Case presentation, meningitis and treatment, Moh'd Sharshir

Case presentation, meningitis and treatment

1. Moh’d Sharshir , Fellow Critical Care King Faisal Specialist Hospital & Research Center

2. What is meningitis?…… The brain and spinal cord are covered by connective tissue layers collectively called the meninges which form the blood-brain barrier. 1-the pia mater (closest to the CNS) 2-the arachnoid mater 3-the dura mater (farthest from the CNS). The meninges contain cerebrospinal fluid (CSF).

3. Meningitis is an inflammatory disease of the leptomeninges , the tissues surrounding the brain and spinal cord, and is defined by an abnormal number of white blood cells in the cerebrospinal fluid (CSF) .

4. Causes of Meningitis: 1.Bacterial Infections 2.Viral Infections 3.Fungal Infections (Cryptococcus neoformans,Coccidiodes immitus ) 4.Inflammatory disease (SLE)

5. Bacterial meningitis: S. pneumoniae 30-50% N. meningitidis 10-35% H. influenzae 1-3% G - ve bacilli 1-10% Listeria species 5% Streptococci 5% Staphylococci 5-15%

6. Viral Meningitis: Enteroviruses (Coxsackie's and echovirus): most common. Denovirus Arbovirus Measles virus Herpes Simplex Virus Varicella

7. CLINICAL FEATURES

8. CLINICAL FEATURES:   The classic triad of acute bacterial meningitis consists of : fever. nuchal rigidity. and a change in mental status. Most patients have high fevers, but a small percentage have hypothermia.

9. CLINICAL FEATURES: CNS symptoms: Some patients will have significant photophobia. Changes in mental and level of consciousnes , seizures, and focal neurologic signs tend to appear later in the course of disease.

10. CLINICAL FEATURES: Nuchal rigidity: Passive or active flexion of the neck will usually result in an inability to touch the chin to the chest Tests to illustrate nuchal rigidity:

11. Brudzinski’s sign:

12. Kernig’s sign:

13. CLINICAL FEATURES: Other findings Some infectious agents, particularly N. meningitidis , can also cause characteristic skin manifestations, petechiae and palpable purpura .

14. LABORATORY FEATURES: Most often the WBC count is elevated with a shift toward immature forms . Platelets may be reduced if disseminated intravascular coagulation is present or in the face of meningococcal bacteremia. Blood cultures are often positive, and can be very useful in the event that CSF cannot be obtained before the administration of antimicrobials. At least one-half of patients with bacterial meningitis have positive blood cultures, with the lowest yield being obtained with meningococcus .

15. LABORATORY FEATURES: CSF analysis – every patient with meningitis should have CSF obtained unless the procedure is contraindicated Chemistry and cytologic findings highly suggestive of bacterial meningitis include a CSF glucose concentration below 45 mg/ dL , a protein concentration above 500 mg/ dL , and a white blood cell count above 1000/mm3 A Gram stain should also be obtained The Gram stain is positive in up to 10 percent of patients with negative CSF cultures and in up to 80 percent of those with positive cultures

16. LABORATORY FEATURES: Opening pressure>180 mmH2O  White blood cells10/ L to 10,000/ L; neutrophils predominateRed blood cellsAbsent in nontraumatic tapGlucose <2.2 mmol /L (<40 mg/ dL )CSF/serum glucose <0.4Protein>0.45 g/L (>45 mg/ dL ) Gram's stainPositive in >60%CulturePositive in >80% Latex agglutinationMay be positive in patients with meningitis due to S. pneumoniae , N. meningitidis , H. influenzae type b, E. coli , group B streptococci Limulus lysatePositive in cases of gram-negative meningitisPCRDetects bacterial DNA

17. Treatment and prevention of bacterial meningitis: Suspected bacterial meningitis is a medical emergency and immediate diagnostic steps must be taken to establish the specific cause. The mortality rate of untreated bacterial meningitis approaches 100 percent and, even with optimal therapy, there is a high failure rate. Empiric treatment should be begun as soon as the diagnosis is suspected using bactericidal agent(s) that achieve significant levels in the CSF.

18. Treatment - Empiric Ceftriaxone 2 gm IV Q 12 h or Cefotaxime 2 gm IV Q 4-6 h PLUS Vancomycin 15 mg/kg Q 6 h . If > 50 years, also add Ampicillin 2 gm IV Q 4 h (for Listeria) .

19. THERAPY FOR SPECIFIC PATHOGENS :

20. Streptococcus pneumoniae : Gram-positive diplococci (in pairs) Encapsulated ovoid or lanceolate coccus Non-motile Fastidious (enriched media) Blood or chocolate agar 5-10 % CO2 Alpha haemolysis + draughtsman appearance Some strains are mucoid Soluble in bile Optochin sensitive

21. Pathogenesis : Virulence factors Capsular polysaccharide The major factor 84 serotypes Both antigenic and type specific Antiphagocytic Serotype 3 , 7 are most virulent 90% of cases of bacteraemic pneumococcal pneumonia and meningitis are caused by 23 serotypes Quellung reaction , india ink Pneumolysin Membrane damaging toxin

