Tolosa Hunt Md Consult

Use of this content is subject to the Terms and Conditions Cavernous sinus thrombosis Last updated: 19 Sep 2007

Contributors

Evidence based answers for the point of care

Summary Description  An uncommon but life-threatening condition  Commonly causes fever, headache, and papilledema  Usually a consequence of infection in the face or paranasal sinuses  Often causes palsies of cranial nerves III, IV, V, and VI  Treated with intravenous broad-spectrum antibiotics Synonyms  Cavernous sinus septic phlebitis  Intracranial venous sinus thrombosis  Cerebral sinus thrombosis  Cavernous sinus thrombophlebitis Immediate action Immediate transfer to hospital for intravenous antibiotics is indicated. Background Cardinal features  Thrombosis of the cavernous sinus with inflammation of its surrounding anatomic structures: cranial nerves III, IV, V, and VI  The classic presentation is of proptosis, ptosis, chemosis, and cranial nerve palsy beginning in one eye and progressing to the other eye  Most cases follow infection of the sphenoid sinuses, eyelid, orbit, face, upper teeth, and middle ear  Most cases present with headache and fever  Papilledema is present in 80% of cases  Treated with broad-spectrum intravenous antibiotics: nafcillin, cefotaxime, ceftriaxon, and metronidazole  Mortality rate is approx. 30% Causes Common causes  Sphenoid sinusitis  Otitis media  Orbital cellulitis  Maxillary sinusitis  Dental infection  Facial cellulitis  Pharyngitis

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Tonsillitis Fungal infections (especially Mucor and Aspergillus spp.)

Rare causes  Head injury  Tumors  Leukemias  Coagulopathies Contributory or predisposing factors  Diabetes mellitus increases the risk for infection, as well as the risk of septic cerebral sinus thrombosis  Combined oral contraceptive use increases the risk for venous thrombosis generally by between 2-fold and 4-fold  Prothrombotic genetic mutations: factor V Leiden and factor II mutation. When combined with oral contraceptives these mutations increase the relative risk of cerebral sinus thrombosis 10fold to 20-fold  Pregnancy  Malignancy  Smoking Epidemiology Incidence and prevalence Cavernous sinus thrombosis is rare. The average physician is unlikely to encounter a single case in an entire career. Incidence The true incidence is unknown. An incidence of <0.01/1000/year has been estimated in Saudi Arabia. Demographics Gender Both sexes are at equal risk, but the strong correlation with oral contraceptive use increases the incidence among women. Genetics Congenital coagulation disorders, factor V Leiden mutation, and factor II mutation increase the relative risk of venous thromboembolism generally. Codes ICD-9 code  325 Phlebitis and thrombophlebitis of intracranial venous sinuses; embolism of cavernous, lateral, or other intracranial or unspecified intracranial venous sinus; endophlebitis of cavernous, lateral, or other intracranial or unspecified intracranial venous sinus; phlebitis, septic or suppurative of cavernous, lateral, or other intracranial or unspecified intracranial venous sinus; thrombophlebitis of cavernous, lateral, or other intracranial or unspecified intracranial venous sinus; thrombosis of cavernous, lateral, or other intracranial or unspecified intracranial venous sinus

 437.6 Nonpyogenic thrombosis of intracranial venous sinus Diagnosis Clinical presentation Symptoms  Headache is unilateral or retro-orbital and is present at initial presentation in 80% of cases  Decreased visual acuity and diplopia  Sensory deficits of the ophthalmic and maxillary branches of the fifth cranial nerve with numbness and/or tingling in the forehead, periorbital, and midface regions Signs 75% of patients have eye complaints at presentation:     

Periorbital edema, initially unilateral but spreading quickly to the contralateral eye Ptosis Proptosis Ophthalmoplegia, especially sixth nerve palsy Chemosis

Other findings may include:       

Fever in nearly all patients Tachycardia Facial cellulitis Papilledema in 70-80% Decreased visual acuity in 20% Nuchal rigidity in 30% Seizures in 10%

Associated disorders Venous thrombosis at another site. Noncerebral thrombotic events occurred in 14% of a series of patients with cerebral venous thrombosis followed up for an average of 63 months. Differential diagnosis Orbital cellulitis Features  Unilateral  Lid edema  Rhinorrhea  Orbital pain  Tenderness  Dark red discoloration of eyelids  Fever  No involvement of the ophthalmic division of the trigeminal nerve Ophthalmoplegic migraine

Features  Unilateral  Recurrent  Retro-ocular headache  Tearing  No fever  Prodromal phase  Temporary ophthalmoplegia Carotid cavernous sinus fistula Features  Ocular bruit  Apyrexial  Headache  Ophthalmoplegia Mucormycosis Features  Infection by Zygomycetes fungi in the paranasal and orbital structures  Fever  Facial pain  Diplopia  Proptosis  Necrotic ulceration of the palate, pharynx, or nasal septum Tolosa-Hunt syndrome Features  Acute idiopathic inflammatory process of the superior orbital fissure or the anterior cavernous sinus  Painful ophthalmoplegia without proptosis  No fever  Magnetic resonance imaging (MRI) might show some abnormal signal in the superior orbital fissure or anterior cavernous sinus  Excellent response to steroids Orbital pseudotumor Features  Idiopathic inflammatory process that involves the orbit (enlargement of the extraocular muscles and other contents of the orbit)  Usually unilateral  Slight proptosis with painful ophthalmoplegia but the patient does not look septic  No fever  No involvement of ophthalmic division of the trigeminal nerve  Computed tomography of the orbit shows enlargement of the orbital contents, like in thyroid ophthalmopathy  Responds to steroids Carotid artery aneurysm or dissection in the cavernous portion

