anticoagulation prior to involvement of the opposite cavernous sinus may reduce mortality and morbidity. Unless the disease is far advanced, a heparin dosageto bring the partial thromboplastin time to 1.5 to 2.0 of the control is recommended until the patient is stable. This practice is consistent with the current treatment for cerebral venous thrombosis (Southwick et al 1986). Thrombolytic agents such as fibrinolysin and streptokinase have been used successfully, but in a limited number of patients (Harvey, 1974); future use of these or similar enzymatic agents should be anticipated, Persistent abscess formation in the brain, pituitary, orbit or offending sinus, despite adequate antibiotic coverage may require surgical drainage.

/ ^ double-blind, placebo-controlled Mali. N ingl J Med 1868;318:B64-B71. f i d levi'M SR, Twyma.^ RE,Gilmn SiTheroteofantlcoagulstion In cevemoutlinutthiombotis Neurology 18BB;36:517-522. 13. Lew D, Southwick FS, Montgomery WW, Weber AL, Baker AS: Sphenoid sinusitis, N Engl J Med 1M3;30t:1146-1154. 14. Parkinson D, Mitchell 8: Homer syndrome and others, Surg Neurol 1B79;11521-223. 15. Sevino PJ, Sroeaman Rl, Shatz NJ, Sergott RC, Bos ley TM; High field magnetic resonance 1 B 8 5 ; t a : 1 3 9 1 4 7 , Imaging In the diagnosis of cavernous sinui thrombosis. Arch Neurol 19M;43:106M082. 8. Qrove WE: Septic and aseptic types of thrombosis of the cavernous sinus. Areh Otolaryngol IS, Sekhar LN, Dujovny M, Rao QR: Carotid-cavernous sinus thrombosis caused by Aspergillus 1636;24:29-50. fumtgatus. J Neuroturg 1980;52:120-125, 7, Harris FS, BhotonAL Jr:Anatomy ofthe cavernous sinus. Amlcrosurgical study, J Neurosurg 17. Shaw RE: Cavernous alnus thrombophlebitis; A review. Brit J Surg 1852;40:40-52. 1B?e;45:1BS-ieo, ia. Southwick FS, Richardson EP Jr, SwartzMN: Septic thrombosis of the dura! venous sinuses, S. Harvey JE; better to the editor: Streptokinase therapy and cavernous sinus thrombosis, Brit Medicine 196a; 6S;82-i06. Med J1874;4:4S. 19, Taylor PJ: Cavernous sinus thrombophlebitis. Br J Ophthalmol 1957;41:228-237. 8, Haynet FIE, Cramblett HQ: Acute ethmoldltis: Us relationship to orbitaJ cellulitis. AJDC 20. Umansky F, Nathan H: The lateral wall ofthe cavernous sinus. With special retemce to the 1967;114:2S1-2?0. nerves related to K, J Neuresung 1882:56:228-234, 10, Hunt WE: Tolosa-Hunt syndrome: One cause of painful ophthalmoplegia. J Neuroeurg 21, Walsh FB; Ocular signs of thrombosis of the Intracranial sinuses. Arch Ophthalmol 1B76.44544-548. 1837;17:46-65, 11, Lebel MH.Freii BJ.SyroglannopoulosGA, Chrane DF, Hoyt MJ, Stewart SM, KennardBD, 22. Yarlngton CT: Cavernous alnus thromboels revisited, Proc R Soc Med 1877;70:456-458. Otsen KD, McCracken GH: Dexanethasone therapy for beeeria! meningitis. Results of two 1. Barf R: Human trichinosis, Canad Med Ass J 1986;9S:812-B17. 2. Clifford-Jones RE, Ellis CJK, Stevens JM, Turner A: Cavernous sinus Ihrambosls, J Neurol Neuroturg Psycni*y 1SS2;48:1Q82-10e7. a. DiNublie MJ: Septic thrombosis of (he cavernous sinus, Arch Neurol 1868;4S:567-572. 4, Friberg TR, Sogg BL: Ischemic optic neuropathy In cavernous slnut thrombotic. Arch Ophthalmol 1878:96:443-456. 5. Goodwin WJ Jt: Orbital complications of ethmoidHs, Otolaryngol Clin North Am

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