22. Predisposing factors: Aspiration of upper airway secretions ( endogenous ) No person-person spread Disturbed consciousness , general anaesthesia , convulsions , CVA , epilepsy , head trauma Prior LRT. VIRAL infection Preexisting respiratory diseases , smoking Chronic bronchitis , bronchogenic malignancy Chronic heart disease Chronic renal disease ( nephrotic syndrome ) Chronic liver disease ( cirrhosis) Diabetes mellitus Old age , (extreme of age ) Malnutrition , alcoholism

23. Meningitis: The most virulent pathogen of meningitis Mortality ( 20% ) Primary Complicate infections at other site ( lung ) Bacteraemia usually coexists Bimodal incidence ( < 3 yr - > 45 yr )

24. The conventional approach to the treatment of pneumococcal meningitis was the administration of penicillin alone for two weeks at a dose of four million units intravenously every four hours. Good results have also been obtained with third generation cephalosporins . However, the problem of treating pneumococcal meningitis has recently been compounded by the widespread and increasingly common reports of pneumococcal strains resistant to penicillin.

25. Cefotaxime or ceftriaxone can be used if the MIC for these drugs is less than 0.5 µg/ mL. It is recommended that vancomycin ( 2 g/day) should be given with cefotaxime or ceftriaxone in the initial treatment of pneumococcal meningitis if there has been beta-lactam resistance noted locally. Vancomycin should be continued if there is high level penicillin resistance and an MIC >0.5 µg/mL to third generation cephalosporins . If corticosteroids are given, rifampin should be added as a third agent since it increases the efficacy of the other two drugs . The usual duration of therapy is two weeks.

26. Haemophilus influenzae A third generation cephalosporin is the drug of choice for H. influenzae meningitis. Patients with H. influenzae meningitis should be treated for five to seven days. For adults, a dose of 2 g every six hours of cefotaxime and 2 g every 12 hours of ceftriaxone is more than adequate therapy. Pharyngeal colonization persists after curative therapy and may require a short course of rifampin if there are other children in the household at risk for invasive Haemophilus infection. The recommended dose is 20 mg/kg per day (to a maximum of 600 mg/day) for four days.

27. Neisseria meningitidis : This infection is best treated with penicillin. Although there are scattered case reports of N. meningitidis resistant to penicillin, such strains are still very rare. A third-generation cephalosporin is an effective alternative to penicillin for meningococcal meningitis. A five day duration of therapy is adequate. However, when penicillin is used, there may still be pharyngeal colonization with the infecting strain. As a result, the index patient may need to take rifampin, a fluoroquinolone , or a cephalosporin.

28. Listeria monocytogenes : Listeria has been traditionally treated with ampicillin and gentamicin, as resistance to these drugs is quite rare. Ampicillin is given in typical meningitis doses ( 2 g intravenously every four to six hours in adults) and gentamicin is used for synergy. An alternative in penicillin-allergic patients is trimethoprim- sulfamethoxazole (dose of 10-50 mg/kg per day in two or three divided doses). The usual duration of therapy is at least three weeks.

29. Enteric Gram negative rods : Prior to the availability of third generation cephalosporins , it was often necessary to instill an aminoglycoside antibiotic such as gentamicin directly into the cerebral ventricles. It is now possible to cure these infections with high doses of third generation antibiotics. A repeat CSF sample should be obtained for culture two to four days into therapy to help assess the efficacy of treatment. The duration of therapy should be at least three weeks.

30. PREVENTION OF MENINGITIS Vaccines A spectacular reduction in H. influenzae meningitis has been associated with the near universal use of a vaccine against this organism in developed countries since 1987 There has been a 94 percent reduction in H. influenzae meningitis between 1987 and 1995 Pneumococcal vaccine administered to the chronically ill and elderly is probably useful in reducing the overall incidence of pneumococcal infections. However, its role in the prevention of meningitis is as yet undetermined

31. PREVENTION OF MENINGITIS Vaccines Meningococcal vaccines are active against many strains of N. meningitidis . However, the majority of meningococcal infections in the United States are caused by type b meningococcus for which there is no vaccine. Vaccines for other types (notably type a) are recommended for travelers and American military personnel to countries with epidemic meningitis. Immunization against meningococci is not warranted as postexposure prophylaxis.

32. PREVENTION OF MENINGITIS Chemoprophylaxis: There is a role for chemoprophylaxis to prevent spread of meningococcal and haemophilus meningitis but not for pneumococcal disease. The use of antimicrobial therapy to eradicate pharyngeal carriage of meningococci is widely accepted to prevent development of disease in close contacts and to eradicate pharyngeal carriage. Rifampin 600 mg PO every 12 h for a total of four doses is recommended. Ciprofloxacin, in a single dose of 500 mg PO, is equally effective and can be used in patients over the age of 18 .

33. Role Of Steroids

34. Role Of Steroids: The addition of anti-inflammatory agents has been attempted as an adjuvant in the treatment of meningitis. Early administration of corticosteroids such as dexamethasone for pediatric meningitis has shown no survival advantage, but there is a reduction in the incidence of severe neurologic complications and deafness.

35. Role Of Steroids: Early intravenous administration of glucocorticoids usually dexamethasone has been evaluated as adjuvant therapy in an attempt to diminish the rate of hearing loss and other neurologic complications as well as mortality in selected patients with bacterial meningitis. The efficacy of dexamethasone therapy has been reported to vary in developed and developing countries.