Features  Clinically almost impossible to differentiate  No signs of sepsis and none of them are preceded by sinus infection  Brain imaging is needed to make the diagnosis Neoplasm Features  Usually the symptoms and signs are not limited to the cavernous sinus  Brain MRI might be sufficient to make the diagnosis Pseudotumor cerebri Features  Headache associated with papilledema  Fever is not expected  Confirmed by normal imaging studies and high cerebrospinal fluid (CSF) pressure on lumbar puncture Temporal arteritis Features  Temporal headache in middle age or elderly patients  Elevated ESR in the vast majority of patients  Temporal artery is thickened and tender  Papilledema is not present  Fever may exist Workup Diagnostic decision The combination of ptosis, proptosis, chemosis, and ophthalmoplegia in an acutely unwell patient with headache are the hallmarks of cavernous sinus thrombosis. The diagnosis is a clinical one as far as the general physician is concerned. The patient should be admitted to the hospital without delay. Guidelines  Einhaupl K, Bousser MG, de Bruijn SF, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis. Eur J Neurol 2006;13:553-9 Don't miss!  The combination of fever, headache, and papilledema is an emergency, and evaluation should be urgent  Referral to specialists in neurology and infectious disease should be considered immediately  In the early stages the only symptom may be headache. If there is a history of facial or sphenoid sinus infection in the previous week, and the headache is unilateral, retro-orbital, or along the ophthalmic or maxillary branches of the trigeminal nerve, give serious consideration to the possibility of cavernous sinus thrombosis Questions to ask Presenting condition  Do you have a headache? Over 80% of patients with cavernous sinus thrombosis have a headache at presentation. It is usually unilateral, retro-orbital, or along the ophthalmic or maxillary branches of the trigeminal nerve

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Can you see normally? Most patients present with evidence of ophthalmoplegia, which causes double vision. Retro-orbital compression of the retinal vein causes reduced visual acuity or blindness Do you feel unwell? Fever, tachycardia, and sepsis are common presenting features Do you have any numbness of the face? Involvement of the facial nerve is not uncommon

Contributory or predisposing factors  Have you recently had any sinus infection or other infection of the face? This is the single most likely predisposing factor for cavernous sinus thrombosis  Do you have diabetes mellitus? This increases the risk of infection as well as the risk of septic cerebral sinus thrombosis  Are you taking the combined oral contraceptive? Use of this class of drugs increases the risk of venous thrombosis generally by between 2-fold and 4-fold  Do you have any prothrombotic genetic mutations? For example, factor V Leiden and factor II mutation. When combined with oral contraceptives these mutations increase the relative risk of cerebral sinus thrombosis 10-fold to 20-fold  Are you pregnant or have you recently been pregnant? This increases the thrombotic risk generally  Do you have any malignancy? This also increases the risk of thrombosis generally  Are you on any immune-suppressant drugs? Corticosteroids and chemotherapeutic agents predispose to cavernous sinus thrombosis Examination  What is the patient's general state of health? In many cases of cavernous sinus thrombosis, the patient is acutely unwell at presentation, with fever, tachycardia, signs of sepsis, drowsiness, or even convulsions or coma  Examine the patient's eyes. Signs of proptosis, ptosis, and chemosis are often present, usually in one eye at presentation but rapidly progressing to the contralateral eye. At the back of the eyes, ophthalmoscopy may reveal papilledema  Examine the patient's face. Evidence of facial edema, eyelid edema, or the facial swelling and redness of acute sinusitis may be present  Can the patient look upward/downward/to the left and right? Ophthalmoplegia is commonly due to involvement of the third, fourth, and sixth cranial nerves as they cross the cavernous sinus  Test the patient's vision. Visual acuity is often reduced, sometimes to complete blindness in one eye  Test the patient's sense of touch on the face. Sensation of the skin and cornea are often reduced in the distribution of the ophthalmic or maxillary branches of the facial nerve  Can the patient flex his/her neck? Nuchal rigidity often accompanies the headache Summary of tests  Magnetic resonance imaging (MRI). This test is the cornerstone of diagnosis, and can be combined with angiography to demonstrate the presence of clot in the cavernous sinus  Complete blood count. This will show a leukocytosis in over three-quarters of cases. Although it can be performed by the general physician, it should not be allowed to delay the urgent transfer of the patient to hospital  Computerized axial tomography (CAT). In the absence of MRI facilities, this will usually demonstrate the anatomy of the cavernous sinus and any surrounding sinusitis. Usually performed by a specialist Order of tests

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Magnetic resonance imaging (MRI) Complete blood count Computerized axial tomography (CAT)

Tests Body fluids Complete blood count Description Take 5mL blood and send to the hematology laboratory in an EDTA specimen tube, requesting urgent complete blood count. Advantages/disadvantages  Advantage: will confirm a leukocytosis in most cases of septic cavernous sinus thrombosis  Disadvantage: there will be a delay in obtaining the result. In unwell patients this should not be allowed to delay the urgent transfer to hospital Normal Normal white cell count 3200-9800/mm3 (3.2-9.8x109/L). Abnormal White cell count >9800/mm3 (9.8x109/L). Cause of abnormal result Sepsis in the paranasal sinuses or facial area. Medications, disorders and other factors that may alter results Other foci of bacterial infection such as orbital cellulitis and sinusitis. Imaging Magnetic resonance imaging Description A sensitive, noninvasive method of imaging the internal structures of the head by placing the patient inside a rotating magnetic field. Can be combined with angiography to demonstrate lack of blood flow in the cavernous sinus. Advantages/disadvantages Advantages:   

The hallmark of diagnosis in cavernous sinus thrombosis Noninvasive, sensitive, and specific No radiation risk

Disadvantages:   

Not possible in some patients with metal prostheses/pacemakers Claustrophobia is a problem with some patients May not be available acutely

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MRI findings may be subtle - if cavernous sinus thrombosis is suspected, this must be specifically asked about

Abnormal  Increased signal from clotted blood within the sinus  Lack of blood flow in the sinus on MRI angiography Cause of abnormal result Clot within the cavernous sinus. Medications, disorders and other factors that may alter results Movements, arterial pulsation, and foreign bodies might produce artifacts and interfere with the interpretation. Computerized axial tomography Description A detailed three-dimensional X-ray imaging technique to demonstrate the internal bony structures of the head. Advantages/disadvantages Advantages:  