36. Role Of Steroids: dexamethasone reduces cerebrospinal fluid (CSF) concentrations of cytokines (such as tumor necrosis factor [TNF]-alpha and interleukin [IL]-1), CSF inflammation, and cerebral edema

37. Role Of Steroids: When indicated, dexamethasone is given 15 to 20 minutes before or at the time of antibiotic administration. Two-dose regimens are recommended: 0.15  mg/kg every six hours for four days in the developed world, based upon the Infectious Diseases Society of America guidelines. and 0.4  mg/kg every 12 hours for four days in the developing world, based upon the Vietnamese trial. Adjunctive dexamethasone should  not  be given to adults who have already received antimicrobial therapy because it is unlikely to improve patient outcomes.

38. Role Of Steroids: For adults in the developed world with suspected or proven acute pneumococcal meningitis, recommend administration of  dexamethasone ( Grade 1B) . Dexamethasone should only be continued if the cerebrospinal fluid (CSF) Gram stain and/or the CSF or blood cultures reveal  Streptococcus pneumoniae .

39. In areas of the developing world where there is a high prevalence of HIV infection, poor nutrition, and significant delays in clinical presentation, such as some regions of Africa, it is unlikely that the use of adjunctive dexamethasone  will be of benefit. Thus, for adults in such regions with known or suspected bacterial meningitis, we recommend not administering dexamethasone ( Grade 1B ). In other regions of the developing world, we suggest administering dexamethasone in patients who have bacterial meningitis confirmed by Gram stain or a rapid diagnostic test ( Grade 2B ). It is also reasonable to empirically administer adjunctive dexamethasone in patients in whom there is a strong clinical suspicion for acute bacterial meningitis until microbiologic results are available. (See  'In developing regions'  above and  'Developing regions'  above.)

40. In patients with known or suspected pneumococcal meningitis who are treated with  dexamethasone , we suggest adding  rifampin  to the standard antibiotic regimen ( vancomycin  plus either  ceftriaxone  or  cefotaxime ) if susceptibility studies show intermediate susceptibility (minimum inhibitory concentration [MIC] ≥2 mcg/ mL ) to ceftriaxone and cefotaxime ( Grade 2C ). A reasonable alternative is to initiate rifampin and then discontinue it if the isolate is susceptible to the cephalosporin. (See  'Antibiotic regimens'  above.)

41. MORTALITY RATE AND LATE SEQUELAE The prognosis of meningitis is linked to age and the presence of underlying disease Bacterial meningitis accompanying advanced liver disease, HIV infection, or organ transplantation is likely to be associated with more morbidity and mortality In addition, the prognosis and complications differ in children and adults

42. Complications are more common in adults A series of 86 adults with meningitis, for example, showed a mortality rate of 18.6 percent with a complication rate of 50 percent The most common problems were: Cerebrovascular involvement – 15.1 percent. Cerebral edema – 14 percent. Hydrocephalus – 11.6 percent. Septic shock – 11.6 percent. Disseminated intravascular coagulation – 8.1 percent. Acute respiratory distress syndrome – 3.5 percent. Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study. Arch Neurol 1993; 50:575

43. Cerebrovascular complications Thrombosis, vasculitis , acute cerebral hemorrhage, and aneurysm formation of large, medium, or small cerebral vessels are potential complications of bacterial meningitis. These diverse processes can manifest similarly as a focal abnormality, such as hemiparesis  

44. In a prospective study of 86 adults with bacterial meningitis, cerebral angiography was performed in 27 (31 percent) because one or more of the following findings were present: focal neurologic deficits, abnormalities on computed tomographic (CT) scanning, or persistent coma after three days of antibiotic therapy [ 16 ]. Abnormal angiograms were found in 13 of these 27 patients; the abnormal findings included:

45. Vessel wall irregularities and focal dilatations Arterial occlusions Focal arterial bleeding Thrombosis of the superior sagittal and cortical veins

46. In another report, a cranial CT scan was performed in 87 of 122 adults with bacterial meningitis seen after 1975 [ 2 ]. A cerebral infarct was noted in four, lesions consistent with septic emboli in two and cavernous sinus thrombosis in one. Four patients without a lesion on initial scan had signs of an infarct on a later CT scan that was performed because of persistent hemiparesis in three and triplegia in one

47. The mortality rates are lowest in children A meta-analysis of prospectively enrolled cohorts of children in developed countries showed a 4.8 percent mortality from 1955 to 1993 The mortality rate varied by organism, ranging from 3.8% for H. influenzae to 7.5 percent for N. meningitidis to 15.3% for S. pneumoniae 83.6 percent of the surviving children had apparently complete recovery The most common sequelae were Deafness – 10.5 percent. Bilateral severe or profound deafness – 5.1 percent. Mental retardation – 4.2 percent. Spasticity and/or paresis – 3.5 percent. Seizures – 4.2 percent.

48.  Cerebral vein and dural sinus thrombosis (CVT)

49. Outline Introduction Epidemiology and Risk Factors for CVT Clinical Diagnosis of CVT Imaging in the Diagnosis of CVT Management and Treatment CVT in Special Populations Clinical Outcomes: Prognosis Summary

50. Introduction : Thrombosis of the dural sinus and/or cerebral veins (CVT) is an uncommon form of stroke. CVT represents approximately 0.5-1% of all strokes. Multiple factors have been associated with CVT, but only some of them are reversible.

51. Major cerebral veins and sinuses

52. Epidemiology and Risk Factors: CVT is an uncommon and frequently unrecognized type of stroke that affects about 5 people per million annually and accounts for 0·5-1% of all strokes.

53. Epidemiology and Risk Factors: CVT is more commonly seen in young individuals ( 78% occurred in patients younger than 50). Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

54. Epidemiology and Risk Factors: Compared with men, women were significantly younger (mean age 34 years, versus 42 years for men). Furthermore, a gender specific risk factor – oral contraceptives, pregnancy, puerperium , and hormone replacement therapy – was identified in 65 percent of women. Women also had a better prognosis when CVT was related to gender specific risk factor . International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

55. Risk factors for CVT: The major risk factors for CVT in adults can be grouped as transient or permanent .

56. Risk factors for CVT: 

57. Risk factors for CVT:

58. Risk factors for CVT:  Although infectious causes of CVT were frequently reported in the past, they are responsible for only 6 to 12 percent of cases in modern-era studies of adults with CVT. International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

59. PATHOGENESIS : The pathogenesis of CVT remains incompletely understood because of the high variability in the anatomy of the venous system.

60. PATHOGENESIS : There are at least two different mechanisms that may contribute to the clinical features of CVT : Thrombosis of cerebral veins or dural sinus leading to cerebral parenchymal lesions or dysfunction. Occlusion of dural sinus resulting in decreased cerebrospinal fluid (CSF) absorption and elevated intracranial pressure.

61. Symptoms and signs

62. Symptoms and signs:  Symptoms and signs of CVT can be grouped in three major syndromes: Isolated intracranial hypertension syndrome (headache with or without vomiting, papilledema , and visual problems). Focal syndrome (focal deficits, seizures, or both). Encephalopathy (multifocal signs, mental status changes, stupor, or coma). Less common presentations include cavernous sinus syndrome, subarachnoid hemorrhage, and multiple cranial nerve palsies.

63. Symptoms and signs: Headache: generally indicative of an increase in ICP, is the most common symptom in CVT and was present in nearly 89%. The headache of CVT is typically diffuse and often progresses in severity over days to weeks. A minority of patients may present with thunderclap headache, and migrainous type headache. Isolated headache without focal neurologic findings or papilledema occurs in up to 25% of patients. International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

64. Symptoms and signs: Focal symptoms and signs  : Motor weakness with monoparesis or hemiparesis , sometimes bilateral, is the most frequent focal deficit associated with CVT 37 percent . Aphasia, in particular of the fluent type, may follow sinus thrombosis, especially when the left lateral sinus is affected. Sensory deficits and visual field defects are less common International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

65. Symptoms and signs: Seizures  :  Focal or generalized seizures, including status epilepticus , are more frequent in CVT than in other stroke types 39 percent . International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

66. Symptoms and signs: Clinical manifestations of CVT may also depend on the location of the thrombosis The superior sagittal sinus, is most commonly involved and may lead to : headache, increased ICP, and papilledema . motor deficits, bilateral deficits. seizures . while presentation as an isolated intracranial hypertension syndrome is infrequent . The lateral sinus thromboses , symptoms of an underlying condition :middle ear infection may be noted.

67. Symptoms and signs: The cavernous sinus thrombosis: ocular signs dominate the clinical picture with orbital pain, chemosis , proptosis , and oculomotor palsies . Approximately 16% of CVT patients have thrombosis of the deep cerebral venous system (internal cerebral vein, Vein of Galen and straight sinus), which can lead to thalamic or basal ganglial infarction International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), Stroke. 2004;35(3):664

68. DIAGNOSIS

69. DIAGNOSIS : Routine Blood Work Class I Recommendations In patients with suspected CVT, routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time and activated partial thromboplastin time should be performed. Screening for potential prothrombotic conditions that may predispose CVT (i.e.: use of contraceptives, underlying inflammatory disease, infectious process, etc) is recommended in the initial clinical assessment (specific recommendations for testing for thrombophilia are found in the long-term management section of the main document). 2011 AHA/ASA , http://stroke.ahajournals.org/cgi/content/full/STROKEAHA.108.189696

70. DIAGNOSIS : D- dimer Testing Class II Recommendation A normal D- dimer level using sensitive immunoassay or rapid Enzyme-Linked ImmunoSorbent Assay (ELISA) may be considered to help identify patients with low probability of CVT. If there is a strong clinical suspicion of CVT, a normal D- dimer level should not preclude further evaluation. 2011 AHA/ASA , http://stroke.ahajournals.org/cgi/content/full/STROKEAHA.108.189696

71. Imaging in the Diagnosis of CVT: Diagnostic imaging of cerebral venous thrombosis may be divided into two categories: Non-Invasive Diagnostic Modalities: Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Ultrasound. Invasive Diagnostic Angiographic Procedures: Cerebral Angiography and Direct Cerebral Venography .

72. Imaging in the Diagnosis of CVT: The neuroimaging features of CVT include findings that suggest the primary underlying pathology of venous thrombosis and associated brain parenchymal lesions,These may include: focal areas of edema. venous infarction. hemorrhagic venous infarction. diffuse brain edema. isolated subarachnoid hemorrhage (rarely).