Rapid test Detailed view of bony structures such as sinuses

Disadvantages:  

Not good at demonstrating soft tissues, blood clot, or inflammation Exposure to radiation

Abnormal Opacification of sinuses containing fluid. Cause of abnormal result Fluid-filled sinus cavities absorb X-radiation, as opposed to air-filled cavities. Medications, disorders and other factors that may alter results Movements, arterial pulsation, and foreign bodies might produce artifacts and interfere with the interpretation. Clinical pearls  The acute form of cavernous sinus thrombosis usually follows infections in the face, sinuses, and middle ear, and patients develop symptoms within a week of the infection  The chronic form of cavernous sinus thrombosis may be due to aseptic causes such as hypercoagulopathy, oral contraceptives, vasculitis. The onset of symptoms is more indolent, and cranial nerve palsies may be the only early manifestations  Unilateral abducens nerve palsy may be an early isolated manifestation of cavernous sinus thrombosis

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Bilateral symptoms and/or findings on examination help distinguish cavernous sinus thrombosis from other conditions in the differential diagnosis Unilateral weakness may be seen secondary to involvement of the internal carotid artery in the cavernous sinus

Consider consult  In the early stages of cavernous sinus thrombosis the only feature is headache. If there is a history of facial or sphenoid sinus infection in the previous week, and the headache is unilateral, retro-orbital, or along the ophthalmic or maxillary branches of the trigeminal nerve, give serious consideration to the possibility of cavernous sinus thrombosis. Referral to a specialist or the Emergency department is indicated. The development of periorbital edema, facial cellulitis, proptosis, or ptosis should indicate the need for urgent care  Conditions such as orbital cellulitis, mucormycosis, and idiopathic intracranial hypertension share many of the features of cavernous sinus thrombosis. Admission to hospital for diagnostic assessment may be indicated. The urgency of admission should be dictated by the patient's general condition, but the combination of ophthalmoplegia, fever, and headache warrants urgent assessment  Referral to specialists in neurology and infectious disease should be considered immediately  Referral for surgical consultation for drainage of infected sinuses Treatment Goals  

To prevent death To prevent morbidity from visual loss, seizures, recurrent cerebral venous thrombosis, other thrombotic events, or cognitive deficit

Immediate action If the diagnosis cannot be confirmed because of the absence of imaging facilities, intravenous antibiotic therapy can be commenced empirically, as most cases of cavernous sinus thrombosis are due to infection. Patient must subsequently be transferred to a facility with further diagnostic capability. Therapeutic options Summary of therapies  Treatment usually begins with nafcillin or oxacillin given in combination with a thirdgeneration cephalosporin such as ceftriaxone or cefotaxime  Metronidazole intravenously, which covers anaerobic organisms  Vancomycin is used for patients with beta-lactam allergy or when methacillin resistance is anticipated  Heparin is often given, although this is controversial  Corticosteroids such as hydrocortisone may be used as an adjunct to antibiotic therapy to relieve inflammation, and are certainly indicated in pituitary failure  Surgery may be done by the specialist to drain any infected sinus of mucus, either endoscopically or directly Guidelines  Einhaupl K, Bousser MG, de Bruijn SF, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis. Eur J Neurol 2006;13:553-9 Order of therapies  Nafcillin

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Oxacillin Ceftriaxone Cefotaxime Metronidazole Vancomycin Heparin Hydrocortisone Surgery

Efficacy of therapies Prior to the advent of antibiotics, the mortality rate for cavernous sinus thrombosis was between 80100%. Even with the use of modern broad-spectrum intravenous antibiotics the mortality rate is still between 20-30%, and morbidity between 25-50%. Some of this improvement in outcome is due to improvements in the general health of the population and in nursing and other supportive care, and should be viewed against a fall in mortality for all infectious diseases over the last 50 years. Medications and other therapies Medications Nafcillin Penicillin-class antibiotic. Dose Adult intravenous:1.5g by infusion over 60min every 4h. Risks/benefits Risks: 

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Warning: serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Do not use if previous hypersensitivity to penicillins. Use extreme caution if previous allergy to cephalosporins. Use caution in patients with history of significant allergies and/or asthma Warning: risk of pseudomembranous colitis, use caution in gastrointestinal disease particularly colitis Use caution in hepatic and renal impairment Use caution in pediatric patients. There are no approved neonatal or pediatric dosage regimens for intravenous nafcillin Use caution in pregnancy (category B) and breast-feeding. Penicillins are amongst the safest antibiotics for pregnancy

Side-effects and adverse effects  Gastrointestinal: nausea, vomiting, diarrhea, elevated hepatic enzymes, pseudomembranous colitis  Genitourinary: interstitial nephritis, renal tubular necrosis, nephrotic syndrome  Hematologic: neutropenia, thrombocytopenia, leukopenia  Nervous system: seizures  Other: injection site reaction, phlebitis, thrombophlebitis Interactions

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Chloramphenicol (inhibits antibacterial activity of nafcillin) Cyclosporine (decreased plasma cyclosporine levels) Macrolides (inhibits antibacterial activity of nafcillin) Methotrexate (increased plasma methotrexate levels) Oral contraceptives (may decrease efficacy of oral contraceptive) Tacrolimus (decreased plasma tacrolimus levels) Tetracyclines (may antagonize the bactericidal effects of penicillins) Warfarin (decreased anticoagulant effect)

Contraindications History of penicillin hypersensitivity. Use extreme caution if previous cephalosporin hypersensitivity. Acceptability to patient Vein irritation at the intravenous administration site can be a problem with nafcillin. This is reduced by infusing each dose over 60min. Oxacillin Penicillin-class antibiotic. Dose Adult intravenous: 1g by slow injection over 10min every 4h. Risks/benefits Risks: 

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Warning: serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Do not use if previous hypersensitivity to penicillins. Use extreme caution if previous allergy to cephalosporins. Use caution in patients with history of significant allergies and/or asthma Warning: risk of pseudomembranous colitis, use caution in gastrointestinal disease particularly colitis Warning: with intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis Use caution in hepatic and renal impairment Use caution in pediatric patients and neonates Use caution in pregnancy (category B) and breast-feeding. Penicillins are amongst the safest antibiotics for pregnancy

Benefits:  

Intravenous therapy maximizes serum availability and tissue penetration of the drug Good coverage of all Gram-positive bacteria, including the penicillinase-producing staphylococci

Side-effects and adverse effects  Gastrointestinal: altered LFTs, pseudomembranous colitis  Genitourinary: interstitial nephritis, nephropathy  Hematologic: thrombocytopenia, bone marrrow suppression, eosinophilia

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Musculoskeletal: myalgia Nervous system: fever, headache, chills Skin: pruritus, rash Other: phlebitis, thrombophlebitis, serum sickness-like reactions

Interactions  Chloramphenicol (inhibits antibacterial activity of oxacillin)  Methotrexate (increased plasma methotrexate levels)  Oral contraceptives (may decrease efficacy of oral contraceptive)  Tetracyclines (may antagonize the bactericidal effects of penicillins) Contraindications History of penicillin hypersensitivity. Use extreme caution if previous cephalosporin hypersensitivity. Acceptability to patient Less likely than nafcillin to cause phlebitis at the injection site. Ceftriaxone Cephalosporin antibiotic. Dose Adult intravenous:  

2g every 12h Must be administered intravenously, other routes are not adequate for this disorder

Risks/benefits Risks: 

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Warning: risk of serious acute hypersensitivity reactions requiring emergency treatment, check for history of allergy to cephalosporins, penicillins or other drugs. Use caution with penicillin or other drug allergy (contraindicated with cephalosporin hypersensitivity) Warning: risk of pseudomembranous colitis. Use caution in gastrointestinal disease particularly colitis Warning: risk of decreased prothrombin activity in patients with renal or hepatic impairment, poor nutritional state or those receiving a protracted course of antibacterial therapy Warning: risk of sonographic gallbladder abnormalities: use caution with gallbadder disease, and discontinue if signs/symptoms of gallbladder disease or sonographic abnormalities develop Use caution in diabetic patients, a false-positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution, or with Clinitest tablets, but not with enzyme-based tests such as Clinistix and Tes-Tape Use caution in renal impairment. Dose should not exceed 2g/day without monitoring of serum concentrations in patients with both renal and hepatic impairment Use caution in pregnancy (category B) and breast-feeding

Benefits: 

First line treatment of this disorder in combination with nafcillin or oxacillin

Side-effects and adverse effects

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Gastrointestinal: diarrhea, nausea, vomiting, abdominal pain, pseudomembranous colitis (more common with high doses), increased LFTs, glossitis, anorexia, bleeding, reversible transient gallbladder disease Genitourinary: candidiasis, vaginitis, transitory rises in BUN have been observed, nephrotoxicity Hematologic: eosinophilia, thrombocytosis, leukopenia, anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia Nervous system: dizziness, headache, anxiety, sleep disturbances, fatigue, fever, chills, paresthesia Respiratory: dyspnea Skin: rash, urticaria, dermatitis, pruritis Other: phlebitis and inflammation at site of injection, induration after intramuscular injection, serum sickness-like reaction (rash, fever, and arthralgia)

Interactions  Estrogens (possible reduced contraceptive effect with broad-spectrum antibacterials)  Nephrotoxic drugs, e.g. aminoglycoside antibiotics, loop diuretics (concomitant use with cephalosporins may increase risk of nephrotoxicity)  Oral anticoagulants (possible enhanced anticoagulant effect with cephalosporins)  Probenecid (reduced excretion of cephalosporins) Contraindications  History of cephalosporin hypersensitivity (use caution with penicillin hypersensitivity)  Porphyria  Neonates with jaundice or to those who are hypoalbuminemic or acidotic or have conditions, such as prematurity, in which bilirubin binding is likely to be impaired Cefotaxime Cephalosporin antibiotic. Dose Adult intravenous: 1.5-2g by injection or infusion every 4h. Risks/benefits Risks:      

Warning: risk of cross-sensitivity with penicillins, use extreme caution with history of penicillin hypersensitivity Warning: risk of pseudomembranous colitis, use caution in gastrointestinal disease particularly colitis Warning: risk of granulocytopenia and (more rarely) agranulocytosis, particularly if given over long periods Warning: potentially life-threatening arrhythmias following rapid (<60s) bolus administration via central venous catheter have been observed Use caution in renal impairment (a dose reduction may be necessary) Use caution in pregnancy (category B) and breast-feeding

Benefits:

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Until microbiologic culture and sensitivities are available, the empiric addition of this antibiotic to the group of three (nafcillin or oxacillin, cefotaxime, and metronidazole) covers the possibility that the patient's condition is due to infection with Gram-negative bacteria

Side-effects and adverse effects  Gastrointestinal: anorexia, bleeding, diarrhea, flatulence, glossitis, heartburn, increased LFTs, nausea, pseudomembranous colitis, taste disturbance, vomiting  Genitourinary:candidiasis, nephrotoxicity, proteinuria, vaginitis  Hematologic: blood cell disorders  Nervous system: chills, confusion, dizziness, fatigue, fever, headache, lethargy, paresthesia  Skin: exfoliative dermatitis, rash, urticaria  Other: injection site reactions Interactions  Estrogens (possible reduced contraceptive effect with broad-spectrum antibacterials)  Nephrotoxic drugs, e.g. aminoglycoside antibiotics, loop diuretics (concomitant use with cephalosporins may increase risk of nephrotoxicity)  Oral anticoagulants, e.g. warfarin (possible enhanced anticoagulant effect with cephalosporins)  Probenecid (reduced excretion of cephalosporins) Contraindications History of cephalosporin hypersensitivity, use extreme caution with history of penicillin hypersensitivity. Acceptability to patient Generally well tolerated intravenously. Metronidazole Antibiotic and antiprotozoal agent. Dose Adult intravenous:  