73. Imaging in the Diagnosis of CVT: In patients with CVT, the proportion who present with intracerebral hemorrhage is 30 to 40 percent. analysis of a multicenter cohort from the United States, J Stroke Cerebrovasc Dis. 2008;17(2):49

74. Imaging in the Diagnosis of CVT: Head CT :   Normal in up to 30 percent of CVT cases, and most of the findings are nonspecific. Bousser MG, Russell RR. Cerebral venous thrombosis. In: Major Problems in Neurology, Warlow CP, Van Gijn J ( Eds ), WB Saunders, London 1997. p.27, 10

75. Imaging in the Diagnosis of CVT: In about one-third of cases,CT demonstrates direct signs of CVT, which are as follows: The dense triangle sign : seen on noncontrast head CT as a hyperdensity with a triangular or round shape in the posterior part of the superior sagittal sinus caused by the venous thrombus. The empty delta sign (also called the empty triangle or negative delta sign): seen on head CT with contrast as a triangular pattern of contrast enhancement surrounding a central region lacking contrast enhancement in the posterior part of the superior sagittal sinus . Bousser MG, Russell RR. Cerebral venous thrombosis. In: Major Problems in Neurology, Warlow CP, Van Gijn J ( Eds ), WB Saunders, London 1997. p.27, 10

76. Imaging in the Diagnosis of CVT: Indirect signs of CVT on head CT are more frequent. These can include: intense contrast enhancement of falx and tentorium . dilated transcerebral veins. small ventricles. parenchyma abnormalities. In addition. associated brain lesions may be depicted in 60 to 80 percent of patients with CVT, these may be hemorrhagic or nonhemorrhagic . Bousser MG, Russell RR. Cerebral venous thrombosis. In: Major Problems in Neurology, Warlow CP, Van Gijn J ( Eds ), WB Saunders, London 1997. p.27, 10

77. Imaging in the Diagnosis of CVT: CT venography : Gives a good visualization of the major dural sinuses, can be used for patients who have contraindications to MRI ( eg , pacemaker) and is quicker than MRI. CT venography is at least equivalent to MR venography in the diagnosis of CVT CT venography is often particularly helpful in subacute or chronic CVT because it can demonstrate heterogeneous density in thrombosed venous sinuses.

78. Imaging in the Diagnosis of CVT: However, its use may be limited because of: low resolution of the deep venous system and cortical veins. the risk of contrast reactions. and radiation exposure.

79. Imaging in the Diagnosis of CVT: MRI: Using gradient echo T2* susceptibility-weighted sequences in combination with magnetic resonance (MR) venography is the most sensitive imaging method for demonstrating the thrombus and the occluded dural sinus or vein . Diffusion-weighted magnetic resonance in cerebral venous thrombosis, Arch Neurol. 2001;58(10):1569 MRI in cerebral venous thrombosis, J Neuroradiol . 1994;21(2):81

80. Imaging in the Diagnosis of CVT: The characteristics of the MRI signal depend on the age of the thrombus: In the first five days, the thrombosed sinuses appear isointense on T1-weighted images and hypointense on T2-weighted images. Beyond five days, venous thrombus becomes more apparent because signal is increased on both T1 and T2-weighted images. After the first month, thrombosed sinuses exhibit a variable pattern of signal, which may appear isointens .

81. Imaging in the Diagnosis of CVT: MR venography  : MR venography , usually performed using the time-of-flight (TOF) technique, is useful for demonstrating absence of flow in cerebral venous sinuses, though interpretation can be confounded by normal anatomic variants such as sinus hypoplasia and asymmetric flow. Other MR techniques may be useful to distinguish these variants from venous thrombosis. Contrast-enhanced MR venography can provide better visualization of cerebral venous channels, and gradient echo or susceptibility-weighted sequences will show normal signal in a hypoplastic sinus and abnormally low signal in the presence of thrombus. A chronically thrombosed hypoplastic sinus will show absence of flow on two-dimensional TOF MR venography and enhancement on contrast-enhanced MRI and MR venography .

82. Imaging in the Diagnosis of CVT: MR venogram confirmed thrombosis (black arrows) of right transverse and sigmoid sinuses and jugular vein.

83. Imaging in the Diagnosis of CVT: Brain MRI in combination with magnetic resonance (MR) venography is the most sensitive examination technique for demonstrating the thrombus and the occluded dural sinus or vein.

84. Imaging in the Diagnosis of CVT: Invasive cerebral angiographic procedures: Less commonly needed to establish the diagnosis of CVT given the availability of MRV and CTV. These techniques are reserved for situations in which the MRV or CTV results are inconclusive or if an endovascular procedure is being considered.

85. Imaging in the Diagnosis of CVT: Cerebral Angiography: Findings include the failure of sinus appearance due to occlusion, venous congestion with dilated cortical, scalp or facial veins, enlargement of typically diminutive veins from collateral drainage, and reversal of venous flow. Venous phase of cerebral angiogram showed extensive thrombosed superior sagittal sinus and many frontal cortical veins

86. Imaging in the Diagnosis of CVT: Direct Cerebral Venography : Direct cerebral venography is usually performed during endovascular therapeutic procedures. Intraluminal thrombus is seen either as a filling defect within the lumen in the setting of non-occlusive thrombosis or as complete nonfilling in occlusive thrombosis. Venous pressure measurements may be performed during direct cerebral venography to identify venous hypertension ( normal venous sinus pressure is less than 10 mm of water) .

87. Imaging in the Diagnosis of CVT: Recommendations: Class I Recommendations: Although a plain CT or MRI is useful in the initial evaluation of patients with suspected CVT, a negative plain CT or MRI does not rule out CVT. A venographic study (either CT or MR venogram ) should be performed in suspected CVT if the plain CT or MRI is negative, or, to define the extent of CVT if the plain CT or MRI suggests CVT. 2011 American Heart Association/American Stroke Association

88. Imaging in the Diagnosis of CVT: Recommendations: Class I Recommendations : An early follow up CTV or MRV is recommended in CVT patients with persistent or evolving symptoms despite medical treatment or with symptoms suggestive of propagation of thrombus. In patients with previous CVT who present with recurrent symptoms suggestive of CVT, repeat CT or MR venogram is recommended. 2011 American Heart Association/American Stroke Association

89. Imaging in the Diagnosis of CVT: Recommendations : Class II Recommendations: Gradient Echo T2 susceptibility weighted images combined with MR venography can be useful to improve the accuracy of CVT diagnosis. Catheter cerebral angiography can be useful in patients with inconclusive CTV or MRV in whom a clinical suspicion for CVT remains high. A follow up CTV or MRV at 3-6 months following diagnosis is reasonable to assess for recanalization of the occluded cortical vein/sinuses in stable patients . 2011 American Heart Association/American Stroke Association

90. Management and Treatment Organized care is one of the most effective interventions to reduce mortality and morbidity following acute stroke CVT is an uncommon but potentially serious and life-threatening cause of stroke Based on findings for stroke unit care in general, management of CVT in a stroke unit is reasonable for the initial management of CVT in order to optimize care and minimize complications

91. PROGNOSIS

92. Prognosis: Neurologic worsening may occur in 23% of the patients, even several days after diagnosis. About one-third of patients with neurologic deterioration will have new parenchymal lesions when neuroimaging is repeated. Patients with depressed consciousness on admission are more likely to deteriorate.

93. Prognosis: Early Death: Approximately 3-15% of patients die in the acute phase of the disorder. In the ISCVT, 21/624 patients ( 3.4 % ) died within 30 days from symptom onset .

94. Prognosis: The main cause of acute death with CVT is transtentorial herniation secondary to a large hemorrhagic lesion. followed by herniation due to multiple lesions or to diffuse brain edema. Status epilepticus, medical complications, and pulmonary embolism are among other causes of early death.

95. Prognosis: Risk factors for 30-day mortality were : Depressed consciousness. Altered mental status. Thrombosis of the deep venous system. Right hemisphere hemorrhage. Posterior fossa lesions .

96. Prognosis: Long-Term Outcome : In the ISCVT study, complete recovery at last follow-up (median 16 months) was observed in 79% of the patients. However, there was an 8.3% overall death rate at the end of follow-up.

97. Prognosis: Risk Factors for Long-Term Poor Outcomes: Central nervous system infection. Any malignancy. Thrombosis of the deep venous system. Intracranial hemorrhage on the admission CT/MR. Glasgow coma scale score (GCS) <9 . Mental status disturbance . Age >37 years. Male gender. International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT, Stroke. 2004;35(3):664

98. Management and Treatment

99. Management and Treatment : The aim of treatment for (CVT) is to improve outcome. The immediate goals of antithrombotic treatment are: To recanalize the occluded sinus/vein. To prevent the propagation of the thrombus. To treat the underlying prothrombotic state, in order to prevent venous thrombosis in other parts of the body, particularly pulmonary embolism, and to prevent the recurrence of CVT. The main treatment option to achieve these goals is anticoagulation, using either heparin or low molecular weight heparin (LMWH).

100. Management and Treatment : Controversy has ensued because cerebral infarction with hemorrhagic transformation or intracerebral hemorrhage is commonly present at the time of diagnosis of CVT, and it may also complicate treatment.

101. Management and Treatment : Anticoagulation: Two randomized controlled trials of anticoagulation in acute CVT have been published. ?? Both have methodologic problems, most importantly their modest sample size.

102. Management and Treatment : Anticoagulation: One trial of 20 patients assessed intravenous unfractionated heparin (UFH) using dose adjustment to achieve an aPTT twice the pre-treatment value compared to placebo. The primary outcome was a CVT severity scale at 3 months , the secondary outcome was ICH. The trial was stopped early after 20 of a planned 60 patients were enrolled because there was a benefit of treatment . Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597

103. Management and Treatment : Anticoagulation: The other trial of 59 patients compared subcutaneous nadroparin to placebo for 3 weeks followed by 3 months of oral anticoagulation (without placebo control) in those randomized to nadroparin . The study was blind during the first 3 weeks and open label thereafter Primary outcomes were scores for activities of daily living, the Oxford Stroke handicap scale, and death Secondary endpoints were symptomatic ICH and other major bleeding At 3 months, 13% in the nadroparin group had a poor outcome compared to 21% with placebo (treatment difference in favor of nadroparin -7%; 95% CI -26 to 12%) More patients treated with LMWH followed by oral anticoagulation had a favorable outcome than controls, but the difference between the groups was not statistically significant de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484

104. Management and Treatment : Anticoagulation: A meta-analysis of these two trials found that anticoagulant treatment compared with placebo was associated with a pooled relative risk of death of 0.33 (95% CI 0.08-1.21) and a risk of death or dependency of 0.46 (95% CI 0.16-1.31). While these data suggest that anticoagulant treatment for CVT may be associated with a reduced risk of death or dependency, the results did not achieve statistical significance.