Loading dose: 15mg/kg infused over 1h (approx. 1g for a 70kg adult) Maintenance dose: 7.5mg/kg infused over 1h every 6h (approx. 500mg for a 70kg adult). The first maintenance dose should be instituted 6h following the initiation of the loading dose

Risks/benefits Risks:      

Warning: reports of convulsive seizures and peripheral neuropathy. Discontinue if abnormal neurologic signs. Use caution in central nervous system diseases Warning: may cause leukopenia. Use caution in patients with current of history of blood dyscrasia Warning: known or unrecognized candidiasis may present more prominent symptoms during therapy Warning: hypersensitivity reactions including urticaria have been reported rarely Use caution in hepatic impairment Use caution in the elderly

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Pregnancy category B. Use in first trimester is controversial with possible association with congenital defects, however this is unlikely. Considered acceptable in second and third trimesters if alternatives failed Use caution in breast-feeding. Monitor infant for gastrointestinal upset

Benefits: 

Good for combination therapy for anaerobic coverage. Until microbiologic culture and sensitivities are available, the empiric addition of this antibiotic to the group of three (nafcillin or oxacillin, cefotaxime, and metronidazole) covers the possibility that the patient's condition is due to infection with anaerobic bacteria

Side-effects and adverse effects  Gastrointestinal: nausea, anorexia, vomiting, diarrhea, constipation, abdominal pain, metallic taste, glossitis, furry tongue, pancreatitis, pseudomembranous colitis  Genitourinary: dysuria, cystitis, dark urine  Hematologic: leukopenia  Nervous: dizziness, vertigo, headache, ataxia, confusion, depression, insomnia, convulsions, peripheral neuropathy  Skin: rash, urticaria, pruritus  Other: candidiasis Interactions  Alcohol (disulfiram-like reaction)  Anticoagulants (enhanced anticoagulant effect)  Barbiturates (decreased plasma metronidazole level)  Cimetidine (increased plasma metronidazole level)  Disulfiram (psychotic reaction)  Estrogens (decreased contraceptive effect)  Fluorouracil (increased plasma fluorouracil level)  Lithium (lithium toxicity)  Phenytoin (increased plasma phenytoin level) Contraindications Hypersensitivity to metronidazole, other nitroimidazole derivatives or any other component. Acceptability to patient Generally well tolerated intravenously. Patient and caregiver information Do not consume alcohol during therapy or for 3 days after completing therapy Vancomycin Vancomycin is used for patients with beta-lactam allergy or when methacillin resistance is anticipated Dose Adult intravenous: 

1g every 12h

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Vancomycin blood levels need to be taken daily and monitored. Dose may require adjustment depending on level

Risks/benefits Risks: 

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Warning: some patients with intestinal inflammation disorders may have significant systemic absorption of drug and may be at risk of adverse effects usually associated with parenteral administration Warning: reports of transient or permanent ototoxicity. Use caution in patients with hearing disorders, renal impairment or receiving other ototoxic drugs Warning: avoid rapid infusion due to risk of anaphylaxis, hypotension and cardiac arrest. Administer over a period of not less than 60min. Rotate sites of infusion to reduce risk of thrombophlebitis. Avoid extravasation Warning: risk of pseudomembranous colitis. Use caution in gastrointestinal disease particularly colitis Monitor renal function, auditory function, blood counts and vancomycin serum levels where appropriate Use caution in renal impairment Use caution in the elderly Safety and efficacy in pediatric patients have not been established Pregnancy category B. No well-controlled human data published, but no association with fetal ototoxicity or renal impairment have been reported Use caution in breast-feeding

Side-effects and adverse effects  Eyes, ears, nose, and throat: hearing loss, tinnitus  Gastrointestinal: nausea  Genitourinary: renal failure, interstitial nephritis  Hematologic: neutropenia, thrombocytopenia, eosinophilia  Nervous: vertigo, dizziness  Skin: rash, Stevens-Johnson syndrome, toxic epidermal necrolysis  Other: drug fever, chills, vasculitis, red man syndrome Interactions  Aminoglycosides (increased risk of ototoxicity and nephrotoxicity)  Anesthetics, general (hypersensitivity-like reactions)  Cisplatin (increased risk of ototoxicity and nephrotoxicity)  Colestyramine (vancomycin effects antagonized)  Colistin (increased risk of ototoxicity and nephrotoxicity)  Cyclosporine (increased risk of nephrotoxicity)  Diuretics (increased risk of ototoxicity)  Estrogens (decreased contraceptive effect)  Polymyxins (increased risk of nephrotoxicity) Contraindications Hypersensitivity to vancomycin or any other component. Patient and caregiver information

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It is important to complete the whole course, even if symptoms improve May reduce the effectiveness of the oral contraceptive pill. Take extra contraceptive precautions Regular blood and laboratory tests are required during therapy

Heparin [EBM] Anticoagulant. Dose Adult intravenous infusion:  

80 units/kg bolus followed by 18 units/kg/h Dose is adjusted based on partial thromboplastin time results

Risks/benefits Risks:   

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Warning: not for intramuscular use Warning: reports of hypersensitivity reactions including angioedema, urticaria, and anaphylaxis Warning: hemorrhage can occur at any site. Use extreme caution in diseases where there is increased risk of hemorrhage including severe hypertension, recent major surgery, spinal or epidural anesthesia, hemophilia, gastrointestinal ulceration, menstruation, and liver disease. Discontinue immediately if hemorrhage occurs Warning: dose should be regulated by frequent blood coagulation tests Warning: contains benzyl alcohol as a preservative, which is known to cause 'gasping syndrome' in premature infants Warning: may cause new thrombus formation in association with thrombocytopenia, the socalled 'white-clot syndrome' Warning: increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and in patients with antithrombin III deficiency Risk of thrombocytopenia, hemorrhage and hyperkalemia Use caution in diabetes and electrolyte disturbances Use caution in hepatic and renal impairment Use caution in the elderly. A higher incidence of bleeding has been reported in women over 60 years of age Pregnancy category C. Does not cross the placenta. No well-controlled human data but reported to be associated with increased incidence of spontaneous abortions, prematurity and still births. Suggested association of cardiovascular defects in first trimester exposure Not excreted into breast milk

Benefits:  

May help to lyse any clot in the cerebral sinuses May also prevent further extension of any clot

Side-effects and adverse effects  Endocrine: osteoporosis (long-term high-dose therapy)  Gastrointestinal: increased LFTs  Hematologic: hemorrhage, bleeding, thrombocytopenia, white-clot syndrome

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Metabolic: hyperkalemia Skin: skin necrosis, alopecia (rare) Injection site: local irritation, erythema, pain or hematoma

Interactions  ACE inhibitors and angiotensin-II antagonists (increased risk of hyperkalemia)  Anticoagulants, oral (prolonged prothrombin time)  Antithrombin III human (enhanced anticoagulant effect)  Clopidogrel and ticlopidine (increased risk of bleeding)  Dipyridamole (enhanced anticoagulant effect)  Nonsteroidal anti-inflammatory drugs (increased risk of bleeding) Contraindications  Hypersensitivity to heparins or any other component  Severe thrombocytopenia  Bleeding disorders and other uncontrollable active bleeding states except when this is due to disseminated intravascular coagulation  Patients who cannot have suitable blood tests at appropriate intervals Evidence  A systematic review evaluated the effects of anticoagulation in cerebral sinus thrombosis and included two small randomized controlled trials: one comparing high dose, subcutaneous, lowmolecular weight heparin vs control; the other comparing intravenous, unfractionated heparin vs control. The reviewers concluded that anticoagulation treatment appeared safe in cases of cerebral sinus thrombosis and was associated with a non significant reduction in the risk of death or dependency [1]Level A Learn about evidence grading system Acceptability to patient Generally well tolerated despite the need for repeated subcutaneous injections. Intravenous therapy is usually well tolerated. Patient and caregiver information  Dose should be adjusted according to the patient's coagulation test results  Patients should report any signs or symptoms of bleeding to physician immediately Hydrocortisone Corticosteroids, such as hydrocortisone, may be used as an adjunct to antibiotic therapy to relieve inflammation, and are certainly indicated in pituitary failure. Dose Adult intravenous: 100mg every 6h. Risks/benefits  Warning: psychic derangements may appear when corticosteroids are used, ranging from euphoria to severe depression. Use caution in psychiatric disorders  Warning: patients on corticosteroid therapy require an increased dosage of rapidly acting corticosteroids before, during, and after unusual stress (e.g. trauma, surgery, illness)  Warning: risk of masking signs of infections or emergence of new infections

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Warning: prolonged use of corticosteroids may increase risk of cataracts, glaucoma, and secondary ocular infections. Use caution in glaucoma Warning: risk of electrolyte disturbances, hypertension, and water retention. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Use caution in cardiac disorders (e.g. congestive heart failure, hypertension, recent myocardial infarction) Warning: do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Response to killed or inactived vaccines may be diminished Warning: generally contraindicated in active tuberculosis. Use caution in latent tuberculosis or tuberculin reactivity: chemoprophylaxis should be used with prolonged therapy Warning: patients who are exposed to chickenpox or measles should seek medical attention Warning: reports of Kaposi's sarcoma and intrauterine device (IUD) contraceptive failure with corticosteroid treatment Use caution in ulcerative colitis and peptic ulcer Use caution in diabetes, hypothyroidism, ocular herpes simplex, epilepsy, and osteoporosis Use caution in hepatic and renal impairment Use caution in the elderly Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed Pregnancy category C. Use only if potential benefits outweigh potential risks to fetus. Possible association between cleft palate and corticosteroid use in the first trimester. Seek advice before prescribing in pregnancy Use caution in breast-feeding. Monitor infant for signs of hypoadrenalism

Side-effects and adverse effects Side-effects are unlikely with short-term therapy.  

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Cardiovascular: congestive heart failure, hypertension, fluid retention Endocrine: cushingoid state, growth suppression in children, secondary adrenocortical unresponsiveness, increased insulin or oral hypoglycemic requirements, decreased glucose tolerance Eyes, ears, nose, and throat: cataracts, increased intraocular pressure Gastrointestinal: nausea, diarrhea, abdominal distention, peptic ulceration, ulcerative esophagitis, altered LFTs, hemorrhage, pancreatitis Genitourinary: menstrual irregularities Metabolic: sodium retention, potassium loss, hypokalemic alkalosis, weight gain Musculoskeletal: muscle weakness, osteoporosis, tendon rupture, fracture Nervous system: vertigo, headache, depression, mood changes, seizures, insomnia, pseudotumor cerebri, psychotic manifestations Skin: impaired wound healing, thin and fragile skin, facial erythema, acne, bruising

Interactions  Aminoglutethimide (increased clearance of corticosteroid)  Antidiabetics (hypoglycemic effect inhibited)  Antihypertensives (antihypertensive effect inhibited)  Barbiturates (increased clearance of corticosteroid)  Cholestyramine (may reduce absorption of corticosteroids)

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Clarithromycin, erythromycin, troleandomycin (may enhance steroid effect) Colestipol (may reduce absorption of corticosteroids) Cyclosporine (may increase levels of both drugs; may cause seizures) Digoxin (digoxin toxicity) Diuretics (diuretic effect inhibited) Isoniazid (decreased plasma isoniazid concentration) Ketoconazole (inhibits corticosteroid metabolism) Nonsteroidal anti-inflammatory drugs (increased risk of bleeding) Oral contraceptives (enhanced effects of corticosteroids) Rifampin (may inhibit hepatic clearance of prednisone) Salicylates (increased clearance of salicylates) Warfarin (alters clotting time)