105. Management and Treatment : Anticoagulation: Limited data suggest that LMWH is more effective than unfractionated heparin and at least as safe for the treatment of CVT:

106. Management and Treatment : Anticoagulation: Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial. Eur J Neurol. 2012 Jul;19(7):1030-6. Epub 2012 Mar 15 In an open-label trial, 66 adults with CVT were randomly assigned to treatment with LMWH or unfractionated heparin. In-hospital mortality was significantly lower in the LMWH group ( versus 19 percent). At three months, the proportion of patients with complete recovery was greater for the LMWH group ( 88 versus 63 percent). But the difference was not statistically significant. Small numbers limit the strength of these findings.

107. Management and Treatment : Anticoagulation: In a nonrandomized case-control study, a greater proportion of adult patients treated with LMWH (n = 119) compared with unfractionated heparin (n = 302) were independent at six months (92 versus 84 percent, adjusted odds ratio 2.4, 95% CI 1.0-5.7) [33]. Treatment with LMWH was also associated with slightly lower rates of mortality (6 versus 8 percent) and new intracranial hemorrhage (10 versus 16 percent), but these outcomes were not statistically significant Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010;41(11):2575.

108. Management and Treatment In the special situation of CVT with cerebral hemorrhage on presentation, even in the absence of anticoagulation, hemorrhage is associated with adverse outcomes In one trial of nadroparin , all 6 deaths in the trial overall occurred in the group of 29 patients with hemorrhage on their pre-treatment CT scan None of the deaths were attributed to new or enlarged hemorrhage Cerebral hemorrhage was strongly associated with mortality, but not with cerebral bleeding on treatmen t

109. Management and Treatment A number of observational studies, both prospective and retrospective, are available, primarily from single centers In a retrospective study of 102 patients with CVT, 43 had an ICH Among 27 (63%) who were treated with dose-adjusted, intravenous heparin after the ICH, 4 died (15%), and 14 (52%) patients completely recovered Mortality was higher (69%) with lower improvement in functional outcomes (3 patients completely r ecovered)

110. Management and Treatment The largest study by far was the ISCVT, which included 624 patients at 89 centers in 21 countries Nearly all patients were treated with anticoagulation initially and mortality was 8.3% over 16 months 79% had complete recovery (modified Rankin scale 0-1), 10.4% had mild to moderate disability ( mRS 2-3) and 2.2% remained severely disabled ( mRS 4-5)

111. Management and Treatment Few studies had sufficient numbers of patients not treated with anticoagulation to adequately address the role of anticoagulation in relation to outcome Data from observational studies suggest a range of risks for ICH after anticoagulation for CVT from zero to 5.4% In conclusion, limited data from randomized controlled clinical trials in combination with observational data on outcomes and bleeding complications of anticoagulation support a role for anticoagulation in treatment of CVT, regardless of the presence of pre-treatment ICH

112. Management and Treatment Fibrinolytic Therapy Although patients with CVT may recover with anticoagulation therapy, 9-13% have poor outcomes despite anticoagulation Anticoagulation alone may not dissolve a large and extensive thrombus and the clinical condition may worsen even during heparin treatment Incomplete recanalization or persistent thrombosis may explain this phenomenon

113. Management and Treatment Combining four studies including 114 CVT patients, partial or complete recanalization at 3-6 months was observed in 94 (82.5%) Recanalization rates may be higher for patients receiving thrombolytic therapy In general, thrombolytic therapy is used if clinical deterioration continues despite anticoagulation or if a patient has elevated intracranial pressure that evolves despite other management approaches

114. Management and Treatment Direct Catheter Thrombolysis A systematic review including 169 patients with CVT treated with local thrombolysis showed a possible benefit for those with severe CVT, indicating that fibrinolytics may reduce case fatality in critically ill patients ICH occurred in 17% of patients after thrombolysis and was associated with clinical worsening in 5%

115. Management and Treatment Mechanical Thrombectomy / Thrombolysis For patients with extensive thrombus persisting despite local administration of fibrinolytic agent, rheolytic catheter thrombectomy may be considered Surgical thrombectomy is uncommonly needed, but may be considered if severe neurological or visual deterioration occurs despite maximal medical th erapy

116. Management and Treatment Mechanical Thrombectomy / Thrombolysis For patients with extensive thrombus persisting despite local administration of fibrinolytic agent, rheolytic catheter thrombectomy may be considered Surgical thrombectomy is uncommonly needed, but may be considered if severe neurological or visual deterioration occurs despite maximal medical th erapy

117. Management and Treatment The use of these direct intrasinus thrombolytic techniques and mechanical therapies are only supported by case reports and small case series If clinical deterioration occurs despite use of anticoagulation, or the patient develops mass effect from a venous infarction or intracerebral hemorrhage causing intracranial hypertension resistant to standard therapies, then these interventional techniques may be considered

118. Management and Treatment Seizures Seizures are present in 37% of adults, 48% of children and 71% of newborns presenting with CVT No clinical trials have studied either the optimal timing or medication choice for anticonvulsants in CVT Since seizures increase the risk of anoxic damage, anticonvulsant treatment after even a single seizure is reasonable In the absence of seizures, the prophylactic use of anti-epileptic drugs may be harmful