Contraindications  Hypersensitivity to corticosteroids or any other components  Acute infections Surgical therapy Sinus surgery Description of operation Surgery to drain any infected sinus of mucus, either endoscopically or directly. Risks/benefits Sinus surgery removes the irritant factor, which predisposed the patient to inflammation of the wall of the cavernous sinus (which caused the thrombophlebitis initially). Summary of evidence Evidence  A systematic review concluded that heparin treatment appeared safe and was associated with a nonsignificant reduction in the risk of death or dependency in cases of cerebral sinus thrombosis [1]Level A Learn about evidence grading system Clinical pearls  Clinical suspicion is key, as the diagnosis can easily be made with MRI  Broad-spectrum antibiotic therapy is the cornerstone of treatment of cavernous sinus thrombosis  Early anticoagulation with intravenous heparin may reduce morbidity from the condition Never Never treat suspected cavernous sinus thrombosis with oral antibiotics. If this condition is suspected or confirmed, treatment should be with intravenous broad-spectrum antibiotics if lives are to be saved. Management in special circumstances Coexisting disease

Diabetes mellitus: diabetic control is likely to be compromised during treatment for cavernous sinus thrombosis. Hypo- and hyperglycemia are both possible. Close monitoring of plasma glucose is necessary. Coexisting medication Oral anticoagulants: patients on warfarin are less likely to suffer an episode of cavernous sinus thrombosis, but if they do, then careful monitoring of clotting times will be necessary if heparin is used. Special patient groups  Allergic patients: a previous anaphylactic reaction to any of the broad-spectrum antibiotics used will require a careful search for a suitable alternative drug. Lesser degrees of allergy may be overlooked  Pregnancy: cavernous sinus thrombosis is more common in pregnancy. The condition is lifethreatening, and intravenous broad-spectrum antibiotics may save the lives of both the mother and fetus  Terminal care: cavernous sinus thrombosis is more common in patients with malignancy. The mortality from cavernous sinus thrombosis without antibiotics is between 80-100%. The patient may decide not to accept intravenous antibiotic therapy, in which case the priority is to maintain comfort and dignity throughout the terminal events Patient satisfaction/lifestyle priorities Most patients will gratefully accept transfer to hospital for intravenous therapy. One feature of the acute toxic state may be that the patient is confused. Reluctance to accept treatment may be a sign of this. Patient and caregiver issues Questions patients ask  Admission to hospital should be strongly recommended. If necessary, the patient should be informed that the mortality rate without intravenous antibiotics is close to 100%. With correct treatment the mortality rate is reduced to around 30%  Some patients do not like taking antibiotics for fear of becoming immune to them. This misconception should be dealt with using the above argument Health-seeking behavior Have you been prescribed any treatment for this episode of illness? If the patient was seen before the onset of severe thrombotic symptoms, oral antibiotics may have been prescribed for suspected sinus infection. These will need to be stopped once intravenous therapy is started. Follow-up During the acute phase of the condition, patients are treated in hospital and their progress is monitored closely. If the acute episode settles, then outpatient follow-up is important because there is a risk of complications such as seizures, focal neurologic deficits, visual problems, and future thrombotic events. Plan for review  Acute phase in hospital: regular monitoring of temperature, blood pressure, pulse, neurologic status, hydration, urine output, and electrolyte balance

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Outpatient follow-up: full neurologic examination 4 weeks after hospital discharge, especially to detect cranial nerve damage and reduced visual acuity, and to ask about seizure activity, symptoms of other thromboses, and return to normal daily living

Information for patient or caregiver With regard to future medical considerations, having suffered a cavernous sinus thrombosis puts the patient in the same category as the patient with a deep vein thrombosis:    

Absolute contraindication to the combined oral contraceptive Caution with estrogen replacement therapy Caution with surgical procedures and long-haul flights Caution with future pregnancy

There is also a small excess risk of developing seizures in the future, although this is not great enough to warrant starting prophylactic anticonvulsants. Ask for advice Question 1 What is the basis of symptoms/findings in the condition? Answer 1 The structures that go through the cavernous sinus: cranial nerves III, IV, VI (ophthalmoplegia), cranial nerve V (facial paresthesia), internal carotid artery (unilateral weakness), ophthalmic artery (unilateral blindness). Question 2 Should cavernous sinus thrombosis be suspected in all patients with unilateral headaches? Answer 2 Only if there is a history of preceding infection in the face or sinuses and/or there are suggestive eye findings on examination. However, in general, infection should be considered in almost all patients who have headache severe enough to require medical attention. Question 3 Are there predisposing factors for cavernous sinus thrombosis? Answer 3 As with other cerebral venous thromboses, states of hypercoagulability, oral contraceptives, and diabetes can predispose to CVT. Sinus infection is a more proximate risk factor for development of cavernous sinus thrombosis. Question 4 Can I prescribe oral contraceptive pills to someone with a history of cavernous sinus thrombosis? Answer 4 No. Combined oral contraceptives represent an increased risk for sinus thrombosis, especially in patients who have already had the condition.

Consider consult  All patients with suspected cavernous sinus thrombosis should be admitted to the hospital urgently for intravenous broad-spectrum antibiotic treatment  There is no place for management with oral antibiotics or nonantibiotic therapy alone. The mortality for cavernous sinus thrombosis before the antibiotic era was between 80-100%  If admission to hospital is impossible or necessarily delayed, intravenous broad-spectrum antibiotic treatment should be started as soon as possible Outcomes Prognosis  The overall mortality in this condition is between 20-30%  The morbidity is between 25-50% Clinical pearls  Cavernous sinus thrombosis is a treatable condition. Mortality and morbidity can be reduced significantly by early treatment with intravenous antibiotics  Multiple antibiotics should always be used initially for broad coverage until culture results allow for more selective use  The use of intravenous heparin may reduce morbidity from the condition  Unilateral blindness may occur secondary to occlusion of the ophthalmic artery Progression of disease Therapeutic failure The first-choice antibiotics nafcillin (or oxacillin), cefotaxime, and metronidazole are used on an empiric basis. If bacterial culture material can be obtained from sinus washings, blood culture, or lumbar puncture, this may guide the choice of antibiotic agent. Recurrence In one series of 77 patients, nine (11.7%) suffered a further cerebral sinus thrombosis, all but one in the first year. In a series of 40 patients with cerebral venous thrombosis, 15-20% had abnormal clotting factors, the majority being factor V Leiden. Therefore, in patients with no obvious cause for their cerebral venous thrombosis, long-term oral anticoagulation may be indicated in those found positive on screening for thrombophilia. There is no direct evidence for this approach, which remains controversial. Deterioration With a mortality rate of about 20%, deterioration is not uncommon. General supportive measures in intensive care may be required, with attention to hydration, temperature control, nutritional status, respiratory support, circulatory support, and skin care. The prevention of seizures may be necessary. Intensive nursing care is essential in the comatose patient. Terminal illness  Pain control - consider intravenous opiates and nonsteroidal anti-inflammatories  Vomiting - antiemetics given in conjunction with analgesics  Anxiety - anxiolytics such as diazepam or midazolam  Respiratory distress - opiates  Seizures - anticonvulsants rectally or intravenously if acute need, and oral maintenance for chronic treatment Clinical complications

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Septic cavernous sinus thrombosis has a high morbidity, with <40% of patients recovering without complications The risk of death is between 20-30% Oculomotor palsies, blindness, and hemiparesis are the most common sequelae Recurrent seizures are seen in 15% of patients who have seizures acutely A second cerebral venous thrombosis is likely in 11.7%, mostly in the first year Noncerebral thromboses occur in 14.3% All thromboses occur in 20% Rare complications include hypopituitarism and arteriovenous fistula

Consider consult  Refer for management of recurrent seizures unless referral is difficult for geographic reasons, in which case anticonvulsant treatment may be started in primary care  Have a high index of suspicion for recurrence of thrombosis, especially in the first year after cavernous sinus thrombosis. Refer urgently to hospital if suspected  Patients with oculomotor palsies and visual acuity problems may benefit from referral to an ophthalmologist  Referral to a hematologist for thrombophilia screening may be indicated in cases where there has been no obvious precipitating cause and in recurrent cases Prevention   

Infections of the face or paranasal sinuses: these are the most common causes of cavernous sinus thrombosis and usually occur in the week or two prior to the onset of the thrombosis Hypercoagulation states: thrombophilia was found in 20% of patients with cavernous sinus thrombosis in one series Intravenous drug misuse: a case report of cavernous sinus thrombosis following illegal injection of heroin into the carotid artery

Primary prevention The timely and comprehensive treatment of infections of the face and paranasal sinuses will help prevent cavernous sinus thrombosis. Modifiable risk factors Alcohol and drugs The avoidance of injection of illegal drugs into the carotid artery will reduce the risk of cavernous sinus thrombosis. Other A family history of recurrent thrombosis may prompt the search for thrombophilia, which has a positive correlation with cavernous sinus thrombosis. Chemoprophylaxis  Long-term oral anticoagulation may be indicated in patients with thrombophilia after cavernous sinus thrombosis, or after recurrent thrombosis, but the evidence for this is lacking at present  The use of anticonvulsants as prophylaxis after cavernous sinus thrombosis is not supported because of the low risk of seizures in patients who do not experience a seizure acutely Secondary prevention

The use of oral anticoagulants for prevention of recurrence following cavernous sinus thrombosis is not commonly practiced. First, there are no trial data to support this practice. Second, the usefulness of anticoagulation during the acute disease is controversial. Screening for prothrombotic mutations may help to select patients at highest risk of recurrence who may benefit from long-term oral anticoagulation in the future. Screening Screening for thrombophilia in the general population, particularly in women starting the combined oral contraceptive, is controversial. Thrombophilia blood testing Screening blood for the presence of prothrombotic mutations. Resources References Evidence references [1] Stam J, de Bruijn SFTM, DeVeber G. Anticoagulation for cerebral sinus thrombosis. Cochrane Database of Systematic Reviews 2001, Issue 4 Cochrane Review Guidelines  Einhaupl K, Bousser MG, de Bruijn SF, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis. Eur J Neurol 2006;13:553-9 Further reading  Laupland KB. Vascular and parameningeal infections of the head and neck. Infect Dis Clin North Am 2007;21:577-90  Wald ER. Periorbital and orbital infections. Infect Dis Clin North Am 2007;21:393-408  Roscoe DL, Hoang L. Microbiologic investigations for head and neck infections. Infect Dis Clin North Am 2007;21:283-304  Belleza WG, Kalman S. Otolaryngologic emergencies in the outpatient setting. Med Clin North Am 2006;90:329-53  Cannon ML, Antonio BL, McCloskey JJ, et al. Cavernous sinus thrombosis complicating sinusitis. Pediatr Crit Care Med 2004;5:86-8  Osborn MK, Steinberg JP. Subdural empyema and other suppurative complications of paranasal sinusitis. Lancet Infect Dis 2007;7:62-7 Associations National Headache Foundation 820 New Orleans, Suite 217 Chicago, IL 60610 Tel: (888) NHF-5552 E-mail: [email protected] www.headaches.org

Thrombophilia Support www.fvleiden.org Related topics Acute and chronic otitis media Cellulitis Pharyngitis Sinusitis Tonsillitis Contributors Karl E Misulis, MD, PhD Fred F Ferri, MD, FACP Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com Bookmark URL: /das/pdxmd/body/0/0?type=med&eid=9-u1.0-_1_mt_1014453