119. Management and Treatment Hydrocephalus The superior sagittal and lateral dural sinuses are the principal sites for cerebrospinal fluid (CSF) absorption by the arachnoid granulations In CVT, function of the arachnoid granulations may be impaired potentially resulting in failure of CSF absorption and communicating hydrocephalus (6.6%) Obstructive hydrocephalus is a less common complication from CVT and results from hemorrhage into the ventricular system

120. Management and Treatment Intracranial Hypertension Up to 40% of patients with CVT present with isolated intracranial hypertension Clinical features include progressive headache, papilledema and third or sixth nerve palsies No randomized trials are available to clarify optimal treatment Measures to reduce the thrombotic occlusion of venous outflow may resolve intracranial hypertension Reduction of increased ICP can be immediately accomplished by lumbar puncture Acetazolamide may have a limited role in the acute management of intracranial hypertension for patients with CVT

121. Management and Treatment: Recommendations Class I Recommendations In patients with CVT and a single seizure with parenchymal lesions, early initiation of anti-epileptic drugs for a defined duration is recommended to prevent further seizures Patients with CVT and a suspected bacterial infection should receive appropriate antibiotics and surgical drainage of purulent collections of infectious sources associated with CVT when appropriate

122. Class I Recommendations In patients with CVT and increased intracranial pressure, monitoring for progressive visual loss is recommended, and when this is observed, increased intracranial pressure should be urgently treated In patients with a past history of CVT who complain of new, persisting or severe headache, evaluation for CVT recurrence and intracranial hypertension should be considered

123. Class II Recommendations For patients with CVT, initial anticoagulation with adjusted-dose unfractionated heparin or weight-based low molecular weight heparin in full anticoagulant doses is reasonable, followed by vitamin K antagonists, regardless of the presence of intracerebral hemorrhage Admission to a stroke unit is reasonable for treatment and for prevention of clinical complications of patients with CVT

124. Class II Recommendations In patients with CVT and a single seizure without parenchymal lesions, early initiation of anti-epileptic drugs for a defined duration is probably recommended to prevent further seizures In patients with CVT and increased intracranial pressure, it is reasonable to initiate treatment with acetazolamide . Other therapies (lumbar puncture, optic nerve decompression or shunts) can be effective if there is progressive visual loss

125. Class II Recommendations Endovascular intervention may be considered if deterioration occurs despite intensive anticoagulation treatment In patients with neurological deterioration due to severe mass effect or intracranial hemorrhage causing intractable intracranial hypertension, decompressive hemicraniectomy may be consid ered

126. Class II Recommendations Testing for prothrombotic conditions, including protein C, protein S, antithrombin deficiency, antiphospholipid syndrome, prothrombin G20210A mutation and Factor V Leiden, can be beneficial for the management of patients with CVT. Testing for protein C, protein S, and antithrombin deficiency is generally indicated 2-4 weeks after completion of anticoagulation. There is a very limited value of testing in the acute setting or in patients on warfarin

127. Class II Recommendations In patients with provoked CVT (associated with a transient risk factor), vitamin K antagonists with a target INR of 2.0-3.0 may be continued for 3 to 6 months In patients with unprovoked CVT, vitamin K antagonists with a target INR of 2.0-3.0 may be continued for 6 to 12 months

128. Class II Recommendations For patients with recurrent CVT, VTE after CVT, or first CVT with severe thrombophilia (i.e. homozygous prothrombin G20210A, homozygous Factor V Leiden, deficiencies of protein C, protein S or antithrombin , combined thrombophilia defects or antiphospholipid syndrome), indefinite anticoagulation may be considered with a target INR of 2.0-3.0 Consultation with a physician with expertise in thrombosis may be considered to assist in the prothrombotic testing and care of patients with cerebral venous sinus thrombosis

129. Class III Recommendations For patients with CVT, steroid medications are not recommended, even in the presence of parenchymal brain lesions on CT/MRI, unless needed for another underlying disease In the absence of seizures, the routine use of anti-epileptic drugs in patients with CVT is not recommended

130. Summary A dural sinus or cerebral venous thrombosis (CVT) accounts for 0.5-1% of all strokes, mostly affecting young individuals and women of childbearing age Patients with CVT commonly present with headache, while some develop a focal neurological deficit, decreased level of consciousness, seizures, or intracranial hypertension without focal neurological signs

131. A prothrombotic factor or a direct cause is identified in about two thirds of patients with sinus thrombosis The diagnosis is usually made by venographic studies using computed tomography (CT venogram ) or magnetic resonance imaging (MR venogram ) Management includes treatment of the underlying condition, symptomatic treatment, the prevention or treatment of complications of increased ICP, ICH, or venous infarction, and typically includes anticoagulation

132. Despite substantial progress in the study of CVT in recent years, much of the literature remains descriptive A randomized clinical trial comparing the benefit of anticoagulation therapy vs. endovascular thrombolysis (TO-ACT Trial - Thrombolysis Or Anticoagulation for Cerebral Venous Thrombosis) is underway Through innovative research and systematic evaluation, the diagnosis, management and therapeutic alternatives will continue to evolve, and consequently lead to better outcomes for patients with CVT

133. Proposed Algorithm for the Management of CVT